Neighboring effect of the lactam functionality in select reactions of 6-azaspiro[4.5]decane-1,7-dione

Article abstract of DOI:10.1016/j.tet.2005.08.091

The susceptibility of 6-azaspiro[4.5]decane-1,7-dione (4) to nucleophilic attack was evaluated. Although steric effects preclude the 1,2-addition of many reagents, more reactive lithium and Grignard species react. Attack from the direction syn to the lact

Full text of DOI:10.1016/j.tet.2005.08.091

Tetrahedron 61 (2005) 11000–11009
Neighboring effect of the lactam functionality in select reactions
of 6-azaspiro[4.5]decane-1,7-dione
*
David G. Hilmey, Judith C. Gallucci and Leo A. Paquette
The Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Received 8 June 2005; revised 15 August 2005; accepted 22 August 2005
Available online 16 September 2005
Abstract—The susceptibility of 6-azaspiro[4.5]decane-1,7-dione (4) to nucleophilic attack was evaluated. Although steric effects preclude
the 1,2-addition of many reagents, more reactive lithium and Grignard species react. Attack from the direction syn to the lactam functionality
predominates. The acid-catalyzed rearrangement of select products delivered allylic alcohols carrying their double bond at varying distances
from the spirocyclic carbon. These designed systems undergo hydrogenation predominantly from that p-surface syn to the amide component,
the more so when a hydroxyl is proximate to these hetero atoms. The same phenomenon operates when N-benzoylated intermediates are
hydrolyzed with potassium carbonate in methanol.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Despite the advances made in this area, surprisingly little
use has been made of stereospecific ring expansion reactions
to generate functionalized targets. The Baeyer-Villiger
oxidation of 1 to give 29 and the Beckmann rearrangement
of 3 to form 410 are illustrative examples. As a consequence,
there has been minimal exploration of spiroacetals and keto
lactams having these general structural characteristics
(Scheme 1). In this report, we detail a selection of reactions
to which 4 has been subjected. Functional group compati-
bility and chemoselectivity are, of course, two ever-present
issues. Where relevant and possible, the level of stereo-
control and the preferred direction of reagent approach are
established unequivocally. As will be made clear, the amide
moiety exerts profound consequences on the stereochemical
course of reactions occurring at the neighboring five-
membered ring. An example is also provided of reciprocal
effects
The structural features peculiar to spirocyclic compounds
have fascinated organic chemists for several decades.
In carbocyclic systems, great strides have been made since
the chemical and chiroptical properties of Fecht’s acid1 and
spiro[3.3]hepta-1,5-diene2 were elucidated in the 1970s.
Particularly striking in the intervening years have been the
many developments involving the adaptation of new
reagents and tactics to bring about spirocyclization events.3
The elaboration of oxygen- and sulfur-containing analogs
has recently been extended to include spirocyclic nucleo-
sides.4 Nature has contributed to the heightened interest in
nitrogen derivatives5 by serving as the source of bioactive
alkaloids such as perhydrohistrionicotoxin,6 pinnaic acid,7
and halichlorine.8
Keywords: Spirocycles; Lactams; Carbonyl additions; Rupe rearrangement;
Heteroatomic effects.
*
Corresponding author. Tel.: C1 614 292 2520; fax: C1 614 292 1685;
e-mail: paquette.1@osu.edu
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.091

D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
11001
2. Results and discussion
consequence if dehydration is ultimately contemplated. For
example, ozonolysis of 6 in the presence of methanolic
sodium hydroxide19 results in smooth conversion to hydroxy
ester 7. Alternate involvement of the 5/6 mixture gave rise to
a diastereomeric mixture with comparable efficiency.
Subsequent treatment of 7 with triflic acid in 1,2-dichlor-
oethane20 provided b,g-unsaturated ester 8 with a minimum
of Wagner-Meerwein rearrangement products.
The determination of SN2 solvolysis rates, which showed
neopentyl systems to react at a level 10K5 that exhibited by
the corresponding ethyl derivative,11 provided a proper
forum for appreciating the strong deceleration effect of alkyl
substitution proximal to a reaction center.12 In a similar
manner, the tetrahedral mechanism for substitution at a
carbonyl carbon is equally slowed or blocked completely
when steric crowding is elevated.13 The pronounced
deceleration associated with both processes is adequate to
render such substrates synthetically useless in most cases.
These consequences can be expected to complicate the
chemistry of 4, although in more subtle ways. With regard to
the diastereotopic faces of the ketone carbonyl group in this
spirocycle, one is syn to a polymethylene chain while
the other is flanked by the nitrogen atom that is part of the
lactam functionality. Depending on the basicity of the
reagent to which 4 is being subjected, deprotonation may
operate at N, chelation may become an operational factor,
and other forms of complexation could play a role in making
matters more mechanistically complex. The extent to which
the title compound is sensitive to one or more of these
phenomena is certain to impact upon its reactivity and to
offer intriguing opportunities for control of stereoselectivity
during nucleophilic capture when operational.
Next to be considered was the possibility of introducing an
acetylide side chain for the purpose of implementing a
subsequent Rupe rearrangement.21 Admixture of 4 with an
excess of lithiated trimethylsilylacetylene resulted in a rapid
reaction at K78 8C and gave rise to a single carbinol, the
stereochemistry of which was assumed to be as shown in
Scheme 3 as a result of the reduced size of the sp-hybridized
nucleophile. Following application of the conventional
protodesilylation protocol,22 the action of potassium
carbonate in methanol on this adduct furnished 9, the
three-dimensional features of which were unequivocally
established by X-ray crystallographic analysis. The iso-
merization of 9 under the standard conditions of sulfuric
acid–acetic acid at the reflux temperature23 gave 10,
although only in an average yield of 25%. An extended
search for an improved way to accomplish this transform-
ation was rewarded with the discovery that modest
quantities of triflic acid (ca. 5 equiv) in 1,2-dichloroethane
at rt promotes rapid and efficient conversion to the
a,b-unsaturated keto lactam 10 (82%).
In line with the points of emphasis made above, 4 proved to
be totally unreactive to such well-known transformations
as the Horner-Wadsworth-Emmons,14 Wittig,15 Refor-
matsky,16 and Peterson reactions.17 When we uncovered
the comparative inertness of 4 toward lithium ynolates such
as H3C–^–OKLiC,18 it was quite apparent that recourse
needed to be made to more reactive organometallic reagents.
To this end, 4 was admixed at 0 8C with 3 equiv of
allylmagnesium bromide in THF. In this instance, the
diastereomeric carbinols 5 and 6 were formed in a 1:3 ratio
and a combined yield of 82% (Scheme 2). The ease of
chromatographic separation of 5 from 6 facilitated the
stereochemical assignments which were made by analogy to
9 (see below) and concluded that the preferred trajectory of
attack was from that direction syn to the amide linkage.
Attempts to gain further confirmation by NOE methods
proved inclusive. However, this product partitioning is of no
Scheme 3.
Interestingly, the stereochemical outcome of the hydro-
genation of 10 at 1 atm proved to be catalyst dependent.
When recourse was made to 10% palladium on charcoal in
ethyl acetate, 11 and 12 were produced in a 1:1.7 ratio
(Scheme 3). When the alternative use of platinum oxide in
methanol or ethyl acetate was screened, diastereomer 11
now predominated. Accordingly, either dihydro product can
be generated as the major constituent simply by switching
the catalyst system.
Our ability to separate 11 from 12 by chromatographic
means allowed for proper assessment of their equilibrium
Scheme 2.

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D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
distribution as well as unequivocal definition of their three-
dimensional structure. Independent admixing of pure
samples of 11 and 12 with DBU in benzene at rt resulted
in quantitative conversion to a 1:1.7 mixture favoring 12 in
both instances as determined by 1H NMR prior to
chromatography. These findings reveal the greater thermo-
dynamic advantage associated with that arrangement where
the acetyl group is oriented anti to the amide functionality
(Scheme 4).
Scheme 4.
Scheme 6.
With 11 and 12 available, the stage was set to scrutinize the
level of stereoselective hydrogenation that operates at an
olefinic site more distal from the spirocyclic carbon. This
phase of the investigation began by exploring the feasibility
of adding vinyllithium individually to this pair of methyl
ketones. In the event, 12 gave rise to the single 1,2-adduct
13 (Scheme 5), whereas 11 was transformed into a 3:1
mixture of diastereomeric carbinols 18 (Scheme 6). This
distinction was not an issue of consequence since our focus
was to effect allylic rearrangement to 14 and 19,
respectively. Best results were achieved with triflic acid as
the promoter in acetic acid solution. In both series, the
geometry about the newly introduced double bond follows
rigorously from unambiguous NMR spectral features that
reveal a syn relationship of the CH3 and CH2OAc groups.
Following the conversion of 14 and 19 to 15 and 20,
respectively, these alcohols were subjected to an array of
hydrogenation catalysts under H2 at different pressures. In
all cases, hydrogenolytic removal of the hydroxyl group
prevailed heavily or operated exclusively. These data
conform to the steric crowding about the double bond and
its trisubstituted nature. Usefully, this unwanted reaction
could be effectively skirted simply by performing the
reduction in THF over a mixture of NaHCO3 and PtO2.24
Under these conditions, 15 led to a 2:1 mixture of the
chromatographically separable carbinols 16 and 17. Proper
structural definition of these diastereomers was achieved by
X-ray crystallographic analysis of the latter. This distinction
revealed the more favored saturation of the double bond in
15 to occur from that p-surface syn to the heteroatomic
component of the lactam in the conformation shown.
While the hydrogenation of 20 proved to be equally optimal
at 94%, we were unable to bring about the separation of 21
from 22. 1H NMR analysis indicated the production
distribution to be 1.5:1, but more specific stereochemical
characterization was not posssible.
It is well to recognize at this point that addition of the
2-propenyl Grignard or lithium reagent to 4 holds the
prospect of ultimately introducing a double bond that is both
tetrasubstituted and positioned immediately adjacent to the
spirocyclic carbon. Another distinction that sets 24 and 25
apart is the rigidly fixed nature of their geometry. As
indicated in Scheme 7, the efficiency associated with use of
the lithium reagent (82%) is more elevated than that of the
bromomagnesium counterpart (67%). Both coupling
reactions gave 23 as a single diastereomer that was directly
rearranged and hydrolyzed as before. The Rf values of 24 and
25 on silica gel are widely disparate, thereby facilitating their
clean separation. The connectivity between 24 and its
dihydro derivatives 26 and 27 rests entirely on the
directionality of hydrogen attachment. In this example, a
4:1 mixture of 26 and 27 was generated. The stereochemistry
assigned to major product 26 followed convincingly from the
results of an X-ray crystallographic determination. This
finding established that the saturation of 24 occurs preferably
from that direction syn to the lactam nitrogen. In the
companion example involving 25, a lone dihydro product
was obtained and formulated as 28 by analogy. Further
verification via the preparation of 29 was not realized
because of the poor crystalline quality of the p-nitrobenzoate.
Beyond this, it was of interest to functionalize the amide
group with a view of assessing possible divergences in
favored reaction pathways operational in at least one set of
geometric isomers. To this end, 23 was transformed into a
3:2 mixture of allylic formates 30 (89%), direct
Scheme 5.

D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
11003
Scheme 7.
benzoylation of which at nitrogen was achieved by stirring
with benzoyl chloride in benzene at the reflux temperature25
(Scheme 8). In practice, this transformation made possible
the independent isolation of 31 and 32. These isomers were
unequivocally identified by three-step chemical conversion
of the previously characterized 23 to 34. Once this issue had
been clarified, it was recognized that brief (15 min)
hydrolysis of 31 and 32 with K2CO3 in methanol had
quite different consequences. Where 32 is concerned,
removal of the formate residue was kinetically dominant.
Deacylation was also experienced by 31, but cleavage of the
lactam ring to furnish 33 was clearly competitive if not
faster. These observations clearly implicate the operation of
neighboring group participation involving the allylic
hydroxyl. When the latter is in close proximity to the
amide linkage, its methanolysis is significantly accelerated.
Scheme 8.
4 requires recourse to reactive Grignard and lithium
reagents to achieve 1,2-addition. These reactions proceed
with a reasonable preference for attack syn to the amido
group. These transformations can be followed by acid-
catalyzed rearrangement to generate intermediates carrying
a double bond at various distances from the spirocyclic
carbon. Despite the diversity in architecture of the resulting
unsaturated alcohols, their catalytic hydrogenation proceeds
most often with an appreciable bias for syn-selective
saturation. This stereoselectivity reaches a maximum
when a hydroxyl group is situated in close proximity to
the lactam functionality. Finally, the differing hydrolysis
pathways adopted by 31 and 32 indicate that this type of
molecular structure has an intrinsic capability to rely on
neighboring group participation involving hetero atoms
resident on the opposite rings.
3. Conclusions
6-Azaspiro[4.5]decane-1,7-dione (4) has proven to be a
versatile device for clarifying the stereoselectivities of
select chemical transformations involving functionalized,
nitrogen-containing spirocycles. Various ways have been
taken to further develop the basic functionality resident in 4
and to identify the chemical consequences of such structural
modifications. The hindered nature of the ketone carbonyl in
4. Experimental
4.1. General
4.1.1. Allylmagnesium bromide addition to 4. A solution
of 4 (0.60 g, 3.6 mmol) in dry THF (50 mL) was cooled to

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D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
0 8C and treated dropwise with 21.5 mL of 0.5 M
allylmagnesium bromide (10.7 mmol) in the same solvent.
The reaction mixture was allowed to warm to rt and
quenched after 10 min with saturated NH4Cl solution. The
separated aqueous layer was extracted with CH2Cl2 (3!),
and the combined organic phases were dried and evaporated
to leave a residue that was chromatographed on silica gel.
Elution with 10% methanol in 1:1 ethyl acetate/hexanes
gave 188 mg (25%) of 5 and 428 mg (57%) of 6, both as
colorless oils.
50 mL of THF was introduced dropwise. The reaction
mixture was allowed to warm slowly to rt, stirred for 2 h,
quenched with saturated NH4Cl solution, and extracted with
CH2Cl2 (3!). The combined organic phases were dried and
freed of solvent to leave the protected propargyl alcohol that
was immediately taken up in methanol (20 mL), treated
with 3 equiv of potassium carbonate and stirred for 30 min.
Water was added and the product was extracted into CH2Cl2
(3!). The combined organic phases were dried and
evaporated to leave a residue that was purified by
chromatography on silica gel. Elution with 8% methanol
in 1:1 ethyl acetate/hexanes gave 9 (1.39 g, 70%) as a white
solid, mp 165 8C; IR (neat, cmK1) 3243 (br), 1642, 1402; 1H
NMR (300 MHz, CDCl3) d 6.08 (br s, 1H), 3.49 (s, 1H),
2.64 (s, 1H), 2.41–2.10 (m, 4H), 2.00–1.52 (series of m,
8H); 13C NMR (75 MHz, CDCl3) d 172.9, 84.6, 78.1, 75.7,
67.1, 37.0, 35.8, 31.2, 25.7, 17.6, 17.2; ES HRMS calcd for
C11H15NO2NaC m/z 216.0995, obsd 216.0995.
1
Compound 5. IR (neat, cmK1) 3390 (br), 1650, 1449; H
NMR (300 MHz, CDCl3) d 6.04 (s, 1H), 5.85 (m, 1H), 5.17
(s, 1H), 5.12 (d, JZ8.5 Hz, 1H), 2.31–2.11 (m, 4H), 2.07 (s,
1H), 1.99–1.41 (m, 10H); 13C NMR (75 MHz, CDCl3) d
172.6, 133.6, 119.3, 83.1, 68.0, 39.5, 38.4, 35.8, 31.5, 27.1,
18.5, 18.2; ES HRMS calcd for C12H19NO2NaC m/z
232.1308, obsd 232.1316.
Compound 6. IR (neat, cmK1) 3381 (br), 1634, 1466; H
1
4.1.5. Rupe rearrangement of 9. A solution of 9 (0.60 g,
3.1 mmol) in dichloroethane (60 mL) was blanketed with
N2 and treated dropwise with trifluoromethanesulfonic acid
(1.37 mL, 15.5 mmol). The reaction mixture developed a
red/purple hue with slow formation of a brown oil, and was
poured onto ice water after 4 h. The product was extracted
into CH2Cl2 (4!), dried, and evaporated. Chromatography
of the residue on silica gel (elution with 8% methanol in 1:1
ethyl acetate/hexanes) furnished 498 mg (82%) of 10 as a
white solid, mp 188–189 8C (from 1:1 ethyl acetate/
hexanes); IR (neat, cmK1) 3192 (br), 1651, 1404; 1H
NMR (300 MHz, CDCl3) d 6.87 (t, JZ1.3 Hz, 1H), 5.77
(br s, 1H), 2.64–2.35 (m, 4H), 2.42 (s, 3H), 2.22–2.14 (m,
2H), 2.00–1.56 (m, 4H); 13C NMR (75 MHz, CDCl3) d
195.1, 172.4, 146.7, 146.6, 67.4, 40.3, 31.2, 30.5, 29.1, 28.0,
18.7; ES HRMS calcd for C11H15NO2NaC m/z 216.0995,
obsd 216.1003.
NMR (300 MHz, CDCl3) d 6.74 (s, 1H), 5.83 (m, 1H), 5.09
(s, 1H), 5.03 (d, JZ8.5 Hz, 1H), 3.52 (s, 1H), 2.31–2.00 (m,
4H), 1.90–1.59 (m, 7H), 1.53–1.45 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 172.2, 133.5, 118.6, 81.3, 65.9, 39.5,
35.6, 35.2, 31.1, 27.0, 17.8, 17.5; ES HRMS calcd for
C12H19NO2NaC m/z 232.1308, obsd 232.1310.
4.1.2. Ozonolysis of 6. An 88 mg (0.42 mmol) sample of 6
was dissolved in CH2Cl2 (5 mL), cooled to K78 8C, and
treated with 0.84 mL of 2.5 M sodium hydroxide in
methanol. Ozone was introduced at this temperature until
a blue color developed. The reaction mixture was diluted
with ether and water, and warmed to rt. The separated
aqueous layer was extracted with CH2Cl2, and the combined
organic phases were dried and concentrated. Chromato-
graphy of the residue on silica gel (elution with 10%
methanol in 1:1 ethyl acetate/hexanes) afforded 65 mg
(65%) of 7 as a colorless oil; IR (neat, cmK1) 3381 (br),
1734, 1646; 1H NMR (300 MHz, CDCl3) d 7.11 (br s, 1H),
5.60 (s, 1H), 3.68 (s, 3H), 2.56 (d, JZ15.5 Hz, 1H), 2.42 (d,
JZ15.5 Hz, 1H), 1.98–1.36 (m, 12H); 13C NMR (75 MHz,
CDCl3) d 173.3, 171.9, 80.2, 66.1, 52.0, 37.9, 35.0, 34.8,
31.2, 27.0, 17.8, 17.5; ES HRMS calcd for C12H19NO4NaC
m/z 264.1206, obsd 264.1214.
4.1.6. Hydrogenation of 10. A. Over 10% palladium on
charcoal. To a solution of 10 (180 mg, 0.93 mmol) in ethyl
acetate (30 mL) was added 18 mg of 10% Pd/C. Hydrogen
was bubbled into the mixture, which was stirred under a
balloon of H2 for 30 min prior to filtration through a pad of
Celite and evaporation of solvent. Chromatography of the
residue on silica gel (elution with 5% isopropyl alcohol in
CH2Cl2) afforded 55 mg of 11 and 95 mg of 12 (83% total)
as colorless oils that solidified on standing.
4.1.3. Dehydration of 7. A solution of 7 (22 mg,
0.09 mmol) in CH2Cl2 was treated with trifluoromethane-
sulfonic acid (0.161 mL, 1.83 mmol) at rt under N2. After
15 min, ice water was added and the product was extracted
in CH2Cl2 (3!). The combined organic layers were dried
and evaporated to leave 10 mg (49%) of oily 8; IR (neat,
1
Compound 11. IR (neat, cmK1) 3207 (br), 1704, 1659; H
NMR (500 MHz, CDCl3) d 6.23 (br s, 1H), 2.93 (t, JZ
6.3 Hz, 1H), 2.35 (t, JZ6.2 Hz, 2H), 2.20 (s, 3H), 2.01–1.87
(m, 8H), 1.74–1.61 (m, 2H); 13C NMR (125 MHz, CDCl3) d
210.0, 171.4, 64.8, 59.5, 40.2, 34.0, 31.4, 31.2, 27.4, 21.4,
18.0; ES HRMS calcd for C11H17NO2NaC m/z 218.1151,
obsd 218.1144.
1
cmK1) 1737, 1658, 1642; H NMR (300 MHz, CDCl3) d
5.85 (s, 1H), 5.78 (s, 1H), 3.69 (s, 3H), 3.04 (q, JZ15.0 Hz,
2H), 2.51–2.10 (m, 4H), 2.04–1.73 (m, 6H); 13C NMR
(75 MHz, CDCl3) d 172.3, 172.0, 139.2, 131.8, 69.3, 52.3,
39.3, 32.2, 31.3, 30.3, 28.7, 18.6; ES HRMS calcd for
C12H17NO3NaC m/z 246.1101, obsd 246.1109.
Compound 12. Mp 138–139 8C; IR (neat, cmK1) 3391 (br),
1703, 1655; 1H NMR (500 MHz, CDCl3) d 7.28 (br s, 1H),
2.96 (t, JZ8.9 Hz, 1H), 2.37 (t, JZ4.9 Hz, 1H), 2.32–2.22
(m, 1H), 2.18 (s, 3H), 2.10–2.02 (m, 1H), 2.01–1.93 (m,
1H), 1.91–1.83 (m, 1H), 1.81–1.68 (m, 5H), 1.67–1.62 (m,
1H), 1.57–1.48 (m, 1H); 13C NMR (125 MHz, CDCl3) d
208.7, 172.8, 65.3, 61.4, 40.5, 32.0, 31.3, 27.7, 24.7, 20.1,
4.1.4. Acetylenic carbinol 9. A cold (K78 8C) solution of
trimethylsilylacetylene (5.75 mL, 40.7 mmol) in dry THF
(100 mL) was treated with n-butyllithium (26.3 mL of
1.55 M in hexane, 40.7 mmol) and allowed to warm to rt.
After return to K78 8C, a solution of 4 (1.7 g, 10.2 mmol) in

D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
11005
17.9; ES HRMS calcd for C11H17NO2NaC m/z 218.1151,
obsd 218.1159.
chromatography on silica (elution with 8% methanol in
1:1 ethyl acetate/hexanes) afforded 15 as a colorless oil; IR
1
(neat, cmK1) 3280 (br), 1649, 1407; H NMR (300 MHz,
B. Over platinum oxide. A solution of 10 (290 mg,
1.5 mmol) in methanol (50 mL) was admixed with platinum
oxide (20 mg) and stirred under H2 at 1 atm for 1.5 h prior to
filtration through Celite, solvent evaporation, and chroma-
tography as above. There was isolated 110 mg of 12 and
150 mg of 11.
CDCl3) d 6.91 (br s, 1H), 5.45 (t, JZ5.3 Hz, 1H), 4.18 (dd,
JZ3.6, 6.5 Hz, 2H), 2.44–2.33 (m, 1H), 2.27 (t, JZ4.3 Hz,
1H), 2.20–2.11 (m, 1H), 1.89–1.51 (series of m, 12H), 1.49–
1.38 (m, 2H); 13C NMR (75 MHz, CDCl3) d 172.6, 136.2,
126.9, 64.7, 59.2, 57.4, 40.0, 31.2, 27.6, 26.0, 20.0, 17.5,
17.3; ES HRMS calcd for C13H21NO2NaC m/z 246.1464,
obsd 246.1469.
4.1.7. Base-promoted equilibration of 11 with 12. Either
keto lactam 11 or its diastereomer 12 (300 mg, 1.54 mmol)
was dissolved in benzene (30 mL), blanketed with N2, and
treated with DBU (1.15 mL, 7.68 mmol). Stirring was
maintained for 3 days prior to removal of the solvent
under reduced pressure. The residue was subjected to
chromatography (elution with 5% isopropyl alcohol in
CH2Cl2) to afford in both cases 189 mg of 12 and 111 mg of
11.
4.1.10. Hydrogenation of 15. A 44 mg (0.20 mmol) sample
of 15 in THF (5 mL) was admixed with sodium bicarbonate
(45 mg) and platinum oxide (4.5 mg). Hydrogen was
bubbled though the mixture for 5 min and stirring was
maintained for 1 h under a balloon filled with H2. The
reaction mixture was filtered through Celite and concen-
trated. Subsequent chromatography on silica gel (elution
with 10% hexanes in acetone) furnished 28 mg of 16 and
14 mg of 17 (91% total).
Vinylation of 12. A cold (K78 8C) solution of tributyl-
vinyltin (0.45 mL, 1.54 mmol) in dry THF (6 mL) was
treated with n-butyllithium (1.0 mL of 1.55 M in hexane),
allowed to warm to rt, returned to K78 8C, and admixed
dropwise with ketone 12 (100 mg, 0.50 mmol) dissolved in
THF (4 mL). The reaction mixture was stirred for 1 h,
warmed to rt, and quenched with saturated NH4Cl solution.
The product was extracted into CH2Cl2 (3!), and the
combined organic phases were dried and evaporated to
leave a residue that was chromatographed on silica gel.
Elution with 8% methanol in 1:1 ethyl acetate/hexanes
afforded colorless oily 13 as a single diastereomer; IR (neat,
cmK1) 3375 (br), 1643, 1408; 1H NMR (300 MHz, CDCl3)
d 7.10 (br s, 1H), 5.94 (dd, JZ10.7, 17.2 Hz, 1H), 5.16 (dd,
JZ1.2, 17.2 Hz, 1H), 4.98 (dd, JZ1.2, 10.8 Hz, 1H), 2.39–
2.23 (m, 3H), 2.00–1.45 (m, 11H), 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 172.8, 145.6, 111.0, 74.2, 64.4, 56.7,
40.4, 29.8, 28.7, 26.1, 24.0, 19.0, 17.8; ES HRMS calcd for
C13H21NO2NaC m/z 246.1464, obsd 246.1474.
Compound 16. White solid, mp 148 8C; IR (neat, cmK1
)
1
3278 (br), 1649, 1408; H NMR (500 MHz, CDCl3) d 6.43
(s, 1H), 3.75–3.70 (m, 1H), 3.67–3.62 (m, 1H), 2.49–2.16
(m, 3H), 2.10–1.89 (m, 2H), 1.88–1.49 (series of m, 10H),
1.40–1.31 (m, 2H), 0.97 (d, JZ7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 172.1, 64.2, 60.3, 54.4, 40.2, 38.3,
31.4, 30.8, 27.7, 24.9, 19.2, 18.0, 17.5; ES HRMS calcd for
C13H23NO2NaC m/z 248.1621, obsd 248.1625.
Compound 17. White solid, mp 165–166 8C; IR (neat, cmK1
)
1
3399 (br), 1654, 1414; H NMR (300 MHz, CDCl3) d 6.84
(s, 1H), 3.76–3.64 (m, 1H), 3.62–3.55 (m, 1H), 2.38–2.27
(m, 2H), 1.98–1.47 (m, 12H), 1.41–1.30 (m, 2H), 0.89 (d,
JZ6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.2, 64.8,
59.9, 53.0, 40.0, 37.8, 31.2, 29.8, 27.4, 26.2, 19.8, 18.7,
18.3; ES HRMS calcd for C13H23NO2NaC m/z 248.1621,
obsd 248.1630.
4.1.11. Allylic acetate 19. Reaction of 11 (174 mg,
0.89 mmol) in dry THF (5 mL) with vinyllithium prepared
in the manner described above from tri-n-butylvinyl-
stannane (1.04 mL, 3.56 mmol) was followed by an
analogous workup protocol. Chromatography afforded an
inseparable 3:1 mixture of diastereomers 18 as a colorless
oil (171 mg, 86%). This mixture was dissolved in acetic acid
(10 mL), treated with triflic acid (67.3 mL, 0.76 mmol) and
processed in the prescribed manner to deliver 130 mg (64%)
of 19 as a colorless oil; IR (neat, cmK1) 3203, 1738, 1658;
1H NMR (300 MHz, CDCl3) d 6.40 (s, 1H), 5.41 (t, JZ
6.8 Hz, 1H), 4.58 (d, JZ6.8 Hz, 2H), 2.36–2.13 (m, 3H),
2.03 (s, 3H), 1.90–1.56 (series of m, 13H); 13C NMR
(75 MHz, CDCl3) d 172.3, 171.0, 140.3, 122.5, 64.8, 61.0,
57.2, 41.0, 33.7, 31.0, 28.3, 21.1, 21.0, 18.1, 16.9; ES
HRMS calcd for C15H23NO3NaC m/z 288.1570, obsd
288.1575.
4.1.8. Allylic acetate 14. A solution of 13 (147 mg,
0.63 mmol) in acetic acid (12 mL) was treated with triflic
acid (61 mL, 0.69 mmol), stirred for 30 min, and quenched
with cold water. The product was extracted with CH2Cl2
(3!), and the combined organic layers were dried and
evaporated. The residue was chromatographed on silica gel
(elution with 8% methanol in 1:1 ethyl acetate/hexanes) to
give 14 (125 mg, 73%) as a colorless oil; IR (neat, cmK1
)
1738, 1658, 1405; 1H NMR (300 MHz, CDCl3) d 6.75 (br s,
1H), 5.38 (t, JZ5.7 Hz, 1H), 4.61 (d, JZ6.4 Hz, 1H); 2.42–
2.15 (m, 3H), 2.03 (s, 3H), 1.87–1.60 (m, 12H), 1.51–1.40
(m, 2H); 13C NMR (75 MHz, CDCl3) d 172.5, 171.0, 139.2,
121.5, 64.8, 61.2, 57.7, 40.3, 31.3, 27.8, 26.7, 21.0, 20.1,
17.54, 17.51; ES HRMS calcd for C15H23NO3NaC m/z
288.1570, obsd 288.1575.
4.1.9. Chemoselective hydrolysis of 14. Acetate 14
(125 mg, 0.47 mmol) was dissolved in 5:1 THF/methanol
(6 mL), treated with 3 N sodium hydroxide solution
(3 equiv), and stirred for 15 min. After dilution with water
and CH2Cl2, the separated aqueous phase was extracted
with CH2Cl2, and the combined organic layers were
dried and evaporated. Purification of the residue by
4.1.12. Allylic alcohol 20. A solution of 19 (125 mg,
0.47 mmol) in methanol (10 mL) and water (1 mL) was
treated with K2CO3 (232 mg, 1.68 mmol), stirred for 2 h,
and worked up in the manner described above. There was
isolated 100 mg (92%) of 20 as a colorless oil; IR (neat,
cmK1) 3263 (br), 1650, 1406; 1H NMR (300 MHz, CDCl3)

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D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
d 7.48 (s, 1H), 5.51 (t, JZ6.0 Hz, 1H), 4.21 (dd, JZ8.3,
12.2 Hz, 1H), 4.00 (dd, JZ5.8, 12.2 Hz, 1H), 3.49 (br s,
1H), 2.39–2.31 (m, 1H), 2.28–2.24 (m, 2H), 1.90–1.71 (m,
8H), 1.68 (s, 3H), 1.67–1.52 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 173.3, 139.3, 126.4, 64.9, 58.7, 55.3, 39.2,
33.8, 30.9, 28.7, 20.8, 18.4, 17.8; ES HRMS calcd for
C13H21NO2NaC m/z 246.1464, obsd 246.1469.
CH2Cl2, the separated aqueous phase was extracted with
CH2Cl2 (3!), and the combined organic phases were dried
and concentrated. Chromatography of the residue on silica
gel (elution with hexanes/acetone 1:1) provided the
rearranged allylic acetates in a 1:1 ratio (250 mg total,
63%). Both are colorless oils.
For the less polar isomer subsequently identified as 35: IR
(neat, cmK1) 1731, 1657, 1230; 1H NMR (300 MHz,
CDCl3) d 5.97 (br s, 1H), 4.68 (s, 2H), 2.41–2.28 (m, 4H),
2.08–2.03 (m, 4H), 1.88–1.69 (m, 6H), 1.63 (s, 3H), 1.52–
1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) d 171.2, 171.0,
145.1, 125.5, 64.5, 63.0, 41.9, 31.7, 31.1, 30.9, 21.2, 20.9,
18.5, 18.4; ES HRMS calcd for C14H21NO3NaC m/z
274.1414, obsd 274.1420.
4.1.13. Hydrogenation of 20. A solution of 20 (100 mg,
0.45 mmol) in THF (10 mL) was treated sequentially with
NaHCO3 (100 mg) and platinum oxide (10 mg). The
mixture was stirred under a balloon of H2 for 2 h, filtered
through Celite, and freed of solvent. The residue was
chromatographed on silica gel (elution with 10% hexanes in
acetone) to give 95 mg (94%) of a 1.5:1 mixture of
inseparable diastereomers consisting of 21 and 22.
For the more polar isomer: IR (neat, cmK1) 1736, 1651,
1230; 1H NMR (300 MHz, CDCl3) d 5.72 (br s, 1H), 4.50 (s,
2H), 2.49–2.20 (m, 4H), 2.07 (s, 3H), 2.01–1.61 (m, 10H),
1.53–1.48 (m, 1H); 13C NMR (75 MHz, CDCl3) d 171.5,
171.1, 156.2, 127.8, 68.6, 64.6, 42.0, 30.5, 30.2, 21.6, 20.9,
20.2, 18.6, 15.2.
For the composite: IR (neat, cmK1) 3275 (br), 1649, 1407;
1H NMR (300 MHz, CDCl3) d 6.93 and 6.64 (s, 1H), 3.70–
3.55 (m, 2H), 3.02 (s, 1H), 2.41–2.21 (m, 2H), 1.90–1.20
(m, 14H), 0.93 and 0.88 (d, JZ6.7, 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 172.8, 172.7, 64.4, 64.2, 60.6, 60.3,
54.2, 53.4, 42.7, 42.2, 39.5, 37.1, 35.6, 35.4, 31.4, 31.3,
29.7, 29.3, 28.1, 27.8, 22.0, 21.9, 20.1, 18.4, 18.3, 17.6; ES
HRMS calcd for C13H23NO2NaC m/z 248.1621, obsd
248.1618.
The acetate mixture (166 mg, 0.66 mmol) was dissolved in
THF (5 mL) and methanol (1 mL), treated with 3 M sodium
hydroxide (0.88 mL), and stirred for 45 min. Water was
introduced and the mixture was extracted three times with
CH2Cl2. The combined organic phases were dried and freed
of solvent. The residue was chromatographed on silica gel
(elution with 6% isopropyl alcohol in CH2Cl2) to furnish 24
and 25 in a 1:1 ratio (83% total).
4.1.14. Stereoselective formation of 23. A. With 2-pro-
penylmagnesium bromide. A cold (0 8C) solution of 4
(0.125 g, 0.75 mmol) in dry THF was treated with
2-propenylmagnesium bromide (3.7 mL, 0.60 M in ether,
2.22 mmol), stirred for 30 min, and quenched with saturated
NH4Cl solution. The product was extracted into CH2Cl2
(3!), dried, concentrated, and chromatographed on silica
gel. Elution with 10% methanol in 1:1 ethyl acetate/
hexanes) gave 23 as a white solid (105 mg, 67%), mp
Compound 24. Colorless oil; IR (neat, cmK1) 3360 (br),
1643, 1406; 1H NMR (300 MHz, CDCl3) d 7.18 (br s, 1H),
4.49 (d, JZ11.4 Hz, 1H), 3.76 (d, JZ11.4 Hz, 1H), 2.52–
2.16 (m, 4H), 2.10–2.00 (m, 2H), 1.87–1.60 (m, 8H), 1.59–
1.45 (m, 2H); 13C NMR (75 MHz, CDCl3) d 172.6, 141.9,
130.4, 64.3, 60.8, 41.6, 32.6, 31.2, 30.7, 21.2, 18.7, 18.3; ES
HRMS calcd for C12H19NO2NaC m/z 232.1308, obsd
232.1311.
1
144 8C; IR (neat, cmK1) 3365 (br), 1645, 1451; H NMR
(300 MHz, CDCl3) d 5.88 (s, 1H), 5.09 (d, JZ1.4 Hz, 1H),
5.04 (d, JZ1.4 Hz, 1H), 2.35–2.10 (m, 3H), 2.09–1.92 (m,
2H), 1.85 (s, 3H), 1.84–1.61 (m, 7H); 13C NMR (75 MHz,
CDCl3) d 172.2, 146.7, 114.6, 85.0, 68.2, 39.3, 36.6, 31.2,
26.8, 21.7, 18.6, 18.3; ES HRMS calcd for C12H19NO2NaC
m/z 232.1308, obsd 232.1317.
Compound 25. White solid, mp 182–183 8C; IR (neat, cmK1
)
1
3270 (br), 1649, 1406; H NMR (300 MHz, CDCl3) d 6.42
(br s, 1H), 4.10 (d, JZ11.6 Hz, 1H), 3.97 (d, JZ11.6 Hz,
1H), 2.51–2.25 (m, 3H), 2.21–1.98 (m, 4H), 1.97–1.50 (m,
8H); 13C NMR (75 MHz, CDCl3) d 172.3, 141.5, 130.4,
65.7, 64.2, 41.8, 31.1, 30.4, 30.0, 21.8, 18.5, 15.3; ES
HRMS calcd for C12H19NO2NaC m/z 232.1308, obsd
232.1319.
B. With 2-propenyllithium. A solution of 2-bromopropene
(232 mg, 1.91 mmol) in dry THF (10 mL) was blanketed
with N2, treated with tert-butyllithium (2.55 mL of 1.5 M in
hexanes, 3.83 mmol) at K78 8C, warmed to 0 8C, stirred for
30 min, and returned to K78 8C prior to the introduction of
4 (80 mg, 0.48 mmol) dissolved in dry THF (5 mL). The
reaction mixture was stirred for 2 h, warmed to rt, and
quenched with saturated NH4Cl solution. The product was
extracted into CH2Cl2 (3!), and the combined organic
layers were dried and evaporated to leave a residue that was
chromatographed on silica gel (elution with 8% methanol in
1:1 ethyl acetate/hexanes). There was isolated 82 mg (82%)
of 23 identical to the material generated in part A.
4.1.16. Hydrogenation of 24. A mixture of 24 (50 mg,
0.24 mmol), sodium bicarbonate (50 mg), platinum oxide
(5 mg), and THF (5 mL) was stirred overnight over 55 psi of
H2, filtered through Celite, and concentrated. Chromato-
graphy of the residue on silica gel (elution with 5%
isopropyl alcohol in CH2Cl2) afforded 20 mg of 26 and 5 mg
of 27.
4.1.15. Allylic alcohols 24 and 25. A solution of 23
(330 mg, 1.58 mmol) in acetic acid (10 mL) was treated
very slowly with triflic acid (0.28 mL, 3.16 mmol). The
reaction mixture gradually darkened while being stirred
during 2 days. Following dilution with cold water and
Compound 26. White crystals, mp 164 8C (from ethyl
acetate); IR (neat, cmK1) 3387, 1656, 1415; 1H NMR
(300 MHz, CDCl3) d 7.57 (d, JZ10.1 Hz, 1H), 3.68
(dd, JZ3.9, 10.7 Hz, 1H), 3.44 (dd, JZ4.1, 10.7 Hz, 1H),
2.97 (br s, 1H), 2.43–2.18 (m, 2H), 1.95–1.48 (m, 11H),

D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
11007
1.41–1.30 (m, 1H) 0.97 (d, JZ6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 172.8, 65.2, 64.0, 49.1, 39.3, 35.2,
31.4, 26.8, 24.9, 19.1, 17.4, 16.8. ES HRMS calcd for
C12H21NO2NaC m/z 234.1464, obsd 234.1466.
1.60–1.49 (m, 1H); 13C NMR (75 MHz, CDCl3) d 176.8,
173.7, 161.2, 146.3, 136.0, 131.8, 128.3, 128.1, 121.3, 71.1,
63.2, 37.9, 34.9, 34.1, 31.0, 22.5, 19.4, 18.2; ES HRMS
calcd for C20H23NO4NaC m/z 364.1519, obsd 364.1509.
Compound 27. White solid, mp 149–150 8C; IR (neat, cmK1
)
Compound 32. Colorless oil; IR (neat, cmK1) 1737, 1641,
1454; H NMR (300 MHz, CDCl3) d 8.05 (t, JZ0.9 Hz,
3274 (br), 2959, 1652; 1H NMR (500 MHz, CDCl3) d 5.83
(br s, 1H), 3.64 (dd, JZ3.4, 10.5 Hz, 1H), 3.45 (dd, JZ6.1,
10.5 Hz, 1H), 2.45–2.36 (m, 1H), 2.25 (dq, JZ6.6, 18.0 Hz,
1H), 2.02–1.73 (m, 5H), 1.70–1.51 (m, 7H), 1.41–1.32 (m,
1H), 1.05 (d, JZ6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 171.8, 67.4, 64.2, 51.3, 40.1, 36.7, 31.5, 27.6, 25.1, 19.3,
17.6, 16.0; ES HRMS calcd for C12H21NO2NaC m/z
234.1464, obsd 234.1467.
1
1H), 7.56 (d, JZ8.5 Hz, 2H), 7.47–7.41 (m, 1H), 7.39–7.30
(m, 2H), 4.71 (d, JZ11.9 Hz, 1H), 4.41 (d, JZ11.9 Hz,
1H), 2.73–2.52 (m, 4H), 2.52–2.43 (m, 1H), 2.21–2.11 (m,
1H), 2.05–1.87 (m, 5H), 1.82 (s, 3H), 1.61–1.48 (m, 1H);
13C NMR (125 MHz, CDCl3) d 175.6, 173.6, 161.0,
145.6, 136.0, 131.5, 128.2, 128.1, 121.5, 71.0, 66.8, 37.6,
34.9, 32.3, 30.8, 22.6, 19.1, 16.4; ES HRMS calcd for
C20H23NO4NaC m/z 364.1519, obsd 364.1500.
4.1.17. Hydrogenation of 25. A 45 mg (0.21 mmol) sample
of 25 was hydrogenated at 55 psi of H2 in the presence of
sodium bicarbonate (45 mg) and platinum oxide (4 mg) as
described above. The analogous workup delivered 26 mg
4.1.19. Hydrolysis of 32. A solution of 32 (106 mg,
0.31 mmol) in methanol (6 mL) was treated with potassium
carbonate (54 mg, 0.59 mmol), stirred for 15 min, diluted
with water, and extracted with CH2Cl2 (3!). The combined
organic layers were dried and evaporated to leave a residue
that was chromatographed on silica gel. Elution with ethyl
acetate–hexanes (1/1) afforded 34 (85 mg, 87%) as a white
solid, mp 148–149 8C; IR (neat, cmK1) 3360, 1684, 1252;
1H NMR (300 MHz, CDCl3) d 7.54 (d, JZ6.6 Hz, 2H),
7.54–7.30 (m, 3H), 3.95 (q, JZ11.8 Hz, 2H), 2.79–2.38 (m,
5H), 2.29–2.15 (m, 1H), 2.01–1.90 (m, 6H), 1.86 (s, 3H),
1.55–1.48 (m, 1H); 13C NMR (75 MHz, CDCl3) d 175.9,
173.9, 141.8, 136.0, 131.5, 128.2, 128.1, 126.9, 71.2, 65.7,
37.6, 34.9, 32.3, 30.4, 22.7, 19.2, 16.2; ES HRMS calcd for
C19H23NO3NaC m/z 336.1570, obsd 336.1576.
(50%) of 28 as a white solid, mp 153 8C; IR (neat, cmK1
)
1
3384 (br), 1652; H NMR (500 MHz, CDCl3) d 6.09 (br s,
1H), 3.65 (dd, JZ3.5, 10.6 Hz, 1H), 3.48 (dd, JZ3.5,
6.3 Hz, 1H), 2.38 (dd, JZ3.5, 12.2 Hz, 1H), 2.24–2.20 (m,
1H), 2.02–1.79 (m, 5H), 1.67–1.50 (m, 7H), 1.37–1.25 (m,
1H), 1.07 (d, JZ6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
171.9, 67.3, 64.1, 51.1, 40.0, 36.7, 31.5, 27.6, 25.0, 19.3,
17.5, 16.0; ES HRMS calcd for C12H21NO2NaC m/z
234.1464, obsd 234.1449.
p-Nitrobenzoate 29 proved to be a white solid exhibiting a
mp of 194 8C; IR (neat, cmK1) 1724, 1657, 1529, 1277; 1H
NMR (300 MHz, CDCl3) d 8.29 (d, JZ7.0 Hz, 2H), 8.20 (d,
JZ7.0 Hz, 2H), 6.60 (s, 1H), 4.37 (dd, JZ3.6, 10.8 Hz,
1H), 4.15 (dd, JZ6.6, 10.8 Hz, 1H), 2.49–2.35 (m, 1H),
2.28–2.16 (m, 1H), 2.03–1.75 (m, 5H), 1.72–1.50 (m, 6H),
1.50–1.39 (m, 1H), 1.13 (d, JZ6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 172.0, 164.7, 150.5, 135.6, 130.7,
123.6, 70.3, 64.1, 51.2, 39.8, 34.2, 31.5, 27.6, 24.9, 19.2,
17.6, 16.5; ES HRMS calcd for C19H24N2O5NaC m/z
383.1577, obsd 383.1665.
4.1.20. Hydrolysis of 31. The formate 31 (130 mg,
0.38 mmol) in methanol (15 mL) was treated with potas-
sium carbonate (53 mg, 0.38 mmol) and stirred for 2 h prior
to the addition of NH4Cl and extraction with CH2Cl2 (3!).
The combined organic phases were dried and evaporated to
leave a residue that was chromatographed on silica gel.
Elution with 50% ethyl acetate in hexane gave 33 as a
colorless oil (125 mg, 90%); IR (neat, cmK1) 3362 (br),
1
1738, 1644; H NMR (300 MHz, CDCl3) d 7.79 (d, JZ
6.9 Hz, 2H), 7.50–7.32 (m, 3H), 7.07 (s, 1H), 4.30 (d, JZ
11.3 Hz, 1H), 4.14 (d, JZ11.3 Hz, 1H), 3.67 (s, 3H), 2.69–
1.89 (series of m, 9H), 1.80 (s, 3H), 1.72–1.52 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 174.6, 166.5, 143.1, 135.2, 131.2,
128.5, 128.4, 126.9, 65.4, 62.6, 51.8, 38.0, 37.9, 33.4, 32.3,
22.6, 20.0, 19.2; ES HRMS calcd for C20H27NO4NaC m/z
368.1832, obsd 368.1841.
4.1.18. Formylation of 23. Alcohol 23 (236 mg,
1.13 mmol) was dissolved in formic acid (15 mL), cooled
to 10 8C, and treated slowly with triflic acid (0.2 mL,
2.25 mmol). The mixture was stirred overnight at rt, diluted
with cold water, and extracted with CH2Cl2 (3!). The
combined organic phases were dried and concentrated to
leave a residue that was chromatographed on silica gel
(elution with 5% isopropyl alcohol in CH2Cl2) to leave
238 mg (89%) of 30 as a 3:2 mixture of isomers.
4.1.21. Conversion of 35 to 34. A solution of 35 (44 mg,
0.175 mmol), generated from 23 as illustrated in Scheme 7,
in dry benzene (5 mL) was blanketed with N2, treated with
benzoyl chloride (81 mL, 0.70 mmol), and refluxed for 10 h.
After solvent removal and chromatographic purification
(silica gel, 50% ethyl acetate in hexane), there was isolated
45 mg (76%) of the benzoyl protected amide as a colorless
oil; IR (neat, cmK1) 1734, 1684, 1247; 1H NMR (300 MHz,
CDCl3) d 7.57 (d, JZ8.1 Hz, 2H), 7.49–740 (m, 1H), 7.39–
7.30 (m, 2H), 4.61 (d, JZ12.1 Hz, 1H), 4.31 (d, JZ12.1 Hz,
1H), 2.73–2.38 (m, 6H), 2.24–2.15 (m, 1H), 2.06–1.81 (m,
7H), 1.79 (s, 3H), 1.55–1.50 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 175.7, 173.5, 171.0, 144.4, 136.0, 131.4, 128.1,
128.0, 122.1, 71.0, 67.1, 37.5, 34.8, 32.2, 30.7, 22.5, 20.8,
This material was taken up into dry benzene (25 mL),
treated with benzoyl chloride (0.58 mL, 5.0 mmol), heated
at reflux for 10 h, and evaporated. Chromatography of the
residue on silica gel (elution with 25% ethyl acetate in
hexanes) afforded 31 (84 mg) and 32 (150 mg) (83%
combined).
Compound 31. White solid, mp 152 8C; IR (neat, cmK1
)
1
1718, 1685, 1249; H NMR (300 MHz, CDCl3) d 7.91 (s,
1H), 7.56 (d, JZ8.0 Hz, 2H), 7.48–7.40 (m, 1H), 7.39–7.32
(m, 2H), 5.28 (d, JZ11.7 Hz, 1H), 4.39 (d, JZ11.7 Hz,
1H), 2.82–2.40 (m, 5H), 2.08–1.91 (m, 6H), 1.63 (s, 3H),

11008
D. G. Hilmey et al. / Tetrahedron 61 (2005) 11000–11009
19.0, 16.2; ES HRMS calcd for C21H25NO4NaC m/z
378.1676, obsd 378.1681.
6. For reviews see: (a) Kotera, M. Bull. Soc. Chim. Fr. 1989, 370.
¨
(b) Grossinger, E. In The alkaloids; Brossi, A., Ed.; Academic:
New York, 1983; pp 139–251. (c) Inubushi, Y.; Ibuka, T.
Heterocycles 1982, 17, 507. For more recent total syntheses,
consult: (d) Stockman, R. A.; Sinclair, A.; Arini, L. G.; Szeto,
P.; Hughes, D. L. J. Org. Chem. 2004, 69, 1598. (e) Diedrichs,
N.; Krelaus, R.; Gedrath, I.; Westermann, D. Can. J. Chem.
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Roughley, S. D.; Smith, C. J.; Williams, G. M.; Davies, J. E.;
Raithby, P. R.; Adams, J. P.; Forbes, I. T.; Press, N. J.;
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R. W. J. Org. Chem. 1999, 64, 5485. (j) Tanner, D.; Hagberg,
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Zhang, Y.; Zheng, X. Chem. Commun. 1998, 2509. (l) Tanner,
D.; Hagberg, L. Tetrahedron 1998, 54, 7907. (m) Kim, D.;
Hong, S. W.; Park, C. W. Chem. Commun. 1997, 2263.
(n) Compain, P.; Gore, J.; Vatele, J. M. Tetrahedron Lett.
1995, 36, 4063. (o) Maezaki, N.; Fukuyama, H.; Yagi, S.;
Tanaka, T.; Iwata, C. J. Chem. Soc., Chem. Commun. 1994,
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Tetrahedron Lett. 1991, 32, 2485. (q) Winkler, J. D.;
Hershberger, P. M. J. Am. Chem. Soc. 1989, 111, 4852. For
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1, 547. (s) Comins, D. L.; Zheng, X. J. Chem. Soc., Chem.
Commun. 1994, 2681. (t) Parsons, P. J.; Angell, R.; Naylor, A.;
Tyrell, E. J. Chem. Soc., Chem. Commun. 1993, 366.
(u) Thompson, C. M. Heterocycles 1992, 34, 379. (v) Venit,
J. J.; DiPierro, M.; Magnus, P. J. Org. Chem. 1989, 54, 4298.
7. (a) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi,
Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867. (b) Arimoto,
H.; Hayakawa, I.; Kuramoto, M.; Uemura, D. Tetrahedron
Lett. 1998, 39, 861.
The above material (12.3 mg, 0.035 mmol) was dissolved in
methanol (3 mL), treated with potassium carbonate (5 mg,
0.035 mmol), and stirred for 2 h. Following the addition of
saturated NH4Cl solution, the product was extracted into
CH2Cl2 (3!) and worked up as before to deliver 9.1 mg
(83%) of 34, which proved to be identical spectroscopically
with the material isolated earlier.
4.2. X-ray crystallographic data available
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 274536, CCDC 274537, and
CCDC 274538. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: C44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
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