Chasing a phantom by total synthesis: The butylcycloheptylprodigiosin case

Article abstract of DOI:10.1002/anie.200462215

The dispute as to whether "butylcycloheptylprodigiosin" is a natural product or solely a misassigned structure lasted for more than a decade. This open question has now been answered by the first total synthesis of this tripyrrole alkaloid (see picture),

Full text of DOI:10.1002/anie.200462215

Angewandte
Chemie
Natural Product Synthesis
Chasing a Phantom by Total Synthesis: The
Butylcycloheptylprodigiosin Case**
Alois Fꢀrstner,* Karin Radkowski, and Hartwig Peters
The deeply red-colored tripyrrole alkaloids of the “prodigio-
sin” series exert pronounced immunosuppressive activities at
doses that are not cytotoxic.[1] Most notably, in vivo studies
have shown that these pigments produced by various Serratia
and Streptomyces strains act synergistically with cyclospor-
ine A, FK 506, or rapamycin, which are presently the
dominating drugs in clinical immunosuppressive regimens.[2,3]
Since the availability of agents that can act at different stages
along the T-cell activation pathway may improve therapeutic
results, the prodigiosins constitute important new lead com-
pounds in the search for supplementary drugs to prevent
allograft rejection. These findings have rejuvenated interest in
this class of pyrrole alkaloids, as evident from many recent
studies mapping their biological profiles in great detail.[1]
During our program aimed at the total synthesis[4–7] and
biochemical validation of various pyrrolic natural products,[8]
our attention was drawn to a secondary metabolite called
“butylcycloheptylprodigiosin”.[9] It was originally isolated
from Streptomyces sp. Y-42 and Streptomyces abikoensis
(formerly, Streptoverticillium rubrireticuli). Gerber and
Stahly assigned structure 1 to this then novel member of the
prodigiosin family (Scheme 1).[10] Floss and co-workers later
attributed the same structure to the “pink pigment” obtained
from a culture broth of Streptomyces coelicolor mutants.[11]
[*] Prof. A. Fꢀrstner, K. Radkowski, Dr. H. Peters
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
Fax: (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Generous financial support from the Deutsche Forschungsge-
meinschaft (Leibniz award program), the Fonds der Chemischen
Industrie, and the Merck Research Council is gratefully
acknowledged. We thank Dr. R. Mynott and C. Wirtz for their
invaluable help with numerous NMR analyses and Prof. H. Floss for
providing a copy of the 1H NMR spectrum of his “pink pigment” for
comparison.
Angew. Chem. Int. Ed. 2005, 44, 2777 –2781
DOI: 10.1002/anie.200462215
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2777

Communications
Scheme 2. Retrosynthetic analysis of 1.
Intramolecular Heck-type reactions of unsaturated oxime
esters pioneered by Narasaka and co-workers might serve this
purpose well (Scheme 3).[17] In this rather unconventional
Scheme 1. The structures of butylcycloheptylprodigiosin (1) and its
meta-bridged isomer streptorubin B (2); an illustration of the charac-
teristic spectral fingerprint of meta-pyrrolophane 3.
However, these assignments were questioned by Weyland and
co-workers, who showed that their sample isolated from the
actinomycete strain B 4358 was the meta-bridged isomer
streptorubin B (2) rather than the ortho-annelated compound
1, thus suggesting that the structure of the latter needed to be
revised.[12] As these three research groups were investigating
samples derived from different bacterial strains, it appeared
to us that this conclusion might have been premature and that
the available data deserved more scrupulous consideration.
A previous synthesis campaign by our research group had
opened a concise route to product 2 and its congeners by a
platinum-catalyzed cycloisomerization reaction.[4,13] All the
meta-pyrrolophanes prepared showed a very characteristic
“fingerprint” in their 1H NMR spectra. Specifically, the
rigidity of the bridging 10-membered ring forces one of the
protons of the ansa chain to reside within the anisotropy cone
of the aromatic pyrrole nucleus, thus causing a significant
upfield shift of the corresponding signal to d = ꢀ1.55 ppm in 2
and d = ꢀ1.88 ppm in its core segment 3 (see Scheme 1).[4,12,14]
Although the reported spectral data of the “pink pigment”
isolated by the groups of Gerber and Floss are incom-
plete,[10,11] no such signal is documented. As it appears
unlikely to us that such a conspicuous detail would have
escaped the attention of two independent groups, we sus-
pected that butylcycloheptylprodigiosin (1) is in fact a natural
product distinct from 2 rather than a phantom. It was only
through synthesis, however, that this open question could be
answered.
Scheme 3. The conversion of unsaturated oxime esters into pyrrole
derivatives by a Narasaka–Heck reaction. Application of this transform
to the preparation of the core segment of 1.
transfomation, the Pd0 catalyst inserts into a suitable oxime
derivative A to give an iminopalladium intermediate B, which
reacts with a suitably located olefin to give a pyrrole
derivative D after isomerization of the methylenedihydro-
pyrrole C initially formed. This reaction, however, is known to
be very sensitive to seemingly minor changes in substrate and
can be plagued by competing side reactions, such as Beck-
mann rearrangements, hydrolysis, or fragmentation.[17] To the
best of our knowledge, no application to a total synthesis has
been reported to date.
In the present context, this method might open a
convenient entry to the core segment 4 of the butylcyclohep-
tylprodigiosin skeleton. Cyclononadienylacetone (9) was
considered to be the optimal substrate for this reaction
because 1) the presence of two double bonds should increase
the number of reactive encounters during the Narasaka–Heck
cyclization of the derived oxime ester 8 and, hence, increase
the yield; 2) the remaining double bond in the expected
product 7 provides a handle for the introduction of the butyl
side chain of the target; and 3) the symmetrical structure of 9
should facilitate the large-scale preparation of this strained
compound.
To this end, the assembly of the pyrrolopyrromethane
chromophore of 1 from building blocks 4–6 by successive
condensation and cross-coupling reactions was envisaged
(Scheme 2).[5,15] Since 5 and 6 are commercially available, the
success of the project hinged on the efficient preparation of
aldehyde 4. Bearing in mind that (the ground-state as well as
the transition-state) strain energy reaches its maximum with
nine-membered cycles,[16] we preferred a strategy based on
the annelation of the pyrrole nucleus to a preexisting cyclo-
nonane template over a late-stage cyclization of the medium-
sized carbocycle.
2778
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2777 –2781

Angewandte
Chemie
Our synthesis started from (Z,Z)-cyclononadienone
(10).[18] 1,2-Reduction of the ketone group with diisobutyl-
aluminum hydride (DIBAL-H) followed by acetylation of the
resulting alcohol gave acetate 11 in almost quantitative yield
(Scheme 4). Exposure of 11 to methyl acetoacetate in the
Krapcho decarboxylation[21] of 12 followed by conversion
of the resulting cyclononadienylacetone (9) into the penta-
fluorobenzoyl oxime ester 13 under standard conditions
proceeded smoothly, thus setting the stage for the envisaged
Narasaka–Heck cyclization.[17] This key transformation was
effected on a multigram scale by a catalyst formed in situ from
Pd(OAc)2 and [P(o-tolyl)3] in DMF (N,N-dimethylform-
amide) at 1108C and delivered the unsaturated bicyclic
imine 14 in 54% yield. Because of its exceptional sensitivity
and unusual volatility, this compound must be treated with
great care and should be elaborated without undue delay.[22]
Although Narasaka–Heck reactions of simple substrates
usually deliver the corresponding pyrrole derivatives directly
(see Scheme 3),[17] a method had to be found for the
aromatization of product 14. We comtemplated that depro-
tonation of this compound at the bridgehead position a to the
nitrogen atom engenders the formation of a stabilized
azapentadienyl anion that might be reprotonated to give the
conjugated diene isomer preferentially, so compound 14 was
treated with KAPA (potassium 3-aminopropylamide)[23] in
1,3-diaminopropane as the reaction medium at ambient
temperature. In line with our expectations, the ensuing
series of “thermodynamic” deprotonation/reprotonation
events resulted in the selective shift of the 9,10-double bond
in 14, thus delivering the highly sensitive pyrrole 7, which was
immediately N-protected to give compound 15.[22,24] Isomeric
by-products formed under these conditions were separated
after the subsequent oxidation step.
The only remaining double bond in 15 is suitably located
for the introduction of the butyl side chain of the final target.
However, all attempts to manipulate this olefin by means of a
Wacker oxidation, a rhodium-catalyzed hydroboration, or an
oxymercuration strategy were unsuccessful. Only the uncata-
lyzed hydroboration with BH3·THF followed by stepwise
oxidation with H2O2 (in the presence of excess Me3N to
protect the alkyl borane against proto-deborylation)[25] and
Dess–Martin periodinane[26] allowed us to functionalize the
alkene, thus furnishing ketone 16 and its anti-Markovnikov
isomer in 65% overall yield (isomer ratio ꢁ 5:1–2.5:1; 75%
based on recovered starting material; Scheme 5). The anti-
Markovnikov isomer and impurities derived from isomeric
olefins (see above) could be removed at this stage by routine
flash column chromatography. The severe steric shielding
exerted by the cyclononyl skeleton also became evident in the
subsequent Wittig olefination of 16, which required forcing
conditions but delivered product 17 in good yield and
Scheme 4. Synthesis of the ortho-pyrrolophane core structure:
a) DIBAL-H, CH2Cl2, 08C, 97%; b) Ac2O, Et3N, DMAP (0.5 mol%),
CH2Cl2, 97%; c) methyl acetoacetate, NaH, [Pd(PPh3)4] (5 mol%),
THF, 558C, 74%; d) aq DMSO, 1808C, 99%; e) H2NOH·HCl, NaOAc,
aq EtOH, 1008C, 97%; f) pentafluorobenzoyl chloride, Et3N, Et2O,
ꢀ788C!RT, 97%; g) Pd(OAc)2 (12 mol%), [P(o-tolyl)3] (12 mol%),
Et3N, DMF, 1108C, 54%; h) KH, 1,3-diaminopropane, 65%; i) Boc2O,
DMAP (10 mol%), MeCN, 508C, 69%. DMAP=4-dimethylaminopyri-
dine, DMSO=dimethyl sulfoxide.
presence of NaH and catalytic amounts of [Pd(PPh3)4]
afforded product 12 in 74% yield. This outcome is remark-
able for various reasons: although one might expect that
oxidative insertion of a Pd0 center into the bisallylic acetate 11
engenders the formation of a pentadienylpalladium inter-
mediate that then reacts with the nucleophile to give a
conjugated diene product,[19] the double bonds are site-
isolated in the major isomer 12. Moreover, it is noteworthy
that both of them are Z configured, although nine-membered
rings are large enough to embody E alkenes without difficulty,
and palladium catalysis is known to isomerize allylic systems
effectively. This regio- and stereochemical outcome therefore
advocates the notion that the two “allylic” sites in 11 remain
uncoupled during the course of the Tsuji–Trost reaction as a
result of the conformational peculiarities of the medium
ring.[20]
excellent purity. Its trisubstituted alkene moiety was hydro-
[27]
genated with [Ir(pyridine)(cod)(PCy3)]PF6
(cod = 1,5-
cyclooctadiene, Cy = cyclohexyl) as the catalyst to give 18
without reduction of the pyrrole causing any interference.
Pyrroles in general are known to be sensitive to oxidizing
agents.[28] Therefore, the conversion of the methyl branch in
18 into the corresponding aldehyde was considered to be
potentially troublesome. In fact, all classical reagents known
to effect such benzylic oxidations failed in the present case.
After some experimentation, however, a satisfactory solution
for this problem was found by using cerium ammonium
nitrate (CAN).[29] Key to success was the careful optimization
of the reaction medium. Although previous reports recom-
Angew. Chem. Int. Ed. 2005, 44, 2777 –2781
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2779

Communications
tylprodigiosin (1) in 70% yield as a deeply red–pink colored
solid. As expected, no signal from this compound is seen
1
upfield of trimethylsilane (TMS) in the H NMR spectrum.
Although the spectrum is clearly different to that of the meta-
bridged streptorubin B (2), the pattern signature is in accord
with the signals reported for 1 (see Table 1 for the spectro-
Table 1: Selected data for cycloheptylprodigiosin (1).[a]
1H NMR (600 MHz, CD2Cl2): d=6.82 (s, 1H; 16-H), 6.72 (brs, 1H; 24-
H), 6.69 (dd, J=3.6, 1.3 Hz, 1H, 22-H), 6.34 (s, 1H, 2-H), 6.20 (dd,
J=3.6, 2.6 Hz, 1H, 23-H), 6.08 (s, 1H, 19-H), 3.97 (s, 3H, 25-H), 2.59
(m, 1H, 11-H), 2.33 (br, 2H, 5-H), 1.68 (m, 1H, 6a-H), 1.62–1.50 (m,
4H, 7a-H, 10a-H, 12-H), 1.41–1.15 (m, 9H; 7b-H, 8-H, 9a-H, 10b-H, 13-
H, 14-H), 1.00 (m, 1H; 6b-H), 0.85 (t, J=6 Hz, 3H; 15-H), 0.83 ppm (m,
1H; 9b-H); 13C NMR (150 MHz, CD2Cl2): d=128.5 (s; C1), 118.6 (d;
C2), 128.2 (s; C3), 142.9 (s; C4), 27.6 (t; C5), 27.7 (t; C6), 28.0 (t; C7),
28.1 (t; C8), 23.3 (t; C9), 38.0 (t; C10), 36.1 (d; C11), 37.1 (t; C12), 30.6
(t; C13), 23.2 (t; C14), 14.2 (q; C15), 116.2 (d; C16), 139.2 (s; C17)*,
169.2 (s; C18), 95.7 (d; C19), 159.6 (s; C20)*, 129.1 (s; C21), 112.6 (d;
C22), 110.6 (d; C23), 122.3 (d; C24), 58.8 ppm (q; C25); IR (KAP):
n˜ =3322, 3103, 2921, 2852, 1738, 1618, 1577, 1552, 1449, 1361, 1333,
1285, 1221, 1148, 1116, 1086, 1057, 998, 954, 890, 767, 728 cmꢀ1; MS
(EI) m/z (%): 391 [M+], (100).
Scheme 5. Completion of the first total synthesis of butylcycloheptyl-
prodigiosin (1): a) 1. BH3·THF, THF, ꢀ108C; 2. H2O2, Me3N·THF, aq
NaOH (3m), 08C; 3. Dess–Martin periodinane, 65% (5:1–2.5:1
=
isomer ratio); b) Ph3P CHCH2CH2CH3, toluene, reflux, 75%; c) H2
(1 atm), [Ir(pyridine)(cod)(PCy3)]PF6 (10 mol%), CH2Cl2, 90%; d) CAN,
CHCl3/DME/H2O, 60–65%; e) 5, aq NaOH, DMSO, 608C, 64–69%;
f) Tf2O, CH2Cl2, 08C, 72–79%; g) 6, [Pd(PPh3)4] (8 mol%), LiCl, aq
Na2CO3, DME, 808C, 70%.
[a] All assignments are unambiguous (except those marked , which
*
mended the use of CAN in aqueous THF/HOAc,[30] com-
pound 18 was rapidly destroyed under these conditions, likely
due to uncontrolled overoxidations. In an attempt to separate
the reagent from the substrate and products, the oxidations
were performed in biphasic media. In fact, the use of CHCl3/
H2O furnished the desired aldehyde 19, although the reaction
rate was unacceptably low. Graftifyingly, the addition of small
amounts of 1,2-dimethoxyethane (DME) as a “phase-trans-
fer” agent led to a significant improvement and allowed the
oxidation of 18 to proceed in only 30 minutes, thus affording
the desired product 19 in respectable yields of 60–65%. The
generality of this novel method for benzylic oxidations of
highly sensitive electron-rich arenes is subject to further
studies in this laboratory.
Now that reliable access to the key building block 19
bearing the ortho-annelated medium-sized ring had been
secured through a sequence of rather unconventional trans-
formations, the assembly of the final target 1 could be pursued
by following established routes.[5,8,15] To this end, the base-
promoted condensation of aldehyde 19 with commercial
lactam 5 was accompanied by cleavage of the N-Boc (Boc =
tert-butoxycarbonyl) protecting group. Treatment of the
resulting product 20 with Tf2O (Tf = trifluoromethanesul-
fonyl) induced a reorganization of the p system and delivered
triflate 21 as the substrate for the final Suzuki coupling.[31]
Exposure of this compound to boronic acid 6 in the presence
of catalytic amounts of [Pd(PPh3)4] and LiCl (3 equivalents)
under previously optimized conditions[5a] afforded cyclohep-
might be mutually interchanged) and are based on 1D and 2D spectra.
The multiplicity of the signals in the 13C NMR spectrum refers to the
geminal protons (DEPT). The insert shows the arbitrary numbering
scheme.
scopic analysis).[10,11] A comparison with the spectrum of an
authentic (although not entirely pure) sample of the “pink
pigment” showed an excellent match. Therefore, it must be
concluded that cycloheptylprodigiosin (1) is a natural product
distinct from streptorubin B (2), as originally suggested by
Gerber and Stahly[10] and Floss and co-workers.[11]
Finally, it should be mentioned that aldehyde 19 can be
used as a common building block for the preparation of a
focused library of analogues by exploiting the late-stage
flexibility inherent in the chosen synthetic route. A detailed
mapping of the biochemical properties of the resuscitated
alkaloid 1 (prepared in a 16-step sequence in approximately
1.5% overall yield from cyclononadienone) and its congeners
22–25 (Scheme 6) are underway and will be reported in due
course.
Received: October 6, 2004
Published online: March 30, 2005
Keywords: alkaloids · cyclophanes · medium-ring compounds ·
.
palladium · pyrroles
2780
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2777 –2781

Angewandte
Chemie
[12] H. Laatsch, M. Kellner, H. Weyland, J. Antibiot. 1991, 44, 187 –
191.
[13] a) A. Fꢀrstner, H. Szillat, F. Stelzer, J. Am. Chem. Soc. 2000, 122,
6785 – 6786; b) A. Fꢀrstner, F. Stelzer, H. Szillat, J. Am. Chem.
Soc. 2001, 123, 11863 – 11869; c) M. Mꢁndez, V. Mamane, A.
Fꢀrstner, ChemTracts 2003, 16, 397 – 425.
[14] N. N. Gerber, A. G. McInnes, D. G. Smith, J. A. Walter, J. L. C.
Wright, L. C. Vining, Can. J. Chem. 1978, 56, 1155 – 1163.
[15] R. DꢃAllessio, A. Rossi, Synlett 1996, 513 – 514.
[16] C. Galli, L. Mandolini, Eur. J. Org. Chem. 2000, 3117 – 3125.
[17] a) H. Tsutsui, M. Kitamura, K. Narasaka, Bull. Chem. Soc. Jpn.
2002, 75, 1451 – 1460; b) H. Tsutsui, K. Narasaka, Chem. Lett.
1999, 28, 45 – 46; c) S. Zaman, M. Kitamura, K. Narasaka, Bull.
Chem. Soc. Jpn. 2003, 76, 1055 – 1062; d) H. Tsutsui, K.
Narasaka, Chem. Lett. 2001, 30, 526 – 527; e) S. Chiba, M.
Kitamura, O. Saku, K. Narasaka, Bull. Chem. Soc. Jpn. 2004, 77,
785 – 796.
[18] The preparation of 10 from the commercially available cyclo-
nonanone follows a literature method; an optimized procedure
affording multigram quantities will be reported in a forthcoming
full paper; see: a) E. W. Garbisch, Jr., J. Org. Chem. 1965, 30,
2109 – 2120; b) see also: R. Noyori, Y. Ohnishi, M. Katꢄ,
Tetrahedron Lett. 1971, 19, 1515 – 1518.
Scheme 6. Analogues of 1 prepared by diversion from the total synthe-
sis route in the final cross-coupling step.
[19] For studies on metal-catalyzed alkylations of pentadienyl
acetates, see: B. M. Trost, M.-H. Hung, J. Am. Chem. Soc.
1984, 106, 6837 – 6839.
[20] DFT optimization of the conformation of the presumed p-
allylpalladium intermediate corroborate this interpretation.
[21] a) A. P. Krapcho, Synthesis 1982, 805 – 822; b) A. P. Krapcho,
Synthesis 1982, 893 – 914.
[22] During the course of this synthesis, we noticed the exceptional
volatility of many cyclononane derivatives even at fairly low
temperatures, which renders the isolation of these compounds
difficult and adversely affects the yields. This phenomenon is
particularly pronounced in compounds 7 and 10–15.
[23] C. A. Brown, P. K. Jadhav, Org. Synth. 1987, 65, 224 – 229.
[24] For a related aromatization reaction of a pyrrole with KAPA, see
Ref.[4]
[25] M. Zaidlewicz, J. Organomet. Chem. 1985, 293, 139 – 146.
[26] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 – 4156;
b) S. D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7549 –
7552.
[27] R. H. Crabtree, H. Felkin, T. Fillebeen-Khan, G. E. Morris, J.
Organomet. Chem. 1979, 168, 183 – 195.
[28] A. Gossauer in Methoden der Organischen Chemie (Houben-
Weyl), Vol. E6a, 4th ed. (Ed.: R. P. Kreher), Thieme, Stuttgart,
1994, pp. 556 – 798.
[29] Reviews: a) G. A. Molander, Chem. Rev. 1992, 92, 29 – 68; b) T.-
L. Ho, Synthesis 1973, 347 – 354; c) for a recent study, see: A. M.
Khenkin, R. Neumann, J. Am. Chem. Soc. 2004, 126, 6356 – 6362,
and references therein.
[30] a) T. Thyrann, D. A. Lightner, Tetrahedron Lett. 1995, 36, 4345 –
4348; b) J. B. Paine, D. Dolphin, Can. J. Chem. 1976, 54, 411 –
414.
[1] a) A. Fꢀrstner, Angew. Chem. 2003, 115, 3706 – 3728; Angew.
Chem. Int. Ed. 2003, 42, 3582 – 3603; b) R. A. Manderville, Curr.
Med. Chem. Anti-Cancer Agents 2001, 1, 195 – 218; c) R. Pꢁrez-
Tomꢂs, B. Montaner, E. Llagostera, V. Soto-Cerrato, Biochem.
Pharmacol. 2003, 66, 1447 – 1452.
[2] a) A. Nakamura, J. Magae, R. F. Tsuji, M. Yamasaki, K. Nagai,
Transplantation 1989, 47, 1013 – 1016; b) J. Magae, M. W. Miller,
K. Nagai, G. M. Shearer, J. Antibiot. 1996, 49, 86 – 90; c) S. M.
Stepkowski, Z. S. Nagy, M.-E. Wang, F. Behbod, R. Erwin-
Cohen, B. D. Kahan, R. A. Kirken, Transplant. Proc. 2001, 33,
3272 – 3273; d) S. M. Stepkowski, R. A. Erwin-Cohen, F.
Behbod, M.-E. Wang, X. Qu, N. Tejpal, Z. S. Nagy, B. D.
Kahan, R. A. Kirken, Blood 2002, 99, 680 – 689.
[3] a) R. DꢃAlessio, A. Bargiotti, O. Carlini, F. Colotta, M. Ferrari, P.
Gnocchi, A. Isetta, N. Mongelli, P. Motta, A. Rossi, M. Rossi, M.
Tibolla, E. Vanotti, J. Med. Chem. 2000, 43, 2557 – 2565; b) A.
Mortellaro, S. Songia, P. Gnocchi, M. Ferrari, C. Fornasiero, R.
DꢃAlessio, A. Isetta, F. Colotta, J. Golay, J. Immunol. 1999, 162,
7102 – 7109.
[4] A. Fꢀrstner, H. Szillat, B. Gabor, R. Mynott, J. Am. Chem. Soc.
1998, 120, 8305 – 8314.
[5] a) A. Fꢀrstner, J. Grabowski, C. W. Lehmann, J. Org. Chem.
1999, 64, 8275 – 8280; b) A. Fꢀrstner, H. Krause, J. Org. Chem.
1999, 64, 8281 – 8286.
[6] a) A. Fꢀrstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817 –
2825; b) A. Fꢀrstner, H. Weintritt, J. Am. Chem. Soc. 1997, 119,
2944 – 2945; c) A. Fꢀrstner, T. Gastner, H. Weintritt, J. Org.
Chem. 1999, 64, 2361 – 2366.
[7] a) A. Fꢀrstner, H. Weintritt, A. Hupperts, J. Org. Chem. 1995,
60, 6637 – 6641; b) A. Fꢀrstner, H. Krause, O. R. Thiel, Tetrahe-
dron 2002, 58, 6373 – 6380; c) A. Fꢀrstner, A. Hupperts, A.
Ptock, E. Janssen, J. Org. Chem. 1994, 59, 5215 – 5229.
[8] a) A. Fꢀrstner, J. Grabowski, C. W. Lehmann, T. Kataoka, K.
Nagai, ChemBioChem 2001, 2, 60 – 68; b) A. Fꢀrstner, E. J.
Grabowski, ChemBioChem 2001, 2, 706 – 709; c) A. Fꢀrstner, K.
Reinecke, H. Prinz, H. Waldmann, ChemBioChem 2004, 5,
1575 – 1579.
[31] a) A. Suzuki, J. Organomet. Chem. 1999, 576, 147 – 168; b) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 – 2483.
[9] Note that this name is not very well chosen because compound 1
is not a cycloheptyl but a cyclononyl derivative.
[10] a) N. N. Gerber, J. Antibiot. 1975, 28, 194 – 199; b) N. N. Gerber,
D. P. Stahly, Appl. Microbiol. 1975, 30, 807 – 810.
[11] S.-W. Tsao, B. A. M. Rudd, X.-G. He, C.-J. Chang, H. G. Floss, J.
Antibiot. 1985, 38, 128 – 131.
Angew. Chem. Int. Ed. 2005, 44, 2777 –2781
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2781