Synthetic studies toward halichlorine: Complex azaspirocycle formation with use of an NBS-promoted semipinacol reaction

Article abstract of DOI:10.1021/jo800336k

(Chemical Equation Presented) The investigations of a synthetic route incorporating a NBS-promoted semipinacol rearrangement to the 6-azaspiro[4.5]decane fragment within halichlorine (1) are presented. A convergent approach was pursued, utilizing two chir

Full text of DOI:10.1021/jo800336k

Synthetic Studies toward Halichlorine: Complex Azaspirocycle
Formation with Use of an NBS-Promoted Semipinacol Reaction
Paul B. Hurley and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, B.C., Canada V6T 1Z1
gdake@chem.ubc.ca
ReceiVed February 8, 2008
The investigations of a synthetic route incorporating a NBS-promoted semipinacol rearrangement to the
6-azaspiro[4.5]decane fragment within halichlorine (1) are presented. A convergent approach was pursued,
utilizing two chiral, enantiomerically enriched building blocks, 2-trimethylstannyl piperidene 10 and
substituted cyclobutanone 19. Noteworthy synthetic operations in this study include the following: (a) a
highly diastereoselective NBS-promoted semipinacol reaction that established four stereogenic centers
in ketone 25 and (b) the use of a N-p-toluenesulfonyl-2-iodo-2-piperidene as a precursor to a basic
organometallic reagent, which was critical to the success of the coupling of fragments 10 and 19.
Introduction
In 1996, Uemura and co-workers analyzed extracts from the
marine sponge Halichondria okadai Kadota. From these extracts,
they isolated a novel compound, halichlorine (1), that was observed
to inhibit vascular cell adhesion molecule-1 (VCAM-1) with
reasonable efficiency (Figure 1).1 Two structurally related alkaloids,
pinnaic acid and tauropinnaic acid, were discovered later by the
Uemura group.2 The novelty of the structures of these secondary
metabolites has inspired a large number of synthetic chemists. That
these compounds also possessed interesting biological activity
renders them, and their synthetic derivatives, of interest to a broader
set of engaged scientists.
As these compounds are appealing targets for the synthetic
community, a significant amount of work related to the synthesis
(1) (a) Kuramoto, M.; Tong, C.; Yamata, K.; Chiba, T.; Hayashi, Y.; Uemura,
D. Tetrahedron Lett. 1996, 37, 3867–3870. (b) Chou, T.; Kuramoto, M.; Otani,
Y.; Shikano, M.; Yazawa, K.; Uemura, D. Tetrahedron Lett. 1996, 37, 3871–
3874.
(2) Arimoto, H.; Kuramoto, M.; Hayakawa, I.; Uemura, D. Tetrahedron Lett.
1998, 39, 861–862.
FIGURE 1. Halichlorine, pinnaic acid, and tauropinnaic acid.
J. Org. Chem. 2008, 73, 4131–4138 4131
10.1021/jo800336k CCC: $40.75
Published on Web 04/30/2008
2008 American Chemical Society

Hurley and Dake
natural product to a spirocyclic system a followed ultimately
to an azaspirocyclic ketone represented by b. It was envisioned
that a compound such as b could be generated by using a
semipinacol reaction that proceeds through either an azacarbe-
nium ion or an intermediate having azacarbenium ion character.
To this end, our research group developed a set of semipinacol
processes forming azaspirocyclic ketones.8,9 One method in the
set involved reaction between a N-sulfonyl enamide (ene-
sulfonamide) and N-bromosuccinimide (NBS) at low temper-
ature. The putative bromonium ion (or bromine-alkene π-com-
plex) intermediate then induced a semipinacol process with
simultaneous ring expansion.8a,b,10 These reactions have the
capability of producing azaspirocyclic ketone products in a
highly selective manner. As an instructive example, the reaction
between cyclobutanol 2 and NBS produced cyclopentanone 3as
a single diastereomer (eq 1). The diastereomer that is produced is
important to the halichlorine problem. The relative configura-
tions of the chirality centers in 3 result from (a) the approach
of the electrophilic brominating reagent on the opposite face of
the 6-allyl substituent of the heterocycle and (b) the anti-
orientation of the semipinacol process. Consequently, the
configuration of the 3° spirocyclic carbon atom in 3 has the
alkyl group that migrated in the semipinacol reaction trans to
the bromine substituent. In considering the elaboration of the
ketone functional group in 3 in a manner to establish the
C13-C14 bond of 1, it is immediately recognizable that
compound 3 possesses the incorrect relative stereochemical
configuration for the successful synthesis of 1.
FIGURE 2. An analysis of 1.
of these compounds has been disclosed since their discovery.
This work (up to 2005) has been summarized in an excellent
review.3 The groups of Danishefsky, Heathcock, and Uemura
each have reported completed total syntheses of either hali-
chlorine or pinnaic acid.4 Other groups have completed signifi-
cant progress to the tricyclic core of halichlorine to construct
relay compounds for the formal total syntheses of these natural
products.5 A number of groups have developed new methods
for the formation of the [4.5]-6-azaspirodecane ring system
within 1.6 Our interest in the synthesis of alkaloids that contain
spiro-fused ring systems led us to consider 1 as an engaging
target for synthesis.7
The [4.5]-6-azaspirodecane ring system embedded within 1
served as our inspiration for a possible synthetic route (Figure
2). Our initial analysis centered on the deconstruction of the
(3) Clive, D. L. J.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem. ReV.
2005, 105, 4483–4514.
(4) (a) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1999, 38, 3542–3545. (b) Carson, M. W.; Kim, G.; Hentmann, M. F.; Trauner,
D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4450–4452. (c) Carson,
M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4453–
4456. (d) Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. 2004, 101,
12079–12084. (e) Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007,
46, 5746.
(5) (a) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733–5735. (b)
Clive, D. L. J.; Yu, M.; Li, Z. Chem. Commun. 2005, 906–908. (c) Matsumura,
Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3249–3252. (d) Matsumura,
Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6, 965–968. (e) Arimoto, H.;
Asano, S.; Uemura, D. Tetrahedron Lett. 1999, 40, 3583–3586. (f) Hayakawa,
I.; Arimoto, H.; Uemura, D. J. Chem. Soc, Chem. Commun. 2004, 1222–1223.
(g) Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70, 4954–
4961. (h) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503–8507.
(i) Yu, M.; Clive, D. L. J.; Yeh, V. S. C.; Kang, S.; Wang, J. Tetrahedron Lett.
2004, 45, 2879–2881. (j) Clive, D. L. J.; Wang, J.; Yu, M. Tetrahedron Lett.
2005, 46, 2853–2855. (k) Feldman, K. S.; Perkins, A. L.; Masters, K. M. J.
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Y.; Kohya, M.; Shindo, M.; Shishido, K. Bioorg. Med. Chem. Lett. 2002, 12,
2069–2072.
This observation led us to devise a new synthetic approach
toward 1 (Figure 3). In reconsidering the ring system and its
substituents present in a, we considered a possible solution that
avoided use of the ketone function to establish the C13-C14
bond. Rather, the C13-C14 bond of the target system a would
be incorporated directly in the semipinacol substrate. It is well-
established that, barring unusual geometrical stereoelectronic
constraints,11 more substituted alkyl groups preferentially
perform 1,2-shifts, with retention of configuration of the
migrating center, to electrophilic atoms.12 The substrate required
for such a semipinacol ring expansion reaction could ultimately
derive from a carbonyl addition reaction between an organo-
metallic of structure c and a substituted cyclobutanone d.
(6) For a review, see: (a) Dake, G. Tetrahedron 2006, 62, 3467–3492. (b)
de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617–1619. (c) Koviach, J. L.;
Forsyth, C. J. Tetrahedron Lett. 1999, 40, 8529–8532. (d) Wright, D. L.; Schulte,
J. P., II; Page, M. A Org. Lett. 2000, 2, 1847–1850. (e) Huxford, T.; Simpkins,
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Yokochi, A. F. T. Org. Lett. 2001, 3, 413–415. (g) Takasu, K.; Ohsato, H.;
Ihara, M. Org. Lett. 2003, 5, 3017–3020. (h) Nieczypor, P.; Mol, J. C.; Bespalova,
N. B.; Bubnov, Y. N. Eur. J. Org. Chem. 2004, 812–819. (i) Lee, S.; Zhao, Z.
(S.). Org. Lett. 1999, 1, 681–683. (j) Lee, S.; Zhao, Z., (S.) Tetrahedron Lett.
1999, 40, 7921–7924. (k) Arini, L. G.; Szeto, P.; Hughes, D. L.; Stockman,
R. A. Tetrahedron Lett. 2004, 45, 8371–8374. (l) Yang, S.-H.; Caprio, V. Synlett
2007, 1219–1222. (m) Roulland, E.; Chiaroni, A.; Husson, H. P. Tetrahedron
Lett. 2005, 46, 4065–4068. (n) Fernandez-Gonzalez, M.; Alonso, R. J. Org. Chem.
2006, 71, 6767–6775. (o) Moore, S. P.; Coote, S. C.; O’Brien, P.; Gilday, J.
Org. Lett. 2006, 8, 5145–5148. (p) Kim, H.; Seo, J. H.; Shin, K. J.; Kim, D. J.;
Kim, D. Heterocycles 2006, 70, 143. (q) Adrien, A.; Gais, H.-J.; Kohler, F.;
Runsink, J.; Raabe, G. Org. Lett. 2007, 9, 2155–2158.
(8) (a) Dake, G. R.; Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. J. Org.
Chem. 2004, 69, 5668–5675. (b) Hurley, P. B.; Dake, G. R. Synlett 2003, 14,
2131–2134. (c) Dake, G. R.; Fenster, M. D. B.; Fleury, M.; Patrick, B. O. J.
Org. Chem. 2004, 69, 5676–5683. (d) Fenster, M. D. B.; Patrick, B. O.; Dake,
G. R. Org. Lett. 2001, 3, 2109–2112.
(9) (a) Planas, L.; Perard-Viret, J.; Royer, J.; Selkti, M.; Thomas, A. Synlett
2002, 1629–1632. (b) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem. 2004,
69, 3087–3092. (c) Eom, K. D.; Raman, J. V.; Kim, H.; Cha, J. K. J. Am. Chem.
Soc. 2003, 125, 5415. (d) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem.,
Int. Ed. 2001, 40, 4765. (e) Overman, L. E.; Pennington, L. D. J. Org. Chem.
2003, 68, 7143. For reviews on the pinacol reaction, see: (f) Rickborn, B. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, U.K., 1991; Vol. 3, p 721. (g) Coveney, D. J. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol.
3, p 777.
(7) This work is taken in part from: Hurley, P. B. Ph.D. Thesis, University
of British Columbia, 2006.
4132 J. Org. Chem. Vol. 73, No. 11, 2008

Synthetic Studies toward Halichlorine
semipinacol reaction transition state introduce too high a reaction
barrier? In our view, although this synthetic route contained (a
great deal of) recognized risk, we believed these questions
dealing with structure and reactivity posed were worth examina-
tion. This report describes our investigations of a route to
halichlorine that would utilize a semipinacol process as described
in eq 2 as a crucial step.
Results and Discussion
Metathesis-Based Formation of the Bicyclic Core and
Fragment Synthesis. Very early on in our studies, we had
determined to use ring-closing metathesis to form the tricyclic
ring system of 1.13 We briefly studied this transformation on
model substrate 4 (eq 3). As this metathesis-based approach
has since been reported by Kibayashi in the literature in a formal
total synthesis of 1,5c,d our work on this transformation merits
comment only for one specific reason. We prepared ruthenium
catalyst 5, which is surprisingly not previously reported in the
literature. The desired transformation was completed in 20 min
with use of 5 mol % of 5 at 80 °C. This result compares
favorably to other catalyst systems that require 2-24 h to
catalyze similar transformations.14 Satisfied that the metathesis
process had a reasonable probability for success, we began the
construction of fragments c and d in earnest.
FIGURE 3. A revised analysis of 1.
The proposed semipinacol transformation, if successful, would
provide a spirocyclic synthetic intermediate with its relative
configurations established at C5, C9, C13, and C14 (eq 2). As
predicted from our previous work, the electrophile approach to
the substrate would occur on the face opposite to that of the
allyl substituent. This process would in turn dictate the config-
uration of the 3° carbon center as the migrating alkyl group
would be expected to be delivered anti to that electrophile. In
this way the configuration at C9 would be established by relayed
substrate control from C5. Set correctly in the semipinacol
precursor, the configurations at C13 and C14 should be retained
throughout the semipinacol process. In terms of the stereo-
chemical outcome, the relative stereochemistry of the 3° carbinol
center (starred) should be irrelevant to the proposed transforma-
tion. However, one might expect that the behavior of each
diastereomeric cyclobutanol will differ in terms of reaction
efficiencyswhether or not the semipinacol process proceeds at
all and/or the rate of each semipinacol reaction 2.
It was envisoned that an organometallic such as c could be
derived from transmetalation of an alkenylstannane, as in our
previous work.8a,c The construction of the necessary alkenyl-
stannane commenced with known chiral alcohol 6, prepared by
(10) For other examples of NBS promoted semipinacol rearrangement
reactions see: (a) Maroto, B. L.; Cerero, S de la M.; Mart´ınez, A. G.; Fraile,
A. G.; Vilar, E. T. Tetrahedron: Asymmetry 2000, 11, 3059–3062. (b) Mart´ınez,
A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S de la M.; Maroto, B. L. Tetrahedron
Lett. 2001, 42, 6539–6541. (c) Paquette, L. A.; Owen, D. R.; Bibart, R. T;
Seekamp, C. K.; Kahane, A. L.; Lanter, J. C.; Corral, M. A. J. Org. Chem.
2001, 66, 2828–2834. (d) Hu, X.-D.; Tu, Y. Q.; Zhang, E.; Gao, S.; Wang, S.;
Wang, A.; Fan, C.-A.; Wang, M. Org. Lett. 2006, 8, 1823–1825. (e) Fan, C.-A.;
Tu, Y.-Q.; Song, Z.-L.; Zhang, E.; Shi, L.; Wang, M.; Wang, B.; Zhang, S.-Y.
Org. Lett. 2004, 6, 4691–4694.
Despite the attraction of using a synthetic route that estab-
lishes four stereogenic centers, there are some obvious draw-
backs and concerns. These include the following: (a) the
necessity to produce both the heterocyclic organometallic c and
the substituted cyclobutanol d individually in enantioenriched
form; (b) the efficiency of the proposed carbonyl addition
reaction between c and d; (c) the efficiency and stereofidelity
of the proposed semipinacol transformation; and (d) the instal-
lation of ultimately superfluous functional groupssthe bromine
substituent and the carbonyl functionsthat, having served their
synthetic purpose, would require removal before elaboration to
1 was possible. A number of questions arose from this analysis.
Would the (presumably axially oriented) allyl substituent induce
a high degree of steric strain in the semipinacol transition state?
Does the configuration of the carbon that is migrating into a
1,3-diaxial relationship with this allyl substituent have to be
retained? Would the formative 1,3 diaxial relationship in the
(11) (a) Goodman, R, M.; Kishi, Y J. Am. Chem. Soc. 1998, 120, 9392–
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1991, 4, 319–335. (d) Hawthorne, M. F.; Emmons, W. D. J. Am. Chem. Soc.
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J. Org. Chem. Vol. 73, No. 11, 2008 4133

Hurley and Dake
SCHEME 1. Preparation of Alkenylstannane 10.
SCHEME 2. Synthesis of Functionalized Cyclobutanone 19.
using the method of Brown (Scheme 1).15 The Mitsonobu
reaction of 6 with TsNHBoc proceeded without incident (52%
yield).16 Conversion to lactam 8 was performed by thermal
removal of the Boc protecting group followed by AlMe3-
promoted lactamization.17 The lactam was elaborated to its enol
triflate by using standard conditions (KHMDS, N-phenyltri-
flimide, 95%). The formation of the alkenylstannane moiety with
Pd(0) catalysis with hexamethyldistannane as we had done
previously was very low-yielding in this instance.8a,c,18 Con-
sequently, an alternative method was developed. McMurry had
previously shown that lithium dialkylcuprates would undergo
coupling with ketone-derived enol triflates.19 We postulated that
a similar process would be possible using the stannylcuprates
studied by Piers.20 In a single example, work in the Piers group
had shown that stannylcuprate insertion forming a new C-Sn
bond occurred at a triflate placed at the ꢀ-position of an R,ꢀ-
unsaturated enoate. Consequently, the mechanisms of this earlier
transformation and our proposed process might differ. The
success of our proposed transformation was not assured. In the
event, however, the treatment of enol triflate 9 with lithium
trimethylstannyl copper(I) cyanide (3 equiv) in THF at 0 °C
formed the desired alkenylstannane 10 in 65-73% yields (scale
dependent). As alkenylstannanes are necessary components for
Stille cross-coupling reactions, this method could prove to be
quite useful as an alternative technique for their formation.
A synthetic route reliant on the method of Cha was used for
the construction of a chiral-substituted cyclobutanone such as
d (Scheme 2).21 This route began by using the known epoxide
11.22 Ring-opening of the epoxide was performed with AlMe3
to produce 1,2-diol 12. Selective oxidation of the 1° hydroxyl
group of 12 proved difficult, and so a circuitous route was used.
Protection of both hydroxyl groups with TBSCl and imidazole
was followed by careful deprotection of the less-hindered silyl
ether. Oxidation to methyl ester 16 was performed in a highly
efficient manner with use of a two-step procedure (Dess-Martin
reagent;23 NIS, K2CO3, MeOH, 93% for two steps). This
conversion of aldehydes to methyl esters by using the NIS
method described by McDonald is recommended.24 The methyl
ester was then subjected to a Kulinkovich cyclopropanation
reaction, providing cyclopropanol 17 in essentially quantitative
yield.25 The silyl ether was cleaved, and activation of the
resulting 2° alcohol with MsCl in pyridine resulted in smooth
ring expansion to produce cyclobutanone 19. The relative
stereochemical configurations within 19 were not rigorously
established at this time, but indirect support for the assignments
comes from X-ray crystallographic analysis of a compound
produced later. Synthetic routes to vinylstannane 10 and
cyclobutanone 17 were established. At this stage our challenge
was the reaction between these two fragments. As we anticipated
that this carbonyl addition reaction might be difficult, an
alternative, “sacrificial” substrate for model studies, 2-isopro-
pylcyclobutanone (20), was prepared by using literature methods
(eq 4).26
Carbonyl Addition. The standard procedure that we devel-
oped to perform similar carbonyl addition reactions on simpler
compounds involved the following: (a) transmetalation of the
alkenylstannane with 2.2 equiv of methyllithium in diethyl ether
at 0 °C; (b) in some cases, addition of a metal salt for
transmetalation (typically 2.6 equiv of MgBr2) at -78 °C; and
(c) addition of cyclobutanone (2.7 equiv) in diethyl ether at
(15) Ramachandran, P. V.; Krzeminski, P. V.; Reddy, M. V. R.; Brown,
H. C. Tetrahedron: Asymmetry 1999, 10, 11–15.
(23) For the preparation and use of Dess-Martin periodinane refer to:
Boeckmann, R. K.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141.
(24) McDonald, M.; Holcomb, H.; Kennedy, K.; Kirkpatrick, E.; Leathers,
T.; Vanemon, P. J. Org. Chem. 1989, 54, 1213–1215.
(16) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D., Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709–5712.
(17) Tietze, L. F.; Steck, P. L. Eur. J. Org. Chem. 2001, 22, 4353–4356.
(18) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.;
Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem.
1986, 51, 279.
(25) (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789–
2834. (b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya,
T. S. Zh. Org. Khim. 1989, 25, 2244. (c) Kulinkovich, O. G.; Sviridov, S. V.;
Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh. Org. Khim. 1991,
27, 294. (d) Kulinkovich, O. G.; Sorokin, V. L.; Kel’in, A. V. Zh. Org. Khim.
1991, 29, 66.
(19) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313–4316.
(20) (a) Piers, E.; McEachern, E. J. Synlett 1996, 1087–1090. (b) Piers, E.;
Wong, T.; Ellis, K. A Can. J. Chem. 1992, 70, 2058–2064.
(21) Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337–1339.
(22) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1–20.
(26) (a) Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 9394–9399.
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4134 J. Org. Chem. Vol. 73, No. 11, 2008

Synthetic Studies toward Halichlorine
SCHEME 3. An Inefficient Carbonyl Addition Reaction
SCHEME 4. Carbonyl Addition Reaction with 24
temperatures at or near -100 °C. Clearly, the inherent value
within 19 (chiral nonracemic; 14-step construction) compared
to cyclobutanone would force a search for experimental
parameters that maintained, as best as possible, a 1:1 stoichi-
ometry between 10 and 19. Trial experiments were carried out
with use of 1 equiv of 19 or 20 (Scheme 3).
The first experiment that replicated the conditions stated above
provided the desired cyclobutanol 21 (25%), unreacted ketone
19 (39%) and its epimer, epi-19 (6%). These compounds were
inseparable by chromatography with use of any number of
solvent conditions. The presence of ketone 19 in the reaction
mixture obviously suggested that a deprotonation-derived reac-
tion path was competitive with the desired carbonyl addition
reaction. Similar results for the reaction between 10 and 20 were
obtained. As expected, two diastereomeric cyclobutanols 22a
and 22b were obtained. Both of these diastereomers resulted
from carbonyl addition on the less-hindered face of the racemic
ketone 20. A combined yield of 14% for the diastereomeric
pair was typical.
Substantial effort to improve this process was expended.
Factors that were examined included the following: reaction
temperature; the solvent for the tin-lithium exchange process;
the solvent for the carbonyl addition process; the effect of
(transmetalative) additives such as magnesium bromide, ceri-
um(III) chloride, or ytterbium(III) triflate; and the effect of Lewis
acidicadditivessuchastitanium(IV)chloride,borontrifluoride ·diethyl
etherate among others, reagent stoichiometry, and reagent order
of addition. Substantial improvements to this reaction were not
made. Significantly, the tin-lithium exchange reaction lacked
reproducibility. It was observed that this transmetalation process
occurred very rapidly and effectively in THF, but quite poorly
and/or irreproducibly in diethyl ether. Unfortunately, the car-
bonyl addition reaction only proceeded in high yields when
diethyl ether was the solvent. Attempts to “titrate” a minimum
amount of additive or solvent to the reaction mix in the first
step to facilitate the tin-lithium exchange process were unsuc-
cessful. Similarly, attempts to perform a “solvent switch” from
THF to diethyl ether between the tin-lithium exchange and
the carbonyl addition reaction failed. It appeared that an impasse
was reached. Unless a reasonable solution for this carbonyl
addition problem was found, the project as a whole would
founder.
lithium exchange. Deprotonation was not believed to be
applicable in this instance as attempts in our laboratory to lithiate
compounds similar to 23 with use of s-BuLi resulted in reaction
on the aromatic ring. We therefore decided to explore
halogen-metal exchange. After some experimentation, it was
found that tin-lithium exchange of alkenylstannane 10 in THF
followed by the addition of iodine (5 equiv) proceeded smoothly
to produce the alkenyl iodide 24 (eq 5). Attempts to synthesize
24 by mixing 10 with electrophilic iodine sources were
unsuccessful. Unsurprisingly, 24 would decompose within hours
on the bench at rt but, somewhat to our surprise, could be stored
indefinitely in a foil-wrapped vial in a freezer.
Treatment of alkenyl iodide 24 with 2 equiv of MeLi in
diethyl ether, followed by 20 produced the desired cyclobutanols
22a and 22b in ∼69% yield (Scheme 4). This procedure was
reproducible and gave consistent results for each trial. This
procedure was then applied to the more complex cyclobutanone
19. This procedure did provide sufficient amounts of 21 for
further study, but at yields (25-54%) that were disappointing.
After reasonably successful trials with 24 and 19 on milligram
scale in which 19 was consumed, our reactions at gram-scale
did not proceed as well. Consequently at gram scale, the isolated
cyclobutanol derivative 21 was contaminated with the chro-
matographically inseparable ketone 19. In the end, we were
An alternative to tin-lithium exchange was then considered.
As is well-known, alternative conditions for generating orga-
nolithium species can involve either deprotonation or halogen-
J. Org. Chem. Vol. 73, No. 11, 2008 4135

Hurley and Dake
SCHEME 5. Ring Expansion Reactions of Complex
Substrates
Attempts to form crystals of 25 that were amenable to X-ray
analysis were unsuccessful. The reaction of 25 with excess
DIBAL-H (10 equiv) produced alcohol 28 (eq 6). The NMR
spectra of 28 were unusual because the molecule’s fluxional
behavior in solution led to broad and poorly defined signals.
Fortunately, recrystallization of 28 led to the isolation of X-ray
quality crystals that provide evidence for the structural constitu-
tion of stereochemical assignments of 25. The solid-state
structure confirms that the most-substituted group did migrate
in the NBS-promoted ring-expansion reaction. In the reduction
reaction, hydride was delivered to the ketone face that is
hindered by the bromine atom and not the face blocked by the
p-tolylsulfonyl group and the C4 side chain.
Obviously, we were delighted by the success of the semipi-
nacol process. This sequence had produced a compound that
might serve as a viable intermediate for a halichlorine synthesis.
Key objectives that would need to be performed include the
removal of the p-toluenesulfonyl protecting group, the bromine
function, and the ketone functional group. Unfortunately,
preliminary investigations to achieve these objections produced
some unexpected results. For example, the reaction of spiro-
cyclopentanone 25 with Bu3SnH and AIBN in PhH lead to the
formation of a new compound, 29, whose spectral data clearly
established a compound lacking both the bromine and p-
toluenesulfonyl functionality (Scheme 6). Spectroscopic experi-
ments eventually established its structure. Its formation involves
a Dowd-Beckwith rearrangement,27 followed by explusion of
a p-toluenesulfonyl group. Proton transfer processes produce
the indicated vinylogous amide 29.
The process outlined in Scheme 6 highlights difficulties often
found in our further investigations. The juxtaposition of the
functional groups within 25 could not be dealt with in a
satisfactory manner. We are currently designing an optimized
approach to the spirocyclic core of 1 that will enable (a) the
replacement of the p-toluenesulfonyl protecting group on
nitrogen for a different, more readily removable group, (b) the
development of a more efficient synthesis of cyclobutanol 21,
and (c) the possibility of utilizing an alternative electrophile to
initiate the semipinacol process.
forced to treat the mixture of 19 and 21 with lithium triethyl-
borohydride and then separate to acquire 21.
Ring Expansion. The crucial ring expansion reaction could
then be examined (Scheme 5). To our delight, the treatment of
cyclobutanol 21 with NBS in i-PrOH provided the desired
spirocyclic ketone 25 in 87% yield. The presence of the ketone
functional group was supported by IR and 13C NMR data (1747
cm-1 and 215.5 ppm). Stereochemical assignments were made
initially by using NMR methods (Figure 4). The hydrogen on
the bromine-substituted carbon in 25 was assigned to be
pseudoaxial on the basis of its large coupling constants (δ 4.32,
J ) 12, 5 Hz). NOESY correlations were used to support
stereochemical assignments. Importantly, it was envisoned
(assumed) that 25 resided in a boat-type conformation. This
assumption was based by analogy with the structurally related
compound 3 that has a boat-type conformation in the solid
state.8a Significant NOE correlations between the protons
identified as H4, H10, and H31b strongly support the assignment
that the bromine atom and the ketone attached to the spirocenter
are on the same face of the piperidine ring. Eventually, the
structure and relative stereochemical assignments were con-
firmed by using X-ray crystallography of a derivative (vide
infra). The reactions of 22a and 22b with NBS gave similar
results. That these ring expansions worked efficiently as
designed was extremely satisfying. In each instance, the more
substituted alkyl group underwent preferential migration, with
retention of configuration, in an anti process, providing a single
diastereomeric product. Potential complications due to steric
clashing between the allyl substituent and the migrating group
during the semipinacol reaction did not appear to be significant.
Concluding Remarks
The synthetic studies in this work uncovered a number of
useful observations. The use of a semipinacol reaction to form
a highly functionalized azaspirocyclic compound as a single
diastereomer proceeded very efficiently as designed. Further
noteworthy points included the use of a stannylcuprate reagent
for the construction of an alkenylstannane, and the formation
and use of an unusual 2-iodoenesulfonamide. The power of the
semipinacol process to generate complex structures in a predict-
(27) (a) Dowd, P.; Choi, S. C. J. Am. Chem. Soc. 1987, 109, 3493–3494. (b)
Dowd, P.; Choi, S. C. J. Am. Chem. Soc. 1987, 109, 6548–6549. (c) Beckwith,
A. L. J.; O’Shea, D. N.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565–
2575.
FIGURE 4. NOE experiments supporting assignment of 25.
4136 J. Org. Chem. Vol. 73, No. 11, 2008

Synthetic Studies toward Halichlorine
SCHEME 6. Formation of the Undesired Fused Ring System
11.6 Hz, 2H), 4.05 (d, J ) 4.6 Hz, 1H), 3.77 (s, 3H), 3.66 (s, 3H),
3.50-3.38 (m, 2H), 2.10-2.10 (m, 1H), 1.81-1.71 (m, 1H),
1.49-1.38 (m, 1H), 0.92 (s, J ) 6.7 Hz, 3H), 0.89 (s, 9H), 0.03 (s,
3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 173.6, 159.0,
130.7, 129.1, 113.7, 76.4, 72.3, 67.9, 55.1, 51.4, 34.9, 31.0, 25.7,
18.2, 16.2, -5.1, -5.5. Anal. Calcd for C21H36O5Si: C, 63.60; H,
9.15. Found: C, 63.63; H, 9.38.
(-)-(1S,2S)-1-[4-(4-Methoxybenzyloxy)-1-(tert-butyldimeth-
ylsilyloxy)-2-methylbutyl]cyclopropanol (17). To a stirred solution
of 4.61 g of ester 16 (11.6 mmol, 1 equiv) and 2.92 mL of 95%
chlorotitanium(IV) trisisopropoxide (3.19 g, 11.6 mmol, 1 equiv,
(Aldrich)) in tetrahydrofuran at rt was added 19.4 mL of ethyl-
magnesium bromide (58.1 mmol, 5 equiv, 3 M in diethyl ether
(Aldrich)) over 1 h. The resulting solution was stirred at rt for 5 h.
Diethyl ether (500 mL) and 100 mL of 1 M aqueous hydrochloric
acid were added and the layers were separated. The aqueous layer
was extracted with diethyl ether (2-200 mL). The combined
organic layers were washed with 200 mL of saturated aqueous
sodium bicarbonate and 200 mL of brine. The organic layer was
dried over magnesium sulfate then filtered, and solvents were
removed in vacuo. Purification by column chromatography on silica
gel (25% diethyl ether-petroleum ether) gave 4.59 g (quantitative)
of a clear colorless oil.
able fashion bodes well for its use in the formation of alkaloid
ring systems.
Experimental Section
(+)-(2R)-2-Allyl-1-(toluene-4-sulfonyl)-6-trimethylstannyl-
1,2,3,4-tetrahydropyridine (10). To a stirred solution of 7.60 g
of hexamethyldistannane (23.2 mmol, 3 equiv) in 120 mL of THF
at -41 °C was added 14.5 mL of methyllithium (23.2 mmol, 3
equiv, 1.6 M in diethyl ether (Aldrich)) and the mixture was warmed
to 0 °C for 20 min. After the reaction mixture was cooled to -41
°C, copper(I) cyanide (2.08 g, 23.2 mmol, 3 equiv) was added and
the resulting mixture was stirred at -41 °C for 20 min. A solution
of 3.29 g of enol triflate 9 (7.73 mmol, 1 equiv) in 60 mL of THF
was added and the resulting mixture was stirred at 0 °C for 5 h.
An aqueous solution of ammonium chloride-ammonium hydroxide
(pH ∼8, 100 mL) was added and the resulting mixture was stirred
at rt until the aqueous layer turned blue. Diethyl ether (200 mL)
and 200 mL of water were added and the layers were separated.
The aqueous layer was extracted with diethyl ether (2 × 200 mL).
The combined organic layers were dried over magnesium sulfate
then filtered, and solvents were removed under reduced pressure.
Purification by column chromatography on silica gel (15% diethyl
ether-petroleum ether) gave 2.20 g (65%) of a pale yellow oil.
[R]23.7D -13.92 (c 1.24, CHCl3). IR (thin film) 3440, 2956, 1613,
1587 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.23, J ) 8.6 Hz, 2H),
6.85 (d, J ) 8.6 Hz, 2H), 4.41 (dd, J ) 19.2, 11.6 Hz, 2H), 3.78
(s, 3H), 3.56-3.38 (m, 2H), 2.99 (d, J ) 5.4 Hz, 1H), 2.67 (s, 1
H), 2.16-1.91 (m, 2H), 1.45-1.30 (m, 1H), 0.97 (d, J ) 6.9 Hz,
3H), 0.90 (s, 9H), 0.66-0.49 (m, 2H), 0.46-0.34 (m, 1 H), 0.07
(s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 159.1, 130.7,
129.2, 113.7, 81.0, 72.4, 68.7, 57.6, 55.2, 35.4, 32.0, 26.0, 18.3,
17.1, 13.8, 11.0,-3.7, -4.6. LRMS for C22H38O4Si (ESI+) m/z
(rel intensity) 417 (M+ + Na, 100). Anal. Calcd for C22H38O4Si:
C, 66.96; H, 9.71. Found: C, 67.28; H, 9.83.
(+)-(R)-2-[(S)-4-(4-methoxybenzyloxy)butan-2-yl]cyclobu-
tanone (19). To a stirred solution of 2.89 g of diol 18 (10.3 mmol,
1 equiv) in 100 mL of pyridine at rt was added 8 mL of
methanesulfonyl chloride (11.8 g, 10 equiv) dropwise and the
resulting solution was stirred at rt for 1 h. The reaction was poured
into 100 mL of ice-water. Diethyl ether (200 mL) was added and
the layers were separated. The aqueous layer was extracted with
diethyl ether (2 × 200 mL). The combined organic layers were
washed with 2 M hydrochloric acid (3 × 200 mL), saturated
aqueous sodium bicarbonate (200 mL), and 200 mL of brine. The
organic layer was dried over magnesium sulfate then filtered, and
solvents were removed in vacuo. Purification by column chroma-
tography on silica gel (30% diethyl ether-petroleum ether) gave
2.44 g (90%) of a clear colorless oil.
[R]23.5 +97.8 (c 1.005, CHCl3). IR (NaCl) 2926, 1643, 1598,
D
1342, 1166 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J ) 8.5
Hz, 2H), 7.24 (d, J ) 7.7 Hz, 2H), 5.76 (dddd, J ) 16.1, 11.2, 7.3,
6.9 Hz, 1H), 5.26 (t, J ) 21 Hz, 1H), 5.01 (br s, 1H), 4.97 (d, J )
6.9 Hz, 1H), 3.94-3.85 (m, 1H), 2.34 (s, 3H), 2.35-2.25 (m, 1H),
2.07 (dt, J ) 14.3, 7.3 Hz, 1H), 1.98-1.81 (m, 1H), 1.76-1.57
(m, 1H), 1.41-1.31 (m, 1H), 0.89-0.70 (m, 1H), 0.19 (s, JSn-H
)
27.7 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ 143.0, 138.9, 136.4,
134.8, 129.5, 127.1, 124.0, 117.1, 53.0, 35.4, 21.9, 21.5, 19.4, -6.1.
LRMS for C18H27NO2S120Sn (ESI+) m/z (rel intensity) 464 (M+
K, 16.3), 442 (M+ + Na, 100), 323 (68.9).
+
(-)-(2S,3S)-Methyl 5-(4-methoxybenzyloxy)-2-(tert-butyldim-
ethylsilyloxy)-3-methylpentanoate (16). A 250-mL foil-wrapped
round-bottomed flask was charged with 4.59 g of aldehyde 15 (12.5
mmol, 1 equiv) and 126 mL of methanol. N-Iodosuccinimide (7.04
g, 31.3 mmol, 2.5 equiv) and 4.32 g of potassium carbonate (31.3
mmol, 2.5 equiv) were added and the resulting mixture was stirred
atrtfor2d.Water(200mL)and9gofsodiumthiosulfate·pentahydrate
were added and the resulting mixture was stirred at rt until the
solution became colorless (∼10 min). Diethyl ether (400 mL) was
added and the layers were separated. The aqueous layer was
extracted with diethyl ether (2 × 200 mL). The combined organic
layers were dried over magnesium sulfate then filtered, and solvents
were removed in vacuo. Purification by column chromatography
on silica gel (15% diethyl ether-petroleum ether) gave 4.61 g (93%)
of a clear colorless oil.
[R]21.2D +21.6 (c 1.09, CHCl3). IR (thin film) 2959, 1778 cm-1
.
1H NMR (400 MHz, CDCl3) δ 7.23 (d, J ) 8.7 Hz, 2H), 6.85 (d,
J ) 6.8 Hz, 2H), 4.41 (d, J ) 11.6 Hz, 1H), 4.37 (d, J ) 11.6 Hz,
1H), 3.77 (s, 3H), 3.45 (t, J ) 6.4 Hz, 2H), 3.26-3.18 (m, 1H),
2.93 (dddd, J ) 17.9, 10.5, 7.2, 2.9 Hz, 1H), 2.79 (dddd, J ) 17.8,
[R]23.8 -20.94 (c 0.999, CHCl3). IR (thin film) 2954, 1756,
D
1
1614, 1515, 1250 cm -1. H NMR (400 MHz, CDCl3) δ 7.22 (d,
J ) 8.9 Hz, 2H), 6.84 (d, J ) 8.9 Hz, 2H), 4.38 (dd, J ) 22.3,
J. Org. Chem. Vol. 73, No. 11, 2008 4137

Hurley and Dake
9.8, 3.2, 2.7 Hz, 1H), 2.09-1.92 (m, 2H), 1.86 (dddd, J ) 12.2,
7.0, 7.0, 2.7 Hz, 1H), 1.79-1.69 (m, 1H), 1.46-1.36 (m, 1H), 0.88
(dd, J ) 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 211.7, 159.0,
130.5, 129.1, 113.6, 72.3, 67.6, 65.8, 55.1, 44.1, 34.1, 30.2, 16.5,
from 10% up to 20% diethyl ether-petroleum ether) gave 2.67 g
(77%) of a yellow solid. The solid was stored in an aluminum foil-
wrapped vial in the freezer.
[R]24.0D -1.81 (c 1.03, CHCl3). IR (thin film) 2932, 1692, 1598
13.7. LRMS for C16H22O3 (ESI+) m/z (rel intensity): 285 (M+
+
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.79 (d, J ) 8.1 Hz, 2H),
Na, 100). Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C,
73.01; H, 8.54.
7.28 (d, J ) 8.1 Hz, 2H), 6.22 (t, J ) 3.9 Hz, 1H), 5.55 (dddd, J
) 17.0, 9.7, 7.1, 7.1 Hz, 1H), 5.07-4.93 (m, 2H), 4.27 (ddd, J )
9.1, 6.7, 3.6 Hz, 1H), 2.41 (s, 3H), 2.41-2.24 (m, 1H), 2.10-1.80
(m, 3H), 1.67-1.69 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 144.0,
136.1, 134.3, 129.5, 128.0, 117.8, 81.0, 56.7, 34.8, 24.2, 23.3, 21.6.
(-)-(4R,5S,7R,10S)-7-Allyl-10-bromo-4-[(1S)-3-(4-methoxy-
benzyloxy)-1-methylpropyl]-6-(toluene-4-sulfonyl)-6-
azaspiro[4.5]decan-1-one (25). To a stirred solution of 41 mg of
allylic alcohol 24 (76.0 µmol, 1 equiv) in 2 mL of a 1:1 mixture of
propylene oxide and 2-propanol at -78 °C was added 16.2 mg of
N-bromosuccinimide (91.2 µmol, 1.2 equiv). The resulting mixture
was stirred at -78 °C for 2 h and warmed to rt overnight (∼14 h).
After concentration in vacuo, purification by column chromatog-
raphy on silica gel (25% diethyl ether-petroleum ether) gave 41
mg (87%) of a clear colorless oil.
Allylic Alcohol 21 via Iodide 24. To a stirred solution of 3.25 g
of alkenyl iodide 24 (8.07 mmol, 1 equiv) in 57 mL of diethyl
ether at -78 °C was added 11.1 mL of methyllithium (16.1 mmol,
2 equiv, 1.46 M in diethyl ether (Aldrich)) and the resulting solution
was stirred at -78 °C for 10 min. A solution of 2.12 g of
cyclobutanone 19 (8.07 mmol, 1 equiv) in 57 mL of diethyl ether
was added and the resulting solution was stirred at -78 °C for 3 h.
After the solution was warmed to rt, water (50 mL) was added and
the layers were separated. The aqueous layer was extracted with
diethyl ether (2 × 50 mL). The combined organic layers were dried
over magnesium sulfate then filtered, and solvents were removed
in vacuo. Purification by column chromatography on silica gel (30%
diethyl ether-petroleum ether) gave 2.35 g of crude product. This
material was used in the next step without further purification.
[R]21.8D +136.0 (c 0.48, CHCl3). IR (thin film) 3527, 2952, 1642,
1614, 1515 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J ) 8.3
Hz, 2H), 7.25 (d, J ) 7.5 Hz, 2H), 7.21 (d, J ) 8.6 Hz, 2H), 6.82
(d, J ) 8.6 Hz, 2H), 5.86-5.71 (m, 2H), 5.08-4.99 (m, 2H), 4.39
(d, J ) 19.0 Hz, 1H), 4.35 (d, J ) 19.0 Hz, 1H), 4.11-4.00 (m,
1H), 3.80-3.77 (m, 1H), 3.77 (s, 3H), 3.59-3.36 (m, 2H),
2.51-3.36 (m, 2H), 2.40 (s, 3H), 2.14-1.91 (m, 3H), 1.91-1.72
(m, 3H), 1.52 (dddd, J ) 18.7, 6.8, 3.3, 3.3 Hz, 1H), 1.30-1.04
(m, 3H), 0.84 (d, J ) 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
158.9, 143.7, 141.5, 135.8, 134.7, 131.0, 129.6, 129.1, 127.7, 119.1,
117.3, 113.6, 77.9, 72.3, 68.7, 55.2, 55.1, 49.9, 37.4, 36.4, 34.7,
30.4, 23.0, 21.6, 20.3, 19.0, 16.1. LRMS for C31H41NO5S (ESI+)
m/z (rel intensity): 562 (M+ + Na, 100).
[R]26.3D -110.4 (c 0.78, CHCl3). IR (thin film) 2953, 1747, 1614,
1
1515 cm-1. H NMR (400 MHz, CDCl3) δ 7.82 (d, J ) 8.3 Hz,
2H), 7.27 (d, J ) 8.2 Hz, 2H), 7.25 (d, J ) 8.9 Hz, 2H), 6.84 (d,
J ) 8.6 Hz, 2H), 5.54 (dddd, J ) 17.1, 10.3, 8.1, 5.7 Hz, 1H),
5.02-4.90 (m, 2H), 4.44 (d, J ) 15.5 Hz, 1H), 4.41 (d, J ) 15.4
Hz, 1H), 4.32 (dd, J ) 12.2, 4.8 Hz, 1H), 3.76 (s, 3 H), 3.67-3.59
(m, 1H), 3.59-3.41 (m, 2H), 2.82-2.70 (m, 2H), 2.58-2.29 (m,
5H), 2.39 (s, 3H), 2.17 (m, 1H), 1.98 (ddd, J ) 18.6, 9.3, 4.6 Hz,
1H), 1.88-1.79 (m, 1H), 1.69 (dd, J ) 13.1, 6.7 Hz, 1H), 1.61-1.50
(m, 1H), 1.35-1.22 (m, 1H), 1.13 (d, J ) 6.8 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 215.5, 159.2, 143.5, 136.8, 134.7, 130.6, 129.5,
129.3, 128.8, 117.9, 113.8, 72.9, 71.6, 67.8, 55.2, 53.9, 53.0, 48.3,
43.2, 39.0, 37.6, 27.8, 25.9, 23.8, 21.5, 21.4, 17.0. LRMS for
C31H4081BrNO5S (ESI+) m/z (rel intensity): 642 (M+ + Na, 100).
(-)-(2R)-2-Allyl-6-iodo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahy-
dropyridine (24). To a stirred solution of 3.80 g of alkenyl stannane
10 (8.6 mmol, 1 equiv) in 38 mL of THF at -78 °C was added
7.10 mL of methyllithium (10.3 mmol, 1.2 equiv, 1.46 M in diethyl
ether (Aldrich)) and the resulting solution was stirred at -78 °C
for 10 min. This solution was transferred to another solution of
11.0 g of iodine (43.2 mmol, 5 equiv) in 28 mL of THF at -78
°C. The resulting reaction mixture was stirred at -78 °C for 1 h
and warmed to rt over 1 h. A solution of 15.0 g of sodium
thiosulfate pentahydrate (60.4 mmol, 1.4 equiv relative to iodine)
in 50 mL of water was added and the resulting biphasic mixture
was stirred at rt for 10 min. Diethyl ether (100 mL) was added and
the layers were separated. The aqueous layer was extracted with
diethyl ether (2 × 50 mL). The combined organic layers were dried
over magnesium sulfate then filtered, and solvents were removed
in vacuo. Column chromatography on silica gel (ran in gradient
Acknowledgement. The authors thank the University of
British Columbia, the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada, GlaxoSmithKline, and
Merck-Frosst for the financial support of our programs. We
thank Dr. Brian Patrick, Manager of the UBC X-Ray Facility,
for the determination of the solid state molecular structure of
28.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 4-29. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800336K
4138 J. Org. Chem. Vol. 73, No. 11, 2008