Formal total synthesis of (-)-haouamine A

Article abstract of DOI:10.1039/b805295f

A largely catalysis based approach to optically active haouamine A (-)-1 is presented, which provides the hexacyclic compound 25 previously used to construct this cytotoxic marine alkaloid. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805295f

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COMMUNICATION
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Formal total synthesis of (ꢀ)-haouamine Awz
Alois Furstner* and Jens Ackerstaff
¨
Received (in Cambridge, UK) 28th March 2008, Accepted 29th April 2008
First published as an Advance Article on the web 2nd June 2008
DOI: 10.1039/b805295f
A largely catalysis based approach to optically active haouamine
A (ꢀ)-1 is presented, which provides the hexacyclic compound 25
previously used to construct this cytotoxic marine alkaloid.
tivity (Z : E 4 9 : 1, Scheme 1), which underwent an
asymmetric hydrogenation in the presence of the rhodium
catalyst 78 to set the directing stereocenter at C-17 exquisitely
well (97% 4 96% ee, 416 g scale). Slow addition of Dibal-H
to a solution of this compound in toluene at ꢀ78 1C afforded
the corresponding aldehyde which was subjected to a Wittig
olefination to give product 9 in good yield without loss of
optical purity (97% ee), provided that preformed Ph3PQCH2
was used as the reagent in toluene at 0 1C.9
Amine 10 released upon cleavage of the N-Cbz group in 9
underwent a smooth Petasis-type three-component coupling
reaction10 on exposure to formaldehyde and the functionalized
allylborane 19.11 The latter was best prepared from O-silylated
propargyl alcohol 16 via hydroboration with pinacolborane in
the presence of catalytic amounts of Cp2Zr(H)Cl,12 followed
Haouamine A (1) and B (2) isolated from the marine ascidian
Aplidium haouarianum collected off the coast of southern
Spain represent an unorthodox new class of alkaloids.1 They
consist of a congested indeno-tetrahydropyridine unit fused to
an 11-membered paracyclophane moiety which is so strained
that one of its phenol rings is forced out of planarity to adopt a
pseudo-boat conformation. The synthetic challenges posed by
this intricate topology are further increased by an anti-Bredt
double bond contained within the heptacyclic framework as
well as by the all-carbon quaternary chiral center at C-26. 1
exhibits significant and selective cytotoxicity against the
human colon carcinoma cell line HT-29 with an IC50 of
0.1 mg mLꢀ1 1
.
Although several elegant approaches toward the haouamines
have been reported in the literature,2 it was only through a
cleverly designed alkyne/pyrone Diels–Alder cycloaddition
that Baran and coworkers were able to overcome the deterrent
ring strain of these targets;3–5 more conventional attempts to
forge the bent aza-cyclophane motif invariably failed.2,3 We
now disclose a largely catalysis based approach to Baran’s
hexacyclic key intermediate 25 in optically pure form, which
therefore represents a formal total synthesis of the naturally
occurring enantiomer (ꢀ)-1.
Our synthesis commenced with 3-methoxybenzaldehyde 3,
which was selectively iodinated by following a literature
route.6 Reaction of 4 with phosphonate 57 in the presence of
DBU gave product 6 in good yield and high diastereoselec-
Max-Planck-Institut fur Kohlenforschung, D-45470 Mulheim/Ruhr,
¨
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
w Dedicated to Prof. Andrew B. Holmes on the occasion of his 65th
birthday.
z Electronic supplementary information (ESI) available: Experimental
part including analytical and spectroscopic data of all new compounds
and the crystallographic summary (CCDC 683071). For ESI and
crystallographic data in CIF or other electronic format see
DOI:10.1039/b805295f
Scheme 1 Reagents and conditions: (a) ref. 6; (b) 5, DBU, CH2Cl2,
86%; (c) complex 7 (1 mol%), H2 (20 atm), EtOAc, 97% (496% ee);
(d) Dibal-H, toluene, ꢀ78 1C, 90%; (e) Ph3PQCH2, toluene, 0 1C,
84%; (f) HBr–HOAc, CH2Cl2, 0 1C, 94%; (g) (i) [CH2O]n, borane 19,
toluene, 90 1C, 69% (ii) CbzCl, K2CO3, EtOAc–H2O, 94%; (h) (i)
second-generation Grubbs catalyst (5 mol%), toluene, 80 1C; (ii)
TBAF, THF, 89% (over both steps); (i) Dess–Martin periodinane,
NaHCO3, CH2Cl2, 85%; (j) Pd(OAc)2 (20 mol%), PPh3 (20 mol%),
Ag2CO3, MeCN, 65 1C, 75%; (k) CuI, 3-MeOC6H4MgBr, THF, 0 1C,
61–78%.
¨
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by an iridium catalyzed double bond isomerization
(Scheme 2).11 Borane 19 is sufficiently nucleophilic to intercept
the imine primarily formed from 10 and formaldehyde in
toluene at 90 1C to give product 11 as a mixture of diaster-
eomers after reprotection with CbzCl under standard condi-
tions. Subsequent ring closing olefin metathesis (RCM) with
the aid of the second-generation Grubbs catalyst,13 followed
by oxidation furnished ketone 12 in excellent overall yield and
set the stage for an intramolecular Heck reaction14 to complete
the core section of haouamine A.
Fig. 1 Molecular structure of 14 from single-crystal X-ray structure
determination.z Anisotropic displacement parameters are drawn at
50% probability and hydrogen atoms are omitted for clarity.
The Heck cyclization, however, required careful optimiza-
tion. Only in the presence of Ag2CO3 ( Z 1 eq.), which turned
out to be the best amongst various silver additives investi-
gated, could this palladium catalyzed C–C-bond formation be
reliably effected.15 The integrity of the resulting tricyclic
product 13 was confirmed by X-ray structure analysis of the
derived endo-configured alcohol 14 which turned out to be a
nicely crystalline compound (Fig. 1).
As expected, the palladium catalyzed reaction of the known
stannane 273 exclusively engaged the C–I bond of 1,2-dihalo-
benzene 26 in cross coupling (Scheme 4).20,21 Product 28 was
then stannylated to provide 29 as a suitably functionalized
building block for the completion of the formal total synthesis
of 1.22
The stereochemical course of the subsequent 1,4-addition of
3-methoxyphenylmagnesium bromide to enone 13 was deter-
mined by the adjacent stereocenter such that the required
cis-annulated ring system was exclusively formed. This reac-
tion was accomplished with the aid of purified CuI16 and
freshly prepared 3-MeOC6H4MgBr,17 whereas the use of other
copper sources and/or the corresponding lithium donor
suffered from lower yields, turned out to be less reproducible,
and was even plagued by competing 1,2- rather than 1,4-
addition to the hindered enone functionality of 13.
The Stille coupling of the sterically encumbered partners 23
and 29, however, was far from trivial (Scheme 3). Attempts to
induce coupling with catalytic [Pd(PPh3)4] alone engendered
rapid decomposition, and even the use of different copper
additives,2b,21,23 which are known to enhance the efficiency of
problematic Stille reactions, led to unacceptably low yields of
the desired compound. Therefore we were particularly pleased
to see that the combination of [Pd(PPh3)4] (5 mol%), copper
thiophene-2-carboxylate (CuTC)23a and the phosphinate salt
[Ph2PO2][NBu4]24 in DMF at ambient temperature resulted in
a remarkably clean formation of product 24. The scope of this
protocol, which has also served our group well in other
complex natural product syntheses,25 is described in more
detail in the accompanying Communication.26
Next, the regioselective conversion of ketone 15 into the
corresponding enol triflate was investigated as the prelude to
the final act of the formal total synthesis of 1 (Scheme 3). In
line with previous observations reported by Garst and co-
workers,18 treatment of 15 with various bases (KHMDS,
NaH, Et3N etc.) and different triflate sources invariably led
to enolization toward nitrogen with formation of 20 as the
major isomer. This undesirable outcome, however, could be
easily rectified by replacement of the N-Cbz group by the
3-butynyl chain that is required for the envisaged intramole-
cular alkyne/pyrone Diels–Alder cycloaddition. The lone pair
on the now basic nitrogen atom in 22 is thought to destabilize
the enolate formed upon deprotonation at C-1; hence, equili-
bration upon warm-up to 0 1C afforded the desired enol
triflate 23 as the only observed product upon treatment with
2-pyridyl–NTf2.19
Scheme 3 Reagents and conditions: (a) cf. Text; (b) Pd/C, H2 (1 atm),
MeOH, 94%; (c) TIPSCRC(CH2)2I, KHCO3, MeCN, 90 1C (sealed
tube), 70%; (d) KHMDS, THF, ꢀ78 1C - 0 1C, then 2-pyridyl–NTf2,
67% (86% based on recovered starting material); (e) stannane 29,
Pd(PPh3)4 (5 mol%), CuTC (1.5 eq.), [Ph2PO2][NBu4] (1.5 eq.), DMF,
65% (86% based on recovered substrate); (f) TBAF, aq. THF, 68%.
Scheme 2 Reagents and conditions: (a) pinacolborane, Cp2Zr(H)Cl
(0.5 mol%), CH2Cl2, 0 1C - RT, 70%; (b) complex 18 (1 mol%,
pre-activated with H2, 1 atm), THF, 80%.
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11. Y. Yamamoto, T. Miyairi, T. Ohmura and N. Miyaura, J. Org.
Chem., 1999, 64, 296.
12. (a) S. Pereira and M. Srebnik, Organometallics, 1995, 14, 3127;
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¨
14. S. Brase and A. de Meijere, in Metal-Catalyzed Cross-
Scheme 4 Reagents and conditions: (a) Pd(PPh3)4 (5 mol%), CuI
(10 mol%), CsF, DMF, 40 1C, 53%; (b) Me3SnSnMe3, Pd(PPh3)4
(5 mol%), toluene, reflux, 31%.
¨
Coupling Reactions, ed. A de Meijere and F Diederich, Wiley-
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15. Other protocols afforded appreciable amounts of the correspond-
ing saturated ketone rather than the desired enone. Under the
optimized conditions, however, the enone : ketone ratio was
Fluoride induced cleavage of the silyl group in product 24
thus formed gave the terminal alkyne 25. As this compound
was identical in all respects to the key intermediate used by
Baran and co-workers in their approach to 1,3,4 a total
synthesis of this intricate alkaloid in optically active form
has been accomplished.27 Despite a somewhat higher step
count, our catalysis based route is similarly productive and
compares favorably in terms of its inherent flexibility.28
Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank
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B1 : 1 mixture of the two possible enol triflates is formed. This
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´ ´
authentic sample for comparison, Dr C. Aıssa for his coopera-
¨
tion in the early stages of the project, Dr C. W. Lehmann for
the crystal structure analysis, Dr R. Mynott and Ms C. Wirtz
for expert NMR support, and Mr A. Deege and his team for
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Chem., Int. Ed., 2008, 47, 205. This paper also corrects the
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small amounts of product allowed us to confirm the absolute
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.
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This journal is The Royal Society of Chemistry 2008
2872 | Chem. Commun., 2008, 2870–2872