Synthesis of the 3-aza-[7]-paracyclophane core of haouamine A and B

Article abstract of DOI:10.1021/ol060455e

The synthesis of the highly strained 3-aza-[7]-paracyclophane core of haouamines A and B is based on a macrocyclization-aromatization protocol, allowing for a stepwise increase in ring strain and establishing the oxygenation pattern of the natural product

Full text of DOI:10.1021/ol060455e

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1901-1904
Synthesis of the
3-Aza-[7]-paracyclophane Core of
Haouamine A and B
Peter Wipf* and Markus Furegati
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received February 21, 2006
ABSTRACT
The synthesis of the highly strained 3-aza-[7]-paracyclophane core of haouamines A and B is based on a macrocyclization
−aromatization
protocol, allowing for a stepwise increase in ring strain and establishing the oxygenation pattern of the natural products.
Haouamines A and B are members of a novel class of
alkaloids recently isolated from the ascidian Aplidium
haouarianum.1 Biological tests against several cell lines
revealed that haouamine A exhibits high and selective activity
the synthesis, whereas the Baran and Burns route ac-
complished this challenging task by an intramolecular
pyrone-alkyne Diels-Alder reaction.2c
As part of a convergent synthetic approach toward
haouamine A we encountered difficulties forming the strained
3-aza-[7]-paracyclophane ring with standard coupling meth-
odologies. In particular, we were not able to effect direct
ring closure of the amino acid HCl salt 2a or the Cbz-
protected activated ester 2b under various macrolactamization
conditions (Scheme 1).3
against the human colon carcinoma HT-29 with an IC50
)
0.1 µg/mL (200 nM), whereas haouamine B shows only weak
cytotoxicity against the MS-1 cell line with an IC50 ) 5 µg/
mL. Both compounds display dynamic behavior in the NMR
and exist at room temperature as a mixture of interconverting
isomers. Zub´ıa and co-workers assigned these properties to
either a restricted bond rotation or to a slow pyramidal
inversion of the tertiary amine in the 3-aza-[7]-paracyclo-
phane moiety.
Scheme 1
The structural features combined with the biological
activity of these polycyclic alkaloids attracted immediate
attention in the chemical community. Recently, two syntheses
of the racemic indenotetrahydro-pyridine moiety were
reported,2a,b in addition to a successful total synthesis by
Baran and Burns.2c In the former approaches, the formation
of the [7]-paracyclophane ring was postponed to the end of
(1) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva´, J. J. Org. Chem. 2003,
68, 293-299.
(2) (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)
Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908-3909.
The application of a recently published protocol for the
synthesis of medium-ring biaryl compounds by organocu-
10.1021/ol060455e CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/04/2006

Scheme 2
prate oxidation also failed (Scheme 2).4 Subjecting the model
compound 3a or 3b to the reaction conditions gave no
cyclization product detectable by mass spectrometry.
We also attempted to construct the strained ring system
by a ring contraction strategy.5a Formation of the silyl ketene
acetals derived from macrolactones 4a and 4b followed by
a [3,3] sigmatropic rearrangement5b upon heating was thought
to overcome the deterrent of the ring strain (Scheme 3).5c-e
Figure 1. (a) X-ray structure of haouamine A (with the original
atom and ring numbering); (b) noteworthy derivations from
planarity in ring B.
carbon atoms are located significantly out of the plane of
the distorted benzene ring B.
Scheme 3
As an alternative to the more traditional strategies for
overcoming the kinetic barriers of ring closure, we envisioned
the preparation of a macrocyclic ring composed of a
tetrahydro derivative and subsequently an introduction of the
ring strain by altering the hybridization of C(12) from sp3
to sp2 by elimination of methanol. Tautomerization to the
phenol would result in the formation of the biaryl system
(Scheme 4).
The formation of the silyl ketene acetals could conveniently
1
be observed by H NMR and took place within 2 days.
Scheme 4
Heating of the Claisen precursors with or without prior
purification in a microwave reactor up to 220 °C, however,
did not lead to the desired rearrangement.
As can be seen from the X-ray diffraction analysis of
haouamine A,1 the 3-aza-[7]-paracyclophane ring is ex-
tremely strained (Figure 1). The six carbon atoms of ring B
are not aligned in a plane, but rather arranged in a boatlike
geometry. Analysis6 of the B-ring of haouamine A revealed
large deviation angles Φ1,2 of the benzene ring from planarity
as well as unusual out-of-plane angles R1,2, which include
the adjacent substituents C(8) and C(15), respectively. These
For the synthesis of precursor 8 we converted 2-iodo-5-
methoxyphenylacetic acid (5), readily available in 66% yield
by iodination of 3-methoxyphenylacetic acid,7 to the corre-
sponding amide (Scheme 5). Borane reduction, followed by
stepwise conversion of the primary amine 6 with 2-nitroben-
zenesulfonyl chloride,8 and then Boc2O/DMAP gave the fully
protected imide 7. The boronic ester 8 was obtained via
palladium-catalyzed reaction with pinacolborane9 in 56%
overall yield (5 steps).
(3) (a) Meng, Q.; Hesse, M. Top. Curr. Chem. 1992, 161, 107-176. (b)
Brady, S. F.; Freidinger, R. M.; Paleveda, W. J.; Colton, C. D.; Homnick,
C. F.; Whitter, W. L.; Curley, P.; Nutt, R. F.; Veber, D. F. J. Org. Chem.
1987, 52, 764-769. (c) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc.
1974, 96, 5614-5616. (d) Schmidt, U.; Lieberknecht, A.; Griesser, H.;
Talbiersky, J. J. Org. Chem. 1982, 47, 3261-3264.
(4) Surry, D. S.; Su, X.; Fox, D. J.; Franckevicius, V.; Macdonald, S. J.
F.; Spring, D. R. Angew. Chem., Int. Ed. 2005, 44, 1870-1873.
(5) (a) Silva, L. F., Jr. Tetrahedron 2002, 58, 9137-9161. (b) Wipf, P.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 827-874. (c) Funk, R.
L.; Abelman, M. M.; Munger, J. D., Jr. Tetrahedron 1986, 42, 2831-2846.
(d) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515-518. (e)
Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 1721-1724.
(6) Lee, T. J.; Rice, J. E.; Allen, W. D.; Remington, R. B.; Schaefer, H.
F. Chem. Phys. 1988, 123, 1-25.
(7) Carson, J. R. (McNeilab, Inc., USA). Eur. Pat. Appl. EP 145361 A2
19850619, 1985; CAN 104:88248.
(8) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373-6374.
1902
Org. Lett., Vol. 8, No. 9, 2006

Scheme 5. Preparation of Precursor 8
Scheme 7
The preparation of precursor 12 started with commercially
available 1,4-cyclohexanedione monoethylene acetal (9)
(Scheme 6). Allylation using Zn and allylbromide10 gave the
Scheme 6. Preparation of Precursor 12
membered 14 was accomplished by an intramolecular
Mitsunobu reaction with the 2-nitrobenzenesulfonamide as
the internal nucleophile in 57% yield.17 Treatment of
macrocycle 14 with mCPBA gave the benzylic epoxide,
which rearranged quantitatively to the allylic alcohol in
chloroform in the presence of 1 mol % HBF4. Subsequent
oxidation with Dess-Martin periodinane18 resulted in the
tertiary alcohol,11 which was methylated with MeI. Ozo-
nolysis of 10 followed by a reductive workup using NaBH4
gave the primary alcohol. The ketal was cleaved with PPTS12
in acetone/H2O, and the alcohol was protected as the
TBDMS-ether.13 Formation of the vinyltriflate using PhNTf2/
KHMDS14 resulted in the formation of 12 in 52% overall
yield (6 steps).
Suzuki-Miyaura reaction15 of a 1:1 mixture of 8 and 12
afforded the coupling product 13 in 66% yield after TBDMS
removal (Scheme 7). Cleavage of the Boc group was
facilitated by the nosyl substituent and occurred thermally
at 165 °C in 90% yield.16 The macrocyclization to the 11-
(9) Broutin, P.-E.; EÅ ero`a, I.; Campaniello, M.; Leroux, F.; Colobert, F.
Org. Lett. 2004, 6, 4419-4422.
(10) Chen, C.; Dai, W.-C.; Chang, H.-G. Org. Prep. Proc. Int. 2002,
34, 507-511.
(11) Jiao, P.; Qiu, Z. Zhongguo Yiyao Gongye Zazhi 2001, 32, 342-
345; CAN 136:401595.
(12) Sterzycki, R. Synthesis 1979, 724-725.
(13) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-
6191.
(14) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem. Eur. J. 2003,
9, 4118-4131.
(15) Ohe, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208.
Figure 2. (a) X-ray structure of 17‚HCl (with atom and ring
numbering based on haouamine A; the structure also contains two
water molecules and a chloride, which are labeled separately); (b)
characteristic angles in ring B.
Org. Lett., Vol. 8, No. 9, 2006
1903

formation of the R,â-unsaturated ketone 15 in 63% (3 steps).
Treatment of 15 with a 1:1 mixture of DIPEA and 2,2,2-
trifluoroethanol in a pressure tube at 170 °C for 1 h followed
by O-methylation of the crude product with dimethyl sulfate
resulted in the formation of the nosyl-protected 3-aza-[7]-
paracyclophane 16. Removal of the nosyl substituent8 gave
the secondary amine 17 in 61% yield.
X-ray analysis of the hydrochloride salt of 17 provided
convincing evidence that ring distortion and folding of this
subunit are a close match of the natural product (Figure 2).
In conclusion, we have demonstrated a new approach
toward the synthesis of the unique and highly strained 3-aza-
[7]-paracyclophane core of the haouamine alkaloids in 21
steps (22 steps from commercially available materials). The
overall yield for the longest linear sequence was 12% (16
steps); the average yield for the 21 steps was 86%. Highlights
of our strategy are the use of a Mitsunobu reaction to close
an 11-membered ring and the formation of the paracyclo-
phane moiety from a partly saturated precursor followed by
stepwise aromatization.19
Acknowledgment. M.F. thanks the Swiss National Sci-
ence Foundation for a postdoctoral fellowship (PBZH2-
104353). We thank Dr. Steve Geib (University of Pittsburgh)
for X-ray crystallographic analysis of the HCl salt of 17.
This work was supported by a grant from the National
Institutes of Health (AI-33506).
(16) Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett.
1982, 23, 465-468.
(17) (a) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.,
Tetrahedron Lett. 1997, 38, 5831-5834. (b) Ribe, S.; Kondru, R. K.;
Beratan, B. N.; Wipf, P. J. Am. Chem. Soc. 2000, 122, 4608-4617.
(18) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(19) For related aromatization strategies, see: (a) Harrowven, D. C.;
Woodcock, T.; Howes, P. D. Angew. Chem., Int. Ed. 2005, 44, 3899-
3901. (b) Hattori, T.; Date, M.; Sakurai, K.; Morohashi, N.; Kosugi, H.;
Miyano, S. Tetrahedron Lett. 2001, 42, 8035-8038. (c) Jung, M. E.;
Starkey, L. S. Tetrahedron 1997, 53, 8815-8824.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060455E
1904
Org. Lett., Vol. 8, No. 9, 2006