Total Synthesis and Structural Refinement of the Cyclic Tripyrrole Pigment Nonylprodigiosin

Article abstract of DOI:10.1021/jo991021i

The first total synthesis of the cyclic prodigiosin derivative 4 is described, which constitutes a potential lead compound for the development of immunosuppressive agents. The key steps of this approach comprise a palladium-catalyzed Suzuki cross coupling reaction of the rather unstable pyrrole boronic acid derivative 17 with the electron rich pyrrolyl triflate 15 followed by a ring-closing metathesis reaction (RCM) of the resulting diene to form the macrocyclic ring of the target molecule. This transformation is best achieved by using the ruthenium indenylidene complex 21 as precatalyst. X-ray data of product 18·HCl thus formed suggest that the tautomeric form B properly describes the electron distribution within the heteroaromatic segment of this alkaloid, in which the central ring constitutes the azafulvene unit of the pyrrolylpyrromethene chromophore.

Full text of DOI:10.1021/jo991021i

J . Org. Chem. 1999, 64, 8275-8280
8275
Tota l Syn th esis a n d Str u ctu r a l Refin em en t of th e Cyclic
Tr ip yr r ole P igm en t Non ylp r od igiosin
Alois Fu¨rstner,* J aroslaw Grabowski, and Christian W. Lehmann
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/ Ruhr, Germany
Received J une 25, 1999
The first total synthesis of the cyclic prodigiosin derivative 4 is described, which constitutes a
potential lead compound for the development of immunosuppressive agents. The key steps of this
approach comprise a palladium-catalyzed Suzuki cross coupling reaction of the rather unstable
pyrrole boronic acid derivative 17 with the electron rich pyrrolyl triflate 15 followed by a ring-
closing metathesis reaction (RCM) of the resulting diene to form the macrocyclic ring of the target
molecule. This transformation is best achieved by using the ruthenium indenylidene complex 21
as precatalyst. X-ray data of product 18‚HCl thus formed suggest that the tautomeric form B
properly describes the electron distribution within the heteroaromatic segment of this alkaloid, in
which the central ring constitutes the azafulvene unit of the pyrrolylpyrromethene chromophore.
In tr od u ction
The deeply red colored prodigiosin alkaloids produced
by a restricted group of actinomycetes are endowed with
potent antibacterial, cytotoxic, and antimalaria proper-
ties.1-3 In addition to this spectrum of biological effects
discovered early on, a series of recent reports claims that
this family of natural products also displays a significant
immunosuppressive activity at doses which are not
cytotoxic.4,5 This finding is particularly noteworthy since
the mechanism of action seems to be distinctly different
from that of cyclosporin and FK-506 which set the
standards in this field.6,7 Although the actual therapeutic
window may be too narrow for direct clinical applications
of the naturally occurring prodigiosins,8 these alkaloids
serve as lead structures in the search for new drugs to
prevent allograft rejection and have already inspired the
development of synthetic analogues with more favorable
pharmacological properties.9
member of this family,4,5 although some preliminary data
indicate significant immunosuppressive activity for its
cyclic analogues such as metacycloprodigiosin (2) and
streptorubin B (3) as well.10,11 Compounds 1-3 and
analogues thereof exist as two stable isomers I and II in
Most pharmacological studies on the prodigiosins have
focused on undecylprodigiosin (1) as the most abundant
(1) For a review of the early studies on prodigiosins see the following
for leading references: (a) Castro, A. J . Nature 1967, 213, 903. (b)
Gerber, N. N. Crit. Rev. Microbiol. 1974, 3, 469 and references therein.
(2) For previous synthetic studies on various prodigiosins, see inter
alia (a) Hearn, W. R.; Elson, M. K.; Williams, R. H.; Medina-Castro,
J . J . Org. Chem. 1970, 35, 142. (b) Wasserman, H. H.; Lombardo, L.
J . Tetrahedron Lett. 1989, 1725. (c) Rapoport, H.; Holden, K. G. J . Am.
Chem. Soc. 1962, 84, 635. (d) Boger, D. L.; Patel, M. Tetrahedron Lett.
1987, 28, 2499. (e) Boger, D. L.; Patel, M. J . Org. Chem. 1988, 53,
1405. (f) Wasserman, H. H.; Rodgers, G. C.; Keith, D. D. J . Am. Chem.
Soc. 1969, 91, 1263. (g) Wasserman, H. H.; Keith, D. D.; Nadelson, J .
J . Am. Chem. Soc. 1969, 91, 1264. (h) Wasserman, H. H.; Keith, D.
D.; Rodgers, G. C. Tetrahedron 1976, 32, 1855. (i) Wasserman, H. H.;
Gosselink, E.; Keith, D. D.; Nadelson, J .; Sykes, R. J . Tetrahedron 1976,
32, 1863. (j) Wasserman, H. H.; Keith, D. D.; Nadelson, J . Tetrahedron
1976, 32, 1867.
(3) For preparation and the biological evaluation of prodigiosin
analogues, see ref 1 and the following for leading references: (a) Brown,
D.; Griffiths, D.; Rider, M. E.; Smith, R. C. J . Chem. Soc., Perkin Trans.
1 1986, 455. (b) Blake, A. J .; Hunter, G. A.; McNab, H. J . Chem. Soc.,
Chem. Commun. 1990, 734. (c) Berner, H.; Schulz, G.; Reinshagen, H.
Monatsh. Chem. 1977, 108, 233. (d) Berner, H.; Schulz, G.; Reinshagen,
H. Monatsh. Chem. 1978, 109, 137. (e) Berner, H.; Schulz, G.;
Reinshagen, H. Monatsh. Chem. 1977, 108, 285. (f) Berner, H.; Schulz,
G.; Fischer, G.; Reinshagen, H. Monatsh. Chem. 1978, 109, 557. (g)
Castro, A. J .; Gale, G. R.; Means, G. E.; Tertzakian, G. J . Med. Chem.
1967, 10, 29. (h) D’Auria, M.; De Luca, E.; Mauriello, G.; Racioppi, R.
Synth. Commun. 1999, 29, 35.
(4) (a) Lin, J . Immunol. Today 1993, 14, 290. (b) Nakamura, A.;
Nagai, K.; Ando, K.; Tamura, G. J . Antibiot. 1986, 39, 1155. (c) Tsuji,
R. F.; Yamamoto, M.; Nakamura, A.; Kataoka, T.; Magae, J .; Nagai,
K.; Yamasaki, M. J . Antibiot. 1990, 43, 1293. (d) Kataoka, T.; Magae,
J .; Nariuchi, H.; Yamasaki, M.; Nagai, K. J . Antibiot. 1992, 45, 1303.
(e) Tsuji, R. F.; Magae, J .; Yamashita, M.; Nagai, K.; Yamasaki, M. J .
Antibiot. 1992, 45, 1295. (f) Kataoka, T.; Magae, J .; Kasamo, K.;
Yamanishi, H.; Endo, A.; Yamasaki, M.; Nagai, K. J . Antibiot. 1992,
45, 1618. (g) Kataoka, T.; Muroi, M.; Ohkuma, S.; Waritani, T.; Magae,
J .; Takatsuki, A.; Kondo, S.; Yamasaki, M.; Nagai, K. FEBS Lett. 1995,
359, 53. (h) Lee, M.-H.; Yamashita, M.; Tsuji, R. F.; Yamasaki, M.;
Kataoka, T.; Magae, J .; Nagai, K. J . Antibiot. 1998, 51, 92. (i) Han, S.
B.; Kim, H. M.; Kim, Y. H.; Lee, C. W.; J ang, E.-S.; Son, K. H.; Kim,
S. U.; Kim, Y. K. Int. J . Immunopharmacol. 1998, 20, 1. (j) Sato, T.;
Konno, H.; Tanaka, Y.; Kataoka, T.; Nagai, K.; Wasserman, H. H.;
Ohkuma, S. J . Biol. Chem. 1998, 273, 21455. (k) Nakamura, A.; Magae,
J .; Tsuji, R. F., Yamasaki, M.; Nagai, K. Transplantation 1989, 47,
1013.
(5) Songia, S.; Mortellaro, A.; Taverna, S.; Fornasiero, C.; Schreiber,
E. A.; Erba, E.; Colotta, F.; Mantovani, A.; Isetta, A.-M.; Golay, J . J .
Immunol. 1997, 158, 3987.
(6) Undecylprodigiosin 1 has been shown to inhibit T cell activation
in the mid to late G1 phase, mostly downstream from the interaction
of IL-2 with its receptor, cf. ref 5.
10.1021/jo991021i CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/29/1999

8276 J . Org. Chem., Vol. 64, No. 22, 1999
Fu¨rstner et al.
Sch em e 1
solution, with the interconversion and equilibrium dis-
tribution being strongly dependent on the pH of the
medium, i.e., on the degree of protonation of the basic
nitrogen atom.9 Because it is unlikely that both conform-
ers show the same affinity to the (yet unknown) biological
receptor, prodigiosin derivatives with a defined configu-
ration may be of significant interest for more detailed
biochemical and pharmaceutical investigations.
however, the activity of the metal carbene is attenuated
and RCM is likely to cease. Therefore, it is of utmost
importance in retrosynthetic planning to assess the
distance as well as the affinity of the polar groups toward
the catalytically active metal species. A suitably biased
ground state conformation of the substrate is not required
for productive RCM, although conformational predisposi-
tion toward ring closure will certainly facilitate matters.
When applied to nonylprodigiosin 4, this “relay model”
suggests to close the macrocyclic ring at (or near) the site
indicated in Scheme 1. In this particular case, however,
a certain risk remains as the required precursor 5 already
contains the intact pyrrolylpyrromethene chromophore
of the target which is known for its good chelating
properties toward metals and may therefore interfere
with or even quench the activity of the metathesis
catalyst.
Therefore we reasoned that the naturally occurring
macrocyclic nonylprodigiosin 4, isolated in 1970 by Ger-
ber from Actinomadura madurae,12 may constitute an
attractive biochemical tool since its alkyl chain spans all
three heterocyclic rings and therefore makes isomer II
energetically highly unfavorable. We now describe the
first total synthesis of this particular natural product
based on a ring-closing metathesis (RCM) reaction as the
key step which is effected by a recently devised metath-
esis catalyst.
Resu lts a n d Discu ssion
The initial steps en route to the required cyclization
precursor, i.e., diene 5, adapt a sequence previously
outlined by D’Alessio for the synthesis of the acyclic
parent compound 1.16 The necessary building blocks are
obtained in excellent yields on a multigram scale by
acylation of the magnesium salt of pyrrole with the
2-pyridylthioesters derived from 4-pentenoic acid or
5-hexenoic acid, respectively (Scheme 2).17 The resulting
ketones 8 and 9 are smoothly reduced by excess NaBH4
in 2-propanol,18 giving rise to the rather unstable alkyl-
pyrroles 10 and 11. Standard formylation of 11 by means
of POCl3 and DMF, followed by condensation of the
resulting aldehyde 12 with commercially available lactam
Syn t h esis. Systematic investigations on RCM have
revealed the truly remarkable scope of this transforma-
tion for the synthesis of macrocycles.13-15 During these
studies it was possible to spell out rules for retrosynthetic
analysis which help to identify those sites within a given
target where productive formation of a large ring can be
expected. According to this rationale,13d a properly bal-
anced interaction of Lewis-basic heteroatoms in the diene
substrate with the emerging Lewis-acidic carbene (and/
or metallacyclobutane) species involved in the catalytic
cycle is necessary in order to achieve an efficient macro-
cylization event. If such a chelation becomes too strong,
(7) These different mechanisms of action also suggest that
a
(14) For RCM-based macrocycle syntheses from our laboratory see:
(a) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 3942. (b)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792. (c) Fu¨rstner, A.;
Kindler, N. Tetrahedron Lett. 1996, 37, 7005. (d) Fu¨rstner, A.;
Langemann, K. J . Org. Chem. 1996, 61, 8746. (e) Fu¨rstner, A.; Mu¨ller,
T. Synlett 1997, 1010. (f) Fu¨rstner, A.; Langemann, K. J . Am. Chem.
Soc. 1997, 119, 9130. (g) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J .
Org. Chem., 1999, 64, 2361. (h) Fu¨rstner, A.; Mu¨ller, T. J . Org. Chem.
1998, 63, 424. (i) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron,
1999, 55, 8215. (j) Fu¨rstner, A.; Mu¨ller, T. J . Am. Chem. Soc. 1999,
121, 7814.
(15) For RCM-based total syntheses of natural products from other
groups see the following for leading references: (a) Nicolaou, K. C.;
King, N. B.; He, Y. Top. Organomet. Chem. 1998, 1, 73. (b) Hoveyda,
A. H. Top. Organomet. Chem. 1998, 1, 105. (c) Miller, S. J .; Blackwell,
H. E.; Grubbs, R. H. J . Am. Chem. Soc. 1996, 118, 9606. (d) Bertinato,
P.; Sorensen, E. J .; Meng, D.; Danishefsky, S. J . J . Org. Chem. 1996,
61, 8000. (e) Martin, S. F.; Humphrey, J . M.; Ali, A.; Hillier, M. C. J .
Am. Chem. Soc. 1999, 121, 866. (f) Magnier, E.; Langlois, Y. Tetrahe-
dron Lett. 1998, 837. (g) Kim, S. H.; Figueroa, I.; Fuchs, P. L.
Tetrahedron Lett. 1997, 38, 2601. (h) Irie, O.; Samizu, K.; Henry, J .
R.; Weinreb, S. M. J . Org. Chem. 1999, 64, 587. (i) Arakawa, K.; Eguchi,
T.; Kakinuma, K. J . Org. Chem. 1998, 63, 4741. (j) May, S. A.; Grieco,
P. A. Chem. Commun. 1998, 1597.
combined use of these drugs may be possible, permitting the use of
relatively low concentrations of each drug and thereby potentially
reducing toxicity, cf. ref 5.
(8) A report in the recent literature shows that the dose-response
curve of 1 on T and B lymphocytes is rather steep, with a maximal
inhibition of proliferation at 40 ng/mL and an IC50 of 3-8 ng/mL (7-
20 M) for both cell types. In mice, the ED50 of 1 was reported to be 1.5
mg/kg i.p. for 6 days, while toxic signs are appreciable from a dose of
4 mg/kg, cf. ref 5.
(9) Rizzo, V.; Morelli, A.; Pinciroli, V.; Sciangula, D.; D’Alessio, R.
J . Pharm. Sci. 1999, 88, 73.
(10) (a) Magae, J .; Miller, M.; Nagai, K.; Shearer, G. M. J . Antibiot.
1996, 49, 86. (b) Abe, F.; Morimoto, M.; Shibuya, K.; Yamazaki, M.;
Nishigori, T.; Saito, S.; Shimada, N. J pn. Kokai Tokkyo Koho J P 02,
250, 828 [90, 250, 828], 08 Oct 1990. Chem. Abstr. 1990, 114, 108967g.
(11) For recent syntheses of these compounds from our laboratory
see: Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J . Am. Chem. Soc.
1998, 120, 8305. (b) For a synthesis of the structurally related alkaloid
roseophilin see: Fu¨rstner, A.; Weintritt, H. J . Am. Chem. Soc. 1998,
120, 2817.
(12) (a) Gerber, N. N. Tetrahedron Lett. 1970, 809. (b) Gerber, N.
N. J . Antibiot. 1971, 24, 636. (c) Gerber, N. N. J . Heterocycl. Chem.
1973, 10, 925.
(13) For recent reviews on RCM see the following for leading
references: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Fu¨rstner, A. Top. Catal. 1997, 4, 285. (c) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 37.
(16) D’Alessio, R.; Rossi, A. Synlett 1996, 513.
(17) Nicolaou, K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron
Lett. 1981, 22, 4647.
(18) Greenhouse, R.; Ramirez, C.; Muchowski, J . M. J . Org. Chem.
1985, 50, 2961.

Total Synthesis of Nonylprodigiosin
J . Org. Chem., Vol. 64, No. 22, 1999 8277
Sch em e 2a
Sch em e 4a
a
(a) Bis(2-pyridyl) disulfide, PPh3, toluene; (b) pyrrolylmagne-
sium chloride, toluene, 97% (n ) 1, 2); (c) NaBH4 (excess), i-PrOH,
63% (n ) 1), 65% (n ) 2).
a
(a) Boc2O, DMAP, CH2Cl2, rt, 92%; (b) (i) lithium 2,2,6,6-
tetramethylpiperidinide, -78 °C, THF; (ii) B(OMe)3; (iii) aq HCl,
58%; (c) 15, Pd(PPh3)4 cat., aq Na2CO3, LiCl, DME, 85 °C, 57%.
Sch em e 3a
immediately in the subsequent Suzuki reaction.20 Despite
considerable experimentation, however, its cross-coupling
with triflate 15 gave only 57% yield of the desired,
N-unprotected pyrrolylpyrromethane derivative 5. This
rather moderate yield is mainly ascribed to concomitant
proto-deborylation of 17 which could not be avoided even
under nonaqueous reaction conditions. Attempts to re-
place the labile boronic acid 17 by zincated 16 as the
nucleophile for the palladium-catalyzed cross-coupling
reaction met with failure.21
Because free amines are generally incompatible with
metathesis reactions mediated by ruthenium carbene
complexes of the Grubbs type,13 we performed the crucial
RCM step with the hydrochloride salt of substrate 5.
Protonation of pyrrolylpyrromethane derivatives bearing
an oxygen substituent at the 4-position of the B-ring,
however, has been shown to favor isomer II over I due
to the formation of a hydrogen bond as indicated in
Scheme 5.9 Although II itself is hardly amenable to ring
closure, cyclization of the minor isomer I in solution may
occur which will then constantly shift the equilibrium
between II and I and hence still allow productive RCM.
In fact, treatment of the deeply red colored diene 5‚HCl
with catalytic amounts of the Grubbs carbene (PCy3)2-
Cl2RudCHCHdCPh222 in refluxing CH2Cl2 solution leads
to the formation of the desired macrocycle 18‚HCl in 42%
yield. This results was improved by using a previously
introduced variant 21 of the catalyst which is formed
upon reaction of (PPh3)3RuCl2 with diphenyl propargyl
alcohol, followed by exchange of the PPh3 ligands for PCy3
(Scheme 6).23 In line with our previous experiences on
a
(a) POCl3, DMF, C2H4Cl2, 80%; (b) NaOH, DMSO, 60 °C, 94%;
(c) triflic anhydride, CH2Cl2, 0 °C f rt, 93%.
13 in the presence of NaOH in DMSO, delivers product
14 in excellent yield, which is converted into the corre-
sponding pyrrolyl triflate derivative 15 on exposure to
Tf2O in CH2Cl2 (Scheme 3). No base must be added, since
the emerging azafulvene itself traps the equivalent of
F3CSO3H liberated in this step.
In contrast to this very productive and uneventful
sequence, the formation of the boronic acid derivative 17
and its subsequent Suzuki cross-coupling with triflate 15
turned out to be rather delicate due to the inherent
lability of 17 (Scheme 4). Its synthesis is best achieved
by directed ortho-metalation of the N-Boc protected
substrate 16 using lithium tetramethylpiperidinide as the
base and quenching of the lithiated pyrrole derivative
thus formed with an excess of B(OMe)3 followed by
hydrolysis of the resulting adduct with dilute HCl.19 This
delivers boronic acid 17 in 58% yield which must be used
(20) Review: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
For recent applications of Suzuki reactions from our laboratory see:
(b) Fu¨rstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165. (c) Fu¨rstner,
A.; Nikolakis, K. Liebigs Ann. 1996, 2107. (d) Fu¨rstner, A.; Konetzki,
I. J . Org. Chem. 1998, 63, 3072.
(21) For a report on cross-coupling reactions using zincated 1-meth-
ylpyrrole, see: Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.;
Kumada, M. Tetrahedron Lett. 1981, 22, 5319.
(22) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem.
Soc. 1993, 115, 9858. (b) See also: Schwab, P.; France, M. B.; Ziller,
J . W.; Grubbs, R. H. Angew. Chem. 1995, 107, 2179.
(23) Originally it has been believed that the species formed from
(PPh3)3RuCl2 and HCtCPh2OH is the diphenylallenylidene complex
19, cf. Harlow, K. J .; Hill, A. F.; Winton-Ely, J . D. E. T. J . Chem. Soc.,
Dalton Trans. 1999, 285. More detailed studies, however, have shown
that the stable product formed is the rearranged product, i.e., the
indenylidene ruthenium complex 20, cf. Hill, A. F.; Fu¨rstner, A.; Liebl,
M.; Mynott, R.; Gabor, B., Nolan, S. P. Manuscript in preparation.
(19) (a) For the borylation of N-Boc-pyrrole see: Martina, S.;
Enkelmann, V.; Wegner, G.; Schlu¨ter, A.-D. Synthesis 1991, 613. (b)
For a recent report on Pd(0)-catalyzed cross-coupling reactions of (N-
Boc-pyrrol-2-yl)boronic acid see: J ohnson, C. N.; Stemp, G.; Anand,
N., Stephen, S. C.; Gallagher, T. Synlett 1998, 1025.

8278 J . Org. Chem., Vol. 64, No. 22, 1999
Fu¨rstner et al.
Sch em e 5a
Str u ctu r a l Asp ects. A survey of the literature on
prodigiosins reveals some conflicting assumptions as to
the best description of the extended π-electron system of
their heterocyclic part. Whereas recent NMR studies on
rotamer interconversions indicate that protonation occurs
at the nitrogen atom of the C-ring and hence tautomer
A dominates the chemical behavior of the prodigiosins
in solution, the older literature uniformly favors tautomer
B in which the basic site resides in the central ring.
Theoretical calculations on the parent pyrrolylpyrro-
methene system lacking the 4-OMe substituent at the
B-ring show that the energy difference between these two
possible tautomers is low, and no definite conclusions
have therefore been drawn.26
a
(a) 21 cat., CH2Cl2, reflux, 16 h, 65%; (b) RhCl(PPh3)3 cat., H2
Because we were able to obtain the metathesis product
18 and the final target 4 as crystalline solids, an X-ray
study has been carried out in order to clarify this point.
The molecular structure of 18‚HCl in the crystal is
depicted in Figure 1.27 The analysis of the relevant bond
length within the heterocyclic perimeter shows beyond
doubt that the structure is best represented by tautomer
B in which the central ring constitutes the azafulvene
entity. Although the crystal structure of nonylprodigiosin
4 itself suffers from substantial disorder,28 there is no
doubt that the tripyrrole chromophore of this product is
also best described by tautomer B.
(1 atm), EtOH, rt, 90%.
Sch em e 6a
For further studies on the preparation of prodigiosin
alkaloids and functionalized derivatives thereof which
may allow a synthesis driven mapping of the immuno-
suppressive properties of this family of natural products,
see the accompanying paper in this issue.
a
(a) THF, reflux, 2 h; (b) PCy3, CH2Cl2, rt, 30 min.
Exp er im en ta l Section
the excellent catalytic performance of this particular
complex,23,24 exposure of diene 5‚HCl to 2123 in refluxing
CH2Cl2 indeed effects a smooth cyclization reaction,
giving rise to the desired cycloalkene product 18‚HCl in
65% isolated yield (E:Z g 10:1).25 Attempted hydrogen-
ation of the disubstituted double bond over Pd on charcoal
led to the destruction of the molecule. The use of
Wilkinson’s catalyst, however, opened a viable alterna-
tive, although rather high catalyst loadings are necessary
in order to achieve quantitative conversion. Under these
conditions, nonylprodigiosin is obtained in excellent yield
as a deeply red colored crystalline material. This com-
pletes the first total synthesis of this interesting alkaloid
and highlights once again the remarkable scope of ring-
closing metathesis which rapidly evolves into a mature
tool for advanced natural product synthesis.
Gen er a l. All reactions were carried out under Ar in
predried glassware using Schlenk techniques. The solvents
were dried by distillation over the drying agents indicated and
were stored and transferred under Ar: CH2Cl2 (P4O10), toluene
(Na/K), THF (magnesium/anthracene), DMF (Desmodur, Bay-
er AG; dibutyltin dilaurate), pyridine (KOH), EtOH (Mg),
MeOH (Mg). Flash chromatography: Merck silica gel (230-
400 mesh) or activated aluminum oxide (Aldrich, neutral,
Brockmann I, STD grade, ≈ 150 mesh) using hexane/ethyl
acetate in various proportions as eluent. For the instrumenta-
(25) One recrystallization provides pure (E)-18 which was used for
the X-ray analysis.
(26) Falk, H.; Stressler, G.; Mu¨ller, N. Monatsh. Chem. 1988, 119,
505.
(27) Crystal structure analysis of compound (E)-18: dark red
crystals grown from CH2Cl2; C24H30Cl3N3O; Mr ) 482.86 g‚mol-1
;
crystal size 0.67 × 0.21 × 0.08 mm; a ) 26.091(5), b ) 8.3912(17), c )
22.571(5) Å; V ) 4773.4(17) Å3; â ) 104.99(3)°; T ) 100 K; dcalcd
)
1.344 Mg‚m-3, Z ) 8; space group: monoclinic, C2/c (no. 15); θ range
for data collection: 1.62 to 27.80°; 21146 collected reflections, 5173
unique reflections; refinement method: full-matrix least squares on
F2; final R indices: R(F) ) 0.082, wR2 ) 0.234. For further information,
see the Supporting Information. The complete set of data has been
deposited at the Cambridge Crystallographic Data Center, Cambridge,
UK, under the deposition number CCDC 121761.
(24) (a) Fu¨rstner, A.; Hill, A.; Liebl, M.; Winton-Ely, J . Chem.
Commun. 1999, 601. For other studies on metathesis catalysts from
our laboratory see: (b) Fu¨rstner, A.; Ackermann, L. Chem. Commun.
1999, 95. (c) Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H.
Chem. Commun. 1998, 1315. (d) Ackermann, L.; Fu¨rstner, A.; Wes-
kamp, T.; Kohl, F. J ., Herrmann, W. A. Tetrahedron Lett. 1999, 40,
4787.
(28) The disorder originates from a 2-fold rotation of the macrocycle
around an axis passing through the N-atom of the central pyrrole ring.

Total Synthesis of Nonylprodigiosin
J . Org. Chem., Vol. 64, No. 22, 1999 8279
CDCl3): δ 190.9, 138.0, 132.1, 124.6, 116.2, 115.2, 110.5, 37.1,
33.3, 24.3. Anal. Calcd for C10H13NO (163.22): C 73.59, H 8.03,
N 8.58. Found: C 73.34, H 7.95, N 8.62.
1-(1H-P yr r ol-2-yl)p en t-4-en -1-on e (8). Compound 8 is
obtained as a colorless syrup (5.93 g, 95%) according to the
procedure described above using 4-pentenoic acid (4.20 g, 41.9
1
mmol) as the starting material. H NMR (300 MHz, CDCl3):
δ 9.71 (bs, 1H), 7.03-7.01 (m, 1H), 6.92-6.90 (m, 1H), 6.27-
6.24 (m, 1H), 5.86 (ddt, J ) 17.0, 10.3, 6.5 Hz, 1H), 5.10-4.95
(m, 2H), 2.86 (t, J ) 7.2 Hz, 2H), 2.50-2.42 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 190.0, 137.3, 131.9, 124.6, 116.2, 115.2,
110.6, 37.0, 28.9. Anal. Calcd for C9H11NO (149.19): C 72.46,
H 7.43, N 9.39. Found: C 72.43, H 7.47, N 9.31.
2-Hex-5-en yl-1H-p yr r ole (11). A solution of compound 9
(4.58 g, 28.1 mmol) in 2-propanol (150 mL) is added dropwise
to a suspension of NaBH4 (2.95 g, 78.0 mmol) in 2-propanol
(100 mL), and the resulting mixture is refluxed for 24 h.
Standard extractive workup followed by flash chromatography
on neutral alumina using hexane/ethyl acetate (20:1) as the
eluent affords compound 11 (2.73 g, 65%) as a colorless syrup.
1H NMR (300 MHz, CD2Cl2): δ 7.97 (bs, 1H), 6.65-6.62 (m,
1H), 6.07 (dd, J ) 5.6, 2.7 Hz, 1H), 5.92-5.78 (m, 2H), 5.07-
4.95 (m, 2H), 2.61 (t, J ) 7.4 Hz, 2H), 2.15-2.07 (m, 2H), 1.69-
1.41 (m, 4H). 13C NMR (75 MHz, CD2Cl2): δ 139.0, 132.6,
115.9, 114.2, 108.1, 104.9, 33.6, 29.3, 28.7, 27.5. Anal. Calcd
for C10H15N (149.24): C 80.48, H 10.13, N 9.39. Found: C
80.29, H 10.06, N 9.42.
2-P en t-4-en yl-1H-p yr r ole (10). Compound 10 is obtained
as a colorless syrup (3.43 g, 63%) according to the procedure
described above using ketone 8 (5.95 g, 39.9 mmol) as the
starting material. 1H NMR (300 MHz, CD2Cl2): δ 7.98 (bs, 1H),
6.65-6.62 (m, 1H), 6.08-6.06 (m, 1H), 5.93-5.79 (m, 2H),
5.08-4.97 (m, 2H), 2.61 (t, J ) 7.7 Hz, 2H), 2.16-2.08 (m, 2H),
1.76-1.66 (m, 2H). 13C NMR (75 MHz, CD2Cl2): δ 138.6, 132.3,
116.0, 114.6, 108.1, 105.0, 33.4, 29.1, 27.0. Anal. Calcd for
C9H13N (135.21): C 79.95, H 9.69, N 10.36. Found: C 79.73,
H 9.62, N 10.40.
5-(Hex-5-en yl)-1H-p yr r ole-2-ca r ba ld eh yd e (12). Phos-
phorus oxychloride (2.91 g, 19.0 mmol) is added dropwise to
DMF (1.39 g, 19.0 mmol) at 0 °C. The mixture is diluted with
1,2-dichloroethane (5 mL), and a solution of compound 11 (2.58
g, 17.3 mmol) in 1,2-dichloroethane (10 mL) is slowly intro-
duced at 0 °C (30 min). After the addition is complete, the
solution is refluxed for 20 min. After cooling to 30 °C, a solution
of sodium acetate (8.2 g, 10 mmol) in water (25 mL) is added,
and the resulting mixture is refluxed for another 15 min.
Standard extractive workup followed by flash chromatography
on silica using hexane/ethyl acetate (6:1) as the eluent gives
compound 12 (2.45 g, 80%) as a colorless solid. mp ) 37-38
°C. 1H NMR (300 MHz, CD2Cl2): δ 10.61 (bs, 1H), 9.36 (s, 1H),
6.94 (dd, J ) 3.7, 2.5 Hz, 1H), 6.12-6.10 (m, 1H), 5.81 (ddt, J
) 17.0, 10.2, 6.7 Hz, 1H), 5.04-4.92 (m, 2H), 2.71 (t, J ) 7.6
Hz, 2H), 2.12-2.04 (m, 2H), 1.74-1.64 (m, 2H), 1.50-1.39 (m,
2H). 13C NMR (75 MHz, CD2Cl2): δ 178.2, 144.1, 138.8, 132.0,
123.2, 114.4, 109.5, 33.5, 28.6, 28.5, 27.6. Anal. Calcd for
F igu r e 1. Structure of compound (E)-18‚HCl‚CH2Cl2 in the
crystal. Selected bond lengths (Å): N1-C10 1.362(7), C10-
C11 1.388(7), C11-C12 1.396(7), C12-C13 1.401(7), C13-N1
1.402(7), C13-C14 1.420(7), C14-C15 1.355(7), C15-N2
1.429(6), C15-C16 1.435(7), C16-C17 1.369(7), C17-C18
1.414(7), C18-N2 1.363(7), C18-C19 1.429(7), C19-N3
1.396(6), C19-C20 1.384(7), C20-C21 1.397(7), C21-C22
1.383(7), C22-N3 1.375(7).
tion used and the spectra formats, see the Supporting Infor-
mation. Mp: Gallenkamp apparatus (uncorrected). Elemental
analyses: Dornis & Kolbe, Mu¨lheim. Commercially available
reagents (Aldrich, Fluka) were used as received.
Hex-5-en oic a cid (7). To a suspension of Mg-turnings (3.43
g, 141 mmol) in Et2O (60 mL) is added 5-bromo-1-pentene
(19.84 g, 133 mmol) in Et2O (60 mL) at room temperature.
The reaction mixture is stirred at 34 °C for 6 h. Residual Mg
is filtered off, and the filtrate containing the Grignard reagent
is added dropwise over a period of 2 h to a saturated solution
of CO2 in Et2O at -20 °C, while passing through the solution
a stream of CO2. The resulting mixture is allowed to warm to
ambient temperature and is quenched by addition of aqueous
HCl (v/v, 1:1, concentrated HCl/water; 100 mL). The organic
phase is dried (Na2SO4), the solvent is evaporated, and the
crude product is distilled (52 °C/10-2 mbar) to give acid 7 (10.32
g, 68%) as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ
11.57 (bs, 1H), 5.75 (ddt, J ) 17.1, 10.3, 6.6 Hz, 1H), 5.04-
4.95 (m, 2H), 2.34 (t, J ) 7.6 Hz, 2H), 2.12-2.05 (m, 2H), 1.76-
1.66 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 180.3, 137.4, 115.5,
33.3, 32.9, 23.7.
C
11H15NO (177.25): C 74.54, H 8.53, N 7.90. Found: C 74.51,
1-(1H-P yr r ol-2-yl)h ex-5-en -1-on e (9). A solution of 5-hex-
enoic acid (4.78 g, 41.87 mmol), 2,2′-dipyridyl disulfide (12.0
g, 54.47 mmol), and triphenylphosphine (14.28 g, 54.47 mmol)
in toluene (60 mL) is stirred at rt for 4 h. The reaction mixture
is then cooled to -78 °C and a solution of pyrrolylmagnesium
chloride [formed by deprotonation of pyrrole (11.7 mL, 168.46
mmol) with methylmagnesium chloride (3 M in THF, 42 mL,
126.0 mmol) in toluene (270 mL) at -40 °C)] is introduced.
After stirring for 1 h, the reaction is quenched with saturated
aqueous ammonium chloride at -78 °C, and the aqueous layer
is repeatedly extracted with tert-butyl methyl ether. The
organic phase is successively washed with aq potassium
carbonate (5%), water, and brine, dried (Na2SO4), and concen-
trated. Flash chromatography of the residue (hexane/ethyl
acetate, 6:1) affords compound 9 (6.67 g, 97.5%) as a colorless
syrup. 1H NMR (200 MHz, CDCl3): δ 9.89 (bs, 1H), 7.03-7.00
(m, 1H), 6.92-6.88 (m, 1H), 6.27-6.23 (m, 1H), 5.80 (ddt, J )
17.1, 10.3, 6.6 Hz, 1H), 5.07-4.94 (m, 2H), 2.77 (t, J ) 7.5 Hz,
2H), 2.18-2.07 (m, 2H), 1.89-1.74 (m, 2H). 13C NMR (50 MHz,
H 8.48, N 7.85.
5-[5-(Hex-5-en yl)-1H-p yr r ol-2-ylm eth ylen e]-4-m eth oxy-
1,5-d ih yd r op yr r ol-2-on e (14). Aqueous NaOH (2 N, 32 mL)
is added to a solution of compound 12 (2.03 g, 11.4 mmol) and
4-methoxy-3-pyrrolin-2-one 13 (2.59 g, 22.8 mmol) in DMSO
(40 mL), and the resulting mixture is stirred at 60 °C for 24
h. After dilution with EtOAc (140 mL), the yellow suspension
is extracted with water and brine, and the organic layers are
dried (Na2SO4) and evaporated. The crude material is rinsed
with hexane affording pure 14 (2.92 g, 94%) as a yellow
crystalline solid. mp ) 139-140 °C. 1H NMR (300 MHz,
CDCl3): δ 10.99 (bs, 1H), 10.43 (bs, 1H), 6.36-6.34 (m, 1H),
6.31 (s, 1H), 5.96-5.95 (m, 1H), 5.80 (ddt, J ) 17.0, 10.2, 6.7
Hz, 1H), 5.05 (s, 1H), 5.02-4.90 (m, 2H), 3.86 (s, 3H), 2.74 (t,
J ) 7.6 Hz, 2H), 2.13-2.06 (m, 2H), 1.79-1.69 (m, 2H) 1.52-
1.42 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 173.1, 168.0, 140.7,
138.2, 125.5, 122.7, 117.7, 114.4, 107.7, 102.9, 89.9, 58.1, 33.6,
29.2, 28.7, 28.0. Anal. Calcd for C16H20N2O2 (272.35): C 70.56,
H 7.40, N 10.29. Found: C 70.66, H 7.43, N 10.19.

8280 J . Org. Chem., Vol. 64, No. 22, 1999
Fu¨rstner et al.
Tr iflu or om eth a n esu lfon ic Acid 5-[5-(Hex-5-en yl)-p yr -
r ol-2-ylid en m eth yl]-4-m eth oxy-1H-p yr r ol-2-yl Ester (15).
Trifluoromethanesulfonic anhydride (0.5 mL, 3.05 mmol) is
added dropwise to a solution of compound 14 (700 mg, 2.57
mmol) in CH2Cl2 (50 mL) at 0 °C. After stirring at this
temperature for 1 h, the reaction mixture is poured into aq
2% NaHCO3 solution, and the aqueous phase is repeatedly
extracted with ethyl acetate. The combined organic layers are
washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the crude material on neutral alumina
using hexane/ethyl acetate (6:1) as the eluent provides triflate
15 (972 mg, 93%) as a yellow solid. 1H NMR (300 MHz,
CDCl3): δ 10.87 (bs, 1H), 7.02 (s, 1H), 6.66 (d, J ) 3.7 Hz,
1H), 6.05 (d, J ) 3.7 Hz, 1H), 5.79 (ddt, J ) 17.1, 10.3, 6.6
Hz), 5.41 (s, 1H), 5.03-4.90 (m, 2H), 2.68 (t, J ) 7.6 Hz, 2H),
) 3.9, 2.3 Hz, 1H), 6.10 (d, J ) 1.9 Hz, 1H), 5.94-5.77 (m,
2H), 5.10-4.91 (m, 4H), 4.00 (s, 3H), 2.91 (t, J ) 7.5 Hz, 2H),
2.78 (t, J ) 7.6 Hz, 2H), 2.18-2.07 (m, 4H), 1.92-1.72 (m, 4H),
1.56-1.46 (m, 2H). 13C NMR (75 MHz, CD2Cl2): δ 166.4, 151.0,
148.9, 145.0, 139.0, 138.3, 127.7, 125.9, 122.2, 121.0, 119.6,
114.9, 114.7, 114.2, 11.8, 111.0, 110.3, 92.9, 59.0, 33.6, 33.3,
28.9, 28.6, 28.2, 28.1, 27.6. UV (CH2Cl2): λmax ) 539, 392, 374,
297 nm. MS (ESI pos): m/z (rel intensity) 390 ([M - Cl)+],
100). Anal. Calcd for C25H31N3O‚HCl (426.01): C 70.49, H 7.57,
N 9.86. Found: C 70.28, H 7.69, N 9.95.
Ma cr ocycle 18‚HCl. A solution diene 5‚HCl (58 mg, 0.136
mmol) in CH2Cl2 (100 mL) is slowly added to a solution of the
ruthenium indenylidene complex 21 (13.4 mg, 0.014 mmol)23,24
in CH2Cl2 (50 mL), and the resulting mixture is refluxed for
16 h. For workup, the reaction mixture is washed with
saturated aqueous Na2CO3, the organic layer is dried (Na2SO4)
and evaporated, and the residue is subjected to flash chroma-
tography on neutral alumina using hexane/ethyl acetate (6:1)
as the eluent. The combined fractions of compound 18 are
concentrated to a small volume, treated with a solution of HCl
in Et2O and evaporated in vacuo. This affords macrocycle 18‚
2.12-2.04 (m, 2H), 1.74-1.63 (m, 2H), 1.51-1.41 (m, 2H). 13
C
NMR (75 MHz, CDCl3): δ 167.9, 160.9, 145.3, 138.4, 128.4,
123.1, 122.0, 118.6, 114.7, 110.3, 110.2, 87.1, 58.7, 33.4, 28.4,
28.2, 28.2. Anal. Calcd for C17H19F3N2O4S (404.41): C 50.49,
H 4.74, N 6.93. Found: C 50.26, H 4.73, N 7.06.
2-(P en t-4-en yl)p yr r ole-1-ca r boxylic Acid ter t-Bu tyl Es-
ter (16). To a solution of compound 10 (546 mg, 4.04 mmol)
and DMAP (50 mg, 0.40 mmol) in CH2Cl2 (3 mL) is added a
solution of Boc2O (1.057 g, 4.84 mmol) in CH2Cl2 (4 mL) at
ambient temperature. The mixture is stirred for 4 h, the
solvent is evaporated, and the residue is purified by flash
chromatography on silica with hexane/tert-butyl methyl ether
(50:1) as the eluent affording compound 16 (875 mg, 92%) as
a colorless syrup. 1H NMR (300 MHz, CDCl3) (rotamer): δ 7.18
(dd, J ) 3.3, 1.8 Hz, 1H), 6.06 (t, J ) 3.3 Hz, 1H), 5.95-5.93
(m, 1H), 5.83 (ddt, J ) 17.0, 10.2, 6.6, 1H), 5.06-4.94 (m, 2H),
2.84 (t, J ) 7.6, 2H), 2.17-2.09 (m, 2H), 1.79-1.65 (m, 2H),
1.58 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 149.5, 138.6, 136.0,
120.8, 114.6, 110.9, 109.8, 83.2, 33.4, 28.3, 28.1, 28.0. Anal.
Calcd for C14H21NO2 (235.33): C 71.46, H 8.99, N 5.95.
Found: C 71.26, H 9.12, N 6.02.
1
HCl (35 mg, 65%)27 as a deeply red solid. H NMR (300 MHz,
CD2Cl2): δ 12.85 (bs, 1H), 12.70 (bs, 1H), 12.58 (bs, 1H), 6.96-
6.93 (m, 2H), 6.75 (dd, J ) 3.6, 2.6 Hz, 1H), 6.15-6.12 (m,
2H), 6.07 (d, J ) 1.9 Hz, 1H), 5.57 (dt, J ) 15.3, 5.6 Hz, 1H),
5.45 (dt, J ) 15.3, 6.5 Hz, 1H), 3.99 (s, 3H), 2.96-2.80 (m,
4H), 2.25-2.03 (m, 4 H), 1.93-1.77 (m, 4H), 1.56-1.44 (m,
2H). 13C NMR (75 MHz, CD2Cl2): δ 167.2, 160.3, 150.9, 149.5,
144.8, 131.2, 129.1, 127.2, 126.6, 123.1, 121.1, 119.8, 115.3,
112.1, 111.6, 92.7, 59.1, 32.1, 30.5, 29.6, 28.9, 28.3, 26.7, 25.9.
HRMS (C23H29N3O): calcd 361.215412; found 361.217201.
Non ylp r od igiosin e Hyd r och lor id e (4‚HCl). A solution
of compound 18 (81 mg, 0.203 mmol) and RhCl(PPh3)3 (97 mg,
0.105 mmol) in EtOH (30 mL) is stirred under H2 (1 atm) at
ambient temperature for 6 h. The reaction mixture is washed
with saturated aqueous Na2CO3, the aq layer is extracted with
CH2Cl2, the combined organic phases are dried (Na2SO4) and
evaporated, and the residue is purified by flash chromatog-
raphy on neutral alumina using hexane/ethyl acetate (10:1 f
6:1). The combined fractions containing compound 4 are
concentrated to a small volume, treated with a solution of HCl
in Et2O, and evaporated. This affords compound 4‚HCl (73 mg,
90%) as a deeply red solid. 1H NMR (300 MHz, CD2Cl2): δ
12.85 (bs, 1H), 12.65 (bs, 2H), 6.96-6.94 (m, 2H), 6.79 (dd, J
) 3.8, 2.5 Hz, 1H), 6.15 (dd, J ) 3.8, 1.9 Hz, 1H), 6.13 (dd, J
) 3.8, 2.3 Hz, 1H), 6.08 (d, J ) 1.9 Hz, 1H), 4.00 (s, 3H), 2.92
(t, J ) 7.2 Hz, 2H), 2.87 (t, J ) 6.4 Hz, 2H), 1.86-1.72 (m,
4H), 1.55-1.13 (m, 10 H). 13C NMR (75 MHz, CD2Cl2): δ 167.1,
151.3, 149.4, 145.2, 127.1, 126.7, 123.0, 121.0, 119.7, 115.2,
111.9, 111.2, 92.7, 59.1, 30.2, 29.5, 28.3, 28.2, 27.9, 27.8, 27.7,
27.3, 26.6. HRMS (C23H31N3O): calcd 363.231062; found 363.
229082.
Dim eth yl [5-(P en t-4-en yl)-1-ter t-bu toxyca r bon ylp yr -
r ol-2-yl]bor on a te (17). n-BuLi (1.6 M in hexane, 1.84 mL,
2.95 mmol) is slowly added to a solution of 2,2,6,6-tetramethyl-
piperidine (434 µL, 2.57 mmol) in THF (10 mL) at -78 °C
under Ar. After stirring for 15 min at that temperature, the
mixture is allowed to warm to 0 °C within 30 min. After cooling
again to -78 °C, a solution of pyrrole 16 (561 mg, 2.38 mmol)
in THF (10 mL) is added at such a rate that the temperature
remains below -65 °C. The reaction mixture is stirred for 2 h
at -78 °C prior to the addition of trimethyl borate (1.24 g,
11.9 mmol). The solution is allowed to warm to ambient
temperature overnight. For workup, aq HCl (0.25 N, 15 mL,
3.75 mmol) is added, the solvent is evaporated, the residue is
extracted with Et2O, and the combined organic phases are
washed with water and dried (Na2SO4). The solution is slowly
concentrated until a solid starts to precipitate. The mixture
is then cooled to 0 °C, and the precipitated product is filtered
off. Tituration with cold Et2O and drying of the residue in
vacuo affords boronic acid 17 (386 mg, 58%) as a rather
unstable pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 6.99
(d, J ) 3.4 Hz, 1H), 6.79 (bs, 2H), 6.03 (d, J ) 3.4 Hz, 1H),
5.87-5.73 (m, 1H), 5.05-4.92 (m, 2H), 2.85-2.76 (m, 2H),
2.15-2.08 (m, 2H), 1.74-1.63 (m, 2H), 1.61 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 153.2, 142.0, 138.2, 127.3, 115.0, 112.6,
85.8, 33.4, 30.1, 28.3, 28.0. 11B NMR (64 MHz, CDCl3): δ 26.0.
5-[5-(H ex-5-en yl)p yr r ol-2-ylid en em et h yl]-4-m et h oxy-
5′-p en t-4-en yl-1H,1′H-[2,2′] bip yr r olyl Hyd r och lor id e (5‚
HCl). A solution of triflate 15 (268 mg, 0.66 mmol), LiCl (85
mg, 1.98 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), boronic acid
17 (370 mg, 1.32 mmol) in DME (20 mL) is treated with aq
Na2CO3 (2 M, 1.3 mL, 2.6 mmol) and the resulting mixture is
stirred at 85 °C for 15 h under Ar. A standard extractive
workup followed by flash chromatography on neutral alumina
using hexane/ethyl acetate (15:1 f 2:1) as the eluent provides
diene 5; treatment of the free base thus formed with a solution
of HCl in Et2O and evaporation of the solvent provides 5‚HCl
(159 mg, 56%) as a dark-red solid. 1H NMR (300 MHz,
CD2Cl2): δ 12.81 (bs, 1H), 12.70 (bs, 2H), 6.97-6.95 (m, 2H),
6.82-6.80 (m, 1H), 6.20 (dd, J ) 3.8, 1.8 Hz, 1H), 6.16 (dd, J
Ack n ow led gm en t. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz Pro-
gram) and by the Fonds der Chemischen Industrie is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Details concerning
the X-ray structure of compound 18‚HCl, listing of the IR and
MS data, compilation of the instrumentation used, copies of
the 1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O991021I