Μπρούτζινη Yδρία από την αρχαία Δημητριάδα
Science (2011)
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Abstract
The role of dopamine in monitoring negative action outcomes and feedback-based learning was tested in a neuroimaging study in humans grouped according to the dopamine D2 receptor gene polymorphism DRD2-TAQ-IA. In a probabilistic learning task, A1-allele carriers with reduced dopamine D2 receptor densities learned to avoid actions with negative consequences less efficiently. Their posterior medial frontal cortex (pMFC), involved in feedback monitoring, responded less to negative feedback than others' did. Dynamically changing interactions between pMFC and hippocampus found to underlie feedback-based learning were reduced in A1-allele carriers. This demonstrates that learning from errors requires dopaminergic signaling. Dopamine D2 receptor reduction seems to decrease sensitivity to negative action consequences, which may explain an increased risk of developing addictive behaviors in A1-allele carriers.
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Μπρούτζινη Yδρία από την αρχαία Δημητριάδα
J . Am. Chem. SOC. 1988, 110, 6265-6266 6265
1.0 equiv of HMP,A, -78 OC, then 2 equiv of Ph2Sz, 0 OC, 1 h)
produced thioethers 8, which were directly oxidized (3 equiv of
MCPBA, solid KzC03, CH2C12, room temperature, 16 h) to yield
the diastereomeric mixture of epoxy sulfones 9; no epoxidation
of the terminal methylene was observed.
Treatment of this diastereomeric mixture with 10 mol% of
Pd(PPh3)4 and 20 mol% diphos in T H F at 60 "C for 1 h led with
dramatic regioselectivity to a mixture of the (E)-cyclononene
alcohol epimers 10 in 67% isolated yield. In contrast to the related
Total Synthesis of (f)-Punctaporonin B
Andrew S. Kende,* Istvan Kaldor, and Robert Aslanian
Department of Chemistry, University of Rochester
Rochester, New York 14627
Received May 12, 1988
Since the landmark total synthesis of the hydrocarbon (*)-
caryophyllene (1) by Corey in 1963, this rare series of bicarbocyclic
1 2 3
sesquiterpenes has received scant attention from the synthetic
chemist.' This hiatus has been challenged in recent years by the
structure elucidation of such intriguing 9-4 bicyclic terpenes as
the 1 2-hydroxycaryophyllene-4,5-oxide,2 the diterpene acetylco-
r i a ~ e n o n e , ~ and in 1984, by the still more highly functionalized
diene triol, punctaporonin B (2)., Triol 2, isolated from extracts
of the drug fungus Poronia punctata (Linnaeus ex Fries) is a
congener of several tricarbocyclic sesquiterpenes of which (-)-
punctaporonin A (3)' has been very recently synthesized by Pa-
quette and Sugimura.6
We describe the first total synthesis of racemic punctaporonin
B by an efficient and potentially general strategy for the con-
struction of such fused 9-4 systems. Our starting material was
the known and readily accessible' cyclobutanone ester 4, which
p 1.NaH,BrCH2COOE[
4 5 7
, 2,PhSSPh 1 .LDA,THI-HMPA ( 5 5 % ) $-yy
S02Ph
8 9
underwent C-alkylation (1.2 equiv of NaH, 1.2 equiv of
BrCH2CO2Et, DMSO, room temperature, 3 h) and subsequent
decarbo-tert-butoxylation (catalyst pTSA, C6H6 reflux, 2 h) to
give the y-keto ester 5 in 78% overall yield. Addition of the
Grignard reagent 6* ( 1 .O equiv of RMgX, THF, room tempera-
ture, 16 h) occurred trans to the ester chain to yield on workup
the y-lactone 7. Phenylsulfenylation (1.1 equiv of LDA, THF,
(1) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J . Am. Chem. SOC. 1963, 85,
362; 1964,86,485. (b) Bertrand, M.; Gras, J.-L. Tetrahedron 1974,30,793.
(2) Wlodzimierz, M. D.; Grieco, P. A.; Huffman, J. C.; Rymkiewicz, A.;
Wawrzun, A. Phytochemistry 1981, 20, 2733.
(3) Ishitsuka, M.; Kusumi, T.; Kakisawa, H.; Kawakami, Y.; Nagai, Y.;
Sato, T. J. Org. Chem. 1983, 48, 1937.
(4) Anderson, J. R.; Edwards, R. L.; Freer, A. A,; Mabelis, R. P.; Poyser,
J. P.; Spencer, H.; Whalley, A. J . S. J. Chem. SOC., Chem. Commun. 1984,
917. The original designation of this group of punctatins has been superseded
by the punctaporonins (Poyser, J. P., personal communication).
( 5 ) (a) Anderson, J. R.; Briant, C. E.; Edwards, R. L.; Mabelis, R. P.;
Poyser, J. P.; Spencer, H.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun.
1984, 405. (b) Poyser, J. P.; Edwards, R. L.; Anderson, J. R.; Hursthouse,
M. B.; Walker, N. P. C.; Sheldrick, G. M.; Whalley, A. J. S. J. Antibiot. 1986,
39. 167.
(6) Paquette, L. A.; Sugimura, T. J . Am. Chem. SOC. 1986, 108, 3841;
(7) Agosta, W. C.; Herron, D. K. J . Org. Chem. 1969, 34, 2782.
(8) Howden, M. E.; Maercker, A.; Burdan, J.; Roberts, J. D. J. Am. Chem.
1987, 109, 3017.
SOC. 1966, 88, 1732.
THF,60"C, Pd(PPh,),.diphos 6 7 6 @ @
'S02Ph 'S02Ph
0 0
10 10 a
10 h 10 c 11
closures described by Trost and Verhoeveng no trace of the re-
gioisomeric cycloheptene products could be discerned by high field
proton NMR, and none of the (Z)-cyclononene stereoisomer was
detected. Product 10 could be readily separated by silica gel into
a 1:2 ratio of fractions corresponding to the two carbinol epimers.
The minor fraction, mp 202-203 OC, was shown by single-crystal
X-ray analysis'0 to have the structure loa, corresponding to the
non-natural series. The major fraction, presumably the carbinol
epimer of loa, unexpectedly appeared to be a mixture of two
similar compounds by 300 MHz 'H NMR. This discrepancy was
resolved by high-temperature 'H N M R studies which showed the
existence of slowly equilibrating cyclononene conformers (lob =+
1Oc) and by careful crystallization from MeCN to give a single
conformer, mp 184-185 "C, for which X-ray crystallography
established the structure in the crystal as conformation 1Oc.Io
With the identity of the major sulfone fraction thus established
as the conformational isomer mixture lObc containing the full
carbon skeleton of the target molecule, we explored the generation
of the second double bond by elimination of PhSO2H. Our direct
attempts to generate a cyclononadiene system using DBU (DMSO,
60 OC, 16 h) or KOt-Bu (DMSO, room temperature)" failed,
presumably because of the strain imposed by developing a
bridgehead double bond within this rigid bicyclic framework.
Vigorous treatment of the mixture 10 with KOMe in MeOH at
reflux for 2 h led to diene keto acids having IR, MS, ' H NMR,
and I3C NMR properties consistent with the Grob fragmentation
product, cycloundecadienones 11.
To alleviate the strain of the requisite diene, the lactone ring
was opened as foIlows. Sodium amalgam reductiongb of IObc gave
lactone 12, which was resulfenylated (2.2 equiv of LDA, THF,
-70 "C, then 2.0 equiv of PhSSOzPh, -50 'C, 1 h) to thioether
13. Reduction of 13 (6 equiv of LiAlH,, THF, room temperature,
20 min) followed by acetylation (excess Ac20-py, CHC13, 8 h,
reflux) gave in 51% overall yield the triol monoacetate 14. Ox-
idation, followed by sulfoxide elimination (5 equiv of NaIO,,
aqueous dioxane, catalyst HOAc, 35 'C, 16 h, then 80 "C in
toluene, 30 min) gave an 80% yield of the (E$)-diene mono-
acetate, which was deacetylated (KOMe, MeOH, room tem-
(9) (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1979,101, 1597.
(b) Trost, B. M.; Verhoeven, T. R. Ibid. 1980, 202,4743. See, also: (c) Trost,
B. M.; Molander, G. A. J . Am. Chem. SOC. 1981, 103, 5969. (d) Tsuji, J.;
Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22, 2575.
(10) Details of the X-ray single crystal structure will be given in our full
paper. We thank Professor W. D. Jones for his guidance in the X-ray analysis.
(1 1) Hofmann, J. E.; Wallace, T. J.; Schriesheim, A. J . Am. Chem. SOC.
1964, 86, 1561. Manchand, P. S.; Rosenberger, M.; Saucy, G.; Wehrli, P.
A.; Wong, H.; Chambers, L.; Ferro, M. P.; Jackson, W. Helu. Chim. Acta
1976, 59, 387.
0002-7863188115 10-6265SO1 .50/0 I , , . 0 1988 American Chemical Society
1.0 equiv of HMP,A, -78 OC, then 2 equiv of Ph2Sz, 0 OC, 1 h)
produced thioethers 8, which were directly oxidized (3 equiv of
MCPBA, solid KzC03, CH2C12, room temperature, 16 h) to yield
the diastereomeric mixture of epoxy sulfones 9; no epoxidation
of the terminal methylene was observed.
Treatment of this diastereomeric mixture with 10 mol% of
Pd(PPh3)4 and 20 mol% diphos in T H F at 60 "C for 1 h led with
dramatic regioselectivity to a mixture of the (E)-cyclononene
alcohol epimers 10 in 67% isolated yield. In contrast to the related
Total Synthesis of (f)-Punctaporonin B
Andrew S. Kende,* Istvan Kaldor, and Robert Aslanian
Department of Chemistry, University of Rochester
Rochester, New York 14627
Received May 12, 1988
Since the landmark total synthesis of the hydrocarbon (*)-
caryophyllene (1) by Corey in 1963, this rare series of bicarbocyclic
1 2 3
sesquiterpenes has received scant attention from the synthetic
chemist.' This hiatus has been challenged in recent years by the
structure elucidation of such intriguing 9-4 bicyclic terpenes as
the 1 2-hydroxycaryophyllene-4,5-oxide,2 the diterpene acetylco-
r i a ~ e n o n e , ~ and in 1984, by the still more highly functionalized
diene triol, punctaporonin B (2)., Triol 2, isolated from extracts
of the drug fungus Poronia punctata (Linnaeus ex Fries) is a
congener of several tricarbocyclic sesquiterpenes of which (-)-
punctaporonin A (3)' has been very recently synthesized by Pa-
quette and Sugimura.6
We describe the first total synthesis of racemic punctaporonin
B by an efficient and potentially general strategy for the con-
struction of such fused 9-4 systems. Our starting material was
the known and readily accessible' cyclobutanone ester 4, which
p 1.NaH,BrCH2COOE[
4 5 7
, 2,PhSSPh 1 .LDA,THI-HMPA ( 5 5 % ) $-yy
S02Ph
8 9
underwent C-alkylation (1.2 equiv of NaH, 1.2 equiv of
BrCH2CO2Et, DMSO, room temperature, 3 h) and subsequent
decarbo-tert-butoxylation (catalyst pTSA, C6H6 reflux, 2 h) to
give the y-keto ester 5 in 78% overall yield. Addition of the
Grignard reagent 6* ( 1 .O equiv of RMgX, THF, room tempera-
ture, 16 h) occurred trans to the ester chain to yield on workup
the y-lactone 7. Phenylsulfenylation (1.1 equiv of LDA, THF,
(1) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J . Am. Chem. SOC. 1963, 85,
362; 1964,86,485. (b) Bertrand, M.; Gras, J.-L. Tetrahedron 1974,30,793.
(2) Wlodzimierz, M. D.; Grieco, P. A.; Huffman, J. C.; Rymkiewicz, A.;
Wawrzun, A. Phytochemistry 1981, 20, 2733.
(3) Ishitsuka, M.; Kusumi, T.; Kakisawa, H.; Kawakami, Y.; Nagai, Y.;
Sato, T. J. Org. Chem. 1983, 48, 1937.
(4) Anderson, J. R.; Edwards, R. L.; Freer, A. A,; Mabelis, R. P.; Poyser,
J. P.; Spencer, H.; Whalley, A. J . S. J. Chem. SOC., Chem. Commun. 1984,
917. The original designation of this group of punctatins has been superseded
by the punctaporonins (Poyser, J. P., personal communication).
( 5 ) (a) Anderson, J. R.; Briant, C. E.; Edwards, R. L.; Mabelis, R. P.;
Poyser, J. P.; Spencer, H.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun.
1984, 405. (b) Poyser, J. P.; Edwards, R. L.; Anderson, J. R.; Hursthouse,
M. B.; Walker, N. P. C.; Sheldrick, G. M.; Whalley, A. J. S. J. Antibiot. 1986,
39. 167.
(6) Paquette, L. A.; Sugimura, T. J . Am. Chem. SOC. 1986, 108, 3841;
(7) Agosta, W. C.; Herron, D. K. J . Org. Chem. 1969, 34, 2782.
(8) Howden, M. E.; Maercker, A.; Burdan, J.; Roberts, J. D. J. Am. Chem.
1987, 109, 3017.
SOC. 1966, 88, 1732.
THF,60"C, Pd(PPh,),.diphos 6 7 6 @ @
'S02Ph 'S02Ph
0 0
10 10 a
10 h 10 c 11
closures described by Trost and Verhoeveng no trace of the re-
gioisomeric cycloheptene products could be discerned by high field
proton NMR, and none of the (Z)-cyclononene stereoisomer was
detected. Product 10 could be readily separated by silica gel into
a 1:2 ratio of fractions corresponding to the two carbinol epimers.
The minor fraction, mp 202-203 OC, was shown by single-crystal
X-ray analysis'0 to have the structure loa, corresponding to the
non-natural series. The major fraction, presumably the carbinol
epimer of loa, unexpectedly appeared to be a mixture of two
similar compounds by 300 MHz 'H NMR. This discrepancy was
resolved by high-temperature 'H N M R studies which showed the
existence of slowly equilibrating cyclononene conformers (lob =+
1Oc) and by careful crystallization from MeCN to give a single
conformer, mp 184-185 "C, for which X-ray crystallography
established the structure in the crystal as conformation 1Oc.Io
With the identity of the major sulfone fraction thus established
as the conformational isomer mixture lObc containing the full
carbon skeleton of the target molecule, we explored the generation
of the second double bond by elimination of PhSO2H. Our direct
attempts to generate a cyclononadiene system using DBU (DMSO,
60 OC, 16 h) or KOt-Bu (DMSO, room temperature)" failed,
presumably because of the strain imposed by developing a
bridgehead double bond within this rigid bicyclic framework.
Vigorous treatment of the mixture 10 with KOMe in MeOH at
reflux for 2 h led to diene keto acids having IR, MS, ' H NMR,
and I3C NMR properties consistent with the Grob fragmentation
product, cycloundecadienones 11.
To alleviate the strain of the requisite diene, the lactone ring
was opened as foIlows. Sodium amalgam reductiongb of IObc gave
lactone 12, which was resulfenylated (2.2 equiv of LDA, THF,
-70 "C, then 2.0 equiv of PhSSOzPh, -50 'C, 1 h) to thioether
13. Reduction of 13 (6 equiv of LiAlH,, THF, room temperature,
20 min) followed by acetylation (excess Ac20-py, CHC13, 8 h,
reflux) gave in 51% overall yield the triol monoacetate 14. Ox-
idation, followed by sulfoxide elimination (5 equiv of NaIO,,
aqueous dioxane, catalyst HOAc, 35 'C, 16 h, then 80 "C in
toluene, 30 min) gave an 80% yield of the (E$)-diene mono-
acetate, which was deacetylated (KOMe, MeOH, room tem-
(9) (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1979,101, 1597.
(b) Trost, B. M.; Verhoeven, T. R. Ibid. 1980, 202,4743. See, also: (c) Trost,
B. M.; Molander, G. A. J . Am. Chem. SOC. 1981, 103, 5969. (d) Tsuji, J.;
Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22, 2575.
(10) Details of the X-ray single crystal structure will be given in our full
paper. We thank Professor W. D. Jones for his guidance in the X-ray analysis.
(1 1) Hofmann, J. E.; Wallace, T. J.; Schriesheim, A. J . Am. Chem. SOC.
1964, 86, 1561. Manchand, P. S.; Rosenberger, M.; Saucy, G.; Wehrli, P.
A.; Wong, H.; Chambers, L.; Ferro, M. P.; Jackson, W. Helu. Chim. Acta
1976, 59, 387.
0002-7863188115 10-6265SO1 .50/0 I , , . 0 1988 American Chemical Society
Page 2
6266 J . Am. Chem. SOC. 1988, 110, 6266-6267
I O b c NaHg.KI12P0, (74’12) e ‘H L D A , P h S S O , P h ~ (91%) ’SPh
0 2 3
1: 13
1 LIAIH..THF x
/\PI” OH
1 haIO,.BOT
11 c I “n
:,MeOH ?.Ac,O,py
...
(51%) OAC (47%) OH
14 15
perature, 20 min, 58%) to the crystalline (E,E)-diene triol 15, mp
The UV maximum of triol 15 (A,, 237 nm, MeOH) and its
300 MHz IH NMR differed appreciably from those of the target
molecule. However, when a dilute solution of 15 in CD30D was
irradiated for 1 h by using a low-pressure UV source,12 the
isomerization monitored by NMR, chromatography, and re-
crystallization from EtOAc gave ca. 60% of colorless racemic
punctaporonin B (2), mp 154-155 OC. The 300 MHz ’H NMR
spectra in both CDCI, and pyridine-d5, the mass spectrum, the
UV spectrum (A,, 209 nm, MeOH, t 6100), and the TLC be-
havior of this material were absolutely identical with the corre-
sponding properties of natural punctaporonin B kindly supplied
by Dr. J . P. Poyser (IC1 Pharmaceuticals Division). Thus the
first synthesis of ( i ) - 2 has been achieved in 13 steps from cy-
clobutanone 4.13
Supplementary Material Available: Spectral data for 2, 5, 7,
8, 11, 12, 13, and 15 (2 pages). Ordering information is given
on any current masthead page.
112-1 14 OC.
(12) Cf. Shumate, K.; Fonken, G. J. J . Am. Chem. SOC. 1966,88, 1073.
(13) Partial support of this research by a Fulbright Award (to I.K.) and
by Grant CA-18846 from the National Cancer Institute, NIH, USPHS, is
gratefully acknowledged.
The Peptide Way to Macrocyclic Bifunctional
Chelating Agents: Synthesis of
2- ( p -Nitrobenzyl)- 1,4,7,10-tetraazacyclododecane-
N,N’,N”,N”’-tetraacetic Acid and Study of Its
Yttrium(II1) Complex
Min K. Moi and Claude F. Meares*
Department of Chemistry, University of California
Davis, California 9561 6
Sally J. DeNardo
Departments of Internal Medicine and
Radiology, University of California, Davis
Medical Center, Sacramento, California 9581 7
Received March 21, 1988
Monoclonal antibody technology allows the specificity of an
antibody for its antigen to be used in targeting cancer cells.’ The
conjugation of metals-particularly radionuclides such as wY or
67C~-to monoclonal antibodies results in agents for radioim-
munotherapy and other medical applications.2d Chelators that
( 1 ) DeNardo, S. J.; Peng, J. S.; Denardo, G. L.; Mills, S. L.; Epstein, A.
L. Nucl. Med. Biol. 1986, 13, 303.
(2) DeNardo, S. J.; Jungerman, J. A,; DeNardo, G. L.; Lagunas-Solar, M.
C.; Cole, W. C.; Meares, C. F. In The Developing Role of Short-Liued
Radionuclides in Nuclear Medical Practice; Paras, P., Theissen, J. W., Eds.;
US Department of Energy: Washington, DC, 1984.
4 5
COCH
6 1
Figure 1. Synthesis of 2-@-nitrobenzyl)-l,4,7,1O-tetraazacyclodode-
cane-N,N’,N’’,N”’-tetraacetic acid, 1. Tetrapeptide [ ~ j - N O ~ P h e - G l y -
Gly-Gly (2) was prepared by standard methods.“ (a) Reflux with 17
equiv of BH,.THF, 31 h; 65% yield after silica gel chromatography. (b)
Toluenesulfonyl chloride (5 equiv) in CH,CN/Et,N, 8 h, room tem-
perature; 49% yield after silica gel HPLC. (c) Cs2C03 in DMF, 5 h, 60
“ C ; 79% yield after silica gel HPLC. (d) 96% H2S04, 16 equiv of
C,H,OH, 48 h, 100 OC; 91% yield after CIS HPLC. (e) BrCH,COO-
(5 equiv), 3 h, pH 10, 70 OC; 58% yield after C I S HPLC.
can hold radiometals with high stability under physiological
conditions are essential to avoid excessive radiation damage to
nontarget cell^.^,^
Derivatives of polyazamacrocycles (bearing a C-substituted
functional group for antibody attachment) can exhibit remarkable
kinetic inertness; for example, the copper complex of the 14-
membered 6-@-nitrobenzyl)- 1,4,8,11 -tetraazacyclotetradecane-
N,N”N”,N”’-tetraacetic acid (nitrobenzyl-TETA) is very stable
in human serum under physiological conditions, and a conjugate
of this complex with a monoclonal antibody has tested well in
tumor-bearing Also, the gadolinium complex of the
12-membered 1,4~7,10-tetraazacyclododecane-N,N’,N’’,N’”-
tetraacetic acid (DOTA) is a stable, useful contrast agent for
magnetic resonance imaging.* Desreux and co-workers9 have
shown that complexes of lanthanides with DOTA have formation
constants that are several orders of magnitude higher than TETA;
thus the 12-membered macrocycle is the favored target for binding
trivalent yttrium.
Macrocyclic polyamines, the key precursors to macrocyclic
bifunctional chelating agents, are synthesized by bimolecular
cyclizations.’0 Competition between polymerization and the
(3) (a) Order, S. E.; Klein, J . L.; Leichner, P. K.; Frinke, J.; Lollo, C.;
Carlo, D. J. Int . J . Radiation Oncology Biol. Phys. 1986, 12, 277. (b)
Deshpande, S. V.; DeNardo, S. J.; Meares, C. F.; McCall, M. J.; Adams, G .
P.; Moi, M. K.; DeNardo, G. L. J . Nucl. Med. 1988, 29, 217.
(4) (a) Halpern, S. E.; Hagan, P. L.; Gamer, P. R.; Kozol, J. A.; Chen,
A. W. N.; Frincke, J. M.; Bartholomew, R. M.; David, G. S.; Adams, T. H.
Cancer Res. 1983.43, 5347. (b) Hnatowich, D. J.; Layne, R. L.; Lanteigne,
D.; Davis, M. A.; Griffin, T. W.; Doherty, P. W. Science (Washington, D.C.)
1983, 220, 613. (c) Pimm, M. V.; Perkins, A. C.; Baldwin, R. W. Eur. J .
Nucl. Med. 1985, 11, 300.
(5) Klein, J. L.; Leichner, P. K.; Callahan, K. M.; Kopher, K. A.; Order,
S. E. Antibody, Immunoconjugates, and Radiopharmaceuticals 1988, I , 55.
(6) Meares, C. F.; Wensel, T. G. Acc. Chem. Res. 1984, 17, 202.
(7) (a) Moi, M. K.; Meares, C. F.; McCall, M. J.; Cole, W. C.; DeNardo,
S. J. Anal. Biochem. 1985, 148, 249. (b) Moi, M. K.; Yanuck, M.; Desh-
pande, S. V.; Hope, H.; DeNardo, S. J.; Meares, C. F. Inorg. Chem. 1987,
26, 3458.
(8) (a) Margerstadt, M.; Gansow, 0. A,; Brechbiel, M. W.; Colcher, D.;
Baltzer, L.; Knop, R. H.; Girton, M. E.; Naegele, M. Magn. Reson. Med.
1986, 3,808. (b) Runge, V. M.; Jacobson, S.; Wood, M. L.; Kaufman, D.;
Adelman, L. S. Radiology 1988, 166, 835. (c) Bousquet, J. C.; Saini, S.;
Stark, D. D.; Hahn, P. F.; Nigam, M.; Wittenberg, J.; Ferrucci, J. T. Ra-
diology 1988, 166, 693.
(9) Loncin, M. F.; Desreux, J. F.; Merciny, E. Inorg. Chem. 1986, 25,
2646.
0002-7863/88/1510-6266$01.50/0 0 1988 American Chemical Society
I O b c NaHg.KI12P0, (74’12) e ‘H L D A , P h S S O , P h ~ (91%) ’SPh
0 2 3
1: 13
1 LIAIH..THF x
/\PI” OH
1 haIO,.BOT
11 c I “n
:,MeOH ?.Ac,O,py
...
(51%) OAC (47%) OH
14 15
perature, 20 min, 58%) to the crystalline (E,E)-diene triol 15, mp
The UV maximum of triol 15 (A,, 237 nm, MeOH) and its
300 MHz IH NMR differed appreciably from those of the target
molecule. However, when a dilute solution of 15 in CD30D was
irradiated for 1 h by using a low-pressure UV source,12 the
isomerization monitored by NMR, chromatography, and re-
crystallization from EtOAc gave ca. 60% of colorless racemic
punctaporonin B (2), mp 154-155 OC. The 300 MHz ’H NMR
spectra in both CDCI, and pyridine-d5, the mass spectrum, the
UV spectrum (A,, 209 nm, MeOH, t 6100), and the TLC be-
havior of this material were absolutely identical with the corre-
sponding properties of natural punctaporonin B kindly supplied
by Dr. J . P. Poyser (IC1 Pharmaceuticals Division). Thus the
first synthesis of ( i ) - 2 has been achieved in 13 steps from cy-
clobutanone 4.13
Supplementary Material Available: Spectral data for 2, 5, 7,
8, 11, 12, 13, and 15 (2 pages). Ordering information is given
on any current masthead page.
112-1 14 OC.
(12) Cf. Shumate, K.; Fonken, G. J. J . Am. Chem. SOC. 1966,88, 1073.
(13) Partial support of this research by a Fulbright Award (to I.K.) and
by Grant CA-18846 from the National Cancer Institute, NIH, USPHS, is
gratefully acknowledged.
The Peptide Way to Macrocyclic Bifunctional
Chelating Agents: Synthesis of
2- ( p -Nitrobenzyl)- 1,4,7,10-tetraazacyclododecane-
N,N’,N”,N”’-tetraacetic Acid and Study of Its
Yttrium(II1) Complex
Min K. Moi and Claude F. Meares*
Department of Chemistry, University of California
Davis, California 9561 6
Sally J. DeNardo
Departments of Internal Medicine and
Radiology, University of California, Davis
Medical Center, Sacramento, California 9581 7
Received March 21, 1988
Monoclonal antibody technology allows the specificity of an
antibody for its antigen to be used in targeting cancer cells.’ The
conjugation of metals-particularly radionuclides such as wY or
67C~-to monoclonal antibodies results in agents for radioim-
munotherapy and other medical applications.2d Chelators that
( 1 ) DeNardo, S. J.; Peng, J. S.; Denardo, G. L.; Mills, S. L.; Epstein, A.
L. Nucl. Med. Biol. 1986, 13, 303.
(2) DeNardo, S. J.; Jungerman, J. A,; DeNardo, G. L.; Lagunas-Solar, M.
C.; Cole, W. C.; Meares, C. F. In The Developing Role of Short-Liued
Radionuclides in Nuclear Medical Practice; Paras, P., Theissen, J. W., Eds.;
US Department of Energy: Washington, DC, 1984.
4 5
COCH
6 1
Figure 1. Synthesis of 2-@-nitrobenzyl)-l,4,7,1O-tetraazacyclodode-
cane-N,N’,N’’,N”’-tetraacetic acid, 1. Tetrapeptide [ ~ j - N O ~ P h e - G l y -
Gly-Gly (2) was prepared by standard methods.“ (a) Reflux with 17
equiv of BH,.THF, 31 h; 65% yield after silica gel chromatography. (b)
Toluenesulfonyl chloride (5 equiv) in CH,CN/Et,N, 8 h, room tem-
perature; 49% yield after silica gel HPLC. (c) Cs2C03 in DMF, 5 h, 60
“ C ; 79% yield after silica gel HPLC. (d) 96% H2S04, 16 equiv of
C,H,OH, 48 h, 100 OC; 91% yield after CIS HPLC. (e) BrCH,COO-
(5 equiv), 3 h, pH 10, 70 OC; 58% yield after C I S HPLC.
can hold radiometals with high stability under physiological
conditions are essential to avoid excessive radiation damage to
nontarget cell^.^,^
Derivatives of polyazamacrocycles (bearing a C-substituted
functional group for antibody attachment) can exhibit remarkable
kinetic inertness; for example, the copper complex of the 14-
membered 6-@-nitrobenzyl)- 1,4,8,11 -tetraazacyclotetradecane-
N,N”N”,N”’-tetraacetic acid (nitrobenzyl-TETA) is very stable
in human serum under physiological conditions, and a conjugate
of this complex with a monoclonal antibody has tested well in
tumor-bearing Also, the gadolinium complex of the
12-membered 1,4~7,10-tetraazacyclododecane-N,N’,N’’,N’”-
tetraacetic acid (DOTA) is a stable, useful contrast agent for
magnetic resonance imaging.* Desreux and co-workers9 have
shown that complexes of lanthanides with DOTA have formation
constants that are several orders of magnitude higher than TETA;
thus the 12-membered macrocycle is the favored target for binding
trivalent yttrium.
Macrocyclic polyamines, the key precursors to macrocyclic
bifunctional chelating agents, are synthesized by bimolecular
cyclizations.’0 Competition between polymerization and the
(3) (a) Order, S. E.; Klein, J . L.; Leichner, P. K.; Frinke, J.; Lollo, C.;
Carlo, D. J. Int . J . Radiation Oncology Biol. Phys. 1986, 12, 277. (b)
Deshpande, S. V.; DeNardo, S. J.; Meares, C. F.; McCall, M. J.; Adams, G .
P.; Moi, M. K.; DeNardo, G. L. J . Nucl. Med. 1988, 29, 217.
(4) (a) Halpern, S. E.; Hagan, P. L.; Gamer, P. R.; Kozol, J. A.; Chen,
A. W. N.; Frincke, J. M.; Bartholomew, R. M.; David, G. S.; Adams, T. H.
Cancer Res. 1983.43, 5347. (b) Hnatowich, D. J.; Layne, R. L.; Lanteigne,
D.; Davis, M. A.; Griffin, T. W.; Doherty, P. W. Science (Washington, D.C.)
1983, 220, 613. (c) Pimm, M. V.; Perkins, A. C.; Baldwin, R. W. Eur. J .
Nucl. Med. 1985, 11, 300.
(5) Klein, J. L.; Leichner, P. K.; Callahan, K. M.; Kopher, K. A.; Order,
S. E. Antibody, Immunoconjugates, and Radiopharmaceuticals 1988, I , 55.
(6) Meares, C. F.; Wensel, T. G. Acc. Chem. Res. 1984, 17, 202.
(7) (a) Moi, M. K.; Meares, C. F.; McCall, M. J.; Cole, W. C.; DeNardo,
S. J. Anal. Biochem. 1985, 148, 249. (b) Moi, M. K.; Yanuck, M.; Desh-
pande, S. V.; Hope, H.; DeNardo, S. J.; Meares, C. F. Inorg. Chem. 1987,
26, 3458.
(8) (a) Margerstadt, M.; Gansow, 0. A,; Brechbiel, M. W.; Colcher, D.;
Baltzer, L.; Knop, R. H.; Girton, M. E.; Naegele, M. Magn. Reson. Med.
1986, 3,808. (b) Runge, V. M.; Jacobson, S.; Wood, M. L.; Kaufman, D.;
Adelman, L. S. Radiology 1988, 166, 835. (c) Bousquet, J. C.; Saini, S.;
Stark, D. D.; Hahn, P. F.; Nigam, M.; Wittenberg, J.; Ferrucci, J. T. Ra-
diology 1988, 166, 693.
(9) Loncin, M. F.; Desreux, J. F.; Merciny, E. Inorg. Chem. 1986, 25,
2646.
0002-7863/88/1510-6266$01.50/0 0 1988 American Chemical Society
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