Total synthesis of polycephalin C and determination of the absolute configurations at the 3′′,4′′ ring junction

Article abstract of DOI:10.1002/1521-3773(20020802)41:15<2786::AID-ANIE2786>3.0.CO;2-Z

Only through total synthesis could the absolute configuration of the 3′′R,4′′R ring junction of the polyenoltetramic acid polycephalin C (1) be unambiguously established. Key features of the synthesis include a double Swern oxidation, double Stille coupli

Full text of DOI:10.1002/1521-3773(20020802)41:15<2786::AID-ANIE2786>3.0.CO;2-Z

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(br d, J ˆ 5.1 Hz, 1H), 3.60 (dddm, J ˆ 5.5, 7.8, 8.4 Hz, 1H), 4.16 (q,
J ˆ 7.1 Hz, 2H), 4.17 (q,J ˆ 7.1 z, 2H), 5.30 (br ddd, J ˆ 5.5, 7.8, 15.2 Hz,
1H), 5.39 (br dd, J ˆ 5.9, 15.2 Hz, 1H), 7.16 7.32 ppm (m, 5H);13C NMR
(100 MHz, CDCl3, TMS): d ˆ 14.1, 20.9, 30.7, 35.3, 38.4, 40.5, 40.8, 44.1,
59.4, 70.2, 125.7, 125.8, 128.5, 133.1, 136.3, 140.3, 172.3 ppm; elemental
analysis calcd for C26H36O5: C 72.87, H 8.47; found: C 72.94, H 8.29.
Total Synthesis of Polycephalin C and
Determination of the Absolute Configurations
at the 3'',4'' Ring Junction**
Deborah A. Longbottom, Angus J. Morrison,
Darren J. Dixon, and Steven V. Ley*
Received: March 15, 2002 [Z18903]
Tetramic acids (2,4-pyrrolidinediones) are an important
family of nitrogen-containing heterocycles, well known for
their potent antibiotic, antiviral, antifungal, and cytotoxic
activity.[1] Many tetramic acid natural products are highly
complex frameworks containing several stereogenic centers.
It is this complexity, together with the fact that these targets
have potential or known biological activity, which makes their
synthesis a worthwhile and challenging goal for the organic
chemist, particularly so when the natural product is in short
supply from the natural source.
[1] J. Tsuji, Transition Metal Reagents and Catalysts, Wiley, Chichester,
2000.
[2] a) G. Wilke, B. Bogdanovic, P. Hardt, P. Heimbach, W. Keim, M.
Krˆner, W. Oberkirch, K. Tanaka, D. Steinbr¸cke, E. Walter, H.
Zimmermann, Angew. Chem. 1966, 78, 157 172; Angew. Chem. Int.
Ed. Engl. 1966, 5, 151 164; b) R. Benn, N. B¸ssemeier, P. Holle, W.
Jolly, R. Mynott, I. Tkatchenko, G. Wilke, J. Organomet. Chem. 1985,
279, 63 86.
[3] a) K. Tamao, K. Kobayashi, Y. Ito, Synlett 1992, 539 546; b) E.
Oblinger, J. Montgomery, J. Am. Chem. Soc. 1997, 119, 9065 9066;
c) M. Kimura, A. Ezoe, K. Shibata, Y. Tamaru, J. Am. Chem. Soc.
1998, 120, 4033 4034; d) M. Kimura, H. Fujimatsu, A. Ezoe, K.
Shibata, M. Shimizu, S. Matsumoto, Y. Tamaru, Angew. Chem. 1999,
111, 410 413; Angew. Chem. Int. Ed. 1999, 38, 397 399; e) Y.
Tamaru, Organomet. Chem. 1999, 576, 215 231; f) J. Montgomery,
Acc. Chem. Res. 2000, 33, 467 473; g) S. Ikeda, Acc. Chem. Res. 2000,
33, 511 520; h) I. N. Houpis, J. Lee, Tetrahedron 2000, 56, 817 846.
[4] a) P. A. Wender, T. E. Jenkins, J. Am. Chem. Soc. 1989, 111, 6432
6434; b) P. A. Wender, T. E. Smith, J. Org. Chem. 1995, 60, 2962
2963; c) P. A. Wender, T. E. Smith, J. Org. Chem. 1996, 61, 824 825;
for rhodium-catalyzed reactions, see: d) L. McKinstry, T. Livinghouse,
Tetrahedron 1994, 50, 6145 6154; e) S-J. Paik, S. U. Son, Y. K. Chung,
Org. Lett. 1999, 1, 2045 2047; f) B. Wang, P. Cao, X. Zhang,
Tetrahedron Lett. 2000, 41, 8041 8044; for palladium-catalyzed
reactions, see: g) X. Xie, X, Lu, X. Tetrahedron Lett. 1999, 40,
8415 8418.
In 1998, Nowak and Steffan isolated polycephalin C (1) as a
new member of this group of natural products from Physarum
polycephalum.[2] Polycephalin C (1) is a bis(trienoyltetramic
acid), linked by an unusual asymmetric cyclohexene ring. The
O
HO
Me
N
H
O
OH
4''
3''
H
O
OH
[5] A. V. Savchenko, J. Montgomery, J. Org. Chem. 1996, 61, 1562 1563.
[6] a) Y. Sato, M. Takimoto, M. Mori, J. Am. Chem. Soc. 2000, 122, 1624
1634; b) K. Shibata, M. Kimura, M. Shimizu, Y. Tamaru, Org. Lett.
2001, 3, 2181 2183.
[7] a) J. Montgomery, E. Oblinger, A. V. Savchenko, J. Am. Chem. Soc.
1997, 119, 4911 4920; b) J. Seo, H. M. P. Chui, M. J. Heeg, J.
Montgomery, J. Am. Chem. Soc. 1999, 121, 476 477; c) S. K.
Chowdhury, K. K. D. Amarasinghe, M. J. Heeg, J. Montgomery, J.
Am. Chem. Soc. 2000, 122, 6775 6776.
[8] a) X.-Q. Tang, J. Montgomery, J. Am. Chem. Soc. 1999, 121, 6098
6099; b) M. V. Chevliakov, J. Montgomery, J. Am. Chem. Soc. 1999,
121, 11139 11143; c) J. Seo, H. Fain, J. B. Blanc, J. Montgomery, J.
Org. Chem. 1999, 64, 6060 6065.
[9] The two isomers of 2 are apparently as a result of the relative
configuration of the 1,5-stereogenic centers and not that of exocyclic
double bonds. For example, PCC oxidation of a 7:1 mixture of 2e
provided the corresponding ketone as a single isomer, which furnished
a 1:1 mixture of 2e upon reduction with NaBH4.
N
HO
Me
O
polycephalin C (1)
showing unknown 3",4" absolute stereochemistry
tetramic acid unit of each terminus is derived from (S)-N-
methyl serine and is linked by a fully conjugated all-E-triene
chain to the cyclohexene ring. This unusual tetramic acid is
thought to be one of several metabolites responsible for the
yellow color of the wild-type plasmodia of Physarum poly-
cepahlum.[2]
Although the structure elucidation had established that the
relative stereochemistry at the 3'',4'' ring junction of the
natural product was trans, the absolute configuration at these
positions had not been determined.[2] Therefore, intrigued by
both the novel structure of this unusual polyenoyltetramic
acid and the need to define the absolute stereochemistry at
[10] CCDC-178844 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ, UK;
fax: (‡44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[11] A similar reaction mechanism has been reported for a Ni-catalyzed
alkylative carbocyclization of alkynyl enones [e.g., Eq. (2)] and for a
Ni-catalyzed three-component coupling reaction of alkynes, alde-
hydes, and organozinc compounds: a) A. V. Savchenko, J. Montgom-
ery, J. Am. Chem. Soc. 1996, 118, 2099 2100; b) X. Q. Tang, J.
Montgomery, J. Org. Chem. 1999, 64, 9310 9313; c) K. K. D. Amar-
asinghe, S. K. Chowdhury, M. J. Heeg, J. Montgomery, Organometal-
lics 2001, 20, 370 372.
[*] Prof. Dr. S. V. Ley, Dr. D. A. Longbottom, Dr. A. J. Morrison,
Dr. D. J. Dixon
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (‡44)1223-336-442
E-mail: svl1000@cam.ac.uk
[**] We gratefully acknowledge financial support from the EPSRC (to
D.J.D. and D.A.L.), AstraZeneca (to A.J.M.), and the Novartis
Research Fellowship (to S.V.L.). The authors also thank Dr. B. Steffan
(Thetis - Institut f¸r biomolekulare Naturstoffforschung) for NMR
and CD spectra of natural polycephalin C.
[12] a) M. Kimura, S. Matsuo, K. Shibata, Y. Tamaru, Angew. Chem. 1999,
111, 3586 3589; Angew. Chem. Int. Ed. 1999, 38, 3386 3388; b) M.
Kimura, K. Shibata, K. Koudahashi, Y. Tamaru, Y. Tetrahedron Lett.
2000, 41, 6789 6793; c) K. Shibata, M. Kimura, K. Kojima, S. Tanaka,
Y. Tamaru, J. Organomet. Chem. 2001, 624, 348 353.
2786
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Angew. Chem. Int. Ed. 2002, 41, No. 15

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the 3'',4'' ring junction, we devised a synthesis route to the
natural product.
Me NH
TBSO
O
OH
O
nBu3Sn
StBu
OMe
As the 3'',4'' ring junction configuration of polycephalin C
(1) could be R,R or S,S, we arbitrarily selected the S,S isomer
as the initial synthesis target. Analysis suggested a convergent
approach, in which 1 is synthesized from two major fragments,
the stannylated dienoyltetramic acid 2 and the bisiodovinyl
intermediate 3 (Scheme 1). It was thought that 2 would be
readily available from thioester 4 and amino ester 5, frag-
ments which had been devised and then used in the total
synthesis of physarorubinic acid previously by our group.[3]
Double Stille coupling to connect bisiodide 3 and tetramic
acid 2,[4] followed by TBS deprotection would then give
polycephalin C (1) in a concise fashion. The synthesis of
dienoyltetramic acid 2 is discussed first, followed by the
synthesis of fragment 3 and the closing steps of the synthesis.
The two-step sequence which leads to the formation of
dienoyltetramic acid 2 begins with a aminolysis reaction
mediated by silver(i) trifluoroacetate (Scheme 2).[5] In this
particular case, it was found that an excess of triethylamine
was crucial in preventing destannylation of the dienoylstan-
nane 4. Under these basic conditions, the silver-salt-mediated
aminolysis reaction was complete after just 20 minutes at 08C
and furnished the desired b-keto amide 6 in an excellent 81%
yield. Exposure of 6 to NaOMe in MeOH at 258C for two
minutes then facilitated Lacey Dieckmann cyclization which
lead directly to dienoyltetramic acid 2 in a pleasing 90%
yield.[6]
4
5
a) 81%
OTBS
OH
O
OMe
nBu3Sn
N
Me
O
6
b) 90%
O
HO
Me
nBu3Sn
N
O
OTBS
2
Scheme 2. Synthesis of dienoyltetramic acid 2. a) CF3CO2Ag, NEt3, THF,
08C, 20 min; b) NaOMe, MeOH, 258C, 2 min.
O
O
H
I
OH
OH
O-(+)-Menthyl
O-(+)-Menthyl
H
I
7
8
3
Scheme 3. Synthetic plan for bisiodovinyl fragment 3.
With the tetramic acid portion of polycephalin C in hand,
attention was focussed on the synthesis of the bisiodovinyl
fragment 3. It was envisaged that, starting from key inter-
mediate cyclohexene diol 7, 1,4-dioxidation and an unprece-
dented double Takai reaction[7] would provide the desired bis-
iodide 3 (Scheme 3). It was expected that diol 7 would be
prepared from Diels Alder adduct 8; double-bond manipu-
lation and exhaustive reduction would subsequently provide
desired diol 7.
The asymmetric Diels Alder reaction employed in this
case combines the dienophile, dimenthyl fumarate 9, with 1,3-
butadiene and is reported to occur with excellent diastereo-
selectivity.[8] Indeed in this case, the low-temperature Lewis
acid mediated reaction proceeded to afford exclusively the
desired Diels Alder adduct (R,R)-10 (d.e. >95% by NMR)
in a 73% yield (Scheme 4).
With the ring junction stereo-
chemistry created in the Diels
O
HO
Me
N
Alder adduct 10, double-bond
transposition was then required. It
H
O
HO
O
OH
was envisaged that overall addition
of phenylselenic acid and a subse-
quent oxidation elimination se-
quence would effect the desired
process. Overall addition of phe-
nylselenic acid to an alkene has
been reported previously.[9] In this
case, phenylselenium bromide in
MeCN/water (15:1) facilitated
smooth addition across the double
bond of Diels Alder adduct 10
and provided analytically pure hy-
droxyselenide 11 as the only dia-
stereomer. m-CPBA oxidation of
the phenylselenium moiety in the
addition product 11 produced hy-
droxyselenoxide 12, which then
underwent elimination in the pres-
S
Me
S
nBu3Sn
N
H
O
O
OTBS
OH
N
2
HO
Me
O
(3"S,4"S)-1
H
I
Me NH
TBSO
O
OH
O
nBu3Sn
StBu
OMe
H
I
3
4
5
Scheme 1. Synthetic plan for polycephalin C (1). TBS ˆ tert-butyldimethylsilyl.
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utilizing this synthetic sequence, gram quantities of diol 7
were accessed.
The 1,4-oxidation of diol 7 was then investigated and the
Swern reaction selected as the optimum method.[12] Unfortu-
nately, initial attempts gave a,b-unsaturated dialdehyde 17
(Scheme 6); the double bond had moved into conjugation
O
a) 73%
(+)-Menthyl-O
O-(+)-Menthyl
O
9
CO2R*
CO2R*
CO2R*
CO2R*
HO
PhSe
b) 75%
O
b) 87%
OH
OH
H
H
10
11
O
c)
7
18
a)
c) 40%
CO2R*
CO2R*
HO
*
HO
CO2R
d) 92%
O
H
H
I
I
PhSe
CO2R*
H
H
O
O
13
12
17
3
Scheme 4. Synthesis of allylic alcohol 13. a) Et2AlCl, 1,3-butadiene,
À608C, 36 h; b) PhSeBr, MeCN/H2O (15:1), 508C, 12 h; c) m-CPBA,
CH2Cl2, À308C, 5 min; d) diisopropylamine, 508C, 14 h. m-CPBA ˆ m-
chloroperoxybenzoic acid.
Scheme 6. Synthesis of bis-iodovinyl fragment 3. a) (COCl)2, DMSO,
CH2Cl2, À788C, 2 h; then NEt3, À78 ! À 108C; b) (COCl)2, DMSO,
CH2Cl2, À788C, 1.5 h; then iPr2NEt, À78 ! À 108C; c) CrCl2, CHI3, THF,
08C !RT, 2 h.
ence of diisopropylamine at 508C to generate allylic alcohol
13 in an excellent 92% yield (Scheme 4).
with the proximal aldehyde as a result of the acidic nature of
the allylic proton in the oxidation product 18. However, this
problem could be overcome by replacement of triethylamine
with a more hindered base.[13] Thus, Swern oxidation with
diisopropylethylamine, followed by a cold acidic workup and
washing with a pH 7buffer solution provided the desired
aldehyde 18 in high yield and purity (Scheme 6). The unstable
nature of this compound meant that it was always freshly
prepared for immediate use in the subsequent step, formation
of the Stille coupling partner 3.
It was clear that the most efficient design of the synthesis
would incorporate removal of the allylic hydroxy group with
concomitant reduction of the (‡)-menthyl esters. We believed
that mesylation and subsequent exhaustive reduction would
be effective. However, attempted mesylate formation at 08C
was found to give diene 14 as the main product of the reaction
(Scheme 5), formed by elimination of the mesylate immedi-
ately after formation. To prevent this side reaction, mesylate
A double Takai olefination reaction[7] was selected to
ensure the required E double-bond geometry in bisiodide 3.
However, because of the nonpolar nature of 3, it was
impossible to separate it from the residual excess of iodoform
employed in the Takai reaction. Therefore, to obtain pure
material for the Stille coupling, it was not possible to use an
excess of iodoform, a constraint which led to a slightly
disappointing but acceptable 40% yield considering the
transformation which has been achieved (Scheme 6); the
reaction was extremely selective for the desired product 3
(>90% bis-trans product by NMR) and hence the bisiodide 3
was formed from diol 7 in just two steps and overall 35% yield
(Scheme 6).
HO
MsO
CO R
CO2R*
CO2R*
*
b) 87%
2
CO R
*
2
13
15
c) 85%
5:1 7:16
a)
H
OH
OH
OH
OH
CO R
*
2
CO R
*
2
SN2 product 7
SN2' product 16
14
Scheme 5. Synthesis of diol 7. a) MsCl, NEt3, CH2Cl2, 08C; b) MsCl, NEt3,
CH2Cl2, À78 ! À 158C; c) LiAlH4, THF, À788C !RT.
A number of catalysts were then screened to ascertain
which would facilitate the desired double Stille coupling in the
most efficient manner, the best of which proved to be
[PdCl2(CH3CN)2]. Following optimization studies, the prod-
uct 19 of the key double Stille coupling was successfully
prepared in a good 53% yield (Scheme 7); two key bonds are
formed in this reaction and, considering the possible palla-
dium-mediated side reactions, this was an extremely pleasing
outcome.
formation was therefore carried out at lower temperature and
pleasingly provided the desired allylic mesylate 15, the
structure of which has been confirmed by X-ray crystallog-
raphy.[10, 11] This was then used directly in the LiAlH4
reduction of both esters and mesylate. The reduction led to
an 85% yield of a separable mixture of diols 7 (product of
direct SN2 attack) and 16 (product of SN2' attack) in a 5:1 ratio
(Scheme 5), and provided a 71% yield of the desired diol 7. By
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COMMUNICATIONS
bis-iodovinyl fragment 20 proceeded uneventfully following
the procedure outlined for 3. Following Stille coupling with
stannane 2, deprotection gave polycephalin C (1), with
3''R,4''R stereochemistry at the ring junction (Scheme 9).
H
H
O
HO
I
I
Me
N
nBu3Sn
O
OTBS
3
2
a) 53%
O
HO
H
I
I
4''
3''
Me
N
nBu3Sn
O
HO
H
O
Me
OTBS
N
H
H
20
2
O
OTBS
OTBS
a) 56%
b) 62%
O
O
HO
Me
OH
N
N
HO
H
Me
O
O
R
19
R
Scheme 7. Stille coupling of fragments 2 and 3. a) [PdCl2(MeCN)2]
(15 mol%), DMF, RT, 1 h.
H
O
OH
N
HO
The final step of the synthesis, removal of the TBS ethers,
was carried out with trifluoroacetic acid (TFA)/water (9:1)
which facilitated smooth deprotection when added
and immediately removed under reduced pressure (three
times).[3a] Because all side products and excess reagents are
volatile, crude 1 was afforded directly (Scheme 8), as no
reaction workup was necessary. Purification by reverse-phase
HPLC then gave (3''S,4''S)-1 in 64% yield and overall 3.7%
yield from dimenthyl fumarate 9.
Me
O
polycephalin C (1)
showing corrrect 3",4"-(R,R) absolute stereochemistry
Scheme 9. Synthesis of (3''R,4''R)-polycephalin C (1). a) [PdCl2(MeCN)2]
(5 mol%), DMF, RT, 1 h; b) TFA/H2O (9:1) Â3, RT.
The spectroscopic data (1H and 13C NMR, MS, IR) of this
synthetic material were in excellent agreement with that
published in the literature and the coupling constants from the
polyene chains again proved that the all-E double-bond
geometry was intact. In this case the optical rotation and the
CD spectrum, crucial for confirmation of configuration, were
also in excellent agreement with the published data.
Thus, the total synthesis of this unusual bistetramic acid,
polycephalin C (1), has been completed in a short and
efficient fashion and the original challenge of defining the
absolute configuration of the ring junction has been met.
Through synthesis, we have been able to unambiguously
assign the 3''R,4''R stereochemical configuration and thus
complete the definition of the structure of this molecule.
O
HO
Me
N
H
O
OH
OH
a) 64%
4''
3''
S
S
19
H
O
O
N
HO
Me
epi,epi-(3''S,4''S)-polycephalin C (1)
Scheme 8. Synthesis of epi,epi-(3''S,4''S)polycephalin C (1). a) TFA/H2O
(9:1) Â3, RT (64%).
Received: March 25, 2002 [Z18980]
[1] B. J. L. Royles, Chem. Rev. 1995, 95, 1981.
[2] a) A. Nowak, B. Steffan, Angew. Chem. 1998, 110, 3341; Angew.
Chem. Int. Ed. 1998, 37, 3139.
[3] a) D. J. Dixon, S. V. Ley, D. A. Longbottom, J. Chem. Soc. Perkin
Trans. 1 1999, 2231; b) D. J. Dixon, S. V. Ley, T. Gratzca, P. Szolcsanyi,
J. Chem. Soc. Perkin Trans. 1 1999, 839.
[4] a) T. N. Mitchell, Synthesis 1992, 803; b) J. K. Stille, Angew. Chem.
1986, 98, 504; Angew. Chem. Int. Ed. Engl. 1986, 25, 508; c) J. K. Stille,
B. L. Groh, J. Am. Chem. Soc. 1987, 109, 813.
[5] a) S. Masamune, S. Kamata, W. Schilling, J. Am. Chem. Soc. 1975, 97,
3515; b) S. Masamune, Y. Hayase, W. Schilling, W. K. Chan, G. S.
Bates, J. Am. Chem. Soc. 1977, 99, 6756; c) S. V. Ley, P. R. Woodward,
Tetrahedron Lett. 1987, 28, 3019.
[6] a) R. N. Lacey, J. Chem. Soc. 1954, 850; b) J. Poncet, P. Jouin, B.
Castro, L. Nicolas, M. Boutar, A. Gaudemer, J. Chem. Soc. Perkin
The spectroscopic data (1H and 13C NMR, MS, IR) of this
synthetic material compared well with that published in the
literature and the coupling constants from the polyene chains
indicated the all-E double-bond geometry. However, despite
being of the correct sign, the optical rotation was found to
differ from that given in the structure elucidation paper.[2] The
CD spectrum in the range from 300 to 450 nm was also
different and from this it was concluded that the 3''S,4''S-
configured compound was in fact epi,epi-(3''S, 4''S)-polyce-
phalin C (Scheme 8) and that the isolated natural product had
the R,R configuration about the ring junction.
To prove that this was correct, the synthesis had to be
repeated beginning with (À)-dimenthyl fumarate to create the
opposite configuration at the 3'',4'' ring junction. Synthesis of
Trans.
1 1990, 611; c) S. V. Ley, S. C. Smith, P. R. Woodward,
Tetrahedron Lett. 1988, 29, 5829; d) S. V. Ley, S. C. Smith, P. R.
Woodward, Tetrahedron 1992, 48, 1145.
Angew. Chem. Int. Ed. 2002, 41, No. 15
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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COMMUNICATIONS
[7] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc.
1986, 108.
OR
RO
RO
OR
[8] a) H. M. Walborsky, L. Barash, T. C. Davis, J. Org.
Chem. 1961, 26, 4778; b) H. M. Walborsky, L.
Barash, T. C. Davis, Tetrahedron 1963, 19, 2333;
c) K. Furuta, I. Iwanga, H. Yamamoto, Tetrahe-
dron Lett. 1986, 27, 4507.
N
N
N
N
Zn
Zn
N
N
N
N
[9] a) M. A. Cooper, A. D. Ward, Tetrahedron Lett.
1995, 36, 2327; b) P. Ceccherelli, M. Curini, F.
Epifano, M. C. Marcotullio, O. Rosati, J. Org.
Chem. 1996, 61, 2882.
RO
OR
OR
RO
Cavity B
RO
OR
[10] CCDC-181952 contains the supplementary crys-
tallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (‡44)1223-336-
033; or deposit@ccdc.cam.ac.uk).
N
N
Zn
N
N
N
Zn
N
N
N
RO
OR
[11] The authors thank Dr. J. E. Davies and Dr. A. D.
Bond for X-ray analysis.
[12] S. C. Howell, S. V. Ley, M. Mahon, J. Chem. Soc.
Chem. Commun. 1981, 507.
Cavity A
[13] D. M. Walba, W. N. Thurmes, R. C. Haltiwanger, J.
Org. Chem. 1988, 53, 1046.
N
N
N
N
N
Zn
Zn
RO
OR RO
OR
N
N
N
1 (OR =
O
)
OR
OR
A Dendritic Porphyrin Receptor for C60 Which
Features a Profound Positive Allosteric Effect
moieties linked with one another through phenylacetylene
units. The dendritic receptor 1 has three rotational axes which
affect the spatial arrangement of porphyrins (Figure 1), and
the shape of the three clefts, each of which consists of two
porphyrin planes. We have already demonstrated that the
Masatsugu Ayabe, Atsushi Ikeda, Yohei Kubo,
Masayuki Takeuchi, and Seiji Shinkai*
The developmental investigation of the novel application of
dendrimers and dendritic compounds has been of recent
concern.[1] Dendrimers, as host molecules have attracted a
great deal of attention because of their unique topology, well-
defined structures, and unusual guest-binding behaviors
compared to general polymers.[2] As [60]fullerene (C60) ex-
hibits outstanding new chemical and physical properties, the
molecular design of C60 receptors is a growing research area.[3]
For the crystal state, several articles have shown that
porphyrin derivatives cocrystallize with C60 because of an
attractive force between C60 and a porphyrin-ring center.[4] In
organic solvents, Aida and co-workers[5] and Reed and co-
workers[6] have shown that the porphyrin dimers have excep-
tionally high affinity for C60. Herein, we describe a rigid star-
shaped D3-symmetric receptor 1[7] bearing six porphyrin
subunits for guest binding, which are rationally arranged
[9]
around a rotational axis such as metal ion,[8] C C bond, or
À
butadiynylene,[10] work cooperatively to bind guest molecules
in a nonlinear fashion (positive homotropic allosterism). In
addition, we have found that this effect is useful to bind guest
molecules which are difficult to bind with a linear, 1:1 guest-
binding fashion. As shown in Figure 1, when two porphyrins
sandwich one C60 molecule, the complexation site successively
suppresses the rotational freedom of the remaining porphyrin
™tweezers∫. This ™domino∫ effect is expected to be effective
for the binding of three equivalents of C60 in an allosteric
manner to attain high C60 affinity.
The formation of the 1-C60 complex in toluene was
indicated by a change in the UV/Vis absorption spectra
induced by successive addition of C60 to 1 (Figure 2). The lmax
of the Soret band (428 nm) slightly shifts to longer wavelength
(429 nm) with a tight isosbestic point (435 nm in Soret band
region). The spectral characteristics are coincident with those
of recent findings for a few porphyrin C60 complexation
systems.[5, 6]
To estimate the stoichiometry between 1 and C60, 1H NMR
spectra for [1]:[C60] ˆ 1:0 1:5 at 258C were measured in
[D8]toluene ([1] ˆ 0.50 mm). The resonance signals of the
meso-aryl protons and b-pyrrole protons shifted upfield on C60
addition (see Supporting Information). As shown in Figure 3,
a plot of Dd versus [C60]/[1] has a clear inflection point at [C60]/
[1] ˆ 3.0. This value supports the view that the complex is
[*] Prof. S. Shinkai, M. Ayabe,[‡] Y. Kubo, Dr. M. Takeuchi
Department of Chemistry and Biochemistry
Graduate School of Engineering
Kyushu University
Fukuoka 812-8581 (Japan)
Fax : (‡81)92-642-3611
E-mail: seijitcm@mbox.nc.kyushu-u.ac.jp
Dr. A. Ikeda[‡]
Graduate School of Materials Science
Nara Institute of Science and Technology
8916-5 Takayama, Ikoma, Nara 630-0101 (Japan)
‡
[ ] PRESTO, Japan Science and Technology Corporation
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
2790
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4115-2790 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 15