D. Y. Gin and K. M. Peese
ing group that would also serve as a convenient dienophile
precursor, the vinyl triflate moiety in 48 was then converted
to ene–nitrile 49 (75%) via Pd-catalyzed cyanation with
KCN. Bromine-mediated aza-Achmatowicz reaction of 50
delivered the oxidopyridinium betaine 50 (65%), which
could be purified by silica gel flash chromatography. Un-
fortunately, heating (up to 1708C) a solution of betaine 50
in a variety of solvents failed to effect the desired intramo-
lecular dipolar cycloaddition (i.e., 50 ! 51 ! 52), as the tri-
cyclic oxidopyridinium betaine 54 was the only discernable
product (73%) after a prolonged reaction time (5 d). The
formation of 54 was the result of direct conjugate addition
of the betaine 53 into the ene-nitrile, followed by aromatiza-
tion, being the dominant reaction pathway. While the forma-
tion of the indolizinium species 54 provides access to an in-
teresting heterocyclic scaffold,[81] the unmet challenges of ac-
vinyl sulfide functionality to the vinylsulfone 57 (75%, 2
steps) with m-CPBA. Introduction of the oxidopyridinium
betaine dipole proceeded with reductive amination of alde-
hyde 57 with furfurylamine to produce amine 58 (91%),
which smoothly underwent aza-Achmatowicz oxidative rear-
rangement to provide the cycloaddition precursor 59 (77%).
Heating of a dilute solution of 3-oxidopyridinium betaine 59
in refluxing toluene provided the desired cycloadduct 61
(70%), the structure of which was unambiguously verified
by its X-ray crystal structure. That none of the isomeric con-
jugate addition product 63 was formed in this reaction rein-
forces the hypothesis of an energetically disfavored bridged
transition state 62 giving way to the more favorable cycload-
dition manifold (60). This promising result presented a
highly efficient route to the entire N-heterocyclic array
within the hetisine framework in the form of 61. Further ad-
vancement of this intermediate toward the hetisine alkaloids
would involve installation of the diene–dienophile pair for
late-stage intramolecular Diels–Alder reaction (i.e., 19,
Scheme 2). While installation of the 1,3-diene moiety onto
61 (Scheme 9) can be envisioned to occur via a variety of
six-membered annulation strategies at the C8–C14 positions,
introduction of a dienophile moiety, required at the C10-po-
sition of 61, is considerably more challenging since a
method for controlled C–H activation at this bridgehead po-
sition is not obvious.
In light of this challenge, installation of an appropriate
C10-dienophile precursor prior to the key dipolar cycloaddi-
tion event was pursued. This involved (Scheme 10) bromina-
tion of the alkene at C10 within our previously prepared
vinyl sulfide 56 to form vinyl bromide 64 (92%), which al-
lowed for metal–halogen exchange with iPrMgCl.[83] The re-
sulting vinyl Grignard reagent was alkylated with BOMCl in
the presence of CuCN to provide tetrasubstituted alkene 65
(81%). The nitrile within 65 was then reduced (DIBAL-H)
to afford the corresponding aldehyde (74%), allowing for
sulfide oxidation (m-CPBA) to provide the vinyl sulfone 66
(62%). Subsequent reductive amination with furfurylamine
furnished amine 67 (78%), allowing for bromine-mediated
oxidative rearrangement to provide the oxidopyridinium be-
taine 68 (67%). Investigation into the cycloaddition reaction
of betaine 68 led to its heating in refluxing toluene with the
hopes of acquiring pyrrolidine 70 via the anticipated transi-
tion state 69. However, none of the cycloadduct 70 was de-
tected; rather, the isomeric intramolecular cycloadduct 73
was isolated (43%) as the primary product; its structure was
initially delineated by a battery of spectroscopic data and ul-
timately unambiguously verified through single crystal X-ray
analysis.
cessing the desired azabicyclo[3.2.1]octane skeleton of the
A
hetisine alkaloids remained.
Since the undesired conjugate addition pathway emerged
as the principal obstacle at this juncture, a strategy was
adopted in which a removable electron-deficient dipolaro-
phile activating group (i.e., a sulfone) was installed at the
vinyl C5-position in a cycloaddition substrate such as 59
(Scheme 9). It was anticipated that reversal of the polariza-
tion of the dipolarophile p-system would preclude a conju-
gate addition pathway (i.e., 59 ! 62 ! 63) that would nec-
essarily proceed via a high energy bridged transition state.
This may provide an opportunity for the favored cycloaddi-
tion process (i.e., 59 ! 60 ! 61) to surface as the dominant
reaction pathway. This approach began with 2-cyano-2-
methylcyclohexanone (55), which was readily prepared from
1,5-dicyanopentane via a previously reported three-step se-
quence.[82] Condensation of ketone 55 with thiophenol pro-
duced the vinyl sulfide 56 (84%). Subsequent reduction of
the nitrile in 56 with DIBAL-H afforded the corresponding
neopentyl aldehyde, which allowed for oxidation of the
This outcome arose from initial isomerization of the tetra-
ꢀ
ꢀ
substituted C5 C10 alkene in 68 to its trisubstituted C1
C10 alkene counterpart 71, eventually leading to intramolec-
ular dipolar cycloaddition of this unactivated dipolarophile
to generate the observed cycloadduct 73. This initial “decon-
jugation” event (68 ! 71) is likely driven by release of
steric strain to allow for access to a lower energy pathway
for intramolecular cycloaddition. Qualitative conformational
Scheme 9. a) PhSH, P2O5, CH2Cl2, 238C, 84%; b) DIBAL-H, toluene,
08C, 82%; c) m-CPBA, CH2Cl2, 08C, 91%; d) furfurylamine·HCl,
NaBH3CN, 3 MS, NEt3, MeOH, 238C, 91%; e) Br2, MeOH, H2O, 0 8C,
77%; f) [0.05m], PhMe, reflux, 70%.
1658
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1654 – 1665