Total synthesis of amphidinolide T4

Article abstract of DOI:10.1002/anie.200290042

Organometallic chemistry in general and catalysis in particular are used in the first total synthesis of amphidinolide T4 (see scheme); a prototype member of a series of macrolide antibiotics of marine origin with rings containing an odd number of carbon

Full text of DOI:10.1002/anie.200290042

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and the interatomic distances and angles in all of the Cp* rings were
fixed. The Cp* rings are disordered. The unit cell contains other
atoms, which probably belong to benzene molecules, but cannot be
accurately assigned and refined. As the molecular structure of 1
clearly shows, the high steric demand of the Cp* units excludes the
formation of higher [Pd(InCp*)2] oligomers. The key for the synthesis
of [Pd(InCp*)2]n (n > 3) is the design of new, sterically less hindered,
yet soluble ligands of the type In(CpR) (R ¼ alkyl). CCDC-187560
contains the supplementary crystallographic 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: (þ 44)1223-336-033;
or deposit@ccdc.cam.ac.uk).
[(tmeda)PdCl2] as the precursor showed that a reduction of
palladium(ii) chlorides by [InCp*] and [GaCp*] leading to
formation of [Cp*ECl2] is in principle possible, but these
reactions are less selective and yields are lower.
In summary, our results confirm the opening quotation that
[InCp*] and [GaCp*] exhibit interesting potential as novel
ligands for transition metals which exceeds the analogy to CO
ligands and phosphanes. In this context, it is worth mentioning
that photolysis of a solution of 1 in C6D6 (258C, 2 h, 150 W)
results in selective cleavage of the Cp* shell of the Pd3In8 in
the form of decamethylfulvalene, and we are currently
investigating the metallic precipitate formed. The results are
indicative of a link to the current field of mixed-metal
nanoparticles and colloids.
[12] U. H‰ussermann, M. Elding-Pontÿn, C. Svensson, S. Lidin, Chem. Eur.
J. 1998, 4, 1007 1015.
[13] R. D. Feltham, G. Elbaze, R. Ortega, C. Eck, J. Dubrawski, Inorg.
Chem. 1985, 24, 1503 1510.
[14] O. T. Beachley, Jr., A. Blom, M. R. Churchill, K. Faegri, Jr., J. C.
Fettinger, J. C. Pazik, L. Victoriano, Organometallics 1989, 8, 346
356.
Experimental Section
[15] O. T. Beachley, Jr., M. R. Churchill, J. C. Fettinger, J. C. Pazik, L.
Victoriano, J. Am. Chem. Soc. 1986, 108, 4666 4668.
[16] T. Steinke, C. Gemel, M. Cokoja, M. Winter, R. A. Fischer,
unpublished results, 2002.
[17] a) W. de Graaf, J. Boersma, W. J. J. Smeets, A. L. Spek, G. van Koten,
Organometallics 1989, 8, 2907 2917; b) J. Krause, G. Cestaric, K.-J.
Haack, K. Seevogel, W. Storm, K.-R. Pˆrschke, J. Am. Chem. Soc.
1999, 121, 9807 9823.
1: A solution of [(tmeda)Pd(CH3)2] (0.100 g, 0.396 mmol) in hexane (4 mL)
was treated with four equivalents of [InCp*] (0.396 g, 1.584 mmol) in
hexane (10 mL). The reaction mixture was warmed to 608C for 1 h,
whereupon a red crystalline precipitate was formed. After recrystallization
from benzene, the crystals were isolated by removal of the mother liquor by
using a cannula, washed twice with a small amount of cold hexane, and
dried in vacuo. Yield: 0.275 g, 90%. M.p. 818C (decomp); 1H NMR (C6D6,
250 MHz, 258C): d ¼ 2.12 ppm (s, 120H); 13C NMR (C6D6, 250 MHz,
[18] D. Weiss, Ph.D. thesis, Ruhr-Universit‰t Bochum, 2001.
[19] a) M. Hackett, G. M. Whitesides, J. Am. Chem. Soc. 1988, 110, 1436
1448; b) M. Hackett, G. M. Whitesides, J. Am. Chem. Soc. 1988, 110,
1449 1462.
258C):
d ¼ 113.7,
11.2 ppm;
elemental
analysis:
calcd
for
C80H120In8Pd3¥C6D6: C 42.97; H 5.53, found: 42.79, 5.64.
Received: June 27, 2002 [Z19628]
[20] Identification of the GaIII and InIII side products by 1H and 13C NMR
1
spectroscopy (C6D6, 250 MHz, 258C). [Cp*Ga(CH3)2]: H NMR: d ¼
À0.15 ppm; 13C NMR: d ¼ À7.8 ppm. [Cp*In(CH3)2]: 1H NMR: d ¼
À0.11 ppm; 13C NMR: d ¼ À6.9 ppm.
[1] R. Murugavel, V. Chandrasekhar, Angew. Chem. 1999, 111, 1289
1293; Angew. Chem. Int. Ed. 1999, 38, 1211 1215.
[2] a) W. Uhl, M. Pohlmann, R. Wartchow, Angew. Chem. 1998, 110,
1007 1009; Angew. Chem. Int. Ed. 1998, 37, 961 963; b) W. Uhl, S.
Melle, Z. Anorg. Allg. Chem. 2000, 626, 2043 2045; c) W. Uhl, M.
Benter, S. Melle, W. Saak, G. Frenking, J. Uddin, Organometallics
1999, 18, 3778 3780.
[3] P. Jutzi, B. Neumann, L. O. Schebaum, A. Stammler, H. G. Stammler,
Organometallics 1999, 18, 4462 4464.
[4] J. Weiss, D. Stetzkamp, B. Nuber, R. A. Fischer, C. Boehme, G.
Frenking, Angew. Chem. 1997, 109, 95 97; Angew. Chem. Int. Ed.
Engl. 1997, 36, 70 72.
[5] a) P. Jutzi, B. Neumann, G. Reumann, H.-G. Stammler, Organo-
metallics 1998, 17, 1305 1314; b) W. Uhl, M. Pohlmann, Organo-
metallics 1997, 16, 2478 2480, and references therein.
[6] J. Uddin, G. Frenking, J. Am. Chem. Soc. 2001, 123, 1683 1693.
[7] a) P. Jutzi, B. Neumann, L. O. Schebaum, A. Stammler, H. G.
Stammler, Organometallics 1999, 18, 4462 4464; b) E. V. Grachova,
P. Jutzi, B. Neumann, L. O. Schebaum, H. G. Stammler, S. P. Tunik, J.
Chem. Soc. Dalton Trans. 2002, 302 304.
Total Synthesis of Amphidinolide T4**
Alois F¸rstner,* Christophe AÔssa, Ricardo Riveiros,
and Jacques Ragot
Marine dinoflagellates of the genus Amphidinium sp. living
in symbiosis with the Okinawan (Japanese) flatworm Am-
phiscolops sp. are exceedingly rich sources of bioactive
macrolides.[1] Though structurally quite diverse, all ™amphidi-
nolides∫ known to date exhibit pronounced cytotoxicity
against various cancer cell lines, with some members reaching
potencies which rank them amongst the most cytotoxic
compounds that are presently known.[2] In contrast to macro-
lide antibiotics derived from terrestrial microorganisms, the
majority of amphidinolides feature an odd-numbered macro-
lide ring, which raises questions concerning the biosynthesis
of these structurally unique secondary metabolites.
[8] C. Dohmeier, H. Krautscheid, H.-G. Schnˆckel, Angew. Chem. 1994,
106, 2570 2571; Angew. Chem. Int. Ed. Engl. 1994, 33, 2482 2483.
[9] a) D. Weiss, T. Steinke, M. Winter, R. A. Fischer, Organometallics
2000, 19, 4583 4588; b) D. Weiss, M. Winter, K. Merz, A. Kn¸fer,
R. A. Fischer, Polyhedron 2002, 21, 535 542.
[10] D. Weiss, M. Winter, R. A. Fischer, C. Yu, K. Wichmann, G. Frenking,
Chem. Commun. 2000, 2495 2496.
[11] Crystal structure analysis of 1¥C6D6: crystal size: 0.35 î 0.28 î 0.20 mm,
ꢀ
triclinic, P1, a ¼ 12.826(3), b ¼ 16.146(4), c ¼ 25.215(6) ä, a ¼
97.595(4), b ¼ 101.316(4), g ¼ 111.313(4)8, V¼ 4650.0(18) ä3, Z ¼ 2,
1calcd ¼ 1.657 mgmÀ3
,
2Vmax. ¼ 50.160, l(MoKa) ¼ 0.71073 ä, T¼
[*] Prof. A. F¸rstner, Dr. C. AÔssa, Dr. R. Riveiros, Dr. J. Ragot
Max-Planck-Institut f¸r Kohlenforschung
45470 M¸lheim an der Ruhr (Germany)
Fax : (þ 49)208-306-2994
213(3) K. A total of 23924 reflections (16005 unique) were collected
on
a
Bruker-axs SMART diffractometer (R(int) ¼ 0.0322). The
structure solution and refinement was performed by using the
programs SHELXS-86 and SHELXL-97. The final values for R1 and
wR2(F2) were 0.0705 and 0.2253, respectively. The reason for the
unusually high value for wR2(F2) is not yet clear and is currently under
investigation. The Cp* rings at In2 and In8 were isotropically refined
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Generous financial support by the Deutsche Forschungsgemeinschaft
(Leibniz award to A.F.) and the Fonds der Chemischen Industrie is
gratefully acknowledged.
Angew. Chem. Int. Ed. 2002, 41, No. 24
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Described below is the first total synthesis of amphidino-
lide T4 (1; Scheme 1), a prototype member of this series
containing a 19-membered lactone core.[3,4] Because its
Dibal-H. Treatment of the resulting aldehyde with (À)-
Ipc2B-allyl[9] at a low temperature affords the alcohol 4 in a
diastereomerically pure form on a multigram scale. While the
tosylate is sufficiently stable to act as a protecting group for
the primary alcohol during the hydride reduction and the
allylation steps, it serves as an appropriate leaving group in
the subsequent reaction with KCN. The resulting nitrile 5 is
again reduced with Dibal-H to afford hemiacetal 6 after acidic
work-up, which is converted into the sulfone 7 upon treatment
with an excess of PhSO2H in the presence of CaCl2 as the
dehydrating agent.[6a]
The coupling partner needed for further elaboration is
obtained from N-propionyl oxazolidinone 8[10] by a sequence
of high yielding steps (Scheme 3). Specifically, a boron aldol
reaction with methacrolein provides the syn-aldol 9 on a
multigram scale which is protected by a MOM group prior to
reduction with LiBH4. The resulting primary alcohol 11 is
converted into the TBS ether 12 which is subjected to
ozonolysis to provide the methyl ketone 13 in excellent
overall yield.[11]
Scheme 1. Structure and retrosynthetic analysis of amphidinolide T4 (1).
congeners T1 and T3 differ from 1 only in the oxygenation
pattern of the C-12/C-14 region,[3,5] the synthesis is planned
such that it can later be adapted to the preparation of these
compounds as well.
For the sake of convergency, it was envisaged to assemble
this target from three building blocks of similar size and
complexity (A C) by means of a stereoselective Lewis acid
mediated alkylation of a silyl enol ether with a lactol-derived
oxocarbenium cation,[6] a palladium-catalyzed acylation of an
organozinc reagent with an enantiomerically pure acid
chloride,[7] as well as a ring-closing metathesis (RCM)
reaction for the formation of the macrocyclic ring
(Scheme 1).[8] In this maneuver, the C-4/C-5 bond is targeted
for efficiency reasons as the required precursors seem to be
particularly easily accessible.
Scheme 3. Synthesis of segment B: a) 1. Bu2BOTf, Et3N; 2. methacrolein,
90%; b) MOMCl, (iPr)2NEt, CH2Cl2, 93%; c) LiBH4, Et2O, 92%;
d) TBSCl, imidazole, DMF, 90%; e) O3, CH2Cl2, 86%; f) TBSOTf, Et3N,
Et2O, 0 8C!RT, 91%. MOMCl ¼ methoxymethylchloride, TBSCl ¼ tert-
butyldimethylsilylchloride
The last segment is easily prepared on a large scale as
shown in Scheme 4. Thus, the b-keto ester 17 is hydrogenated
in the presence of [{(R)-binap)RuCl2}2]¥(NEt3) as the catalyst
to give 18 in excellent enantiomeric purity (ee ¼ 98%).[12] This
alcohol is then esterified with the acid 16 which is readily
available from the N-acyl oxazolidinone 15 by a standard
This aspect is evident from Scheme 2, which shows the
preparation of compound 7 as the synthetic equivalent of A.
Compound 7 is readily available from the commercial hy-
droxyester 2 which is tosylated prior to reduction with
Scheme 4. Synthesis of segment C: a) NaHMDS, THF, À788C, then allyl
bromide, 60%; b) LiOH, H2O2, THF/H2O, 93%; c) cat. [{(R)-binap)-
RuCl2}2]¥NEt3, H2 (10 atm), MeOH, 958C, 84%; d) EDCI, DMAP, CH2Cl2,
93%; e) F3CCOOH, Et3SiH, CH2Cl2, quantitative; f) (COCl)2, CH2Cl2/
DMF cat., quantitative. NaHMDS ¼ sodium hexamethyldisilazide, binap ¼
2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, EDCI ¼ 1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide hydrochloride.
Scheme 2. Synthesis of segment A: a) TsCl, Et3N, DMAP, CH2Cl2, 94%;
b) Dibal-H, toluene, À958C; c) (À)-Ipc2B-allyl, Et2O, À1008C, 70% (over
both steps); d) KCN, DMSO, 99%; e) Dibal-H, CH2Cl2, À788C, 91%;
f) PhSO2H, CaCl2, CH2Cl2, 08C, 87%. DMAP ¼ 4-dimethylaminopyridine,
Ts ¼ tosyl, Dibal-H ¼ diisobutylaluminum hydride, Ipc2B-allyl ¼ allyldiiso-
pinocamphanylborane.
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allylation reaction[13] followed by hydrolytic cleavage of the
auxiliary. Deprotection of the tert-butyl ester in 19 with
F3CCOOH in the presence of Et3SiH and subsequent
conversion of the resulting acid 20a into the corresponding
acid chloride 20b furnishes the missing building block C
needed for the envisaged synthesis of amphidinolide T4.
With all building blocks in hand, the assembly of the
metathesis precursor was investigated. For this purpose, the
ketone 13 is transformed into the tert-butyldimethylsilyl enol
ether 14 which is stable in air and can be rigorously purified by
flash chromatography.[14] While the reaction of enol ethers
with tetrahydropyranyl sulfones mediated by Lewis acids has
an excellent record, the corresponding tetrahydrofuranyl
sulfones have the reputation of poor stereoselectivity.[6a]
Gratifyingly, however, the reaction of the anomeric sulfone 7
gave very satisfactory results. After careful optimization of
the individual parameters, treatment of a solution of 7 and 14
in CH2Cl2 at À788C with SnCl4 afforded the desired ketone 21
in 86% yield after standard work-up. The product 21 is
obtained as the desired trans isomer (trans:cis ꢀ 26:1) as can
be deduced from the strong NOE effect indicated in
Scheme 5. This outcome probably reflects the shielding of
the a side of the intermediate oxocarbenium cation by the
methyl- and the allyl units.[6b,15] The reason why SnCl4 is far
superior to all other Lewis acids tested, however, is far from
obvious.
organozinc reagent which reacts with the enantiomerically
pure acid chloride 20b in the presence of [Pd2(dba)3] catalyst
and tris(2-furyl)phosphane as the ligand to give the desired
ketone 26 together with small amounts of the reduced
product 25b.[7] To date, attempts to improve on this result
by using nucleophiles other than the organozinc reagent and/
or different catalysts and ligands have been in vain. Notably,
however, this reaction is one of the most advanced examples
of an acyl-Negishi coupling reaction reported to date.[17]
In line with our expectations,[8,18] the subsequent formation
of the macrocyclic ring by RCM of the diene 26 worked
exquisitely well when carried out in the presence of the
™second-generation∫ ruthenium carbene complex 27 as the
catalyst bearing an imidazol-2-ylidene ligand (Scheme 6).[19]
Hydrogenation of the resulting cycloalkene 28 (E:Z ¼ 6:1)
Scheme 6. Completion of the total synthesis: a) catalyst 27, CH2Cl2, reflux,
86%; b) H2 (1 atm), Pd/C, EtOAc, 86%; c) Nysted©s reagent 31 (excess),
THF, reflux, 64%; d) TMSCl, nBu4NBr, CH2Cl2, 08C, 85%; e) Dess
Martin periodinane, CH2Cl2, 83%; f) HF¥pyridine, MeCN, 87%.
delivers 29 in high yield and sets the stage for the conversion
of the keto group into the exo-methylene branch of the target.
This reaction, however, turned out to be quite delicate. While
¼
Ph3P CH2 was far too basic and led only to a b elimination of
Scheme 5. Fragment coupling: a) SnCl4, CH2Cl2, À788C, 86%; b) L-
Selectride, THF, À788C, 72%; c) KHMDS, TBDPSCl, THF, 77%;
d) TsOH, aq. MeOH, 75%; e) I2, PPh3, imidazole, toluene, 80%; f) 1. Zn/
Cu couple, THF; 2. 20b, cat. Pd2(dba)3, cat. P(2-furyl)3, 40 50% (26) þ
28% (25b). TBDPSCl ¼ tert-butyldiphenylsilylchloride, dba ¼ dibenzyli-
dene acetone.
the aldol with concomitant opening of the macrocycle, the use
of CH2Br2 in the presence of TiX4/Zn (X ¼ Cl, OiPr) gave the
desired olefin in somewhat variable yields.[20] The best results
were obtained by applying Nysted©s reagent 31,[21] which
delivers 30 in up to 64% yield.
Having secured good access to the intact carbon skeleton of
1, removal of the MOM group in 30 by using TMSBr
generated in situ followed by oxidation of the resulting
alcohol on treatment with Dess Martin periodinane[22] cleanly
led to the ketone 32. The final deprotection step was readily
achieved by using HF¥pyridine to give amphidinolide T4 (1).
The analytical and spectroscopic data of the synthetic material
are in excellent agreement with those published for the
natural product, thus rigorously confirming the assignments
previously made.[3]
Reduction of this compound with L-Selectride affords the
desired S-configured alcohol 22 in 72% yield,[16] which was
protected as the silyl ether 23 by treatment with KHMDS and
TBDPSCl. Cleavage of the orthogonal TBS group at the
terminal position of 23 under acidic conditions, followed by
conversion of the resulting primary alcohol 24 into the
corresponding iodide 25 sets the stage for the last segment
coupling. Thus, exposure of 25 to Zn/Cu couple activated with
TMSCl immediately prior to use gives the corresponding
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As mentioned above, the other members of the amphidi-
nolide T family, that is, amphidinolide T1-T3, differ from T4
(1) mainly or exclusively in the C-12 to C-14 region of the
macrocycle;[3] because the stereocenter at C-13 in 30 is
appropriately set, however, the synthesis of these compounds
is just a matter of a different timing of the final deprotection
steps and/or simple inversion reactions. Therefore it is
expected that the synthesis summarized above will give access
to these valuable marine natural products as well. This and
related aspects are subject to ongoing studies in our labo-
ratory.
This assignment was ultimately confirmed by the conversion of 22 into
1 and comparison of the data of the synthetic sample with those of the
natural product.
[17] For another advanced example see: A. F¸rstner, H. Weintritt, J. Am.
Chem. Soc. 1998, 120, 2817 2825.
[18] These expectations stem from results in the following projects: a) A.
F¸rstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R.
Mynott, J. Am. Chem. Soc. 2002, 124, 7061 7069; b) A. F¸rstner, F.
Jeanjean, P. Razon, Angew. Chem. 2002, 114, 2203 2206; Angew.
Chem. Int. Ed. 2002, 41, 2097 2101; c) A. F¸rstner, T. Dierkes, O. R.
Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5284 5296; d) A. F¸rstner,
O. R. Thiel, N. Kindler, B. Bartkowska, J. Org. Chem. 2000, 65, 7990
7995; e) A. F¸rstner, T. M¸ller, J. Am. Chem. Soc. 1999, 121, 7814
7821; f) A. F¸rstner, K. Langemann, J. Am. Chem. Soc. 1997, 119,
9130 9136; g) A. F¸rstner, K. Langemann, J. Org. Chem. 1996, 61,
3942 3943.
Received: August 16, 2002 [Z19984]
[1] a) M. Ishibashi, J. Kobayashi, Heterocycles 1997, 44, 543 572; b) T. K.
Chakraborty, S. Das, Curr. Med. Chem. Anti Cancer Agents 2001, 1,
131 149.
[2] Specifically, amphidinolides H and
N exhibit antitumor potency
similar to that of the spongistatins, see ref. [1] and references therein.
[3] J. Kobayashi, T. Kubota, T. Endo, M. Tsuda, J. Org. Chem. 2001, 66,
134 142.
[19] a) M. Scholl, T. M. Trnka, J. P. Morgan, R. H. Grubbs, Tetrahedron
Lett. 1999, 40, 2247 2250; b) J. Huang, E. D. Stevens, S. P. Nolan, J. L.
Pedersen, J. Am. Chem. Soc. 1999, 121, 2674 2678; c) L. Ackermann,
A. F¸rstner, T. Weskamp, F. J. Kohl, W. A. Herrmann, Tetrahedron
Lett. 1999, 40, 4787 4790; d) A. F¸rstner, L. Ackermann, B. Gabor,
R. Goddard, C. W. Lehmann, R. Mynott, F. Stelzer, O. R. Thiel, Chem.
Eur. J. 2001, 7, 3236 3253.
[20] K. Takai, Y. Hotta, K. Oshima, H. Nozaki, Tetrahedron Lett. 1978,
2417 2420;b) T. Okazoe, J. Hibino, K. Takai, H. Nozaki, Tetrahedron
Lett. 1985, 26, 5581 5584; c) for a highly successful application in a
case where the Wittig reaction had also failed see: A. F¸rstner, O.
Guth, A. D¸ffels, G. Seidel, M. Liebl, B. Gabor, R. Mynott, Chem.
Eur. J. 2001, 7, 4811 4820.
[4] For total syntheses of other amphidinolides see: a) D. R. Williams,
W. S. Kissel, J. Am. Chem. Soc. 1998, 120, 11198 11199; b) D. R.
Williams, B. J. Myers, L. Mi, Org. Lett. 2000, 2, 945 948; c) D. R.
Williams, K. G. Meyer, J. Am. Chem. Soc. 2001, 123, 765 766;
d) H. W. Lam, G. Pattenden, Angew. Chem. 2002, 114, 526 529;
Angew. Chem. Int. Ed. 2002, 41, 508 511; e) T. K. Chakraborty, S.
Das, Tetrahedron Lett. 2001, 42, 3387 3390; f) R. E. Maleczka, L. R.
Terrell, F. Geng, J. S. Ward, Org. Lett. 2002, 4, 2841 2844; g) B. M.
Trost, J. D. Chisholm, S. T. Wrobleski, M. Jung, J. Am. Chem. Soc.
2002, 124, 12420 12421.
[5] a) M. Tsuda, T. Endo, J. Kobayashi, J. Org. Chem. 2000, 65, 1349
1352; b) T. Kubota, T. Endo, M. Tsuda, M. Shiro, J. Kobayashi,
Tetrahedron 2001, 57, 6175 6179.
[6] a) D. S. Brown, M. Bruno, R. J. Davenport, S. V. Ley, Tetrahedron
1989, 45, 4293 4308; b) A. Schmitt, H.-U. Rei˚ig, Eur. J. Org. Chem.
2001, 1169 1174.
[21] S. Matsubara, M. Sugihara, K. Utimoto, Synlett 1998, 313 315.
[22] R. K. Boeckman, Jr., P. Shao, J. J. Mullins, Org. Synth. 2000, 77, 141
152.
[7] a) E. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller, A. T.
Stoll, Tetrahedron Lett. 1983, 24, 5181 5184; b) E. Negishi, F. Liu, in
Metal-catalyzed Cross-coupling Reactions (Eds.: F. Diederich, P. J.
Stang), Wiley-VCH, Weinheim, 1998, pp. 1 47; c) Y. Tamaru, H.
Ochiai, F. Sanda, Z.-I. Yoshida, Tetrahedron Lett. 1985, 26, 5529
5532; d) P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117 2188.
[8] a) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18 29; b) A.
F¸rstner, Angew. Chem. 2000, 112, 3140 3172; Angew. Chem. Int. Ed.
2000, 39, 3012 3043; c) M. Schuster, S. Blechert, Angew. Chem. 1997,
109, 2124 2144; Angew. Chem. Int. Ed. Engl. 1997, 36, 2037 2056.
[9] U. S. Racherla, Y. Liao, H. C. Brown, J. Org. Chem. 1992, 57, 6614
6617.
Tuning PCR Specificity by Chemically
Modified Primer Probes**
Michael Strerath and Andreas Marx*
Dedicated to Professor Peter Welzel
on the occasion of his 65th birthday
[10] J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 83 91.
[11] For a similar sequence see: K. Makino, K. Kimura, N. Nakajima, S.
Hashimoto, O. Yonemitsu, Tetrahedron Lett. 1996, 37, 9073 9076.
[12] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994; b) T. Ohkuma, R. Noyori in Comprehensive Asymmetric
Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 199 246.
Since the publication of the first draft of the human genome
sequence in 2001, the discovery of genomic dissimilarities
such as single nucleotide polymorphisms (SNPs) between
different individuals has been a main focus of many research
[13] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104,
1737 1739.
[*] Dr. A. Marx, Dipl.-Chem. M. Strerath
Kekulÿ-Institut f¸r Organische Chemie und Biochemie
Universit‰t Bonn
[14] The corresponding TMS enol ether is labile and leads to erratic results.
[15] For a review on the stereoselective synthesis of natural products with
polysubstituted THF units see: U. Koert, Synthesis 1995, 115 132.
[16] Protection of the alcohol 22 as a PMB ether [PMB ¼ para-methoxy-
benzyl; a) PMBBr, KHMDS], cleavage of the terminal TBS group
[b) TBAF, THF] and treatment of the resulting alcohol with c) I2,
PPh3, and imidazole delivers the tetrahydrofuran shown in Equa-
tion (1) rather than the expected primary iodide, compare O. R.
Martin, F. Yang, F. Xie, Tetrahedron Lett. 1995, 36, 47 50. Its relative
stereochemistry was elucidated by NOE measurements, from which
the stereochemistry of 22 formed with L-Selectride can be deduced.
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax : (þ 49)228-73-5388
E-mail: a.marx@uni-bonn.de
[**] This work was supported by the DFG, the Volkswagenstiftung, and the
Fonds der Chemischen Industrie. We thank Prof. Dr. M. Famulok for
his continuing support and Prof. Dr. A. Pingoud and his co-workers
for many stimulating discussions. PCR ¼ polymerase chain reaction.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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0044-8249/02/4124-4766 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 24