1,4-Diazaspiro[2.2]pentanes as a flexible platform for the synthesis of diamine-bearing stereotriads

Article abstract of DOI:10.1021/jo3000282

Nitrogen-containing stereotriads occur in a number of biologically active compounds, but general and flexible methods to access these compounds are limited mainly to the manipulation of chiral olefins. An alternative approach is to employ a highly chemo-, regio-, and stereocontrolled allene oxidation that can install a new carbon-heteroatom bond at each of the three original allene carbons. In this paper, an intramolecular/intermolecular allene bis-aziridination is described that offers the potential to serve as a key step for the construction of stereotriads containing vicinal diaminated motifs. The resultant 1,4-diazaspiro[2.2]pentane (DASP) scaffolds contain two electronically differentiated aziridines that undergo highly regioselective ring openings at C1 with a variety of heteroatom nucleophiles to give chiral N,N-aminals. Alternatively, the same DASP intermediate can be induced to undergo a double ring-opening reaction at both C1 and C3 to yield vicinal diaminated products corresponding to formal ring opening at C3. The chirality of a propargyl alcohol is easily transferred to the DASP with good fidelity, providing a new paradigm for the construction of enantioenriched nitrogen-containing stereotriads.

Full text of DOI:10.1021/jo3000282

Article
pubs.acs.org/joc
1,4-Diazaspiro[2.2]pentanes as a Flexible Platform for the Synthesis
of Diamine-Bearing Stereotriads
Jared W. Rigoli,† Luke A. Boralsky,† John C. Hershberger, Dagmara Marston, Alan R. Meis, Ilia A. Guzei,
and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: Nitrogen-containing stereotriads occur in a number
of biologically active compounds, but general and flexible
methods to access these compounds are limited mainly to the
manipulation of chiral olefins. An alternative approach is to
employ a highly chemo-, regio-, and stereocontrolled allene
oxidation that can install a new carbon−heteroatom bond at
each of the three original allene carbons. In this paper, an
intramolecular/intermolecular allene bis-aziridination is de-
scribed that offers the potential to serve as a key step for the construction of stereotriads containing vicinal diaminated motifs.
The resultant 1,4-diazaspiro[2.2]pentane (DASP) scaffolds contain two electronically differentiated aziridines that undergo
highly regioselective ring openings at C1 with a variety of heteroatom nucleophiles to give chiral N,N-aminals. Alternatively, the
same DASP intermediate can be induced to undergo a double ring-opening reaction at both C1 and C3 to yield vicinal
diaminated products corresponding to formal ring opening at C3. The chirality of a propargyl alcohol is easily transferred to the
DASP with good fidelity, providing a new paradigm for the construction of enantioenriched nitrogen-containing stereotriads.
suitably protected substituent at the allylic position. This can
inhibit the reactivity of the olefin or lead to mixtures of
regioisomers when two different heteroatoms are introduced.
Even in cases when regiocontrol is not an issue, problems with
stereochemical mismatching can lead to mixtures of diaster-
eoisomers that can be inconvenient to separate. Thus, methods
to directly oxidize all three carbons of an allene to generate
these complex nitrogen-containing stereotriads with good levels
of chemo-, regio- and diastereocontrol would be a valuable
addition to methodology centered on hydrocarbon oxidation.
We hypothesized that allenic carbamates of the form 1
(Scheme 1) could serve as flexible substrates to develop a
challenging, yet potentially powerful, approach to the rapid
preparation of chiral nitrogen-containing stereotriads. Our
group has demonstrated that the treatment of 1 with catalytic
amounts of Rh2esp2 (esp = α,α,α′,α′-tetramethyl-1,3-benzene-
dipropionic acid) or Rh2TPA4 (TPA = triphenylacetate) in the
presence of a hypervalent iodine oxidant yields the bicyclic
methyleneaziridines (MA) E-2a and Z-2b.5,6 The major isomer
is generally E-2a, although greater amounts of Z-2b can be
obtained if Rh2(OAc)4 is employed as the catalyst. Typically,
the minor amounts of Z-2b are easily separated from the
desired E-2a. If E-2a could be induced to undergo a second,
metal-free aziridination with N-aminophthalimide (PhthNNH2),
the resulting 1,4-diazaspiro[2.2]pentane (DASP) E-3a could
potentially undergo further ring opening at either C1 or C3 to
elaborate these reactive intermediates to diamine-containing
INTRODUCTION
■
Diamines are privileged synthetic motifs found in a host of bio-
logically active natural products and pharmaceuticals.1,2 These
compounds can be prepared with varying levels of chemo-,
regio-, and stereoselectivity, typically via diamination or
aziridination of an olefin.1 However, the generality of these
methods in terms of the substrate scope has often been problem-
atic, as some approaches work well only for terminal olefins or
those having a specific alkene geometry. In addition, the ring
opening of aziridines with nitrogen nucleophiles to access
vicinal diamines often suffers from reactivity and regioselectivity
issues.3
Many diamine-containing molecules contain additional
complexity that can be difficult to install using currently avail-
able synthetic methods. For example, several vicinal diamine-
containing pharmaceuticals contain an additional contiguous
oxygen-bearing chiral center (Figure 1).4 In order to employ
Figure 1. Examples of biologically active molecules containing a
C−N/C−N/C−O stereotriad.
standard olefin oxidation protocols to accomplish the construc-
tion of these stereotriads, the substrates are required to bear a
Received: January 14, 2012
Published: February 3, 2012
© 2012 American Chemical Society
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Scheme 1
stereotriads of the form 4a and 5a. In addition, if the second
aziridination and subsequent reactions of the DASP proved to
be highly stereoselective, then transformation of the corre-
sponding Z bicyclic MA Z-3b could be expected to yield motifs
such as 4b and 5b.
DASP formation. When the E isomer 7 (entry 2) was subjected
to the reaction conditions, a 72% yield of the DASP 7a was
obtained. The structure of 7a was determined unambiguously
by X-ray crystallography (see Supporting Information for fur-
ther details).
The introduction of multiple carbon−heteroatom bonds into
an allene is not a new concept, but it has been limited mainly
to the installation of C−O bonds. Pioneering studies by the
Crandall and Williams groups have demonstrated that bis-
epoxidation of an allene to a spirodiepoxide (SDE) can be
followed by elegant transformations of these highly reactive
intermediates to 1,2,3-trioxygenated triads and other motifs.7
More recently, the Williams group has greatly expanded the
usefulness of spirodiepoxides by showcasing how allene epoxi-
dation can be used in the synthesis of a number of complex
natural products, including epoxomicin, psymberin, pecteno-
toxin 4, and the erythronolides.7d−g However, the correspond-
ing aziridination chemistry was not explored, despite the potential
for facile access to densely functionalized and enantioenriched
vicinal diamines.
The additional valency of nitrogen as compared to oxygen
imbues DASPs with several advantageous features not available
to SDEs. Foremost is the potential to electronically differentiate
between the two aziridines to control the reactivity independent of
the substitution pattern of the allene. Regioselective ring
opening at either C1 or C3 of a single DASP E-3a or Z-3b
could then be achieved depending on the identity of these two
activating groups. Another beneficial feature of substituting the
oxygens of an SDE with nitrogen is that the additional valency
of N allows DASPs to be prepared using an intra/intermolecular
approach that enables excellent regiocontrol in the first
aziridination.
Examination of the X-ray crystal structure of 7a indicated
that the second aziridination occurred on the face of the
methyleneaziridine opposite that of the first aziridine, as would
be expected on steric grounds. The E configuration of 7 trans-
lated into a syn relationship between the C5H11 side chain and
the central C1−C2 bond in 7a. The reaction of the Z-MA 8
(entry 3) gave a different stereoisomeric product 8a in a poor
yield of 33%. The reason for the decreased reactivity of the
Z-methyleneaziridine compared to the E is not completely
clear. However, it is possible that the change from sp2 to sp3
geometry at C2 and C3 in the second aziridination event forces
unfavorable steric interactions between the proximal methylene
of the side chain and the nitrogen of the C1−C2 aziridine.
Nonetheless, the stereoselective nature of the reaction was
illustrated.9
t
Methyleneaziridines bearing a Bu or Ph(CH2)2 group
(entries 4 and 5) also gave even better yields of the desired
DASPs 9a and 10a. The relative configuration was established
based on analogy to the X-ray crystal structure of 7a. Since it
would be much more convenient to simply utilize the E:Z
mixtures of bicyclic MAs for the DASP formation, a 3.5:1 E:Z
mixture of 11 (entry 6) was attempted in the intermolecular
aziridination. The desired product 11a was obtained in 62% yield
based on the amount of E-methyleneaziridine present in the
mixture. No DASP product from the Z isomer was isolated.
Similarly, the DASPs 13a and 14a (entries 8 and 9) were obtained
as single stereoisomers when E:Z mixtures of the bicyclic
methyleneaziridines were employed as the starting substrates.
The much slower rate of DASP formation from the Z isomer
compared to the E MA isomer proved helpful in this regard.
However, if the DASP from the Z-methyleneaziridine (as in
12a, entry 7) is desired, it was best to separate the two isomers
prior to the second aziridination. In this manner, any unreacted
Z MA could be recovered and resubjected to the reaction
conditions. Finally, the trisubstituted bicyclic methyl-
eneaziridine 15 (entry 10) gave a lower yield of the DASP 15a,
likely due to steric hindrance. Nonetheless, this type of scaffold
RESULTS AND DISCUSSION
■
Treatment of the bicyclic methyleneaziridines 6−15 (Table 1)8
with PhthNNH2 and PhIO induced formation of the desired
DASPs 6a−15a in moderate to good yields in most cases.
Substitution in the carbamate linker did not greatly affect the
second aziridination event, as both the unsubstituted 6 and the
gem-dimethyl-substituted 7 gave similar yields of 6a and 7a
(entries 1 and 2). However, the olefin geometry of the MA was
crucial in determining the stereochemical outcome of the
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Table 1. Synthesis of 1,4-Diazaspiro[2.2]pentanes
a
b
c
Yield based on recovered E-methyleneaziridine. The starting material was the Z-methyleneaziridine. Yield based on the amount of E-methyl-
d
eneaziridine present in the mixture. Yield based on recovered Z-methyleneaziridine.
Scheme 2. Transfer of the Chirality of an Enantioenriched Propargyl Alcohol to a DASP
represents potential access to a quaternary nitrogen-bearing
stereocenter.
convenient alternative for the preparation of enantioenriched
stereotriads.11
With a suitable method in hand to prepare DASPs containing
two electronically differentiated aziridines, we set about
understanding how to induce regioselective ring opening at
both C1 and C3 with heteroatom-containing nucleophiles. Ring
opening at C1 to yield chiral N,N-aminals 4a,b (Scheme 1) was
examined first, as these motifs are found in a number of
biologically active natural products and pharmaceuticals that
exhibit promising anticancer, anti-inflammatory, antiplasmodial,
and anticholinesterase activities.12 Treatment of a series of
DASPs with weak nucleophiles gave exclusive ring opening at
the internal aziridine (C1 of the original allene). For example,
acetic acid opened the DASP 6a in 95% yield to give one
regioisomer 20 (Table 2, entry 1). The gem-dimethyl DASP 7a
gave only 21 (entry 2). For a DASP derived from the
A convenient aspect of allene oxidation is that the axial
chirality of the substrate can be potentially transferred to the
products in a diastereoselective process.7c The enantioenriched
propargyl alcohol 16 was prepared according to literature
procedure and converted to the allene 17 (Scheme 2).10 The
synthesis of the DASP 19 from the alcohol 16a resulted in no
degradation in the enantiopurity, and a simple recrystallization
enhanced the er to 96:4. The stereoselective nature of the
DASP formation ensured that the axial chirality of the original
allene could be transferred to the product with excellent fidelity.
The number of methods available for the synthesis of enantio-
enriched allenes, as well as the continued focus on the develop-
ment of new approaches, should render allene oxidation a
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Table 2. Synthesis of N,N-Aminals via Ring Opening at C1 of a 1,4-Diazaspiro[2.2]pentane
Table 3. One-Pot Synthesis of N,N-Spiroaminals from an Allenic Carbamate
a
Combined yield of the three individual steps.
Z-methyleneaziridine 12a (entry 4), reaction with acetic acid
gave an 85% yield of the equivalent ring-opened product 23.
The bulky pivalic acid was also successful and delivered the
N,N-aminal 24 in 80% yield (entry 5). The unsaturated tiglic
acid (entry 6) gave 25 in moderate yield. A new C−S bond
could be introduced into the N,N-aminal by treatment of 7a
with thioacetic acid to give 26 (entry 7) in 82% yield. Chloride
was also a good nucleophile, opening both DASPs 6a and 7a in
excellent yields using either LiCl or TMSCl as the halogen
source (entries 8 and 9) to yield 27 and 28. NaN3 successfully
opened the bicyclic methyleneaziridine, but a subsequent elimina-
tion event destroyed the newly formed chiral centers. Carbon-
based nucleophiles, such as malonates, were not sufficiently
nucleophilic to open the ring, while stronger Grignard reagents
and cuprates preferred to attack the phthalimide group. These
issues have been addressed by employing a sulfamate-based
nitrene precursor, which will be described in a future com-
munication.
We were pleased to find an allenic carbamate 29 could be
converted directly to functionalized N,N-aminals in one flask as
a single diastereomer (Table 3). Four new carbon−heteroatom
bonds and three chiral centers are generated in a stereoselective
fashion using operationally simple procedures under mild
reaction conditions. The yields were also increased significantly
in the one-pot reaction; for example, the yield of 21 (Table 3)
improved to 46%, compared to 33% for the three-step process.
As part of our initial design of the DASP scaffold, we
employed a Phth-protected aziridine to promote ring opening
at C1 and discourage competing ring opening at C3. How-
ever, it would be desirable to be capable of manipulating the
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protecting groups on the two aziridines such that ring opening
at either C1 or C3 could be accomplished. Unfortunately, all
attempts to aziridinate a bicyclic methyleneaziridine with
nitrene precursors other than N-aminophthalimide met with
limited success. This precluded the intermolecular installation
of an aziridine containing a more electron-withdrawing group
to direct ring opening to C3 (5a in Scheme 1). While one
possible solution would be to introduce additional substitution
in the allene to minimize subsequent ring opening of the DASP
at C1, this would limit the flexibility of the method. Thus, we
opted to implement a double nucleophilic ring opening as the
best way to achieve a formal ring opening at C3 (eq 1).
CONCLUSION
■
The intra/intermolecular bis-aziridination of a series of allenic
carbamates to an unusual heterocyclic ring system, the 1,4-
diazaspiro[2.2]pentane, was demonstrated for the first time.
The ability to electronically differentiate the two aziridine rings
of the DASPs enabled regioselective ring opening at the
terminal carbon of either aziridine depending on the reaction
conditions. As the chirality from a propargyl alcohol could be
transferred to all three of the new carbon−heteroatom bonds to
yield an enantioenriched DASP, these strained rings represent
useful scaffolds for the preparation of a diverse range of func-
tionalized, enantioenriched vicinal diamines. Future work will
focus on the expansion of the substrate scope, the identification
of other nitrene precursors, and further manipulations of the
ketones/imines resulting from ring opening at both C1 and C3
of the DASP.
EXPERIMENTAL SECTION
■
General Methods. All glassware were either oven-dried overnight
at 130 °C or flame-dried under a stream of dry nitrogen prior to use.
Unless otherwise specified, reagents were used as obtained from the
vendor without further purification. Tetrahydrofuran and diethyl ether
were freshly distilled from purple Na/benzophenone ketyl. Dichloro-
methane, acetonitrile, and toluene were dried over CaH2 and freshly
distilled prior to use. All other solvents were purified in accordance
with “Purification of Laboratory Chemicals”.13 Air- and moisture-
sensitive reactions were performed either in a glovebox under an
atmosphere of nitrogen or using standard Schlenk techniques under an
atmosphere of nitrogen. Analytical thin layer chromatography (TLC)
was performed utilizing precoated silica gel 60 F254 plates containing a
fluorescent indicator, while preparative chromatography was per-
formed using silica gel (230−400 mesh) via Still’s method.14 Unless
otherwise stated, the mobile phases for column chromatography were
mixtures of hexanes/ethyl acetate. Columns were typically run using a
gradient method, beginning with 100 mL of 100% hexanes, then
progressing to 100 mL of 9:1 hexane/EtOAc, 3:1 hexane/EtOAc, 2:1
hexane/EtOAc, and 1:1 hexane/EtOAc. If necessary, the column was
continued using 1:2 hexane/EtOAc and then 100% EtOAc until all of
the products had been eluted from the column. Various stains were
used to visualize reaction products, including p-anisaldehyde, KMnO4,
ceric ammonium nitrate, and phosphomolybdic acid in ethanol stain.
Unless otherwise stated, rt refers to temperatures between 21 and
23 °C. 1H NMR and 13C NMR spectra were obtained using either 300
Treatment of 2a (Table 4, entry 1) with 6 equiv of TMSBr,
followed by direct loading of the reaction mixture onto a silica
Table 4. Directing the Nucleophilic Ring Opening of the
DASP to C3
1
or 500 MHz NMR spectrometers. For H NMR, chemical shifts are
reported relative to residual protiated solvent peaks (δ 7.26, 2.49, 7.15,
and 4.80 ppm for CDCl3, (CD3)2SO, C6D6, and CD3OD, res-
pectively). 13C NMR spectra were measured at either 125 or 150 MHz
1
on the same instruments noted above for recording H NMR spectra.
a
Methanol was substituted for THF as the solvent for the reaction.
Chemical shifts were again reported in accordance to residual pro-
tiated solvent peaks (δ 77.0, 39.5, 128.0, and 49.0 ppm for CDCl3,
(CD3)2SO, C6D6, and CD3OD, respectively). IR spectral data were
obtained using either a thin film or an ATR adapter. High-pressure
liquid chromatography (HPLC) analyses were performed at 224 and
254 nm using an AD-H column (4.6 μm diameter × 258 mm) at a
temperature of 40 °C, using a flow rate of 1 mL/min and a gradient
starting at 10% isopropyl alcohol in hexanes for 10 min and increasing
to 30% isopropyl alcohol in hexanes. The eluant was then held at 30%
isopropyl alcohol in hexanes until the run was completed. Accurate
mass measurements were acquired by high-resolution mass spectrom-
etry utilizing electrospray ionization, time-of-flight analyzer, or electron
impact methods.
General Procedure for Preparation of 1,4-Diazaspiro[2.2]-
pentanes. The bicyclic methyleneaziridines 6−10 and 13−15 were
prepared as described in the literature.5a,b If necessary, the E and
Z bicyclic methyleneaziridines were separated by column chromatog-
raphy before initiating the DASP formation. The general procedure
uses 1.0 mmol of substrate as a standard amount; however, reactions
gel column, resulted in formation of the expected N,N-aminal
product 30 in 89% yield. A minor amount of the desired
stereotriad 31 was also observed. The second ring opening at
C3 could be pushed to completion by slow concentration of the
reaction mixture at 40 °C prior to purification, giving a 59%
yield of a single diastereomer proposed as 31 (entry 2). Indeed,
treatment of the likely intermediate 30 with additional TMSBr
under more concentrated conditions also yielded 31 as the
major product. Poorer leaving groups, including acetate (Table 4,
entry 3), could also function for ring opening at C3, albeit with
some epimerization at C3 to give 32a and 32b. This ability to
control the regioselectivity of the ring opening of DASPs is a
promising approach to access a range of diverse stereotriads
from the same core allenic carbamate substrate.
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were run at many different scales, and the total amount of isolated
product is reported for each compound. A solution of the methyl-
eneaziridine (1.0 mmol, 1.0 equiv) in 10 mL of dry dichloromethane
was cooled to 0 °C and treated with N-aminophthalimide (1.5 mmol,
1.5 equiv) and dry potassium carbonate (3.5 mmol, 3.5 equiv),
followed by PhI(OAc)2 or PhIO as the oxidant (1.6 mmol, 1.6 equiv).
The resulting light yellow slurry was allowed to warm slowly to rt and
monitored carefully by TLC. In some cases, the DASP product was
sensitive to ring opening by acetate and it was best to stop the reaction
when conversion of the methyleneaziridine to the DASP stalled. When
reaction was complete, the dichloromethane was removed under
reduced pressure on a vacuum line, the residue was diluted with dry
Et2O, and the organics were decanted. The residual salts were washed
two more times with Et2O and the volatiles removed under reduced
pressure on a vacuum line. A silica gel column was packed using
99.5:0.5 hexanes/triethylamine, followed by flushing with four column
volumes of hexanes prior to loading the sample onto the column to
improve the separation and prevent the decomposition of sensitive
DASPs. The residue was loaded onto the column and eluted using a
hexanes/ethyl acetate gradient (see General Information for amounts
of solvent). Phenyl iodide eluted first from the column, followed by
unreacted MA (if present), then the desired 1,4-diazaspiro[2.2]-
pentane(s) and, finally, N-aminophthalimide/hydrolysis products and/
or products arising from DASP ring opening. The DASPs were stored
in a freezer at −20 °C. It was best to run any NMRs in deuterated
benzene if the sample was to be recovered, as any residual acid in the
CDCl3 caused decomposition of the product.
(E)-2-(2′-Oxo-3-pentyl-1H-spiro[aziridine-2,7′-[3]oxa[1]-
azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione (6a).
The E-methyleneaziridine 6 was utilized as the starting material.5a,b
The product 6a (149.5 mg) was obtained in 58% yield after column
chromatography as a single diastereomer; the yield based on recovered
starting material was 65%. The material was obtained as a light yellow
solid: mp 143−144 °C; IR 2959, 2858, 1736, 1714, 1465, 1378, 1246,
1226, 1196, 1143 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.75−7.65 (Ar,
4H), 4.56 (dd, 1H, J = 11.0, 1.2 Hz), 4.46 (dd, 1H, J = 5.4, 4.8 Hz),
3.93 (2 overlapping signals, 2H), 2.46 (m, 1H), 2.03−1.08 (several
signals, 9H), 0.86 (t, 3H, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) δ
165.3, 157.7, 134.3, 130.8, 123.5, 68.8, 66.9, 45.9, 42.2, 31.8, 29.6, 26.1,
22.8, 22.7, 14.2. The NMRs pictured in the Supporting Information
were run in C6D6: 1H NMR (500 MHz, C6D6) δ 7.21, 7.20
(Ar, AA′BB′ pattern, 2H), 6.62, 6.61 (Ar, AA′BB′ pattern, 2H), 4.28
(dd, 1H, J = 5.9, 5.9 Hz), 3.52−3.46 (2 overlapping signals, 2H), 3.36
(ddd, 1H, J = 10.9, 4.0, 1.9 Hz), 1.66−1.60 (overlapping signals, 4H
total), 1.39−1.28 (br m, 4H total), 1.05 (dd, 1H, J = 14.0, 6.5 Hz), 0.9
(t, 3H, J = 6.5 Hz), 0.8 (overlapping m, 1H); 13C NMR (125 MHz,
C6D6) δ 165.1, 157.1, 133.4, 130.9, 122.8, 68.0, 67.0, 45.5, 41.9, 31.9,
29.5, 26.2, 22.8, 22.3, 14.2; HRMS (ESI) m/z calcd for C19H21N3O4Na
[M + Na]+ 378.1425, found 378.1421.
(E)-2-(3-Pentyl-5′,5′-dimethyl-2′-oxo-1H-spiro[aziridine-2,7′-[3]-
oxa[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione
(7a). The product (582.4 mg) was obtained as a single diastereomer in
72% yield using PhIO as the oxidant and the E-methyleneaziridine 7 as
the substrate. The compound was a white solid: mp 101−102 °C; IR
2953, 2932, 2859, 1736, 1472, 1374, 1297, 1232, 1208, 1126, 1100 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.77, 7.76 (Ar, AA′BB′ pattern, 2H),
7.69, 7.68 (Ar, AA′BB′ pattern, 2H), 4.34 (d, 1H, J = 10.6 Hz), 4.11
(dd, 1H, J = 9.2, 3.5 Hz), 3.79 (d, 1H, J = 11.3 Hz), 3.66 (s, 1H), 1.92
(m, 1H), 1.86−1.79 (br m, 2H), 1.58−1.22 (overlapping signals, 5H
total), 1.29 (s, 3H), 0.93 (s, 3H), 0.90 (t, 3H, J = 7.2 Hz); 13C NMR
(125 MHz, CDCl3) δ 165.2, 157.5, 134.1, 130.5, 123.2, 78.0,
65.0, 51.1, 46.0, 31.6, 31.2, 29.6, 25.8, 24.0, 22.5, 21.0, 14.0; HRMS
(ESI) m/z calcd for C21H26N3O4 [M + H]+ 384.1918, found 384.1926.
(Z)-2-(3-Pentyl-5′,5′-dimethyl-2′-oxo-1H-spiro[aziridine-2,7′-[3]-
oxa[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione
(8a). The compound was obtained as a white solid in 33% yield as a
single diastereomer using PhIO as the oxidant and the Z-methyl-
eneaziridine 8 as the substrate. The remainder of the mass balance was
unreacted starting material, but the addition of additional aliquots
of PhthNNH2 and PhIO did not push the reaction to completion: IR
2959, 2932, 2859, 1736, 1472, 1374, 1297, 1232, 1208, 1126,
1
1100 cm−1; H NMR (500 MHz, CDCl3) δ 7.82, 7.81 (Ar, AA′BB′
pattern, 2H), 7.75, 7.74 (Ar, AA′BB′ pattern, 2H), 4.31 (d, J = 12.0 Hz,
1H), 3.87−3.83 (m(overlapping signals), 2H), 3.33 (s, 1H), 2.18−1.99
(m, 2H), 1.77−1.59 (m, 2H), 1.43−1.33 (m, 3H), 1.26−1.22 (m(over-
lapping signals), 4H), 1.05 (s, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 165.6, 155.8, 134.4, 130.2, 123.4, 77.6, 63.3, 48.7,
48.6, 31.5, 29.4, 29.2, 26.7, 24.0, 22.4, 19.9, 14.0; HRMS (ESI) m/z
calcd for C21H25N3O4Na [M + Na]+ 406.1738, found 406.1744.
(E)-2-(3-tert-Butyl-2′-oxo-1H-spiro[aziridine-2,7′-[3]oxa[1]-
azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione (9a). The
product (158.8 mg) was obtained in 79% yield: mp 174−176 °C; IR
2964, 2927, 2856, 1776, 1718, 1470, 1367, 1251, 1218, 1189, 1148,
1
1134 cm−1; H NMR (500 MHz, CDCl3) δ 7.77, 7.76 (Ar, AA′BB′
pattern, 2H), 7.69, 7.68 (Ar, AA′BB′ pattern, 2H), 4.60 (app td, J =
11.3, 2.1 Hz, 1H), 4.40 (ddd, J = 10.6, 4.7, 1.7 Hz, 1H), 3.97
(overlapping signals, 2H total), 2.50 (dddd, J = 14.9, 6.8, 2.6, 2.1 Hz,
1H), 1.72 (m, 1H), 1.14 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
165.1, 157.5, 134.0, 130.5, 123.1, 68.4, 65.5, 53.6, 42.2, 31.3, 27.1, 23.8;
HRMS (ESI) m/z calcd for C18H20N3O4 [M + H+] 342.1449, found
342.1451.
(E)-2-[2′-Oxo-3-(2-phenylethyl)-1H-spiro[aziridine-2,7′-[3]oxa[1]-
azabicyclo[4.1.0]heptan]-1-yl]-1H-isoindole-1,3(2H)-dione (10a).
The product (103.0 mg) was obtained in 75% yield as a yellow oil:
1
IR 2955, 2926, 2857, 1737, 1716, 1372, 1251, 1147 cm−1; H NMR
(500 MHz, CDCl3) δ 7.79, 7.78 (Ar, AA′BB′ pattern, 2H), 7.69, 7.68
(Ar, AA′BB′ pattern, 2H), 7.33−7.29 (Ar, m, 2H), 7.26−7.19 (Ar, m,
3H), 4.50 (app td, J = 11.6, 2.4 Hz, 1H), 4.25 (ddd, J = 11.6, 4.0, 2.2 Hz,
1H), 4.00 (dd, J = 6.2, 6.2 Hz, 1H), 3.84 (dd, J = 8.7, 7.1 Hz, 1H), 3.05
(m, 2H), 2.19 (overlapping signals, 3H total), 1.09 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 165.1, 157.2, 141.0, 134.1, 130.5, 128.7, 128.5,
126.2, 123.2, 68.5, 66.5, 45.4, 41.8, 32.7, 31.8, 21.6; HRMS (ESI) m/z
calcd for C22H20O4N3 [M + H+] 390.1449, found 390.1463.
(E)-6-(Benzyloxy)-2,2-dimethylhexa-3,4-dien-1-yl carbamate. The
precursor for compound 11 was prepared in the following manner. The
corresponding homoallenic alcohol (524.3 mg, 2.26 mmol, 1.0 equiv)
was dissolved in 9.0 mL of CH2Cl2 and cooled to 0 °C. To this was
added dropwise trichloroacetyl isocyanate (350 μL, 2.9 mmol,
1.3 equiv) at 0 °C and warmed to rt. After approximately 1 h, the
solvent was removed via rotary evaporation and redissolved in 6 mL of
MeOH. To this was added K2CO3 (78.0 mg, 0.56 mmol, 0.25 equiv)
in one portion. After TLC indicated complete consumption of starting
material, the reaction mixture was quenched with saturated NH4Cl,
extracted with three portions of CH2Cl2, washed with brined, dried
over MgSO4, and concentrated under reduced pressure. The crude
material was purified via flash column chromatography to afford the
carbamate in 91% yield (565.6 mg) as a thick, clear oil: IR 2973, 1963,
1
1708, 1601, 1405, 1380, 1331 cm−1; H NMR (500 MHz, CDCl3) δ
7.35−7.34 (Ar, 4H), 7.29 (ddd, J = 8.5, 4.1, 1.0 Hz, 1H), 5.37 (dd, J =
13.2, 6.8 Hz, 1H), 5.21 (ddd, J = 6.3, 2.5, 2.2 Hz, 1H), 4.54
(overlapping signals, 4H), 4.06 (dd, J = 6.8, 2.3 Hz, 2H), 3.87 (AB
quartet, J = 10.4, 2H), 1.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
203.6, 156.9, 138.2, 128.4, 127.8, 127.6, 99.3, 90.8, 72.8, 71.8, 68.5,
35.5, 24.9, 24.8; HRMS (ESI) m/z calcd for C16H21NO3 [M+]
276.1595, found 276.1606.
(E)-7-[2-(Benzyloxy)ethylidene]-5,5-dimethyl-3-oxa-1-azabicyclo-
[4.1.0]heptan-2-one (11). Dry CH2Cl2 (12 mL) was added to a flask
containing 3 Å molecular sieves (0.5 g) and Rh2esp2 (0.022 g, 0.029 mmol,
0.027 equiv). The material prepared above (0.300 g, 1.08 mmol,
1.0 equiv) was added, and the reaction mixture was stirred for 10 min.
PhIO (0.660 g, 3.0 mmol, 2.8 equiv) was then added in one portion,
and the reaction was stirred vigorously until the starting material was
consumed. The mixture was filtered through a silica gel pad and
washed several times with EtOAc. The filtrate was concentrated under
reduced pressure, and the crude material indicated a 1:1 ratio of the
1
E:Z olefin isomers by H NMR. The crude material was purified via
flash column chromatography through silica gel pretreated with 0.5%
triethylamine to obtain 11 in 80% yield (0.236 g) as a clear oil: IR
2882, 1731, 1472, 1454, 1373, 1309, 1208, 1118 cm−1. The 1H and 13
C
NMR spectra in the Supporting Information reflect an E:Z isomer
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1
ratio of approximately 1:0.6 (isomer A = E, isomer B = Z): H NMR
(500 MHz, C6D6) δ 7.35−7.07 (isomer A + B, m, 8H), 5.66 (isomer A,
ddd, J = 6.7, 5.7, 0.9 Hz, 1H), 5.39 (isomer B, ddd, J = 8.2, 6.6,
0.5 Hz, 0.6H), 4.72 (isomer B, dd, J = 11.7, 7.9 Hz, 0.6H), 4.51
(isomer B, dd, J = 12.0, 6.1 Hz, 0.6H), 4.45 (isomer B, AB quartet, J =
11.8 Hz, 1.2H), 4.21 (isomer A, AB quartet, J = 11.8 Hz, 2H), 3.73
(isomer A, d, J = 5.5 Hz, 2H), 3.54 (isomer A, d, J = 10.7 Hz, 1H),
3.47 (isomer B, d, J = 10.5 Hz, 0.6 H), 3.16 (isomer A, d, J = 10.7 Hz,
1H), 3.13 (isomer B, J = 10.7 Hz, 0.6H), 2.59 (isomer A, 1H), 2.50
(isomer B, 0.6H), 0.53 (isomer A, 3H), 0.44−0.39 (isomer A + B, m,
6.6H); 13C NMR (125 MHz, C6D6) δ 154.3, 154.0, 138.9, 138.3,
128.3, 128.2, 128.2, 128.0, 127.6, 127.3, 126.6, 126.1, 101.3, 99.8, 77.2,
76.7, 72.2, 72.1, 66.8, 66.3, 47.9, 47.7, 28.6, 28.2, 22.8, 22.8, 19.8, 19.7;
HRMS (ESI) m/z calcd for C16H20NO3 [M + H+] 274.1438, found
274.1426.
50% EtOAc in hexanes to give 12 in 86% yield (0.39 g) as a 36% yield
of a mixture of E:Z and 50% isolated as the pure Z isomer as a thick
oil: IR 2981, 1726, 1376, 1336, 1296, 1209, 1184, 1128, 1108 cm−1.
Z isomer: 1H NMR (300 MHz, C6D6) δ 5.40 (t, J = 7.4 Hz, 1H), 3.91
(q, J = 7.2 Hz, 2H), 3.65 (dd, J = 18.1, 7.2 Hz, 1H), 3.55 (dd J =
18.1 Hz, 1H), 3.42 (d, J = 10.6 Hz, 1H), 3.13 (d, J = 10.6 Hz, 1H),
2.47 (s, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.49 (s, 3H), 0.37 (s, 3H); 13C
NMR (125 MHz, C6D6) δ 171.3, 154.8, 126.9, 97.3, 60.9, 49.0, 33.1,
28.9, 23.5, 20.6, 14.5; HRMS (ESI) m/z calcd for C12H17NO4Na
[M + Na]+ 262.1050, found 262.1050.
(Z)-Ethyl-[1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5′,5′-di-
methyl-2′-oxospiro[aziridine-2,7′ [3]oxa[1]azabicyclo[4.1.0]-
heptan]-3-yl]acetate (12a). The compound was obtained in 42%
yield (70.1 mg) as a single diastereomer using PhIO as the oxidant and
the Z-methyleneaziridine 12 as the substrate (there was a small amount of
contamination from remaining PhtNNH2). The remainder of the
mass balance was unreacted starting material, and the yield based on
recovered starting material was 58%. The material was an off-white
solid: mp 51−52 °C; 1H NMR (300 MHz, CDCl3) δ 7.82, 7.81
(Ar, AA′BB′ pattern, 2H), 7.75, 7.74 (Ar, AA′BB′ pattern, 2H), 4.33
(d, J = 10.5 Hz, 1H), 4.26 (t, J = 6.6 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H),
3.88 (d, J = 10.5 Hz, 1H), 3.38 (s, 1H), 3.35 (dd, J = 18.0, 6.6 Hz, 1H),
3.12 (dd, J = 18.0, 6.6 Hz, 1H), 1.27 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H),
1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.8, 165.7, 156.3,
134.7, 130.3, 123.7, 78.1, 62.2, 61.3, 49.5, 43.4, 34.8, 29.8, 24.4, 20.1,
14.3; HRMS (ESI) m/z calcd for C20H21O6N3Na [M + Na]+
422.1323, found 422.1323.
(E)-2-{3-[(Benzyloxy)methyl]-5′,5′-dimethyl-2′-oxo-1H-spiro-
[aziridine-2,7′-[3]oxa[1]azabicyclo[4.1.0]heptan]-1-yl}-1H-isoin-
dole-1,3(2H)-dione (11a). A 3.5:1 E:Z ratio of the methyleneaziridine
11 was utilized as the starting material. The product (36.2 mg) was
obtained in 62% isolated yield (based on the amount of 11 present in
1
the starting material) as a white solid: mp 105−107 °C; H NMR
(500 MHz, CDCl3) δ 7.74, 7.73 (Ar, AA′BB′ pattern, 2H), 7.69, 7.68
(Ar, AA′BB′ pattern, 2H), 7.36−7.29 (m, 5H), 4.72 (d, J = 11.8 Hz,
1H), 4.61 (d, J = 11.6 Hz, 1H), 4.36 (d, J = 10.4 Hz, 1H), 4.25 (dd, J =
3.8, 3.6 Hz, 1H), 4.16 (dd, J = 11.5, 3.1 Hz, 1H), 3.93 (dd, J = 11.7,
3.7 Hz, 1H), 3.82 (d, J = 10.5 Hz, 1H), 3.70 (s, 1H), 1.23 (s, 3H), 0.93
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.1, 157.5, 137.4, 134.1,
130.6, 128.4, 127.9, 127.9, 123.3, 78.2, 73.6, 66.5, 63.0, 50.9, 44.9, 29.7,
23.7, 19.7; HRMS (ESI) m/z calcd for C24H24N3O5 [M + H+]
434.1711, found 434.1703.
(E)-2-(4′-Methyl-2′-oxo-3-pentyl-1H-spiro[aziridine-2,7′-[3]oxa-
[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione (13a).
The product was obtained in 79% yield (120.5 mg) based on the amount
of 13 present in the starting material as a white solid: mp 143−144 °C;
Ethyl 7-(carbamoyloxy)-6,6-dimethylhepta-3,4-dienoate. The
precursor for 12 was prepared in the following manner. Chlorosulfonyl
isocyanate (10.8 mmol, 1.5 equiv) was dissolved in dry CH2Cl2 (25 mL)
and placed in an ice bath. The homoallenic alcohol (1.43 g, 7.2 mmol,
1.0 equiv) was then added slowly over 20 min. Once the addition was
complete, the ice bath was removed and the reaction mixture was
stirred at rt until the starting material was consumed by TLC. The
reaction was then placed in an ice bath, and THF (6 mL) and water
(3 mL) were added to the reaction. The vessel was fitted with a reflux
condenser and refluxed until TLC indicated the reaction was com-
plete. Brine (50 mL) was added to the reaction mixture, and the
solution was extracted with CH2Cl2 (2 × 50 mL) and dried with
Mg2SO4, and the solvents were removed under reduced pressure. The
residue was subjected to silica gel chromatography (100 mL portions
of 0−50% EtOAc in hexanes gradient increased in increments of 10%)
to give the product in 87% yield (1.38 g) as a clear oil: IR 2978, 1723,
1604, 1404, 1379, 1330, 1259, 1161 cm−1; 1H NMR (300 MHz,
CDCl3) δ 5.34 (m, 1H), 5.17 (m, 1H), 4.83 (br, 2H), 4.16 (q, J =
7.3 Hz, 2H), 3.86 (s, 2H), 3.02 (dd, J = 7.0, 2.8 Hz, 2H), 1.27 (t, J =
7.3 Hz, 3H), 1.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 203.8,
171.73, 157.3, 99.7, 86.5, 72.8, 61.0, 35.8, 35.4, 25.0, 24.8, 14.4; HRMS
(ESI) m/z calcd for C12H19NO4Na [M + Na]+ 264.1207, found
264.1214.
(Z)-Ethyl 3-(5,5-dimethyl-2-oxo-3-oxa-1-azabicyclo[4.1.0]hept-7-
ylidene)propanoate (12). Dry CH2Cl2 (20 mL) was added to a flask
that containing 4 Å molecular sieves (1.5 g) and Rh2(esp)2 (0.062 mmol,
0.03 equiv). The material prepared above (0.46 g, 2.07 mmol, 1 equiv)
was added, and the reaction mixture was stirred for 10 min. PhIO
(4.14 mmol, 2 equiv) was then added in one portion, and the reaction
was stirred vigorously until the starting material was consumed by
TLC. The mixture was filtered through a silica gel pad and washed
several times with EtOAc. The filtrate was then concentrated under
reduced pressure. Crude NMR indicated a ratio of 1:2.8 of the E:Z
olefin isomers. The crude material was purified by silica gel
chromatography (the column was pretreated with 1% triethylamine
in hexanes). A gradient of 0−20% EtOAc in hexanes was used,
increasing the more polar component by increments of 10%. The
column was eluted with 80/20 hexanes/ethyl acetate until the green
band corresponding to Rh2(esp)2 was collected. The polarity of the
eluant was then increased to 20% ethyl acetate and slowly increased to
1
IR 2914, 1720, 1352, 1283, 1245, 1143 cm−1; H NMR (500 MHz,
CDCl3) δ 7.77, 7.76 (Ar, AA′BB′ pattern, 2H), 7.69, 7.68 (Ar, AA′BB′
pattern, 2H), 4.77 (m, 1H), 3.94 (dd, J = 7.0, 4.4 Hz, 1H), 3.86 (dd,
J = 9.3, 7.0 Hz, 1H), 2.45 (ddd, J = 14.4, 6.0, 2.1 Hz, 1H), 1.95−1.88
(m, 1H), 1.78−1.67 (overlapping signals, 3H total), 1.42−1.27
(m, 8H), 0.92 (t, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
165.0, 157.9, 134.0, 130.5, 123.1, 76.7, 66.9, 45.5, 41.4, 31.5, 29.4, 29.2,
25.8, 22.4, 20.6, 13.9; HRMS (ESI) m/z calcd for C20H23N3O4Na
[M + Na+] 392.1581, found 392.1586.
(E)-2-(4′,4′-Dimethyl-2′-oxo-3-pentyl-1H-spiro[aziridine-2,7′-[3]-
oxa[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione
(14a). The product was obtained in 58% yield (125.3 mg) based on
the amount of 14 present in the starting material as a white solid: mp
1
125−126 °C; H NMR (500 MHz, CDCl3) δ 7.77, 7.76 (Ar, AA′BB′
pattern, 2H), 7.69, 7.68 (Ar, AA′BB′ pattern, 2H), 3.93 (dd, J = 7.8,
4.2 Hz, 1H), 3.83 (dd, J = 9.1, 6.8 Hz, 1H), 2.31 (dd, J = 14.9, 7.1 Hz,
1H), 1.94−1.89 (m, 1H), 1.73−1.67 (m, 3H), 1.64 (s, 3H), 1.58−1.20
(m, 8H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
167.7, 160.5, 136.7, 133.3, 125.9, 87.2, 70.8, 48.2, 42.7, 35.6, 34.3, 32.4,
32.0, 32.0, 28.6, 27.8, 25.1, 16.7; HRMS (ESI) m/z calcd for
C21H25N3O4Na [M + Na+] 406.1738, found 406.1730.
(E)-2-(6′-Methyl-2′-oxo-3-pentyl-1H-spiro[aziridine-2,7′-[3]oxa-
[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione (15a).
The product was obtained in 46% yield (53.5 mg) as an off-white,
mushy solid: mp 27−30 °C; IR 2955, 2930, 2859, 1719, 1467, 1374,
1
1277, 1246, 1185, 1158 cm−1; H NMR (500 MHz, CDCl3) δ 7.77,
7.76 (Ar, AA′BB′ pattern, 2H), 7.69, 7.68 (Ar, AA′BB′ pattern, 2H),
4.59 (ddd, J = 14.2, 11.4, 1.8 Hz, 1H), 4.38 (ddd, J = 11.4, 3.8, 2.6 Hz,
1H), 3.96 (dd, J = 7.0, 4.6 Hz, 1H), 2.14 (ddd, J = 15.0, 3.4, 2.0 Hz,
1H), 2.00 (s, 3H), 1.95−1.90 (m, 1H), 1.74−1.65 (m, 4H), 1.42−1.34
(m, 4H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
165.3, 158.0, 134.0, 130.4, 123.1, 71.3, 67.4, 48.8, 46.1, 31.6, 29.3, 29.3,
25.7, 22.4, 18.2, 13.9; HRMS (ESI) m/z calcd for C20H23N3O4Na
[M + Na+] 392.1581, found 392.1570.
(E)-2-(3-Pentyl-5′,5′-dimethyl-2′-oxo-1H-spiro[aziridine-2,7′-[3]-
oxa[1]azabicyclo[4.1.0]heptan]-1-yl)-1H-isoindole-1,3(2H)-dione
(19). The enantioenriched propargyl alcohol 16 was prepared accord-
ing to literature procedure.9 The same procedure previously reported
for the synthesis of racemic 17 was used to prepare the enantioenriched
sample. High-pressure liquid chromatography (HPLC) analyses were
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performed at 224 and 254 nm. An AD-H column (4.6 μm diameter ×
258 mm) at a temperature of 40 °C was employed, using a flow rate of
1 mL/min and a gradient starting at 10% isopropyl alcohol in hexanes
for 10 min and increasing to 30% isopropyl alcohol in hexanes. The
eluant was then held at 30% isopropyl alcohol in hexanes until the run
was completed. For the recrystallized 19, the HPLC run was started at
5% isopropyl alcohol in hexanes. The er of 16a was determined to be
88:12 by synthesizing the ester using (S)-(−)-α-methoxy-α-
(trifluoromethyl)phenyl acetic acid and measuring the ratio of the
resulting diastereomers.
General Procedure for Acetic Acid DASP Ring Openings. The
DASP was dissolved in enough THF to prepare a 0.1 M solution and
cooled to 0 °C. Glacial acetic acid (50.0 equiv) was added dropwise to
the reaction mixture over 2 min, ensuring that the reaction
temperature remained at 0 °C. The reaction was warmed to room
temperature and monitored by TLC until complete (3−10 h). After
consumption of the starting material, the reaction mixture was concen-
trated under reduced pressure and purified via column chromatog-
raphy (hexanes/ethyl acetate gradient; see General Information for the
amounts) to afford the desired ring-opened DASPs.
(E)-1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-2-pentyl-6-
oxa-1,4-diazaspiro[2.6]non-9-yl acetate (20). The ring-opened
DASP 20 was obtained in 95% yield as an off-white solid (86.9 mg):
1H NMR (500 MHz, C6D6) δ 7.83, 7.82 (Ar, AA′BB′ pattern, 2H), 7.76,
7.75 (Ar, AA′BB′ pattern, 2H), 7.28 (NH, 1H), 4.35 (dt, J = 11.1, 4.3 Hz,
1H), 4.22 (app t, J = 11.9 Hz, 1H), 3.64 (dd, J = 11.9, 5.1 Hz, 1H), 3.59
(dd, J = 6.0, 6.0 Hz, 1H), 2.09−2.04 (m, 1H), 1.98 (s, 3H), 1.93−1.68 (m,
5H), 1.43−1.36 (m, 4H), 0.93 (t, J = 7.7 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.0, 165.9, 153.7, 134.5, 130.0, 123.5, 74.9, 65.1, 53.9, 53.6,
31.5, 28.6, 26.2, 23.9, 22.4, 20.8, 14.0; HRMS (ESI) m/z calcd for
C21H26N3O6 [M + H+] 416.1817, found 416.1821.
(1.5 mL), and pivalic acid (1.3 mmol, 10 equiv) was added. The
reaction was stirred until complete by TLC (∼72 h). The reaction was
quenched with a saturated solution of NaHCO3 (15 mL) and extracted
with EtOAc (3 × 15 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel chromatog-
raphy (gradient 0−100% EtOAc in hexanes in increments of 20%) to
give 24 in 80% yield (62.9 mg) as a white solid: mp 165−166 °C;
1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.83, 7.82 (Ar, AA′BB′
pattern, 2H), 7.76, 7.75 (Ar, AA′BB′ pattern, 2H), 3.92 (d, J = 10.9 Hz,
1H), 3.87 (dd, J = 9.6, 3.3 Hz, 1H), 3.76 (d, J = 10.9 Hz, 1H), 3.32
(s, 1H), 2.03 (m, 1H), 1.78 (m, 2H), 1.42 (m, 5H), 1.19 (s, 3H), 1.13
(s, 3H), 0.93 (overlapping signals, 12H); 13C NMR (125 MHz,
CDCl3) δ 177.0, 166.0, 153.4, 134.8, 129.9, 123.6, 77.4, 75.5, 62.3,
55.1, 39.4, 31.2, 30.5, 26.7, 26.4, 23.0, 22.6, 19.1, 14.2. (line broadening
set at 10 to observe the quaternary carbons); HRMS (ESI) m/z calcd
for C26H35N3O6Na [M + Na]+ 508.2419, found 508.2413.
(E)-1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-8,8-trimethyl-5-
oxo-2-pentyl-6-oxa-1,4-diazaspiro[2.6]non-9-yl tiglate (25). The
DASP 7a (31.2 mg, 0.081 mmol, 1.0 equiv) was dissolved in 2.0 mL
of CH2Cl2 and cooled to 0 °C. Tiglic acid (51.0 mg, 0.51 mmol, 6.3
equiv) was added to this solution in one portion and warmed to rt,
followed by sonication for 5 h. After TLC indicated complete con-
sumption of starting material, the reaction mixture was quenched with
NaHCO3, extracted with three portions of CH2Cl2, washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
crude material was purified via flash column chromatography to afford
1
25 as a white solid in 74% yield (28.8 mg): H NMR (500 MHz,
C6D6) δ 8.05 (NH, 1H), 7.32, 7.31 (Ar, AA′BB′ pattern, 2H), 6.84,
6.82 (Ar, AA′BB′ pattern, 2H), 6.72 (qq, J = 7.0, 1.5 Hz, 1H), 4.37
(dd, J = 9.7, 3.7 Hz, 1H), 3.42 (d, J = 10.6 Hz, 1H), 3.40 (d, J =
11.0 Hz, 1H), 3.15 (s, 1H), 1.93−1.87 (m, 3H), 1.50−1.37 (m, 8H),
1.07 (s, 3H), 0.96 (overlapping signals, 6H), 0.81 (s, 3H); 13C NMR
(125 MHz, C6D6) δ 165.9, 152.4, 141.0, 133.7, 129.9, 128.0, 127.4,
122.7, 76.7, 76.1, 61.7, 54.6, 31.7, 30.7, 30.2, 26.4, 22.7, 22.2, 18.4,
14.0, 13.8, 11.3; HRMS (ESI) m/z calcd for C26H34N3O6 [M + H+]
484.2443, found 484.2419.
(E)-1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-8,8-trimethyl-5-
oxo-2-pentyl-6-oxa-1,4-diazaspiro[2.6]non-9-yl acetate (21). The
product was obtained in 65% yield (354.1 mg) as a white solid: mp
1
115−117 °C; H NMR (300 MHz, CDCl3) δ 7.84, 7.83 (Ar, AA′BB′
pattern, 2H), 7.75, 7.74 (Ar, AA′BB′ pattern, 2H), 7.72 (br, 1H), 4.06
(dd, J = 9.7, 3.8 Hz, 1H), 3.93 (d, J = 10.9 Hz, 1H), 3.78 (d, J =
10.9 Hz, 1H), 3.30, (s, 1H), 2.01 (m, 1H), 1.90 (s, 3H), 1.76 (m, 2H),
1.39 (m, 5H), 1.16 (s, 3H), 1.15 (s, 3H), 0.93 (t, J = 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.6, 166.3, 153.4, 134.8, 129.9, 123.7,
77.6, 75.3, 61.8, 54.6, 31.8, 31.2, 30.2, 26.3, 22.6, 21.6, 18.6, 14.2;
HRMS (ESI) m/z calcd for C23H29N3O6Na [M + Na]+ 466.1949,
found 466.1937.
(E)-(S)-[1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-pentyl-8,8-
dimethyl-5-oxo-6-oxa-1,4-diazaspiro[2.6]non-9-yl] ethanethioate
(26). Thioacetic acid (600 μL, 8.4 mmol, 105 equiv) was dissolved
in 1.5 mL of THF and cooled to −78 °C. The DASP 7a (30.5 mg,
0.080 mmol, 1.0 equiv) dissolved in 2.5 mL of THF was added drop-
wise to the solution over 2 min. The reaction mixture was maintained
at −78 °C for an additional 15 min, warmed to 0 °C for 2 h, and then
left to warm to rt overnight. After TLC indicated complete consump-
tion of the starting materials, the volatiles were removed under
reduced pressure and the crude material was purified via column
chromatography (hexanes/ethyl acetate gradient) to afford 26 in 82%
yield (29.9 mg) as an off-white solid. The reaction was repeated on a
larger scale to give an 84% yield of 26 (275.9 mg): mp 185−186 °C;
IR 2930, 1704, 1479, 1374, 1279, 1262, 1120 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.86 (br signal, 2H), 7.75, 7.74 (Ar, AA′BB′
pattern, 2H), 7.25 (NH, 1H), 4.07 (d, J = 10.5 Hz, 1H), 3.88 (dd, J =
10.1, 3.8 Hz, 1H), 3.80 (d, J = 11.4 Hz, 1H), 3.35 (s, 1H), 2.27
(s, 3H), 2.19−2.12 (m, 1H), 1.89−1.75 (m, 2H), 1.62−1.53 (m, 1H),
1.46−1.37 (m, 4H), 1.17 (s, 3H), 1.14 (s, 3H), 0.94 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 193.3, 167.0, 165.1, 153.2,
134.6, 130.4, 129.3, 123.7, 123.5, 76.1, 63.4, 60.9, 56.8, 31.8, 31.5, 31.2,
31.1, 26.7, 24.6, 22.5, 19.7, 14.1 (line broadening set at 5 in order to
observe quaternary carbons); HRMS (ESI) m/z calcd for
C23H30N3O5S [M + H+] 460.1901, found 460.1897.
(E)-2-(9-Chloro-5-oxo-2-pentyl-6-oxa-1,4-diazaspiro[2.6]non-1-
yl)-1H-isoindole-1,3(2H)-dione (27). DASP 6a (50.0 mg, 0.14 mmol,
1 equiv) was dissolved in acetone (1.4 mL), and dry, powdered LiCl
(1.4 mmol, 10 equiv) was added to the reaction mixture. The suspen-
sion was stirred at rt until TLC indicated complete consumption of 6a.
Water (15 mL) was added and the reaction mixture extracted with
EtOAc (3 × 15 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel chromatog-
raphy (gradient 0−100% EtOAc in hexanes in increments of 20%)
to give 27 in 84% yield (45.9 mg) as a white solid: mp 133−135 °C;
(E)-2-tert-Butyl-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-
6-oxa-1,4-diazaspiro[2.6]non-9-yl acetate (22). The product was
obtained in 68% yield (47.4 mg) as a white solid: mp 134−136 °C;
1
IR 2957, 2926, 2854, 1767, 1713, 1467, 1376, 1188 cm−1; H NMR
(500 MHz, CDCl3) δ 7.83, 7.82 (Ar, AA′BB′ pattern, 2H), 7.76, 7.75 (Ar,
AA′BB′ pattern, 2H), 7.54 (NH, 1H), 4.30 (ddd, J = 11.1, 4.6, 2.3 Hz,
1H), 4.18 (app td, J = 11.7, 2.6 Hz, 1H), 3.86 (dd, J = 10.7, 5.2 Hz, 1H),
3.70 (s, 1H), 2.13−2.08 (m, 1H), 1.97−1.92 (overlapping signals,
4H total), 1.20 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.9, 165.9,
153.8, 134.6, 129.8, 123.5, 75.6, 64.8, 60.8, 53.7, 32.1, 29.6, 28.4, 24.4,
20.9; HRMS (ESI) m/z calcd for C20H23N3O6Na [M + Na+]
424.1480, found 424.1488.
(Z)-Ethyl-[9-(acetyloxy)-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)-8,8-dimethyl-5-oxo-6-oxa-1,4-diazaspiro[2.6]non-2-yl]acetate
(23). The product was obtained in 85% yield (52.8 mg) as a light
1
yellow solid: mp 175−176 °C; H NMR (300 MHz, CDCl3) δ 7.85,
7.84 (Ar, AA′BB′ pattern, 2H), 7.77, 7.76 (Ar, AA′BB′ pattern, 2H),
6.77 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 (d, J = 10.9 Hz, 1H), 3.81
(d, J = 10.9 Hz, 1H), 3.70 (dd, J = 7.4, 4.6 Hz, 1H), 3.28 (d, J =
0.7 Hz, 1H), 3.18 (dd, J = 17.3, 4.6 Hz, 1H), 2.64 (dd, J = 17.3, 7.4 Hz,
1H), 2.16 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.22 (s, 3H), 1.20 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.3, 168.7, 152.6, 135.0, 130.3, 123.9,
76.3, 61.4, 61.1, 44.5, 33.1, 32.3, 23.7, 21.5, 20.2, 14.4; HRMS (ESI) m/z
calcd for C22H25N3O8Na [M + Na]+ 482.1534, found 482.1519.
(E)-1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-8,8-trimethyl-5-
oxo-2-pentyl-6-oxa-1,4-diazaspiro[2.6]non-9-yl pivalate (24). The
DASP 7a (50.0 mg, 0.13 mmol, 1 equiv) was dissolved in dry THF
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Article
IR 2995, 2929, 1721, 1467, 1376, 1300, 1249 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.01−7.80 (overlapping signals, Ar, 4H), 7.10 (s, 1H), 4.41
(m, 1H), 4.26 (m, 1H), 3.71 (m, 2H), 2.22 (m, 1H), 1.99
(m, 1H), 1.70−1.10 (m, 8H), 0.93 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 164.0 (indirectly observed by HMBC), 153.9, 134.8, 130.0
(indirectly observed by HMBC), 124.0, 71.0, 64.7, 55.1, 54.3, 31.8,
29.0, 26.5, 24.4, 22.6, 14.2; HRMS (ESI) m/z calcd for C19H23N3ClO4
[M + H]+ 392.1372, found 392.1376.
(E)-2-(9-Chloro-8,8-dimethyl-5-oxo-2-pentyl-6-oxa-1,4-
diazaspiro[2.6]non-1-yl)-1H-isoindole-1,3(2H)-dione (28). Chlorotri-
methylsilane (150 μL, 1.18 mmol, 14 equiv) was dissolved in 1 mL of
THF and cooled to −78 °C. The DASP 7a (33.2 mg, 0.086 mmol,
1.0 equiv) in 2.5 mL of THF was added dropwise over 2 min. After the
addition was complete, the reaction mixture was warmed to 0 °C for
2 h and then to room temperature for an additional 2 h. The reaction
mixture was concentrated under reduced pressure and the residue
purified via column chromatography (hexanes/ethyl acetate gradient)
to afford 28 in 93% yield (33.5 mg) as a white solid: mp 122−124 °C;
IR 2954, 1715, 1480, 1467, 1375, 1261, 1120 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.87 (br s, Ar, 1H), 7.79 (br s, Ar, 1H), 7.75,
7.74 (Ar, AA′BB′ pattern, 2H), 7.00 (NH, 1H), 4.39 (d, J = 11.2 Hz,
1H), 4.12 (dd, J = 11.2, 3.9 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 3.32
(s, 1H), 2.00−1.94 (m, 1H), 1.76−1.67 (m, 2H), 1.43−1.34 (m, 5H),
1.25 (s, 3H), 1.22 (s, 3H), 0.93 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.6, 165.0, 153.2, 134.6, 130.4, 129.1, 123.8, 123.3, 73.9,
70.8, 62.8, 54.2, 31.6, 31.0, 30.5, 26.5, 26.4, 22.5, 20.5, 14.0; HRMS
(ESI) m/z calcd for C21H27N3O4Cl [M + H+] 420.1685, found
420.1666.
General Procedure for Tandem Reactions. A 50 mL flame-
dried round-bottom flask was charged with 3 Å molecular sieves
(500 mg), followed by Rh2(esp)2 (0.041 mmol, 0.025 equiv). The
allenic carbamate (1.6 mmol, 1.0 equiv) in 15 mL of dry CH2Cl2 was
added to the reaction flask. The resulting blue-green mixture was
stirred for 10 min at rt under a flow of nitrogen, then iodosobenzene
(4.1 mmol, 2.5 equiv) was added in one portion. The reaction was
monitored by TLC until it was complete, then cooled to 0 °C in an ice
bath. A portion of N-aminophthalimide (3.1 mmol, 1.9 equiv) and dry
potassium carbonate (6.4 mmol, 4.0 equiv), followed by additional
oxidant (3.0 mmol, 1.9 equiv), was added, and the resulting light
yellow slurry was allowed to warm slowly to rt. The reaction mixture
was monitored by TLC, and additional portions of PhthNNH2
and oxidant were added until no further conversion to the
1,4-diazaspiro[2.2]pentane was noted. The desired nucleophile was
then added (3.0−15.0 equiv) and the reaction stirred at rt until complete.
The reaction mixture was passed through a plug of silica gel to remove
solids using first Et2O, then EtOAc to flush the plug. The solvents were
removed under reduced pressure, and the residue was purified via silica
gel column chromatography (hexanes/ethyl acetate gradient). Phenyl
iodide eluted first from the column, followed by the Rh catalyst,
unreacted methyleneaziridine (if present), unreacted 1,4-diazaspiro-
[2.2]pentane(s) (if present), products of the hydrolysis of the excess
N-aminophthalimide and, finally, the desired N,N-aminal product as a
single diastereomer. The following amounts of material were obtained:
21 (315.1 mg) for a 46% yield; 26 (328.1 mg) for a 48% yield; and 28
(345.0 mg) for a 53% yield.
3.24 (d, J = 3.24 Hz, 1H), 2.03−1.96 (m, 1H), 1.77−1.67 (m, 1H),
1.44−1.33 (m, 6H), 1.25 (s, 3H), 1.22 (s, 3H), 0.93 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 166.5, 164.7, 153.1, 134.6,
134.5, 130.3, 129.1, 123.9, 123.4, 73.4, 66.8, 63.3, 54.5, 31.6, 31.0, 30.7,
27.2, 26.4, 22.5, 20.4, 14.0; HRMS (ESI) m/z calcd for C21H27N3O4Br
[M + H+] 464.1180, found 464.1161.
(E)-2-{[2-Bromo-1-(5,5-dimethyl-2-oxo-1,3-oxazinan-4-yl)-
heptylidene]amino}-1H-isoindole-1,3(2H)-dione (31). The DASP 7a
(42.1 mg, 0.11 mmol, 1.0 equiv) was dissolved in 4 mL of THF and
cooled to 4 °C. Bromotrimethylsilane (60 μL, 0.46 mmol, 4.2 equiv)
was added to the solution in one portion. The reaction was stirred for
2 h at 4 °C until TLC indicated complete consumption of the starting
material. The volatiles were removed under reduced pressure, and the
crude reaction mixture was purified via column chromatography to
afford 31 in 59% yield (30.0 mg) as a white solid: mp 101−103 °C; 1H
NMR (500 MHz, CDCl3) δ 7.89, 7.88 (Ar, AA′BB′ pattern, 2H), 7.77,
7.76 (Ar, AA′BB′ pattern, 2H), 5.99 (d, NH, J = 3.2 Hz, 1H), 5.00 (d,
J = 10.7 Hz, 1H), 4.62 (dd, J = 11.3, 3.3 Hz, 1H), 4.32 (dd, J = 4.3,
1.2 Hz, 1H), 3.85 (dd, J = 11.0, 1.6 Hz, 1H), 2.31−2.24 (m, 1H),
1.87−1.79 (m, 1H), 1.38−1.26 (m, 12H), 0.88 (t, J = 6.7 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 175.9, 163.6, 152.6, 134.7, 131.0, 124.0,
74.7, 58.1, 48.5, 33.9, 31.7, 30.7, 27.0, 26.3, 22.4, 21.0, 13.9; HRMS
(ESI) m/z calcd for C21H26N3O4BrNa [M + Na+] 486.0999, found
486.0996.
(E)-2-{[2-Methoxy-1-(5,5-dimethyl-2-oxo-1,3-oxazinan-4-yl)-
heptylidene]amino}-1H-isoindole-1,3(2H)-dione (32a,b). The DASP
7a (100.0 mg, 0.261 mmol, 1 equiv) was dissolved in 3 mL of methanol,
and acetic acid (0.261 mmol, 1 equiv) was added to the reaction. The
mixture was stirred at rt until the starting material was consumed as
indicated by TLC. The reaction mixture was quenched with saturated
sodium bicarbonate (10 mL) and extracted with 2 × 10 mL of ethyl
acetate. The combined organics were washed with brine and dried
over sodium sulfate, and the volatiles were removed under reduced
1
pressure. The product ratio was determined by H NMR analysis of
the crude reaction mixture. The two diastereomers were difficult to
separate by conventional column chromatography (obtained as a
mixture in 61% yield (65.9 mg) using a gradient of 0−1% MeOH in
CHCl3, increasing in 0.2% increments), and preparative TLC (75%
ethyl acetate/hexane) was used to obtain samples for analysis. The
mixture was a white solid, but due to the small amounts of material
separated for analysis, no mp was obtained. Minor diastereomer:
1H NMR (300 MHz, CDCl3) δ 7.88 (Ar, AA′BB′ pattern, 2H), 7.77
(Ar, AA′BB′ pattern, 2H), 5.38 (br d, J = 3.1 Hz, 1H), 4.37 (t, J =
6.2 Hz, 1H), 4.33 (d, J = 11.4 Hz, 1H), 4.18 (dd, J = 3.1, 1 H), 3.79
(dd, J = 10.9, 1 H), 3.45 (s, 3H), 1.92 (m, 2H), 1.36−0.86 (several
overlapping signals, 15H); 13C NMR (125 MHz, CDCl3) δ 177.8,
164.1, 152.3, 134.8, 131.0, 124.0, 77.2, 74.1, 60.1, 54.6, 31.7, 31.6, 29.7,
26.7, 24.7, 22.5, 20.1, 14.0; HRMS (ESI) m/z calcd for C22H30N3O5
[M + H+] 416.2180, found 416.2179. Major diastereomer (containing
some of the minor diastereomer): 1H NMR (300 MHz, CDCl3) δ 7.90
(Ar, AA′BB′ pattern, 2H), 7.80 (Ar, AA′BB′ pattern, 2H), 6.10 (br s,
1H), 4.47 (dd, J = 8.2, 6.4 Hz, 1H), 4.44 (d, J = 0.9 Hz, 1H), 3.93
(d, J = 11.2 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.35 (s, 3H), 2.04 (m,
1H), 1.88 (m, 1H), 1.38 (m, 6H), 1.10 (s, 3H), 0.94 (6H); 13C NMR
(125 MHz, CDCl3) δ 174.9, 164.1, 152.6, 135.0, 131.2, 124.3, 78.2,
76.1, 60.9, 52.8, 32.9, 31.9, 28.1, 25.5, 23.7, 22.7, 19.6, 14.2; HRMS
(ESI) m/z calcd for C22H29N3O5Na [M + Na+] 438.2000, found
438.2000.
(E)-2-(9-Bromo-8,8-dimethyl-5-oxo-2-pentyl-6-oxa-1,4-
diazaspiro[2.6]non-1-yl)-1H-isoindole-1,3(2H)-dione (30). DASP 7a
(44.8 mg, 0.117 mmol, 1.0 equiv) was dissolved in 3.0 mL of THF and
cooled to 0 °C. Bromotrimethylsilane (90 μL, 0.682 mmol, 5.8 equiv)
was added to the solution in one portion. The reaction was maintained
at 0 °C for 2 h until complete consumption of starting material was
observed by TLC. The reaction mixture was loaded directly onto the
column without removal of the solvent and purified via flash column
chromatography to afford the desired compound 30 and a byproduct
31 (see below) in a 6.7:1.0 ratio in 89% overall yield (48.2 mg,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. X-ray crystal
structure data tables for 7a. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
77% yield 30) as a white solid. The H and 13C NMR spectra of the
ring-opened DASP were obtained on a sample further purified by
recrystallization: mp 88−90 °C; 1H NMR (500 MHz, CDCl3) δ 7.90−
7.87 (m, 1H), 7.81−7.74 (m, 3H), 7.01 (NH, 1H), 4.55 (d, J = 11.2
Hz, 1H), 4.26 (dd, J = 10.8, 3.2 Hz, 1H), 3.69 (d, J = 11.3 Hz, 1H),
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schomakerj@chem.wisc.edu.
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The Journal of Organic Chemistry
Article
(8) (a) Atkinson, R. S.; Malpass, J. R. Tetrahedron Lett. 1975, 4305.
(b) Siu, T.; Yudin, A. K. J. Am. Chem. Soc. 2002, 124, 530. (c) Li, J.;
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Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
(10) Larock, R. C.; Babu, S. Tetrahedron 1987, 43, 2013.
(11) (a) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259.
(b) Kim, H.; Williams, L. J. Curr. Opin. Drug Discovery 2008, 11, 870.
(c) Ma, S. M. Pure Appl. Chem. 2006, 78, 197. (d) Krause, N.;
ACKNOWLEDGMENTS
■
This work was supported by start-up funds from the University
of WisconsinMadison and the Wisconsin Alumni Research
Foundation.
Hoffmann-Roder, A. Tetrahedron 2004, 60, 11671. (e) Krause, N. A.,
̈
Hashmi, S. K., Eds. Modern Allene Chemistry; Wiley-VCH: Weinheim,
Germany, 2004.
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