Revisiting the Kinnel-Scheuer hypothesis for the biosynthesis of palau'amine

Article abstract of DOI:10.1039/c0cc02214d

We propose herein an alternative biosynthetic pathway for palau'amine in order to resolve the stereochemical issue from the original Kinnel-Scheuer hypothesis. Furthermore, we use this revised hypothesis as a guide toward the laboratory synthesis of palau

Full text of DOI:10.1039/c0cc02214d

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Revisiting the Kinnel–Scheuer hypothesis for the biosynthesis of
palau’aminewz
Zhiqiang Ma, Jianming Lu, Xiao Wang and Chuo Chen*
Received 29th June 2010, Accepted 3rd September 2010
DOI: 10.1039/c0cc02214d
We propose herein an alternative biosynthetic pathway for
palau’amine in order to resolve the stereochemical issue from
the original Kinnel–Scheuer hypothesis. Furthermore, we use
this revised hypothesis as a guide toward the laboratory synthesis of
palau’amine.
synthesized 9, a close analog of 8, in its protected form as a
step toward the laboratory synthesis of 1.
Central to our synthetic strategy is a Mn(III)-mediated
oxidative radical cyclization reaction,10,11 that, in an intra-
molecular way, resembles the biogenic [4+2] dimerization to
construct the cyclohexenyl core of 7 (Scheme 2). Specifically,
oxidation of b-ketoester 15 with Mn(OAc)3 initiated a cascade
radical cyclization sequence to deliver 16 that bears the
ageliferin skeleton. Two C–C bonds (C-11/C-20 and C-12/C-18)
and three stereogenic centers (C-11, C-12, and C-18) were
established in this single transformation.
Dimeric pyrrole-imidazole alkaloids1 form a class of structurally
unique marine natural products that have, over the past
decades, inspired chemists to develop numerous synthetic
strategies and methods.2,3 In particular, the recent completion
of the syntheses of the [3+2] dimers axinellamines,4
massadines,5 and palau’amine6 by the Baran group stands as
a landmark in modern synthesis. The biosynthetic pathway of
these pyrrole-imidazole dimers has also been proposed.7 We
present herein a plausible biosynthetic pathway of palau’amine
(1), and use it as a strategy for the laboratory synthesis of 1.
Kinnel, Scheuer, and co-workers have suggested in their
isolation paper that ‘‘palau’amine’’ (2) may arise from a [4+2]
cycloaddition of 3-amino-1-(2-aminoimidazolyl)prop-1-ene
(3) and 11,12-dehydrophakellin (4), followed by a chloro-
peroxidase-mediated chlorination and ring contraction
(Scheme 1).7cy However, the structure of palau’amine was
recently revised from 2 to 1.8 The C-11/C-12 anti stereo-
chemistry in 1 cannot easily be explained by this proposed
pathway. The thermal Diels–Alder reaction pathway will
result in a syn stereochemistry, and the photo Diels–Alder
reaction pathway is not likely considering the lack of sufficient
UV-light to the sponges.7a Meanwhile, the difficulty in
constructing the piperazine moiety of 1 at a late stage6,9
indicates that this transformation is highly endothermic, and
requires significant energy input. We therefore suspected
that the ring strain of 1 may be introduced stepwise, both
biosynthetically and synthetically.
To construct 15, we used a convergent approach that
comprises an aldol reaction between aldehyde 11 and ester
14 (LiHMDS, THF; 79% over three steps), and an alcohol
oxidation (Dess–Martin periodinane, H2O, CH2Cl2).
Aldehyde 11 was prepared in one-pot from imidazole (10)
(NaH, BOMCl, DMF, then NaH, CuCl2, O2, then POCl3;
68%). Ester 14 was prepared from coupling (DCC, CH2Cl2)
of Cbz-b-Ala-OH with the known alcohol 13, which was in
turn synthesized in two steps from Garner’s aldehyde (12)
((i) Ph3PQCHCOOMe, benzene; (ii) DIBAL, THF) according
to the literature.12
Treating b-ketoester 15 with Mn(OAc)3 in warm acetic acid
results in a quite clean transformation. The ageliferin core
skeleton 16 was obtained as the only diastereomer in 36%
yield over two steps from the aldol product of 11 and 14.13 The
stereochemical course of this reaction was controlled by the
C-10 stereogenic center through an A1,3 strain.10 The ester
tether, used for the intramolecular Mn(III) oxidation reaction,
was then removed. The decarboxylation (LiOH, THF, H2O)
of 16 gave rise to a product with cis-C-12/C-18 stereochemistry
as the thermodynamic product. The N-14 nitrogen atom
was then introduced as an azide by a Mitsunobu reaction
((PhO)2P(O)N3, DEAD, PPh3, THF; 42% for two steps). The
C-18 stereocenter was subsequently epimerized through
kinetic protonation of the corresponding enolate (LiHMDS,
THF, then HOAc) and the C-17 carbonyl group was
deoxygenated (Ca(BH4)2, THF,14 then NaBH3CN, HOAc)
to afford 17.
In addition to Baran’s macrocycle strategy,6 we consider the
original Kinnel–Scheuer hypothesis a viable pathway. To
reconcile the stereochemical issue of the [4+2] cycloaddition,
we propose the intermediacy of ageliferin analog 7 (Scheme 1).
Specifically, a [4+2] cycloaddition reaction of 3 and clathrodin
(6) would give rise to 7, and set the anti C-11/C-12 stereo-
chemistry. An oxidative bicyclization would then provide
the modified Kinnel–Scheuer intermediate 8, which could
undergo a chlorinative ring contraction to afford 1. We have
In order to implement the oxidative bicyclization strategy to
install the piperazine ring, we converted the C-11 side chain of
17 to an imidazolinone group by a three-pot procedure. The
acetonide protecting group was first removed (TFA, CH2Cl2)
and the resulting alcohol was oxidized (Dess–Martin periodinane,
H2O, CH2Cl2). The Boc protecting group was next removed
under acidic conditions, followed by in situ treatment of the
amino aldehyde with potassium cyanate at pH 4 to afford 18
(HCl, MeOH, H2O, then o-(HO2C)C6H4(CO2K), NaOH,
KOCN).15 It is noteworthy that Myers and co-workers
have previously reported that amino aldehydes are stable in
Department of Biochemistry, UT Southwestern Medical Center at
Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
E-mail: Chuo.Chen@UTSouthwestern.edu; Fax: 214 648 0320;
Tel: 214 648 5048
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c0cc02214d
c
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Chem. Commun., 2011, 47, 427–429 427

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Scheme 1 The original (top) and revised (bottom) Kinnel–Scheuer biosynthesis of palau’amine.
Scheme 2 The synthesis of 20, a close analog of the Kinnel–Scheuer intermediate. (a) NaH, BOMCl, DMF, 23 1C, then NaH, CuCl2, O2, 23 1C,
then POCl3, 23 1C; 68%. (b) Ph3PQCHCOOMe, benzene, 23 1C; 95%. (c) DIBAL, THF, 0 1C. (d) Cbz-b-Ala-OH, DCC, CH2Cl2, 23 1C.
(e) LiHMDS, THF, ꢀ78 1C; 79% over three steps. (f) Dess–Martin periodinane, H2O, CH2Cl2, 23 1C. (g) Mn(OAc)3, HOAc, 60 1C; 36% over two
steps. (h) LiOH, THF, H2O, 23 1C. (i) (PhO)2P(O)N3, DEAD, PPh3, THF, 23 1C; 42% over two steps. (j) LiHMDS, THF, then HOAc, ꢀ78-0 1C.
(k) Ca(BH4)2, THF, 0 1C, then NaBH3CN, HOAc, 50 1C. (l) TFA, CH2Cl2, 0 1C. (m) Dess–Martin periodinane, H2O, CH2Cl2, 23 1C.
(n) HCl, MeOH, H2O, 40 1C, then o-(HO2C)C6H4(CO2K), NaOH, KOCN, 110 1C. (o) PPh3, H2O, THF, 80 1C; 7–10% over 6 steps.
(p) (Br2-Pyrrole)COCCl3, NEt3, DMF, 70 1C; 33%. (q) PhIO, Na2CO3, TFE, 23 1C. (r) DMSO, 50 1C; 20% over two steps.
aqueous media below pH 5, with the aldehyde group existing
in its hydrate form.16 In our hands, buffering the aqueous
methanol solution of the amino aldehyde with potassium
hydrogen phthalate gave the best results.
With 18 in hand, we next sought to introduce the pyrrole
group and set the stage for the oxidative bicyclization. The
azido group was reduced by a Staudinger reduction (PPh3,
H2O, THF) and the product was obtained in 7–10% yield over
c
428 Chem. Commun., 2011, 47, 427–429
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6 steps after HPLC purification. The pyrrole group was then
installed ((Br2-Pyrrole)COCCl3, NEt3, DMF; 33%). Use of a
less pure amine for this reaction resulted in significantly less or
no product.
A. L. Zografos, Angew. Chem., Int. Ed., 2004, 43, 2674–2677;
(i) V. B. Birman and X.-T. Jiang, Org. Lett., 2004, 6, 2369–2371;
(j) H. Garrido-Hernandez, M. Nakadai, M. Vimolratana, Q. Li,
T. Doundoulakis and P. G. Harran, Angew. Chem., Int. Ed., 2005,
44, 765–769; (k) I. Kawasaki, N. Sakaguchi, A. Khadeer,
M. Yamashita and S. Ohta, Tetrahedron, 2006, 62, 10182–10192;
(l) M. S. Bultman, J. Ma and D. Y. Gin, Angew. Chem., Int.
Ed., 2008, 47, 6821–6824; (m) J. Hudon, T. A. Cernak,
J. A. Ashenhurst and J. L. Gleason, Angew. Chem., Int. Ed.,
2008, 47, 8885–8888.
4 (a) J. Yamaguchi, I. B. Seiple, I. S. Young, D. P. O’Malley,
M. Maue and P. S. Baran, Angew. Chem., Int. Ed., 2008, 47,
3578–3580; (b) D. P. O’Malley, J. Yamaguchi, I. S. Young,
I. B. Seiple and P. S. Baran, Angew. Chem., Int. Ed., 2008, 47,
3581–3583.
We previously reported a hypervalent iodine(III)-mediated
oxidative bicyclization reaction of dihydro-14-oxo-oroidin to
give dibromophakellstatin in quantitative yield.17 Pleasingly,
use of the same reaction conditions (PhI(OAc)2, Na2CO3,
TFE) to oxidize 19 did afford 20, though inconsistently in
0–5% yield. After extensive optimization, we found PhIO to
be a better oxidant, which gave rise to an unstable product
that slowly converted to the Kinnel–Scheuer intermediate
analog 20 at elevated temperature in DMSO in 20% yield
over two steps. A similar unstable intermediate, which was
suspected to be the monocyclized product, was also observed
5 S. Su, I. B. Seiple, I. S. Young and P. S. Baran, J. Am. Chem. Soc.,
2008, 130, 16490–16491.
6 I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi and
P. S. Baran, Angew. Chem., Int. Ed., 2009, 49, 1095–1098.
7 (a) R. P. Walker, D. J. Faulkner, D. V. Engen and J. Clardy,
J. Am. Chem. Soc., 1981, 103, 6772–6773; (b) P. A. Keifer,
R. E. Schwartz, M. E. S. Koker, J. R. G. Hughes, D. Rittschof
and K. L. Rinehart, J. Org. Chem., 1991, 56, 2965–2975;
(c) R. B. Kinnel, H.-P. Gehrken, R. Swali, G. Skoropowski and
P. J. Scheuer, J. Org. Chem., 1998, 63, 3281–3286; (d) A. Al
Mourabit and P. Potier, Eur. J. Org. Chem., 2001, 237–243;
(e) Ref. 3h; (f) B. H. Northrop, D. P. O’Malley, A. L. Zografos,
P. S. Baran and K. N. Houk, Angew. Chem., Int. Ed., 2006, 45,
by Buchi and co-workers when oxidizing dihydrooroidin with
¨
bromine to form dibromophakellin.15b,18
In summary, as part of our palau’amine synthesis project,
we have synthesized a close analog of the modified Kinnel–
Scheuer intermediate from their biosynthesis proposal. The
stereochemistry of this advanced synthetic intermediate is
consistent with the revised structure of palau’amine. The
biomimetic oxidative ring contraction of the Kinnel–Scheuer
intermediate has previously been realized in model systems in
the laboratory by Romo,3d Lovely,3c Baran19 and us.10 In
particular, the method developed by Romo allowed for the
introduction of the chlorine atom. We are currently examining
the practicality of these methods in converting advanced
synthetic intermediates such as 20 into palau’amine (1).
We thank the NIH (Grant NIGMS R01-GM079554), the
Welch Foundation (I-1596), and UT Southwestern for financial
support, and Prof. Joseph Fox (University of Delaware) for
the suggestion of the use of ethyltrichlorosilane-deactivated
silica gel.
4126–4130; (g) C. Poverlein, G. Breckle and T. Lindel, Org. Lett.,
2006, 8, 819–821.
¨
8 (a) M. S. Buchanan, A. R. Carroll, R. Addepalli, V. M. Avery,
J. N. A. Hooper and R. J. Quinn, J. Org. Chem., 2007, 72,
2309–2317; (b) M. S. Buchanan, A. R. Carroll and R. J. Quinn,
Tetrahedron Lett., 2007, 48, 4573–4574; (c) A. Grube and
M. Kock, Angew. Chem., Int. Ed., 2007, 46, 2320–2324;
¨
(d) H. Kobayashi, K. Kitamura, K. Nagai, Y. Nakao,
N. Fusetani, R. W. M. v. Soest and S. Matsunaga, Tetrahedron
Lett., 2007, 48, 2127–2129.
9 Z. Ma and C. Chen, unpublished results.
10 X. Tan and C. Chen, Angew. Chem., Int. Ed., 2006, 45, 4345–4348.
11 (a) B. B. Snider, Chem. Rev., 1996, 96, 339–363;
(b) G. G. Melikyan, Org. React., 1997, 49, 427–675.
12 (a) S. Lin, Z.-Q. Yang, B. H. B. Kwok, M. Koldobskiy,
C. M. Crews and S. J. Danishefsky, J. Am. Chem. Soc., 2004,
126, 6347–6355; (b) L. Devel, L. Hamon, H. Becker, A. Thellend
and A. Vidal-Cros, Carbohydr. Res., 2003, 338, 1591–1601.
13 While the crude 1H NMR indicated 16 to be the only significant
product, it was not stable to silica gel column chromatography,
leading to its diminished isolated yield. The stereochemistry of 16
was assigned based on the stereochemical studies from ref. 10, and
confirmed by ROESY experiments of subsequent synthetic
intermediates.
Notes and references
y This biosynthetic pathway was a ‘‘better alternative’’ suggested by a
reviewer of ref. 7c.
1 B. Forte, B. Malgesini, C. Piutti, F. Quartieri, A. Scolaro and
G. Papeo, Mar. Drugs, 2009, 7, 705–753.
2 (a) T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657–4673;
(b) B. Heasley, Eur. J. Org. Chem., 2009, 1477–1489;
(c) H.-D. Arndt and M. Riedrich, Angew. Chem., Int. Ed., 2008,
14 (a) J. Kollonitsch, O. Fuchs and V. Gabor, Nature, 1954, 173,
´
125–126; (b) H. C. Brown, S. Narasimhan and Y. M. Choi, J. Org.
Chem., 1982, 47, 4702–4708.
15 (a) K. J. Wiese, K. Yakushijin and D. A. Horne, Tetrahedron Lett.,
47, 4785–4788; (d) M. Kock, A. Grube, I. B. Seiple and P. S. Baran,
¨
Angew. Chem., Int. Ed., 2007, 46, 6586–6594; (e) D. E. N. Jacquot
and T. Lindel, Curr. Org. Chem., 2005, 9, 1551–1565;
(f) H. Hoffmann and T. Lindel, Synthesis, 2003, 1753–1783.
3 For example: (a) L. E. Overman, B. N. Rogers, J. E. Tellew and
W. C. Trenkle, J. Am. Chem. Soc., 1997, 119, 7159–7160;
(b) J. T. Starr, G. Koch and E. M. Carreira, J. Am. Chem. Soc.,
2000, 122, 8793–8794; (c) C. J. Lovely, H. Du and H. V. R. Dias,
Org. Lett., 2001, 3, 1319–1322; (d) A. S. Dilley and D. Romo, Org.
Lett., 2001, 3, 1535–1538; (e) I. Kawasaki, N. Sakaguchi,
N. Fukushima, N. Fujioka, F. Nikaido, M. Yamashita and
2002, 43, 5135–5136. See also: (b) L. H. Foley and G. Buchi, J. Am.
¨
Chem. Soc., 1982, 104, 1776–1777; (c) Ref. 3g.
16 A. G. Myers, D. W. Kung and B. Zhong, J. Am. Chem. Soc., 2000,
122, 3236–3237.
17 (a) J. Lu, X. Tan and C. Chen, J. Am. Chem. Soc., 2007, 129,
7768–7769. See also: (b) K. S. Feldman and A. P. Skoumbourdis,
Org. Lett., 2005, 7, 929–931; (c) Ref. 15a; (d) Ref. 15b.
18 Besides Buchi’s proposed formation of a C-10/N-14 linkage in
¨
ref. 15b for his dibromophakellin synthesis, it is also possible that a
N-1/C-6 macrocycle, resembling Baran’s palau’amine intermediate
40 in ref. 6, was formed during the oxidation of 19.
S.
Ohta,
Tetrahedron
Lett.,
2002,
43,
(f) S. G. Koenig, S. M. Miller, K. A. Leonard, R. S. Lowe,
4377–4380;
¨
B. C. Chen and D. J. Austin, Org. Lett., 2003, 5, 2203–2206;
(g) P. S. Baran, A. L. Zografos and D. P. O’Malley, J. Am. Chem.
Soc., 2004, 126, 3726–3727; (h) P. S. Baran, D. P. O’Malley and
19 D. P. O’Malley, K. Li, M. Maue, A. L. Zografos and P. S. Baran,
J. Am. Chem. Soc., 2007, 129, 4762–4775.
c
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Chem. Commun., 2011, 47, 427–429 429