Synthetic study of pyrrocidines: First entry to the decahydrofluorene core of pyrrocidines

Article abstract of DOI:10.1021/ol3022116

The first synthesis of decahydrofluorene core 4 of pyrrocidines was accomplished. The cis,trans-fused tricyclic ring system was stereoselectively constructed via Diels-Alder reaction using two Danishefsky dienes.

Full text of DOI:10.1021/ol3022116

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4886–4889
Synthetic Study of Pyrrocidines: First
Entry to the Decahydrofluorene
Core of Pyrrocidines
Ryo Tanaka, Kentaro Ohishi, Noriyuki Takanashi, Tomohiko Nagano, Hiroshi Suizu,
Takahiro Suzuki, and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI),
2641Yamazaki, Noda-shi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received August 9, 2012
ABSTRACT
The first synthesis of decahydrofluorene core 4 of pyrrocidines was accomplished. The cis,trans-fused tricyclic ring system was stereoselectively
constructed via DielsÀAlder reaction using two Danishefsky dienes.
Pyrrocidine A (1) and B (2) were isolated from the
fermentation broth of a fungus, LL-Cyan 426.1 These
compounds exhibit significant antibiotic activities against
most Gram-positive bacteria, including drug-resistant
strains, and have been recognized as promising lead anti-
microbial agents.1,2 Recently, a dimeric pyrrocidine was
also isolated by the Shiono group.3 Structural features of
pyrrocidines include the following: (i) a cis,trans-fused
tricyclic decahydrofluorene core (ABC-ring) and (ii) a
13-membered macrocycle containing a γ-hydroxy-γ-lac-
tam ring and including a para-substituted aryl ether moi-
ety. Naturealsoproduces structurally related GKK1032s,4
hirsutellones,5 and pyrrospirones,6 which have a trans,
trans-fused ABC-ring system. The complex molecular
architecture of this family of compounds makes them very
attractive target molecules from a synthetic point of view.
Indeed, to date there have been numerous reports of
synthetic investigations involving a trans,trans-fused ABC-
ring system (GKK1032s,7 hirsutellones8). By contrast, there
have been no reports in the literature concerning synthesis
of the fully elaborated tricyclic decahydrofluorene core
of pyrrocidines.9 With the total synthesis of pyrrocidines
in mind, we initially attempted to establish a stereoselective
and scalable method for the synthesis of the cis,trans-
fused 6À5À6 tricyclic system. Herein, we describe the first
(7) Synthetic studies of GKK1032s: (a) Arai, N.; Ui, H.; Omura, S.;
Kuwajima, I. Synlett 2005, 1691. (b) Asano, M.; Inoue, M.; Katoh, T.
Synlett 2005, 1539. (c) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005,
2599. (d) Asano, M.; Inoue, M.; Watanabe, K.; Abe, H.; Katoh, T. J. Org.
Chem. 2006, 71, 6942. (e) Uchiro, H.; Kato, R.; Sakuma, Y.; Takagi, Y.;
Arai, Y.; Hasegawa, D. Tetrahedron Lett. 2011, 52, 6242. (f) Shiwaku, M.;
Nagae, K.; Noyama, C.; Shinkawa, T.; Miyazaki, Y.; Kurosaka, J.;
Munakata, R.; Takao, K.; Tadano, K. Symposium Papers, 48th Sympo-
sium on the Chemistry of Natural Products, Sendai, Japan, 2006; p 403.
(g) Shimizu, Y.; Takao, K;Tadano, K. Symposium Papers, 8thSymposium
on Organic Chemistry À The Next Generation, Tokyo, Japan, 2010; 38. (h)
Nagai, S.; Shimizu, Y.; Takao, K.; Tadano, K. Symposium Papers, 100th
Symposium on Organic Synthesis, Japan, Tokyo, Japan, 2011; 64.
(8) Total synthesis of hirsutellone B: (a) Nicolaou, K. C.; Sarlah, D.;
Wu, T. R.; Zhan, W. Angew. Chem., Int. Ed. 2009, 48, 6870. (b) Uchiro,
H.; Kato, R.; Arai, Y.; Hasegawa, M.; Kobayakawa, Y. Org. Lett. 2011,
13, 6268. Synthetic studies of hirsutellones: (c) Tilley, S. D.; Reber, K. P.;
Sorensen, E. J. Org. Lett. 2009, 11, 701. (d) Reber, K. P.; Tilley, S. D.;
Sorensen, E. J. Chem. Soc. Rev. 2009, 38, 3022. (e) Huang, M.; Huang,
C.; Liu, B. Tetrahedron Lett. 2009, 50, 2797. (f) Huang, M.; Song, L.;
Liu, B. Org. Lett. 2010, 12, 2504. (g) Halvorsen, G. T.; Roush, W. R.
Tetrahedron Lett. 2011, 52, 2072.
(1) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.;
Carter, G. T. Tetrahedron Lett. 2002, 43, 1633.
(2) Wicklow, D. T.; Poling, S. M. Phytopathology 2009, 99, 109.
(3) Shiono, Y.; Kosukegawa, A.; Koseki, T.; Murayama, T.; Kwon,
E.; Uesugi, S.; Kimura, K. Phytochem. Lett. 2012, 5, 91.
(4) Koizumi, F.; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara, M. Jpn.
Kokai Tokkyo Koho, JP 2001247574 A2 20010911, 2001; Chem. Abstr.
2001, 135, 209979.
(5) (a) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai,
S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (b) Isaka, M.;
Prathumpai, W.; Wongsa, P.; Tanticharoen, M. Org. Lett. 2006, 8, 2815.
(6) Shiono, Y.; Shimanuki, K.; Hiramatsu, F.; Koseki, T.; Tetsuya,
M.; Fujisawa, N.; Kimura, K. Bioorg. Med. Chem. Lett. 2008, 18, 6050.
(9) There has been only one report concerning the construction of the
cis-fused cyclohexene ring of pyrrocidines, see: Abdelkafi, H.; Evanno,
L.; Deville, A.; Dubost, L.; Chiaroni, A.; Nay, B. Eur. J. Org. Chem.
2011, 2011, 2789.
r
10.1021/ol3022116
Published on Web 08/31/2012
2012 American Chemical Society

Scheme 1. Retrosynthesis
ring system. The requisite cis-fused AB-ring moiety of 5
could be constructed by DielsÀAlder reaction between
DanishefskyÀKitahara diene 610 and bicyclo enone 7.11
The C-ring moiety in 7 could be synthesized by DielsÀ
Alder reaction between dimethyl-substituted Danishefsky
diene 812 and the doubly activated dienophile 9.13
Scheme 2. Synthesis of Ketone 11a
Our synthesis commenced with the construction of the
C-ring moiety (Scheme 2). Thus, DielsÀAlder reaction
between diene 8and dienophile 9, followed by acid treatment
in one pot, afforded a fully substituted cyclohexenone 10a,b
in 64% total yield (10a:10b = 1:0.7).14 The aldehyde group
of 10a,b was chemoselectively reduced with Zn(BH4)2, and
the resulting alcohol was then protected as a triethylsilyl
ether. The conventional Pd-catalyzed hydrogenation of the
mixture of two diastereomeric enones provided cyclohexa-
nones 11aÀc in 83% overall yield for three steps.15 The
obtained mixture of three diastereomers 11aÀc was sub-
jected to DBU-promoted epimerization of methyl groups
adjacent to the ketone moiety. Under thermodynamic con-
trol conditions, the desired ketone 11a was obtained (67%
yield) along with its stereoisomer 11b (29% yield). Undesired
ketone 11b was easily removed and could be recycled to 11a
under the same equilibrium conditions. The stereochemistry
of 11a and 11b was determined by NOE measurements.
Next, we turned our attention toward the transforma-
tion to bicyclic enone 7 (Scheme 3). The ketone 11a was
stereoselectively reduced with L-Selectride, and the resulting
stereoselective synthesis of decahydrofluorene 4, which
corresponds to the ABC-ring moiety of pyrrocidines.
Our retrosyntheticanalysisis illustratedinScheme 1. We
envisioned that pyrrocidines might be synthesized from
tricyclic hydroxyphenol 3 by formation of a 13-membered
ring via a Mitsunobu reaction and generation of a
γ-hydroxy-γ-lactam moiety. The cyclization precursor 3,
in turn, might be derived from key intermediate nitrile 4 via
the aldehyde by an aldol-type homologation. The stereo-
controlled access to cis,trans-fused decahydrofluorene
4 might be possible from tricyclic enone 5 by utilizing
the stereochemical characteristics of the cis,trans-fused
(12) Danishefsky, S.; Yan., C.-F.; Singh, R. K.; Gammill, R. B.;
McCurry, P. M., Jr.; Fritsch, N.; Clardy, J. J. Am. Chem. Soc. 1979,
101, 7001.
(13) Diene 8 was found to be less reactive with trisubstituted
olefin because of the steric hindrance of its two methyl groups. Thus,
electronically favored dienophile 9 was employed in the present study.
See ref 7d.
(14) The moderate yield of 10a-b was due to the competitive hetero-
DielsÀAlder reaction between the aldehyde function of 9 and diene 8 to
afford a diastereomeric mixture of dihydropyranones 21a,b(12%, dr = 1:1).
(10) Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth. 1983,
61, 147.
(11) Several research groups achieved excellent stereoselective synth-
eses of the trans-fused AB-ring in GKK1032s by using an intramolecular
DielsÀAlder reaction approach. However, the secondary orbital inter-
action between the diene HOMO and dienophile LUMO prevents the
construction of the cis-fused AB-ring in pyrrocidines. See ref 7dÀ7f.
(15) The hydrogenation of one diastereomer stereoselectively af-
forded the ketone 11b, while the other diastereomer afforded an almost
equimolecular mixture of 11a and its epimer 11c.
Org. Lett., Vol. 14, No. 18, 2012
4887

product 16a (16a:16b = 0.8:1). As expected, the angular
methyl group served to block the R-face of the dienophile
so that the diene approached from the β-face (Figure 1).
Mild acidic treatment of obtained 16a,b provided the
tricyclic diketone 5 in 85% overall yield for the two steps.
The stereochemistry of 5 was assigned by analysis of the
NOE spectra.
Scheme 3. Preparation of Bicyclic Enone 7
Scheme 4. Construction of the Tricyclic Diketone 5
alcohol 1216 was deoxygenated by the BartonÀMcCombie
protocol17 to give 13. In order to construct the cyclopente-
none moiety of 7, the triethylsilyl-protected hydroxymethyl
moiety of 13 was directly oxidized under Swern conditions,18
and the resulting aldehyde was homologated by Wittig
reaction to afford olefin 14. The ester group of 14 was
reduced to aldehyde through a reliable two-step transforma-
tion involving DIBALH reduction and Swern oxidation.
Sequential Grignard reactions proceeded stereoselectively
under FelkinÀAnh control to give allylic alcohol 15 in 70%
overall yield for four steps. The trans-fused bicyclic enone 7
was obtained by ring-closing metathesis using the Grubbs’
second-generation catalyst and DessÀMartin oxidation in a
one-pot reaction.19
Figure 1. Proposed transition state for the DielsÀAlder reaction.
Finally, the synthesis of decahydrofluorene 4 was ac-
complished (Scheme 5). The remaining task was to intro-
duce the requisite substituents in a stereoselective manner
to the A-ring moiety of 5. Prior to the manipulation of the
A-ring moiety, diketone 5 was stereoselectively reduced
withNaBH4 toaffordthe diol in 75% yield.20 The resulting
diol was then converted to enone 17 in two oxidation and
protection steps. R-Methylation of ketone and conjugate
addition of cyanide anion proceeded in a stereoselective
manner to afford nitrile 18 in 71% overall yield for the
two steps. The stereochemical course of the reaction can
be well explained by considering the cis-fused AB ring.
Installation of a vinyl group in the R-position of the ketone
With bicyclo enone 7 in hand, we next attempted the
key DielsÀAlder cycloaddition (Scheme 4). DanishefskyÀ
Kitahara diene 6 and cyclic dienophile 7 reacted at 110 °C
without solvent to afford the endo product 16b and the exo
(16) The resolution of (()-12 could be carried out by the formation of
diastereomeric esters using (R)-O-acetyl mandelic acid. The detailed
procedure of resolution and the determination of the absolute config-
uration of optically active 12 by the conversion to a known compound
are provided in the Supporting Information. In the present study,
racemic 12 was used for further transformation.
(17) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(18) Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetra-
´
(20) We also found that DIBALH reduction of diketone 5 afforded
the diol 24 as a major isomer. In contrast to NaBH4, the approach of
bulky DIBALH from the convex face might be less favorable due to the
presence of the angular methyl group. The present approach involves the
Mitsunobu reaction for the formation of a 13-membered ring. The
alternative Ullmann-type metal-catalyzed intramolecular arylation ap-
proach might also be possible using 24.
hedron Lett. 1999, 40, 5161.
(19) The most straightforward intramolecular aldol reaction of keto
aldehyde 22 afforded cis-fused compound 23 through the isomerization
of the initially formed trans-fused bicyclic enone 7 under basic
conditions.
4888
Org. Lett., Vol. 14, No. 18, 2012

Scheme 5. Synthesis of Decahydrofluorene 4
Figure 2. X-ray crystallography of xanthate 20.
the enolate.23 The β,γ-unsaturated ketone moiety was
converted to the pyrrocidine-type unconjugated diene as
follows. The ketone was reduced by sodium borohydride,
and the resulting β-alcohol was regioselectively dehydrated
by the Chugaev method24 to furnish the decahydrofluor-
ene 4 (64% yield from 19). The relativeconfiguration ofthe
intermediate xanthate 20 was unambiguously determined
through its X-ray crystallographic analysis (Figure 2).25
In conclusion, we have accomplished the synthesis of the
fully elaborated tricyclic decahydrofluorene core (ABC-
ring system) of pyrrocidines. Our results are significant for
the following reasons: (i) the present synthesis provides the
first entry to an ABC-ring moiety of pyrrocidines, and (ii)
DielsÀAlder reaction using two Danishefsky dienes was
employed to build the 6À5À6 tricyclic carbon skeleton. On
thebasisofthepresent results, furtherinvestigationtoward
the total synthesis of pyrrocidines is currently underway.
18 was best achieved by following the two-step procedure
described by Clive and Russel.21 The aldol reaction of
18 with phenylselenoacetaldehyde gave the β-hydroxy
ketone, whichwas convertedtothe β,γ-unsaturatedketone
19 upon treatment with methanesulfonyl chloride and
triethylamine (65% yield from 18). It was gratifying to
find that the stereochemistry of the vinyl group was the
same as that of pyrrocidines.22 This result indicates that
phenylselenoacetaldehyde approached from the concave
face of lithium enolate derived from 18. We reasoned that
the cyano group occupies a pseudoaxial orientation to
avoid the 1,2-allylic strain and shields the convex face of
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research (B) (KAKENHI
No.22390004) fromtheJapanSocietyforthe Promotion of
Science.
(21) Clive, D. L. J.; Russell, C. G. J. Chem. Soc., Chem. Commun.
1981, 434.
(22) The relative stereochemistry of 19 was elucidated by measure-
ment of NOESY correlations.
Supporting Information Available. Experimental de-
1
tails, H and 13C NMR spectra for all new compounds,
and X-ray data for the xanthate (CIF). This material
is available free of charge via the Internet at http://
pubs.acs.org.
(23) Our explanation was supported by the conformational analysis
of trimethylsilyl enolate derived from 18. The strong NOE interaction
between H-1 and H-2 was observed.
(24) (a) Chugaev, L. (Tschugaeff). Chem. Ber. 1899, 32, 3332.
(b) Depuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431. (c) Nace,
H. R. Org. React 1962, 12, 57.
(25) CCDC 894936 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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