Substituted 2,2′-bipyrroles and pyrrolylfurans via intermediate isoxazolylpyrroles

Article abstract of DOI:10.1016/j.tetlet.2013.03.034

We describe a new synthesis of the 3-chloro-(4′-methoxy)-2,2′- pyrrolylfuran segment (3) of (+)-roseophilin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as a β-diketone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole. Subsequent reduction of the N-O bond and acid promoted cyclization afford roseophilin segment 3b in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(4′-alkoxy)-2,2′-pyrrolylfurans (16a-c) and 4-alkoxy-2,2′-bipyrroles (20a-c), which are building blocks to synthesize bioactive prodiginine natural products and their congeners.

Full text of DOI:10.1016/j.tetlet.2013.03.034

Tetrahedron Letters 54 (2013) 2645–2647
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Substituted 2,20-bipyrroles and pyrrolylfurans via intermediate
isoxazolylpyrroles
⇑
James H. Frederich, Jennifer K. Matsui, Randy O. Chang, Patrick G. Harran
Department of Chemistry and Biochemistry, University of California at Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095, United States
a r t i c l e i n f o
a b s t r a c t
We describe a new synthesis of the 3-chloro-(40-methoxy)-2,20-pyrrolylfuran segment (3) of (+)-roseo-
philin. The route exploits a isoxazoylpyrrole intermediate, wherein the isoxazole ring serves as a b-dike-
tone equivalent and a directing group for palladium catalyzed chlorination of the attached pyrrole.
Subsequent reduction of the N–O bond and acid promoted cyclization afford roseophilin segment 3b
in five steps and 19% overall yield. This strategy was extended to the synthesis of 3-chloro-(40-alkoxy)-
2,20-pyrrolylfurans (16a–c) and 4-alkoxy-2,20-bipyrroles (20a–c), which are building blocks to synthesize
bioactive prodiginine natural products and their congeners.
Article history:
Received 26 February 2013
Accepted 7 March 2013
Available online 16 March 2013
Keywords:
Prodiginine
Isoxazole
C–H bond functionalization
3-Alkoxyfurans
3-Chloro-(40-alkoxy)-2,20-pyrrolylfuran
Ó 2013 Elsevier Ltd. All rights reserved.
As part of a program to synthesize (ꢀ)-marineosin A (1),1 (+)-
roseophilin (2),2 and related complex prodiginines, we had occa-
sion to revisit the problem of preparing selectively functionalized
2,2-bipyrroles and pyrrolylfurans (Fig. 1). Roseophilin segment 3
is a benchmark in this area.3 Its 3,40-substitution pattern presents
an atypical challenge. Published syntheses of structures 3a4 and
3b5 require 8 and 12 steps, respectively. For our purposes, we
sought more concise and generic access to targets 4, wherein X,
Y, and R groups could be varied along a common reaction
sequence.
In line with Terishima’s original approach to 3a, the alkoxy
substituted heterocycle in 4 was viewed as an enolic derivative
of its keto tautomer 5, which itself is a cyclocondensation product
of a functionalized b-diketone.5 However, rather than append an
acyclic b-diketone to a substituted pyrrole, we planned a ring-to-
ring conversion to generate the requisite heterocycle. The isoxazole
in 6 could serve as a b-diketone equivalent, wherein mild reduction
of the N–O bond unveils an intermediate able to convert into 4 by
way of 5.6,7 This strategy had the benefit of positioning a non-con-
jugated nitrogen lone pair proximal to C3 of the pendant pyrrole in
6, an arrangement that lends itself to directed C–H bond function-
alization.8 We could therefore plan routes to 4 that required no ini-
tial tailoring of the pyrrole ring.
To prepare pyrrolylfuran 3b along these lines, commercial dib-
romoformaldoxime (7)9 was reacted with benzyl propargyl ether
(8) to afford 3-bromoisoxazole 9 in high yield (Scheme 1).10 Subse-
quent Sadighi cross-coupling11 with in situ generated pyrrolylzinc
chloride gave pyrrolylisoxazole 10.12 The pyrrole in 10 was then
converted into a triisopropylsilyl derivative (11) and treated with
NCS in the presence of catalytic amounts of Pd(OAc)2. This pro-
vided chlorinated pyrrole 12 in 57% isolated yield.13 Regioisomeric
mono-chlorides and/or products resulting from over-chlorination
were not detected in the crude reaction mixture.14 In contrast,
when 11 was subjected to the same reaction conditions in the ab-
sence of Pd(OAc)2, a mixture of chlorinated products was isolated
along with recovered starting material (ca. 50%). These results
Figure 1. An approach to synthesize selectively functionalized 2,20-pyrrolylfurans
and bipyrroles employing an isoxazole ring as a directing group and b-diketone
synthon.
⇑
Corresponding author. Tel.: +1 310 825 6578; fax: +1 310 206 0204.
E-mail address: harran@chem.ucla.edu (P.G. Harran).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.034

2646
J. H. Frederich et al. / Tetrahedron Letters 54 (2013) 2645–2647
Table 1
Preparation of 3-chloro-(40-alkoxy)-2,20-pyrrolylfurans 3b and 15a–d
Entrya
R–OH
Acid
R
Yieldb (%)
1c
2d
3
MeOH
MeOH
MeOH
MeOH
PhCH2OH
CF3CH2OH
H2CCHCH2OH
i-PrOH
HCl
Me (3b)
Me (3b)
Me (3b)
Me (3b)
Bn (15a)
CH2CF3 (15b)
allyl (15c)
i-Pr (15d)
0
TsOHꢁH2O
31
89
85
83
85
72
<10
CSA
4e
5
PPTS
CSA
CSA
CSA
CSA
6
7
8f
Scheme 1. Regioselective synthesis of 3-chloro-pyrrolylisoxazole 13. Reagents and
conditions: (a) 8 (1.2 equiv), 1 M KHCO3, DME, rt, 6 h 94%; (b) pyrrole (4 equiv), NaH
(4 equiv), DMF, rt, 4 h; ZnCl2 (4 equiv), rt, 1 h; 10 mol % Pd2dba3, 10 mol % X-Phos,
DMF, 100 °C, 16 h 49%; (c) KH (1.1 equiv), 18-crown-6 (1.1 equiv), THF, rt, 1 h;
TIPSOTf, rt 18 h, 82%; (d) NCS (1.05 equiv), 12 mol % Pd(OAc)2, MeCN, reflux, 8 h,
57%; (e) CsF, THF:H2O (10:1), rt, 2 h, >95%.
a
General conditions: 12 (1.5 mmol), 10 mol % Pd/C, H2 (1 atm) 0.5 M MeOH, rt,
3 h; acid (1.1 equiv), 0.2 M 1:1 R–OH/(CH2Cl)2, rt.
b
Isolated yield ( 3%).
0.2 M HCl in MeOH.
Mass balance was primarily desilylated 3b.
Requires 10 h reaction time.
c
d
e
f
Cyclodehydration performed at 50 °C, 18 h.
are consistent with directed, Pd-catalyzed functionalization of the
C3–H bond during formation of 12.15 The structure of 12 was con-
firmed by X-ray crystallographic analysis of desilylated material
13.16 The sequence from 7 to 12 was easily executed on multi-
gram scale.
amine (18) provided isoxazole 19 in high yield.21 When 19 was ex-
posed to 1 equiv Mo(CO)6 in wet MeCN22 and the resultant crude
reduction product treated with CSA (0.5 M in MeOH), target meth-
oxypyrrole 20a was isolated in 81% yield. Analogous to results
shown in Table 1, changing the alcohol vehicle for CSA treatment
allowed congeners 20b and 20c to be prepared in good yield.23
In summary, we have developed new, concise routes to linked
heterocycles 4, wherein X, Y, and R groups can be controllably var-
ied. By utilizing an isoxazole as a b-diketone equivalent, 3-chloro-
(40-alkoxy)-2,20-pyrrolylfurans can be accessed using directed C–H
bond functionalization. This considerably simplifies the prepara-
tion of roseophilin segment 3b. We anticipate variations of the di-
rected functionalization will allow for incorporation of aryl and
alkyl groups at C3 of the target heterocycles.24,25 Lastly, we have
With 12 in hand, we explored conditions to convert the ben-
zyloxymethylated isoxazole into a methoxyfuran. Hydrogenolysis
of 12 over 10% Pd/C in MeOH (0.5 M) reduced the isoxazole N–O
bond and cleaved the benzyl ether to afford enaminone 14. Crude
solutions of this unstable substance were filtered to remove solids
and immediately treated with Brønsted acids in attempts to gener-
ate the target furan. The results of these experiments are summa-
rized in Table 1. The use of methanolic HCl caused decomposition
(entry 1). However, treatment with an equivalent of TsOHꢁH2O
gave desired pyrrolylfuran 3b in 31% yield within 15 min. The mass
balance was largely desilylated 3b. Camphor sulfonic acid (CSA)
and pyridinium p-toluene sulfonate (PPTS) provided more con-
trolled reactions, affording 3b in 89% and 86% yields, respectively
(entries 3 and 4). CSA had the added advantage of shorter reaction
times (1–2 h) at rt.
When unpurified solutions containing 14 were evaporated and
dissolved in other alcohols prior to acid treatment, various alkoxy
groups could be incorporated into the target heterocycle (entries
5–7). A variety of primary alcohols were tolerated, providing high
yields of products 15a–c. However, to date, secondary alcohols are
unreactive using these conditions (entry 8).17 Further studies
aimed at more general introduction of alkoxy and thiol groups in
this reaction are ongoing.
demonstrated
a
straightforward synthesis of 4-methoxy-2,20-
bipyrrole 20a (four steps, 70% overall yield) and related alkoxy
congeners. The use of this chemistry to support total syntheses
of (ꢀ)-1 and (+)-226 is the subject of on-going experiments.
Having completed a versatile synthesis of roseophilin segment
3b (five steps, 19% overall yield), we sought to adapt the route to
syntheses of 4-alkoxy-2,20-bipyrroles (Scheme 2). 4-methoxy-
(2,20-bipyrrole) carboxaldehyde (MBP, 16) is a key intermediate
for the synthesis of prodiginines.18 Tripathy and coworkers have
developed a three-step synthesis of 16 (36% overall yield) from
4-methoxy-3-pyrolin-2-one and N-Boc-pyrrole.19 Decarbonylated
variants of 16 are less conveniently available.20 Toward this end,
commercial pyrrole-2-carboxaldehyde was converted into N-tosyl
oxime 17 in two-steps. Both reactions scaled effectively
(>100 mmol) and provided crystalline 17 (toluene/hexanes;
mp = 136–138 °C) as a 2:1 mixture of geometric isomers in 92%
yield. Generating a nitrile oxide from this material in situ with
aqueous NaOCl in the presence of (tert-butoxycarbonyl)propargyl
Scheme 2. Synthesis of 4-alkoxy-2,20-bipyrroles 20a–c. Reagents and conditions:
(a) TsCl (1.1 equiv), i-Pr2NEt (1.5 equiv), 5 mol % DMAP, CH2Cl2, rt, 18 h; (b)
H2NOHꢁHCl (1.1 equiv), NaOAc (1.5 equiv), MeOH/H2O (10:1), rt, 2 h, 92% (two
steps); (c) 18 (1.3 equiv), 6.15% aq NaOCl, 10 mol % Et3N, CH2Cl2, 0 °C, 5 h, 94%. (d)
Mo(CO)6, MeCN/H2O (20:1), 85 °C, 3 h; 1:1 CH2Cl2/TFA, rt, 2 h; CSA (1.1 equiv),
0.2 M 1:1 R–OH/(CH2Cl)2, rt, 81%.

J. H. Frederich et al. / Tetrahedron Letters 54 (2013) 2645–2647
2647
14. The mass balance consisted primarily of a complex mixture of desilylated
chloropyrroles suggesting the TIPS group facilitates controlled catalysis.
15. (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523–
2526; (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Stanford, M. S. Tetrahedron 2006,
62, 11483–11498.
16. X-ray diffraction data for 13 have been deposited at The Cambridge
Crystallographic Data Center as entry CCDC 924179 and can be obtained free
of charge at www.ccdc.cam.ac.uk.
Acknowledgments
This research was supported by a program project grant from
the National Cancer Institute (PO1CA95471) and the Donald J.
and Jane M. Cram Endowment. R. Chang thanks the UCLA Under-
graduate Research Scholars Program for support. We thank Dr.
Saeed I. Kahn for X-ray crystallographic analysis of 13.
17. Exposure of crude 14 to CSA at ambient temperature in i-PrOH (0.5 M) afforded
no product after 10 h. Heating of the reaction mixture to 50 °C resulted in
decomposition.
18. (a) Rapoport, H.; Holden, K. G. J. Am. Chem. Soc. 1962, 84, 635–642; (b)
Rapoport, H.; Castagnoli, N. J. Am. Chem. Soc. 1962, 84, 2178–2181; (c) Boger, D.
L.; Patel, M. J. Org. Chem. 1988, 53, 1405–1415; (d) Wasserman, H. H.;
Lombardo, L. J. Tetrahedron Lett. 1989, 30, 1725–1728; (e) Wasserman, H. H.;
Xia, M.; Wang, J.; Petersen, A. K.; Jorgensen, M.; Power, P.; Parr, J. Tetrahedron
2004, 60, 7419–7425.
19. Dairi, K.; Tripathy, S.; Attardo, G.; Lavallée, J.-F. Tetrahedron Lett. 2006, 47,
2605–2606.
20. (a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8, 2007–2010;
(a) Jolicoeur, B.; Lubell, W. D. Org. Lett. 2006, 8, 6107–6110; (b) Jolicoeur, B.;
Lubell, W. D. Can. J. Chem. 2008, 86, 213–218.
21. Attempts to chlorinate N-tosyl pyrrole 19 using NCS and catalytic Pd(OAc)2
resulted in formation of the undesired 2-chloropyrrole as the major product.
For similar outcomes see Ref. 15b.
22. Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982, 877–878.
23. As outlined below, this route also provided access to 40-methoxy-2,20-
pyrrolylfuran 22. Consistent with our earlier observations, N-tosyl pyrrole 21
could not be regioselectively chlorinated via Pd-catalyzed C–H bond activation.
See Supplementary data for more detail.
Supplementary data
Supplementary data (experimental procedures and copies of 1H
and 13C NMR data for all new compounds) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.03.034.
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