A brief total synthesis of Pyrrolostatin

Article abstract of DOI:10.1016/j.tetlet.2016.05.010

A novel total synthesis of the unusual naturally occurring 2,4-disubstituted pyrrole, Pyrrolostatin 1, is described, which features formation of the central pyrrole ring by a recently developed silver(I)-catalysed 5-endo-dig cyclisation.

Full text of DOI:10.1016/j.tetlet.2016.05.010

Accepted Manuscript
A brief total synthesis of Pyrrolostatin
Damian G. Dunford, David W. Knight
PII:
S0040-4039(16)30519-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.010
TETL 47624
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 March 2016
20 April 2016
4 May 2016
Please cite this article as: Dunford, D.G., Knight, D.W., A brief total synthesis of Pyrrolostatin, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.010
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A brief total synthesis of Pyrrolostatin
Damian G. Dunford and David W. Knight*
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
_
_________________________________________________________________________________
Abstract- A novel total synthesis of the unusual naturally occurring 2,4-disubstituted pyrrole, Pyrrolostatin 1, is described,
which features formation of the central pyrrole ring by a recently developed silver(I)-catalysed 5-endo-dig cyclisation.
Keywords: Pyrrolostatin; synthesis; pyrroles; silver-catalysed; cyclisation.
Corresponding author: Tel. 02920 874210; Fax 02920 874030
E-mail: knightdw@cf.ac.uk

In contrast to the ubiquitous occurrence of tetrapyrroles in the form of haem and the chlorophylls and
their metabolites in almost all life forms, there are many fewer examples of naturally occurring
pyrroles that have come to light thus far. Probably the best known are the Prodigiosins
1
,2
(
Prodiginines), based on a pyrrolyl-dipyrromethane core, along with the unique Roseophilin in
1
which the central pyrrole residue is replaced by a furan. Monopyrroles are even rarer, thus far being
3
4
represented by Pyrrolostatin 1, together with the highly oxidised 3-farnesyl pyrrole, Glaciapyrrole A
5
and four unprecedented derivatives of 4-farnesyl-2-nitropyrrole –Nitropyrrolin A and the
6
Heronapyrroles A-C. Once again, the farnesyl side chain in these latter derivatives is also highly
oxidised by bis-hydroxylation and subsequent bis-tetrahydrofuran formation. The latter biosynthetic
idea has recently been beautifully illustrated in a polyene epoxide cascade synthetic sequence leading
7
to Heronapyrrole C. This contrasted with the somewhat dismal selectivities achieved in preparing
suitable 4-substituted-2-nitropyrroles or 4-substituted pyrrole-2 carboxylates, which resulted in an
8
entirely separate study in search of solutions to this problem. In fact, 2,4-disubstituted pyrroles in
general are a challenge to synthesise efficiently, a problem which clearly was encountered in Brimble
9
and co-workers recent successful alternative synthesis of Heronapyrrole C. The New Zealand group
were fortunately able to define suitable N-protecting groups and conditions to facilitate efficient 4-
iodination of 2-nitropyrrole derivatives.
CO H
2
1
N
H
Figure 1. The structure of Pyrrolostatin 1
Much the same is true of the only previously reported synthesis of pyrrolostatin 1 which, while being
agreeably brief, suffers from a very poor 18% yield in the key pyrrole forming step using the Barton-
10
Zard method. Given that pyrrolostatin possesses lipid peroxidation inhibitory activity on a par with

Vitamin E, it is a worthwhile target, especially in view of its close relationship with the foregoing
oxidized farnesylpyrrole derivatives.
We have recently developed an extremely efficient and general approach to pyrroles 3, including 2,4-
1
1
disubstituted examples, which features silver(I)-catalysed cyclisations of aminoalkynol derivatives 2
(
Scheme 1). We therefore reasoned that it should be possible to use this methodology in a relatively
brief synthesis of pyrrolostatin 1, hopefully in good overall yield. Herein, we report on the successful
outcome this idea.
R3
OH
R2
R2
AgNO -SiO
R3
3
2
o
N
R1
CH Cl , 20 C
2
2
R1 NHR4
R4
~100%
2
3
3 2
Scheme 1. Pyrrole formation from amino alkynol derivatives using AgNO -SiO .
Given that a key step would be a cyclisation of the type outlined in Scheme 1, an obvious
disconnection led back to aminoalkyne diol derivatives 4.
OR2
OH
1
NHX(O)R1
4
OR2
Br
M
6
5
O
NHX(O)R1
7
Scheme 2. The basic retrosynthetic plan.

Two further disconnections then seemed clear: firstly the geranyl chain would be introduced as an
electrophilic unit, most likely in the form of geranyl bromide 5, which would be followed by addition
of the alkyne unit as a nucleophile 6. This reasonably obvious strategy, however, then left an odd-
looking umpolung amino-ketone unit 7 (Scheme 2).
This naturally suggested a 1,3-dithiane intermediate; fortunately, such a species, in the form of dianion
1
2
8
, has been well studied by Seebach and colleagues. Given the correct solvents and conditions, it can
be readily formed from the corresponding neutral precursor 9 which, in turn, is prepared from
commercially available aminoacetaldehyde dimethyl acetal 10 (Scheme 3).
MeO
OMe
NH2
7
HS
S
S
S
NCO Me
NHCO Me
2
2
8
9
10
Scheme 3. Steps leading to the amino-dithiane nucleophile 8.
In the event, the first step proceeded smoothly: double deprotonation of the amino-dithiane 9, crucially
1
2
in the presence of DMPU, and addition of bromide 5 gave a reproducible 90% yield of the
homologous dithiane 11 (Scheme 4). Then the problems began: application of many of the standard
dithiane deprotection methods resulted in complete decomposition or generated intractable mixtures. It
was only when we realised just how sensitive the desired ketone (12) was that we were able to produce
1
3
it, in essentially quantitative yield, using the established N-chlorosuccinimide-silver nitrate method,
o
crucially with a work-up after two minutes at 0 C. Remarkably, prolonging the reaction to five
minutes resulted in essentially complete decomposition of the desired product, as did silica gel
chromatography, which happily was unnecessary.

n-BuLi
S
9
(
8) + 5
DMPU, THF
S
90%
NHCO Me
2
11
AgNO3
NCS
98%
o
aq. MeCN 0 C, 2 min.
O
NHCO Me
2
12
Scheme 4. The initial steps.
Subsequent nucleophilic addition of O-TBS-propargyl alcohol to the ketone 12 gave variable yields of
the desired aminoalkyne diol derivative 14, the best of which was around 85% when using the
o
Grignard species 13 at -10 C in THF, based on ca. 30% recovered ketone 12, which was separated
following rapid silica gel chromatography (Scheme 5). Many alternative metallated alkynes, including
lithiated and ceric species, proved less efficient.
We were then horrified to discover that the key aminoalkyne diol 14 was inert to silver nitrate on silica
gel (cf. Scheme 1). Fortunately, it appeared that this was due to excessive steric crowding, as the
corresponding deprotected diol 15 underwent perfectly smooth 5-endo-dig cyclisation when exposed
14
to AgNO -SiO to provide a quantitative yield of the 2-pyrrylmethanol 16 (Scheme 5). However, this
3
2
did require complete separation from any tetrabutylammonium fluoride and other by-products: it
appeared that any residual fluoride had a significant deleterious effect on the subsequent silver-
catalysed cyclisation. Due to it also being rather sensitive, there was some loss of the resulting diol 15
during the necessary column chromatographic purification; under optimum conditions (30-100%
EtOAc in hexanes), around an 80% yield of very pure material could be recovered.

OTBS
OR
HO
BrMg
13
12
NHCO Me
2
o
THF, - 10 C, 5h
1
4; R = TBDMS
5; R = H
TBAF, THF
o
20 C, 16h
1
80%
o
1
0%AgNO -SiO
CH Cl , 3 h, 20 C
3
2
2
2
~100%
OH
N
16
CO Me
2
Scheme 5. Homologation by alkyne addition and the key silver-catalysed step leading to the first pyrrole 16.
Completion of the synthesis then required oxidation and deprotection. Direct oxidation of the alcohol
1
5
1
6 to the corresponding acid 18 (as its methyl ester) using Corey’s MnO
2
-NaCN method failed,
perhaps because the resulting aldehyde is, in effect, a masked formamide. Happily, a standard two-step
1
6
combination of MnO and a Lindgren-Pinnick oxidation delivered an excellent overall yield of the 2-
2
pyrrolecarboxylic acid 18, via the isolated aldehyde 17 (Scheme 6). A final base-induced hydrolysis of
the carbamate group then gave Pyrrolostatin 1, which displayed spectroscopic and analytical data,
1
3
3,10
especially from its C spectrum, identical to those recorded previously.
OH
N
MnO , CH Cl
2
2
2
16
CO Me
2
>95%
O
N
17
NaClO2
CO Me
2
LiOH
aq. MeOH, 20 C
0%
CO H
2
1
N
o
18
CO Me
2
8

Scheme 6. Completion of the synthesis by oxidation.
A new synthesis of Pyrrolostatin 1 has thus been achieved, which delivers the natural product in
around 50% overall yield from the known dithiane 9.
Acknowledgements
We thank GSK Ltd and the EPSRC for financial support.
References and notes
1
2
Furstner, A. Angew. Chem. Int. Ed. 2003, 42, 3582; Bauer, J.; Knoelker, H.-J. Topics Curr. Chem. 2012, 309, 203.
For a remarkable example of stereochemical asymmetry in the this series, see Haynes, S. W.; Sydor, P. K.; Corre,
C.; Song, L.; Challis, G. L. J. Am. Chem. Soc. 2011, 133, 1793.
.
3
4
.
.
Kato, S.; Shindo, K.; Kawai, H.; Odagawa, A.; Matsuoka, M.; Mochizuki, J. J. Antibiot. 1993, 46, 892.
Macherla, V. R.; Liu, J.; Bellows, C.; Teisan, S.; Nicholson, B.; Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2005,
6
8, 780.
5
.
Kwon, H. C.; Espindola, A. P. D. M.; Park, J.-S.; Prieto-Davo, A.; Rose, M.; Jensen, P. R.; Fenical, W. J. Nat.
Prod. 2010, 73, 2047.
6
7
8
9
.
.
.
.
Raju, R.; Piggott, A. M.; Barrientos Diaz, L. X.; Khalil, Z.; Capon, R. J. Org. Lett., 2010, 12, 5158.
Schmidt, J.; Stark, C. B. W. Org. Lett. 2012, 14, 4042.
Schmidt, J.; Stark, C. B. W. J. Org. Chem. 2014, 79, 1920.
Ding, X.-B.; Furkert, D. P.; Capon, R. J.; Brimble, M. A. Org. Lett. 2014, 16, 378. For some alternative solutions,
see Kiren, S,; Hong, X.; Leverett, C. A.; Padwa, A. Org. Lett. 2009, 11, 1233; Barton, D. H. R.; Zard, S. Z. J.
Chem. Soc., Chem. Commun., 1985, 1098; Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46,
7
587; Sharland, C. M.; Knight, D. W.; Singkhonrat, J.; NajeebUllah, M.; Hayes, S. J.; Dunford, D. G. Tetrahedron
Lett. 2011, 52, 2320.
1
1
1
0.
1.
2.
Fumoto, Y.; Eguchi, T.; Uno, H.; Ono, N. J. Org. Chem. 1999, 64, 6518.
Rost, H. C.; Knight, D. W.; Sharland, C. M.; Singkhonrat, J. Tetrahedron Lett. 2007, 48, 7906.
Seebach, D.; Maestro, M. A.; Sefkow, M.; Neidlein, A.; Sternferd, F.; Adam, G.; Sommerfeld, T. Helv. Chim.
Acta 1991, 74, 2112.
1
3.
For a review, see Bulman Page, P. C.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643.

1
4.
(E)-Methyl 4-(3,7-dimethylocta-2,6-dienyl)-2-(hydroxymethyl)-1H-pyrrole-1-carboxylate 16: A solution of (E)-
methyl 2-hydroxy-2-(3-hydroxyprop-1-ynyl)-5,9-dimethyldeca-4,8-dienylcarbamate 15 (0.12 g, 0.38 mmol) in dry
dichloromethane (1 mL) was added to a suspension of 10% silver(I) nitrate on silica gel (0.07 g, 0.04 mmol) in
dichloromethane (1 mL), contained in a foil-wrapped flask, and the resulting mixture stirred at ambient
temperature for 3 h then filtered through a pad of celite. Evaporation of the filtrate and dichloromethane washings
gave pyrrole 16 (0.11 g, ~100%) as a pale orange oil, (400 MHz, CDCl ) 6.95 (1H, s, 5-H), 6.09 (1H, s, 3-H),
H
3
5
.29 (1H, br. t, J = 6.7 Hz, 2’-H), 5.12 (1H, br. t, J = 6.8 Hz, 6’-H), 4.64 (2H, s, CH OH), 3.97 (3H, s, OMe), 3.70
2
(
1H, br s, OH), 3.10 (2H, d, J = 7.2 Hz, 1’-CH ), 2.16-2.02 (4H, m, 4’- and 5’-CH ), 1.71 (3H, s, Me), 1.67 (3H, s,
2
2
Me), 1.63 (3H, s, Me); C (125 MHz, CDCl ) 151.9 (C=O), 136.4 (C), 135.1 (C), 131.5 (C), 126.4 (C), 124.2 (CH),
3
1
21.9 (CH), 118.0 (CH), 115.3 (CH), 57.6 (CH OH), 54.1 (OMe), 39.6 (1’-CH ), 26.5 (4’ or 5’-CH ), 25.7 (Me),
2
2
2
-
1
2
5.3 (4’- or 5’-CH ), 17.7 (Me), 16.0 (Me); /cm (CHCl ) 3408, 1733, 1444, 1349, 1280, 1252, 1100; m/z
2
max
3
(
APCI) 274 (M-H O, 100%). Found: M-H O, 274.1811. C H NO requires M, 274.1807.
2
2
17 24
2
1
1
5.
6.
Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968, 90, 5616; Foot, J. S.; Kanno, H.; Giblin, G.
M. P.; Taylor, R. J. K. Synthesis 2003, 1055.
Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888; Pinnick, H. Tetrahedron 1981, 37, 2091.
Graphical Abstract
A brief total synthesis of Pyrrolostatin
Damian G. Dunford and David W. Knight
A total synthesis of the unusual
naturally occurring 2,4-disubstituted
pyrrole, Pyrrolostatin, is described,
which features formation of the
central pyrrole ring by a silver(I)-
catalysed 5-endo-dig cyclisation.
CO H
2
N
H
Pyrrolostatin

The major highlights of this total synthesis are:
1
2
3
4
.
.
.
.
Efficient 2,4-disubstituted pyrrole synthesis by 5-endo-dig cyclisation.
The approach work to this key precursor is reasonably straightforward.
2,4-Disubstituted pyrroles are quite difficult to obtain regioselectively.
The overall yield from an easily-prepared and known precursor is around 50%.