Evaluation of Amino Substituants as Nucleofugal Controllers of Regioselectivity and as Chelate Modulators of Stereoselectivity in Squarate Ester Cascades

Article abstract of DOI:10.1021/jo9722919

The tandem addition of an alkenyllithium reagent and a 2-lithioallylamine to squarate esters has been systematically examined. The effect of the sequencing of this twofold addition has been investigated. The extent to which the amino group is eliminated was found to be dependent on the structural features of the companion nucleophile. Also assessed was the comparative ease with which the amino and methoxy groups experience competitive β-elimination from the highly reactive, medium-ring dianionic intermediates. Attempts were made to curtail the level of competing 1,4-addition, and success was achieved by increasing the effective size of the O-alkyl groups in the squarate ester. The highly stereocontrolled transformations described represent a notably direct means for producing highly fused polycyclic compounds. Mechanistic considerations surrounding these reactions, which are characterized by an impressive enhancement of molecular scaffolding, are discussed.

Full text of DOI:10.1021/jo9722919

2010
J . Org. Chem. 1998, 63, 2010-2021
Eva lu a tion of Am in o Su bstitu en ts a s Nu cleofu ga l Con tr oller s of
Regioselectivity a n d a s Ch ela te Mod u la tor s of Ster eoselectivity in
Squ a r a te Ester Ca sca d es
Leo A. Paquette,* Lung Huang Kuo, and J insung Tae
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received December 18, 1997
The tandem addition of an alkenyllithium reagent and a 2-lithioallylamine to squarate esters has
been systematically examined. The effect of the sequencing of this twofold addition has been
investigated. The extent to which the amino group is eliminated was found to be dependent on
the structural features of the companion nucleophile. Also assessed was the comparative ease
with which the amino and methoxy groups experience competitive â-elimination from the highly
reactive, medium-ring dianionic intermediates. Attempts were made to curtail the level of competing
1,4-addition, and success was achieved by increasing the effective size of the O-alkyl groups in the
squarate ester. The highly stereocontrolled transformations described represent a notably direct
means for producing highly fused polycyclic compounds. Mechanistic considerations surrounding
these reactions, which are characterized by an impressive enhancement of molecular scaffolding,
are discussed.
Sch em e 1
The sequence of mechanistic events triggered by the
twofold addition of alkenyl anions to squarate esters
elaborates complex polycyclic products.1 In those cases
where the reactants are minimally functionalized, linear
and angular polyquinanes are formed.2 An effective
solution to the control of regioselectivity has been realized
by positioning a leaving group â to one of the two enolate
anions that develop in an advanced medium-ring inter-
mediate.3 Halogen atoms and oxygenated substituents
have been studied with considerable effectiveness.4 Upon
elimination, irreversible aldol ring closure gives rise to
one product (Scheme 1).
Another important facet of these remarkable processes
is the directionality of entry of the second nucleophile.
While trans stereoselectivity unalterably guides the
ensuing reaction into two sequential conrotatory opera-
tions capped by equilibration of a helical octatetraenyl
intermediate (as A / A′),5 cis addition is followed by
concerted dianionic oxy-Cope rearrangement (Scheme 2).6
Since the consequences of second-stage stereocontrol on
product stereochemistry can be profound, the discovery
that selected ether and amide groups are capable of
augmenting cis delivery, presumably because of their
capacity for lithium ion chelation, has ushered in further
development of this chemistry.7,8
This paper gives attention to the union of these two
phenomena in the context of substitution involving amino
substituents. The initial question at issue is whether
(1) Negri, J . T.; Morwick, T.; Doyon, J .; Wilson, P. D.; Hickey, E.
R.; Paquette, L. A. J . Am. Chem. Soc. 1993, 115, 12189.
(2) (a) Paquette, L. A.; Morwick, T. J . Am. Chem. Soc. 1995, 117,
1451. (b) Paquette, L. A.; Morwick, T. J . Am. Chem. Soc. 1997, 119,
1230.
(3) Paquette, L. A.; Morwick, T. M.; Negri, J . T.; Rogers, R. D.
Tetrahedron 1996, 52, 3075.
tertiary amino groups will exhibit nucleofugal properties9
under these circumstances. Should elimination be pos-
sible, to what extent and under what circumstances
would the expulsion of nitrogen-containing residues be
competitive with the â-elimination of alkoxide anions?
Additionally, can variously substituted amino groups be
(4) (a) Paquette, L. A.; Doyon, J . J . Am. Chem. Soc. 1995, 117, 6799.
(b) Paquette, L. A.; Doyon, J . J . Org. Chem. 1997, 62, 1723.
(5) Paquette, L. A.; Hamme, A. T., II.; Kuo, L. H.; Doyon, J .;
Kreuzholz, R. J . Am. Chem. Soc. 1997, 119, 1242.
(6) Review: Paquette, L. A. Tetrahedron 1997, in press.
(7) (a) Paquette, L. A.; Kuo, L. H.; Doyon, J . Tetrahedron 1996, 52,
11625. (b) Paquette, L. A.; Kuo, L. H.; Doyon, J . J . Am. Chem. Soc.
1997, 119, 3038.
(8) Paquette, L. A.; Tae, J . Tetrahedron Lett. 1997, 38, 3151.
(9) Stirling, C. J . M. Acc. Chem. Res. 1979, 12, 198.
S0022-3263(97)02291-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/26/1998

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2011
Sch em e 2
species in general. As the “hardness” of the ion is
reduced through the introduction of electron-withdrawing
groups at R, inductive and resonance stabilization com-
bine to render the â-elimination pathway increasingly
feasible kinetically. The first part of the present inves-
tigation was undertaken to establish the likelihood of
elimination of amino groups during squarate ester cas-
cades in selected cases and to broadly define possible
limits to the process.
The first example, which consisted of the sequential
addition of 2-lithioallylamine 212 and 2-lithiopropene to
dimethyl squarate (1), provided initial positive encour-
agement. In this instance, the diastereomerically homo-
geneous amino ketone 6 was isolated in 48% yield
alongside a lesser amount of 7. This cis relationship of
the methyl and alkylamino substituents in 6 was initially
defined by NOE analysis (see Figure 1). The relative
orientation of the carbonyl and methoxy functionalities
in ring A was established by semiselective DEPT studies
at 300 MHz.
expected to exert a kinetic bias that would eventuate in
chaperoning the second anion into the cis 1,2-addition
reaction channel? Finally, one may inquire as to the
possible relationship of the bulk of the substituents on
nitrogen with possible redirection of the second-stage
addition into the 1,4-manifold.3 These issues are herein
explored in turn.
The observation of cross-peaks between H-10 (δ 2.59)
and C-1 (201.5 ppm), C-4 (84.4 ppm) and C-5 (57.9 ppm),
as well as between H-8 (δ 2.25) and C-3 (170.9 ppm) and
Resu lts a n d Discu ssion
Th e Nu cleofu ga lity of Am in o Su bstitu en ts. Al-
though Michael reactions are inherently reversible pro-
cesses, few examples are documented where an amide
ion (e.g., R2N-, where R is alkyl and/or aryl) serves as
the leaving group in a base-promoted retrograde step.10,11
This is as expected in view of the high basicity of amide
(10) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959,
10, 179. (b) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLough-
lin, J . I. Org. React. 1995, 47, 315.
(11) For a leading reference to â-nitrogen elimination involving
aluminum or boron enolate derivatives, see: Carlsson, S.; Lawesson,
S.-O. Tetrahedron 1982, 38, 413.

2012 J . Org. Chem., Vol. 63, No. 6, 1998
Paquette et al.
F igu r e 2. ORTEP diagram of 10‚HCl with the non-hydrogen
atoms represented by 50% probability thermal ellipsoids. The
hydrogen atoms are drawn with an artificial radius.
F igu r e 1. Representative NOE results.
C-4 (84.4 ppm) were particularly diagnostic. This prod-
uct distribution reveals that the kinetically favored
reaction trajectory consists of 1,2-addition of the 2-lithio-
propene and transient formation of dienolate 3. The
substitution level in the two alkenyl anions is recognized
to be too low to permit a determination of the extent to
which 3 was formed by potentially competitive sigmat-
ropic and electrocyclic avenues. At this point, this dis-
tinction holds little relevance. It is more significant that
3 experiences protonation regioselectively at the less
sterically encumbered position a more rapidly than at
site b (not observed) and at a rate considerably faster
than the â-elimination option. The formation of 7 is the
result of 1,4-addition, with ensuing conrotatory opening
of the four-membered ring, arrival at 4, and â-elimination
of the amino substituent, to give 5 in advance of tran-
sannular ring closure.
considerations, this mechanistic model is utilized in the
ensuing discussion.
When the steric demands of the second nucleophile
were increased somewhat to the cyclopentenyl level and
were preceded by the addition of N,N-dimethyllithioal-
lylamine 8,12 three triquinanes made their appearance
A relevant consideration is whether the elimination
process associated with the conversion of 4 to 5 operates
at the dienolate stage or only after quenching with
aqueous ammonium chloride solution. Our global expe-
rience with the examples given here has been that TLC
analysis of reaction mixtures prior to workup invariably
revealed the products to be already formed. While these
observations might be attributed to acceleration of the
final stages of the cascade while the intermediates are
adsorbed for a brief time on the silica gel, mechanistic
analysis of our observations is better served by focusing
on the options available to the dienolate intermediates
generated in each instance. Relevantly, the energetics
associated with the alleviation of the heightened charge
repulsion that is resident within any dienolate during
the amide elimination process can be expected to con-
tribute to a favorable lowering of the overall enthalpy of
the process. Analogies do exist. For example, the aza-
Wittig rearrangement consists of the isomerization of an
R-lithiated tertiary amine to a lithium amide.13 The
driving force underlying this process has been attributed
to transfer of the formal negative charge from the less
electronegative R-carbon to the more electronegative
heteroatom,14,15 with accompanying favorable conse-
quences in the HOMO/LUMO gap.16 In light of these
in a combined yield of 69%. Proof of the structure for
the major product 10 was secured by single-crystal X-ray
analysis of its hydrochloride salt (Figure 2). The stereo-
isomeric distinction between 10 and 11 was made ap-
parent on the basis of NOE studies (Figure 1). Unequivo-
cal structural definition of 12 was again made possible
by semiselective DEPT studies: H-10 (δ 2.06) showed
appropriate cross-peaks with C-1 (202.8 ppm), C-4 (81.4
ppm), and C-5 (65.8 ppm), while H-6 (δ 2.35) expectedly
interacts strongly with C-1, C-4, C-5, and C-8 (150.7
ppm). The coproduction of 12 is consistent with a
somewhat improved capability within 9 (relative to 3) for
the ejection of amide ion. One of the consequences of
cyclopentannulation as in 9 is to rigidify one tublike
conformation significantly and to deter tub-to-tub con-
formational interconversion. The thermodynamically
(12) (a) Barluenga, J .; Canteli, R.-M.; Flo´rez, J . J . Org. Chem. 1994,
59, 602. (b) Barluenga, J .; Canteli, R.-M.; Flo´rez, J . J . Org. Chem. 1996,
61, 3646. (c) Barluenga, J .; Canteli, R.-M.; Flo´rez, J . J . Org. Chem.
1996, 61, 3753.
(13) Vogel, C. Synthesis 1997, 497.
(14) Reetz, M. T.; Schinzer, D. Tetrahedron Lett. 1975, 40, 3485.
(15) Broka, C. A.; Shen, T. J . Am. Chem. Soc. 1989, 111, 2981.
(16) Murata, Y.; Nakai, T. Chem. Lett. 1990, 2069.

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2013
favored conformer is depicted in A. The partitioning of
creased basicity of the tetrahydrofuranyl oxygen in 16,
one consequence of which can be construed to be stronger
“backside” chelation. With this improved state of
affairs, loss of either amide ion has increased opportun-
ity to materialize and does so with reasonable effective-
ness.
A between progression to 10 or to 11 has its origins in
the directionality of protonation at the cyclopentylic
enolate site. Note that endo attack is more prevalent by
a factor in excess of 2:1. Although postequilibration is
possible, this is not viewed as particularly likely since
the quenching is accomplished with saturated NH4Cl
solution.
Once again, protonation is seen to operate across the
cyclooctatriene ring (position c) from the site of the amino
substituent (position d). These observations raise the
interesting prospect that internal chelation of the
O-‚‚‚Li+‚‚‚NR3 type so attenuates the basicity of the
associated enolate that its protonation is not competitive.
Loss of lithium dimethylamide from A leads to B,
whose topology is highly conducive to transannular aldol
cyclization.
Dir ect Com petition between Disu bstitu ted Am in o
a n d Meth oxy a s th e P r efer r ed Lea vin g Gr ou p . The
next objective of our research was to develop reaction
conditions that allow for the competitive excision of
oxygen- and nitrogen-containing substituents. The use
of 6-methoxycyclohexenyllithium 1917 in advance of either
2 or 8 considerably expands the range of options available
to the intermediate dienolate 20. The 8π conrotatory
An especially informative experiment involved the
combined use of 8 and lithiated ethyl vinyl ether. In this
example, a mixture of 14 and 15 was produced in a 1:1
ratio! The reagent combination was intended to lead to
a mesocyclic intermediate, viz. 13, in which a six-centered
nitrogen chelate substructure was counterbalanced by an
oxygen-centered five-ring complex. It was hoped that the
attenuated reactivity intimately associated with the
properly positioned ethoxy group would provide added
time for amide elimination to take place. The production
of comparable levels of diquinanes 14 (Figure 1) and 15
supports this line of reasoning.
The success associated with the above experiment
immediately prompted the consideration of 2-lithio-4,5-
dihydrofuran as a reaction partner in view of the previ-
ously described advantages that accrue to the use of
cyclopentenyllithium. Irrespective of whether the initial
reactant was 2 or 8,12 the exomethylene tricyclic ketone
18 was isolated as the only characterizable product. As
before, the promixity of H-6 (δ 2.68) to the carbonyl group
(C-1, 197.2 ppm), oxygen-substituted carbons (C-4 and
C-5, 90.3 and 78.2 ppm), and the C-8 methylene center
(C-8, 147.1 ppm) was confirmed by the same NMR
technique. This observation is in accord with the in-
event that leads to the generation of 20 can be expected
to come under steric control and to lead only to that
diastereoisomer having the methoxyl group positioned on
the less crowded exterior face of the structure, as shown.5
The working model that accounts for arrival at the
tricyclic amino alcohols parallels that we have previously
invoked for self-immolative chirality transfer.17 Evi-
dently, methoxide ion is the nucleofuge of choice, experi-
ences the more rapid â-elimination, and guides the
regioselectivity of the ultimate transannular aldol step.
The observation of a 1,4-relationship between the oxygen
atoms in 21a and 21b, confirmed in the established way
(17) Paquette, L. A., Kuo, L. H.; Hamme, A. T., II.; Kreuzholz, R.;
Doyon, J . J . Org. Chem. 1997, 62, 1730.

2014 J . Org. Chem., Vol. 63, No. 6, 1998
Paquette et al.
by long-range DEPT measurements,18 signaled the pos-
sibility that 1,2-addition was singularly operative. How-
ever, because the yields of these products were modest,
the initiative was taken to explore this feature in greater
depth. Accordingly, 1 was converted by reaction with 1
equiv of 19 into a 2.8:1 mixture of cyclobutenones 22
and 23, which were purified but not separated. When
Independent generation of 25 and 26 for the purpose
of capturing 1917 independently provided no bias toward
an alternative explanation. In both examples, product
distributions similar to those determined for the one-pot
procedures were observed.
Mod u la tion of th e Levels of Com p etitive 1,4-
Ad d ition . It will be recognized that 1,4-addition pro-
ceeds by attack of the second nucleophile at an alkoxy-
substituted site. Consequently, the expectation is that
an effective increase in the steric bulk of the RO groups
resident on the squarate ester might well be met with a
significant dropoff in conjugate addition. Diisopropyl
squarate (27) was considered to be appropriately tailored
these intermediates were independently treated with 2
and 8, only 21a and 21b were again isolated at signifi-
cantly improved levels of efficiency. The preponderance
of 1,2-addition is obviously very high for these examples.
These results are not duplicated when the order of
addition of the same reagents is reversed. Although 21a
and 21b continue to be major products, they are now
formed alongside the R-hydroxy ketone 24 (13-18%).
Evidence for the regioreversed placement of the oxygen-
ated centers in 24 was derived from long-range DEPT
analysis in C6D6 solution, which showed H-5 (δ 3.38) to
exhibit three-bond coupling to C-3 (166.3 ppm), C-12 (84.4
ppm), and C-16 (57.4 ppm), alongside two-bond coupling
to C-4 (60.2 ppm) and C-6 (28.3 ppm). Accordingly, the
order of addition holds importance. The energetic dif-
ference between the two possible reaction channels
cannot be attributed to a diminished ability on the part
of secondary amine substituents to direct 1,2-entry of the
second nucleophile. Such behavior was encountered
earlier to a very modest level (5%) only with 2 and
2-lithiopropene as the reagent twosome. More likely, the
combination of subtle effects which are operative as this
nucleophile begins to engage in bonding to the monoad-
duct dictates the relative orientation of 19.
to this purpose. Indeed, the involvement of this substrate
with alkenyllithiums 2 and 19 was such that only 28 was
formed irrespective of the mode of addition. 1,4-Addition
appeared to have been totally suppressed. Confirmation
of this conclusion was achieved by means of the two-step
variants of these reactions.
The latter exhibited greater overall efficiency and were
consequently more convincing of the fact that a product
analogous to 24 was not detectable. Comparable addition
of 2 to the previously reported dextrorotatory 328 likewise
gave evidence of adherence to the 1,2-addition option.
A more detailed appreciation of steric effect analysis
prompted consideration of the annulated squarate ester
34.19 Examination of molecular models of 34 reveals that
conformers having alkyl oxygen substituents projecting
well above and below the plane of the four-membered ring
can be excluded from consideration. The trimethylene
tether interconnecting the pair of oxygen atoms is, of
course, not planarized, but it is certainly not free to incur
significant angular deformation either. Consequently,
our expectation was that 34 would exhibit a return to
competitive 1,4-addition. As anticipated, 36 is formed
alongside 35. While the proportion of 36 does not exceed
(18) For 21a : Long-range DEPT (C6D6): irradiate Ha-13 (δ 2.65)
and observe cross-peaks for C-1 (200.9 ppm, 3J ), C-4 (82.5 ppm, 3J ),
C-12 (56.5 ppm, 2J ), and C-14 (41.7 ppm, 3J ). For 21b: Long-range
DEPT (C6D6): irradiate Ha-13 (δ 2.75) and observe cross-peaks for C-1
(200.7 ppm, 3J ), C-4 (82.5 ppm, 3J ), C-12 (56.1 ppm, 2J ), and C-14 (45.7
ppm, 3J ).
(19) Fischer, H.; Bellus, D. U.S. Patent 4,092,146, May 30, 1978.

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2015
thought to represent a compromise between chelation
control and nonbonded steric interactions in the vicinity
of the cyclohexenyl substituent, with the first of these
options lacking in its ability to direct cis attack of the
second anion at the carbonyl site.
A decrease in the bulk of the second-stage nucleophile
to the 2-propenyl level results in a significant propor-
tional increase in 1,2-addition. Where 38a is concerned,
the level of 44 is more than double that determined for
42. For 39a , 44 and 45 are coproduced in essentially
equal amounts, illustrating that the structural features
of the alkenyllithium can have a significant impact on
product distribution.
that of 35 under either mode of nucleophilic addition, the
initial involvement of 2 is more conducive to its formation
(Scheme 3).
Im p a ct of a Cycloh exen yla m in e on th e Regiocon -
tr ol of Secon d -Sta ge Nu cleop h ilic Ad d ition . Atten-
tion was next turned to evaluation of the relative kinetic
selectivity of 1,2- vs 1,4-addition of second-stage alkenyl
anion addition in monoadducts of the type 38 and 39
(Scheme 4). These representative amino alcohols, readily
accessible as a consequence of the ease of generation of
lithiated cyclohexenylamines such as 37, make possible
direct comparison with the methoxy derivatives 29 and
30. There also exists a structural link between 37 and
the acyclic lithio amine 2, although the presence of a six-
membered ring in the former has major conformational
consequences. When 27 was condensed with 3720 in THF
at -78 °C, there was produced an inseparable 1:1.8
mixture (1H NMR analysis) of 38a and 39a .
Su m m a r y
Once O-silylation had been accomplished with tert-
butyldimethylsilyl chloride in the presence of imidazole,
38b and 39b could be isolated in isomerically pure form.
Subsequent individual treatment with TBAF returned
samples of 38a and 39a not contaminated with each
other. To establish the structural identity of these two
alcohols, the major diastereomer was hydrogenated under
conditions which chemoselectively saturated the cyclo-
hexene double bond and effected N-debenzylation. Sub-
sequent direct conversion to carbamate 41 provided a
nicely crystalline substance conveniently conducive to
X-ray crystallographic analysis. With the structure of
41 established in this manner (Figure 3), it became
possible to make proper assignment to 38-40.
At this point, 38a and 39a were subjected to the action
of 1-lithiocyclopentene as the second-stage reactant.
Both examples led to the isolation of 42 and 43, but with
rather different relative proportions. In the case of 38a ,
the distribution of 1,2- and 1,4-addition products is near
unity. The major constituent from the second experiment
was 43. This dominance of the R-hydroxy ketone isomer
is noteworthy because its magnitude far exceeds that of
any comparable methoxycyclohexene analogue.
We have demonstrated that cyclic and acyclic 2-lithio
allylamines enter effectively into the squarate ester
cascade to give highly fused di-, tri-, and tetracyclic
compounds. The multiple functionality and stereochem-
ical features in the resultant products, and the one-flask
nature of these transformations hold promise for the
application of this methodology in a variety of synthetic
contexts. The salient features of the overall process
include (1) the capacity for ejection of the nitrogen
functionality, the extent of which is closely linked to the
nature of the companion alkenyl anion, (2) the greater
relative ease with which methoxy groups are excised from
the dianionic intermediates, and (3) one’s ability to
attenuate the extent of 1,4-addition simply by increasing
the steric bulk of the alkoxy group in the starting
squarate ester or the level of N-substitution in the lithio
allylamine when added first.
Whereas earlier work has shown that steric effects
such as those exerted by the R group in Scheme 1 are
capable of controlling the stereochemical course of poly-
cycle construction, the present results reveal that sub-
stituent influences resident in the alkenyllithium reactants
can be effectively utilized to exert control over the â-elim-
ination and later events. We are unaware of any prior
use of substituent effects in this manner. So far, we have
noted no limitation to this general stratagem since
Proper distinction between 42 and 43 was accom-
plished by X-ray diffraction analysis of the second isomer
(Figure 4). The increased production of 43 from 39a is

2016 J . Org. Chem., Vol. 63, No. 6, 1998
Paquette et al.
Sch em e 3
Sch em e 4
F igu r e 3. ORTEP diagram of 41 with the non-hydrogen
atoms represented by 50% probability thermal ellipsoids. The
hydrogen atoms are drawn with an artificial radius.
F igu r e 4. ORTEP diagram of 43 with the non-hydrogen
atoms represented by 50% probability thermal ellipsoids. The
hydrogen atoms are drawn with an artificial radius.
various readily available 2-bromoallylamines have in-
variably entered into this reaction cascade. Recourse to
chiral nitrogen substituents would set the stage for
possible 1,5-asymmetric induction prior to the â-elimina-
tion event. The scope of this chirality transfer has been
explored and is detailed in the accompanying paper.21
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under
an inert atmosphere of argon or nitrogen. Glassware was
generally oven-dried or flame-dried in vacuo and purged with
argon or nitrogen. Tetrahydrofuran was distilled from sodium-

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2017
benzophenone ketyl immediately prior to use. Reactions were
monitored by thin-layer chromatography. Melting points are
uncorrected. The column chromatographic separations were
performed with Woelm silica gel (230-400 mesh). Solvents
were reagent grade and in most cases dried prior to use. The
purity of all compounds was shown to be >95% by TLC and
high-field 1H (300 MHz) and 13C (75 MHz) NMR. The high-
resolution and fast-atom-bombardment mass spectra were
obtained at The Ohio State University Campus Chemical
Instrumentation Center. Elemental analyses were performed
at Atlantic Microlab, Inc., Norcross, GA.
ppm; MS m/z (M+) calcd 295.1783, obsd 295.1776. Anal. Calcd
for C16H25NO4: C, 65.06; H, 8.53. Found: C, 64.99; H, 8.59.
For 12: colorless oil; IR (film, cm-1) 3440, 1700, 1625, 1460
1
1330, 1210; H NMR (300 MHz, CDCl3) δ 5.29 (s, 1 H), 5.14
(s, 1 H), 4.15 (s, 3 H), 3.82 (s, 3 H), 2.45-2.35 (m, 2 H), 2.25
(br s, 1 H), 2.20-2.10 (m, 1 H), 1.95-1.85 (m, 3 H), 1.85-1.60
(m, 2 H), 1.20 (m, 1 H); 13C NMR (75 MHz, CDCl3) 203.0, 166.2,
150.7, 135.4, 110.1, 81.2, 65.5, 59.7, 59.6, 46.7, 35.2, 33.5, 29.8,
27.2 ppm; MS m/z (M+) calcd 250.1205, obsd 250.1207. Anal.
Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.02; H,
7.25.
Gen er a l P r oced u r e for th e Use of 2 a n d 8 a s th e Lea d
An ion . A. To a cold (-78 °C), magnetically stirred solution
of 2-bromo-N-benzyl-N-methylallylamine (940 mg, 4.16 mmol)
in dry THF (10 mL) was added dropwise 4.9 mL of 1.7 M tert-
butyllithium in pentane (8.33 mmol). After 30 min at this
temperature, a solution of 1 (394 mg, 2.77 mmol) in dry THF
(5 mL) was similarly introduced, followed 1 h later with
2-lithiopropene [from 2-bromopropene (0.49 mL, 5.54 mmol)
and tert-butyllithium (6.5 mL of 1.7 M, 11.1 mmol) in THF (5
mL)] as rapidly as possible. The reaction mixture was kept
at -78 °C for 2 h, allowed to warm to room-temperature
overnight, recooled to 0 °C, and treated with deoxygenated
saturated NH4Cl solution (10 mL). After 30 min, the two-
phase system was stirred at 20 °C for 20 h and diluted with
brine (20 mL). The separated aqueous phase was extracted
with ether (2 × 30 mL), the combined organic layers were dried
and evaporated, and the residue was chromatographed on
silica gel (elution with 2:1 hexanes/ethyl acetate). There was
isolated 466 mg (48%) of 6 and 31 mg (5%) of 7.
For 6: white solid, mp 169-171 °C; IR (film, cm-1) 3250,
1698, 1621, 1462, 1325, 1232; 1H NMR (300 MHz, C6D6) δ
7.25-6.90 (m, 5 H), 3.78 (s, 3 H), 3.60 (s, 3 H), 3.45 (d, J )
13.2 Hz, 1 H), 3.06 (d, J ) 13.2 Hz, 1 H), 3.01 (d, J ) 12.9 Hz,
1 H), 2.59 (d, J ) 12.9 Hz, 1 H), 2.25 (m, 1 H), 1.95 (m, 1 H),
1.88 (s, 3 H), 1.45 (m, 1 H), 1.17 (d, J ) 7.0 Hz, 3 H), 1.12 (m,
1 H), 1.00 (m, 1 H) (OH not observed); 13C NMR (75 MHz, C6D6)
201.5, 170.9, 138.2, 137.8, 129.1, 128.7, 127.5, 84.4, 62.8, 62.4,
59.0, 58.7, 57.8, 46.2, 42.2, 34.9, 31.0, 15.4 ppm; MS m/z (M+)
calcd 345.1939, obsd 345.1938. Anal. Calcd for C20H27NO4: C,
69.54; H, 7.88. Found: C, 69.67; H, 7.91.
C. Coupling of 2-bromo-N,N-dimethylallylamine (513 mg,
3.12 mmol) and ethyl vinyl ether (0.40 mL, 4.17 mmol) to 1
(296 mg, 2.08 mmol) as described above afforded 107 mg (20%)
of 14 and 127 mg (20%) of 15.
For 14: colorless oil; IR (film, cm-1) 3500, 1698, 1621, 1462,
1326; 1H NMR (300 MHz, CDCl3) δ 4.19 (s, 3 H), 3.86 (dd, J )
5.2, 7.8 Hz, 1 H), 3.81 (s, 3 H), 3.71 (m, 1 H), 3.58 (m, 1 H),
2.81 (d, J ) 12.8 Hz, 1 H), 2.56 (d, J ) 12.8 Hz, 1 H), 2.15 (s,
6 H), 1.83 (m, 1 H), 1.74 (m, 1 H), 1.52 (m, 1 H), 1.25 (m, 1 H),
1.14 (t, J ) 7.0 Hz, 3 H) (OH not observed); 13C NMR (75 MHz,
CDCl3) 201.0, 170.6, 137.0, 87.1, 85.0, 65.6, 63.5, 59.5, 59.2,
55.4, 45.8 (2 C), 30.7, 28.4, 15.3 ppm; MS m/z (M+) calcd
299.1732, obsd 299.1735. Anal. Calcd for C15H25NO5: C, 60.18;
H, 8.42. Found: C, 60.09; H, 8.47.
For 15: colorless oil; IR (film, cm-1) 3471, 1704, 1614, 1462,
1
1425, 1337, 1296; H NMR (300 MHz, CDCl3) δ 5.41 (d, J )
2.3 Hz, 1 H), 5.16 (d, J ) 2.3 Hz, 1 H), 4.18 (s, 3 H), 3.89 (m,
1 H), 3.83 (s, 3 H), 3.70 (m, 1 H), 2.35 (m, 2 H), 1.98 (m, 1 H),
1.62 (m,1 H), 1.16 (t, J ) 7.0 Hz, 3 H) (OH not observed); 13C
NMR (75 Mz, CDCl3) 196.2, 168.2, 149.2, 136.2, 111.1, 83.2,
78.1, 61.5, 59.8, 59.6, 29.9, 28.3, 15.6 ppm; MS m/z (M+) calcd
254.1154, obsd 254.1158. Anal. Calcd for C13H18O5: C, 61.41,
H, 7.13. Found: C, 61.15, H, 7.17.
D. Coupling of 2-bromo-N,N-dimethylallylamine (443 mg,
2.70 mmol) and 4,5-dihydrofuran (0.27 mL, 3.60 mmol) to 1
(256 mg, 1.80 mmol) in the predesdribed manner furnished
145 mg (32%) of 18 as a colorless oil: IR (film, cm-1) 3452,
1713, 1621, 1462, 1335; 1H NMR (300 MHz, CDCl3) δ 5.48 (s,
1 H), 5.23 (s, 1 H), 4.15 (s, 3 H), 4.06 (m, 2 H), 3.83 (s, 3 H),
3.05 (s, 1 H), 2.70 (m, 1 H), 2.45-2.10 (series of m, 3 H), 1.55
(m, 1 H); 13C NMR (75 MHz, CDCl3) 197.3, 167.1, 147.0, 136.8,
113.4, 90.3, 78.2, 71.8, 59.8, 59.4, 43.7, 33.3, 32.1 ppm; MS
m/z (M+) calcd 252.0997, obsd 252.0994. Anal. Calcd for
For 7: white solid, mp 111-113 °C; IR (film, cm-1) 3420,
1690, 1610, 1460, 1425, 1340, 1295; 1H NMR (300 MHz, CDCl3)
δ 5.31 (m, 1 H), 5.11 (m, 1 H), 4.16 (s, 3 H), 3.75 (s, 3 H), 3.19
(s, 1 H), 2.31 (m, 1 H), 2.20 (m, 1 H), 2.05 (m, 1 H), 1.45 (ddd,
J ) 7.2, 7.6, 12.7 Hz, 1 H), 1.19 (s, 3 H); 13C NMR (75 MHz,
CDCl3) 198.1, 173.7, 151.7, 132.8, 110.6, 82.2, 59.8, 59.5, 52.8,
32.3, 29.7, 19.5 ppm; MS m/z (M+) calcd 224.1048, obsd
C
13H16O5: C, 61.90; H, 6.39. Found: C, 61.81; H, 6.44.
(3a R*,7a R*,8a S*)-8a -[(Ben zylm et h yla m in o)m et h yl]-
5,6,7,7a ,8,8a -h exa h yd r o-3a -h yd r oxy-2,3-d im eth oxycyclo-
p en t[a ]in d en -1(3a H)-on e (21a ). A 100 mL flask charged
with 1-bromo-6-methoxycyclohexene (0.46 g, 2.42 mmol) and
THF (12 mL) was treated dropwise at -78 °C with tert-
butyllithium (3.2 mL, 1.7 M in pentane, 5.44 mmol), and the
mixture was stirred at this temperature for 1 h. A solution of
1 (0.33, 2.32 mmol) in THF (12 mL) was introduced and the
solution was stirred at this temperature for another 2.5 h
before 2 [generated from the vinyl bromide (0.90 g, 3.77 mmol)
in THF (19 mL) and tert-butyllithium (5.0 mL, 1.7 M in
pentane, 8.50 mmol) at -78 °C for 1 h] was transferred in via
cannula. After 11 h at room temperature, deoxygenated
saturated aqueous ammonium chloride solution (10 mL) was
added, the mixture was extracted with ether (2 × 20 mL), and
the combined organic layers were washed with water (20 mL)
and brine (20 mL) prior to drying and solvent evaporation.
The residue was purified by flash chromatography on silica
gel (elution with hexanes-ethyl acetate 6:1) to give 21a as a
yellow liquid (0.35 g, 39%); IR (film, cm-1) 1698, 1622, 1454,
224.1041. Anal. Calcd for
Found: C, 64.35; H, 7.24.
C12H16O4: C, 64.27; H, 7.19.
B. Coupling of 2-bromo-N,N-dimethylallylamine (611 mg,
3.73 mmol) and 1-bromocyclopentene (963 mg, 4.97 mmol) to
1 (353 mg, 2.48 mmol) in the predescribed manner gave after
chromatography (elution with 1:1 hexanes/ethyl acetate) 300
mg (41%) of 10, 133 mg (18%) of 11, and 59 mg (10%) of 12.
For 10: colorless oil; IR (film, cm-1) 3500, 1690, 1625, 1460,
1
1330, 1230, 1205; H NMR (300 MHz, CDCl3) δ 4.19 (s, 3 H),
3.84 (s, 3 H), 2.87 (d, J ) 12.9 Hz, 1 H), 2.73 (d, J ) 12.9 Hz,
1 H), 2.19 (s, 6 H), 2.15-1.80 (series of m, 5 H), 1.65-1.40 (m,
2 H), 1.35-0.90 (series of m, 3 H); 13C NMR (75 MHz, CDCl3)
201.9, 169.6, 138.0, 79.6, 63.3, 63.0, 60.8, 59.4, 59.1, 45.9, 45.7,
37.8, 27.7, 25.1, 22.6 ppm; MS m/z (M+) calcd 295.1783, obsd
295.1776. Anal. Calcd for
Found: C, 64.96; H, 8.48.
C16H25O4: C, 65.06; H, 8.53.
For 11: colorless oil; IR (film, cm-1) 3450, 1695, 1625, 1460,
1
1
1330, 1200; H NMR (300 MHz, CDCl3) δ 4.18 (s, 3 H), 3.82
1327, 1017; H NMR (300 MHz, C6D6) δ 7.12-6.98 (m, 5 H),
(s, 3 H), 2.90 (m, 1 H), 2.76 (d, J ) 12.8 Hz, 2 H), 2.48 (m, 1
H), 2.20 (s, 6 H), 1.90-1.25 (series of m, 8 H) (OH not
observed); 13C NMR (75 MHz, CDCl3) 201.9, 170.7, 134.2, 86.1,
63.2, 59.3, 59.0, 58.8, 55.8, 44.9 (2 C), 40.0, 29.4, 27.5, 24.8
6.43-6.40 (m, 1 H), 3.83 (s, 3 H), 3.64 (s, 3 H), 3.44 (d, J )
13.1 Hz, 1 H), 3.12 (d, J ) 13.1 Hz, 1 H), 3.08 (d, J ) 12.9 Hz,
1 H), 2.63 (d, J ) 12.9 Hz, 1 H), 2.28-2.17 (m, 1 H), 2.16-
2.11 (m, 1 H), 2.07-1.90 (m, 2 H), 1.89 (s, 3 H), 1.86-1.65 (m,
1 H), 1.54-1.47 (m, 1 H), 1.28-1.19 (m, 2 H), 0.96-0.84 (m, 2
H); 13C NMR (75 MHz, C6D6) 200.9, 170.4, 142.9, 137.8, 136.1,
128.9, 128.4, 127.3, 122.3, 82.5, 62.6, 62.2, 58.6 (2 C), 56.5,
42.0, 41.7, 34.8, 28.8, 25.0, 21.9 ppm; MS m/z (M+) calcd
(20) He, M. unpublished results from this laboratory.
(21) Paquette, L. A.; Tae, J . J . Org. Chem. 1998, 63, 2022 (following
paper in this issue).

2018 J . Org. Chem., Vol. 63, No. 6, 1998
Paquette et al.
383.2063, obsd 383.2080. Anal. Calcd for C23H29NO4: C, 72.04;
H, 7.62. Found: C, 71.75; H, 7.73.
(9 mL) and then 19 [prepared from 0.53 g (2.79 mmol) of the
bromide] also dissolved in THF (14 mL) according to the
general procedure. Chromatographic purification gave 70 mg
(13%) of 24 and 110 mg (19%) of 21b.
(3a R*,7a R*,8a S*)-8a -[(Dim et h yla m in o)m et h yl]-5,6,7,-
7a ,8,8a -h exa h yd r o-3a -h yd r oxy-2,3-d im eth oxycyclop en t-
[a ]in d en -1(3a H)-on e (21b). Comparable treatment of 1 (0.32
g, 2.25 mmol) first with 19 and then with 8 afforded a brown
liquid whose purification by flash chromatography on silica
gel (elution with ethyl acetate/methanol 100:1) afforded 21b
4-[1-[(Ben zylm et h yla m in o)m et h yl]vin yl]-4-h yd r oxy-
2,3-d im eth oxy-2-cyclobu ten -1-on e (25). A solution of 2
[prepared from 0.59 g (2.47 mmol) of the bromide] in dry THF
(12 mL) was added dropwise to 1 (0.35 g, 2.46 mmol) dissolved
in THF (12 mL) at -78 °C. The usual workup and flash
chromatographic purification (silica gel, elution with hexanes/
ethyl acetate 5:1) yielded 25 (0.63 g, 84%) as a yellow liquid:
IR (film, cm-1) 1769 1650, 1454, 1348; 1H NMR (300 MHz,
C6D6) δ 8.20 (br s, 1 H), 7.23-7.01 (m, 5 H), 5.17 (br s, 1 H),
4.87 (br s, 1 H), 3.64 (s, 3 H), 3.59 (s, 3 H), 3.57 (d, J ) 12.5
Hz, 1 H), 3.29 (d, J ) 12.7 Hz, 1 H), 3.19 (d, J ) 12.7 Hz, 1 H),
2.81 (d, J ) 12.5 Hz, 1 H), 1.84 (s, 3 H); 13C NMR (75 MHz,
C6D6) 185.7, 165.1, 142.5, 137.3, 134.9, 129.2, 128.4, 127.4,
115.4, 90.3, 62.9, 61.1, 59.0, 57.8, 40.2 ppm; MS m/z (M+) calcd
303.1504, obsd 303.1487.
Rea ction of An ion 19 w ith 25. A solution of 19 [prepared
from 0.91 g (4.79 mmol) of the bromide] in THF (24 mL) was
added dropwise at -78 °C to a solution of 25 (0.47 g, 1.55
mmol) in the same solvent (15 mL). Adherence to the usual
protocol and subsequent flash chromatography (SiO2, elution
with hexanes/ethyl acetate 6:1) provided 0.31 g (53%) of 21a
and 0.14 g (31%) of 24.
4-[1-[(Dim e t h yla m in o)m e t h yl]vin yl]-4-h yd r oxy-2,3-
d im eth oxy-2-cyclobu ten -1-on e (26). A solution of 8 [pre-
pared from 0.47 g (2.87 mmol) of the bromide] in dry THF (14
mL) was added dropwise to 1 (0.42 g, 2.96 mmol) dissolved in
THF (15 mL) at -78 °C. The usual workup and chromato-
graphic purification (silica gel, elution with hexanes/ethyl
acetate 1:2) gave 26 (0.25 g, 38%) as a yellow oil: IR (film,
cm-1) 1769 1635, 1470, 1336; 1H NMR (300 MHz, C6D6) δ 8.22
(br s, 1 H), 5.09 (br s, 1 H), 4.83 (br s, 1 H), 3.65 (s, 3 H), 3.63
(s, 3 H), 3.39 (d, J ) 12.3 Hz, 1 H), 2.59 (d, J ) 12.3 Hz, 1 H),
1.85 (s, 6 H); 13C NMR (75 MHz, C6D6) 185.7, 165.2, 142.7,
134.7, 114.8, 90.3, 64.2, 59.0, 57.7, 43.8 (2 C) ppm; MS m/z
(M+) calcd 227.1153, obsd 227.1155.
Rea ction of An ion 19 w ith 26. A solution of 19 [prepared
from 0.72 g (3.79 mmol) of the bromide] in THF (19 mL) was
added dropwise at -78 °C to a solution of 26 (0.28 g, 1.23
mmol) in the same solvent (13 mL). Adherence to the usual
protocol and subsequent flash chromatography (elution with
ethyl acetate/methanol 100:1) delivered 62 mg (17%) of 24 and
160 mg (42%) of 21b.
(0.21 g, 31%) as a yellow solid: mp 78-91 °C; IR (film, cm-1
)
1698, 1622, 1454, 1312, 1105; 1H NMR (300 MHz, C6D6) δ 6.34
(s, 1 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 2.77 (d, J ) 12.7 Hz, 1 H),
2.42 (d, J ) 12.7 Hz, 1 H), 2.21-2.03 (m, 2 H), 1.98-1.87 (m,
3 H), 1.85 (s, 6 H), 1.81-1.63 (m, 1 H), 1.51-1.44 (m, 1 H),
1.34-1.14 (m, 1 H), 0.93-0.77 (m, 2 H); 13C NMR (75 MHz,
C6D6) 200.7, 170.1, 142.7, 136.1, 122.2, 82.5, 63.7, 58.7, 58.5,
56.1, 45.7 (2 C), 41.9, 34.7, 28.9, 25.0, 21.9 ppm; MS m/z (M+)
calcd 307.1777, obsd 307.1780. Anal. Calcd for C17H25NO4: C,
66.41; H, 8.20. Found: C, 66.25; H, 8.23.
(R*)-4-Hyd r oxy-2,3-d im eth oxy-4-[(S*)-6-m eth oxy-1-cy-
cloh exen -1-yl]-2-cyclobu ten -1-on e (22) a n d (R*)-4-Hy-
d r oxy-2,3-d im eth oxy-4-[(R*)-6-m eth oxy-1-cycloh exen -1-
yl]-2-cyclobu ten -1-on e (23). Treatment of 1 (0.37 g, 2.61
mmol) with 19 [from 0.48 g (2.53 mmol) of the bromide] at
-78 °C was followed by 1 h of stirring at this temperature,
addition of water (10 mL), and extraction with ether (2 × 15
mL). The combined organic phases were dried, concentrated,
and subjected to flash chromatography on silica gel (elution
with hexanes/ethyl acetate 2.8:1) to give rise to a inseparable
2.8:1 mixture of 22 and 23 in 56% yield as a yellow oil: IR
(film, cm-1) 3404, 1775, 1631, 1335, 1044; 1H NMR (300 MHz,
C6D6) δ [6.41-6.38 (m, minor isomer), 5.99-5.97 (m, major
isomer), total 1 H], 5.23 (br s, 1 H), [4.29 (br s, major isomer),
3.90 (br s, minor isomer), total 1 H], [3.70 (s, minor isomer),
3.63 (s, major isomer), total 3 H], [3.65 (s, minor isomer), 3.58
(s, major isomer), total 3 H], 2.99 (s, 3 H), 1.85-1.73 (m, 1 H),
1.69-1.60 (m, 2 H), 1.58-1.43 (m, 1 H), 1.24-1.13 (m, 2 H);
13C NMR (75 MHz, C6D6) [(major isomer: 185.9, 165.3, 134.5,
134.4, 128.9, 89.6, 74.7, 59.1, 51.8, 55.4, 25.3, 25.0, 16.8),
(minor isomer: 184.7, 165.3, 134.2, 133.8, 129.4, 88.4, 73.3,
58.9, 57.8, 55.7, 25.9, 25.6, 16.8] ppm; MS m/z (M+) calcd
254.1145, obsd 254.1149.
Tr ea tm en t of th e 22/23 Mixtu r e w ith 2. The alcohol
mixture (0.24 g, 0.94 mmol) was treated with 2 (from 2.93
mmol of the bromide) in THF (25 mL) at -78 °C, stirred at
room temperature for 16 h, and processed as described above
to give 21a (0.23 g, 63%), identical in all respects to the
material isolated earlier.
(3a R*,7a R*,8a S*)-8a -[(Ben zylm et h yla m in o)m et h yl]-
5,6,7,7a ,8,8a -h exa h yd r o-3a -h yd r oxy-2,3-d iisop r op oxycy-
clop en t[a ]in d en -1(3a H)-on e (28). A. By Sequ en tia l Ad -
d ition of An ion s 2 a n d 19. A solution of 2 [prepared from
0.52 g (2.18 mmol) of the bromide] in dry THF (11 mL) cooled
to -78 °C was treated sequentially with a solution of 27 (0.43
g, 2.17 mmol) in THF (9 mL) and then 19 [prepared from 0.64
g (3.37 mmol) of the bromide] also dissolved in THF (17 mL)
in the manner detailed earlier. After workup and flash
chromatography, there was isolated 0.27 g (28%) of 28 as a
pale yellow liquid: IR (film, cm-1) 1692, 1613, 1380, 1299,
1107; 1H NMR (300 MHz, C6D6) δ 7.12-6.98 (m, 6 H), 6.36 (s,
1 H), 5.45 (heptet, J ) 6.0 Hz, 1H), 5.17 (heptet, J ) 6.0 Hz,
1 H), 3.46 (d, J ) 13.0 Hz, 1 H), 3.14 (d, J ) 13.0 Hz, 1 H),
3.10 (d, J ) 12.9 Hz, 1 H), 2.64 (d, J ) 12.9 Hz, 1 H), 2.30-
2.16 (m, 2 H), 2.15-1.96 (m, 2 H), 1.90 (s, 3 H), 1.76-1.73 (m,
1 H), 1.56-1.51 (m, 1 H), 1.31-1.27 (m, 1 H), 1.21 (d, J ) 6.0
Hz, 3 H), 1.17 (d, J ) 6.0 Hz, 3 H), 1.15 (d, J ) 6.0 Hz, 3 H),
1.05 (d, J ) 6.0 Hz, 3 H), 0.98-0.88 (m, 2 H); 13C NMR (75
MHz, C6D6) 201.3, 170.1, 143.5, 138.1, 134.2, 129.2, 128.6,
127.5, 121.9, 82.9, 73.4, 71.8, 62.9, 62.5, 56.6, 42.5, 42.0, 35.2,
29.2, 25.3, 22.9, 22.8, 22.7, 22.6, 22.4 ppm; MS m/z (M+) calcd
439.2766, obsd 439.2744. Anal. Calcd for C27H37NO4: C, 73.77;
H, 8.48. Found: C, 73.53; H, 8.55.
Tr ea tm en t of th e 22/23 Mixtu r e w ith 8. Reaction of the
mixture (0.24 g, 0.94 mmol) with 8 [from 0.50 g (3.05 mmol)
of the bromide] under the previously described conditions
provided 0.14 g (48%) of 21b, a yellow solid spectroscopically
identical to the sample obtained before.
(3a R*,5a S*,9S*,9a S*)-3a ,4,5,5a ,6,7,8,9-Oct a h yd r o-3a -
h yd r oxy-1,2,9-tr im eth oxy-4-m eth ylen e-3H-cyclop en t[c]-
in d en -3-on e (24). A. Via th e Use of 2. A solution of 2
[prepared from 0.58 g (2.43 mmol) of the bromide] in dry THF
(12 mL) cooled to -78 °C was treated sequentially with a
solution of 1 (0.34 g, 2.39 mmol) in THF (12 mL) and then 19
[prepared from 0.69 g (3.63 mmol) of the bromide] also
dissolved in THF (18 mL) in the manner given above. The
standard workup and flash chromatography on silica gel
(elution with hexanes/ethyl acetate 8:1) furnished 0.28 g (31%)
of 21a and 0.13 g (18%) of 24 as a yellow solid: mp 64-66 °C;
IR (film, cm-1) 3520, 1715, 1633, 1461, 1329; 1H NMR (300
MHz, CDCl3) δ 5.48 (d, J ) 2.6 Hz, 1 H), 5.14 (d, J ) 2.6 Hz,
1 H), 4.16 (s, 3 H), 3.77 (s, 3 H), 3.50 (dd, J ) 11.7, 5.6 Hz, 1
H), 3.28 (s, 3 H), 2.43 (m, 1 H), 2.15-2.00 (m, 3 H), 1.85-1.55
(m, 3 H), 1.35-1.15 (m, 2 H) (OH not observed); 13C NMR (75
MHz, CDCl3) 198.5, 168.0, 148.8, 134.7, 112.9, 83.8, 79.5, 59.9,
59.8, 59.3, 57.8, 37.5, 36.6, 28.1, 27.5, 22.2 ppm; MS m/z (M+)
calcd 294.1467, obsd 294.1464. Anal. Calcd for C16H22O5: C,
65.29; H, 7.53. Found: C, 65.40; H, 7.54.
B. By Sequ en tia l Ad d ition of An ion s 19 a n d 2. Com-
parable treatment of 27 (0.42 g, 2.12 mmol) first with 19
(2.11 mmol) and then with 2 (3.22 mmol) afforded 0.37 g (40%)
of 28.
B. Via th e Use of 8. A solution of 8 [prepared from 0.30 g
(1.83 mmol) of the bromide] in dry THF (9 mL) was treated
sequentially with a solution of 1 (0.27 g, 1.90 mmol) in THF

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2019
(R*)-4-Hyd r oxy-2,3-d iisop r op oxy-4-[(S*)-6-m eth oxy-1-
cycloh exen -1-yl]-2-cyclobu ten -1-on e (29) a n d (R*)-4-Hy-
d r oxy-2,3-d iisop r op oxy-4-[(R*)-6-m eth oxy-1-cycloh exen -
1-yl]-2-cyclobu ten -1-on e (30). Treatment of 27 (0.35 g, 1.77
mmol) with 19 [from 0.34 g (1.79 mmol) of the bromide] at
-78 °C in THF (18 mL) in the manner given above followed
by flash chromatography (SiO2, elution with hexanes/ethyl
acetate 8:1) gave a mixture of 29 and 30 in a 1.8: 1 ratio (1H
m e t h o x y -4-m e t h y le n e -1,1-(t r im e t h y le n e d io x y )-3H -
cyclopen t[c]in den -3-on e (36). A. By Sequ en tial Addition
of An ion s 19 a n d 2. A cold (-78 °C), magnetically stirred
solution of 34 (0.20 g, 1.29 mmol) in dry THF (7 mL) was
treated sequentially with THF solutions of 19 [from 0.30 g
(1.57 mmol) of the bromide] and 2 [from 0.48 g (2.00 mmol) of
the bromide]. The reaction mixture was stirred at room
temperature for 21 h and processed in the usual way. The
dark residue was subjected to flash chromatography on silica
gel (elution with hexanes/ethyl acetate 1:1) to give 150 mg
(23%) of 35 and 32 mg (8%) of 36, both as yellow oils.
For 35: IR (film, cm-1) 1706, 1626, 1268, 1077; 1H NMR
(300 MHz, C6D6) δ 7.20-7.00 (m, 5 H), 6.42-6.41 (m, 1 H),
3.91-3.76 (m, 2 H), 3.69-3.59 (m, 1 H), 3.55-3.42 (m, 2 H),
3.16 (d, J ) 12.6 Hz, 1 H), 3.12 (d, J ) 12.9 Hz, 1 H), 2.72 (d,
J ) 12.9 Hz, 1 H), 2.33-2.26 (m, 1 H), 2.21-2.12 (m, 1 H),
2.08-1.99 (m, 2 H), 1.94 (s, 3 H), 1.89-1.75 (m, 1 H), 1.59-
1.55 (m, 1 H), 1.52-1.37 (m, 2 H), 1.36-1.22 (m, 2 H), 1.02-
0.90 (m, 2 H); 13C NMR (75 MHz, C6D6) 199.4, 164.7, 143.3,
138.0, 136.3, 128.8, 128.4, 127.2, 121.4, 82.5, 73.0, 71.0, 62.9,
61.9, 56.9, 41.9, 41.8, 34.9, 32.2, 28.9, 25.0, 22.0 ppm; MS m/z
(M+) 395.2122, obsd 395.2109.
NMR analysis) as a yellow liquid in 72% yield: IR (film, cm-1
)
3416, 1766, 1613, 1383, 1101; 1H NMR (300 MHz, C6D6) δ
[6.47-6.44 (m, minor isomer), 6.15-6.12 (m, major isomer),
total 1 H], [51.0 (br s, major isomer, 4.65 (br s, minor isomer),
total 1 H], 4.92 (heptet, J ) 6.1 Hz, 1 H), 4.84-4.72 (m,1 H),
[4.25 (br s, major isomer), 3.70 (br s, minor isomer), total 1
H], [3.06 (s, minor isomer), 3.05 (s, major isomer), total 3 H],
1.93-1.43 (m, 4 H), 1.30-1.08 (m, 14 H); 13C NMR (75 MHz,
C6D6) [(major isomer: 185.9, 164.9, 134.8, 132.4, 128.5, 89.0,
76.0, 74.6, 73.0, 55.4, 25.7, 25.0, 22.5 (2 C), 22.2, 21.8, 16.8
ppm) (minor isomer: 184.6, 167.9, 134.4, 132.3, 129.3, 88.1,
76.3, 73.6, 72.8, 55.6, 26.0, 25.3, 22.6, 22.5, 22.3, 21.9, 16.8
ppm)]; MS m/z (M+) calcd 310.1806, obsd 310.1793.
Rea ction of An ion 2 w ith 29/30. A solution of 2 [prepared
from 0.40 g (1.67 mmol) of the bromide] in THF (9 mL) was
added dropwise at -78 °C to a solution of the 29/30 mixture
(0.17 g, 0.54 mmol) in the same medium (3 mL). After 12 h,
the customary workup was applied and 0.12 g (53%) of
diquinane 28 was isolated after chromatography.
For 36: IR (film, cm-1) 3498, 1719, 1633, 1273, 1102; 1H
NMR (300 MHz, C6D6) δ 5.84 (d, J ) 2.6 Hz, 1 H), 5.12 (d, J
) 2.6 Hz, 1 H), 3.77-3.64 (m, 2 H), 3.61-3.53 (m, 1 H), 3.41-
3.35 (m, 2 H), 2.92 (s, 3 H), 2.42-2.33 (m, 1 H), 2.05-1.97 (m,
1 H), 1.94-1.71 (m, 4 H), 1.65-1.58 (m, 1 H), 1.56-1.48 (m, 2
H), 1.46-1.24 (m, 2 H), 1.10-0.95 (m, 1 H); 13C NMR (75 MHz,
C6D6) 195.6, 161.8, 149.7, 135.6, 112.9, 84.6, 79.5, 72.7, 70.9,
60.0, 57.2, 37.7, 36.7, 32.0, 28.2, 27.2, 22.5 ppm; MS m/z (M+)
calcd 306.1475, obsd 306.1471.
B. By Sequ en tia l Ad d ition of An ion s 2 a n d 19. Adapta-
tion of the above procedure to 0.45 g (2.92 mmol) of 34, followed
by 2 [from 0.77 g (3.22 mmol) of the bromide] and 19 [from
0.86 g (4.52 mmol) of the bromide] led to the isolation of 0.55
g (48%) of 35 and 0.16 g (18%) of 36.
4-[1-[(Ben zylm et h yla m in o)m et h yl]vin yl]-4-h yd r oxy-
2,3-d iisop r op oxy-2-cyclobu ten -1-on e (31). The addition of
2 [from 0.26 g (1.08 mmol) of the bromide] in dry THF (6 mL)
to 27 (0.21 g, 1.06 mmol) dissolved in THF (6 mL) at -78 °C
followed by chromatography on silica gel (elution with dichlo-
romethane/ ethyl acetate 5:1) provided 0.23 g (61%) of 31 as a
yellow oil: IR (film, cm-1) 1769, 1633, 1316, 1099; 1H NMR
(300 MHz, C6D6) δ 8.02 (br s, 1 H), 7.18-7.10 (m, 2 H), 7.09-
6.99 (m, 3 H), 5.30 (br s, 1 H), 4.94 (heptet, J ) 6.1 Hz, 1 H),
4.90 (br s, 1 H), 4.74 (heptet, J ) 6.1 Hz, 1 H), 3.60 (d, J )
12.3 Hz, 1 H), 3.30 (d, J ) 12.7 Hz, 1 H), 3.20 (d, J ) 12.7 Hz,
1 H), 2.85 (d, J ) 12.3 Hz, 1 H), 1.84 (s, 3 H), 1.19-1.06 (m,
12 H); 13C NMR (75 MHz, C6D6) 185.6, 164.9, 142.8, 137.4,
132.8, 129.2, 128.3, 127.2, 115.0, 89.8, 75.9, 73.0, 63.1, 61.1,
40.3, 22.5, 22.4, 22.1, 21.9 ppm; MS m/z (M+) calcd 359.2104,
obsd 359.2100.
(R*)-4-[(S*)-6-(Ben zylm et h yla m in o)-1-cycloh exen -1-
yl]-4-(ter t-b u t yld im et h ylsiloxy)-2,3-d iisop r op oxy-2-cy-
clob u t en -1-on e (38b ) a n d (R*)-4-[(R*)-6-(Ben zylm et h -
ylam in o)-1-cycloh exen -1-yl]-4-(ter t-bu tyldim eth yl-siloxy)-
2,3-d iisop r op oxy-2-cyclobu ten -1-on e (39b). A cold (-78
°C), magnetically stirred solution of 27 (1.50 g, 7.58 mmol) in
dry THF (40 mL) was treated with 37 [prepared from 2.09 g
(7.46 mmol) of the bromide], stirred at this temperature for 1
h, quenched with water (20 mL), and extracted with ether (2
× 50 mL). After the usual processing, flash chromatography
on silica gel (elution with hexanes/ethyl acetate 10:1) led to
the isolation in 75% yield of a 1:1.8 mixture of 38a and 38b.
A 2.29 g (5.74 mmol) sample of this mixture was dissolved
in DMF (15 mL), treated with tert-butyldimethylsilyl chloride
(1.73 g, 11.5 mmol) and imidazole (1.56 g, 22.9 mmol), and
stirred for 18 h. Water (20 mL) was introduced and the
products were extracted into ether (2 × 50 mL), washed with
water (50 mL) and brine (50 mL), dried, and evaporated. The
residue was subjected to flash chromatography on silica gel
(elution with hexanes/ethyl acetate 50:1) to give 0.85 g (29%)
of 38b and 1.38 g (47%) of 39b, both as yellow oils.
Rea ction of An ion 19 w ith 31. Dropwise addition at -78
°C of a solution of 19 [from 0.21 g (1.11 mmol) of the bromide]
in dry THF (5 mL) to 31 (0.13 g, 0.36 mmol) dissolved in the
same medium (4 mL) at -78 °C followed by stirring at 20 °C
for 17 h, the usual workup, and chromatography on silica gel
delivered 62 mg (39%) of 28.
(-)-(3a R ,6R ,7S ,7a R ,8a S )-8a -[(Be n zylm e t h yla m in o)-
m et h yl]-5,6,7,7a ,8,8a -h exa h yd r o-3a -h yd r oxy-2,3-d iiso-
p r op oxy-6,7-(isop r op ylid en ed ioxy)cyclop en t [a ]in d en -
1(3a H)-on e (33). The analogous protocol involving 2 [from
0.28 g (1.17 mmol) of the bromide] in dry THF (6 mL) and
(+)-32 (0.15 g, 0.39 mmol) dissolved in THF (2 mL) led to the
isolation of 86 mg (43%) of (-)-33 as a pale yellow oil following
chromatography on silica gel (elution with dichloromethane/
ethyl acetate 100:1): IR (film, cm-1) 1693, 1609, 1379, 1301,
1
For 38b: IR (film, cm-1) 1769, 1614, 1383, 1101; H NMR
1
1062; H NMR (300 MHz, C6D6) δ 7.11-6.97 (m, 6 H), 6.29-
(300 MHz,
6.25 (m, 1 H), 5.40 (heptet, J ) 6.1 Hz, 1 H), 5.20 (heptet, J )
6.1 Hz, 1 H), 3.99 (q, J ) 5.7 Hz, 1 H), 3.77 (t, J ) 5.1 Hz, 1
H), 3.45 (d, J ) 13.0 Hz, 1 H), 3.13-3.07 (m, 2 H), 2.71-2.56
(m, 3 H) 2.40-2.36 (m, 2 H), 1.90 (s, 3 H), 1.39 (s, 3 H), 1.28
(s, 3 H), 1.22 (d, J ) 6.1 Hz, 3 H), 1.17-1.13 (m, 1 H), 1.12 (d,
J ) 6.1 Hz, 3 H), 1.06 (d, J ) 6.1 Hz, 3 H), 1.04 (d, J ) 6.1 Hz,
3 H); 13C NMR (75 MHz, C6D6) 200.9, 169.6, 142.0, 138.0,
133.7, 129.2, 128.6, 127.6, 119.3, 107.7, 82.5, 79.6, 73.6, 72.6,
71.8, 62.8, 62.6, 56.3, 42.1, 41.6, 39.5, 29.0, 28.5, 26.0, 22.8,
22.7, 22.6, 22.5 ppm; MS m/z (M+) calcd 511.2933, obsd
C6D6) δ 7.48-7.46 (m, 2 H), 7.27-7.22 (m, 2 H), 7.14-7.10
(m, 1 H), 6.63 (dt, J ) 3.8, 0.9 Hz, 1 H), 5.09 (heptet, J ) 6.1
Hz, 1 H), 4.72 (heptet, J ) 6.1 Hz, 1 H), 3.67 (d, J ) 13.0 Hz,
1 H), 3.57 (d, J ) 13.0 Hz, 1 H), 3.37-3.36 (m, 1 H), 2.14 (s,
3 H), 1.97-1.87 (m, 3 H), 1.49-1.29 (m, 3 H), 1.25 (d, J ) 6.1
Hz, 3 H), 1.15 (d, J ) 6.1 Hz, 3 H), 1.09 (d, J ) 6.1 Hz, 3 H),
1.05 (s, 9 H), 1.04 (d, J ) 6.1 Hz, 3 H), 0.39 (s, 3 H), 0.32 (s, 3
H); 13C NMR (75 MHz, C6D6) 183.1, 163.4, 139.6, 135.0, 133.7,
130.3, 129.3, 128.0, 126.6, 90.3, 75.1, 72.8, 59.6, 56.6, 36.5, 26.0,
25.2, 22.9, 22.6, 22.3, 22.1, 21.5, 20.4, 18.5, -3.1, -3.4 ppm;
MS m/z (M+) calcd 513.3220, obsd 513.3247.
511.2946; [R] -172.17 (c 0.51, C6H6). Anal. Calcd for C30H41
-
1
NO6: C, 70.42; H, 8.08. Found: C, 70.32; H, 8.04.
For 39b: IR (film, cm-1) 1768, 1613, 1321, 1099; H NMR
(3a R*,7a R*,8a S*)-8a -[(Ben zylm et h yla m in o)m et h yl]-
5,6,7,7a ,8,8a -h exa h yd r o-3a -h yd r oxy-2,3-(t r im et h ylen e-
d ioxy)cyclop en t [a ]in d en -1(3a H )-on e (35) a n d (3a R*,-
5a S*,9S*,9a S*)-3a ,4,5,5a ,6,7,8,9-Octa h yd r o-3a -h yd r oxy-9-
(300 MHz, C6D6) δ 7.44-7.41 (m, 2 H), 7.24-7.18 (m, 2 H),
7.14-7.09 (m, 1 H), 6.59 (dt, J ) 3.8, 1.1 Hz, 1 H), 5.05 (heptet,
J ) 6.1 Hz, 1 H), 4.93 (heptet, J ) 6.1 Hz, 1 H), 3.63 (br s, 1
H), 3.56 (d, J ) 12.5 Hz, 1 H), 3.43 (d, J ) 12.5 Hz, I H), 2.03

2020 J . Org. Chem., Vol. 63, No. 6, 1998
Paquette et al.
(s, 3 H), 1.99-1.91 (m, 2 H), 1.89-1.81 (m, 1 H), 1.53-1.29
(m, 3 H), 1.25 (d, J ) 6.1 Hz, 3 H), 1.18 (d, J ) 6.1 Hz, 3 H),
1.13 (d, J ) 6.1 Hz, 3 H), 1.03 (s, 9 H), 0.96 (d, J ) 6.1 Hz, 3
H), 0.35 (s, 3 H), 0.33 (s, 3 H); 13C NMR (75 MHz, C6D6) 183.8,
167.3, 140.1, 135.2, 132.1, 130.9, 129.6, 127.8, 126.6, 89.2, 75.4,
72.7, 60.0, 58.2, 36.0, 25.9, 25.2, 22.9, 22.7, 22.1, 21.7, 21.6,
20.3, 18.4, -3.2, -3.4 ppm; MS m/z calcd 513.3220, obsd
513.3262.
(3a R*,6a S*,6bS*,10bR*)-5,6,6a ,6b,7,8,9,10b-Octa h yd r o-
10b -h yd r oxy-1,2-d iisop r op oxyd icyclop e n t [a ,b]in d e n -
3(4H)-on e (42) an d (3aR*,6aS*,6bS*,10bR*)-5,6,6a,6b,7,8,9,-
10b -Oct a h yd r o-10b -h yd r oxy-2,3-d iisop r op oxyd icyclo-
p en t[a ,b]in d en -1(4H)-on e (43). A. F r om 38a . tert-Butyl-
lithium (3.2 mL of 1.7 M in pentane, 5.44 mmol) was added
dropwise at -78 °C to a solution of 1-iodocyclopentene (0.46
g, 2.37 mmol) in dry THF (12 mL), stirred for 1 h in the cold,
treated with 0.26 g (0.65 mmol of 38a dissolved in dry THF (7
mL), and stirred at room temperature for 19 h. The usual
workup and chromatographic purification (elution with hex-
anes/ethyl actate 10:1) furnished 45 mg (20%) of 42 and 36
mg (16%) of 43, both as white solids.
(R*)-4-[(S*)-6-(Ben zylm et h yla m in o)-1-cycloh exen -1-
yl]-4-h yd r oxy-2,3-d iisop r op oxy-2-cyclobu ten -1-on e (38a ).
A 100 mL flask was charged with silyl ether 38b (0.94 g, 1.83
mmol) and THF (20 mL). Tetrabutylammonium fluoride (3.8
mL, 1 M in THF, 3.80 mmol) was added at 0 °C, and the
mixture was stirred at room temperature for 30 min. Water
(10 mL) was introduced, the mixture was extracted with ether
(2 × 20 mL), and the combined organic layers were washed
with water (20 mL) and brine (20 mL) and then concentrated.
Purification by flash chromatography on silica gel (elution with
hexanes/EtOAc 6:1) gave 38a as a yellow oil (0.53 g, 73%): IR
(film, cm-1) 3452, 1766, 1454, 1103; 1H NMR (300 MHz, C6D6)
δ 9.06 (br s, 1 H), 7.41-7.39 (m, 2 H), 7.15-7.10 (m, 2 H),
7.07-7.02 (m, 1 H), 6.12 (dt, J ) 4.2, 1.6 Hz, 1 H), 5.02 (heptet,
J ) 6.1 Hz, 1 H), 4.74 (heptet, J ) 6.1 Hz, 1 H), 3.74 (br s, 1
H), 3.66 (br s, 1 H), 3.22-3.18 (m, 1 H), 2.08 (s, 3 H), 2.03-
1.68 (m, 2 H), 1.58-1.49 (m, 1 H), 1.42-1.20 (m, 3 H), 1.16 (d,
J ) 6.1 Hz, 3 H), 1.14 (d, J ) 6.1 Hz, 3 H), 1.12 (d, J ) 6.1 Hz,
3 H), 1.08 (d, J ) 6.1 Hz, 3 H); 13C NMR (75 MHz, C6D6) 185.4,
165.4, 138.2, 135.1, 134.0, 129.5, 128.5, 128.4, 127.2, 90.2,
75.8, 72.8, 60.1, 57.9, 36.2, 25.1, 22.6, 22.4, 22.1, 22.0, 20.7,
19.8 ppm; MS m/z (M+) calcd 399.2441, obsd 399.2405. Anal.
Calcd forC24H33NO4: C, 72.15; H, 8.33. Found: C, 72.00; H,
8.21.
(R*)-4-[(R*)-6-(Ben zylm et h yla m in o)-1-cycloh exen -1-
yl]-4-h yd r oxy-2,3-d iisop r op oxy-2-cyclobu ten -1-on e (39a ).
A 100 mL flask was charged with silyl ether 39b (1.33 g, 2.59
mmol) and THF (25 mL). Tetrabutylammonium fluoride (5.2
mL, 1 M in THF, 5.20 mmol) was added at 0 °C, and the
mixture was stirred at room temperature for 30 min. Water
(10 mL) was introduced, the mixture was extracted with ether
(2 × 20 mL), and the combined organic layers were washed
with water (20 mL) and brine (20 mL), dried, and concentrated.
Purification by flash chromatography on silica gel (elution with
hexanes/EtOAc 6:1) gave 39a as a yellow oil (0.80 g, 78%); IR
(film, cm-1) 3464, 1766, 1454, 1098; 1H NMR (300 MHz, C6D6)
δ 9.13 (br s, 1 H), 7.33-7.31 (m, 2 H), 7.14-7.02 (m, 3 H),
6.17 (dt, J ) 3.9, 1.5 Hz, 1 H), 5.00 (heptet, J ) 6.1 Hz, 1 H),
4.82 (heptet, J ) 6.1 Hz, 1 H), 4.07 (br s, 1 H), 3.52 (br s, 1 H),
3.34 (br s, 1 H), 1.90 (s, 3 H), 1.88-1.80 (m, 1 H), 1.73-1.57
(m, 2 H), 1.43-1.20 (m, 3 H), 1.17 (d, J ) 6.1 Hz, 3 H), 1.14
(d, J ) 6.1 Hz, 3 H), 1.12 (d, J ) 6.1 Hz, 3 H), 1.10 (d, J ) 6.1
Hz, 3 H); 13C NMR (75 MHz, C6D6) 186.9, 164.9, 138.2, 134.2,
132.6, 129.2, 128.4, 127.9, 127.7, 90.7, 75.7, 72.8, 59.8, 57.8,
35.9, 24.7, 22.6, 22.5, 22.2, 21.9, 20.1, 19.9 ppm; MS m/z (M+)
calcd 399.2441, obsd 399.2425. Anal. Calcd for C24H33NO4: C,
72.15; H, 8.33. Found: C, 72.00; H, 8.27.
B. F r om 39a . tert-Butyllithium (7.8 mL of 1.7 M in
pentane, 13.3 mmol) was added dropwise at -78 °C to a
solution of 1-iodocyclopentene (1.15 g, 5.92 mmol) in dry THF
(30 mL), stirred for 1 h in the cold, treated with 0.75 g (1.87
mol) of 39a dissolved in THF (20 mL), and stirred at room
temperature for 16 h. The usual workup and chromatographic
purification (elution with hexanes/ethyl acetate 10:1) gave 39
mg (6%) of 42 and 180 mg (28%) of 43.
For 42: mp 88-90 °C; IR (film, cm-1) 3428, 1693, 1613,
1
1380, 1100; H NMR (300 MHz, C6D6) δ 6.12-6.09 (m, 1 H),
5.33 (heptet, J ) 6.0 Hz, 1 H), 5.29 (heptet, J ) 6.0 Hz, 1 H),
2.51-2.44 (m, 1 H), 2.30-2.16 (m, 2 H), 2.08 (s, 1 H), 1.99-
1.69 (m, 7 H), 1.55-1.46 (m, 2 H), 1.37-1.18 (m, 1 H), 1.16 (d,
J ) 6.0 Hz, 3 H), 1.13 (d, J ) 6.0 Hz, 3 H), 1.11 (d, J ) 6.0 Hz,
3 H), 1.08 (d, J ) 6.0 Hz, 3 H), 0.93-0.81 (m, 1 H); 13CNMR
(75 MHz, C6D6) 202.6, 165.6, 147.3, 129.5, 120.0, 80.3, 73.4,
71.1, 66.4, 53.7,46.0, 32.4, 31.8, 28.6, 27.0, 24.7, 22.6 (2 C),
22.3, 22.2, 21.9 ppm; MS m/z (M+) calcd 346.2144, obsd
346.2144. Anal. Calcd for
Found: C, 72.65; H, 8.83.
C21H30O4: C, 72.80; H, 8.73.
For 43: mp 134-136 °C; IR (film, cm-1) 3363, 1694, 1613,
1
1380, 1103; H NMR (300 MHz, C6D6) δ 6.14-6.11 (m, 1 H),
5.29 (heptet, J ) 6.1 Hz,1 H), 5.23 (heptet, J ) 6.1 Hz, 1 H),
3.96 (s, 1 H), 2.45-2.37 (m, 2 H), 2.09-2.03 (m, 1 H), 1.94-
1.81 (m, 3 H), 1.79-1.61 (m, 4 H), 1.54-1.48 (m, 2 H), 1.35-
1.14 (m, 1 H), 1.10 (d, J ) 6.1 Hz, 3 H), 1.06 (d, J ) 6.1 Hz, 3
H), 1.04 (d, J ) 6.1 Hz, 3 H), 1.03 (d, J ) 6.1 Hz, 3 H), 0.98-
0.89 (m, 1 H); 13C NMR (75 MHz, C6D6) 198.3, 171.5, 145.3,
128.3, 120.7, 81.9, 73.2, 71.1, 63.1, 54.3, 47.0, 33.0, 31.2, 29.7,
27.3, 24.9, 22.7, 22.6, 22.5, 22.4 (2 C) ppm; MS mlz (M+) calcd
346.2144, obsd 346.2137. Anal. Calcd for C21H30O4: C, 72.80;
H, 8.73. Found: C, 72.67; H, 8.65.
(3a R*,7a R*,8a R*)-5,6,7,7a ,8,8a -Hexa h yd r o-3a -h yd r oxy-
2,3-d iisop r op oxy-8a -m et h ylcyclop en t [a ]in d en -1(3a H )-
on e (44) a n d (3a R*,7a R*,8a R*)-5,6,7,7a ,8,8a -Hexa h yd r o-
3a-h ydr oxy-1,2-diisopr opoxy-8a-m eth ylcyclopen t[a ]in den -
3(3a H)-on e (45). A. F r om 38a . 2-Propenyllithium [prepared
from 0.38 g (3.14 mmol) of the bromide] in dry THF (14 mL)
was added dropwise at -78 °C to solution of 38a (0.36, 0.90
mmol) in THF (19 mL). After being stirred at room temper-
ature for 12 h, the predescribed workup led to the isolation of
44 and 45 in a 2.9:1 ratio (1H NMR analysis) in 62% yield: IR
(film, cm-1) 3435, 1692, 1613, 1380, 1106; 1H NMR (300 MHz,
C6D6) δ [6.21-6.19 (m, minor isomer), 5.91-5.89 (m, major
isomer), total 1 H], 5.30 (heptet, J ) 6.1 Hz, 1 H), 5.23 (heptet,
J ) 6.1 Hz, I H), [2.77 (br s, major isomer), 2.69 (br s, minor
isomer), total 1 H], 2.44-2.38 (m, 1 H), 2.17-1.93 (m, 1 H),
1.91-1.72 (m, 2 H), 1.71-1.64 (m, 1 H), 1.53-1.48 (m, 1 H),
[1.41 (s, minor isomer), 1.29 (s, major isomer), total 3 H], 1.26-
1.07 (m, 12 H), 1.06-0.78 (m, 3 H); 13C NMR (75 MHz, C6D6)
[(major isomer 44: 202.8, 166.0, 145.8, 132.0, 121.3, 81.4, 73.4,
71.8, 55.7, 41.5, 35.9, 28.9, 25.3, 22.9, 22.8, 22.6, 22.5, 22.3,
19.4 ppm) (minor isomer 45: 202.8, 166.2, 146.3, 129.1, 121.6,
80.7, 73.6, 71.5, 54.4, 43.2, 39.7, 29.1, 25.1, 22.9, 22.8, 22.6,
22.5, 22.1, 18.1 ppm)]; MS mlz (M+) calcd 320.1961, obsd
320.1974.
(4R*,4a R*,8a R*)-4a ,5,6,7,8,8a -Hexa h yd r o-2′,3′-d iisop r o-
p o x y -1-m e t h y ls p ir o [4H -3,1-b e n zo x a zin e -4,1′-[2]c y -
clobu ten e]-2,4′(1H)-d ion e (41). A mixture of 39a (0.16 g,
0.40 mmol) and palladium(II) hydroxide (5 mg) in methanol
(5 mL) was stirred under 1 atm of hydrogen at room temper-
ature for 12 h, filtered, and concentrated. The residue was
dissolved in dry THF (5 mL), treated with 1,1′-carbonyldiimi-
dazole, refluxed for 12 h, and concentrated. Flash chroma-
tography of the residue on silica gel (elution with hexanes/
ethyl acetate 1:2) afforded 43 mg (30% overall) of 41 as a white
solid: mp 112-114 °C;1H NMR (300 MHz, C6D6) δ 4.88 (heptet,
J ) 6.1 Hz, 1 H), 4.63 (heptet, J ) 6.1 Hz, 1 H), 3.37 (dt, J )
11.0, 3.6 Hz, 1 H), 2.72 (s, 3 H), 1.77-1.72 (m, 1 H), 1.70-
1.63 (m, I H), 1.59-1.49 (m, 1 H), 1.39-1.25 (m, 2 H), 1.16-
1.09 (m, 1 H), 1.07 (d, J ) 6.1 Hz, 3 H), 1.05 (d, J ) 6.1 Hz, 3
H), 1.04 (d, J ) 6.1 Hz, 3 H), 1.01 (d, J ) 6.1 Hz, 3 H), 0.92-
0.75 (m, 2 H), 0.57-0.48 (m, 1 H); 13C NMR (75 MHz, C6D6)
181.2, 161.4, 152.5, 134.7, 92.1, 77.0, 74.0, 56.8, 39.7, 31.6, 30.7,
B. F r om 39a . Comparable addition of 2-propenyllithium
[prepared from 0.56 g (4.62 mmol) of the bromide] to 39a (0.59
g, 1.47 mmol) furnished a 1.1:1 mixture of 44 and 45 in 73%
yield.
26.1, 24.7, 24.0, 22.6, 22.5, 22.2, 22.0. Anal. Calcd for C18H17
NO5: C, 64.06; H, 8.07. Found: C, 63.98; H, 8.14.
-

Amino Groups as Nucleofugal Controllers of Selectivity
J . Org. Chem., Vol. 63, No. 6, 1998 2021
and B(eq) values, anisotropic displacement parameters, and
positional parameters for the hydrogen atoms of 10•HCl.
Tables giving the crystal data and structure refinement
information, bond lengths and bond angles, atomic and
hydrogen coordinates, and isotropic and anisotropic displace-
ment coordinates for 41 and 43 (33 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. Financial support was provided
by the National Science Foundation. In addition, we
thank Prof. Robin Rogers (University of Alabama) and
Dr. J udith Gallucci (Ohio State University) for the X-ray
crystallographic analyses and Dr. Kurt Loening for
assistance with nomenclature.
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawings
for 10‚HCl, 41, and 43. Crystallographic experimental details,
tables of X-ray crystal data, bond lengths and angles, bond
lengths involving the hydrogen atoms, positional parameters
J O9722919