Formal syntheses of (-)- and (+)-phalarine

Article abstract of DOI:10.1002/anie.201006367

A core challenge: The asymmetric formal syntheses of the title compounds have been accomplished. By using a modular approach, phenolic tosylamide 1 was synthesized through palladium cross-couplings (blue bonds), and its participation in a hypervalent iodine mediated oxidative coupling reaction (red bonds) enabled the construction of the challenging heterocyclic core of (-)-phalarine. Copyright

Full text of DOI:10.1002/anie.201006367

Communications
DOI: 10.1002/anie.201006367
Natural Products
Formal Syntheses of (ꢀ)- and (+)-Phalarine**
Hanfeng Ding and David Y.-K. Chen*
Careful assessment of the chemical constituents in vegetation
is a critical process to ensure the safety of livestock. In a
recent chemical investigation of the perennial grass Phalaris
coerulescens, Colegate and co-workers reported the isolation
and structural elucidation of a novel furanobisindole alkaloid
that they subsequently named (ꢀ)-phalarine [(ꢀ)-1,
Scheme 1a].[1] Although the toxicity effect of this new class
tion, which then evolved into an effective hypervalent iodine
mediated oxidative cyclization process.
A cursory inspection of the molecular structure of (ꢀ)-
phalarine [(ꢀ)-1] immediately revealed its central heterocy-
clic framework containing the C4a–O and C9a–N linkages
and the C4a and C9a quaternary centers as the most daunting
challenges in our foreseeable synthetic campaign
(Scheme 1a; bond formations a). With a cascade process in
mind,[3] we were inspired by a recent report from the Muniz
group who had demonstrated a highly efficient palladium-
catalyzed oxidative coupling reaction engaging phenolic
tosylamide 4 to furnish the fused indoline dihydrobenzofuran
tetracycle 5 in 87% yield (Scheme 1b).[4] The structural
relationship between (ꢀ)-1 and tetracycle 5 was immediately
apparent, therefore, retrosynthetically, the targeted molecule
(ꢀ)-1 can be traced back to phenolic tosylamide 2 (accessed
through bond formations b) that can undergo a late-stage
expansion of its diol-containing cyclopentane ring to install
the N-methyl piperidine moiety of (ꢀ)-1. Finally, the optically
active and readily accessible cyclopentenone 3[5] was envis-
aged to provide traceless transfer of chirality to the C4a and
C9a stereogenic centers.
Scheme 1. a) Molecular structure of (ꢀ)-phalarine [(ꢀ)-1] and retrosyn-
As shown in Scheme 2, realization of the synthetic
strategy commenced with an iodination of the optically pure
cyclopentenone 3[5] to give the 2-iodo enone 6 in 64% yield.
Stille[6] cross-coupling between the iodide 6 and aryl stannane
ꢀ
thetic analysis leading to 2 and 3. b) Palladium-catalyzed tandem C N
[4a]
ꢀ
and C O bond formation reported by Muniz leading to 5.
DMF=N,N-dimethylformamide, Ts=toluenesulfonyl.
7
[6b] afforded 2-aryl enone 8, which was then subjected to 1,4-
of indole alkaloid is yet to be established, the intricate
molecular architecture of (ꢀ)-phalarine [(ꢀ)-1] presents an
enticing challenge to the synthetic community and an
opportunity to showcase the modern synthetic technologies
and strategies. Indeed, the Danishefsky group was the first to
accomplish this feat with an ingenious and highly instructive
approach to access 1 in its racemic form.[2b,c] The same group
subsequently formulated a strategy based on a traceless
transfer of chirality from l-tryptophan to achieve an asym-
metric synthesis.[2d] Herein we report the formal synthesis of
both (ꢀ)-1 and (+)-1 by using an approach inspired by a
palladium-catalyzed carbon–heteroatom bond-forming reac-
reduction using K-selectride to furnish the a-aryl ketone 9 in
86% yield as an inconsequential mixture of diastereoisomers
(ca. 11:1). The attachment of the second aryl unit onto 9 was
carried out under the Suzuki–Miyaura[7] conditions through
the intermediacy of the triflate 10 and boronic acid 11 to
deliver cyclopentene 12 in 83% yield. Conversion of the nitro
functionality within 12 into the corresponding tosylamide
took place uneventfully, through hydrogenation and subse-
quent tosyl protection of the aniline intermediate 13; the
tosylamide 14 was isolated in 94% yield over the two steps. In
preparation for the crucial oxidative double cyclization to cast
the indoline dihydrobenzofuran core of (ꢀ)-1, the BOM-
protected phenolic hydroxy group within 14 was liberated
under hydrogenolysis conditions to furnish the phenolic
tosylamide 15 in 87% yield.
[*] Dr. H. Ding, Prof. Dr. D. Y.-K. Chen
In accordance to the conditions reported by Muniz,[4a]
indeed, substrate 15 underwent palladium-catalyzed oxida-
tive double cyclization to afford the targeted phalarine
framework as a mixture of diastereoisomers (16/16’ ca.
1.4:1), despite the disappointing 12% yield (Table 1,
entry 1). With this initial result in hand, we set out to
optimize this key reaction and our findings are summarized in
Table 1. Changing the source of the oxidant from a hyper-
valent-iodine-based reagent (PIDA) to CuBr2 (entry 2) or
molecular oxygen (entry 3) had no beneficial effect on the
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and
Engineering Sciences (ICES) Agency for Science
Technology and Research (A*STAR), 11 Biopolis Way
The Helios Block, #03-08, Singapore 138667 (Singapore)
Fax: (+65)6874-5869
E-mail: david_chen@ices.a-star.edu.sg
[**] We thank Doris Tan (ICES) for high-resolution mass spectrometric
(HRMS) assistance. Financial support for this work was provided by
A*STAR, Singapore.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006367.
676
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 676 –679

Scheme 2. Formal syntheses of (ꢀ)- and (+)-phalarine [(ꢀ)- and [(+)-
1]. Reagents and conditions: a) I2 (1.5 equiv), py (2.0 equiv), 4-DMAP
(0.2 equiv), CH2Cl2, 258C, 3 h, 64%; b) 7 (1.2 equiv), [PdCl2(PhCN)2]
(0.05 equiv), AsPh3 (0.1 equiv), CuI (0.1 equiv), NMP, 708C, 2.5 h,
63%; c) K-selectride (1.0m in THF, 1.5 equiv), THF, 58C, 15 min, 86%
(ca. 11:1 mixture of diastereoisomers by 1H NMR); d) NaH (60%
wt/wt, 2.0 equiv), PhNTf2 (1.5 equiv), DMF, 08C, 3 h, 90%; e) 11
(1.5 equiv), [Pd(PPh3)4] (0.1 equiv), Na2CO3 (6.6 equiv), THF/H2O
(5:1), 708C, 2.5 h, 83%; f) H2, Pd/C (10% wt/wt, 0.49 equiv), EtOH,
258C, 1.5 h; g) TsCl (2.0 equiv), py (10.0 equiv), CH2Cl2, 258C, 12 h,
94% over two steps; h) H2, Pd(OH)2 (20% wt/wt, 0.93 equiv), EtOAc,
258C, 1.5 h, 87%; i) AcOH/H2O (4:1), 258C, 20 h, 63% (75% brsm);
j) PIFA (1.2 equiv), CH2Cl2, ꢀ5!08C, 30 min, 68% (ca. 9:1 mixture of
diastereoisomers by 1H NMR); k) Pb(OAc)4 (1.5 equiv), NaHCO3
(6.0 equiv), CH2Cl2, 08C, 15 min, filtered and concentrated; then
MeNH2 (1.0m in THF, 7.8 equiv), NaBH(OAc)3 (5.0 equiv), AcOH
(0.1 equiv), 1,2-dichloroethane, 258C, 48 h, 73%; l) Pb(OAc)4
(1.5 equiv), NaHCO3 (6.0 equiv), CH2Cl2, 08C, 15 min, filtered and
concentrated; then MeNH2 (1.0m in THF, 7.8 equiv), NaBH(OAc)3
(5.0 equiv), AcOH (0.1 equiv), 1,2-dichloroethane, 258C, 48 h, 71%.
4-DMAP=4-dimethylaminopyridine, BOM=benzyloxy methyl, K-selec-
tride=potassium tri-sec-butylborohydride, NMP=N-methyl-2-pyrroli-
done, PIFA=phenyliodine-bis-trifluoroacetate, py=pyridine, Tf=tri-
fluorosulfonyl, Ts=toluenesulfonyl, brsm=based on recovered start-
ing material.
and K3[Fe(CN)6] proved ineffective for this process, but
interestingly, the use of DDQ at elevated temperature gave
16ꢀ as the sole product in 21% yield (entry 13). Since the
variation in the reaction conditions had little effect on the
productivity and diastereoselectivity of the oxidative double
cyclization process, we turned our attention to alternative
phenolic tosylamide substrates to seek additional improve-
ments. We speculated that the steric environment around the
secondary alcohols residing on the cyclopentene ring may
have an influence on the diastereoselectivity of the cyclization
reaction. Indeed, whereas the acetonide 15a[9] and TBS ether
15b[9] showed little affect on the diastereoselectivity of the
reaction (entries 14 and 15), the diol 2 (prepared from
deketalization of 15, AcOH, 63% yield, 75% yield brsm)
displayed a significantly improved diastereoselectivity in
favor of the syn isomer (16c/16c’ ca. 3:1). Changing the
solvent from CH3CN to CH2Cl2 and performing the reaction
at ꢀ5!08C ultimately led to a 9:1 diastereoselectivity
(entry 17). Stereoisomerically pure diols 16c and 16c’ were
independently elaborated into the piperidines 17 and ent-17,
respectively, through a two-step procedure involving oxida-
tive diol cleavage and double reductive amination
(Scheme 2). All physical characteristics of the pentacycle 17
were identical to those reported by the Danishefsky group,[2d]
a key intermediate en-route to their asymmetric total syn-
thesis of (ꢀ)-phalarine [(ꢀ)-1]. Thus, the successful prepara-
tion of 17 and ent-17 constitute an asymmetric formal
synthesis of (ꢀ)-phalarine [(ꢀ)-1] and (+)-phalarine [(+)-
1], respectively.
reaction. However, we were pleasantly surprised to find that
the oxidative double cyclization also took place in the absence
of the palladium catalyst, giving a diastereomeric mixture of
16 and 16’ (ca. 1.4:1) in 30% yield (entry 4). This finding
subsequently channeled our interest and investigation to the
hypervalent iodine mediated oxidative cyclization process.[8]
The use of the more reactive PIFA reagent led to a notable
increase in the reaction yield (entry 5), but variation in the
solvent (entries 6–10) and reaction temperature (entries 11
and 12) had little influence on either the yield or diastereo-
selectivity of the reaction. Other oxidants such as I2, N-
iodosuccinimide, cerric ammonium nitrate, Ag2O, Pb(OAc)4,
Next, a working model was put forward to rationalize the
diastereoselectivities observed for the hypervalent iodine
mediated, oxidative double cyclization of the phenolic
tosylamides 15, 15a, 15b, and 2 (Scheme 3). We hypothesized
that in the presence of free secondary alcohols (e.g., 2),
PhI(OCOCF3)2 is likely to form a chelated species as depicted
Angew. Chem. Int. Ed. 2011, 50, 676 –679
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
677

Communications
Table 1: Oxidative double cyclizations of phenolic tosylamides 15–15b
and 2.
Entry Sub. Conditions
Product syn/
Yield
anti[b]
[%][a]
1
2
3
15
15
15
Pd(OAc)2 (0.2 equiv), PIDA (1.5 equiv),
CH2Cl2, 258C, 15 min
Pd(OAc)2 (0.2 equiv), CuBr2 (2.0 equiv), 10
K2CO3 (1.1 equiv), CH2Cl2, 258C, 48 h
Pd(OAc)2 (0.2 equiv), O2 (1 atm), NaOAc N.D.
(1.1 equiv), DMF, 258C, 24 h
12
1.4:1
1:1
–
4
5
6
7
15
15
15
15
PIDA (1.5 equiv), CH2Cl2, 258C, 15 min
PIFA (1.5 equiv), CH2Cl2, 258C, 15 min
PIFA (1.5 equiv), CH3CN, 258C, 10 min
PIFA (1.5 equiv), CH3CN/H2O (20:1),
258C, 10 min
30
40
45
42
1.4:1
1.4:1
1.4:1
1.4:1
8
15
PIFA (1.5 equiv), CF3CH2OH, 258C,
15 min
N.D.
–
9
10
11
15
15
15
PIFA (1.5 equiv), THF, 258C, 15 min
PIFA (1.5 equiv), toluene, 258C, 15 min 40
21
1:1
1:2
1:1.3
PIFA (1.5 equiv), toluene, ꢀ5!08C,
51
54
21
42
60
46
68
35 min
12
13
14
15
16
17
15
15
PIFA (1.5 equiv), CH3CN, ꢀ5!08C,
30 min
DDQ (10 equiv), THF, 25!708C, 48 h
2:1
anti
only
1.1:1
15a PIFA (1.5 equiv), CH3CN, ꢀ5!08C,
30 min
15b PIFA (1. equiv), CH3CN, ꢀ5!08C,
1.4:1
3:1
30 min
2
2
PIFA (1.1 equiv), CH3CN, ꢀ5!08C,
15 min
PIFA (1.2 equiv), CH2Cl2, ꢀ5!08C,
9:1
30 min
Scheme 3. Working model for the diastereoselectivity observed in the
hypervalent iodine mediated oxidative double cyclization.
[a] Yields refer to chromatographically and spectroscopically homoge-
neous materials. [b] Determined by H NMR spectroscopic analysis of
1
the crude reaction mixture. The ratios are approximate. DDQ=2,4-
dichloro-5,6-dicyanobezoquinone, N.D.=not detected.
are likely to generate stabilized and equilibrating species (21–
ꢀ
by the intermediate 18. As a result of this coordination, the
phenol-containing aromatic ring is rotated away from pla-
narity with the cyclopentene olefin. This loss of planarity and
24) upon activation with PhI(OCOCF3)2. Sequential C N and
ꢀ
C O bond formations in 21 and 24 then give rise to the anti-
16’, anti-16a’, and anti-16b’, and syn-16, syn-16a, and syn-16b
oxidative double cyclization products. A competing pathway
leading to the formation of the spirocyclic dienone 25’ was
also observed; presumably through the conformationally
preferred dienone 23 wherein the electrostatic interaction is
minimized.
In summary the asymmetric formal total syntheses of (ꢀ)-
and (+)-phalarine [(ꢀ)- and (+)-1] have been accomplished.
The developed synthetic sequence featured a modular
assembly of the phenolic tosylamide 2, and a hypervalent
ꢀ
subsequent C O bond formation with concomitant liberation
of PhI generates the intermediate 19 and its resonance
ꢀ
stabilized form 20. Finally, C N bond formation preferen-
tially delivered the syn-isomer 16c as a consequence of the
initially formed coordinated species 18. The enhancement in
diastereoselectivity upon changing solvent from CH3CN
(Table 1, entry 16) to CH2Cl2 (entry 17) is also supportive of
the formation of the chelated substrate/PIFA complex 18 in a
nonpolar solvent. In contrast, the substrates 15, 15a, and 15b
678
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 676 –679

[3] a) K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun.
2003, 551 – 564; b) L. F. Tietza, G. Brasche, K. M. Gericke
Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
2006, p. 617; c) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger,
Angew. Chem. 2006, 118, 7292 – 7344; Angew. Chem. Int. Ed.
2006, 45, 7134 – 7186.
[4] a) K. Muꢀiz, J. Am. Chem. Soc. 2007, 129, 14542 – 14543. For
related palladium-catalyzed vicinal aminoalkoxylation reactions
of alkenes: b) E. J. Alexanian, C. Lee, E. J. Sorensen, J. Am.
Chem. Soc. 2005, 127, 7690 – 7691; c) G. Liu, S. S. Stahl, J. Am.
Chem. Soc. 2006, 128, 7179 – 7181; d) L. V. Desai, M. S. Sanford,
Angew. Chem. 2007, 119, 5839 – 5842; Angew. Chem. Int. Ed.
2007, 46, 5737 – 5740; e) P. Szolcsꢁnyi, T. Gracza, Chem. Commun.
2005, 3948 – 3950.
iodine mediated oxidative double cyclization inspired by
palladium (IV) chemistry. The synthetic strategy disclosed
herein should find application beyond the synthesis of
phalarine, and enable the preparation of rationally designed
molecules having this privileged scaffold, for chemical and
biological investigations. Furthermore, mechanistic studies
and application of the hypervalent iodine mediated oxidative
double cyclization is currently in progress.
Received: October 11, 2010
Published online: December 15, 2010
Keywords: cross-coupling · natural products · palladium ·
[5] W. Li, X. Yin, S. W. Schneller, Bioorg. Med. Chem. Lett. 2008, 18,
220 – 222.
.
total synthesis
[6] a) L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133 – 173. For
preparation of the stannane 7, see: b) T. Ohshima, Y. Xu, R.
Takita, M. Shibasaki, Tetrahedron 2004, 60, 9569 – 9588.
[7] S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633 –
9695.
[1] N. Anderton, P. A. Cockrum, S. M. Colegate, J. A. Edgar, K.
Flower, D. Gardner, R. I. Willing, Phytochemistry 1999, 51, 153 –
157.
[2] a) C. Chan, C. Li, F. Zhang, S. J. Danishefsky, Tetrahedron Lett.
2006, 47, 4839 – 4841; b) C. Li, C. Chan, A. C. Heimann, S. J.
Danishefsky, Angew. Chem. 2007, 119, 1466 – 1469; Angew. Chem.
Int. Ed. 2007, 46, 1444 – 1447; c) C. Li, C. Chan, A. C. Heimann,
S. J. Danishefsky, Angew. Chem. 2007, 119, 1470 – 1472; Angew.
Chem. Int. Ed. 2007, 46, 1448 – 1450; d) J. D. Trzupek, D. Lee,
B. M. Crowley, V. M. Marathias, S. J. Danishefsky, J. Am. Chem.
Soc. 2010, 132, 8506 – 8512.
[8] A palladium-free oxidative aminoacetoxylation of alkene in the
presence of hypervalent iodine reagent under acidic conditions
was observed by Sorensen and co-workers, see Ref. [4b].
[9] The acetonide 15a and TBS ether 15b were prepared from ketal
14 by a three-step procedure, involving deketalization, either
acetonide formation (for 15a) or TBS protection (for 15b), and
removal of the BOM ether. For details, see the Supporting
Information.
Angew. Chem. Int. Ed. 2011, 50, 676 –679
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
679