A second generation synthesis of roseophilin and chromophore analogues

Article abstract of DOI:10.1021/jo982088t

A concise, flexible, and high-yielding synthesis of the macrocyclic compound 4 is outlined which served as a key intermediate in a previous total synthesis of the antitumor active alkaloid roseophilin 1. The key steps of this approach consist of a Pd(0)-catalyzed reaction of vinyloxirane 6 with sulfone 7 and in a subsequent ring closing metathesis (RCM) reaction for the formation of the 13-membered ring catalyzed by the ruthenium carbene Cl₂(PCy₃)₂Ru=CHCH=CPh₂ introduced by Grubbs. Moreover, nitrile ylide cycloaddition reactions are used for the preparation of roseophilin side chain mimics. Finally, the synthesis of various chromophore analogues of 1 is reported, including deschlorodesmethoxyroseophilin 12 which is the most elaborate derivative of this complex target reported so far.

Full text of DOI:10.1021/jo982088t

J . Org. Chem. 1999, 64, 2361-2366
2361
A Secon d Gen er a tion Syn th esis of Roseop h ilin a n d Ch r om op h or e
An a logu es
Alois Fu¨rstner,* Thomas Gastner, and Holger Weintritt
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim/ Ruhr, Germany
Received October 16, 1998
A concise, flexible, and high-yielding synthesis of the macrocyclic compound 4 is outlined which
served as a key intermediate in a previous total synthesis of the antitumor active alkaloid roseophilin
1. The key steps of this approach consist of a Pd(0)-catalyzed reaction of vinyloxirane 6 with sulfone
7 and in a subsequent ring closing metathesis (RCM) reaction for the formation of the 13-membered
ring catalyzed by the ruthenium carbene Cl2(PCy3)2RudCHCHdCPh2 introduced by Grubbs.
Moreover, nitrile ylide cycloaddition reactions are used for the preparation of roseophilin side chain
mimics. Finally, the synthesis of various chromophore analogues of 1 is reported, including deschloro-
desmethoxyroseophilin 12 which is the most elaborate derivative of this complex target reported
so far.
Sch em e 1
In tr od u ction
The intricate structure of roseophilin 1, a macrocyclic
pigment isolated from Streptomyces griseoviridis,1 poses
formidable challenges for a synthesis-driven mapping of
the pharmacophore of this promising cytotoxic agent.
Only recently, we have achieved the first total synthesis
of this topologically unique alkaloid.2,3 Our approach
(Scheme 1) was based on a manifold of palladium-cata-
lyzed reactions for the construction of the complex macro
tricyclic core 2, a cross coupling/dehydrative cyclization
strategy delivering the labile pyrrolylfuran segment 3,
and a newly devised way of making azafulvenes which
takes advantage of the high nucleophilicity of heteroaryl-
cerium reagents.2
We now disclose further efforts meant to bring this
demanding target into range of systematic biological
evaluation. Specifically, a flexible “second generation”
synthesis of its core segment 2 based on ring closing
metathesis (RCM)4 as well as the preparation of various
elaborate chromophore analogues of roseophilin are
outlined, including compound 12 which differs from the
natural product 1 only by the missing chloro and methoxy
substituents in the side chain.
requirements for successful macrocyclization reactions of
appropriate dienes via RCM and have demonstrated the
exceptional performance of this method by various natu-
ral product syntheses.5-7 Compelling evidence has ac-
cumulated during these studies that polar functional
groups of the substrate act as “relays” (e.g. via complexes
of type A or similar, Scheme 2) which help to assemble
the reacting sites within the coordination sphere of the
metal and thus confer bias to cyclization over competing
intermolecular metathesis events. However, if such a
chelate becomes too stable, the catalyst will be seques-
tered in an unproductive form and RCM is likely to cease.
This interpretation suggests that an adequate assess-
ment of the distance between the alkenes and the polar
groups as well as their relative orientation and affinity
allows identification of the proper site for productive
RCM within a given target. Although conformational
predisposition of the substrate toward ring closure is a
Resu lts a n d Discu ssion
RCM Ap p r oa ch to th e Ma cr otr icyclic Segm en t.
In recent work we have gained insights into the basic
(5) (a) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 3942-
3943. (b) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803. (c)
Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005-7008. (d)
Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 8746-8749. (e)
Fu¨rstner, A.; Mu¨ller, Th. Synlett 1997, 1010-1012. (f) Fu¨rstner, A.;
Langemann, K. J . Am. Chem. Soc. 1997, 119, 9130-9136. (g) Fu¨rstner,
A.; Mu¨ller, Th. J . Org. Chem. 1998, 63, 424-425.
(6) For methodological studies on metathesis reactions from this
laboratory, see: (a) Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf,
P. H. Chem. Commun. 1998, 1315-1316. (b) Fu¨rstner, A.; Koch, D.;
Langemann, K.; Leitner, W.; Six, Ch. Angew. Chem., Int. Ed. Engl.
1997, 36, 2466-2469. (c) Fu¨rstner, A.; Seidel, G. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1734-1736. (d) Fu¨rstner, A.; Ackermann, L. Chem.
Commun. 1999, 95-96.
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701-2704.
(2) (a) Fu¨rstner, A.; Weintritt, H. J . Am. Chem. Soc. 1998, 120,
2817-2825. (b) Fu¨rstner, A.; Weintritt, H. J . Am. Chem. Soc. 1997,
119, 2944-2945.
(3) For studies toward roseophilin see: (a) Nakatani, S.; Kirihara,
M.; Yamada, K.; Terashima, S. Tetrahedron Lett. 1995, 36, 8461-8464.
(b) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.; Katoh, T.;
Terashima, S. Tetrahedron Lett. 1998, 39, 6911-6914. (c) Kim, S. H.;
Fuchs, P. L. Tetrahedron Lett. 1996, 37, 2545-2548. (d) Kim, S. H.;
Figueroa, I.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 2601-2604. (e)
Luker, T.; Koot, W.-J .; Hiemstra, H.; Speckamp, W. N. J . Org. Chem.
1998, 63, 220-221.
(4) For recent reviews on RCM see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (b) Fu¨rstner, A. Top. Catal. 1997,
4, 285-299. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036-2055.
(7) For reviews on other RCM-based macrocycle syntheses, see: (a)
Nicolaou, K. C. Top. Organomet. Chem. 1998, 1, 73-104. (b) Hoveyda,
A. H. Top. Organomet. Chem. 1998, 1, 105-132. (c) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 37-72 and literature cited.
10.1021/jo982088t CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/12/1999

2362 J . Org. Chem., Vol. 64, No. 7, 1999
Fu¨rstner et al.
Sch em e 2
Sch em e 49
Sch em e 3
priori unnecessary, one has to keep in mind that macro
cyclizations by RCM are essentially entropy driven and
that the ability of this method to build up strain in the
molecule is therefore rather limited.5-7
function, and shows that this catalyst rigorously distin-
guishes between terminal and trisubstituted alkenes.4
Subsequent hydrogenation of 9 in the presence of RhCl-
(PPh3)3 cat. selectively saturates the disubstituted double
bond formed by RCM without affecting the trisubstituted
olefin. The resulting product 4 is identical to that ob-
tained by our previous route in all respects and can be
transformed into 2 in only five high-yielding steps as
described in ref 2.
The following aspects of this “second generation”
approach to 2 are noteworthy: although the metathesis
route is one step longer than our previous palladium-
based macrocyclization strategy,2 the overall yield is in
a comparable range (51% over four steps compared to
48% over three steps starting from 5 each). More impor-
tant, however, is its flexible design. It is obvious that this
sequence of reactions can be easily adapted to the
synthesis of roseophilin analogues differing in the ring
size of the macrocycle if 5-hexenal is replaced by other
unsaturated aldehydes or if nucleophiles other than 7 are
employed for the Pd(0)-catalyzed vinyl epoxide opening
When applied to the tricyclic core 2 of roseophilin, this
analysis suggests forging the macrocycle in an early stage
and rigidifying the backbone of the target during subse-
quent, kinetically favorable cyclizations of the five-mem-
bered rings. This basic concept has already contributed
to the success of our previous synthesis of this product,
which involved compound 4 as a key precursor formed
by a Pd(0)-catalyzed macrocyclization reaction.2 We felt
that this compound might also be accessible by RCM
provided that the 13-membered ring is closed at (or near)
the site indicated in Scheme 3.
This synthesis plan was reduced to practice as sum-
marized in Scheme 4. Reaction of 5-hexenal with the
sulfur ylide formed from sulfonium salt 52,8 upon depro-
tonation with tert-BuLi at -78 °C provides epoxide 6 in
80% yield. Treatment of this product with catalytic
amounts of Pd(PPh3)4 in the presence of methyl 2-(phen-
ylsulfonyl)-6-heptenoate 7 as an external nucleophile
readily delivers the desired triene 89 as a mixture of
isomers via the selective activation of the vinyloxirane
entity of 6 without interference of its adjacent allyl ether
site. In line with our expectations, exposure of 8 to the
ruthenium carbene Cl2(PCy3)2RudCHCHdCPh2 [Ru] (10
mol %)10 in refluxing CH2Cl2 under high dilution condi-
tions effects a slow but smooth and high-yielding mac-
rocyclization reaction.11 This transformation features the
excellent compatibility of the Grubbs catalyst [Ru] with
various functional groups, including an unprotected OH
(11) In preparative runs, the cyclization can been carried out with
a mixture of different isomers of substrate 8 since all isomers of product
9 formed converge into the desired target 2. For analytical purposes,
however, small scale experiments using individual isomers have been
performed which are described in the Experimental Section. During
these reactions it was noticed that the rate of cyclization of (Z)-8 is
significantly higher than that of (E)-8, although both runs lead
essentially to the same yields of the corresponding macrocycles. NOE
data have been used to assign the configuration of the trisubstituted
double bond of (E)-8. We thank Mrs. B. Gabor for the NOE measure-
ments.
(8) For an application of this building block to the synthesis of
furans, see: Fu¨rstner, A.; Gastner, T.; Rust, J . Synlett 1999, 29-32.
(9) Products 4, 6, 8, and 9 are obtained as mixtures of several
stereoisomers. Because all of them converge into product 2, the
synthesis depicted in Scheme
4 was carried through with these
mixtures, and no attempts were made to separate the individual
compounds; see, however, ref 11.
(10) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem.
Soc. 1993, 115, 9858. (b) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R. H.;
Ziller, J . W. J . Am. Chem. Soc. 1992, 114, 3974-3975. (c) See also:
Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew. Chem.
1995, 107, 2179-2181.

Synthesis of Roseophilin and Chromophore Analogs
J . Org. Chem., Vol. 64, No. 7, 1999 2363
Sch em e 5
Sch em e 6
reaction. Finally, a comparison of this route with another
RCM-based approach to 2 (Scheme 5)3d sheds light on a
more general notion concerning the use of metathesis in
synthetic maneuvers: We avoid difficulties caused by the
inherent strain in 2 by deliberately forging the macro-
cycle in an early stage of the synthesis, prior to the
formation of the five-membered rings. As reported by
Fuchs et al., the inverse order of events, i.e. cyclization
of the five-membered rings preceding the construction of
the ansa chain is significantly more delicate: thus,
cyclization of diene 10 required substantial amounts of
catalyst and succeeded only after it was strongly biased
by the introduction of a conformational control element
X which helps to bring the unsaturated chains close
together and thereby lowers the enthalpic barrier during
ring formation.3d
Roseop h ilin Ch r om op h or e An a logu es. As experi-
enced during our total synthesis of roseophilin,2a the
unusual substitution pattern of the heterocyclic segment
3 and the inherent lability of this compound and some
of its precursors pose considerable problems. Therefore
the development of improved entries into pyrrolylfuran
derivatives in general and the biological evaluation of
truncated roseophilin analogues mimicing its intricate
chromophore entity constitute prime goals for further
studies in this field. In this context we now report the
synthesis of deschloro-desmethoxyroseophilin 12 as a
rather elaborate derivative of 1 as well as the preparation
of the simplified targets 13-15.12
Cl) albeit in lower yield. Unfortunately, however, the
incorporation of a methoxy substituent at the 4-position
of the furan ring leads to intractable mixtures. That is
why the fully substituted side chain 3 was prepared
according to the route previously described.2a
After protection of the pyrrolic N-H function with a
TIPS () triisopropylsilyl) group,14 derivatives 3 and 21,
respectively, can be selectively metalated with n-BuLi in
THF at the 2-position of their furan ring. Transmetala-
tion with CeCl3 and addition of the resulting organocer-
ium reagents 2215 to the potassium salt of 2-acetylpyrrole
delivers the corresponding tertiary alcohols 23 which
spontaneously lose water on addition of aqueous HCl.
Fluoride-induced desilylation affords the labile azaful-
vene derivatives 13-15 which are protonated for con-
venience of workup. This sequence of reactions provides
the desired truncated chromophore analogues of roseo-
philin in 23-32% overall yield.
A better result is obtained if N-SEM protected 2-acetyl-
pyrrole 24 is used as substrate for the condensation
reaction instead of the potassium salt (Scheme 8). This
particular protecting group has been chosen i.a. because
it is concomitantly cleaved with the TIPS group on the
side chain and therefore does not prolongate the sequence
by an additional deprotection step.16 This method fur-
nishes pigment 15 in 55% overall yield.
For this purpose, unsubstituted pyrrolylfuran 20a (X
) H) was prepared according to a procedure of Steglich
et al. (Scheme 6).13 Thus, acylation of allylamine 16a with
furan-2-carboxylic acid chloride under standard condi-
tions delivers amide 17a . Reaction of this compound with
a solution of phosgene in toluene affords iminoyl chloride
18 which is exposed to tert-BuOK without further puri-
fication. The resulting nitrile ylide 19 cycloaromatizes
spontaneously to the desired product 20a . We were
pleased to find that this method also applies to the
preparation of the chloro-substituted analogue 20b (X )
(13) Engel, N.; Steglich, W. Angew. Chem. 1978, 90, 719-720.
(14) TIPS was chosen since it prevents metalation of the pyrrole by
mere steric bulk, cf.: (a) Muchowski, J . M.; Solas, D. R. Tetrahedron
Lett. 1983, 24, 3455-3456. (b) Bray, B. L.; Mathies, P. H.; Naef, R.;
Solas, D. R.; Tidwell, T. T.; Artis, D. R.; Muchowski, J . M. J . Org. Chem.
1990, 55, 6317-6328.
(15) For reviews on organocerium compounds, see: (a) Imamoto, T.
Lanthanides in Organic Synthesis; Academic Press: New York, 1994.
(b) Molander, G. A. Chem. Rev. 1992, 92, 29-68. (c) See also: Imamoto,
T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka,
Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904-3912.
(16) The SEM protecting group was essential in our previous total
synthesis of roseophilin, cf. ref 2a. For another application of N-SEM
protected pyrrole derivatives see: Edwards, M. P.; Doherty, A. M.; Ley,
S. V.; Organ, H. M. Tetrahedron 1986, 42, 3723-3729.
(12) Terashima et al. have described an alternative synthesis of
compound 13 and related products by acid-catalyzed condensation
reactions, cf. ref 3a.

2364 J . Org. Chem., Vol. 64, No. 7, 1999
Fu¨rstner et al.
Sch em e 7
models 13-15 it will help to assess the structure/activity
profile of this promising cytotoxic agent in more detail.
Work along these lines as well as complementary syn-
thetic endeavors directed to bioactive pyrrole alkaloids
are underway and will be reported in due course.17
Finally, a noteworthy physicochemical property of
these compounds is briefly mentioned. Whereas roseo-
philin 1 and its truncated analogue 13 are intensively
red-colored pigments, all derivatives lacking the methoxy
substituent on the furan ring, i.e. 12, 14, and 15, are ink
blue compounds.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under Ar in flame-
dried 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), pyridine (KOH), DMF
(dibutyltin laurate and Desmodur-15, Bayer AG), EtOH (Mg).
Flash chromatography: Merck silica gel (230-400 mesh) or
alumina (Macherey-Nagel, Darmstadt, activity 1, neutral)
using hexane/ethyl acetate in various proportions as eluent.
For the instrumentation used and the spectra formats see
Supporting Information. Elemental analyses: Dornis & Kolbe,
Mu¨lheim. CAUTION: Pure KH, free of mineral oil, is highly
pyrophoric! It is obtained by repeatedly washing the com-
mercially available suspension of KH in mineral oil with
pentane on a sinter funnel under Ar and subsequent drying
of the powder in vacuo. Anhydrous CeCl3 was obtained by
flame-drying commercially available CeCl3‚7H2O (Aldrich,
99.9%) in vacuo; the material was then rapidly pulverized in
a mortar and redried for 24 h at 150 °C at ca. 10-2 Torr. Other
commercially available reagents (Aldrich, Fluka) were used
as received.
Sch em e 8
Meth yl 2-(P h en ylsu lfon yl)-6-h ep ten oa te (7). Methyl
(phenylsulfonyl)acetate (1.596 g, 7.45 mmol) is added in
portions to a suspension of KH (298 mg, 7.45 mmol) in DMF
(10 mL) at ambient temperature, and stirring is continued
until the evolution of gas has ceased. 5-Bromo-1-pentene (0.8
mL, 6.77 mmol) is added, and the resulting mixture is stirred
overnight at room temperature. A standard extractive workup
followed by flash chromatography on silica with hexane/ethyl
acetate (10/1) affords product 7 as a colorless syrup (1.378 g,
1
72%). H NMR (200 MHz, CDCl3): δ 7.53-7.96 (m, 5H), 7.21
(ddt, J ) 16.9, 10.3, 6.6, 1H), 4.93-5.04 (m, 2H), 3.95 (dd, J )
10.2, 4.9, 1H), 3.67 (s, 3H), 1.86-2.14 (m, 4H), 1.40 (quint, J
) 7.5, 2H). 13C NMR (50 MHz, CDCl3): δ 166.0, 136.8, 136.7,
133.9, 128.9, 128.7, 115.2, 70.4, 52.6, 32.6, 25.8, 25.7.
{2-[3-(4-P en t en -1-yl)oxir a n yl]a llyloxy}-ter t-b u t yld i-
m eth ylsila n e (6). tert-BuLi (787 µL, 1.26 mmol, 1.6 M in
hexane) is added via syringe to a solution of sulfonium salt 5
(450 mg, 1.25 mmol)2 in THF (25 mL) at -78 °C. After 15 min
at that temperature, 5-hexenal (123 mg, 1.25 mmol) is
introduced, and the mixture is stirred for an additional 15 min
at -78 °C and then slowly warmed to room temperature. The
reaction is extracted with H2O/ethyl acetate, and the organic
layer is dried over Na2SO4 and evaporated. Purification of the
crude product by flash chromatography (SiO2, hexane/ethyl
acetate ) 50/1) furnishes compound 6 as a pale yellow oil (283
mg, 80%, mixture of isomers): 1H NMR (200 MHz, CDCl3): δ
Sch em e 9
(17) For syntheses of other bioactive pyrrole and indole derivatives
from this laboratory, see: (a) Fu¨rstner, A.; Szillat, H.; Gabor, B.;
Mynott, R. J . Am. Chem. Soc. 1998, 120, 8305-8314. (b) Fu¨rstner, A.;
Weintritt, H.; Hupperts, A. J . Org. Chem. 1995, 60, 6637-6641. (c)
Fu¨rstner, A.; Hupperts, A.; Ptock, A.; J anssen, E. J . Org. Chem. 1994,
59. 5215-5229. (d) Fu¨rstner, A.; Ernst, A.; Krause, H.; Ptock, A.
Tetrahedron 1996, 52, 7329-7344. (e) Fu¨rstner, A.; Ernst, A. Tetra-
hedron 1995, 51, 773-786. (f) Fu¨rstner, A.; Ptock, A.; Weintritt, H.;
Goddard, R.; Kru¨ger, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 678-
681. (g) Fu¨rstner, A.; J umbam, D. N.; Seidel, G. Chem. Ber. 1994, 127,
1125-1130. (h) Fu¨rstner, A.; J umbam, D. N. J . Chem. Soc., Chem.
Commun. 1993, 211-212. (i) Fu¨rstner, A.; Bogdanovic, B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2442-2469.
Having good access to the macrotricyclic core 2 (vide
supra) as well as to the side chain analogue 21a , we were
able to prepare deschloro-desmethoxyroseophilin 12 by
closely following the above-mentioned protocol. As shown
in Scheme 9, this product was obtained without incident
and constitutes the most elaborate derivative of roseo-
philin reported so far. Together with the less complex

Synthesis of Roseophilin and Chromophore Analogs
J . Org. Chem., Vol. 64, No. 7, 1999 2365
5.76 (m, 1H), 5.22-5.12 (m, 1.6H) 5.06-4.88 (m, 2.4H), 4.17-
4.13 (m, 1.2H), 4.08 (m, 0.8H), 3.43 (m, 0.6H), 3.14 (d, J ) 2.2
Hz, 0.4H), 3.04 (m, 0.6H), 2.86 (m, 0.4H), 2.18-1.98 (m, 2H),
1.67-1.33 (m, 4H), 0.89 (s, 5.4H), 0.88 (s, 3.6H), 0.05 (s, 3.6H),
0.04 (s, 2.4H). 13C NMR (50 MHz, CDCl3): δ 144.8, 142.2,
138.3, 138.2, 114.9, 114.7, 112.0, 111.3, 64.5, 62.7, 59.9, 58.6,
58.4, 56.3, 33.5, 33.4, 31.7, 26.1, 25.9, 25.5, 25.1, 18.4, 18.3,
-5.4. Anal. Calcd for C16H30O2Si: C 68.03, H 10.70. Found C
68.15, H 10.65.
Tr ien e 8. Epoxide 6 (170 mg, 0.6 mmol) is added to a
solution of Pd(PPh3)4 (75 mg, 0.06 mmol) and sulfone 7 (165
mg, 0.58 mmol) in THF (20 mL), and the resulting yellow
mixture is stirred at room temperature for 24 h. An extractive
work up with H2O/ethyl acetate, drying of the organic layer
over Na2SO4, evaporation of the solvent, and flash chroma-
tography (SiO2, hexane/ethyl acetate ) 10/1) afford (E)-8 (118
mg, 36%) and (Z)-8 (160 mg, 49%) as colorless syrup each. Data
of (E)-8: 1H NMR (300 MHz, CDCl3): δ 7.83-7.78 (m, 2H),
7.64 (m, 1H), 7.58-7.48 (m, 2H), 5.86-5.67 (m, 2H), 5.59 (d,
J ) 9.3 Hz, 1H), 5.04-4.89 (m, 4H), 4.48 (dt, J ) 9.2, 6.0 Hz,
1H), 3.96 (dd, J ) 13.7, 1.1 Hz, 1H), 3.84 (dd, J ) 13.7, 1.0
Hz, 1H), 3.61 (s, 3H), 3.17 (d, J ) 14.3 Hz, 1H), 2.64 (d, J )
14.3 Hz, 1H), 2.18-1.20 (m, 13H), 0.80 (s, 9H), -0.03 (s, 3H),
-0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 168.5, 138.5,
138.0, 136.8, 134.1, 134.0, 133.8, 130.5, 128.5, 115.2, 114.6,
76.3, 67.5, 66.4, 52.7, 36.6, 34.2, 33.6, 31.4, 30.0, 25.8, 24.5,
23.5, 18.2, -5.3, -5.4. HRMS (C30H48O6SSi + Na): calcd
587.28386; found 587.28182. Anal. Calcd for C30H48O6SSi: C
63.79, H, 8.56. Found C 63.81, H, 8.66.
For workup the solvent is evaporated, and the crude product
is purified by flash chromatography (SiO2, hexane/ethyl acetate
) 10/1 f 4/1) affording compound 4 (54 mg, 90%) as a colorless
oil. Its analytical and spectroscopic data are identical in all
respects to those previously reported.2a
N-Allylfu r a n -2-ca r boxylic Acid Am id e (17a ). A solution
of furan-2-carboxylic acid chloride (2.0 mL, 20.3 mmol) in
CH2Cl2 is slowly added to a stirred solution of allylamine (1.27
mL, 16.9 mmol) and catalytic amounts of DMAP in CH2Cl2
(30 mL) and pyridine (3 mL). After stirring for 2 h, the reaction
is quenched with sat. aqueous NaHCO3. Standard extractive
work up followed by flash chromatography (SiO2, hexane/ethyl
acetate 4/1 f 2/1) provides compound 17a as a colorless syrup
(1.73 g, 68%). 1H NMR (200 MHz, CDCl3): δ 7.39 (dd, J ) 1.8,
0.9, 1H), 7.08 (dd, J ) 3.5, 0.8, 1H), 6.50 (br s, 1H), 6.45 (dd,
J ) 3.5, 1.7, 1H), 5.97-5.78 (m, 1H), 5.27-5.10 (m, 2H), 4.01
(tt, J ) 5.8, 1.5, 2H). 13C NMR (50 MHz, CDCl3): δ 158.2,
147.9, 143.8, 133.9, 116.6, 114.2, 112.1, 41.4. Anal. Calcd for
C8H9NO2: C 63.57, H 6.00, N 9.27. Found: C 63.62, H 5.98,
N 9.21.
N-(3-Ch lor o-2-pr open yl)fu r an -2-car boxylic Acid Am ide
(17b). Obtained as described above starting from (E,Z)-3-
amino-1-chloro-1-propene (1.01 g, 11.0 mmol) and furan-2-
carboxylic acid chloride (1.36 mL, 13.8 mmol) as a pale yellow
oil (1.167 g, 59%). Mixture of stereoisomers, characteristic
data: 1H NMR (200 MHz, CDCl3): δ 7.39 (dd, J ) 1.8, 0.8,
1H), 7.09-7.07 (m, 1H), 6.60 (br s, 1H), 6.46 (dd, J ) 3.4, 2.0,
1H), 6.24-6.13 (m, 1H), 6.03-5.85 (m, 1H), 4.19 (dt, J ) 6.2,
1.5, 1H), 4.00 (dt, J ) 6.2, 1.3, 1H). 13C NMR (50 MHz,
CDCl3): δ 158.3, 158.1, 147.6, 147.5, 144.0, 143.9, 129.2, 127.7,
121.3, 120.9, 114.5, 114.3, 112.1, 112.0, 38.9, 35.8. Anal. Calcd
for C8H8ClNO2: C 51.77, H 4.34, N 7.55. Found: C 51.85, H
4.30, N 7.48.
2-(F u r a n -2-yl)-1H-p yr r ole (20a ). Amide 17a (1.69 g, 11.2
mmol) is added to a solution of phosgene in toluene (20% w/w,
25 mL) containing a catalytic amount of DMF. The resulting
mixture is stirred for 16 h at ambient temperature. The
volatiles are removed in vacuo (1 mbar) at 40-50 °C, the
residue is dissolved in THF (15 mL), and the resulting solution
is added dropwise to a solution of tert-BuOK (3.76 g, 33.6
mmol) in DMF (15 mL) at 5-10 °C. After stirring for 10 min
at that temperature, the mixture is poured into chilled water,
the aqueous phase is extracted with ether, the organic layer
is dried (Na2SO4), and the solvent is evaporated. Flash
chromatography of the residue (SiO2, hexane/ethyl acetate 10/
1) affords the compound 20a as a pale yellow solid (0.847 g,
57%).13 1H NMR (200 MHz, CDCl3): δ 8.51 (br s, 1H), 7.34
(dd, J ) 1.8, 0.7, 1H), 6.81-6.77 (m, 1H), 6.44-6.41 (m, 2H),
6.35-6.33 (m, 1H), 6.28-6.25 (m, 1H). 13C NMR (50 MHz,
CDCl3): δ 148.3, 140.3, 118.1, 111.4, 109.7, 105.3, 102.2.
Data of (Z)-8: 1H NMR (300 MHz, CDCl3): δ 7.94-7.76 (m,
2H), 7.63 (m, 1H), 7.58-7.47 (m, 2H), 5.84-5.65 (m, 2H), 5.60
(d, J ) 9.5 Hz, 0.75H), 5.29 (d, J ) 8.3 Hz, 0.25H), 5.04-4.88
(m, 4H), 4.33 (m, 0.25H), 4.20 (m, 0.75H), 4.09 (m, 0.5H), 3.93-
3.86 (m, 1.5H), 3.67 (s, 2.25H), 3.61 (s, 0.75H), 2.88 (d, J )
13.7 Hz, 0.75H), 2.78 (d, J ) 13.7 Hz, 0.75H), 2.77 (m, 0.5H),
2.19-1.26 (m, 13H), 0.82 (s, 6.75H), 0.80 (s, 2.25H), -0.03 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 168.84, 168.48, 138.50,
138.36, 137.89, 137.65, 137.08, 137.02, 136.41, 135.00, 134.60,
134.00, 133.90, 133.19, 130.89, 130.57, 128.48, 115.20, 115.09,
114.69, 114.59, 76.48, 76.31, 67.36, 66.99., 66.07, 61.19, 52.65,
52.49, 37.45, 36.55, 36.36, 34.26, 34.19, 33.58, 32.74, 31.98,
30.61, 25.79, 25.74, 24.62, 24.56, 23.69, 23.45, 18.23, 18.05,
-5.33, -5.38, -5.48. HRMS (C30H48O6SSi + Na): calcd
587.28386; found 587.28327.
Ma cr ocycle 9. Solutions of (E)-8 (52 mg, 0.09 mg) and of
the ruthenium carbene Cl2(PCy3)2RudCHCHdCPh2 (8 mg,
0.009 mmol)10 in CH2Cl2 (30 mL each) are simultaneously
added via two dropping funnels to refluxing CH2Cl2 (30 mL)
over a period of ≈10 h. Stirring is continued at that temper-
ature until TLC shows complete conversion of the substrate
(≈120 h). For workup the solvent is evaporated and the crude
product purified by flash chromatography (SiO2, hexane/ethyl
acetate ) 10/1 f 4/1) affording compound 9 (40 mg, 81%,
3-Ch lor o-2-(fu r a n -2-yl)-1H-p yr r ole (20b). Prepared as
described above starting from amide 17b (1.167 g, 6.29 mmol).
This product is a rather unstable syrup (255 mg, 24%) and is
immediately N-silylated for characterization.
1
mixture of isomers) as a pale yellow oil. H NMR (300 MHz,
CDCl3): δ 7.93-7.78 (m, 2H), 7.69-7.46 (m, 3H), 5.86 (d, J )
9.0 Hz, 0.3H), 5.62 (d, J ) 8.7 Hz, 0.7H), 5.53-5.22 (m, 2H),
4.49 (m, 1H), 4.39 (d, J ) 15.2 Hz, 0.3H), 4.13 (d, J ) 15.2 Hz,
0.3H), 3.84 (s, 1.4H), 3.61 (s, 0.9H), 3.60 (s, 2.1H), 3.17 (m,
0.6H), 3.01 (d, J ) 15.0 Hz, 0.7H), 2.59 (d, J ) 15.0 Hz, 0.7H),
2.33-1.15 (m, 13H), 0.90 (s, 2.7H), 0.86 (s, 6.3H) 0.07 (s, 1.8H),
0.00 (s, 2.1H), -0.01 (s, 2.1H). 13C NMR (75 MHz, CDCl3): δ
169.44, 169.22, 137.60, 135.08, 134.32, 133.94, 131.87, 131.78,
131.54, 130.76, 130.72, 130.08, 128.63, 128.52, 68.01, 66.52,
66.36, 66.12, 52.81, 52.57, 36.47, 34.14, 33.94, 32.54, 31.77,
30.99, 30.44, 30.33, 27.29, 26.96, 25.96, 25.89, 25.81, 25.31,
24.68, 23.54, 23.12, 22.02, 18.29, -5.27, -5.32. Anal. Calcd
for C28H44O6SSi: C 62.65, H, 8.26. Found C 62.67; H, 8.28.
The cyclization of (Z)-8 (87 mg, 0.15 mmol) proceeds
analogously and is worked up after a reaction time of 72 h
affording 9 (67 mg, 81%) as a mixture of isomers. A cyclization
carried out with a (E,Z)-mixture of 8 afforded product 9 in 85%
yield.
2-(F u r a n -2-yl)-1-tr iisop r op ylsilyl-1H-p yr r ole (21a ). A
solution of compound 20a (400 mg, 3.01 mmol) in THF (5 mL)
is added to a suspension of KH (132 mg, 3.31 mmol) in THF
(20 mL). After the evolution of H2 has ceased, TIPSCl (0.71
mL, 3.31 mmol) is added, and the resulting mixture is stirred
for 15 min. Standard extractive workup followed by flash
chromatography (SiO2, hexane/ethyl acetate 20/1) delivers
compound 21a as a pale yellow syrup (739 mg, 85%). 1H NMR
(200 MHz, CDCl3): δ 7.39 (dd, J ) 1.8, 0.9, 1H), 6.94 (dd, J )
2.8, 1.5, 1H), 6.44-6.39 (m, 2H), 6.34-6.27 (m, 2H), 1.38-
1.19 (m, 3H), 1.06 (d, J ) 6.8, 18H). 13C NMR (50 MHz,
CDCl3): δ 149.1, 140.9, 127.6, 115.1, 111.1, 109.8, 18.3, 12.9.
HRMS (C17H27NOSi) calcd 289.18619; found 289.18653.
3-Ch lor o-2-(fu r a n -2-yl)-1-t r iisop r op ylsilyl-1H -p yr -
r ole (21b). Prepared as described above from substrate 20b
(210 mg, 1.25 mmol), KH (55 mg, 1.38 mmol), and TIPSCl (0.30
mL, 13.8 mmol). Colorless syrup (336 mg, 83%). 1H NMR (200
MHz, CDCl3): δ 7.44 (dd, J ) 1.8, 0.8, 1H), 6.82 (d, J ) 3,
1H), 6.51-6.45 (m, 2H), 6.28 (d, J ) 3, 1H), 1.29-1.12 (m,
3H), 1.05 (d, J ) 6.4, 18H). 13C NMR (50 MHz, CDCl3): δ 145.1,
Ma cr ocycle 4. A solution of compound 9 (60 mg, 0.112
mmol) and RhCl(PPh3)3 (26 mg, 0.028 mmol) in EtOH (20 mL)
is stirred under H2 (1 atm) for 16 h at ambient temperature.

2366 J . Org. Chem., Vol. 64, No. 7, 1999
Fu¨rstner et al.
141.7, 126.3, 116.8, 112.0, 111.2, 110.6, 18.2, 12.6. HRMS
(C17H26ClNOSi): calcd 323.14722; found 323.14594.
by flash chromatography of the crude product (SiO2, hexane/
ethyl acetate 10/1) affords compound 24 as a colorless syrup
(157 mg, 82%). 1H NMR (200 MHz, CDCl3): δ 7.04 (dd, J )
2.6, 1.7, 1H), 6.96 (dd, J ) 4.0, 1.7, 1H), 6.17 (dd, J ) 4.0, 2.6,
1H), 5.70 (s, 2H), 3.41 (m, 2H), 2.35 (s, 3H), 0.86 (m, 2H), -0.06
(s, 9H). 13C NMR (50 MHz, CDCl3): δ 188.5, 130.6, 129.7,
P r ototyp e Con d en sa tion P r oced u r e: 2-{5-[1-(2H-P yr -
r ol-2-ylid en e)et h yl]-2-fu r a n yl}-1H -p yr r ole H yd r och lo-
r id e (15‚HCl). n-BuLi (1.6 M in hexane, 275 µL, 0.44 mmol)
is added to a solution of compound 21a (128 mg, 0.44 mmol)
in THF (5 mL) at -78 °C. After stirring for 6 h at that
temperature, the resulting solution is transferred via cannula
to a cooled (-78 °C) suspension of CeCl3 (108 mg, 0.44 mmol)
in THF (5 mL), which has been stirred for 4 h at room
temperature prior to use. After another 2 h, a solution of the
potassium salt of 2-acetylpyrrole [prepared upon treatment of
2-acetylpyrrole (34 mg, 0.31 mmol) with KH (12 mg, 0.31
mmol) in THF (3 mL)] is added at -78 °C, and the resulting
mixture is allowed to reach ambient temperature overnight.
The reaction mixture is extracted with aq NH4Cl and ether,
and the organic layer is treated with aq HCl (10% w/w, ca.
0.5 mL) for 5 min, neutralized (Na2CO3), and dried (Na2SO4).
The resulting, labile product is rapidly passed through a plug
of alumina (neutral) using hexane/ethyl acetate (10/1) as the
eluent. The product-containing fractions are concentrated to
a total volume of ca. 3 mL, diluted with THF (5 mL), and then
treated with TBAF (1 M in THF, ca. 0.2 mL) for 5 min.
Extraction of the resulting labile product 15 with ether, drying
of the organic layer, rapid flash chromatography over alumina
(neutral; hexane/ethyl acetate, 2/1), treatment of the combined,
product-containing fractions with a saturated solution of HCl
in THF, and subsequent evaporation of the solvents provides
the desired condensation product 15‚HCl as a dark blue solid
120.9, 109.2, 77.3, 66.0, 27.3, 17.8, -1.5. Anal. Calcd for C12H21
-
NO2Si: C 60.21, H 8.84, N 5.85. Found: C 60.05, H 8.88, N
5.83.
Alt er n a t ive Con d en sa t ion P r oced u r e: 2-{5-[1-(2H -
P yr r ol-2-ylid en e)et h yl]-2-fu r a n yl}-1H -p yr r ole H yd r o-
ch lor id e (15‚HCl). A solution of compound 21a (200 mg, 0.69
mmol) in THF (5 mL) is treated with n-BuLi (1.6 M in hexane,
430 µL, 0.69 mmol) at -50 °C for 4 h. The resulting mixture
is transferred via cannula to a cooled (-78 °C) suspension of
CeCl3 (170 mg, 0.69 mmol) in THF (5 mL), which has been
stirred for 4 h at room temperature prior to use. After stirring
for 1.5 h at that temperature, a solution of compound 24 (100
mg, 0.42 mmol) in THF (5 mL) is introduced and the temper-
ature gradually raised to room temperature overnight. Extrac-
tion with aq NH4Cl and ether, drying of the organic phase
(Na2SO4), evaporation of the solvent, and passing of the crude
product through a plug of alumina (neutral, hexane/ethyl
acetate 10/1) affords alcohol 23 (180 mg, 81%) as a rather
unstable oil which is deprotected without delay. For this
purpose, a mixture of 23 (90 mg, 0.17 mmol) and TBAF (1 M
in THF, 0.7 mL, 0.7 mmol) in THF (5 mL) is stirred for 3 h at
60 °C. Et2O and aqueous NaHCO3 (sat.) are added, and the
resulting organic layer is acidified with HCl (10% w/w) and
stirred for 5 min at room temperature to effect the elimination
of the OH group. Neutralization with aqueous Na2CO3 (5%
w/w), drying of the organic phase (Na2SO4), rapid elution of
the crude material through a plug of alumina (hexane/ethyl
acetate, 2/1), and treatment of the concentrated, product-
containing fractions with a saturated solution of HCl in THF,
followed by evaporation of the solvent in vacuo, affords product
15‚HCl as a dark blue solid. The analytical and spectroscopic
data are identical to those compiled above.
Desch lor o-d esm eth oxyr oseop h ilin Hyd r och lor id e (12‚
HCl). Prepared as described above starting from substrates
21a (37 mg, 0.128 mmol) and 2 (R ) Si(iPr)3, 11 mg, 0.027
mmol). The product is obtained as a dark blue solid (5.5 mg,
48%) which exhibits the following spectroscopic properties: 1H
NMR (600 MHz, CDCl3): δ 14.27 (br s, 1H), 13.61 (br s, 1H),
7.47 (d, J ) 4.3, 1H), 7.33 (m, 1H), 6.90 (m, 1H), 6.80 (d, J )
4.3, 1H), 6.32 (m, 1H), 6.26 (s, 1H), 3.69-3.64 (m, 1H), 3.60
(m, 1H), 2.90 (ddd, J ) 13, 5.6, 3.8, 1H), 2.77 (d, J ) 6.3, 1H),
2.20-2.16 (m, 2H), 1.88-1.78 (m, 2H), 1.41-1.34 (m, 2H),
1.20-1.17 (m, 2H), 1.09-1.01 (m, 1H). 1.02 (d, J ) 6.7, 3H),
0.96-0.92 (m, 2H), 0.83-0.76 (m, 2H), 0.81 (d, J ) 6.7, 3H),
0.43-0.34 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 170.6 (s),
162.9 (s), 161.5 (s), 145.6 (s), 144.4 (s), 137.4 (s), 131.4 (d), 127.9
(d), 121.0 (s), 115.8 (d), 112.2 (d), 111.8 (d), 110.3 (d), 56.5 (d),
51.9 (d), 35.8 (t), 33.1 (d), 28.7 (t), 28.2 (t), 27.9 (t), 27.2 (t),
26.8 (t), 24.7 (t), 24.5 (t), 21.4 (q), 19.6 (q). 15N NMR (60 MHz,
CDCl3): δ -211, -218. MS (ESI pos): m/z (rel intensity) 389
(100, [(M + H)+].
1
(20 mg, 25%). H NMR (300 MHz, CDCl3): δ 14.36 (br s, 1H),
12.83 (br s, 1H), 8.17 (virt quint, J ) 1.8, 1H), 7.80 (d, J )
4.7, 1H), 7.49 (m, 1H), 7.23 (m, 1H), 7.05 (m, 1H), 6.86 (d, J )
4.7, 1H), 6.50 (m, 1H), 6.39 (virt quint, J ) 2.0, 1H), 2.54 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 164.7, 150.3, 142.7, 137.4,
133.8, 132.4, 130.4, 128.6, 121.6, 120.6, 115.9, 114.2, 114.0,
17.7. MS (ESI pos): m/z (rel intensity) 225 (100, [(M + H)+].
3-Ch lor o-2-{5-[1-(2H-pyr r ol-2-yliden e)eth yl]-2-fu r an yl}-
1H-p yr r ole Hyd r och lor id e (14‚HCl). Prepared as described
above employing substrate 21b (145 mg, 0.45 mmol), n-BuLi
(281 µL, 0.45 mmol), CeCl3 (111 mg, 0.45 mmol), and the
potassium salt of 2-acetylpyrrole [prepared from 2-acetylpyr-
role (35 mg, 0.32 mmol) and KH (13 mg, 0.32 mmol)]. The
product is obtained as a dark blue solid (22 mg, 23%). 1H NMR
(400 MHz, CDCl3): δ 14.34 (br s, 1H), 13.13 (br s, 1H), 8.34
(m, 1H), 7.86 (d, J ) 4.6, 1H), 7.43 (d, J ) 4.6, 1H), 7.39 (m,
2H), 6.61 (m, 1H), 6.38 (virt. t, J ) 2.3, 1H), 2.65 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 162.3, 149.8, 145.5, 137.1, 135.5,
131.2, 130.5, 129.6, 123.4, 117.3, 116.9, 114.2, 113.7, 18.1. MS
(ESI pos): m/z (rel intensity) 259 (100, [(M + H)+].
3-Ch lor o-2-{4-m eth oxy-5-[1-(2H-pyr r ol-2-yliden e)eth yl]-
2-fu r a n yl}-1H-p yr r ole Hyd r och lor id e (13‚HCl). Prepared
as described above employing substrate 3 (R ) Si(iPr)3, 39 mg,
0.11 mmol), n-BuLi (69 µL, 0.11 mmol), CeCl3 (27 mg, 0.11
mmol), and the potassium salt of 2-acetylpyrrole [prepared
from 2-acetylpyrrole (6 mg, 0.06 mmol) and KH (3.2 mg, 0.08
mmol)]. The product is obtained as a dark red solid (5.7 mg,
32%). 1H NMR (400 MHz, CDCl3): δ 14.50 (br s, 1H), 12.50
(br s, 1H), 8.10 (m, 1H), 7.44 (m, 1H), 7.24 (m, 1H), 7.08 (br s,
1H), 6.50 (virt. quint. J ) 2.1, 1H), 6.40 (t, J ) 2.3, 1H), 4.21
(s, 3H), 2.67 (s, 3H). All other spectroscopic data are identical
to those reported in the literature.3a
Ack n ow led gm en t. H.W. is indebted to the Fonds
der Chemischen Industrie, Frankfurt, for a stipend.
2-Acetyl-1-(tr im eth ylsilyleth oxym eth yl)-1H-pyr r ole (24).
To a suspension of KH (48 mg, 1.20 mmol) in DMF (5 mL) is
added 2-acetylpyrrole (87 mg, 0.80 mmol). After stirring for 5
min at room temperature, SEMCl (0.29 mL, 1.6 mmol) is added
via syringe, and the resulting mixture is stirred for 1 h to reach
complete conversion. A standard extractive workup followed
Su p p or tin g In for m a tion Ava ila ble: Compilation of the
instrumentation used, list of IR and MS (EI) data, and copies
of NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O982088T