such work reveals that a dozen or so different approaches
have been explored including ones that are relevant to the
studies described below and involving B-ring annulation to
a C5-spiro-tetrahydroisoquinoline or ACD-tricyclic sub-
structure.4 The method by which the latter substructure is
obtained and then annulated with the B-ring varies consider-
ably. For example, in the Danishefsky synthesis of (()-3-
demethoxyerythratidinone4a this tricyclic motif was as-
sembled by using a two-step cyclization/fragmentation
sequence involving a readily accessible AD-ring precursor.
The B-ring was then incorporated through a radical cycliza-
tion process that led to site-specific enol acetate formation
and, thence, completely regioselective introduction of the
∆
1(6)-double bond within the target natural product. In the
Mariano synthesis4b of the erythrina alkaloid framework, the
ACD system was generated via an electron-transfer-induced
photocyclization process and this was followed by the
application of Claisen or ketone-enolate alkylation/cycliza-
tion sequences to install the B-ring. On the other hand, in
their synthesis of (()-3-demethoxyerythratidinone, Irie and
co-workers4d employed, as key steps, an iminium ion-
mediated spirocyclization reaction to assemble the ACD
substructure from an AD-ring precursor and then an intramo-
lecular Wittig olefination protocol to annulate the B-ring.
The continuing need for the development of more efficient
routes to the D-ring aromatic erythrina alkaloid framework,2-4
as well as our interest in exploiting gem-dihalocyclopropanes
as building blocks for the synthesis of natural products,5
prompted us to pursue the synthetic strategy defined in Figure
1. In particular, we considered the possibility that the
framework, 2, associated with the title alkaloids (e.g., 1)
could be assembled from the ACD-ring precursor 3 by using
a C-radical-initiated 5-exo-trig cyclization/Cl-radical elimina-
tion process to annulate the B-ring.6 It was expected that an
appropriate precursor to compound 3 would be accessible
via a spirocyclization process initiated by the Ag(I)-promoted
electrocyclic ring-opening of the gem-dichlorocyclopropane
4 then trapping of the resulting π-allyl cation by a tethered
nitrogen nucleophile. Such a sequence of events would not
only serve to simultaneously establish the A- and C-rings
of the target framework but also introduce the chlorocyclo-
hexene residue required for the anticipated B-ring forming
step. To the best of our knowledge, no such spirocyclization
processes (i.e., ones initiated by electrocyclic ring-opening
of gem-dihalocyclopropanes) have been reported previously.
We now detail the successful implementation of this strategy.
Figure 1. Key ring-forming steps leading to compound 2.
The synthesis of an appropriate form of the gem-dihalo-
cyclopropane 4 required for investigating the pivotal elec-
trocyclic ring-opening/spirocyclization sequence was achieved
in the manner shown in Scheme 1. Thus, bromopiperonal
57 was subject to reaction with (methoxymethylene)triph-
enylphosphorane and the resulting E/Z mixture of vinyl ethers
then hydrolyzed in aqueous acid to give the expected but
rather unstable R-arylacetaldehyde. Reduction of this latter
material with lithium borohydride in diethyl ether then
afforded the previously reported alcohol 68 in 81% yield
(from 5). The readily derived TBDPS-ether 7 (99%) was
then treated with n-butyllithium in the presence of triiso-
propylborate and after acidic workup the boronic acid 8
(89%) was obtained. Suzuki-Miyaura cross-coupling9 of
compound 8 with the enol triflate 910 derived from cyclo-
pentanone gave the arylated cyclopentene 10, which was then
treated with tetra-n-butylammonium fluoride. The ensuing
alcohol 11 (49% from 8) was converted, under standard
conditions, into the corresponding acetate 12 (84%). Com-
pound 12 was then subjected to reaction with dichlorocarbene
generated under Makosza’s phase-transfer catalysis (PTC)11
conditions and with accompanying ultrasonication as defined
by Xu and Brinker.12 The resulting cyclopropane-acetate 13
was treated with potassium carbonate in methanol and the
ensuing alcohol (97% from 12) converted into the corre-
sponding mesylate (94%), which was, in turn, reacted with
(5) (a) Banwell, M. G.; Gable, R. W.; Peters, S. C.; Phyland, J. R. J.
Chem. Soc., Chem. Commun. 1995, 1395. (b) Banwell, M.; Edwards, A.;
Harvey, J.; Hockless, D.; Willis, A. J. Chem. Soc., Perkin Trans. 1 2000,
2175. (c) Banwell, M. G.; Harvey, J. E.; Hockless, D. C. R.; Wu, A. W. J.
Org. Chem. 2000, 65, 4241. (d) Banwell, M. G.; Ebenbeck, W.; Edwards,
A. J. J. Chem. Soc., Perkin Trans. 1 2001, 114. (e) Banwell, M. G.; Harvey,
J. E.; Jolliffe, K. A. J. Chem. Soc., Perkin Trans. 1 2001, 2002. (f) Banwell,
M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-
Pinard, P. Org. Biomol. Chem. 2003, 1, 296. (g) Taylor, R. M. Aust. J.
Chem. 2003, 56, 631. (h) Banwell, M. G.; Sydnes, M. O. Aust. J. Chem.
2004, 57, 537. For a review of certain aspects of our work in this area see:
(i) Banwell, M. G.; Beck, D. A. S.; Stanislawski, P. C.; Sydnes, M. O.;
Taylor, R. M. Curr. Org. Chem. 2005, 9, 1589.
(7) Conrad, P. C.; Kwiatkowski, P. I.; Fuchs, P. L. J. Org. Chem. 1987,
52, 586.
(8) Ogata, Y.; Ikeda, M.; Nomoto, S.; Okita, M.; Shimomura, N.; Kaneko,
T.; Yamanaka, T.; Hishinuma, I.; Nagakawa, J.; Hirota, K.; Miyamoto, K.;
Horie, T.; Wakabayashi, T. European patent EP0281098, 1988; Chem. Abstr.
1989, 110, 95206.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(10) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem.
Soc. 2002, 124, 8001 and references therein.
(11) (a) Makosza, M.; Wawrzyniewicz, M. Tetrahedron Lett. 1969, 4659.
For a discussion of the methods available for the generation of dihalocar-
benes see: (b) Banwell, M. G.; Reum, M. E. In AdVances in Strain in
Organic Chemistry; Halton, B., Ed.; JAI Press: London, UK, 1991; Vol.
1, pp 19-64.
(12) Xu, L.; Brinker, U. H. In Synthetic Organic Sonochemistry; Luche,
J.-L., Ed.; Plenum Press: New York, 1998; pp 344-345.
(6) For a related cyclization process involving C-radical addition to a
haloalkene see: Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett.
1990, 31, 5397.
2144
Org. Lett., Vol. 8, No. 10, 2006