Use of a tandem Prins/Friedel-Crafts reaction in the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids: Formal synthesis of (-)-haouamine A

Article abstract of DOI:10.1021/ol200725m

A tandem Prins/Friedel-Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (-)-haouamine A are described.

Full text of DOI:10.1021/ol200725m

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2614–2617
Use of a Tandem Prins/FriedelꢀCrafts
Reaction in the Construction of the
Indeno-Tetrahydropyridine Core of the
Haouamine Alkaloids: Formal Synthesis
of (ꢀ)-Haouamine A
ꢀ
Erik Fenster, Charlie Fehl, and Jeffrey Aube*
KU Chemical Methodologies and Library Development Center, University of Kansas,
2121 Simons Drive, Lawrence, Kansas 66047, United States
jaube@ku.edu
Received March 17, 2011
ABSTRACT
A tandem Prins/FriedelꢀCrafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal
synthesis of (ꢀ)-haouamine A are described.
Haouamines A and B were isolated in 2003 from a
marine ascidian (Aplidium haouarianum) collected off of
the southern coast of Spain (Figure 1).1 The potent and
selective cytotoxic activity displayed by haouamine A
against the HT-29 human colon carcinoma cell line (IC50
= 0.1 μg/mL) has made it an appealing target for total
synthesis.2ꢀ4 The structural features comprise a congested
indeno-tetrahydropyridine core fused to an 11-membered
paracyclophane containingastrained, nonplanararomatic
ring. In addition, the presence of a quaternary stereogenic
center and the unusual biosynthetic oxidation pattern
make the haouamines a formidable synthetic challenge.
ꢀ
(1) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva, J. J. Org. Chem. 2003,
68, 293–299.
(2) For previous total syntheses of haouamine A, see: (a) Baran, P. S.;
Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908–3909. (b) Burns, N. Z.;
Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205–208. (c) Burns, N. Z.;
Krylova, I. N.; Hannoush, R. N.; Baran, P. S. J. Am. Chem. Soc. 2009,
131, 9172–9173.
Figure 1. Haouamines A and B.
(3) For previous formal syntheses of haouamine A, see: (a) Jeong,
€
J. H.; Weinreb, S. M. Org. Lett. 2006, 8, 2309–2312. (b) Furstner, A.;
Ackerstaff, J. Chem. Commun. 2008, 2870–2872. (c) Taniguchi, T.;
Zaimoku, H.; Ishibashi, H. J. Org. Chem. 2009, 74, 2624–2626.
(4) For previous approaches to the haouamines, see: (a) Smith, N. D.;
Hayashida, J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312. (b) Grundl,
M. A.; Trauner, D. Org. Lett. 2006, 8, 23–25. (c) Wipf, P.; Furegati, M.
Org. Lett. 2006, 8, 1901–1904. (d) Tanaka, T.; Inui, H.; Kida, H.;
Kodama, T.; Okamoto, T.; Takeshima, A.; Tachi, Y.; Morimoto, Y.
Chem. Commun. 2011, 47, 2949–2951.
To date, the only total syntheses of houamines A and B
have been reported by Baran and workers, who used either
an alkyne/pyrone DielsꢀAlder cycloaddition or a cyclo-
hexenone to phenol oxidation to install the paracyclo-
phane moiety.2 A number of other workers have focused
on the preparation of the indeno-tetrahydropyridine core.
r
10.1021/ol200725m
Published on Web 04/25/2011
2011 American Chemical Society

With the exception of an intramolecular MizorokiꢀHeck
sequence reported by Ishibashi and co-workers,3c all other
approaches sequentially form each of the rings in the core.
Both of the Rawal4a and Trauner4b laboratories have used
a FriedelꢀCrafts alkylation to prepare the indene ring
from a tetrahydropyridine-containing starting material.
Herein, we report an approach to the indeno-tetrahydro-
pyridine core in which the indene and tetrahydropyridine
rings are formed concurrently in a tandem Prins/Friedelꢀ
Crafts reaction and the use of this reaction in a formal syn-
thesis of (ꢀ)-haouamine A.
Table 1. Acid Promoted Prins/FriedelꢀCrafts Reaction of Enal
Substrates 8
yield (%)b
Scheme 1. Retrosynthetic Analysis of Haouamine A
entry
enal
Hþ or LAa
solvent
t (°C)
9
10 (R:β)
1
8a
8a
8a
8a
8b
8b
8b
8b
8c
8c
8c
8c
CSA
AlCl3
BF3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
MeNO2
CH2Cl2
CH2Cl2
MeNO2
MeNO2
0
ꢀ41
ꢀ41
ꢀ41
0
76
2
90 (1.6:1)
94 (1.1:1)
85 (1.9:1)
3
4
TiCl4
CSA
AlCl3
AlCl3
BF3
12
72
28
5
5
6
ꢀ41
ꢀ20
ꢀ20
rt
54 (1.6:1)
74 (1.3:1)
7
8
2
84 (1.4:1)
c
9
CSA
AlCl3
AlCl3
BF3
c
10
11
12
0
0
5 (1:1)c
7 (1:1)c
0
a A slight excess of protic or Lewis acid was used (1.1 equiv). b Yield
of the isolated product. c The major isolated products in these reactions
was that resulting from a Prins reaction only.
Our approach was based on forming the indeno-tetrahy-
dropyridine core 3 from an amino acid starting material as
shown in Scheme 1. In this scenario, an acid-promoted Prins
reaction of enal 4 would form a carbocation that could in
principle be attacked by an aromatic ring in an intramole-
cular FriedelꢀCrafts reaction. Deriving confidence from a
few previously reported examples,5 we began by preparing
test substrates 8aꢀ8d from the Weinreb amide 5 (Scheme 2;
see Supporting Information for detail).
Enals 8 were treated with various protic and Lewis
acids (Table 1). Treating 8a with camphorsulfonic acid
resulted in a clean reaction yielding the bridged tricyclic
compound 9a (entry 1). This product presumably re-
sults from a Prins reaction followed by a dehydration
yielding an intermediate allylic cation, which is then
intercepted by the arene in an intermolecular Friedelꢀ
Crafts manner at the less hindered allyl carbon. In
contrast, the use of various Lewis acids (entries 2ꢀ4)
resulted predominantly in the fused tricyclic product
10a, in which the initial Prins cation intermediate is
intercepted directly by the tethered arene. When 8b was
treated with protic acid (entry 5), the bridged tricycle 9b
was obtained exclusively. When Lewis acids were used
instead (entry 6), significant amounts of the bridged
tricycle 9b were observed in addition to 10b, which was
still the major product. The formation of 9b could be
minimized if the reaction was performed in a polar
aprotic solvent such as nitromethane (entries 7 and 8).
Whithin products 9b and 10b, FriedelꢀCrafts aromatic
substitution occurred para to the methoxy group.
When enal 8c was treated under protic or Lewis acid
conditions (entries 9ꢀ12), no appreciable amounts of
Scheme 2. Preparation of Model Prins/FriedelꢀCrafts Sub-
strates
(5) (a) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005,
1912–1916. (b) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem.
2006, 71, 3176–3183. (c) Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9,
57–60. (d) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. J. Org. Chem.
2009, 74, 2605–2608. (e) Reddy, U. C.; Saikia, A. K. Synlett 2010, 1027–
1032.
Org. Lett., Vol. 13, No. 10, 2011
2615

conversion could be attained in higher overall yield by
cross-coupling 12 with 3-iodoanisole followed by treat-
ment with NBS. The second aryl ring was installed by
preparing Weinreb amide 14 from ester 13 using the Merck
Scheme 3. Prins/FriedelꢀCrafts Attempt with 8d
protocol (i-PrMgCl, MeNH(OMe) HCl),9 followed by
3
addition of 3-methoxyphenylmagnesium bromide. Methy-
lenation of the resulting aryl ketone 15 was effected cleanly
in a two-step Peterson olefination protocol to yield 16 in
good overall yield.10 Finally, the two-carbon aldehyde was
attached by N-alkylation with TBS-protected 2-bro-
moethanol, deprotection, and oxidation of the resulting
alcohol to produce enal 18.
FriedelꢀCrafts products were obtained, demonstrating
the requirement for the arene to be electron rich.
Reaction of 8d, lacking the vinylic phenyl group, led
solely to 11, resulting from a direct FriedelꢀCrafts
acylationꢀdehydration reaction (Scheme 3).
Scheme 5. Synthesis of the Enal Substrate for the Prins/
FriedelꢀCrafts Approach to Haouamine A
These results allowed us to narrow our strategy for
synthesizing the core of haouamine A (Scheme 4): (1) use
Lewis instead of protic acids to obtain product having the
Scheme 4. Plan for the Prins/FriedelꢀCrafts Approach to
Haouamine A
desired ring system, (2) further drive the selectivity using
nitromethane as solvent,6 (3) preinstall the vinyl aromatic
group, and (4) use a blocking group to force formation of
an ortho CꢀC bond in the FriedelꢀCrafts step (following
precedent set by Rawal4a).
This route required the unusual amino ester 13, which
was prepared from 127 by a route analogous to that of
Jackson and co-workers (Scheme 5).8 We found that this
The enal 18 was then subjected to a variety of protic and
Lewis acid conditions in an attempt to promote a Prins/
FriedelꢀCrafts reaction (Scheme 6). However, the only
observable product in all cases resulted from the
Scheme 6. Prins/FriedelꢀCrafts Attempt with Enal 18
(6) We suspect that the dehydration leading to 9 occurs competitively
with the desired FriedelꢀCrafts reaction. In a polar aprotic solvent such
as nitromethane, the intermediate Prins carbocation remains longer
lived so as to allow sufficient time for the FriedelꢀCrafts arene to react
directly.
(7) Serine iodide 12 is prepared in three steps from serine (methyl
ester formation, Boc protection, iodination) in 61% overall yield
according to the procedure of Rudd, M. T.; Trost, B. M. Org. Lett.
2003, 5, 4599–4602.
(8) (a) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701–
ꢀ
2719. (b) Oswald, C. L.; Carrillo-Marquez, T. S.; Caggiano, L.; Jackson,
R. F. W. Tetrahedron 2008, 64, 681–687. (c) Ross, A. J.; Lang, H. L.;
Jackson, R. F. W. J. Org. Chem. 2010, 75, 245–248.
2616
Org. Lett., Vol. 13, No. 10, 2011

cyclization of the Boc amide onto the aldehyde with
concomitant loss of isobutylene to produce the hydroxy
oxazolidinone 20. Since it became obvious that the Boc
protecting group was not compatible with the required
acid conditions, the enal substrate was then retuned with a
change in protecting group. Boc deprotection and repro-
tection of the free amine in the form of a Cbz group,
followed by a similar homologation sequence performed
previously (Scheme 5), yielded enal 19.
In contrast, use of AlCl3 in methylene chloride did yield a
Prins/FriedelꢀCrafts product exclusively, albeit the unde-
sired bridged tricycle 22 rather than the expected fused
tricycle 24 (entry 2). We next turned to the use of AlCl3 in
nitromethane, since the use of this solvent was predicted to
favor formation of 24 over 22 (entry 3). Under these
conditions, chlorohydrins 23 were obtained, apparently
from the addition of a chloride anion originating from the
Lewis acid. These results suggest that the presence of a
bromine on the FriedelꢀCrafts arene nucleophile of 19
decreases its reactivity. Gratifyingly, however, when Lewis
acids bearing “non-nucleophilic” anions were used in
nitromethane (entries 4ꢀ5) in the form of BF3 or Al(OTf)3,
the requisite fused Prins/FriedelꢀCrafts tricycle 24 was
obtained exclusively as a mixture of diatereomers at C2.
The mixture of diastereomers 24 was oxidized to the
ketone and the Cbz protecting group was removed by
hydrogenolysis with concomitant hydrodebromination to
produce the haouamine tricyclic core 26 (Scheme7). Since26
was identical in all respects to an intermediate prepared in a
Table 2. Acid Promoted Prins/FriedelꢀCrafts Reaction of Enal
Substrate 19
synthesis of haouamine A by Furstner and co-workers,3b this
€
constitutes a formal synthesis of (ꢀ)-haouamine A.
Scheme 7. Formal Synthesis of Haouamine A
entry Hþ or LAa solvent t (°C) product yield (%) (R:β)b
1
2
3
4
5
CSA
CH2Cl2
CH2Cl2
MeNO2
MeNO2
MeNO2
rt
0
21
22
23
24
24
81 (1.6:1)
70
AlCl3
AlCl3
BF3
ꢀ20
ꢀ20
ꢀ20
70
62 (1.2:1)
65 (1.5:1)
Al(OTf)3
In conclusion, we have successfully demonstrated the
utility of a tandem Prins/FriedelꢀCrafts reaction in the
concise construction of the tricyclic core of haouamine A.
This culminated in a formal synthesis of (ꢀ)-haouamine A,
in which the indeno-tetrahydropyridine was constructed in
13 steps from serine. Future efforts will concentrate on
evaluating the utility of tandem Prins/FriedelꢀCrafts re-
action in the construction of fused and bridged tricycles.
a A slight excess of protic or Lewis acid was used (1.1 equiv). b Yield
of the isolated product.
Acid treatment of the Cbz-protected enal 19 was more
promising (Table 2). Use of CSA yielded a mixture of
allylic alcohols 21 resulting from a simple Prins reaction
(entry 1). Although we had expected, according to the
model study, to obtain the bridged tricycle 22, further
treatment of 21 with CSA with heating under prolonged
reaction times did not produce a FriedelꢀCrafts reaction.
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences is grate-
fully acknowledged (KU-CMLD, PO50-GM069663)
(9) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
H., U.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
(10) Various olefination methods involving Wittig and Tebbe re-
agents failed to produce substantial amounts of the product. The
Peterson olefination method was successful only in the cases where the
intermediate silane was treated in acid conditions (base conditions were
found to be incompatible with the Boc protecting group).
Supporting Information Available. Experimental in-
formation for the preparation of new compounds in-
cluding X-ray data and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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