Asymmetric synthesis of the nakijiquinones - Selective inhibitors of the Her-2/Neu protooncogene

Article abstract of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3710::AID-ANIE3710>3.0.CO;2-H

A Wieland-Miescher type ketone and a tetramethoxyaryl derivative are the key building blocks for the enantioselective total synthesis of nakijiquinone C (1). The nakijiquinones are the only natural products known that selectively inhibit the Her-2/Neu tyr

Full text of DOI:10.1002/(SICI)1521-3773(19991216)38:24<3710::AID-ANIE3710>3.0.CO;2-H

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[8] G. Fachinetti, T. Funaioli, L. Lecci, F. Marchetti, Inorg. Chem. 1996,
35, 7217 ± 7224.
[9] To date, only the osmium analogue [Os2X2(CO)6] (X ˆ I) has been
reported: G. L. Geoffroy, S. Rosenberg, A. W. Herlinger, A. L.
Rheingold, Inorg. Chem. 1986, 25, 2916 ± 2919.
[10] a) R. Mason, K. M. Thomas, D. F. Gill, B. L. Shaw, J. Organomet.
Chem. 1972, 40, C67 ± C69; b) D. F. Jones, P. H. Dixneuf, A. Benoit,
J. Y. Le Marouille, Inorg. Chem. 1983, 22, 29 ± 33; c) J. S. Field, R. J.
Haines, C. N. Sampson, J. Sundermeyer, J. Organomet. Chem. 1986,
2/Neu-protooncogene (also called erbB-2). This receptor is
vastly overexpressed in about 30% of primary breast, ovary,
and gastric carcinomas.[1, 3, 4] Amplification is closely corre-
lated with the clinical behavior of these neoplasms, such that
tumors with Her-2 amplification are more agressive and
associated with reduced patient survival. Therefore, com-
pounds that can selectively block Her-2 activity are of
paramount importance for the development of new anti-
cancer drugs;[1, 2, 5] a monoclonal antibody against Her-2 has
already been introduced by Genentech into the clinic as a new
revolutionary treatment for breast cancer. In addition, such
drugs are likely to be useful in dissecting signalling path-
ways.[2, 6, 7] Until today only a few natural products with
intrinsic tyrosine kinase inhibiting activity per se were isolated
and, in particular, a natural product that inhibits Her-2 has not
been synthesized.[2, 6] Recently, however, the nakijiquinones
1a ± d (see Scheme 1) were identified as selective inhibitors of
the Her-2/Neu kinase, displaying pronounced cytotoxicity
against L 1210 murine leukemia cells and KB human
epidermoid carcinoma cells.[8] We now disclose the first
enantioselective total synthesis of the nakijiquinones.
The nakijiquinones embody three basic structural elements,
an amino acid, a central p-quinoid unit, and a diterpenoid
system. To reach a high degree of convergency, the nakijiqui-
nones were first, dissected in a retrosynthetic sense into
isospongiaquinone (2), an interesting natural product in its
own right[9] and an amino acid that can be introduced in the
last step by conjugate addition to the vinylogous methyl ester
present[8] (Scheme 1). It was further planned to generate the
selectively functionalized quinoid system by oxidation of a
tetramethoxy-substituted aromatic precursor 3 to a 1,4-
dicarbonyl compound and subsequent selective saponification
Â
310, C42 ± C46; d) A. Colombie, G. Lavigne, J.-J. Bonnet, J. Chem.
Soc. Dalton Trans. 1986, 899 ± 901.
[11] Review: R. J. Haines in Comprehensive Organometallic Chemistry II,
Vol. 7 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon
Elsevier, Oxford, 1996, Chap. II, p. 625.
[12] A related methoxycarbonyl-bridged species is known: G. Süss-Fink, J.-
Â
M. Soulie, G. Rheinwald, H. Stoeckli-Evans, Y. Sazaki, Organo-
metallics 1996, 15, 3416 ± 3422.
[13] The first crystals of 3 were obtained from methanol/ethanol in a
systematically twinned crystalline form (orthorhombic, space group
Immm, a ˆ 14.919(1), b ˆ 20.006(2), c ˆ 22.279(3) Š). Acetone/etha-
nol mixtures gave single crystals of a different form, albeit containing
solvent molecules: [NEt4]2Na2[Ru8(m-CO3)4(m-Cl)4(CO)16] ´ 2EtOH ´
0.5(CH3)2CO ´ 1.5H2O: triclinic, space group P1, a ˆ 16.405(3), b ˆ
19.109(4), c ˆ 23.073(8) Š; a ˆ 85.26(3), b ˆ 85.64(3), g ˆ 72.97(2);
Vˆ 6882(3) Š3; R ˆ 0.035, Rw ˆ 0.079 (refinement on F 2).[7b]
[14] a) P. Süsse, Acta Crystallogr. 1967, 22, 146 ± 149; b) M.-C. Suen, G.-W.
Tseng, J.-D. Chen, T.-C. Keng, J.-C. Wang, Chem. Commun. 1999,
1185± 1186; c) E. G. Lundquist, K. Foltig, J. C. Huffman, K. G. Caulton,
Inorg. Chem. 1987, 26, 205 ± 208.
‡
[15] For the [(Ph3P)2N] (PPN) salt of 4 (obtained by different routes), see:
Â
a) G. Lavigne, N. Lugan, P. Kalck, J.-M. Soulie, O. Lerouge, J.-Y.
Saillard, J.-F. Halet, J. Am. Chem. Soc. 1992, 114, 10669 ± 10670; b) N.
Â
Lugan, G. Lavigne, J.-M. Soulie, P. Kalck, J.-Y. Saillard, J.-F. Halet,
Organometallics 1995, 14, 1713 ± 1731.
[16] Crystal data for the tetraethylammonium salt of 4: monoclinic, space
group C2/c; a ˆ 23.862(2), b ˆ 24.107(2), c ˆ 19.045(2) Š; b ˆ
128.2(1)8; Z ˆ 8.
[17] The soluble anionic building block of the polymer 2 can be generated
and kept in acetonitrile as a ªlightly stabilizedº species that is still
incompletely formulated.
[18] T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 1998, 98, 2599 ±
2660.
R
OMe
OH
HN
COOH
O
O
O
H
O
H
1
13OH
9
Asymmetric Synthesis of the NakijiquinonesÐ
Selective Inhibitors of the Her-2/Neu
Protooncogene**
8
3
4
1
2
1a: R = H: Nakijiquinone A
1b: R = iPr: Nakijiquinone B
Petra Stahl and Herbert Waldmann*
1c: R = CH2OH: Nakijiquinone C
1d: R = CH(CH3)OH: Nakijiquinone D
Extracellular growth-promoting signals are recognized in
many cases by transmembrane receptors with tyrosine kinase
activity. These proteins trigger numerous intracellular signal-
ling cascades by which cell growth, proliferation, and other
genetic programs are regulated.[1] Dysregulation of these
signal sequences may contribute to or cause many diseases.
For instance, enhanced activity of receptor tyrosine kinases
can promote tumor growth and has been implicated in
carcinogenesis.[2] A particularly relevant example is the Her-
OMe
MeO
OMe
OMe
MeO
OMe
Hal
OMe
OMe
H
5
+
O
O
[*] Prof. H. Waldmann, Dipl.-Chem. P. Stahl
Max-Planck-Institut für molekulare Physiologie
Otto-Hahn-Strasse 11, D-44227 Dortmund (Germany)
Fax: (‡49)231-133-2499
3
O
O
4
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[**] This research was supported by the Fonds der Chemischen Industrie.
Scheme 1. Retrosynthetic analysis of the nakijiquinones 1.
3710
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of one of the two vinylogous methyl esters generated thereby.
For the synthesis of the diterpene structure and its coupling
with the alkoxy-substituted aromatic compound, we resorted
to the reductive alkylation of a,b-unsaturated Wieland ±
Miescher type enone 4 with a benzyl halide 5. This strategy
had already proven to be useful in the construction of related
natural products.[10] Finally, we envisaged generating the
endocyclic 3,4-alkene by olefination of a ketone at C-4 and
subsequent isomerization of the generated exocyclic double
bond. It was also planned to introduce the C-13 methyl group
by an olefination/reduction sequence of an intermediary
generated ketone.
halides 8 and 9 and enone 4 the reaction conditions reported
for related structures could not be employed successfully.
Benzyl chloride 8 did not react at all with the radical anion
generated from enone 4 by treatment with lithium in
ammonia. However, a yield of 76% was obtained reprodu-
cibly if a solution of twelve equivalents of benzyl bromide 9 in
THF was added rapidly at 788C to a preformed solution of
the radical anion in NH3/THF (final ratio NH3:THF ˆ 1.0:0.7)
and subsequent refluxing at 338C for 2 h. The radical anion
was generated by adding a solution of enone 4 in THF/water
(1:0.018) at 788C to 30 equivalents of Li/NH3 followed by
refluxing for 45 min and recooling to 788C.
Benzyl halides 8 and 9 were prepared from catechol (6) in
five-step sequences as shown in Scheme 2. To this end, 6 was
oxidized to the corresponding ortho-quinone, which rapidly
added NaOMe. Subsequent reoxidation led once again to an
The conversion of the keto group present in 10 into the
corresponding exo-methylene compound 11 was unexpectedly
difficult. Several established methylenation reagents such as
the Tebbe reagent[13] and [Cp2TiMe2][14] failed completely, and
under various conditions the Wittig reaction either yielded no
product at all or only an unsatisfactory low amount of the
desired olefin. Finally, the use of nine equivalents of
H3CPPh3Br together with nine equivalents of KOtBu in
refluxing toluene[15] turned out to be the method of choice,
yielding the exocyclic olefin 11 in nearly quantitative yield.
Disappointingly, reduction of the olefin 11 with PtO2 pro-
ceeded without recordable stereoselectivity. We felt that this
might be due to an unfavourable conformation of the bicyclic
system and envisaged that removal of the acetal protecting
group might improve the situation. This turned out to be the
case. After cleavage of the acetal, the stereoselectivity of the
reduction with PtO2 in CH2Cl2 was raised to 80:20, and use of
Pd/C as catalyst in NEt3 as solvent yielded ketone 3 in 92% as
a 97:3 mixture of epimers at C-8 (Scheme 3). As planned, the
ketone at C-4 was converted in very high overall yield to
endocyclic alkene 12 by olefination (for which the conditions
described above once more proved to be very efficient), and
subsequent rhodium-catalyzed isomerization of the exocyclic
to the endocyclic double bond.
The next two steps in the synthetic sequence, that is the
oxidation of the tetramethoxyphenyl ring to the para-quinoid
system and the subsequent selective removal of the correct O-
methyl group posed major problems. Oxidation of the
aromatic system was initially attempted by applying CrO3 or
cerium ammonium nitrate which had proven to be useful
reagents in related studies.[10c,d, 16] However, oxidized inter-
mediate 13 was formed only in low yield or not at all. After
substantial variation of the reaction conditions, finally the use
of AgO and catalytic amounts of HNO3 at room temperature
in dioxane as solvent evolved as the method of choice.[17]
Under these conditions p-diketone 13 and the regioisomeric
o-diketone were obtained in a total yield of 82% as an
isomeric mixture. The undesired o-diketone was readily
rearranged to 13 by treatment with acid.
1) PbO2, NaOMe, 65%
2) MeOH, H2SO4, 96%
OMe
OH
MeO
HO
3) NaBH4, EtOH, 0°C
4) DMS, NaOH/EtOH,
NaHSO3, ∆
OMe
MeO
75% (2 steps)
6
7
HBr, HCHO
74%
Cl(CH2)4OCH2Cl
SnCl4, 71%
8
9
OMe
OMe
MeO
Li, NH3,
THF, H2O
76%
OMe
OMe
MeO
Hal
H
O
OMe
O
OMe
O
O
8: Hal = Cl
9: Hal = Br
O
O
10
4
9 equiv CH3PPh3Br,
9 equiv KOtBu,
toluene, ∆
98%
OMe
MeO
OMe
H
O
OMe
CH2
O
11
Scheme 2. Synthesis of tetramethoxyaryl intermediates 8 and 9.
ortho-quinone that was rearranged under acidic conditions to
the corresponding para-quinoid compound.[11] The keto
groups were then reduced, and the resulting 1,4-diphenol
was O-methylated to give tetramethoxybenzene 7. Compound
7 was converted efficiently in one-step reactions into benzyl
halides 8 and 9. Wieland ± Miescher type ketone 4 required for
the critical reductive coupling step was synthesized by
Robinson-annelation and subsequent selective monoprotec-
tion by transacetalization.[12] In the decisive coupling of benzyl
Selective removal of the correct O-methyl group was
attempted by a variety of methods. In particular, the use of
various different Lewis acids (BCl3, BBr3, AlCl3, BF3 ´ OEt2/
EtSH, HClO4 and trimethylsilyl iodide) was unsuccessful and
led to decomposition of the starting material. Also, attempts
to cleave a methyl ether before the oxidation did not succeed
and resulted exclusively in Lewis acid mediated rearrange-
ments of the terpene backbone. Finally, treatment of vinyl-
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3711

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specific rotation, whereas for the compound isolated from
natural sources a negative rotation was reported.[8] But as
described above, the IR and NMR data of 1c are in full accord
with the published values for natural nakijiquinone C, and the
diastereomer formed from isospongiaquinone and d-serine
shows a markedly different specific rotation.[8] Thus, in the
conversion of intermediate 2 to target compound 1c an
undesired diastereomer cannot have been formed. In addi-
tion, all data (including the specific rotation) recorded for
isospongiaquinone synthesized as shown in Scheme 3, are in
full accord with the values published for this natural product.
Thus, if the absolute configuration of synthetic 2 is correct,
nakijiquinone C (1c) must have been formed with the correct
absolute configuration, as well.[20]
In conclusion we have developed the first enantioselective
access to the nakijiquinones, the only natural products known
to selectively inhibit the Her-2/Neu protooncogene. This
synthetic route should give access to various analogues of
these interesting and biologically relevant kinase inhibitors.
Thereby new opportunities for the development of selective
inhibitors of the Her-2/Neu receptor tyrosine kinase and for
the study of the signaling pathways influenced by this enzyme
may be opened up.
OMe
MeO
OMe
OMe
MeO
OMe
OMe
1) HCl, THF
quant.
H
O
H
OMe
CH2
8
4
2) H2, Pd/C,
NEt3
92% (97:3)
O
O
11
3
1) CH3PPh3Br, KOtBu,
toluene, ∆
98%
2) RhCl3,
CHCl3/EtOH,
∆, 95%
OMe
OMe
OMe
O
MeO
O
OMe
OMe
H
H
AgO, HNO3,
dioxane, rt
82%
13
12
KOH,
CH3OH/H2O
71%
Received: June 15, 1999 [Z13571IE]
OH
German version: Angew. Chem. 1999, 111, 3935 ± 3938
OH
OMe
HN
O
O
O
Keywords: nakijiquinones ´ protein kinase inhibitors ´ signal
transduction ´ terpenoids ´ total synthesis
O
O
H
H
L-serine,
OH
OH
EtOH, NaHCO3
[1] a) Protein Phosphorylation (Ed.: F. Marks), VCH, Weinheim, 1996;
b) Protein Kinases (Ed.: J. R. Woodgett), Oxford University Press,
Oxford, 1994; c) G. F. Cooper, Oncogenes, 2nd ed., Jones and Bartlett,
Boston, 1995.
57%
cf. ref. 8
2
1c
[2] a) A. Levitzki, A. Gazit, Science 1995, 267, 1782 ± 1788; b) A. Levitzki,
Eur. J. Biochem. 1994, 226, 1 ± 13; c) D. W. Fry, Annu. Rep. Med.
Chem. 1996, 31, 151 ± 160.
[3] a) D. J. Shamon, W. Godolphin, L. A. Jones, J. A. Holt, S. G. Wong,
D. E. Keith, W. J. Levin, S. G. Stuart, J. Udove, A. Ullrich, M. F. Press,
Science 1989, 244, 707 ± 712; b) R. M. Hudziak, A. Ullrich, J. Biol.
Chem. 1991, 266, 24109 ± 24115.
[4] E. M. Dobrusin, D. W. Fry, Annu. Rep. Med. Chem. 1992, 27, 169 ± 178.
[5] N. Osherov, A. Gazit, C. Gilou, A. Levitzki, J. Biol. Chem. 1992, 268,
11134 ± 11142.
[6] For the use of tyrosine kinase inhibitors in the dissection of signaling,
pathways, see for example: a) H. Daub, F. U. Weiss, C. Wallasch, A.
Ullrich, Nature 1996, 379, 557 ± 560; b) A. Novogrodsky, A. Vanichin,
M. Patya, A. Gazit, N. Osherov, A. Levitzki, Science 1994, 264, 1319 ±
1322; c) N. Meydan, T. Grünberger, H. Dadi, M. Shahar, E. Arpaia, Z.
Lapidot, J. S. Leeder, M. Freedman, A. Cohen, A. Gazit, A Levitzki,
C. M. Raiffman, Nature 1996, 379, 645 ± 648; d) D. T. Dudley, L. Pong,
S. J. Decker, A. J. Bridges, A. R. Saltiel, Proc. Natl. Acad. Sci. USA
1995, 92, 7686 ± 7689; e) R. A. Lepley, F. A. Kirkpatrick, Arch.
Biochem. Biophys. 1996, 331, 141 ± 144; f) E. Buchdunger, J. Zimmer-
mann, H. Mett, T. Meyer, M. Myller, U. Regenass, N. B. Lydon, Proc.
Natl. Acad. Sci. USA 1995, 92, 2558 ± 2562.
Isospongiaquinone
Nakijiquinone C
Scheme 3. Synthesis of isospongiaquinone (2) and nakijiquinone C (1c).
ogous diester 13 with KOH in aqueous methanol led to
saponification of the correct methoxy group and gave rise to
the desired product 2 in 71% yield. Presumably, the reaction
proceeds by conjugate addition of hydroxide to one of the
vinylogous esters and elimination of methanol. Compound 2
is identical with isospongiaquinone, a natural product isolated
from Stelospongia conulata.[9] Specific rotation, IR and NMR
spectroscopic data of synthetic 2 were in full accord with the
data reported for the natural product, thereby proving the
absolute configuration of the synthesized compound.[18]
Isospongiaquinone (2) may be employed as a central
intermediate for the synthesis of all nakijiquinones. Treatment
of this compound with amino acids in ethanol in the presence
of NaHCO3 results in the conversion of the remaining
vinylogous ester in 2 into the corresponding vinylogous
amide.[8] We have verified this finding and converted iso-
spongioquinone (2) into nakijiquinone C (1c) by treatment
with l-serine (Scheme 3). The IR and NMR spectroscopic
data recorded for the synthetic sample completely matched
the data published for the natural product.[19] Unexpectedly,
however, synthetic nakijiquinone 1c displayed a positive
Â
a recent review see: K. Hinterding, D. Alonso-Diaz, H.
[7] For
Waldmann, Angew. Chem. 1998, 110, 716 ± 780; Angew. Chem. Int.
Ed. 1998, 37, 688 ± 749.
[8] J. Kobayashi, T. Madono, H. Shigumori, Tetrahedron 1995, 51, 10867 ±
10874.
[9] R. Kazulauskas, P. T. Murphy, R. G. Warren, R. J. Wells, J. B. Blount,
Aust. J. Chem. 1978, 31, 2685 ± 2697.
[10] For syntheses of sesquiterpenes with the underlying diterpenoid
structure occurring in the nakijiquinones see: a) A. S. Sarma, P.
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Chattopadhyay, J. Org. Chem. 1982, 47, 1727 ± 1731; b) J. An, D. F.
Wiemer, J. Org. Chem. 1996, 61, 8775 ± 8779; c) S. D. Bruner, H. S.
Radeke, J. A. Tallarico, M. L. Snapper, J. Org. Chem. 1995, 60, 1114,
1115; d) S. Poigny, M. Guyot, M. Samadi, J. Org. Chem. 1998, 63,
5890 ± 5894.
constitutional information. In recent years, the phenomenon
has been studied with various chemical model systems based
on oligonucleotides,[1] peptides,[2] and other synthetic supra-
molecular systems,[3] aiming to gain an improved understand-
ing of prebiotic replication.[4] A common problem of these
template-mediated catalytic systems, regardless of whether
they are autocatalytic or cross-catalytic, is product inhibition
leading to parabolic amplification. Recently, an exponential
amplification procedure based on oligonucleotides immobi-
lized on a solid support was reported by Luther et. al.[5] Here
we report a new scheme for stepwise replication that is based
on a Trögerꢁs base analogue and utilizes macrocyclization and
covalent templating.
Trögerꢁs base with its rigid V-shaped geometry has become
attractive in recent years in the general area of supramolec-
ular chemistry.[6] For the design of a novel replicating system
based on a Trögerꢁs base analogue, we realized that a thiol ±
disulfide exchange reaction[7] could be integrated with the
formation of Trögerꢁs base.[6b] Molecular modeling using the
PCMODEL[8] program supported the geometric feasibility of
the ªdimericº macrocyclic structure 4 (see Scheme 1). We
chose compound 1, which has two appended thiol groups at
the 2- and 8-methyl groups of Trögerꢁs base, as a template. It
occurred to us that reaction of 1 with 2 will produce 3 by a
thiol ± disulfide exchange reaction (Scheme 1). Intramolecu-
lar condensation of the two aniline units of 3 will produce 4.
Reductive cleavage of the disulfide linkages of 4 will generate
a replica of 1 along with the parent template.
[11] H.-W. Wanzlick, U. Jahnke, Chem. Ber. 1968, 101, 3744 ± 3752.
[12] J. B. P. Wijnberg, L. H. D. Jenniskens, G. A. Brunekreef, A. de Groot,
J. Org. Chem. 1990, 55, 941 ± 948.
[13] a) F. N. Tebbe, W. G. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978,
100, 3611 ± 3613; b) S. H. Pine, G. S. Shen, H. Hoang, Synthesis 1991,
165 ± 167.
[14] N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392 ± 6394.
[15] L. Fitjer, U. Quadbeck, Synth. Commun. 1985, 15, 855 ± 864.
[16] H. S. Rodeke, C. A. Digits, S. D. Brunner, M. L. Snapper, J. Org.
Chem. 1997, 62, 2823 ± 2831.
[17] a) C. O. Snyder, H. Rapoport, J. Am. Chem. Soc. 1972, 94, 227 ± 231;
b) C. B. de Koning, R. G. F. Giles, L. S. Knight, M. L. Nisen, S. C.
Yorke, J. Chem. Soc. Perkin Trans 1 1988, 2477 ± 2483.
[18] Analytical data for 2: M.p. 13598C (hexene) [ref. [9]: m.p. 135.5 ±
13698C (hexene)]; IR (KBr): nÄ ˆ 3337, 1645, 1609, 1460, 1380, 1320,
1
1234, 1209, 1043 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.48 (br.s,
1H), 5.85 (s, 1H), 5.12 (br.s, 1H), 3.84 (s, 3H), 2.63 (d, 1H, J ˆ
13.7 Hz), 2.49 (d, 1H, J ˆ 13.7 Hz), 2.06 ± 1.97 (m, 1H), 1.92 ± 1.83
(m, 1H), 1.63 (dt, 1H, J ˆ 12.7, 3.3 Hz), 1.54 (s, 3H), 1.47 ± 1.04 (m,
6H), 1.00 (s, 3H), 0.97 (d, 3H, J ˆ 6.1 Hz), 0.92 ± 0.88 (m, 1H), 0.84 (s,
3H); 13C NMR (125.8 MHz, CDCl3): d ˆ 182.4, 182.1, 161.8, 153.2,
144.0, 120.9, 117.6, 102.0, 56.8, 47.8, 43.1, 38.5, 37.8, 36.0, 32.3, 27.9, 27.0,
‡
20.2, 19.8, 18.2, 17.7, 17.4; MS: (EI, 70 eV, 858 C): m/z: 358 [M ], 281,
236, 191, 168; HRMS (EI) calcd for C22H30O4 358.2144, found
358.2131; [a]2D0 ˆ ‡62.4 (c ˆ 0.25, CHCl3) [ref.[9] [a]2D0 ˆ ‡64.8 (c ˆ
1, CHCl3)].
[19] Analytical data for 1c: IR (KBr): nÄ ˆ 3417, 1679, 1650, 1597, 1556,
1
1391, 1209 cm
;
1H NMR (500 MHz, [D6]DMSO): d ˆ 7.16 (d, 1H,
J ˆ 7.3 Hz), 5.34 (s, 1H), 5.06 (s, 1H), 4.21 (m, 1H), 3.82 (m, 1H), 3.78
(m, 1H), 2.43 (d, 1H, J ˆ 13.5 Hz), 2.32 (d, 1H, J ˆ 13.5 Hz), 2.01 ±
1.89 (m, 3H), 1.54 (m, 1H), 1.47 (s, 3H), 1.39 ± 1.15 (m, 4H), 1.03 ± 0.98
(m, 2H), 0.93 (s, 3H), 0.89 (d, 3H, J ˆ 7.3), 0.77 (s, 3H); MS: ( FAB,
diethanolamine matrix): m/z: 432 [M‡H], [a]2D0 ˆ ‡62 (c ˆ 0.13,
EtOH) [ref.[8] ([a]D20
ˆ
738 (c ˆ 0.03, EtOH)].
[20] The direction of the specific rotation reported for nakijiquinone C
isolated from natural sources is indeed incorrect. Reexamination of
the original sample yielded a value of [a]2D0 ˆ ‡1388 (c ˆ 0.1, EtOH):
Prof. Junꢁichi Kobayashi, Hokkaido University, Sapporo; personal
communication.
Stepwise Replication of a Trögerꢀs Base
Analogue**
Braja G. Bag and Günter von Kiedrowski*
Molecular replication lies in the heart of biological systems.
In its minimal representation, molecular replication is the
ability of a molecule to form a copy of itself with transfer of
Scheme 1. Stepwise replication of Trögerꢁs base analogue 1 by macro-
cyclization and covalent templating.
We have previously reported the synthesis of compound 1.[9]
Indirect evidence for the practicability of the replication
Scheme came from the fact that oxidation of 1 with iodine[10]
under high dilution conditions in THF afforded 4 as the major
product detectable by HPLC (Table 1). Treatment of a
solution of 1 in chloroform with 2 in the presence of p-
toluenesulfonic acid afforded 3 in quantitative yield. The
insoluble byproduct 4-thiopyridone was separated by filtra-
tion and the bis-amine 3 was directly used for the macro-
cyclization. Condensation of 3 with formalin in chloroform/
[*] Prof. Dr. G. von Kiedrowski, Dr. B. G. Bag
Lehrstuhl für Organische Chemie I ± Bioorganische Chemie
der Universität
Universitätsstrasse 150, D 44780 Bochum (Germany)
Fax: (‡49)234-32-14355
E-mail: kiedro@ernie.orch.ruhr-uni-bochum.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 452) and the Fonds der Chemischen Industrie. We thank Rolf
Breuckmann, Beate Materue and Klaus Körner for their technical
assistance.
Angew. Chem. Int. Ed. 1999, 38, No. 24
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3824-3713 $ 17.50+.50/0
3713