Enantioselective synthesis of angularly substituted 1-azabicylic rings: Coupled dynamic kinetic epimerization and chirality transfer

Article abstract of DOI:10.1021/jo4018099

A new strategy for enantioselective synthesis of azacyclic molecules in which dynamic kinetic equilibration of diastereomeric iminium ions precedes a stereochemistry-determining sigmatropic rearrangement is reported. The method is illustrated by the synthesis, in high enantiomeric purity (generally 95-99% ee), of a variety of 1-azabicyclic molecules containing angular allyl or 3-substituted 2-propenyl side chains adjacent to nitrogen and up to three stereogenic centers. In these products, the size of the carbocyclic ring is varied widely (5-12 membered); however, useful yields are obtained in forming 1-azabicyclic products containing only fused pyrrolidine and piperidine rings. Chirality transfer from substituents at carbons 1 and 2 of the 3-butenylamine fragment of the starting material is investigated, with methyl and phenyl substituents at the allylic position shown to provide exquisite stereocontrol (generally 98-99% chirality transfer). An attractive feature of the method is the ability to carry out the key transformation in the absence of solvent. Illustrated also is the high yielding conversion of four such products to a new family of bicyclic β-amino acids of high enantiomeric purity.

Full text of DOI:10.1021/jo4018099

Article
pubs.acs.org/joc
Enantioselective Synthesis of Angularly Substituted 1‑Azabicylic
Rings: Coupled Dynamic Kinetic Epimerization and Chirality Transfer
Zachary D. Aron, Tatsuya Ito, Tricia L. May, Larry E. Overman,* and Jocelyn Wang
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences II, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: A new strategy for enantioselective synthesis of
azacyclic molecules in which dynamic kinetic equilibration of
diastereomeric iminium ions precedes a stereochemistry-determining
sigmatropic rearrangement is reported. The method is illustrated by
the synthesis, in high enantiomeric purity (generally 95−99% ee), of a
variety of 1-azabicyclic molecules containing angular allyl or 3-
substituted 2-propenyl side chains adjacent to nitrogen and up to three
stereogenic centers. In these products, the size of the carbocyclic ring is varied widely (5−12 membered); however, useful yields
are obtained in forming 1-azabicyclic products containing only fused pyrrolidine and piperidine rings. Chirality transfer from
substituents at carbons 1 and 2 of the 3-butenylamine fragment of the starting material is investigated, with methyl and phenyl
substituents at the allylic position shown to provide exquisite stereocontrol (generally 98−99% chirality transfer). An attractive
feature of the method is the ability to carry out the key transformation in the absence of solvent. Illustrated also is the high
yielding conversion of four such products to a new family of bicyclic β-amino acids of high enantiomeric purity.
1, particularly in high enantiomeric purity, could be responsible
for their limited use to date.5
INTRODUCTION
1-Azabicyclic rings having an angular substituent adjacent to
nitrogen (1, Figure 1) have a variety of potential applications.
■
We reported earlier a general method for the synthesis of
racemic, angularly substituted, 1-azabicylic molecules 1.6 The
method is illustrated in Scheme 1 for the preparation of cis-
cyclopentapyrrolidine 4 from aminoketal 2. In this synthesis, a
mixture of aminoketal 2, 1 equiv of trifluoroacetic acid (TFA),
and 2.5 equiv of dimedone is heated for several hours at 120
°C. The tetrasubstituted iminium ion A is formed initially and
upon heating undergoes [3,3]-sigmatropic equilibration with
iminium ion isomer B. The inclusion of dimedone (5,5-
dimethylcyclohexane-1,3-dione, 3) selectively traps the less-
stable formaldiminium ion isomer B to give presumably adduct
C, which upon fragmentation delivers the cis-cyclopentapyrro-
lidine product 4.7 To aid in purification, this product is
converted to benzyloxy (Cbz) derivative 5, which was isolated
in 8696% yield. The exomethylene fragment of the iminium
ion intermediate eventually emerges as the well-known
dimedone-formaldehyde adduct 6.
Figure 1. Angularly substituted 1-azabicyclic ring systems 1 and
examples of compounds containing this ring system.
During the development of this method, we discovered that
when the synthesis of the corresponding cis-octahydroindole 8
was carried out in CD3OD containing 3 equiv of D2O,
deuterium was incorporated into the angular methine (C3a)
and C7 methylene positions of product 8-d3 (Scheme 2).6 This
deuterium incorporation signified that the initially formed
iminium ion D equilibrated with enamonium ion iomers E and
F more rapidly than formaldiminium ion intermediate G was
trapped to yield cis-octahydroindole product 8.
These ring systems are found in natural products exhibiting
potentially useful therapeutic properties such as deoxyharring-
tonine1 and in a few molecules of medicinal chemistry
significance, such as 8a-phenyldecahydroquinolines (Figure
1).2 One can also readily envisage applications of conforma-
tionally constrained β-amino acids of the type depicted in
Figure 1 in peptidomimetics or as organocatalysts. Nonetheless,
there are remarkably few reports of applications of angularly
substituted nitrogen heterocycles 1,3 particularly in light of the
presence of other substituted 1-azabicyclic nonaromatic hetero-
cycles in marketed drugs and exploratory drug candidates.4 The
lack of general methods for the synthesis of heterocycles of type
Received: August 16, 2013
Published: September 10, 2013
© 2013 American Chemical Society
9929
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
Scheme 1. Methylene Transfer-Driven Cationic 2-Aza-Cope Rearrangement
Scheme 2. Deuterium Incorporation by Iminium/Enamonium Ion Tautomerization
On the basis of the rapid pre-equilibrium that occurs
between iminium ion and enamonium ion intermediates in this
synthesis of angularly substituted heterocycles, we postulated
that incorporating a nonracemic stereocenter on the homo-
allylic side chain of an aminoketal precursor such as 9 should
result in the [3,3]-sigmatropic rearrangement occurring faster
with one C3a epimer to deliver potentially one enantiomer of
the azabicyclic product (Scheme 3). For this process to occur
with high chirality transfer, the C3a epimers of iminium ion
intermediate H must equilibrate rapidly, one epimer must
preferentially undergo [3,3]-sigmatropic rearrangement, and
dimedone trapping also must occur more rapidly than product
iminium ion J equilibrates with its enantiomer.8 At the outset,
we anticipated that sigmatropic rearrangement via transition
state geometry I would be preferred, because bond formation
from the convex face and placement of the substituent R in a
quasi-equatorial orientation should be favored.
In this article, we describe the development of this new
strategy into a general method for enantioselective synthesis of
angularly substituted 1-azabicyclic molecules.9 Experiments that
illuminate some of the mechanistic details of the cationic 2-aza-
Cope rearrangement and other steps in the sequence are
discussed also.
RESULTS AND DISCUSSION
■
Synthesis of Aminoketals Containing Enantiomeri-
cally Enriched 1-Substituted 3-Butenyl Fragments and
Their Conversion to 1-Azabicyclic Products. Our inves-
tigations began by preparing five aminoketal precursors 9 that
varied in the nature of the homoallylic substituent. The
synthesis begins with benzyl 2-oxocyclohexaneacetate (11),10
which we found most convenient to prepare by fluoride-
mediated alkylation of 1-(trimethylsiloxy)cyclohexene (10)
with benzyl 2-bromoacetate (Scheme 4).11 Ketalization of 11
catalyzed by scandium triflate yielded dioxolane derivative 12 in
68% overall yield from 10. Cleavage of the benzyl ester by
hydrogenolysis, followed by carbodiimide-promoted coupling
with (R)-1-substituted-3-butenylamines 13a−e provided
amides 14a−e. The enantiomerically enriched (R)-1-substi-
tuted-3-butenylamines 13a−e were available in three steps from
the corresponding aldehyde and (R)-phenylglycinol by the
method of Vilaivan and co-workers.12,13 Reduction of amide
intermediates 14a−e with lithium aluminum hydride delivered
aminoketals 9a−e in good overall yields from ketal ester 12.
Scheme 3. Potential Synthesis of Enantiomerically Enriched
cis-Octahydroindole 8 by Coupled Dynamic Kinetic
Epimerization and Chirality Transfer
9930
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
of p-Cl or o-Cl substituents or a p-OMe group in the aryl
fragment (entries 4−6). Most notable was the significant
decrease in chirality transfer observed when the homoallylic
substituent was isopropyl (entry 7). In addition, carrying out
the reaction in CD3OD at 110 °C in a sealed tube (1 equiv of
TFA and 2.5 equiv dimedone) provided ent-8 in 75% yield,
however with unsatisfactory (68%) chirality transfer. The
absolute configuration of ent-8 was secured by single crystal X-
ray analysis of its hydrobromide salt.
Scheme 4. Synthesis of Aminoketals 9
We briefly investigated the scope of this enantioselective
construction of allyl-substituted 1-azabicyclic molecules by
examining three additional precursors containing a (R)-1-
phenyl-3-butenyl fragment. Aminoacetal substrates 15−17 were
prepared by sequences identical (or analogous) to that reported
in Scheme 4.15 As summarized in Scheme 5, cis-
Scheme 5. Enantioselective Synthesis of Allyl-Substituted
Heterocycles 18−20
In our initial study, the reaction temperature and the effect of
the homoallylic substituent on chirality transfer were examined
(Table 1). All reactions were conducted neat by heating
Table 1. Enantioselective Synthesis of Octahydroindole 8
from Aminoketals 9a−e
ee
chirality
transfer
(%)
(%) temp time yield ee (%)
a
b
entry
R
9
(°C)
(h)
(%)
ent-8
hexahydrocyclopenta[b]pyrrole carbamate 18 and cis-
octahydrocyclopenta[b]pyridine carbamate 19 were formed in
95% and 80% yield from precursors 15 and 16, respectively,
and with 96−97% chirality transfer. In each case, only the cis
steroisomer of the product was detected. In contrast,
decahydroquinoline carbamate 20 was produced as a nearly
1:1 mixture of cis and trans epimers. These isomers could be
separated, and each was shown to have an enantiomeric purity
of 93% ee, corresponding to 97% chirality transfer. The
absolute configuration of 18 was determined by single crystal
X-ray analysis of the hydrobromide salt of the parent
hexahydrocyclopenta[b]pyrrole;9 the absolute configuration
for 19 and 20 was assigned in analogy to that of related
products 8 and 18.
1
2
3
4
Ph (9a)
Ph (9a)
Ph (9a)
93
93
93
92
120
100
80
5
22
1
92
84
0
89
88
96
95
4-OMeC6H4
(9b)
120
5
92
82
89
87
24
89
95
93
52
5
6
7
4-ClC6H4
(9c)
94
94
46
120
120
120
5
5
90
88
51
2-ClC6H4
(9d)
i-Pr (9e)
22
a
Enantiomeric purity of the homoallylic amine fragment of 9 was
b
determined by enantioselective HPLC. Enantiomeric purity was
determined by enantioselective HPLC analysis of the corresponding
N-benzoyl derivative.
Synthesis of 2-Substituted 3-Butenylamines of High
Enantiomeric Purity. Although chirality transfer was typically
high with substrates having an aryl substituent at the
homoallylic position, we entertained the possibility that this
selectivity might be even higher with substrates having a
substituent at the allylic carbon. We initiated these studies by
developing an enantioselective synthesis of (R)-2-phenylbut-2-
enylamine. To have convenient access to both enantiomers, we
chose a route wherein the stereocenter is set by a catalytic
enantioselective reaction using a catalyst for which both
enantiomers are commercially available (Scheme 6). Through
the use of a microwave modification16 of a method first
introduced by Trost,17 molybdenum-catalyzed enantioselective
mixtures of the aminoketal 9, trifluoroacetic acid (TFA) (1.0
equiv), and dimedone (2.5 equiv). In these small-scale
reactions, 0.1 equiv of morpholine was added to ensure that
excess TFA was not present, because dimedone is decomposed
at elevated temperatures in the presence of this acid. At 120 °C,
phenyl-substituted aminoketal 9a was converted to cis-
octahydroindole ent-8 in 92% yield with 96% chirality transfer
(entry 1).14 When this reaction was conducted at 100 °C, the
rearrangement was significantly slower (entry 2); however, the
extent of chirality transfer was not enhanced. No reaction was
observed at 80 °C after 1 h (entry 3). The degree of chirality
transfer was affected to only a small extent by the incorporation
9931
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
hexahydrocyclopenta[b]pyrrole carbamate 31 was formed in
89% yield and a remarkable 99% ee, corresponding to complete
chirality transfer (eq 1). When the morpholine buffer was
omitted, the yield was depressed slightly (80%).
Scheme 6. Synthesis of (R)-2-Phenylbut-2-en-1-amine
We next examined whether dimedone was essential to the
success of the transformation shown in eq 1 (Table 2). In the
Table 2. Reaction of Aminoacetal 30 with Trifluoroacetic
Acid to Form Product 31 in the Presence of Various
Additives
allylic alkylation of cinnamyl methyl carbonate (21) with
dimethyl sodiomalonate to give (S)-pentenoate 23 in high yield
and 99% ee. Krapcho decarboxylation of the malonate,18
followed by saponification of the carboxylic ester delivered (R)-
acid 24.19 Curtius rearrangement of 24 with diphenylphos-
phoryl azide in t-BuOH, followed by cleavage of the Boc group
with trifluoroacetic acid delivered (R)-2-phenylbut-2-enylamine
(26) in 83% yield from the precursor acid. This sequence has
been demonstrated on multigram scale.
To explore the effect of the 2-butenyl substituent on chirality
transfer of reactions of the corresponding aminoacetals, a short
synthesis of (S)-2-methylbut-3-en-1-ammonium chloride (29)
was developed also (Scheme 7). Enantioselective allylic
a
temp
(°C)
time
(h)
yield
(%)
entry
additive
b
1
dimedone (2.5 equiv)
120
120
0.5
0.5
80
89
2
dimedone (2.5 equiv), morpholine
(0.1 equiv)
c
3
none
120
120
60
0.5
0.5
24
21
21
24
7
Scheme 7. Synthesis of (S)-2-Methylbut-3-en-1-ammonium
Chloride
4
5
6
1,3-propanediol (3 equiv)
d
MeOH
d
5% H2O in MeOH
60
24
a
Reactions used a 1:1 molar ratio of rac-30 and trifluoroacetic acid and
b
the indicated additive(s). Reactant 30 was prepared from (S)-
butenylamine 26 (99% ee). When enantioenriched 30 was used,
product 31 was formed with >98% chirality transfer. Methanol was
c
d
the solvent in these reactions; the starting concentration of rac-30 was
0.5 M.
absence of dimedone (and morpholine), product 31 was
formed in 21% yield (entry 3). On the assumption that 1,3-
propanediol was the agent trapping what would be in this case a
formaldiminium ion of the 2-aza-Cope rearrangement product,
the reaction was carried out in the presence of 3 equiv of this
additive. However, the yield of 31 was not improved (entry 4).
Methanol was considered also to be a potential trap for the
formaldiminium ion intermediate; however, carrying out the
reaction in methanol did not result in appreciably higher yields
after 24 h at 60 °C (entries 5 and 6). Although we believe that
other trapping agents as efficacious as dimedone could likely be
found, we decided to explore instead the scope of the efficient,
highly enantioselective, reaction shown in eq 1.
A comparison of phenyl and methyl stereocontrolling groups
and results of our initial exploration of this route to
functionalized 1-azacyclic ring systems is summarized in
Table 3. Angularly substituted cis-hexahydropenta[b]pyrroles
31, cis-octahydroindoles 32, and cis-octahydrocyclopenta[b]-
pyridines 33 containing a (E)-3-substituted-2-propenyl side
chain were obtained in good yields (71−89% yields) and high
95−99% ee (entries 1−6). Chirality transfer was complete,
alkylation of allylbromide 27 (available in one step from (E)-
1,4-dibromobut-2-ene)20 with methylmagnesium bromide,
catalyzed by 1 mol % CuBr·SMe2 and 1.2 mol % Taniaphos
delivered allylic carbamate 28 in 91% yield and in 95% ee.21
Subsequent removal of the tosyl and tert-butoxycarbonyl groups
gave the enantiomerically enriched butenylamine hydrochloride
salt 29 in 78% overall yield from allylic bromide 27.
Synthesis of Enantiomerically Enriched Aminoacetal
Precursors Containing 2-Substituted 3-Butenyl Frag-
ments and Their Conversion to 1-Azabicyclic Products.
From homoallylic amine 26 or ammonium salt 29, a variety of
aminoacetal precursors were prepared from the corresponding
cycloalkanone acetal acids by the general method shown in
Scheme 4.15 Our initial studies focused on the reaction of
aminoacetal 30 and used the conditions utilized in our earlier
studies with the analogous substrate 15 having the phenyl
substituent at the homoallylic position. In this way, cis-
9932
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
slightly diminished diastereoselectivity (9:1 dr) and chirality
transfer (96%, entry 8). The absolute configuration of cis-
octahydrocyclopenta[b]pyridine 33a was determined by X-ray
analysis of the corresponding secondary amine hydrobromide
salt,9 whereas the absolute configuration of products 31a and
32a was determined by chemical correlation with azacyclic
products 18 and 8. Absolute configurations of the other
azabicyclic products reported in Table 3 were assigned by
analogy.
Table 3. Enantioslective Synthesis of 1-Azabicyclic
Molecules Containing an Angular 3-Phenyl or 3-
Methylpropenyl Substituents
Results of our further investigations of the scope of this
chemistry using precursors containing a (R)-2-phenylbutenyl-
amine fragment are summarized in Table 4. At 120 °C,
decahydroquinoline 35 was formed as a 1.7:1 mixture of cis and
trans stereoisomers (entry 1). Stereoselectivity was increased
slightly when the reaction was conducted in methanol at 60 °C
(entry 2).22 Both the cis- and trans-decahydroquinoline
products were formed in 99% ee. 1-Azabicyclic products
containing an (E)-3-phenyl-2-propenyl side chain adjacent to
nitrogen can be prepared with various sized rings carbocyclic
rings (entries 3−5). The cis steroisomer of the product was
strongly favored when the azacyclic ring is five-membered.
Extension of this chemistry to the synthesis of 1-azabicyclic
molecules in which the azacyclic unit is a medium ring appears
problematic. For example, decahydrocyclopenta[b]azocine 38
was formed in only 16% yield after an extended reaction time of
22 h at 120 °C (entry 6). We attribute this low conversion to
low efficiency in forming the initial 8-membered-ring iminium
ion.
As the stereocontrolling step in this construction of 1-
azacyclic molecules is an iminium ion [3,3]-sigmatropic
rearrangement, the organized six-membered chair-transition
structure should allow the geometry of a double bond in the
starting material to be transformed to a new stereocenter at C1
of the allylic side chain of the product. To examine this
possibility, three unsaturated aminoacetal substrates, 39a−c,
were prepared from (R)-2-phenyl-3(E)-alkenylamines having
Me, Ph, or cyclohexyl substituents at C4. Exposure of
aminoketal 39a, prepared from (R)-2-phenyl-3(E)-pentenyl-
amine of 87% ee, to trifluoroacetic acid at 120 °C for 30 min,
followed by Cbz protection gave cis-hexahydrocyclopenta[b]-
pyrrole 40 as a single stereoisomer in 75% yield (Scheme 8).
The enantiomeric purity (87% ee) of 40 indicated again that
chirality transfer was essentially complete. Similar results were
obtained in the formation of products 41 and 42, with the
exception of their higher enantiomeric purity (99% ee)
resulting from the greater diastereomeric purity of precursors
39b and 39c.23 However, the yields of 41 and 42 were
diminished, presumably because the larger size of the phenyl
and cyclohexyl substituents results in destabilizing steric
interactions in the iminium ion [3,3]-sigmatropic rearrange-
ment.
a
Enantiomeric excess was determined by enantioselective HPLC.
This product was a 9:1 mixture of epimers at the angular methine
b
carbon.
Synthesis of Uncommon β-Amino Acids in High
Enantiomeric Purity. β-Amino acids are valuable building
blocks in peptide-based drug design, as proteolytic degradation
is greatly reduced in vivo, increasing their bioavailability.24 For
example, replacing proline with a more rigid analog,
octahydroindole-2-carboxylic acid, has been exploited in several
bradykinin B2 antagonists to improve both enzymatic stability
and potency.25 Moreover, proline-based catalysts have been
shown to be powerful catalysts for a wide variety of
transformations26 with recent examples exemplifying 3-
pyrrolidinecarboxylic acid catalysts.27 Oxidative cleavage of
the angular-allyl side chain of the 1-azabicyclic molecules
within experimental uncertainty, regardless of the nature of the
allylic substituent on the butenyl fragment. Carrying out the
synthesis of 31a (87% yield, 99% ee) on a gram scale gave the
product in comparable yield with no reduction in enantiose-
lectivity, demonstrating the practicality of this method. The
high-yield formation of cis-octahydroindole 34a as exclusively a
single C7 methyl epimer indicates that both stereogenic centers
of the carbocyclic aminoacetal precursor epimerized by
iminium/enamonium tautomerization prior to 2-aza-Cope
rearrangement/dimedone trapping. In this case, the methyl-
substituted aminoketal provided cis-octahydroindole 34b in
9933
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
Table 4. Further Scope of the Enantioselective Synthesis of 1-Azabicyclic Molecules Containing an Angular 3-Phenylpropenyl
Substituent
a
b
1
Diastereoselectivities were determined by analysis of the H NMR spectra. Enantiomeric excess was determined by enantioselective HPLC.
c
d
e
Reaction carried out in methanol (0.5 M). Both isomers were obtained in 99% ee. Enantiomeric excess of the major isomer; the enantiomeric
f
excess of the minor isomer was not determined. Enantiomeric excess was not determined.
prepared in the manner reported herein would provide a variety
of new, potentially useful, β-amino acids. To demonstrate this
potential, we optimized a high-yielding, two-step sequence to
achieve this objective. Application of this sequence to prepare
four Cbz-protected β-amino acids is reported in Scheme 9.
Mechanistic Discussion. Our current understanding of the
high transfer of chirality observed in the azacyclic construction
reported in this article is derived in part from our studies of the
transformation of aminoketal 30 to cis-hexahydrocyclopenta-
[b]pyrrole 47. The success of this dynamic kinetic epimeriza-
tion rearrangement sequence was predicated on iminium/
enamonium equilibration occurring faster than the [3,3]-
sigmatropic rearrangement step. The rapid tautomerization of
iminium ion and enamonium ion intermediates K−M was
confirmed to occur more rapidly than the 2-aza-Cope
rearrangement when the reaction of aminoketal 30 was carried
out in CD3OD (Scheme 10). As expected, azabicyclic
carbamate 31 was isolated with deuterium incorporated in
the angular C3a and C6 methylene positions; analysis of this
Scheme 8. Enantioselective Synthesis of cis-
Hexahydrocyclopenta[b]pyrrole Carbamates Having Chiral
Allylic Side Chains
9934
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
major component is iminium ion O (diagnostic 13C NMR
signal at 221 ppm), with additional products assigned as
enamonium ions P and Q (diagnostic vinylic 13C NMR signals
between 132−123 ppm). This mixture was largely unchanged
after heating at 60 °C for 12 h or at 120 °C for 5 min. Addition
of excess dimedone to the latter sample and further heating at
130 °C generated ent-51 as the major azacyclic product.
On the basis of the studies reported in Schemes 10−12, we
propose the following mechanism (Scheme 13). In the
presence of 1 equiv of TFA, an aminoketal such as 30 is
transformed at elevated temperatures, by way of enamonium
tautomer L, into an equilibrium mixture composed largely of
tetrasubstituted iminium ions R and S. In the slow step of the
sequence, iminium ion diastereomer S preferentially undergoes
[3,3]-sigmatropic rearrangement via favored chair-transition
structure T having the phenyl substituent pseudoequatorial to
give cis-hexahydrocyclopenta[b]pyrrole formaldiminium ion U.
The exquisite chirality transfer observed in the transformations
reported herein requires that intermediate U, once formed,
does not equilibrate with isomers S and R, because [3,3]-
sigmatropic rearrangement of the latter (vide infra) would
generate ent-U and erode enantioselectivity. Thus, trapping of
intermediate U by dimedone and fragmentation of the
dimedone adduct must be irreversible to form the 3aS,6aR
product 47 in high enantioselectivity.29
The mechanism proffered in Scheme 13 ascribes the high
chirality transfer (>98%) observed in the transformation of 30
to 47 to preferential [3,3]-sigmatropic rearrangement of
iminium ion diastereomers S via transition structure T. As
depicted in Figure 2, ent-47 would be the result of [3,3]-
sigmatropic rearrangement of diastereomer R from the convex
face via boat geometry V.30 The near perfect chirality transfer
observed in forming 47 is consistent with transition structure V
being at least 3 kcal/mol (more likely 3.5 kcal/mol) higher in
energy than that of the chair-transition structure T.31 In
addition to the high enantioselectivity observed in forming cis-
hexahydrocyclopenta[b]pyrrole 47, the side chain of 47 is
introduced with high E stereoselectivity. Quantitative HPLC
analysis calibrated with an authentic sample of the (Z)-3-
phenyl-2-propenyl isomer of the Cbz derivative 3032
demonstrated that stereoselectivity in forming product 47
having a (E)-3-phenyl-2-propenyl side chain was 150:1. This
Scheme 9. Synthesis of Four Representative Cbz-Protected
β-Aminoacids
product by electrospray mass spectrometry indicated an 8:4:0:1
ratio of d3:d2:d1:d0 deuterium incorporation.28
We next probed the reversibility of the aza-Cope rearrange-
ment and methylene transfer steps (Scheme 11). The
irreversibility of the methylene transfer step was demonstrated
by heating secondary amine 47 with dimedone−formaldehyde
adduct 6 (1.25 equiv), trifluoroacetic acid (1 equiv), and
morpholine (0.1 equiv) at 120 °C in CD3OD for 48 h.
Benzyloxycarbonyl protection of recovered 47 and mass
spectrometric analysis showed that deuterium had not been
incorporated. In contrast, heating cis-hexahydrocyclopenta[b]-
pyrrole 47 in CD3OD at 120 °C for 24 h with
paraformaldehyde (3 equiv), trifluoroacetic acid (1 equiv),
and morpholine (0.1 equiv), followed by the addition of excess
dimedone at 120 °C provided, after Cbz protection, carbamate
31 containing extensive deuterium incorporation (d3:d2:d1:d0 =
36:15:2:1). This latter result establishes that in the absence of
dimedone, iminium ion isomers K and N (see Scheme 10)
equilibrate under the reaction conditions.
To gain additional insight into this chemistry, the reaction of
amino acetal ent-48 with 1 equiv of TFA was studied by NMR
(Scheme 12). Within 3 min at room temperature, ent-48 was
converted to a 1:1 mixture of diastereomeric bicyclic isomers
49 and 50. This mixture was essentially unchanged after 12 h at
room temperature. At temperatures above 40 °C, loss of 1,3-
propanediol occurred to generate a mixture of products. The
Scheme 10. Deuterium Incorporation in cis-Hexahydrocyclopenta[b]pyrrole 47 via Rapid Iminium/Enamonium Ion
Equilibratium
9935
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
Scheme 11. Probing the Reversibility of the Aza-Cope Rearrangement and Dimedone-Trapping Steps
Scheme 12. Intermediates Formed During the Formation of cis-Hexahydrocyclopenta[b]pyrrole ent-51
Scheme 13. Proposed Mechanism for the Formation of (3aS,6aR)-cis-Hexahydrocyclopenta[b]pyrrole 47 from Amino Acetal 30
isomer ratio establishes that chair-transition structure W for
[3,3]-sigmatropic rearrangement of iminium ion diastereomer
R is similarly disfavored (by 3.9 kcal/mol relative to the favored
transition structure T).
case trapping of the less-stable iminium isomer of a 2-aza-Cope
equilibration by reaction with dimedoneto dictate stereo-
selection.
The method was illustrated by the enantioselective synthesis
of a variety of 1-azabicyclic molecules containing angular allyl
or 3-substituted 2-propenyl side chains. In these structures, the
size of the carbocyclic ring was varied widely (5−12
membered); however, useful yields were obtained in forming
bicyclic products containing only fused pyrrolidine and
piperidine rings. A notable aspect of the method is formation
of the structurally rare 1-azacyclic products in high enantio-
meric purity (95−99% ee). Also demonstrated is the high
yielding conversion of four such products to a new family of
bicyclic β-amino acids of high enantiomeric purity, molecules of
potential utility for the synthesis of peptidomimetics, and
CONCLUSIONS AND OUTLOOK
■
In summary, a method of some generality for the
enantioselective synthesis of angularly substituted 1-azabicyclic
structures having up to three stereocenters is reported. This
synthesis illustrates a new strategy for enantioselective synthesis
of azacyclic molecules in which dynamic kinetic equilibration of
diastereomeric iminium ions precedes a stereochemistry-
determining sigmatropic rearrangement. Critical to the success
of this method is the facility of iminium ion/enamonium ion
interconversions, and identifying an irreversible stepin this
9936
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
(R)-1-Butyl-3-butenyl-1-(2-chlorophenyl)amine (13d). Following
general procedure A, 13d (1.10 g, 6.11 mmol, 73% yield) was obtained
as a colorless oil. Characterization data were consistent with previously
reported values.12 HPLC analysis indicated an enantiomeric excess of
94% [CHIRALCEL AD column; flow, 0.5 mL/min; hexanes:i-
PrOH:Et2NH = 950:50:1; λ = 254 nm; major enantiomer tR = 11.9
23
589
23
577
min; minor enantiomer tR = 11.4 min]: [α] +72.2, [α] +75.4,
23
23
[α] +87.1, [α] +155 (c 1.27, CH2Cl2).
546
435
General Procedure B for the Fluoride-Mediated Alkylation of
Enoxysilanes. Benzyl 2-(2-Oxocyclohexyl)acetate (11). To a stirred
suspension of TASF(Me) (330 mg, 1.20 mmol) in THF (1.2 mL) at
−78 °C was added a solution of 1-cyclohexenyloxytrimethylsilane (200
mg, 1.20 mmol) and benzyl 2-bromoacetate (0.22 mL, 1.4 mmol) in
THF (1.8 mL) dropwise via syringe over 5 min. The resulting mixture
was stirred at room temperature for 24 h and then diluted with
hexanes (25 mL), washed with H2O (10 mL), dried (MgSO4), filtered,
and concentrated in vacuo. Purification of the crude residue by flash
chromatography on silica gel (9:1 hexanes:EtOAc) provided 11 as a
colorless oil (0.22 g, 0.91 mmol, 77%): 1H NMR (500 MHz, CDCl3) δ
7.37−7.30 (m, 5H), 5.18−5.08 (m, 2H), 2.94−2.80 (m, 2H), 2.48−
2.32 (m, 2H), 2.26−2.07 (m, 3H), 1.92−1.85 (m, 1H), 1.79−1.58 (m,
2H), 1.44 (qd, J = 12.6, 3.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
210.8, 172.4, 136.0, 128.5, 128.09, 128.05, 66.2, 47.1, 41.8, 34.4, 33.8,
27.7, 25.1; IR (film, cm−1) 3066, 3035, 2937, 2861, 1733, 1710. Anal.
Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 72.89; H, 7.47.
General Procedure C for Ketalization of Cycloalkanones. (1,5-
Dioxaspiro[5.5]undec-7-yl)acetic Acid Benzyl Ester (12). To a
solution of ketoester 11 (3.9 g, 16 mmol), 1,3-propanediol (22 mL,
39 mmol), and trimethylorthoformate (8.6 mL, 78 mmol) in
acetonitrile (160 mL) at 0 °C was added scandium triflate (77 mg,
0.16 mmol). The reaction was maintained at 0 °C for 30 min and then
quenched with saturated aqueous NaHCO3 (∼5 mL) and extracted
with Et2O (3 × 75 mL). The combined organic layers were washed
with water (3 × 50 mL) and brine (25 mL), dried (MgSO4), filtered,
concentrated in vacuo, and purified on silica gel by flash
chromatography (1:9 Et2O:pentane) to provide 12 (4.2 g, 14 mmol,
88%) as a colorless oil. Characterization data were consistent with
previously reported values.6
Figure 2. Higher energy pathways leading to azacyclic products ent-47
and 52.
scaffolds for medicinal chemistry (Scheme 9). An attractive
feature of the method is the ability to carry out the key
transformation in the absence of solvent. An unappealing
feature of the method as currently practiced is the
stoichiometric formation of the dimedone-formaldehyde
adduct. The potential to mitigate this drawback by identifying
alternate, more attractive, iminium ion trapping steps is
suggested by preliminary studies but to date has not been
realized in a high-yielding manner.
EXPERIMENTAL SECTION
■
Preparation of Aminoketals Containing a Homoallylic
Stereogenic Center. General Procedure A for Oxidative Cleavage
of the Chiral Auxiliary. (R)-1-Phenylbut-3-en-1-amine (13a).12 Lead
acetate (4.50 g, 10.1 mmol) was added to a solution of (2R)-2-phenyl-
2-[(1′R)-1′-phenylbut-3′-enylamino]ethanol12 (2.26 g, 8.45 mmol),
CH2Cl2 (15 mL), and MeOH (15 mL) at 0 °C. The mixture was
stirred at 0 °C for 30 min. Hydroxylamine hydrochloride (5.87 g, 84.5
mmol) was added, and the mixture was stirred at 0 °C for 30 min
before concentration in vacuo. The residue was washed with hexanes
(50 mL) and suspended in CH2Cl2 (50 mL) followed by filtration of
the lead precipitate. The filtrate was extracted with 1 N HCl (3 × 30
mL). The combined aqueous layers were washed with Et2O (30 mL),
treated with 10% NaOH until pH 14, and extracted with Et2O (30
mL). The organic layer was washed with brine (20 mL), dried
(MgSO4), and concentrated in vacuo to afford 13a as a pale yellow oil
(890 mg, 6.08 mmol, 72%). Characterization data were consistent with
previously reported values.12 HPLC analysis indicated an enantiomeric
excess of 93% [CHIRALCEL OD-H column; flow, 0.5 mL/min;
hexanes:i-PrOH:Et2NH = 900:100:1; λ = 254 nm; major enantiomer
General Procedure D for Sequential Debenzylation and Amide
Bond Formation. 2-(1,5-Dioxaspiro[5.5]undec-7-yl)-N-[(1R)-1-phe-
nylbut-3-en-1-yl]acetamide (14a). Ketal ester 12 (1.82 g, 5.98
mmol), NaHCO3 (1.82 g, 21.7 mmol), and Pd(OH)2/C (182 mg,
20% on carbon, wet) in EtOAc (60 mL) were evacuated and backfilled
three times with N2 and then three times with H2. The mixture was
stirred at room temperature under a balloon atmosphere of H2 for 2.5
h before filtering the solution over Celite, eluting with EtOAc (30
mL). The filtrate was concentrated to give the resulting acid, which
was used without further purification.
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
(EDCI, 1.9 g, 7.2 mmol) was added to a solution of the crude acid,
amine 13a (0.88 g, 5.9 mmol), and DMAP (73 mg, 0.60 mmol) in
CH2Cl2 (13 mL). The solution was maintained at room temperature
for 21 h and concentrated in vacuo. The crude residue was purified by
flash chromatography (1:3 EtOAc:hexanes) to afford 14a (1.8 g, 5.1
23
589
23
577
tR = 10.5 min; minor enantiomer tR = 14.3 min]: [α] + 42.5, [α]
23
23
+43.2, [α] +50.8, [α] +85.5 (c 1.15, CH2Cl2).
546
435
1
mmol, 86%) as a colorless solid: mp 128−130 °C; H NMR (500
(R)-1-(4-Methoxyphenyl)but-3-en-1-amine (13b). Following gen-
eral procedure A, 13b (1.08 g, 6.11 mmol, 74% yield) was obtained as
a yellow oil. Characterization data were consistent with previously
reported values.12 HPLC analysis indicated an enantiomeric excess of
92% [CHIRALCEL OD-H column; flow, 0.5 mL/min; hexanes:i-
PrOH:Et2NH = 900:100:1; λ = 254 nm; major enantiomer tR = 13.1
MHz, CDCl3) δ 7.34−7.22 (m, 5H), 6.30 (app dd, J = 31.7, 8.3 Hz,
1H), 5.70−5.65 (m, 1H), 5.12−5.05 (m, 3H), 4.07−4.05 (m, 1H),
3.92−3.89 (m, 1H), 3.80−3.66 (m, 2 H), 2.81−2.77 (m, 1H), 2.60−
2.54 (m, 3H), 2.10−2.00 (m, 1H), 2.00−1.80 (m, 2H), 1.65−1.55 (m,
3H), 1.40−1.05 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 173.1,
142.4, 142.3, 134.44, 134.41, 128.7, 127.3, 126.70, 126.67, 118.2,
118.1, 98.94, 98.92, 59.3, 59.18, 59.17, 52.5, 52.4, 41.0, 40.9, 37.1, 29.2,
28.2, 25.89, 25.85, 25.0, 22.4; IR (thin film, cm−1) 3290, 1644, 1536,
1447, 1337; HRMS (ESI) m/z [M + H]+ calcd for C21H30NO3
344.2226, found 344.2237.
23
589
23
577
min; minor enantiomer tR = 16.8 min]: [α] +31.0, [α] +32.2,
23
23
[α] +36.7, [α] +66.5 (c 2.64, CH2Cl2).
546
435
(R)-1-Butyl-3-butenyl-1-(4-chlorophenyl)amine (13c). Following
general procedure A, 13c (1.21 g, 6.70 mmol, 72% yield) was obtained
as a colorless oil. Characterization data were consistent with previously
reported values.12 HPLC analysis indicated an enantiomeric excess of
94% [CHIRALCEL AD column; flow, 0.5 mL/min; hexanes:i-
PrOH:Et2NH = 950:50:1; λ = 254 nm; major enantiomer tR = 14.6
2-(1,5-Dioxaspiro[5.5]undec-7-yl)-N-[(1R)-1-(4-methoxyphenyl)-
but-3-en-1-yl]acetamide (14b). Following general procedure D, 14b
(1.75 g, 4.71 mmol, 88% yield) was obtained as a colorless solid: mp
23
589
23
577
1
min; minor enantiomer tR = 14.0 min]: [α] +38.1, [α] +39.6,
79−80 °C; H NMR (500 MHz, CDCl3) δ 7.33−7.23 (m, 2H), 6.81
23
23
[α] +44.9, [α] +78.5 (c 2.13, CH2Cl2).
(app d, J = 7.0 Hz, 2H), 6.30 (app dd, J = 35.0, 7.8 Hz, 1H), 5.77−5.70
546
435
9937
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
(m, 1H), 5.15−5.06 (m, 3H), 3.99 (app ds, J = 11.7, 2.9 Hz, 1H), 3.84
(app dq, J = 15.6, 5.2 Hz, 1H), 3.84 (s, 3H), 3.73−3.71 (m, 1H), 2.74
(app dt, J = 15.1, 5.0 Hz, 1H), 2.51−2.48 (m, 3H), 2.01−1.80 (m,
3H), 1.59−1.52 (m, 3H), 1.47−1.23 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 173.0, 172.9, 158.8, 134.57, 134.55, 134.5, 134.4, 127.81,
127.79, 118.0, 117.9, 114.1, 114.04, 114.02, 98.90, 98.89, 98.88, 98.87,
59.2, 59.1, 55.45, 52.0, 51.88, 40.9, 40.8, 37.01, 36.99, 29.10, 28.14, 5.9,
25.8, 25.0, 22.4; IR (thin film, cm−1) 3296, 2935, 1638, 1513, 1246;
HRMS (ESI) m/z [M + H]+ calcd for C22H32NO4 374.2331, found
374.2334.
N-[(1R)-1-(4-Chlorophenyl)but-3-en-1-yl]-2-(1,5-dioxaspiro[5.5]-
undec-7-yl)acetamide (14c). Following general procedure D, 14c
(1.80 g, 4.76 mmol, 89% yield) was obtained as a colorless solid: mp
135−138 °C; 1H NMR (500 MHz, CDCl3) δ 7.27 (app t, J = 8.4 Hz),
7.20 (app t, J = 6.8 Hz, 2H), 6.38 (dd, J = 21.4, 7.6 Hz, 1H), 5.68−
5.61 (m, 1H), 5.10−5.02 (m, 3H), 4.04 (app q, J = 11.8, 2.8 Hz, 1H),
3.90 (app q, J = 10.3, 2.5 Hz, 1H), 3.80−3.75 (m, 2H), 2.80 (ddd, J =
19.5, 9.4, 6.8 Hz, 1H), 2.63 (broad s, 1H), 2.50 (t, J = 6.8 Hz, 2H),
2.03−1.84 (m, 3H), 1.72−1.56 (m, 3H), 1.43−1.15 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 173.2, 173.1, 141.1, 141.0, 133.99, 133.96,
133.0, 128.82, 128.80, 128.2, 128.0, 118.6, 118.5, 99.0, 98.9, 59.3,
59.21, 59.19, 52.0, 51.8, 40.8, 37.0, 28.1, 25.9, 22.4; IR (thin film,
cm−1) 3288, 2935, 1638, 1542, 1493; HRMS (ESI) m/z [M + H]+
calcd for C21H29ClNO3 378.1836, found 378.1834.
1H), 2.53−2.42 (m, 2H), 2.40−2.34 (m, 3H), 1.99−1.84 (m, 2H),
1.54−1.47 (m, 5H), 1.43−1.15 (m, 7H); 13C NMR (125 MHz,
CDCl3) δ 158.68, 158.67, 136.5, 136.0, 128.41, 128.38, 117.40, 117.36,
113.80, 113.79, 99.17, 99.16, 62.4, 62.2, 59.13, 59.12, 59.07, 59.06,
55.42, 55.41, 46.9, 46.4, 43.29, 43.25, 28.8, 28.44, 28.35, 28.0, 27.8,
25.9, 22.48, 22.46; IR (thin film, cm−1) 2933, 2860, 1511, 1245, 1106;
HRMS (ESI) m/z [M + H]+ calcd for C22H34NO3 360.2539, found
360.2536.
(1R)-N-[2-(1,5-Dioxaspiro[5.5]undec-7-yl)ethyl]-1-phenylbut-3-
en-1-amine (9a). Following general procedure E, 9a (1.56 g, 1.62
mmol, 97% yield) was obtained as a pale yellow oil; changes from the
standard procedure include the use of THF (70 mL) and Et2O (30
mL) as the solvent mixture (to assist in the solubility of the amide):
1H NMR (500 MHz, CDCl3) δ 7.32−7.31 (m, 4H), 7.26−7.21 (m,
1H), 5.76−5.68 (m, 1H), 5.10−5.02 (m, 2H), 4.01 (td, J = 11.5, 3.0
Hz, 1H), 3.88 (td, J = 11.0, 2.5 Hz, 1H), 3.80−3.74 (m, 2H), 3.66 (q, J
= 6.2 Hz, 1H), 2.54−2.45 (m, 2H), 2.44−2.36 (m, 3H), 2.00−1.84 (m,
2H), 1.63−1.47 (m, 7H), 1.44−1.16 (m, 7H); 13C NMR (125 MHz,
CDCl3) δ 144.4, 135.9, 128.42, 128.41, 128.39, 128.38, 127.44, 127.43,
127.42, 127.39, 127.38, 127.01, 126.99, 117.53, 117.49, 99.14, 99.13,
63.0, 62.8, 59.12, 59.11, 59.05, 59.0, 47.0, 46.4, 43.3, 43.2, 28.8, 28.5,
28.4, 28.3, 28.0, 27.8, 25.8, 22.5, 22.4; IR (thin film, cm−1) 2931, 2860,
1453, 1245, 1108; HRMS (ESI) m/z [M + H]+ calcd for C21H32NO2
330.2433, found 330.2426.
N-[(1R)-1-(2-Chlorophenyl)but-3-en-1-yl]-2-(1,5-dioxaspiro[5.5]-
undec-7-yl)acetamide (14d). Following general procedure D, 14d
(1.81 g, 4.78 mmol, 91% yield) was obtained as a colorless solid: mp
86−88 °C; H NMR (500 MHz, CDCl3) δ 7.34 (dt, J = 7.7, 1.5 Hz,
(1R)-1-(4-Chlorophenyl)-N-[2-(1,5-dioxaspiro[5.5]undec-7-yl)-
ethyl]but-3-en-1-amine (9c). Following general procedure E, 9c (1.50
g, 4.13 mmol, 98% yield) was obtained as a colorless oil; changes from
the standard procedure include the use of THF (16 mL) as the solvent
mixture (to assist in the solubility of the amide): 1H NMR (500 MHz,
CDCl3) δ 7.32−7.24 (m, 4H), 5.69 (ddt, J = 10.5, 7.5 Hz, 1H), 5.08−
5.02 (m, 2H), 4.01 (tt, J = 11.0, 2.0 Hz, 1H), 3.88 (td, J = 11.5, 3.0 Hz,
1H), 3.77−3.75 (m, 2H), 3.64 (q, J = 6.5 Hz, 1H), 2.50−2.45 (m,
2H), 2.38−2.33 (m, 3H), 1.99−1.84 (m, 2H), 1.55−1.46 (m, 5H),
1.42−1.15 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 143.0, 142.9,
135.34, 135.33, 132.47, 132.45, 128.81, 128.80, 128.79, 128.78, 128.77,
128.75, 128.74, 128.73, 128.72, 128.52, 128.50, 117.9, 117.8, 99.08,
99.07, 99.06, 62.36, 62.35, 62.19, 62.18, 62.17, 59.10, 59.09, 59.03,
59.01, 47.0, 46.4, 43.21, 43.19, 30.5, 28.8, 28.4, 28.3, 28.2, 28.1, 27.8,
25.8, 24.5, 22.42, 22.40; IR (thin film, cm−1) 2933, 2860, 1490, 1245,
1108; HRMS (ESI) m/z [M + Na]+ calcd for C21H30ClNO2Na
386.1863, found 386.1860.
1
1H), 7.27−7.16 (m, 3H), 6.50 (t, J = 6.5 Hz, 1H), 5.73−5.65 (m, 1H),
5.39 (dtd, J = 13.5, 7.9, 5.5 Hz, 1H), 5.13−5.07 (m, 2H), 4.05 (dtd, J =
18.5, 12.0, 3.0 Hz, 1H), 3.92 (qd, J = 11.5, 2.5 Hz, 1H), 3.83−3.68 (m,
2H), 2.82 (ddd, J = 15.0, 10.0, 5.0 Hz, 1H), 2.63−2.49 (m, 3H), 2.10−
2.02 (m, 1H), 2.00−1.84 (m, 2H), 1.66−1.54 (m, 3H), 1.44−1.15 (m,
5H);13C NMR (125 MHz, CDCl3) δ 173.1, 173.0, 139.70, 139.65,
134.21, 134.17, 133.0, 132.9, 130.22, 130.21, 128.4, 128.0, 127.9,
127.0, 126.96, 126.95, 118.4, 118.3, 98.93, 98.92, 98.91, 98.90, 59.23,
59.18, 59.17, 50.6, 50.5, 39.3, 39.2, 36.83, 36.82, 29.14, 29.08, 28.2,
25.9, 25.8, 25.0, 22.4; IR (thin film, cm−1) 3319, 3070, 1642, 1538,
1478; HRMS (ESI) m/z [M + Na]+ calcd for C21H28ClNO3Na
400.1655, found 400.1659.
2-(1,5-Dioxaspiro[5.5]undec-7-yl)-N-[(1R)-1-isopropylbut-3-en-1-
yl]-acetamide (14e). Following general procedure D, 14e (747 mg,
2.40 mmol, 68% yield) was obtained as a colorless solid from (R)-2-
(1R)-1-(2-Chlorophenyl)-N-[2-(1,5-dioxaspiro[5.5]undec-7-yl)-
ethyl]but-3-en-1-amine (9d). Following general procedure E, 9d
(1.35 g, 3.69 mmol, 83% yield) was obtained as a colorless oil; changes
from the standard procedure include the use of THF (16 mL) as a
solvent (to assist in the solubility of the amide) and the purification of
9d on silica gel by flash chromatography (100:100:1 hexanes:EtOA-
methylhex-5-en-3-amine (51% ee):33 mp 88−92 °C; H NMR (500
1
MHz, CDCl3) δ 5.80−5.73 (m, 2H), 5.07−5.03 (m, 2H), 4.06 (tt, J =
12.0, 3.0 Hz, 1H), 3.95−3.84 (m, 2H), 3.83−3.77 (m, 2H), 2.80 (dt, J
= 14.5, 3.0 Hz, 1H), 2.61 (br s, 1H), 2.26 (dt, J = 15.0, 5.0 Hz, 1H),
2.15−2.10 (m, 2H), 1.93 (ddd, J = 14.6, 7.5, 2.8 Hz, 2H), 1.78−1.71
(m, 2H), 1.69−1.63 (m, 1H), 1.62−1.55 (m, 2H), 1.43−1.18 (m, 5H),
0.90 (ddd, J = 14.5, 6.8, 2.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
173.41, 173.38, 135.4, 117.24, 117.21, 99.0, 98.9, 59.3, 59.22, 59.19,
53.4, 53.3, 37.12, 37.09, 37.0, 31.5, 31.4, 29.1, 29.0, 28.3, 28.2, 25.9,
25.0, 22.5, 19.48, 19.46, 18.1; IR (thin film, cm−1) 3294, 2941, 1654,
1538, 1108; HRMS (ESI) m/z [M + Na]+ calcd for C18H31NO3Na
332.2202, found 332.2210.
1
c:Et3N): H NMR (500 MHz, CDCl3) δ 7.55 (ddd, J = 7.8, 4.2, 1.7
Hz, 1H), 7.34 (dt, J = 7.9, 0.9 Hz, 1H), 7.27 (tt, J = 7.5, 1.5 Hz, 1H),
7.17 (td, J = 7.4, 1.7 Hz, 1H), 5.83−5.75 (m, 1H), 5.14−5.06 (m, 2H),
4.25 (ddd, J = 12.5, 8.0, 5.0 Hz, 1H), 4.06−4.00 (m, 1H), 3.90 (tt, J =
11.0, 3.0 Hz, 1H), 3.82−3.76 (m, 2H), 2.55−2.48 (m, 3H), 2.44−2.36
(m, 1H), 2.30 (dt, J = 14.0, 8.0 Hz, 1H), 2.03−1.95 (m, 1H), 1.94−
1.86 (m, 1H), 1.57−1.53 (m, 4H), 1.42 (dq, J = 13.0, 2.5 Hz, 1H),
1.38−1.28 (m, 2H), 1.27−1.17 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 141.39, 141.36, 135.43, 135.42, 133.8, 133.7, 129.58, 129.56,
128.32, 128.25, 127.86, 127.85, 127.1, 127.0, 117.9, 117.8, 99.13,
99.12, 59.13, 59.11, 59.05, 59.0, 58.4, 58.2, 46.8, 46.4, 41.5, 41.4, 31.8,
31.1, 28.8, 28.5, 28.4, 28.3, 28.0, 27.8, 25.83, 25.82, 24.5, 22.8, 22.5,
22.4, 14.3; IR (thin film, cm−1) 2933, 2860, 1461, 1441, 1108; HRMS
(ESI) m/z [M + H]+ calcd for C21H31ClNO2 364.2043, found
364.2043.
General Procedure E for Reduction of an Amide with Lithium
Aluminum Hydride. (1R)-N-[2-(1,5-Dioxaspiro[5.5]undec-7-yl)ethyl]-
1-(4-methoxyphenyl)but-3-en-1-amine (9b). Under an atmosphere
of dry N2, LiAlH4 (1.64 g, 43.1 mmol) was added to a solution of 14b
(1.61 g, 4.31 mmol) and Et2O (110 mL) at 0 °C. The suspension was
stirred at room temperature for 22 h. After the suspension was cooled
to 0 °C, water (3 mL), 10% NaOH (3 mL), and water (3 mL) were
slowly added sequentially, and the mixture was stirred at room
temperature for 0.5 h. After filtration, the filtrate was dried (MgSO4)
and concentrated in vacuo. The crude residue was purified by flash
chromatography (100:1 EtOAc:Et3N) to afford 9b as a colorless oil
(1.31 g, 3.66 mmol, 85%): 1H NMR (500 MHz, CDCl3) δ 7.23 (dd, J
= 8.7, 3.9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.71 (ddt, J = 17.4, 10.0,
7.2 Hz, 1H), 5.09−5.01 (m, 2H), 4.01 (td, J = 11.5, 2.5 Hz, 1H), 3.88
(td, J = 11.5, 3.0 Hz, 1H), 3.81−3.73 (m, 5H), 3.62 (q, J = 6.6 Hz,
(1R)-N-[2-(1,5-Dioxaspiro[5.5]undec-7-yl)ethyl]-1-isopropylbut-3-
en-1-amine (9e). Following general procedure E, 9e (488 mg, 1.65
1
mmol, 85% yield) was obtained as a pale yellow oil: H NMR (500
MHz, CDCl3) δ 5.80 (ddt, J = 17.0, 10.0, 7.5 Hz, 1H), 5.10−5.04 (m,
2H), 4.03 (td, J = 11.0, 3.0 Hz, 1H), 3.90 (td, J = 11.5, 3.0 Hz, 1H),
3.82−3.79 (m, 2H), 2.68−2.62 (m, 1H), 2.55−2.45 (m, 2H), 2.37−
2.33 (m, 1H), 2.23−2.18 (m, 1H), 2.08−2.01 (m, 1H), 1.99−1.87 (m,
2H), 1.84−1.77 (m, 1H), 1.66−1.53 (m, 6H), 1.45−1.21 (m, 8H),
9938
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
1
0.91−0.88 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 137.2, 116.7,
99.19, 99.18, 62.92, 62.91, 62.89, 59.10, 59.09, 59.03, 47.1, 47.0, 42.8,
35.34, 35.31, 30.2, 30.1, 28.9, 28.8, 28.42, 28.36, 27.9, 25.9, 24.4, 22.47,
22.46, 19.0, 18.9, 18.19, 18.17; IR (thin film, cm−1) 2935, 2863, 1465,
1445, 1109; HRMS (ESI) m/z [M + H]+ calcd for C18H34NO2
296.2590, found 296.2585.
89%) was obtained as a colorless oil: H NMR (500 MHz, CDCl3) δ
7.33−7.23 (m, 5H), 7.07 (br s, 0.5H), 6.90 (br s, 0.5H), 5.74−5.66
(m, 1H), 5.11−5.01 (m, 3H), 3.94−3.78 (m, 4H), 3.75−3.71 (m, 1H),
2.69 (ddd, J = 15.7, 7.8, 3.6 Hz, 1H), 2.62−2.52 (m, 2H), 2.29−2.03
(m, 3H), 1.96−1.81 (m, 3H), 1.75−1.57 (m, 3H), 1.39−1.24 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 172.5, 142.3, 142.1, 134.5, 128.64,
Representative Procedure for the Synthesis of Octahydroindole
ent-8 from Aminoacetals 9 (3aR,7aS)-7a-Allyloctahydro-1H-indole
(ent-8). A stirring mixture of 9a (0.20 g, 0.62 mmol), TFA (47 μ L,
0.62 mmol), and morpholine (5.4 μL, 0.062 mmol) was heated at 120
°C. Dimedone (0.22 g, 1.5 mmol) was added, and the solution was
maintained at 120 °C for 5 h. After cooling to room temperature, the
reaction mixture was dissolved in Et2O (10 mL). The mixture was
extracted with 1 N HCl (2 × 10 mL), and the combined aqueous
layers were washed with Et2O (30 mL), treated with 10% NaOH until
pH 14, and extracted with Et2O (30 mL). The organic layer was
washed with brine (20 mL), dried (MgSO4), filtered, and concentrated
in vacuo to afford ent-8 as a yellow oil (94 mg, 0.57 mmol, 92%):
128.63, 127.4, 127.3, 126.9, 126.73, 126.70, 126.69, 117.90, 117.89,
108.2, 108.1, 62.4, 62.3, 60.7, 60.6, 52.9, 52.7, 46.2, 46.1, 41.0, 40.7,
36.2, 36.1, 30.7, 30.54, 30.53, 30.2, 30.0, 25.9, 25.7, 21.5, 21.3; IR (thin
film, cm−1) 3292, 1638, 1542, 1152; HRMS (ESI) m/z [M + Na]+
calcd for C20H27NO3Na 352.1889, found 352.1894.
N-[2-(6,10-Dioxaspiro[4.5]dec-1-yl)-ethyl]-(1R)-1-phenylbut-3-en-
1-amine (S5). Following general procedure E, S5 (1.15 g, 3.67 mmol,
1
93%) was obtained as a colorless oil: H NMR (500 MHz, CDCl3) δ
7.27−7.22 (m, 4H), 7.19−7.16 (m, 1H), 5.67 (ddt, J = 16.9, 9.4, 7.5
Hz, 1H), 5.04−4.97 (m, 2H), 3.85−3.75 (m, 4H), 3.62 (t, J = 6.9,
1H), 2.50−2.34 (m, 4H), 2.10−1.99 (m, 1H), 1.90−1.49 (m, 8H),
1.39−1.27 (m, 2H), 1.24−1.13 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 144.44, 144.38, 135.8, 128.36, 128.35, 127.41, 127.40, 127.0,
126.9, 117.4, 108.83, 108.81, 62.83, 62.75, 62.19, 62.17, 60.7, 46.9,
46.8, 46.6, 46.5, 43.21, 43.20, 30.7, 29.4, 29.22, 29.17, 29.1, 26.07,
26.05, 21.28, 21.25; IR (thin film, cm−1) 2954, 2861, 1453, 1246, 1108;
HRMS (ESI) m/z [M + H]+ calcd for C20H30NO2 316.2277, found
316.2282.
Benzyl 3-(2-Oxocyclopentyl)propanoate (S6). Ketone S6 was
prepared using an adaptation of the procedure of Cotarco and co-
workers.35 A stirring solution of cyclopentanone (19 mL, 0.21 mol), 4-
methoxyphenol (0.17 g, 1.4 mmol), cyclohexylamine (1.7 mL, 15
mmol), and acetic acid (0.15 mL, 2.5 mmol) was heated to 80 °C for
10 min and then warmed to 130 °C over 30 min. Benzyl acrylate (16
mL, 0.11 mol) was added via syringe pump at a rate of 6.8 mL/h.
Upon complete addition, the reaction was cooled to 25 °C, and the
residue was purified directly on silica gel by flash chromatography
(1:9−1:4 EtOAc:hexanes) to provide S6 (13 g, 52 mmol, 47%) as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.40−7.31 (m, 5H), 5.15
(s, 2H), 2.55−2.45 (m, 2H), 2.31 (dd, J = 18.8, 8.6 Hz, 1H), 2.23−
2.17 (m, 1H), 2.16−2.07 (m, 3H), 2.05−1.97 (m, 1H), 1.82−1.73 (m,
1H), 1.73−1.63 (m, 1H), 1.56−1.46 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 219.9, 172.7, 135.8, 128.3, 128.1, 128.0, 65.9, 47.9, 37.7,
31.9, 29.2, 24.6, 20.3; IR (thin film, cm−1) 2960, 2877, 1733; HRMS
(ES) m/z [M + Na]+ calcd for C15H18O3Na 269.1154, found
269.1144. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C,
73.26; H, 7.40.
23
23
23
[α] +18.2, [α] +16.2, [α] +19.2 (c 0.450, CH2Cl2); HPLC
589
577
546
analysis of the derived benzoyl protected amine S1 indicated an
enantiomeric excess of 88% (see below); 1H NMR (500 MHz, CDCl3)
δ 5.87−5.79 (m, 1H), 5.09−5.02 (m, 2H), 3.03−2.91 (m, 2H), 2.25
(ddt, J = 13.9, 8.0, 1.2 Hz, 1H), 2.11 (ddt, J = 15.1, 7.0, 6.3 Hz, 1H),
1.89−1.82 (m, 1H), 1.76−1.63 (m, 3H), 1.57−1.50 (m, 1H), 1.48−
1.27 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 135.0, 117.8, 61.9,
42.8, 42.5, 42.3, 31.4, 29.8, 26.8, 22.5, 22.1; IR (thin film, cm−1) 3300,
2923, 1667, 1407; HRMS (ESI) m/z [M + H]+ calcd for C11H20N
166.1596, found 166.1594.
7a-Allyl-1-benzoyloctahydro-1H-indole (S1). Benzoyl chloride (37
mg, 0.26 mmol) was added to a solution of ent-8 (31 mg, 0.19 mmol),
Et3N (40 mg, 0.40 mmol), and CH2Cl2 (0.5 mL) at room temperature.
The solution was maintained at room temperature for 1 h. After the
addition of Et2O (10 mL), the organic layer was washed with water (5
mL), 1 N HCl (5 mL), 10% NaOH (5 mL), and brine (5 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in vacuo.
The crude residue was purified by flash chromatography (1:10
EtOAc:hexanes) to afford the title compound as a colorless solid (44
mg, 0.17 mmol, 87%). HPLC analysis indicated an enantiomeric
excess of 89% [CHIRALCEL AD column; flow, 1.0 mL/min; 96.5% n-
hexane/3.5% i-PrOH; λ = 220 nm; major enantiomer tR = 28.3 min;
23
23
minor enantiomer tR = 25.5 min]: mp 46−47 °C; [α] +76.8, [α]
589
577
23
23
1
+79.5, [α] +90.8, [α] +171 (c 1.04, CH2Cl2); H NMR (500
546
435
MHz, CDCl3) δ 7.41−7.35 (m, 5H), 5.91−5.83 (m, 1H), 5.16−5.13
(m, 2H), 3.33−3.30 (m, 2H), 3.25 (dd, J = 13.9, 6.5 Hz, 1H), 2.60−
2.53 (m, 2H), 2.28−2.23 (m, 1H), 1.91−1.83 (m, 1H), 1.77 (td, J =
13.1, 4.1 Hz, 1H), 1.71−1.56 (m, 4H), 1.50−1.30 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.0, 139.0, 134.7, 129.4, 128.4, 126.6, 118.3,
65.5, 50.7, 39.7, 37.5, 32.8, 27.3, 25.2, 22.8, 21.5; IR (thin film, cm−1)
1630, 1403, 1218, 1189, 1138; HRMS (ESI) m/z [M + Na]+ calcd for
C18H23NONa 292.1677, found 292.1680.
Synthesis and Characterization of Aminoketals 15−17 and Their
Precursors. Benzyl 2-(2-Oxocyclopentyl)acetate (S2). Following
general procedure B, S2 (2.3 g, 9.9 mmol, 78%) was obtained as a
colorless oil. This product was purified on silica gel by flash
chromatography (19:1 hexanes:EtOAc to 9:1 hexanes:EtOAc).
Characterization data were consistent with previously reported
values.34
Benzyl 3-(6,10-Dioxaspiro[4.5]decan-1-yl)propanoate (S7). Fol-
lowing general procedure C, S7 (4.6 g, 16 mmol, 56%) was obtained as
1
a colorless oil: H NMR (500 MHz, CDCl3) δ 7.38−7.27 (m, 5H),
5.14−5.08 (m, 2H), 3.90−3.79 (m, 4H), 2.54−2.42 (m, 2H), 2.09 (dt,
J = 13.3, 8.5 Hz, 1H), 1.90−2.01 (m, 2H), 1.87−1.74 (m, 3H), 1.70−
1.53 (m, 3H) 1.37−1.24 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
173.7, 136.2, 128.3, 128.2, 128.0, 108.3, 65.8, 61.9, 60.4, 47.9, 32.8,
30.5, 28.7, 25.7, 23.7, 20.9; IR (thin film, cm−1) 2956, 2865, 1733;
HRMS (ES) m/z [M + Na]+ calcd for C18H24O4Na 327.1572, found
327.1564. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C,
71.12; H, 7.94.
3-(6,10-Dioxaspiro[4.5]dec-1-yl)-N-[(1R)-1-phenylbut-3-en-1-yl]-
propionamide (S8). Following general procedure D, S8 (1.66 g, 4.85
1
mmol, 97%) was obtained as a colorless oil: H NMR (500 MHz,
Benzyl 2-(6,10-Dioxaspiro[4.5]decan-1-yl)acetate (S3). Following
general procedure C, S3 (5.8 g, 20 mmol, 96%) was obtained as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.37−7.28 (m, 5H), 5.14
(d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.4 Hz, 1H), 3.90−3.77 (m, 4H),
2.71 (dd, J = 15.0, 3.8 Hz, 1H), 2.38−2.25 (m, 2H), 2.11 (ddd, J =
13.1, 8.7, 6.9 Hz, 1H), 1.96−1.86 (m, 2H), 1.82 (ddd, J = 13.1, 9.4, 6.1
Hz, 1H), 1.71−1.62 (m, 2H), 1.39−1.31 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 173.5, 136.3, 128.4, 128.1, 128.0, 108.1, 65.9, 62.1,
60.6, 45.1, 33.8, 29.9, 28.6, 25.8, 20.8; IR (thin film, cm−1) 2958, 2867,
1733; HRMS (ES) m/z [M + Na]+ calcd for C17H22O4Na 313.1416,
found 313.1420.
CDCl3) δ 7.30−7.22 (m, 5H), 6.41 (app br d, J = 20.8 Hz, 1H), 5.71−
5.63 (m, 1H), 5.08−5.05 (m, 3H), 3.87−3.80 (m, 4H), 2.53−2.51 (m,
2H), 2.48−2.41 (m, 1H), 2.29−2.22 (m, 1H), 2.18−2.10 (m, 1H),
2.02−1.74 (m, 5H), 1.69−1.49 (m, 3H), 1.41−1.36 (m, 1H), 1.31−
1.19 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 173.19, 173.16, 142.3,
142.2, 134.5, 134.4, 128.74, 128.69, 128.6, 127.4, 127.33, 127.27,
126.8, 126.7, 126.6, 118.2, 118.03, 118.00, 109.0, 108.9, 62.39, 62.36,
62.1, 60.5, 52.6, 52.4, 47.5, 47.4, 40.9, 35.3, 34.3, 31.0, 30.9, 29.6, 29.5,
26.2, 25.0, 21.34, 21.25; IR (thin film, cm−1) 3288, 2956, 1638, 1542,
1248; HRMS (ESI) m/z [M + Na]+ calcd for C21H29NO3Na
366.2045, found 366.2037.
2-(6,10-Dioxaspiro[4.5]dec-1-yl)-N-[(1R)-1-phenylbut-3-en-1-yl]-
acetamide (S4). Following general procedure D, S4 (1.5 g, 4.5 mmol,
N-[3-(6,10-Dioxaspiro[4.5]dec-1-yl)-propyl]-(1R)-1-phenylbut-3-
en-1-amine (16). Following general procedure E, 16 (1.27 g, 3.84
9939
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
1
mmol, 88%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 7.30−7.27 (m, 4H), 7.21−7.18 (m, 1H), 5.72−5.64 (m,
1H), 5.06−4.99 (m, 2H), 3.87−3.79 (m, 4H), 3.62 (t, J = 6.9 Hz, 1H),
2.43−2.36 (m, 4H), 2.06−2.00 (m, 1H), 1.95−1.88 (m, 1H), 1.84−
1.68 (m, 6H), 1.34 (dq, J = 7.9, 2.6 Hz, 1H), 1.26−1.19 (m, 1H),
1.17−1.08 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 144.31, 144.26,
135.8, 128.4, 127.39, 127.37, 127.0, 117.5, 108.9, 62.9, 62.8, 62.11,
62.10, 60.8, 48.9, 48.8, 48.4, 48.3, 43.2, 43.1, 30.71, 30.68, 29.1, 29.02,
28.99, 28.9, 26.34, 26.27, 26.1, 21.12, 21.09; IR (thin film, cm−1) 2952,
2860, 1453, 1246, 1109; HRMS (ESI) m/z [M + H]+ calcd for
C21H32NO2 330.2433, found 330.2433.
Preparation of (3aR,6aS)-Benzyl 6a-Allylhexahydrocyclopenta[b]-
pyrrole-1(2H)-carboxylate (18). A stirring mixture of 15 (228 mg,
0.722 mmol), TFA (56.0 μL, 0.722 mmol), and morpholine (6.30 μL,
0.0722 mmol) was heated to 120 °C. Dimedone (253 mg, 1.81 mmol)
was added, and the solution was maintained at 120 °C for 2 h. After
cooling to room temperature, the reaction mixture was dissolved in
CHCl3 (5 mL). A saturated aqueous solution of Na2CO3 (2.4 mL),
water (2.4 mL), and benzyl chloroformate (310 μL, 2.17 mmol) was
added, and the biphasic solution was stirred at room temperature for
18 h. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and
the combined organic layer was dried (Na2SO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (1:20 EtOAc:hexanes) to afford 18 as a colorless oil
(196 mg, 95%). HPLC analysis indicated an enantiomeric excess of
92% [CHIRALCEL OJ column; flow, 1.0 mL/min; 96% n-hexane:4%
i-PrOH; λ = 220 nm; major enantiomer tR = 6.7 min; minor
Benzyl 3-(2-oxocyclohexyl)propanoate (S9). Ketone S9 was
prepared using an adaptation of the procedure of Cotarco and co-
workers.35 A stirring solution of cyclohexanone (24 mL, 0.21 μmol), 4-
methoxyphenol (0.17 g, 1.4 mmol), cyclohexylamine (1.7 mL, 15
mmol), and acetic acid (0.15 mL, 2.5 mmol) was heated to 80 °C for
10 min and then warmed to 130 °C over 30 min. Benzyl acrylate (16
mL, 0.11 mol) was added via syringe pump at a rate of 6.8 mL/h.
Upon complete addition, the reaction was cooled to 25 °C, and the
residue was purified directly on silica gel by flash chromatography
(1:9−1:4 EtOAc:hexanes) to provide S9 (23 g, 87 mmol, 83%) as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.32−7.24 (m, 5H), 5.06
(s, 2H), 2.45−2.1 (m, 5H), 2.09−1.95 (m, 3H), 1.83−1.74 (m, 1H),
1.64−1.49 (m, 3H), 1.31 (dq, J = 8.9, 3.7 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 211.0, 173.0, 135.8, 128.2, 128.0, 127.9, 65.8, 49.3,
41.8, 33.8, 31.5, 27.7, 24.8, 24.5; IR (thin film, cm−1) 2935, 2861,
1733, 1708; HRMS (ES) m/z [M + Na]+ calcd for C16H20O3Na
283.1310, found 283.1297. Anal. Calcd for C16H20O3: C, 73.82; H,
7.72. Found: C, 73.88; H, 7.72
23
23
23
enantiomer tR = 8.5 min]: [α] −11.4, [α] −11.0, [α] −12.2,
589
577
546
23
435
1
[α] −18.5 (c 1.99, CH2Cl2); H NMR (500 MHz, DMSO-d6, 388
K) δ 7.36 (app d, J = 4.5 Hz, 4H), 7.32−7.28 (m, 1H), 5.79−5.71 (m,
1H), 5.13−5.00 (m, 2H), 3.53−3.42 (m, 2H), 2.81−2.77 (m, 2H),
2.50−2.44 (m, 1H), 2.37 (dd, J = 18.8, 7.5 Hz, 1H), 2.16 (dt, J = 12.3,
6.3 Hz, 1H), 1.93 (dq, J = 12.6, 8.1 Hz, 1H), 1.87−1.80 (m, 1H),
1.72−1.65 (m, 1H), 1.64−1.51 (m, 3H), 1.45−1.38 (m, 1H); 13C
NMR (125 MHz, DMSO-d6, 388 K) δ 152.6, 136.7, 134.2, 127.4,
126.7, 126.6, 116.4, 73.1, 64.9, 47.3, 47.0, 40.5, 40.0, 39.8, 39.7, 39.5,
39.3, 39.2, 39.0, 37.3, 31.1, 27.8, 24.0; IR (thin film, cm−1) 2946, 1696,
1405, 1355; HRMS (ESI) m/z [M + Na]+ calcd for C18H23NO2Na
308.1626, found 308.1622.
(3aR,7aS)-Benzyl 7a-Allyloctahydro-1H-indole-carboxylate (Cbz-
ent-8). Following general procedure F, (164 mg, 0.549 mmol, 85%)
was obtained as a colorless oil; changes from the standard procedure
include heating 9a at 120 °C for 5 h and purification by flash
chromatography on silica gel (20:1 hexanes:Et2O). HPLC analysis
indicated an enantiomeric excess of 89% [CHIRALCEL OJ column;
Benzyl 3-(1,5-Dioxaspiro[5.5]undecan-7-yl)propanoate (S10).
Following general procedure C, S10 (4.1 g, 13 mmol, 78%) was
obtained as a colorless oil; changes from the standard procedure
include the exposure of this substrate to reaction conditions at 25 °C
1
for 3 h: H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 5.08 (s,
flow, 1.0 mL/min; 96% n-hexane:4% i-PrOH; λ = 220 nm; major
2H), 3.98 (app td, J = 11.5, 2.7 Hz, 1H), 3.85 (app td, J = 11.3, 2.7 Hz,
1H), 3.77−3.72 (m, 2H), 2.49−2.40 (m, 1H), 2.39−2.30 (m, 1H),
2.22−2.13 (m, 1H), 1.93−1.83 (m, 1H), 1.62−1.46 (m, 6H), 1.41−
1.26 (m, 3H), 1.25−1.12 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
174.0, 136.2, 128.4, 128.1, 128.0, 98.9, 65.9, 58.8, 58.7, 44.0, 32.9, 28.0,
27.3, 25.5, 24.2, 23.4, 22.2; IR (thin film, cm−1) 2935, 2861, 1735.
Anal. Calcd for C19H26O4: C, 71.67; H, 8.23. Found: C, 71.62; H, 8.39.
3-(1,5-Dioxaspiro[5.5]undec-7-yl)-N-[(1R)-1-phenylbut-3-en-1-yl]-
propionamide (S11). Following general procedure D, S11 (1.45 g,
4.03 mmol, 99%) was obtained as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 7.34−7.24 (m, 5H), 6.51 (app t, J = 9.4 Hz, 1H), 5.76−5.67
(m, 1H), 5.17−5.08 (m, 3H), 4.07 (tdd, J = 11.9, 5.9, 3.0 Hz, 1H),
3.92 (td, J = 11.7, 2.8 Hz, 1H), 3.82−3.73 (m, 2H), 2.62−2.59 (m,
1H), 2.57−2.52 (m, 2H), 2.44−2.38 (m, 1H), 2.25−2.14 (m, 2H),
2.02−1.90 (m, 1H), 1.66−1.50 (m, 4H), 1.44−1.11 (m, 7H); 13C
NMR (125 MHz, CDCl3) δ172.8, 172.7, 142.4, 142.3, 134.7, 134.5,
128.7, 128.6, 127.4, 127.3, 126.8, 126.7, 118.0, 99.53, 99.52, 59.19,
59.17, 59.1, 52.51, 52.45, 41.0, 40.8, 35.3, 35.2, 28.4, 28.1, 28.0, 25.9,
24.3, 24.2, 22.44, 22.4; IR (thin film, cm−1) 3305, 2935, 1640, 1541,
1448; HRMS (ESI) m/z [M + H]+ calcd for C22H32NO3 358.2382,
found 358.2390.
23
enantiomer tR = 7.8 min; minor enantiomer tR = 11.6 min]: [α]
589
23
23
23
1
−11.4, [α] −11.0, [α] −12.2, [α] −18.5 (c 1.99, CH2Cl2); H
577
546
435
NMR (500 MHz, DMSO-d6, 398 K) δ 7.36−7.28 (m, 5H), 5.78−5.70
(m, 1H), 5.12−5.00 (m, 4H), 3.62−3.57 (m, 1H), 3.34−3.29 (m, 1H),
2.72 (dd, J = 15.0, 7.1 Hz, 1H), 2.50−2.44 (m, 1H), 2.14−2.09 (m,
1H), 1.94−1.60 (m, 5H), 1.51−1.28 (m, 5H); 13C NMR (125 MHz,
DMSO-d6, 398 K) δ 152.9, 136.8, 133.8, 127.4, 126.6, 126.5, 116.3,
64.7, 63.1, 45.4, 39.0, 38.8, 31.3, 25.4, 24.8, 20.7, 20.4 ; IR (thin film,
cm−1) 2927, 1696, 1401, 1337; HRMS (ESI) m/z [M + Na]+ calcd for
C19H25NO2Na 322.1783, found 322.1777.
(4aR,7aS)-Benzyl 7a-Allyloctahydro-1H-cyclopenta[b]pyridine-1-
carboxylate (19). Following general procedure F, 19 (155 mg, 0.517
mmol, 80%) was obtained as a colorless oil; changes from the standard
procedure include heating at 120 °C for 5 h and purification of the
product by silica gel column chromatography (10:1 hexanes:Et2O).
HPLC analysis indicated an enantiomeric excess of 91% [CHIR-
ALCEL OJ column; flow, 1.0 mL/min; 96% n-hexane:4% i-PrOH; λ =
220 nm; major enantiomer tR = 5.8 min; minor enantiomer tR = 7.3
23
23
577
23
546
23
435
min]: [α] +63.8, [α] +64.8, [α] +72.9, [α] +124 (c 0.79,
589
1
CH2Cl2); H NMR (500 MHz, DMSO-d6, 298 K) δ 7.38−7.29 (m,
5H), 5.80 (ddt, J = 16.7, 10.4, 7.5 Hz, 1H), 5.08−4.96 (m, 4H), 3.81
(ddd, J = 13.4, 6.4, 3.3 Hz, 1H), 2.96 (ddd, J = 13.4, 11.2, 5.0 Hz, 1H),
2.61 (dd, J = 13.8, 7.4 Hz, 1H), 2.26 (dd, J = 13.8, 7.6 Hz, 1H), 2.20−
2.14 (m, 1H), 2.04−1.97 (m, 2H), 1.78−1.71 (m, 1H), 1.67−1.34 (m,
7H); 13C NMR (125 MHz, DMSO-d6, 298 K) δ 155.3, 137.1, 134.7,
128.3, 127.6, 127.5, 117.5, 66.6, 65.7, 41.7, 40.9, 40.1, 37.5, 28.7, 24.0,
21.1, 20.7; IR (thin film, cm−1) 2948, 1702, 1410, 1218; HRMS (ESI)
m/z [M + Na]+ calcd for C19H25NO2Na 322.1783, found 322.1778.
(4aR,8aS)-Benzyl 8a-Allyloctahydroquinoline-1(2H)-carboxylate
(cis-20) and (4aR,8aR)-Benzyl 8a-Allyloctahydroquinoline-1(2H)-
carboxylate (trans-20). Octahydroquinoline cis-20 was isolated as a
colorless oil (80 mg, 0.25 mmol, 41%) and trans-20 was isolated as a
colorless oil (66 mg, 0.21 mmol, 34%). Changes from the standard
procedure include heating at 120 °C for 5 h and separation of the
products by flash chromatography on silica gel (20:1 hexanes:Et2O).
N-[3-(1,5-Dioxaspiro[5.5]undec-7-yl)-propyl]-(1R)-1-phenylbut-3-
en-1-amine (17). Following general procedure E, 17 (1.17 g, 3.41
1
mmol, 89%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 7.34−7.31 (m, 4H), 7.25−7.22 (m, 1H), 5.76−5.67 (m,
1H), 5.10−5.03 (m, 2H), 4.01 (td, J = 11.4, 3.1 Hz, 1H), 3.88 (td, J =
10.5, 2.7 Hz, 1H), 3.79−3.75 (m, 2H), 3.65 (t, J = 6.8 Hz, 1H), 2.49−
2.41 (m, 5H), 1.91−1.83 (m, 1H), 1.78−1.70 (m, 1H), 1.66−1.62 (m,
1H), 1.57−1.46 (m, 4H), 1.44−1.30 (m, 3H), 1.27−1.20 (m, 3H),
1.14−1.06 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 144.2, 135.8,
128.5, 127.43, 127.40, 127.1, 117.6, 99.3, 62.8, 62.7, 59.10, 59.09, 59.0,
48.3, 48.1, 43.1, 28.7, 28.4, 28.34, 28.29, 27.33, 27.25, 25.8, 25.2, 25.1,
24.3, 22.5; IR (thin film, cm−1) 2933, 2860, 1453, 1244, 1107; HRMS
(ESI) m/z [M + H]+ calcd for C22H34NO2 344.2590, found 344.2581.
General Procedure F for 2-Aza-Cope Rearrangement and Cbz
Protection To Yield 1-Azabicyclic Products ent-8 and 18−20.
9940
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
cis-20. HPLC analysis indicated an enantiomeric excess of 93%
[CHIRALCEL OJ column; flow, 1.0 mL/min; 96% n-hexane/4% i-
PrOH; λ = 220 nm; major enantiomer tR = 6.2 min; minor enantiomer
(2R)-N-(2-(1,5-Dioxaspiro[5.5]undecan-7-yl)ethyl)-2-phenylbut-3-
en-1-amine (S15). Following general procedure E, S15 (228 mg,
1
0.692 mmol, 80%) was obtained as a light yellow oil: H NMR (500
23
23
23
23
MHz, CDCl3) δ 7.32 (t, J = 7.9 Hz, 2H), 7.24−7.21 (m, 3H), 6.01−
5.94 (m, 1H), 5.15−5.10 (m, 2H), 4.01 (tt, J = 11.4, 3.2 Hz, 1H), 3.88
(t, J = 10.1 Hz, 1H), 3.78−3.76 (m, 2H), 3.55 (q, J = 7.6 Hz, 1H),
2.95−2.87 (m, 2H), 2.72−2.65 (m, 1H), 2.62−2.55 (m, 1H), 2.46
(app broad s, 1H), 1.99−1.86 (m, 2H), 1.59−1.52 (m, 3H), 1.45−1.22
(m, 8H); 13C NMR (125 MHz, CDCl3) δ 142.7, 140.40, 140.37,
128.9, 128.8, 127.94, 127.92, 126.77, 126.75, 116.0, 115.9, 99.2, 59.14,
59.08, 54.7, 54.6, 50.1, 48.92, 48.86, 28.6, 28.3, 28.1, 25.8, 24.5, 22.5;
IR (thin film, cm−1) 3319, 3080, 2933, 1108; HRMS (ESI) m/z [M +
H]+ calcd for C21H32NO2 330.2433, found 330.2437.
tR = 7.9 min]: [α] +50.1, [α] +53.2, [α] +60.4, [α] +104 (c
589
577
546
435
1
1.05, CH2Cl2); H NMR (500 MHz, DMSO-d6, 348 K) δ 7.39−7.28
(m, 5H), 5.76 (ddt, J = 17.5, 10.0, 7.3 Hz, 1H), 5.07−5.00 (m, 4H),
3.79 (dt, J = 13.2, 4.7 Hz, 1H), 3.26−3.20 (m, 1H), 2.68 (dt, J = 7.3,
1.2 Hz, 1H), 2.33 (ddd, J = 12.7, 8.3, 3.8 Hz, 1H), 1.83−1.64 (m, 4H),
1.60−1.48 (m, 5H), 1.46−1.27 (m, 3H); 13C NMR (125 MHz,
DMSO-d6, 348 K) δ 154.9, 136.9, 133.8, 127.8, 127.1, 127.0, 116.9,
65.3, 60.1, 40.8, 38.3, 35.7, 32.2, 27.3, 23.1, 21.9, 21.7, 20.6; IR (thin
film, cm−1) 2934, 1697, 1398, 1261; HRMS (ESI) m/z: [M + Na]+
calcd for C20H27NO2Na 336.1939, found 336.1938. trans-20: HPLC
analysis indicated an enantiomeric excess of 93% [CHIRALCEL OJ
column; flow, 1.0 mL/min; 96% n-hexane:4% i-PrOH; λ = 220 nm;
major enantiomer tR = 6.5 min; minor enantiomer tR = 8.0 min];
N-((S)-2-Methylbut-3-en-1-yl)-2-(1,5-dioxaspiro[5.5]undecan-7-
yl)acetamide (S16). Following general procedure D, S16 (83 mg, 0.29
mmol, 80%) was obtained as a colorless solid; changes to the general
procedure involve the addition of Et3N (56.0 μL) to the amide
23
23
23
23
[α] +20.3, [α] +20.5, [α] +22.7, [α] +35.7 (c 1.17, CH2Cl2);
589
577
546
435
1
1H NMR (500 MHz, DMSO-d6) δ 7.37−7.28 (m, 5H), 5.69 (ddt, J =
coupling step: H NMR (500 MHz, CDCl3) δ 5.92 (broad s, 1H),
5.71−5.64 (m, 1H), 5.07−5.05 (m, 2H), 4.05 (app dt, J = 11.8, 2.8 Hz,
1H), 3.93 (app dt, J = 11.8, 2.8 Hz, 1H), 3.80−3.78 (m, 2H), 3.35−
3.27 (m, 1H), 3.07−2.98 (m, 1H), 2.76 (dd, J = 14.3, 4.6 Hz, 1H),
2.61 (broad d, J = 12.9 Hz, 1H), 2.35−2.29 (m, 1H), 2.04−1.95 (m,
1H), 1.94−1.87 (m, 2H), 1.65−1.58 (m, 3H), 1.41−1.18 (m, 5H),
1.01 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.80,
173.79, 141.84, 141.82, 115.14, 115.09, 98.8, 59.20, 59.15, 44.51,
44.48, 38.34, 38.26, 36.9, 36.8, 29.03, 28.98, 28.2, 25.8, 25.0, 22.4, 17.8,
17.7; IR (thin film, cm−1) 3079, 2933, 1643; HRMS (ESI) m/z [M +
Na]+ calcd for C16H27NO3Na 304.1889, found 304.1881.
17.2, 10.1, 7.2 Hz, 1H), 5.10 (d, J = 17.1 Hz, 1H), 5.00−4.93 (m, 3H),
3.97 (dt, J = 14.0, 4.4 Hz, 1H), 3.08 (ddd, J = 14.3, 11.4, 3.0 Hz, 1H),
2.88 (br d, J = 13.1 Hz, 1H), 2.64 (dd, J = 15.0, 7.6 Hz, 1H), 2.40 (dd,
J = 14.8, 6.9 Hz, 1H), 1.64−1.52 (m, 5H), 1.51−1.30 (m, 5H), 1.29−
1.18 (m, 2H); 13C NMR (125 MHz, DMSO-d6, 298 K) δ 155.1, 137.3,
134.0, 128.3, 127.6, 127.4, 117.2, 65.5, 62.5, 45.2, 41.2, 35.0, 30.7, 29.6,
26.6, 25.3, 24.8, 22.7; IR (thin film, cm−1) 2930, 1702, 1391, 1160;
HRMS (ESI) m/z [M + Na]+ calcd for C20H27NO2Na 336.1939,
found 336.1947.
Preparation and Characterization of Aminoketals Employed
in the Transformations Reported in Table 3. The direct
precursors of 1-azabicyclic products 31a and 34a have been reported
previously.9
(2S)-N-(2-(1,5-Dioxaspiro[5.5]undecan-7-yl)ethyl)-2-methylbut-3-
en-1-amine (S17). Following the general procedure, S17 (24 mg,
1
0.095 mmol, 74%) was obtained as a colorless oil: H NMR (500
MHz, CDCl3) δ 5.65−5.61 (m, 1H), 5.06−4.98 (m, 2H), 4.01 (app dt,
J = 11.5, 2.8 Hz, 1H), 3.88 (app dt, J = 11.2, 2.1 Hz, 1H), 3.78−3.76
(m, 2H), 2.66−2.29 (m, 1H), 2.57−2.43 (m, 4H), 2.36−2.33 (m, 1H),
1.96−1.88 (m, 2H), 1.60−1.55 (m, 4H), 1.42−1.24 (m, 7H), 0.99 (d, J
= 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 143.0, 114.6, 114.5,
99.2, 59.2, 59.1, 55.83, 55.76, 49.2, 49.0, 38.5, 38.4, 28.7, 28.6, 28.4,
28.3, 28.1, 25.8, 24.4, 22.5, 18.53, 18.48; IR (thin film, cm−1) 2933,
2862, 1446; HRMS (ESI) m/z [M + H]+ calcd for C16H30NO2
268.2277, found 268.2271.
N-((R)-2-Phenylbut-3-enyl)-3-(6,10-dioxaspiro[4.5]decan-1-yl)-
propanamide (S18). Following general procedure D, S18 (408 mg,
1.19 mmol, 73%) was obtained as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 7.32 (t, J = 7.5 Hz, 2H), 7.24−7.21 (m, 3H), 5.99−5.92 (m,
2H), 5.14−5.09 (m, 2H), 3.88 (tt, J = 11.7, 2.4 Hz, 1H), 3.83−3.78
(m, 2H), 3.77−3.72 (m, 1H), 3.70−3.61 (m, 1H), 3.54−3.46 (m, 2H),
2.41−2.35 (m, 1H), 2.24−2.17 (m, 1H), 2.14−2.08 (m, 1H), 1.98−
1.87 (m, 1H), 1.85−1.66 (m, 4H), 1.64−1.52 (m, 3H), 1.34 (dt, J =
13.2, 2.4 Hz, 1H), 1.29−1.19 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 173.98, 173.97, 141.5, 139.34, 139.28, 128.84, 128.82, 128.02,
127.98, 127.0, 116.33, 116.31, 108.8, 62.31, 62.28, 60.5, 49.62, 49.57,
47.5, 43.5, 35.2, 30.81, 30.77, 29.55, 29.54, 26.1, 25.1, 21.29, 21.27; IR
(thin film, cm−1) 3299, 3083, 2958, 1646; HRMS (ESI) m/z [M +
Na]+ calcd for C21H29NO3Na 366.2045, found 366.2044.
N-((S)-2-Methylbut-3-en-1-yl)-2-(6,10-dioxaspiro[4.5]decan-1-yl)-
acetamide (S12). Following general procedure D, S12 (63 mg, 0.24
mmol, 85%) was obtained as a colorless solid; changes to the general
procedure involve adding Et3N (42 μL) to the amide-coupling step:
1H NMR (500 MHz, CDCl3) δ 6.35 (broad s, 1H), 5.72−5.69 (m,
1H), 5.08−5.03 (m, 2H), 3.94−3.87 (m, 4H), 3.32−3.29 (m, 1H),
3.09−3.08 (m, 1H), 2.62 (dd, J = 15.6, 7.0 Hz, 1H), 2.38−2.31 (m,
1H), 2.28−2.21 (m, 1H), 2.14−2.07 (m, 2H), 2.02−1.85 (m, 3H),
1.70−1.65 (m, 2H), 1.42−1.25 (m, 2H), 1.03 (d, J = 6.8 Hz, 3H); 13C
NMR (125 MHz) δ 173.3, 141.83, 141.78, 115.1, 115.0, 108.3, 62.4,
60.8, 60.8, 46.19, 46.15, 44.67, 44.65, 38.2, 38.1, 36.2, 30.6, 29.85,
28.82, 26.06, 26.05, 21.3, 17.79, 17.75; IR (thin film, cm−1) 3304,
3079, 2962, 1735, 1103; HRMS (ESI) m/z [M + H]+ calcd for
C15H26NO3 268.1913, found 268.1915.
(2S)-N-(2-(6,10-Dioxaspiro[4.5]decan-1-yl)ethyl)-2-methylbut-3-
en-1-amine (S13). Following general procedure E, S13 (28 mg, 0.11
1
mmol, 46%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 5.70−5.63 (m, 1H), 5.07−4.99 (m, 2H), 3.93−3.84 (m,
4H), 2.72−2.61 (m, 2H), 2.56−2.46 (m, 2H), 2.39−2.33 (m, 1H),
2.11 (dddd, J = 7.7, 7.7, 7.7, 7.7 Hz, 1H), 2.02−1.97 (m, 1H), 1.87−
1.79 (m, 3H), 1.68−1.57 (m, 3H), 1.43−1.25 (m, 4H), 1.00 (d, J = 6.7
Hz, 3H); 13C NMR (125 MHz) δ 143.0, 114.6, 114.5, 108.9, 62.2,
60.79, 55.77, 55.76, 49.1, 48.9, 47.1, 47.0, 38.5, 38.4, 30.70, 30.66, 29.4,
29.3, 29.2, 26.2, 21.3, 18.50, 18.46; IR (thin film, cm−1) 3315, 3075,
2955, 1111; HRMS (ESI) m/z [M + H]+ calcd for C15H28NO2
254.2120, found 254.2127.
(2R)-N-(3-(6,10-Dioxaspiro[4.5]decan-1-yl)propyl)-2-phenylbut-
3-en-1-amine (S19). Following general procedure E, S19 (330 mg,
1.00 mmol, 88% yield) was obtained as light yellow oil: 1H NMR (500
MHz, CDCl3) δ 7.32 (t, J = 7.6 Hz, 2H), 7.24−7.21 (m, 3H), 6.01−
5.94 (m, 1H), 5.15−5.11 (m, 2H), 3.93−3.82 (m, 4H), 3.55 (q, J = 7.4
Hz, 1H), 2.90 (d, J = 7.4 Hz, 2H), 2.68−2.59 (m, 2H), 2.11−2.05 (m,
1H), 2.03−1.93 (m, 1H), 1.89−1.37 (m, 9H), 1.30−1.12 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 142.6, 140.3, 128.9, 127.9, 126.8, 116.1,
109.0, 62.2, 60.8, 54.5, 50.3, 50.1, 48.9, 30.7, 29.0, 28.9, 26.3, 26.2,
21.2; IR (thin film, cm−1) 3332, 3081, 2863, 1148, 1109; HRMS (ESI)
m/z [M + H]+ calcd for C21H32O2N 330.2433, found 330.2429.
N-((S)-2-Methylbut-3-en-1-yl)-3-(6,10-dioxaspiro[4.5]decan-1-yl)-
propanamide (S20). Following general procedure D, S20 (59 mg,
0.21 mmol, 72%) was obtained as a colorless solid; changes in the
procedure include the addition of Et3N (45 μL) to the amide-coupling
N-((R)-2-Phenylbut-3-enyl)-2-(1,5-dioxaspiro[5.5]undecan-7-yl)-
acetamide (S14). Following general procedure D, S14 (307 mg, 0.893
1
mmol, 55%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 7.32 (t, J = 7.5 Hz, 2H), 7.25−7.21 (m, 3H), 6.00−5.93 (m,
2H), 5.15−5.09 (m, 2H), 3.98 (t, J = 11.7 Hz, 1H), 3.86 (t, J = 11.7
Hz, 1H), 3.74−3.58 (m, 3H), 3.55−3.44 (m, 2H), 2.72 (d, J = 14.6
Hz, 1H), 2.59 (d, J = 11.7 Hz, 1H), 1.95 (broad s, 1H), 1.89−1.75 (m,
2H), 1.57 (app d, J = 9.9 Hz, 3H), 1.39−1.22 (m, 4H), 1.12 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 173.9, 173.8, 141.54, 141.46, 139.3,
128.9, 128.03, 127.99, 127.0, 116.4, 116.3, 98.8, 98.7, 59.13, 59.10,
49.7, 49.6, 43.7, 43.6, 36.9, 36.8, 29.1, 28.9, 28.1, 25.8, 25.0, 22.4; IR
(thin film, cm−1) 3301, 2933, 1644, 1108; HRMS (ESI) m/z [M +
Na]+ calcd for C21H29NO3Na 366.2045, found 366.2051.
1
step: H NMR (500 MHz, CDCl3) δ 5.95 (broad s, 1H), 5.73−5.66
9941
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
(m, 1H), 5.08−5.03 (m, 2H), 3.95−3.87 (m, 4H), 3.32 (ddd, J = 12.7,
6.0, 6.0 Hz, 1H), 3.08−3.03 (m, 1H), 2.41−2.39 (m, 1H), 2.31−2.29
(m, 1H), 2.26−2.22 (m, 1H), 2.18−2.12 (m, 1H), 2.02−2.00 (m, 1H),
1.90−1.81 (m, 3H), 1.78−1.76 (m, 1H), 1.66−1.60 (m, 3H), 1.39 (d, J
= 13.3 Hz, 1H), 1.31−1.27 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 173.9, 141.8, 141.7, 115.1, 115.0, 108.9,
62.3, 60.5, 47.72, 47.71, 44.5, 44.4, 38.2, 38.1, 35.4, 30.9, 30.8, 29.50,
29.46, 26.1, 25.1, 25.0, 21.29, 21.27, 17.72, 17.68; IR (thin film, cm−1)
3298, 3080, 2960, 1644; HRMS (ESI) m/z [M + Na]+ calcd for
C16H27NO3Na 304.1889, found 304.1882.
mmol, 73%) of 31b as a colorless oil. HPLC analysis indicated an
enantiomeric excess of 95% [CHIRALCEL AD column; flow, 1 mL/
min; 98% n-hexane:2% i-PrOH; λ = 210 nm; major enantiomer tR23=
23
11.25 min; minor enantiomer tR = 13.89 min]: [α] −7.88, [α]546
577
23
435
1
−6.81, [α] −14.0 (c 0.45, CH2Cl2); H NMR (500 MHz, DMSO-
d6, 393 K) δ 7.36−7.28 (m, 5H), 5.46−5.32 (m, 2H), 5.11 (d, J = 12.7
Hz, 1H), 5.06 (d, J = 12.7 Hz, 1H), 3.52−3.46 (m, 1H), 3.43−3.39
(m, 1H), 2.69 (dd, J = 12.1, 6.3 Hz, 1H), 2.43 (dddd, J = 8.6, 8.6, 5.3,
5.3 Hz, 1H), 2.27 (dd, J = 15.8, 8.4 Hz, 1H), 2.15−2.11 (m, 1H),
1.93−1.86 (m, 1H), 1.81 (dddd, J = 15.4, 7.3, 7.3, 7.3 Hz, 1H), 1.72−
1.45 (m, 4H), 1.62 (d, J = 5.8 Hz, 3H), 1.43−1.37 (m, 1H); 13C NMR
(125 MHz, DMSO-d6, 393 K) δ 152.8, 136.9, 127.5, 126.8, 126.70,
126.67, 125.8, 125.0, 73.4, 64.9, 47.3, 47.1, 37.3, 31.2, 27.8, 24.1, 16.7;
IR (thin film, cm−1) 2948, 1699; HRMS (ESI) m/z [M + H]+ calcd for
C19H26NO2 300.1964, found 300.1960.
(2S)-N-(3-(6,10-Dioxaspiro[4.5]decan-1-yl)propyl)-2-methylbut-
3-en-1-amine (S21). Following general procedure E, S21 (26 mg,
1
0.097 mmol, 46%) was obtained as a colorless oil: H NMR (500
MHz, CDCl3) δ 5.69−5.62 (m, 1H), 5.11−5.00 (m, 2H), 3.93−3.85
(m, 4H), 2.62−2.52 (m, 3H), 2.49−2.45 (m, 1H), 2.38−2.35 (m, 1H),
2.11−2.05 (m, 1H), 1.98−1.96 (m, 1H), 1.89−1.78 (m, 3H), 1.65−
1.51 (m, 5H), 1.39 (d, J = 14.7 Hz, 1H), 1.32−1.12 (m, 2H), 1.00 (d, J
= 6.7 Hz, 3H), 0.89−0.88 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
142.8, 114.69, 114.68, 108.9, 62.1, 60.6, 55.50, 55.49, 60.4, 48.87,
48.85, 38.3, 36.8, 30.6, 30.4, 29.8, 28.9, 28.8, 28.6, 26.2, 26.1, 24.9,
23.7, 21.1, 18.5, 18.4, 17.8; IR (thin film, cm−1) 3076, 2955, 2863;
HRMS (ESI) m/z [M + H]+ calcd for C16H30NO2 268.2277, found
268.2271.
2-(11-Methyl-1,5-dioxaspiro[5.5]undecan-7-yl)-N-((S)-2-methyl-
but-3-en-1-yl)acetamide (S22). Following general procedure D, S22
(31 mg, 0.11 mmol, 70%) was obtained as a colorless solid; changes to
the general procedure include addition Et3N (23 μL) to the amide
coupling step: 1H NMR (500 MHz, CDCl3) δ 5.85 (broad d, J = 26.6
Hz, 1H), 5.69−5.66 (m, 1H), 5.07−5.04 (m, 2H), 3.95−3.80 (m, 4H),
3.34−3.29 (m, 1H), 3.04−3.01 (m, 1H), 2.78−2.58 (m, 1H), 2.50−
2.44 (m, 1H), 2.35−2.29 (m, 1H), 2.19−2.10 (m, 1H), 2.03 (dd, J =
14.3, 4.6 Hz, 1H), 1.98−1.90 (m, 1H), 1.85−1.81 (m, 1H), 1.67−1.52
(m, 2H), 1.52−1.42 (m, 1H), 1.39−1.32 (m, 3H), 1.02 (d, J = 6.6 Hz,
3H), 0.96 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.0,
141.7, 141.6, 115.24, 115.16, 58.7, 58.6, 48.13, 48.11, 45.6, 44.50,
44.46, 44.4, 38.31, 38.30, 38.24, 38.19, 37.4, 37.12, 37.11, 36.8, 35.58,
35.56, 25.51, 25.48, 19.7, 17.69, 17.65, 14.6, 13.7; IR (thin film, cm−1)
3296, 3078, 2963, 1640; HRMS (ESI) m/z [M + Na]+ calcd for
C17H29NO3Na 318.2045, found 318.2047.
(3aS,7aR)-Benzyl 7a-((E)-But-2-en-1-yl)octahydro-1H-indole-1-
carboxylate) (32b). Following general procedure G, 32b (25 mg,
0.078 mmol, 75%) was obtained as a colorless oil. HPLC analysis
indicated an enantiomeric excess of 95% [CHIRALCEL AD column;
flow, 1.0 mL/min; 98% n-hexane:2% i-PrOH; λ = 210 nm; major
23
enantiomer tR = 13.47 min; minor enantiomer tR = 17.22 min]: [α]
589
23
23
23
1
−47.2, [α] −48.0, [α] −54.7, [α] −94.3 (c 0.43, CH2Cl2); H
577
546
435
NMR (500 MHz, DMSO-d6, 393 K) δ 7.38−7.27 (m, 5H), 5.41−5.37
(m, 1H), 5.30−5.29 (m, 1H), 5.07 (d, J = 12.7 Hz, 1H), 5.01 (d, J =
12.2 Hz, 1H), 3.56−3.52 (m, 1H), 3.24 (app dd, J = 16.3, 7.9 Hz, 1H),
2.43 (dd, J = 16.2, 6.0 Hz, 1H), 2.33 (dd, J = 13.6, 7.8 Hz, 1H), 2.06−
2.02 (m, 1H), 1.89−1.64 (m, 4H), 1.58 (d, J = 5.6 Hz, 3H), 1.46−1.26
(m, 6H); 13C NMR (125 MHz, DMSO-d6, 393 K) δ 152.9, 137.0,
127.6, 126.8, 126.7, 126.3, 124.9, 64.8, 63.3, 45.5, 40.1, 37.4, 31.5, 25.4,
24.8, 21.0, 20.6, 16.8; IR (thin film, cm−1) 3029, 2928, 2857, 1701;
HRMS (ESI) m/z [M + Na]+ calcd for C20H27NO2Na 336.1939,
found 336.1934.
(4aS,7aR)-Benzyl 7a-((E)-But-2-en-1-yl)octahydro-1H-
cyclopenta[b]pyridine-1-carboxylate (33b). Following general pro-
cedure G, 33b (42 mg, 0.13 mmol, 71%) was obtained as a colorless
oil. HPLC analysis indicated an enantiomeric excess of 95%
[CHIRALCEL OJ column; flow, 0.5 mL/min; 99.9% n-hexane:0.1%
i-PrOH; λ = 210 nm; major enantiomer tR = 44.40 min; minor
enantiomer tR = 55.46 min (for the opposite enantiomer as shown
23
589
23
577
23
546
23
435
above)]: [α] −13.0,[α] −13.8, [α] −14.9, [α] −28.8 (c 0.36,
(2S)-2-Methyl-N-(2-(11-methyl-1,5-dioxaspiro[5.5]undecan-7-yl)-
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.35−7.31 (m, 5H), 5.46−
5.38 (m, 2H), 5.15 (d, J = 12.4 Hz, 1H), 3.96 (d, J = 12.6 Hz, 1H),
3.96 (app dd, J = 13.4, 5.7 Hz, 1H), 2.97 (app dt, J = 13.2, 4.8 Hz,
1H), 2.62 (dd, J = 12.7, 4.4 Hz, 1H), 2.19−2.12 (m, 3H), 2.10−2.08
(m, 1H), 1.77−1.67 (m, 3H), 1.64 (d, J = 4.9 Hz, 3H), 1.57−1.42 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 156.6, 137.3, 128.53, 128.52,
128.49, 128.2, 128.0, 127.9, 127.1, 67.6, 66.7, 42.3, 41.4, 39.5, 38.3,
29.5, 24.7, 21.8, 21.4, 18.2; IR (thin film, cm−1) 3031, 2922, 2851,
1745; HRMS (ESI) m/z [M + Na]+ calcd for C20H27NO2Na
336.1939, found 336.1931.
ethyl)but-3-en-1-amine (S23). Following general procedure E, S23
1
(42 mg, 0.15 mmol, 48%) was obtained as a colorless oil: H NMR
(500 MHz, CDCl3) δ 5.71−5.63 (m, 1H), 5.08−5.00 (m, 2H), 3.84
(broad s, 4H), 2.71−2.63 (m, 1H), 2.60−2.45 (m, 3H), 2.39−2.34 (m,
1H), 1.90−1.51 (m, 7H), 1.44−1.36 (m, 5H), 1.01 (d, J = 6.6 Hz,
3H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 143.0,
114.61, 114.56, 100.7, 58.7, 58.5, 55.74, 55.67, 49.1, 48.9, 38.5, 38.4,
25.6, 19.7, 18.5, 18.4, 13.9; IR (thin film, cm−1) 3076, 2931, 2861;
HRMS (ESI) m/z [M + H]+ calcd for C17H32NO2 282.2433, found
282.2428.
(3aS,7R,7aS)-Benzyl 7a-((E)-But-2-en-1-yl)-7-methyloctahydro-
1H-indole-1-carboxylate (34b). Following general procedure G, 34b
(12 mg, 0.035 mmol, 70%) was obtained as a colorless oil. HPLC
analysis indicated an enantiomeric excess of 91% [CHIRALCEL AD
column; flow, 1.0 mL/min; 98% n-hexane:2% i-PrOH; λ = 210 nm;
major enantiomer tR = 9.02 min; minor enantiomer tR = 20.11 min
Preparation and Characterization Data of 1-Azabicyclic
Products Reported in Table 3. Characterization data for azabicyclic
compounds 31a, 32a, 33a, and 34a have been described.9
General Procedure G for the 2-Aza-Cope Rearrangement and
Subsequent Cbz Protection to Provide Products Reported in Tables
3
and 4. (3aS,6aR)-Benzyl 6a-((E)-But-2-en-1-yl)-
23
23
hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (31b). A mixture
of aminoketal S13 (28 mg, 0.12 mmol), morpholine (1 μL, 0.011
mmol), TFA (13 μL, 0.11 mmol), and dimedone (29 mg, 0.28 mmol)
was stirred at 120 °C in a sealed 1-dram vial using an aluminum
heating block. After 30 min, the reaction vessel was cooled in an ice
bath for approximately 1 min. The reaction mixture was allowed to
warm to room temperature and was dissolved in CHCl3 (1 mL), and
the solution was transferred to a larger reaction vessel. To this flask
was added saturated aqueous Na2CO3 (0.5 mL), H2O (0.5 mL), and
benzyl chloroformate (57 μL, 0.34 mmol). The reaction was
vigorously stirred at room temperature for 24 h and then extracted
with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified on silica gel (1:19 EtOAc:hexanes) to provide 24 mg (0.081
(for the opposite enantiomer as shown above)]: [α] −34.3, [α]
589
577
23
23
−39.4, [α] −44.8, [α] −78.3 (c 0.87, CH2Cl2; data is for the
546
435
1
opposite enantiomer as shown above); H NMR (500 MHz, DMSO-
d6, 393K) δ 7.42−7.34 (m, 5H), 5.49−5.47 (m, 1H), 5.23−5.19 (m,
1H), 5.13 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.6 Hz, 1H), 3.54−3.51
(m, 1H), 3.40−3.33 (m, 1H), 3.26−3.22 (m, 1H), 2.21−2.14 (m, 2H),
1.98−1.90 (m, 2H), 1.71−1.42 (m, 7H), 1.61 (d, J = 23.9 Hz, 3H),
1.00 (broad s, 3H); 13C NMR (125 MHz, DMSO-d6, 393K) δ 154.4,
128.7, 128.5, 128.2, 128.1, 127.8, 127.64, 127.55, 125.7, 67.4, 65.7,
46.4, 37.1, 31.8, 29.9, 24.9, 24.7, 24.4, 20.2, 17.8, 17.1; IR (thin film,
cm−1) 3028, 2826, 2885, 1704; HRMS (ESI) m/z [M + Na]+ calcd for
C21H29NO2Na 350.2096, found 350.2098.
Synthesis and Characterization Data of 1-Azabicyclics
Reported in Table 4 and Their Precursors. N-((R)-2-Phenylbut-
9942
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
3-enyl)-3-(1,5-dioxaspiro[5.5]undecan-7-yl)propanamide (S24).
Following general procedure D, S24 (496 mg, 1.39 mmol, 86%) was
obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J =
7.5 Hz, 2H), 7.27−7.21 (m, 3H), 6.00−5.93 (m, 2H), 5.15−5.10 (m,
2H), 4.03−3.97 (m, 1H), 3.88 (tt, J = 11.7, 3.1 Hz, 1H), 3.77−3.60
(m, 3H), 3.53−3.46 (m, 2H), 2.54 (app d, J = 12.7 Hz, 1H), 2.35−
2.28 (m, 1H), 2.15−2.02 (m, 2H), 1.96−1.83 (m, 1H), 1.59−1.53 (m,
3H), 1.39−1.07 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 173.65,
173.63, 141.54, 141.52, 139.29, 139.25, 128.9, 128.8, 128.01, 127.97,
126.99, 126.98, 116.41, 116.37, 99.3, 59.15, 59.13, 59.0, 49.6, 49.5,
44.7, 43.7, 35.4, 35.3, 28.2, 28.0, 25.8, 24.8, 24.43, 24.41, 22.4; IR (thin
film, cm−1) 3299, 3083, 2861, 1644; HRMS (ESI) m/z [M + Na]+
calcd for C22H31NO3Na 380.2202, found 380.2200.
0.20 mmol, 58%) was obtained as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 7.32 (t, J = 7.5 Hz, 2H), 7.25−7.20 (m, 3H), 6.01−5.95 (m,
1H), 5.14−5.10 (m, 2H), 4.02 (t, J = 11.9 Hz, 1H), 3.84 (q, J = 11.4
Hz, 1H), 3.77−3.69 (m, 2H), 3.57 (q, J = 7.3 Hz, 1H), 2.92 (d, J = 7.3
Hz, 2H), 2.72−2.69 (m, 2H), 2.32−2.26 (m, 1H), 2.07−1.93 (m, 2H),
1.56−1.23 (m, 22H), 1.12−1.08 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 142.77, 142.75, 140.52, 140.48, 128.8, 127.94, 127.90, 126.7,
115.9, 115.8, 103.31, 103.27, 59.5, 59.4, 54.6, 50.3, 50.2, 50.1, 39.9,
39.8, 29.93, 29.91, 27.1, 27.0, 26.6, 26.4, 25.6, 25.11, 25.09, 24.0, 23.14,
23.10, 23.0, 22.6, 22.3, 19.5; IR (thin film, cm−1) 3327, 3026, 2929,
2861, 1467, 1245, 1112; HRMS (ESI) m/z [M + H]+ calcd for
C27H44O2N 414.3372, found 414.3362.
(3aS,13aR)-Benzyl 13a-((Z)-3-Phenylallyl)tetradecahydro-1H-
cyclododeca[b]pyrrole-1-carboxylate (36). Following general proce-
dure E, 36 (41 mg, 89 μmol, 74%) was obtained as a colorless
(2R)-N-(3-(1,5-Dioxaspiro[5.5]undecan-7-yl)propyl)-2-phenylbut-
3-en-1-amine (S25). Following general procedure E, S25 (229 mg,
1
1
amorphous solid (9:1 mixture of diastereomers by H NMR). The
0.667 mmol, 49%) was obtained as a light yellow oil: H NMR (500
major diastereomer was partially purified by preparatory TLC (9:1
hexanes/EtOAc) for characterization. HPLC analysis indicated an
enantiomeric excess of 99% [CHIRALCEL OD column; flow, 1.0 mL/
min; 99.5% n-hexane:0.5% i-PrOH; λ = 254 nm; major enantiomer tR
= 19.16 min; minor enantiomer tR = 27.21 min]: 1H NMR (500 MHz,
DMSO-d6, 393 K) δ 7.32−7.25 (m, 9H), 7.19−7.18 (m, 1H), 6.28 (d,
J = 15.4 Hz, 1H), 6.15−6.11 (m, 1H), 5.12 (d, J = 12.6 Hz, 1H), 5.03
(d, J = 12.6 Hz, 1H), 3.51 (t, J = 9.8 Hz, 1H), 3.30−3.24 (m, 1H),
2.82−2.68 (m, 2H), 2.32 (dd, J = 14.0, 7.4 Hz, 1H), 2.26−2.22 (m,
1H), 2.09−2.07 (m, 1H), 1.90 (td, J = 12.8, 7.1 Hz, 1H), 1.69 (t, J =
11.8 Hz, 1H), 1.51−1.27 (m, 18H); 13C NMR (125 MHz, DMSO,
393 K) δ 137.2, 131.1, 127.9, 127.7, 127.1, 126.3, 125.2, 67.2, 65.0,
46.7, 26.3, 25.9, 25.1, 23.5, 21.59, 21.56, 21.4, 21.1, 17.9; IR (thin film,
cm−1) 3027, 2925, 2852, 1702, 1459, 1402; HRMS (ESI) m/z [M +
Na]+ calcd for C31H41NO2Na 482.3035, found 482.3034. The ring
MHz, CDCl3) δ 7.32 (t, J = 7.6 Hz, 2H), 7.23−7.22 (m, 3H), 5.99−
5.93 (m, 1H), 5.14−5.11 (m, 2H), 4.02 (t, J = 11.2 Hz, 1H), 3.89 (dt, J
= 11.3, 2.3 Hz, 1H), 3.78 (app broad s, 2H), 3.54 (q, J = 7.5 Hz, 1H),
2.90 (d, J = 7.4 Hz, 2H), 2.64−2.60 (m, 2H), 2.45 (broad d, J = 8.8
Hz, 1H), 1.90−1.10 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 142.6,
140.3, 128.8, 128.0, 127.9, 126.8, 116.0, 99.3, 59.1, 59.0, 54.5, 50.3,
50.1, 28.5, 28.3, 27.3, 25.8, 25.2, 24.4, 22.5; IR (thin film, cm−1) 3315,
3081, 2933; HRMS (ESI) m/z: [M + H]+ calcd for C22H34NO2
344.2589, found 344.2583.
Characterization data for azabicyclic compound 35 has been
described.9
Benzyl 2-(2-Oxocyclododecyl)acetate (S26). Following general
procedure B, S26 (825 mg, 2.50 mmol, 64%) was obtained as a
1
colorless solid: mp 64−65 °C; H NMR (500 MHz, CDCl3) δ 7.38−
7.31 (m, 5H), 5.13−5.06 (m, 2H), 3.18−3.13 (m, 1H), 2.96−2.87 (m,
2H), 2.32 (dd, J = 16.7, 5.2 Hz, 1H), 2.25 (ddd, J = 17.7, 5.8, 3.6 Hz,
1H), 2.04−1.98 (m, 1H), 1.89−1.83 (m, 1H), 1.60−1.53 (m, 1H),
1.42−1.17 (m, 14H), 1.08−1.06 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 212.4, 172.7, 136.1, 128.8, 128.43, 128.40, 66.6, 47.3, 37.6,
34.3, 28.6, 26.3, 24.1, 23.3, 22.7, 22.4, 21.8, 21.2; IR (thin film, cm−1)
3033, 2931, 2864, 1735, 1709, 1164; HRMS (ES) m/z [M + Na]+
calcd for C21H30O3Na 353.2093, found 353.2084.
1
fusion geometry was assigned by H NOE analysis as depicted in the
drawing below.
(1,5-Dioxaspiro[5.11]heptadec-7-yl)acetic acid benzyl ester
(S27). Following general procedure C, ketal S27 was obtained as a
colorless oil (430 mg, 1.10 mmol, 91%). This product was purified by
flash chromatography on silica gel (100:0 to 98:2 to 95:5
hexanes:EtOAc): 1H NMR (500 MHz, CDCl3) δ 7.40−7.29 (m,
5H), 5.15−5.08 (m, 2H), 4.00 (t, J = 11.5 Hz, 1H), 3.78−3.73 (m,
2H), 3.53 (dd, J = 11.0, 4.1 Hz, 1H), 2.82 (dd, J = 15.3, 8.7 Hz, 1H),
2.43 (t, J = 8.7 Hz, 1H), 2.30−2.23 (m, 1H), 2.10 (dd, J = 15.3, 2.4 Hz,
1H), 1.98−1.90 (m, 1H), 1.61−1.22 (m, 19H), 1.11−1.06 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 174.7, 136.9, 128.5, 128.3, 128.0,
102.4, 65.8, 59.6, 59.5, 39.1, 34.4, 26.43, 26.37, 25.8, 25.4, 24.6, 23.6,
22.9, 22.7, 22.4, 22.2, 19.3; IR (thin film, cm−1) 3063, 2931, 2862,
1736, 1248, 1142; HRMS (ES) m/z [M + Na]+ calcd for C24H36O4Na
411.2511, found 411.2515.
Benzyl 2-(2-Oxocycloheptyl)acetate (S30). Keto ester S30 was
prepared by using an adapted procedure from Cotarco and co-
workers.35 A 250 mL round-bottom flask with stir bar fitted with a
Dean−Stark trap was charged with cycloheptanone (11 mL, 89
mmol), pyrrolidine (6.4 g, 89 mmol), and benzene (60 mL) and the
solution was heated to reflux. After 20 h, the reaction was concentrated
in vacuo at 55 °C for 1 h. The resultant red oil was dissolved in
benzene (45 mL), 2-bromobenzylacetate (8.0 mL, 12 mmol) was
added, and the reaction was heated to reflux. After 24 h, the reaction
was allowed to cool to 22 °C, concentrated in vacuo, taken up in
MeOH (30 mL) and water (6 mL), heated to reflux for 2 h, allowed to
cool to 22 °C, and partitioned between Et2O (400 mL) and 1 M HCl
(200 mL). The organic layer was washed with 1 M HCl (2 × 100 mL),
saturated aqueous sodium bicarbonate (1 × 50 mL), and brine (1 × 15
mL), dried (MgSO4), filtered, and concentrated in vacuo, and the
residue was purified by flash chromatography on silica gel (2:25−3:25
EtOAc:hexanes) to give S30 (6.3 g, 24 mmol, 45%) as a colorless oil:
1H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 5.12−5.05 (m,
2H), 3.10 (dddd, J = 10.9, 8.5, 5.7, 2.9 Hz, 1H), 2.87 (dd, J = 16.8, 8.4
Hz, 1H), 2.59 (dt, J = 16.3, 7.8 Hz, 1H), 2.50−2.38 (m, 1H), 2.33 (dd,
J = 16.8, 5.7 Hz, 1H), 1.92−1.76 (m, 3H), 1.76−1.63 (m, 2H), 1.57−
1.47 (m, 1H), 1.40−1.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
213.8, 172.2, 135.8, 128.4, 128.02, 127.98, 66.1, 47.2, 43.2, 36.5, 31.0,
29.1, 28.8, 23.3; IR (thin film, cm−1) 2925, 2854, 1733, 1702. Anal.
Calcd for C16H20O3: C, 73.82; H, 7.72. Found: C, 73.49; H, 7.73.
Benzyl 2-(1,5-Dioxaspiro[5.6]dodecan-7-yl)acetate (S31). Follow-
ing general procedure C, S31 (5.2 g, 16 mmol) was isolated as a
colorless oil in 84% yield; changes from the general procedure include
N-((R)-2-Phenylbut-3-enyl)-2-(1,5-dioxaspiro[5.11]heptadecan-7-
yl)acetamide (S28). Following general procedure D, S28 (171 mg,
1
0.400 mmol, 71%) was obtained as an amorphous colorless solid: H
NMR (500 MHz, CDCl3) δ 7.32 (t, J = 7.9 Hz, 2H), 7.23 −7.21 (m,
3H), 6.31 (d, J = 18.8 Hz, 1H), 5.96 (dddd, J = 17.2, 9.9, 6.9, 2.5 Hz,
1H), 5.14 −5.07 (m, 2H), 3.99 (t, J = 12.1 Hz, 1H), 3.80−3.69 (m,
3H), 3.64−3.42 (m, 4H), 2.78 (dt, J = 15.1, 5.8 Hz, 1H), 2.25 (ddd, J
= 14.8, 11.7, 7.5 Hz, 1H), 2.06 (t, J = 7.7 Hz, 1H), 1.93 (ddd, J = 15.3,
7.6, 2.6 Hz, 1H), 1.88−1.77 (m, 2H), 1.56−1.20 (m, 17H), 1.09−1.04
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 174.9, 174.8, 141.64,
141.58, 139.6, 139.5, 128.87, 128.85, 128.03, 127.99, 126.9, 116.2,
116.1, 102.9, 59.64, 59.58, 59.3, 49.6, 49.4, 43.5, 43.4, 39.5, 39.4, 37.5,
37.4, 27.2, 27.1, 26.4, 26.3, 25.5, 24.5, 23.6, 22.74, 22.65, 22.47, 22.45,
22.1, 19.3; IR (thin film, cm−1) 3323, 2931, 2863, 1647, 1140, 1117,
1089; HRMS (ESI) m/z [M + Na]+ calcd for C27H41NO3Na
450.2984, found, 450.2972.
(2R)-N-(2-(1,5-Dioxaspiro[5.11]heptadecan-7-yl)ethyl)-2-phenyl-
but-3-en-1-amine (S29). Following general procedure E, S29 (81 mg,
1
the exposure of the substrate to the reaction conditions for 2 h: H
9943
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
NMR (500 MHz, CDCl3) δ 7.37−7.25 (m, 5H), 5.15 (d, J = 12.4 Hz,
1H), 5.07 (d, J = 12.4 Hz, 1H), 3.94 (td, J = 11.9, 2.9 Hz, 1H), 3.81
(td, J = 11.7, 2.4 Hz, 1H), 3.73−3.67 (m, 2H), 2.92−2.84 (m, 1H),
2.27−2.18 (m, 2H), 2.09 (ddd, J = 14.8, 9.6, 2.2 Hz, 1H), 1.96−1.80
(m, 2H), 1.76−1.63 (m, 2H), 1.58−1.35 (m, 6H), 1.28 (dt, J = 10.9,
2.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 173.8, 136.2, 128.1,
127.9, 127.7, 101.2, 65.5, 59.04, 58.96, 45.8, 35.8, 29.4, 28.0, 27.8, 26.6,
25.3, 20.3; IR (thin film, cm−1) 2931, 2863, 1733. Anal. Calcd for
C19H26O4: C, 71.67; H, 8.23. Found: C, 71.45; H, 8.34.
116.5, 108.9, 62.0, 60.7, 49.5, 48.8, 43.6, 36.9, 30.6, 28.9, 28.13, 28.09,
26.2, 26.1, 21.0; IR (thin film, cm−1) 3295, 3078, 2944, 1645; HRMS
(ESI) m/z [M + Na]+ calcd for C23H33O3NNa 394.2358, found
394.2365.
N-((R)-2-Phenylbut-3-enyl)-5-(6,10-dioxaspiro[4.5]decan-1-yl)-
pentan-1-amine (S37). Following general procedure E, S37 (146 mg,
1
0.408 mmol, 66%) was obtained as a light-yellow oil: H NMR (500
MHz, CDCl3) δ 7.32 (t, J = 7.4 Hz, 2H), 7.23−7.18 (m, 3H), 6.00−
5.93 (m, 1H), 5.14−5.11 (m, 2H), 3.92−3.85 (m, 5H), 3.54 (q, J = 6.9
Hz, 1H), 2.89 (d, J = 7.4 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.10−0.90
(m, 17H); 13C NMR (125 MHz, CDCl3) δ 142.5, 140.3, 128.8, 127.8,
126.8, 116.0, 109.1, 62.1, 60.8, 54.6, 50.1, 49.9, 48.9, 30.7, 30.1, 28.9,
28.5, 28.4, 27.9, 26.2, 21.1; IR (thin film, cm−1) 2930, 2858, 1453,
1149, 1111; HRMS (ESI) m/z [M + H]+ calcd for C23H36NO2
358.2746, found 358.2741.
N-((R)-2-Phenylbut-3-enyl)-2-(1,5-dioxaspiro[5.6]dodecan-7-yl)-
acetamide (S32). Following general procedure D, S32 (369 mg, 1.03
1
mmol, 66%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 7.32 (t, J = 7.4 Hz, 2H), 7.25−7.21 (m, 3H), 6.00−5.93 (m,
1H), 5.83 (app broad d, J = 5.3 Hz, 1H), 5.15−5.10 (m, 2H), 3.96 (t, J
= 11.7 Hz, 1H), 3.82 (t, J = 11.6 Hz, 1H), 3.76−3.59 (m, 3H), 3.56−
3.45 (m, 2H), 2.66 (dd, J = 14.6, 4.0 Hz, 1H), 2.10−2.04 (m, 2H),
2.01−1.95 (m, 2H), 1.91−1.76 (m, 2H), 1.70−1.61 (m, 2H), 1.52−
1.32 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 173.90, 173.87, 141.50,
141.46, 139.3, 128.9, 128.0, 127.0, 116.39, 116.36, 102.1, 59.5, 59.43,
59.41, 49.7, 49.6, 46.43, 46.38, 43.7, 43.6, 38.14, 38.09, 29.79, 29.77,
28.4, 28.1, 28.0, 27.1, 25.6, 20.6; IR (thin film, cm−1) 3296, 3080,
2928, 1643; HRMS (ESI) m/z [M + Na]+ calcd for C22H31NO3Na
380.2202, found 380.2201.
Preparation and Characterization Data for 1-Azabicyclics
Reported in Scheme 8 and Their Aminoketal Precursors. (R,E)-
tert-Butyl 2-Phenylpent-3-enylcarbamate (S38). Diphenylphosphor-
yl azide (0.33 mL, 1.5 mmol) was added dropwise via syringe to a
solution of (R,E)-3-phenylhex-4-enoic acid36 (0.29 g, 1.5 mmol) and
Et3N (0.21 mL, 1.5 mmol) in t-BuOH (2.2 mL) at room temperature.
The resulting solution was heated at 85 °C for 48 h, cooled to room
temperature, diluted with EtOAc (50 mL), and washed sequentially
with H2O (10 mL), saturated aqueous NaHCO3 (10 mL), and brine
(10 mL). The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the crude residue by flash
chromatography on silica gel (19:1 hexanes:EtOAc to 9:1
hexanes:EtOAc) gave S38 (0.31 g, 1.2 mmol, 77%) as a colorless
solid (mp 47−48 °C). HPLC analysis indicated an enantiomeric excess
of 84%. The product was recrystallized with n-hexane/i-PrOH to an
enantiomeric excess of 87% [CHIRALCEL OD-H column; flow, 1.0
mL/min; 99.7% n-hexane/0.3% i-PrOH; λ = 220 nm; major
enantiomer tR = 44.75 min; minor enantiomer tR = 55.41 min]:
(2R)-N-(2-(1,5-Dioxaspiro[5.6]dodecan-7-yl)ethyl)-2-phenylbut-3-
en-1-amine (S33). Following general procedure E, S33 (225 mg,
1
0.655 mmol, 70%) was obtained as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.32 (t, J = 7.5 Hz, 2H), 7.24−7.21 (m, 3H), 6.02−
5.95 (m, 1H), 5.15−5.11 (m, 2H), 3.97 (tt, J = 11.3, 2.9 Hz, 1H) 3.86
(t, J = 11.0 Hz, 1H), 3.81−3.74 (m, 2H), 3.56 (q, J = 7.5 Hz, 1H),
2.97−2.88 (m, 2H), 2.71 (tt, J = 10.1, 4.8 Hz, 1H), 2.64−2.57 (m,
1H), 2.25−2.18 (m, 1H), 1.97−1.84 (m, 2H), 1.77−1.72 (m, 4H),
1.61−1.26 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 142.7, 140.4,
128.84, 128.82, 127.94, 127.92, 126.8, 126.7, 116.0, 115.9, 102.6, 59.5,
59.4, 54.73, 54.71, 50.2, 49.11, 49.08, 46.23, 46.19, 30.51, 30.49, 30.3,
28.74, 28.72, 27.20, 27.17, 27.0, 26.9, 25.7, 20.9; IR (thin film, cm−1)
3027, 2929, 2861, 2809, 1454, 1108; HRMS (ESI) m/z [M + H]+
calcd for C22H34O2N 344.2590, found 344.2581.
23
589
23
577
23
546
23
435
[α] −17.7, [α] −19.6, [α] −24.0, [α] −45.6 (c = 1.0,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 7.4 Hz, 2H),
7.25−7.20 (m, 3H), 5.58−5.55 (m, 2H), 4.50 (broad s, 1H), 3.42−
3.36 (m, 3H), 1.70 (d, J = 4.5 Hz, 3H), 1.43 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 156.0, 142.3, 131.9, 128.9, 127.9, 127.4, 126.9, 79.4,
49.2, 45.5, 28.6, 18.3; IR (thin film, cm−1) 3357, 2975, 2931, 1702,
1506, 1171; HRMS (ESI) m/z [M + Na]+ calcd for C16H23NO2Na
284.1626, found 284.1628.
Characterization data for azabicyclic compound 37 has been
described previously.9
Benzyl 5-(2-Oxocyclopentyl)pentanoate (S34). Following general
procedure B, S34 (385 mg, 1.40 mmol, 55%) was obtained as a
colorless oil after flash chromatography on silica gel (19:1
hexanes:EtOAc to 9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc): 1H
NMR (500 MHz, CDCl3) δ 7.37−7.32 (m, 5H), 5.12 (s, 2H), 2.37 (t,
J = 7.4 Hz, 2H), 2.29 (dd, J = 18.7, 8.4 Hz, 1H), 2.22−2.16 (m, 1H),
2.13−2.05 (m, 1H), 2.02−1.96 (m, 2H), 1.80−1.74 (m, 2H), 1.71−
1.61 (m, 2H), 1.48 (qd, J = 10.8, 6.7 Hz, 1H), 1.37 (app quintet, J =
7.9 Hz, 2H), 1.26 (dq, J = 16.1, 8.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 221.5, 173.6, 136.3, 128.7, 128.37, 128.36, 66.3, 49.1, 38.3,
34.3, 29.7, 29.4, 27.2, 25.0, 20.9; IR (thin film, cm−1) 3033, 2940,
2860, 1735, 1158; HRMS (ES) m/z [M + Na]+ calcd for C17H22O3Na
297.1467, found 297.1467.k
5-(6,10-Dioxaspiro[4.5]dec-1-yl)pentanoic acid benzyl ester
(S35). Following general procedure C, ketal S35 was obtained as a
colorless oil (622 mg, 1.87 mmol, 64%): 1H NMR (500 MHz, CDCl3)
δ 7.39−7.32 (m, 5H), 5.12 (s, 2H), 3.93−3.82 (m, 4H), 2.38 (t, J = 7.6
Hz, 2H), 2.09−2.05 (m, 1H), 2.05−1.88 (m, 1H), 1.86−1.76 (m, 3H),
1.70−1.59 (m, 5H), 1.41−1.19 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 174.0, 136.4, 128.7, 128.4, 128.3, 109.0, 66.2, 62.0, 60.8,
48.9, 34.6, 30.7, 29.0, 28.2, 28.1, 26.2, 25.6, 21.2; IR (thin film, cm−1)
3066, 3034, 2950, 1737, 1151, 1106; HRMS (ES) m/z [M + Na]+
calcd for C20H28O4Na 355.1885, found 355.1884.
(R,E)-2-Phenylpent-3-en-1-amine (S39). To a solution of N-Boc
amine S38 (180 mg, 0.690 mmol) in CH2Cl2 (3.4 mL) was added
TFA (0.530 mL, 6.90 mmol) dropwise via syringe at 0 °C. The
resulting solution was stirred at room temperature for 1.5 h and
quenched with 10% aqueous NaOH at 0 °C until a pH of 14 was
reached. The mixture was allowed to warm to room temperature and
extracted with Et2O (3 × 15 mL). The organic layers were combined,
dried (MgSO4), filtered, and concentrated in vacuo to provide S39
(140 mg) as a yellow oil that was used in subsequent reactions without
further purification.
N-((R,E)-2-Phenylpent-3-enyl)-2-(6,10-dioxaspiro[4.5]decan-1-yl)-
acetamide (S40). Following general procedure D, S40 (35 mg, 0.10
1
mmol, 16%) was obtained as a colorless oil: H NMR (500 MHz,
CDCl3) δ 7.32 (t, J = 7.9 Hz, 2H), 7.24−7.21 (m, 3H), 6.26 (broad s,
1H), 5.57−5.54 (m, 2H), 3.87−3.75 (m, 4H), 3.63−3.44 (m, 3H),
2.56 (dd, J = 14.9, 6.6 Hz, 1H), 2.20−2.08 (m, 1H), 2.08−2.04 (m,
2H), 1.87−1.80 (m, 3H), 1.69 (d, J = 5.2 Hz, 3H), 1.65−1.62 (m,
1H), 1.33−1.26 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 173.25,
173.23, 142.5, 142.4, 132.19, 132.16, 131.9, 128.9, 128.8, 127.93,
127.88, 127.2, 127.1, 127.0, 126.8, 108.3, 108.2, 62.30, 62.28, 60.74,
60.71, 48.8, 48.7, 46.03, 45.98, 44.23, 44.17, 36.05, 36.04, 30.47, 30.46,
29.6, 29.5, 26.0, 25.99, 21.2, 18.3; IR (thin film, cm−1) 3299, 2961,
2932, 2867, 1642, 1544; HRMS (ESI) m/z [M + Na]+ calcd for
C21H29NO3Na 366.2045, found 366.2044.
N-((R)-2-Phenylbut-3-enyl)-5-(6,10-dioxaspiro[4.5]decan-1-yl)-
pentanamide (S36). Following general procedure D, S36 (242 mg,
1
0.651 mmol, 72%) as a colorless oil: H NMR (500 MHz, CDCl3) δ
7.31 (t, J = 7.5 Hz, 2H), 7.23−7.18 (m, 3H), 5.98−5.91 (m, 1H), 5.54
(broad s, 1H), 5.14−5.09 (m, 2H), 3.90−3.82 (m, 4H), 3.59−3.58 (m,
1H), 3.51−3.48 (m, 2H), 2.11−2.03 (m, 3H), 1.97−1.93 (m, 1H),
1.85−1.73 (m, 3H), 1.64−1.54 (m, 5H), 1.38−1.14 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 173.3, 141.3, 139.0, 128.8, 127.9, 127.0,
(2R,E)-N-(2-(6,10-Dioxaspiro[4.5]decan-1-yl)ethyl)-2-phenylpent-
3-en-1-amine (39a). Following general procedure E, 39a (33 mg, 0.10
1
mmol, 98%) was obtained as a light-brown oil: H NMR (500 MHz,
CDCl3) δ 7.31 (t, J = 7.7 Hz, 2H), 7.23−7.19 (m, 3H), 5.58−5.55 (m,
2H), 3.92−3.82 (m, 4H), 3.49 (q, J = 7.2 Hz, 1H), 2.88−2.85 (m,
9944
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
2H), 2.69−2.64 (m, 2H), 2.10−2.06 (m, 1H), 2.00−1.91 (m, 1H),
1.84−1.74 (m, 5H), 1.69−1.62 (m, 8H), 1.40−1.36 (m, 2H), 1.31−
1.26 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.59, 143.55, 133.2,
133.1, 128.77, 128.75, 127.81, 127.79, 126.8, 126.7, 126.56, 126.55,
108.9, 62.2, 60.8, 55.2, 49.3, 48.9, 47.1, 30.6, 30.5, 29.9, 29.3, 29.1,
26.1, 21.3, 18.3; IR (thin film, cm−1) 3305, 3206, 2954, 2861, 1451,
1149, 1110; HRMS (ESI) m/z [M + H]+ calcd for C21H32NO2
330.2433, found 330.2423.
(3aS,6aS)-Benzyl 6a-((R,E)-4-Phenylbut-3-en-2-yl)-
hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (40). Following
general procedure G, 40 (28 mg, 0.075 mmol, 75%) was obtained as a
colorless oil. HPLC analysis indicated an enantiomeric excess of 87%
[CHIRALCEL OD-H column; flow, 1.0 mL/min; 99.8% n-
hexane:0.2% i-PrOH; λ = 254 nm; major enantiomer tR = 43.90
min; minor enantiomer tR = 40.20 min]: 1H NMR (500 MHz, CDCl3)
δ 7.38−7.29 (m, 9H), 7.20 (t, J = 7.3 Hz, 1H), 6.43 (d, J = 15.8 Hz,
1H), 6.17 (dd, J = 15.8, 8.5 Hz, 1H), 5.14−5.09 (m, 2H), 3.60−3.47
(m, 2H), 3.34 (m, 1H), 2.67−2.50 (m, 1H), 2.14−2.10 (m, 1H),
2.00−1.92 (m, 2H), 1.76−1.72 (m, 1H), 1.60−1.55 (m, 2H), 1.50−
1.38 (m, 2H), 0.88 (d, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 152.7, 137.0, 136.8, 132.4, 129.8, 127.7, 127.6, 126.9, 126.6, 126.2,
125.3, 76.6, 65.0, 47.3, 44.1, 41.4, 36.7, 32.3, 28.6, 24.3, 15.2; IR (thin
film, cm−1) 3027, 2955, 2868, 1698, 1402; HRMS (ESI) m/z [M +
Na]+ calcd for C25H29NO2Na 398.2096, found 398.2097.
2960, 2866, 1721; HRMS (ESI) m/z [M + Na]+ calcd for
C26H31NO3Na 428.2202, found 428.2203.
(2R,E)-N-(2-(6,10-Dioxaspiro[4.5]decan-1-yl)ethyl)-2,4-diphenyl-
but-3-en-1-amine (39b). Following general procedure E, 39b (204
1
mg, 0.520 mmol, 81% yield) was obtained as a light-yellow oil: H
NMR (500 MHz, CDCl3) δ 7.46−7.26 (m, 10H), 6.55 (dd, J = 15.9,
4.0 Hz, 1H), 6.42 (dd, J = 15.9, 8.0 Hz, 1H), 3.97−3.76 (m, 5H), 3.08
(d, J = 7.4 Hz, 2H), 2.78−2.68 (m, 2H), 2.18−2.12 (m, 1H), 2.02−
2.00 (m, 1H), 1.94−1.83 (m, 3H), 1.73−1.65 (m, 3H), 1.50−1.22 (m,
4H); 13C NMR (125 MHz) δ 142.71, 142.67, 137.42, 137.39, 132.1,
132.0, 131.14, 131.07, 128.89, 128.88, 128.7, 128.65, 128.59, 128.4,
128.3, 127.96, 127.94, 127.7, 127.44, 127.43, 126.8, 126.84, 126.82,
126.4, 126.3, 108.8, 62.7, 62.2, 62.1, 60.8, 54.9, 49.41, 49.39, 48.84,
48.82, 46.97, 46.96, 30.53, 30.50, 29.23, 29.21, 29.0, 26.0, 21.2; IR
(thin film, cm−1) 3654, 3025, 2951, 1147; HRMS (ESI) m/z [M + H]+
calcd for C26H34NO2 392.2590. found 392.2585.
(3aS, 6aS)-Benzyl 6a-((1S, E)-1,3-Diphenylallyl)-
hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (41). Following
general procedure G, 41 (6 mg, 14 μmol, 65% yield) was obtained as a
light colorless oil. HPLC analysis indicated an enantiomeric excess of
99% [CHIRALCEL AD column; flow, 1.0 mL/min; 98% n-hexane/2%
i-PrOH; λ = 254 nm; major enantiomer tR = 29.97 min; minor
589
577
546
enantiomer tR = 23.72 min]: [α] −66.0, [α] −69.9, [α] −79.7,
22
22
22
435
1
[α] −148.6 (c 1.2, CH2Cl2); H NMR (500 MHz, DMSO-d6, 393
22
K) δ 7.50−7.40 (m, 6H), 7.35−7.30 (m, 3H), 7.24−7.15 (m, 6H),
6.73 (dd, J = 15.6, 9.9 Hz, 1H), 6.48 (d, J = 15.5 Hz, 1H), 5.22 (d, J =
12.6, 1H), 5.12 (broad d, J = 13.4 Hz, 1H), 4.50 (broad d, J = 12.8 Hz,
1H), 3.30 (ddd, J = 10.5, 8.0, 8.0 Hz, 1H), 3.02−2.97 (m, 1H), 2.69
(ddd, J = 10.7, 8.8, 4.7 Hz, 1H), 2.24 (broad s, 1H), 2.04 (ddd, J =
14.3, 7.3, 7.3 Hz, 1H), 1.90−1.84 (m, 1H), 1.60−1.46 (m, 2H), 1.42−
1.37 (m, 1H), 1.31−1.28 (m, 1H), 1.18−1.12 (m, 1H); 13C NMR
(125 MHz, DMSO-d6, 393 K) δ 152.7, 141.4, 136.82, 136.78, 131.9,
129.5, 127.9, 127.8, 127.6, 127.1, 127.0, 126.9, 126.5, 125.6, 125.5,
77.5, 65.1, 51.6, 46.6, 43.9, 37.1, 32.6, 27.6, 24.3; IR (thin film, cm−1)
3028, 2951, 1699, 1132; HRMS (ESI) m/z [M + Na]+ calcd for
C30H31NO2Na 460.2252, found 460.2243.
(R,E)-tert-Butyl (4-Cyclohexyl-2-phenylbut-3-en-1-yl)carbamate
(S44). To a stirring solution of HG-II37 (23 mg, 0.036 mmol) in
CH2Cl2 (1.2 mL) was added homoallylic carbamate 25 (0.090 g, 0.36
mmol) and vinylcyclohexane (0.25 mL, 1.8 mmol). The green solution
was heated to reflux for 12 h. After 22 h, the solution was cooled to
room temperature and concentrated under reduced pressure to a
brown solid. The crude material was purified by flash chromatography
on silica gel (100% hexanes to 9:1 hexanes:Et2O) to yield S44 as a
colorless solid (49 mg, 0.15 mmol, 41%) that was a 9:1 mixture of E:Z
double-bond isomers: mp 83−84 °C; 1H NMR (600 MHz, CDCl3) δ
7.33−7.31 (m, 2H), 7.24−7.20 (m, 3H), 5.54−5.48 (m, 2H), 5.44−
5.39 (m, 0.18 H), 3.41 (broad s, 1H), 3.37−3.32 (m, 2H), 3.22−3.18
(m, 0.11H), 1.97−1.93 (m, 1H), 1.74−1.69 (m, 5H), 1.65−1.63
(1.3H), 1.43 (s, 10.5 H), 1.29−1.22 (m, 2.4 H), 1.18−1.10 (m, 3.3 H);
13C NMR (125 MHz, CDCl3) δ 156.0, 142.5, 138.8, 128.8, 128.0,
(R,E)-tert-Butyl (2,4-Diphenylbut-3-en-1yl)carbamate (S41). To a
solution of the catalyst HG-II37 (13 mg, 0.02 mmol) in CH2Cl2 (1.3
mL) was added homoallylamine 25 (0.10 g, 0.40 mmol) and styrene
(0.16 mL, 1.2 mmol). The green solution was heated to reflux for 12 h.
After 12 h, the solution was cooled to room temperature and
concentrated under reduced pressure to a brown solid. The crude
material was purified by silica gel chromatography (100% hexanes to
4:1 hexanes:Et2O) to yield S41 as a colorless solid (92 mg, 0.28 mmol,
589
577
546
435
70%): mp 80−81 °C; [α] −6.35, [α] −7.12, [α] −8.15, [α]
22
22
22
22
−7.48 (c 1.3, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.34−7.21 (m,
10H), 6.49 (d, J = 15.9 Hz, 1H), 6.34 (dd, J = 15.9, 7.8 Hz, 1H), 4.57
(broad s, 1H), 3.69−3.68 (m, 1H), 3.57−3.56 (m, 1H), 3.52−3.48 (m,
1H), 1.43 (s, 9H); 13C NMR (125 MHz) δ 156.1, 141.7, 137.2, 131.7,
130.8, 129.0, 128.7, 128.0, 127.6, 127.1, 126.5, 79.5, 49.5, 45.5, 28.6; IR
(thin film, cm−1) 3430, 3358, 3060, 2979, 1710; HRMS (ESI) m/z [M
+ Na]+ calcd for C21H25O2NNa 346.1783, found 346.1793.
(R,E)-2,4-Diphenylbut-3-en-1-amine (S42). To a solution of Boc-
amide S41 (89 mg, 0.28 mmol) in CH2Cl2 (1.3 mL) at 0 °C was
added TFA (0.21 mL, 2.8 mmol) dropwise over 3 min. The resulting
clear and colorless solution was warmed to room temperature and
maintained for 1.5 h. The reaction was quenched by the addition of
10% aqueous solution of NaOH until the solution is basic (pH >10
analyzed by pH paper) at 0 °C. The solution was allowed to warm to
room temperature and extracted with Et2O (3 × 50 mL). The organic
layers were combined, dried with MgSO4, filtered, and concentrated to
provide the amine S42 as a slightly yellow oil (61 mg, 0.28 mmol).
589
577
This amine was used without further purification: [α] +6.24, [α]
22
22
127.90, 127.88, 127.8, 127.6, 126.8, 79.3, 49.0, 45.7, 40.9, 33.2, 28.6,
26.2; IR (thin film, cm−1) 3438, 3363, 2975, 1704, 1601, 1171; HRMS
(ESI) m/z [M + Na]+ calcd for C21H31NO2Na 352.2252, found
352.2254.
546
435
1
+6.61, [α] +8.33, [α] +22.2 (c 1.9, CH2Cl2); H NMR (500
22
22
MHz, CDCl3) δ 7.39−7.20 (m, 10H), 6.51 (d, J = 15.7 Hz, 1H), 6.25
(dd, J = 15.7, 8.1 Hz, 1H), 3.59 (broad d, J = 7.2 Hz, 1H), 3.47 (broad
s, 2H), 3.10 (broad s, 2H); 13C NMR (125 MHz) δ 141.1 136.9,
132.3, 130.1, 129.2, 128.8, 127.9, 127.8, 127.4, 126.5, 50.9, 46.0; IR
(thin film, cm−1) 3357, 3290, 2929; HRMS (ESI) m/z [M + H]+ calcd
for C16H18N 224.1439, found 224.1445.
N-((R,E)-2,4-Diphenylbut-3-en-1-yl)-2-(6,10-dioxaspiro[4.5]-
decan-1yl)acetamide (S43). Following general procedure D, S43 (45
mg, 0.11 mmol, 65%) was obtained as a colorless solid: 1H NMR (500
MHz, CDCl3) δ 7.39−7.20 (m, 10H), 6.47 (dd, J = 12.7, 4.5 Hz, 1H),
6.36−6.31 (m, 1H), 3.85−3.54 (m, 7H), 2.58 (dd, J = 14.4, 6.8 Hz,
1H), 2.21−2.13 (m, 1H), 2.11−2.00 (m, 2H), 1.91−1.71 (m, 3H),
1.65−1.54 (m, 3H), 1.29−1.22 (m, 2H); 13C NMR (125 MHz) δ
173.38, 173.36, 141.9, 141.7, 137.3, 137.2, 131.4, 131.0, 129.0, 128.72,
128.71, 128.1, 128.0, 127.63, 127.60, 127.1, 126.4, 108.2, 62.3, 60.7,
49.04, 49.01, 46.09, 46.05, 44.2, 44.1, 36.08, 36.05, 30.52, 30.45, 30.4,
29.9, 29.7, 29.6, 26.0, 21.2, 21.2; IR (thin film, cm−1) 3330, 3059,
(R,E)-4-Cyclohexyl-2-phenylbut-3-en-1-amine (S45). To a solu-
tion of Boc-amide S44 (49 mg, 0.15 mmol) in CH2Cl2 (0.68 mL) at 0
°C was added TFA (0.12 mL, 1.5 mmol) dropwise over 3 min. The
resulting clear and colorless solution was warmed to room temperature
and maintained for 1.5 h. The reaction was quenched by the addition
of 10% aqueous solution of NaOH until the solution was basic (pH
>10 analyzed by pH paper) at 0 °C. The solution was warmed to room
temperature and extracted with Et2O (3 × 50 mL). The organic layers
were combined, dried with MgSO4, filtered, and concentrated to
provide the amine as a colorless oil. The crude material could be used
without further purification or purified to obtain an analytically pure
sample (>98% E olefin isomer) by flash chromatography on silica gel
(99:1 Et2O:Et3N) to yield S45 as a colorless oil (25 mg, 0.11 mmol.
589
577
546
435
73%): [α] −25.1, [α] −27.0, [α] −30.7 [α] −56.4 (c 1.3,
22
22
22
22
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.34−7.16 (m, 5H), 5.52−
9945
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
5.51 (m, 2H), 3.23−3.19 (m, 1H), 2.95−2.87 (m, 2H), 2.00−1.92 (m,
1H), 1.73−1.63 (m, 5H), 1.47 (broad s, 1H), 1.28−1.07 (m, 6H); 13C
NMR (125 MHz) δ 143.3, 138.7, 128.7, 128.6, 127.9, 126.5, 53.0, 47.7,
40.9, 33.4, 33.3, 26.3, 26.2, 25.1; IR (thin film, cm−1) 3366, 3284,
3026, 2920, 2850, 1074, 1029; HRMS (ESI) m/z [M + H]+ calcd for
C16H24N 230.1909, found 230.1909.
N-((R,E)-4-Cyclohexyl-2-phenylbut-3-en-1-yl)-2-(6,10-dioxaspiro-
[4.5]decan-1-yl)acetamide (S46). Following general procedure D,
S46 (27 mg, 0.065 mmol, 64% yield) was obtained as a colorless oil:
1H NMR (500 MHz, CDCl3) δ 7.38−7.35 (m, 2H), 7.28−7.25 (m,
3H), 6.23 (broad d, J = 17.1 Hz, 1H), 5.55 (s, 1H), 5.54 (dd, J = 3.0,
1.2 Hz, 1H), 3.93−3.76 (m, 4H), 3.71−3.60 (m, 1H), 3.56−3.41 (m,
2H), 2.60 (dd, J = 15.1, 6.7 Hz, 1H), 2.67−2.20 (m, 1H), 2.13−2.07
(m, 2H), 2.10−1.90 (m, 1H), 1.91−1.58 (m, 12H), 1.41−1.05 (m,
5H); 13C NMR (125 MHz) δ 173.24, 173.21, 142.6, 142.5, 138.6,
138.5, 128.8, 128.3, 128.0, 127.9, 126.8, 108.3, 108.2, 62.30, 62.27,
60.73, 60.70, 48.7, 48.6, 46.1, 45.9, 44.33, 44.26, 40.9, 36.1, 33.21,
33.17, 30.51, 30.47, 29.9, 29.6, 29.5, 26.3, 26.2, 26.01, 25.99, 21.2; IR
(thin film, cm−1) 3296, 3061, 2920, 1644; HRMS (ESI) m/z [M +
Na]+ calcd for C26H37NO3Na 434.2671, found 434.2680.
t2O:AcOH) provided 46 (10 mg, 25 μmol, 99% yield) as a colorless
589
577
546
435
oil: [α] −2.90, [α] −3.46, [α] +1.24, [α] +1.88 (c 0.31,
22
22
22
22
1
CH2Cl2); H NMR (500 MHz, DMSO-d6, 393 K) δ 11.56 (broad s,
1H), 7.36 (broad s, 4H), 7.30 (broad s, 1H), 5.16 (d, J = 1.8 Hz, 1H),
5.06 (broad m, 1H), 3.53−3.41 (broad m, 2H), 3.27 (broad s, 1H),
2.09−2.03 (broad m, 1H), 1.92−1.84 (broad m, 2H), 1.73−1.38
(broad m, 11H), 1.32−0.86 (broad m, 6H); 13C NMR (125 MHz,
DMSO-d6, 393 K) δ 174.6, 152.6, 137.5, 128.4, 128.3, 128.0, 127.6,
127.1, 75.7, 65.2, 53.0, 47.0, 43.4, 38.5, 36.6, 33.5, 32.7, 30.9, 29.4,
26.3, 26.1, 25.8, 25.0; IR (thin film, cm−1) 2921, 2851, 1214; HRMS
(ESI) m/z [M + Na]+ calcd for C23H31NO4Na 408.2151, found
408.2153.
2,2,2-Trifluoro-1,3-ethan-1-one, 6a-(3-Hydroxypropoxy)-1-((S)-2-
methylbut-3-en-1-yl)octahydrocyclopenta[b]pyrrol-1-ium Salt (Dia-
1
stereomers 49 and 50). H NMR (500 MHz, DMSO-d6) δ: 8.38−
8.29 (br d, 2H), 5.73−5.66 (m, 1H), 5.13−5.05 (m, 2H), 3.85−3.74
(m, 4H), 2.98−2.84 (m, 1H), 2.84−2.83 (m, 2H), 2.52−2.48 (m, 1H),
2.11−2.06 (m, 2H), 1.81−1.69 (m, 5H), 1.55−1.50 (m, 3H), 1.34 (d, J
= 2.4 Hz, 1H), 1.18−1.16 (m, 1H), 0.98 (d, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, DMSO-d6, contains a mixture of diastereomers, signals
observed are reported) δ: 258.4, 158.2, 139.8, 139.8, 139.8, 116.2,
116.2, 107.7, 107.6, 61.5, 59.9, 51.5, 46.58, 46.55, 45.97, 45.96, 34.8,
29.9, 28.4, 25.5, 24.7, 24.7, 24.6, 20.72, 20.71, 14.5.
(2R,E)-N-(2-(6,10-Dioxaspiro[4.5]decan-1-yl)ethyl)-4-cyclohexyl-
2-phenylbut-3-en-1-amine (39c). Following general procedure E, 39c
1
(18 mg, 0.045 mmol, 67% yield) was obtained as a colorless oil: H
NMR (500 MHz, CDCl3) δ 7.31−7.29 (m, 2H), 7.23−7.20 (m, 3H),
5.51−5.50 (m, 2H), 3.89−3.84 (m, 4H), 3.51−3.45 (m, 1H), 2.89−
2.83 (m, 2H), 2.69−2.67 (m, 2H), 2.11−2.06 (m, 1H), 2.00−1.90 (m,
2H), 1.82−1.55 (m, 11H), 1.44−1.04 (m, 9H); 13C NMR (125 MHz)
δ 138.4, 129.1, 128.7, 128.7, 127.8, 126.51, 126.49, 108.90, 108.88,
62.23, 62.22, 60.79, 60.77, 55.3, 55.2, 49.0, 48.82, 48.76, 47.0, 46.9,
41.0, 40.9, 33.33, 33.30, 33.24, 33.23, 30.7, 30.6, 29.31, 29.25, 29.0,
26.4, 26.27, 26.26, 26.15, 21.24, 21.23; IR (thin film, cm−1) 3430,
3313, 3052, 2923, 1264; HRMS (ESI) m/z: [M + H]+ calcd for
C26H40NO2 398.3059, found 398.3053.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for new compounds,
HPLC traces used to determine enantiomeric purity, CIF files
for compounds ent-8 and 18, and general experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*L. E. Overman. E-mail: leoverma@uci.edu.
Present Addresses
Z.A.D.: Department of Chemistry, Indiana University, 800 E.
Kirkwood Ave., Bloomington, IN 47405.
(3aS,6aS)-Benzyl 6a-((R,E)-1-Cyclohexyl-3-phenylallyl)-
hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (42). Following
general procedure G, 42 (31 mg, 0.071 mmol, 49%) was obtained as a
colorless oil. HPLC analysis indicated an enantiomeric excess of 99%
[CHIRALCEL AD column; flow, 0.5 mL/min; 98% n-hexane:2% i-
PrOH; λ = 254 nm; major enantiomer tR 57=7 28.77 min; minor
■
589
22
546
22
enantiomer tR = 32.53 min]: [α] +41.9, [α]22 +42.1, [α] +49.7,
[α]24235 +92.1 (c = 0.34, CH2Cl2); 1H NMR (500 MHz, DMSO-d6, 393
K) δ 7.42−7.35 (m, 6H), 7.32−7.29 (m, 3H), 7.22−7.19 (m, 1H),
6.34 (d, J = 15.8 Hz, 1H), 6.14 (dd, J = 15.7, 10.6, 1H), 5.15 (d, J =
12.7 Hz, 1H), 5.06 (d, J = 12.6 Hz, 1H), 3.62−3.51 (m, 1H), 2.97 (d, J
= 9.5 Hz, 1H), 2.09 (broad s, 1H), 2.00 (dddd, J = 12.9, 8.5, 8.5, 8.5
Hz, 1H), 1.85 (dddd, J = 7.7, 7.7, 7.7, 7.7 Hz, 1H), 1.77−1.73 (m,
2H), 1.69−1.66 (m, 1H), 1.63−1.39 (m, 8H), 1.31−1.29 (m, 1H),
1.23−1.14 (m, 3H), 1.11−1.01 (m, 3H); 13C NMR (125 MHz,
DMSO-d6, 393 K) δ 152.7, 137.0, 136.9, 132.0, 129.4, 127.8, 127.6,
126.9, 126.8, 126.2, 125.4, 76.7, 65.0, 53.3, 47.3, 44.6, 37.9, 33.03,
32.99, 29.4, 28.4, 25.9, 25.7, 25.3, 23.8; IR (thin film, cm−1) 3028,
2925, 2851, 1699; HRMS (ESI) m/z [M + Na]+ calcd for
C30H37NO2Na 466.2722, found 466.2714.
T.I.: Current address: Chemical Development Laboratories,
Takeda Pharmaceutical Company Limited, 17-85, Jusohonma-
chi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
T.L.M.: AstraZeneca, 35 Gatehouse DR, E0.25B, Waltham, MA
02451.
J.W.: The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, CA 92037.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institute on
Neurological Disorders and Stroke (R01NS12389), National
Institute of General Medical Sciences (R01GM098601),
Takeda Pharmaceutical Co., and a NIH postdoctoral fellowship
for T.L.M. (F32GM096690). NMR, mass spectra, and X-ray
analyses were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH Shared
Instrumentation programs. We thank Dr. Joseph Ziller and
Dr. John Greaves, Department of Chemistry, UC Irvine, for
their assistance with X-ray and mass spectrometric analyses.
The synthesis and characterization of amino acids 43−45 have been
reported previously.9
(S)-2-((3aS,6aS)-1-((Benzyloxy)carbonyl)octahydrocyclopenta[b]-
pyrrol-6a-yl)-2-cyclohexylacetic acid (46). Ozone was bubbled
through a solution of 42 (12 mg, 25 μmol) in MeOH (1.7 mL) at
−78 °C for approximately 30 s until a persistent blue color was
observed. The solution was purged with O2 until colorless, quenched
with dimethyl sulfide (81 μL, 1.1 mmol), and warmed to room
temperature. After 24 h, the reaction mixture was concentrated in
vacuo, dissolved in MeCN (1.8 mL) and H2O (0.17 mL), and the
solution was cooled to 0 °C. Sodium chlorite (23 mg, 0.25 mmol) was
added to the solution, and the reaction mixture was warmed to room
temperature. After stirring for 24 h, the reaction mixture was
concentrated in vacuo, diluted with brine (5 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated. Purification of the crude residue
by flash chromatography on silica gel (100:100:1 hexanes:E-
REFERENCES
■
(1) (a) Morita, H.; Arisaka, M.; Yoshida, N.; Kobayashi, J.
Tetrahedron 2000, 56, 2929−2934. Other examples of alkaloid
natural products containing these structural frameworks: Huperzine B
(b) Liu, J.-S.; Whu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu, F.-
9946
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
W.; Qi, N.-F. Can. J. Chem. 1986, 64, 837−839.
Malycorin C
(13) We found it most convenient to determine the enantiomeric
purity of these primary amines by enantioselective chromatography of
the corresponding benzamides (see the Supporting Information).
(14) Enantioselectivities were determined by enantioselective HPLC
after benzolylation of ent-8; details are provided in the Experimental
Section and Supporting Information.
(15) Details are provided in the Experimental Section.
(16) Kaiser, N.-K. K.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. Angew. Chem., Int. Ed. 2000, 39, 3596−3598.
(17) (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104−
1105. (b) Palucki, M.; Um, J. M.; Conlon, D. A.; Yasuda, N.; Hughes,
D. L.; Mao, B.; Wang, J.; Reider, P. J. Adv. Synth. Catal. 2001, 343, 46−
50.
(18) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G.
E., Jr.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138−147.
(19) (a) Brown, E.; Deroye, C.; Touet, J. Tetrahedron: Asymmetry
1998, 9, 1605−1614. (b) Mitsui, K.; Sato, T.; Urabe, H.; Sato, F.
Angew. Chem., Int. Ed. 2004, 43, 490−492. (c) Gao, M.; Wang, D.-X.;
Zheng, Q.-Y.; Wang, M.-X. J. Org. Chem. 2006, 71, 9532−9535.
(20) Blanco, B.; Christensen, J.; Maurel, I.; Pleixats, R.; Serra, A.; Pla-
Quintana, A.; Roglans, A.; Benet-Buchholz, J. Synthesis 2005, 374−
380.
(c) Hirasawa, Y.; Tanaka, T.; Kobayashi, J.; Kawahara, N.; Goda, Y.;
Morita, H. Chem. Pharm. Bull. 2008, 56, 1473−1476. Serratine
(d) Inubushi, Y.; Tsuda, Y.; Ishii, H.; Sano, T.; Hosokawa, M.;
Harayama, T. Yakugaski Zasshi 1964, 84, 1108−1113.
(2) Chen, C.; Kozikowski, A. P.; Wood, P. L.; Reynolds, I. J.; Ball, R.
G.; Pang, Y. P. J. Med. Chem. 1992, 35, 1634−1638.
(3) Substructure searches for 1 (n = 0−2 and m = 0−2) in SciFinder
finds only 23 compounds for which an analysis criteria of biological
study or use is recorded; 19 of these are 8a-substituted
decahydroquinolines.
(4) Examples include moxifloxacin, which contains an octahydro-
pyrrolopyridine fragment, and ramipril, which contains a hexahy-
dropenta[b]pyrrole unit.
(5) For reports of the direct enantioselective construction of specific
angularly substituted 1-azacyclic molecules, see: (a) Trauner, D.;
Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38,
3542−3545. (b) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner,
D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38, 4450−4452.
(c) Aldous, D. J.; Drew, M. G. B.; Draffin, W. N.; Hamelin, E. M.-N.;
Harwood, L. M.; Thurairatnam, S. Synthesis 2005, 3271−3278.
(d) Reggelin, M.; Junker, B.; Heinrich, T.; Slavik, S.; Buhle, P. J.
̈
́
(21) (a) van Zijl, A. W.; Lopez, F.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2006, 128, 4023−4034. (e) Xu, S.; Arimoto, H.;
Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746−5749. (f) Keck, G.
E.; Heumann, S. A. Org. Lett. 2008, 10, 4783−4786. (g) Ranatunga, S.;
Del Valle, J. R. Tetrahedron Lett. 2009, 50, 2464−2466. (h) Sethofer, S.
G.; Mayer, T.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 8276−8277.
(i) Nama, K.; Inai, M.; Sundermeier, U.; Greshock, T. J.; Williams, R.
M. Tetrahedron Lett. 2010, 51, 6557−6559. (j) Fustero, S.; Mateu, N.;
Org. Chem. 2007, 72, 2558−2563. (b) The enantiomeric purity of 28
was determined by enantioselective HPLC analysis of the correspond-
ing primary alcohol obtained by an ozonolysis/reduction sequence.
(22) This reaction could be carried out also neat; however, because
the reaction is heterogeneous at this lower temperature, inconsistent
reaction times were observed.
(23) The configuration assigned to the side chain stereocenter of 40
is consistent with the expectation that it would be established in the
aza-Cope rearrangement step. This assignment is further supported by
́
Simon-Fuentes, A.; Acena, Luis J. Org. Lett. 2010, 12, 3014−3017.
̃
(k) Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegal, D. J. Am. Chem. Soc.
2010, 132, 5924−5925. Enantiomerically enriched angularly
substituted 1-azabicyclic molecules have been accessed also by
separation of a 1:1 mixtures of diastereomers or enantiomers, see:
(l) Kozikowski, A. P.; Chen, C. Tetrahedron 1990, 31, 5869−5872.
(m) Chen, C.; Kozikowski, A. P.; Wood, P. L.; Reynolds, I. J.; Ball, R.
G.; Pang, Y.-P. J. Med. Chem. 1992, 35, 1634−1638. (n) Verbist, B. M.
P.; De Borggraeve, W. M.; Toppet, S.; Compernolle, F.; Hoornaert, G.
J. Eur. J. Org. Chem. 2005, 2941−2950. (o) Meyer, U.; Bisel, P.;
Weckert, E.; Frahm, A. W. Chirality 2006, 18, 383−394. (p) Kopylova,
N. A.; Grygorenko, O. O.; Komarov, I. V.; Groth, U. Tetrahedron:
Asymmetry 2010, 21, 2868−2871.
1
a strong H NOE enhancement observed between C3a−H and the
methyl substituent of the side chain; The relative configuration of 40
was assigned by comparing the NOESY data to the lowest energy
conformation calculated using ab initio studies with DFT/B3LYP/6-
31G* as implemented in Spartan 2008.
(6) Aron, Z. D.; Overman, L. E. Org. Lett. 2005, 7, 913−916.
(7) For representative examples of selective bimolecular trapping of
one iminum ion isomer of a 2-aza-Cope rearrangement, see:
(a) Overman, L. E.; Yokomatsu, T. J. Org. Chem. 1980, 45, 5229−
5230. (b) Castelhano, A. L.; Krantz, A. J. Am. Chem. Soc. 1984, 106,
1877−1879. (c) Bennett, D. J.; Hamilton, N. M. Tetrahedron Lett.
2000, 41, 7961−7964.
(24) For recent representative applications, see: (a) Hanessian, S.;
Auzzas, L. Acc. Chem. Res. 2008, 41, 1241−1251. (b) Seebach, D.;
Gardiner, J. Acc. Chem. Res. 2008, 41, 1366−1375. (c) Newman, D. J.;
Cragg, G. M. J. Nat. Prod. 2012, 75, 311−335.
́
(25) Sayago, F. J.; Laborda, P.; Calaza, M. I.; Jimenez, A. I.; Cativiela,
(8) For a recent review of dynamic kinetic resolution, see: Pellissier,
H. Tetrahedron 2011, 67, 3769−3802.
C. Eur. J. Org. Chem. 2011, 2011−2028.
(26) For a review, see: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. Rev. 2007, 107, 5471−5569.
(9) Some of these studies were reported in a preliminary
communication, see: Ito, T.; Overman, L. E.; Wang, J. J. Am. Chem.
Soc. 2010, 132, 3272−3273.
(10) Previously prepared by alkylation of a gallium enolate of
cyclohexanone: (a) Usugi, S.; Yorimitsu, H.; Shinokubo, H.; Oshima,
K. Bull. Chem. Soc. Jpn. 2002, 75, 2049−2052. Or by trans-
esterification of commercially available methyl 2-oxocyclohexaneace-
tate: (b) Meidong, L.;Gu, Q.; He, Y.; Huang, W.Faming Zhuanli
Shenqing, CN 150049 A 20050105, 2005.
(11) The route utilized to prepare 11 is an optimization of previous
disclosures.6,9 TASF(Me) was found to promote the alkylation to
afford ketoester 11 in the highest efficiency. The use of CsF,
tetrabutylammonium diflurotriphenylstannate, tetrabutylammonium
difluorotriphenylsilicate, or benzyltrimethylammonium fluoride as
promoter afforded the product in lower yields (30%, 32%, 58%, and
60%, respectively).
(27) For example, Tanaka and Barbas have found that (R)-3-
pyrrolidinecarboxylic acid can efficiently catalyze a highly antiselective
Mannich reactions, see: (a) Zhang, H.; Mitsumori, S.; Utsumi, N.;
Imai, M.; Garcia-Delgado, N.; Mifsud, M.; Albertshofer, K.; Cheong, P.
H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2008, 130, 875−886. See also (b) Armstrong, A.; Bhonoah, Y.;
Colorless, A. J. P. J. Org. Chem. 2009, 74, 5041−5048.
(28) Isotopic analysis was performed using MassLynx mass
spectrometry software.
(29) In our initial report of these transformations in the racemic
series, we suggested on the basis of an experiment, which in hindsight
was potentially flawed, that the allylic iminium ion sigmatropic isomers
studied at that time were in equilibrium.6 As already noted, the high
chirality transfer observed in the substituted allyl series that is the
subject of this report rigorously establishes that the sigmatropic
isomers are not in equilibrium.
(12) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.;
Ohfune, Y. J. Org. Chem. 2005, 70, 3464−3471.
9947
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948

The Journal of Organic Chemistry
Article
(30) See the Supporting Information of ref 9 for a scheme detailing
all possible chair and boat transition structures for the 2-aza-Cope
rearrangement and the corresponding products produced.
(31) Enantiomers 47 and ent-47 exhibited baseline resolution in the
enantioselective HPLC separation used in this study, allowing us to
confidently say that less than 2% of ent-47 (more likely < 1%) was
formed. See the Supporting Information provided for ref 9.
(32) Wang, J. Ph.D. Dissertation, UC Irvine, Irvine, CA, 2011.
(33) van der Sluis, M.; Dalmolen, J.; de Lange, N.; Kaptein, B.;
Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3, 3943−3946.
(34) Kohno, K.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 322−
329.
(35) Cotarco, L.; Delogu, P.; Maggioni, P.; Nardelli, A.; Bianchini, R.;
Sguassero, S. Synthesis 1997, 328−332.
(36) Ocejo, M.; Carrillo, L.; Badía, D. J. Org. Chem. 2009, 74, 4404−
4407.
(37) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168−8179.
9948
dx.doi.org/10.1021/jo4018099 | J. Org. Chem. 2013, 78, 9929−9948