Synthesis and Desymmetrization of meso Tricyclic Systems Derived from Benzene Oxide

Article abstract of DOI:10.1021/acs.joc.8b00523

Ozonolysis of the Diels-Alder adducts derived from benzene oxides and N-alkylmaleimides resulted in fully substituted, meso bicyclic systems bearing six contiguous stereocenters, isolated as diols upon reductive workup with NaBH₄. Variation in the workup allowed for isolation of two different diastereoisomers, through double epimerization of the imide stereocenters. Desymmetrization of the resulting meso diols via asymmetric nucleophilic epoxide opening and acylation reactions provided access to highly substituted, enantioenriched fused rings.

Full text of DOI:10.1021/acs.joc.8b00523

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis and Desymmetrization of meso Tricyclic Systems Derived
from Benzene Oxide
Desiree M. Matías and Jeffrey S. Johnson*
́
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: Ozonolysis of the Diels−Alder adducts derived from benzene
oxides and N-alkylmaleimides resulted in fully substituted, meso bicyclic systems
bearing six contiguous stereocenters, isolated as diols upon reductive workup
with NaBH4. Variation in the workup allowed for isolation of two different
diastereoisomers, through double epimerization of the imide stereocenters.
Desymmetrization of the resulting meso diols via asymmetric nucleophilic
epoxide opening and acylation reactions provided access to highly substituted,
enantioenriched fused rings.
rendering it an attractive building block. Enzymatic oxidation of
aromatic compounds has prompted a number of studies
focused on the biosynthetic pathway and structural properties
of arene oxides;5−7 however, the utility of these molecules as
building blocks in organic synthesis has not been extensively
researched. Epoxide opening8 (including one enantioselective
case),8b diene functionalization,9 and Diels−Alder reactivity10
have been reported with benzene oxide, but the scope of these
transformations are limited or underexplored. This is most
likely due to the rapid equilibrium that exists between benzene
oxide and its valence-tautomer, oxepin, and the facile
rearrangement of arene oxide to phenol by way of a 1,2-
hydride shift and rearomatization promoted by acids or heat
(Scheme 1b).11
Nonetheless, benzene oxide derivatives offer interesting
possibilities in the realm of desymmetrization chemistry. The
desymmetrization of meso compounds has proven to be a
powerful approach for the synthesis of chiral scaffolds bearing
multiple stereocenters.12 This strategy rapidly builds complexity
by differentiating enantiotopic groups through the use of a
chiral catalyst. A variety of transformations have been deployed
in enantioselective desymmetrizations, including epoxide open-
ings,13 alcohol functionalizations,14 and C−C bond formation15
of prochiral or meso compounds. We envisioned that
symmetrical benzene oxide derived cycloadducts containing
multiple contiguous stereocenters could be oxidatively cleaved
and subsequently desymmetrized to access stereochemically
dense molecules.
he synthesis of highly substituted, enantioenriched
Tcyclohexanes is an ongoing challenge in organic syn-
thesis.1 Cyclohexadienes serve as versatile building blocks for
the efficient synthesis of these molecules, and complex natural
products and pharmaceuticals have benefited from their
manipulation.2 Specifically, functionalization of 1,2-disubsti-
tuted cyclohexadienes has allowed access to complex molecules
with multiple stereocenters (Scheme 1a).3
1,2-Disubstituted cyclohexa-3,5-dienes are useful precursors
for the synthesis of chiral, functionalized cyclohexanes.4 One
type of 1,2-disubstituted cyclohexa-3,5-diene, benzene oxide,
offers the potential of both diene and epoxide functionalization,
Scheme 1. Synthesis of meso Compounds Derived from
Aromatic Molecules and Challenges Associated with
Benzene Oxide
The direct oxidative dearomatization of aromatic feedstocks
to arene oxide derivatives has primarily been accomplished via
Received: February 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00523
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The Journal of Organic Chemistry
Note
Table 1. Synthesis of meso Bicyclic Compounds from Benzene Oxides 1 and 2
entry
product
R
X
Y
solvent
time (h)
yield (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
O
CH
CH
CH
CH
N
Et2O
Et2O
Et2O
Et2O
acetone
Et2O
72
24
24
72
1
71
50
53
61
65
57
H
NBn
H
NPh
H
H
NC8H17
NPh
CH2CH2CH2
NBn
CH
24
enzymatic pathways, but in most cases, the presence of
electron-withdrawing groups is needed in order to isolate the
desired oxides and prevent rearomatization.16 Nonenzymatic
pathways have been limited by low yields and operational
practicality.17 To date, an efficient, dearomative, nonenzymatic
synthesis of benzene oxide has not been reported. As part of a
long-term goal of utilizing aromatic feedstocks for the creation
of chiral compounds, we sought to explore the reactivity of
benzene oxide. Herein, we present stage one of this
investigation, the synthesis of new, chiral, fully substituted
cyclohexanes using benzene oxide as the starting building block
(Scheme 1c).
Scheme 2. Ozonolysis Reaction of meso Compound 3b and
the Effect of Quenching Conditions on the
Diastereoselectivity
To elucidate the identity of the diastereoisomers, an X-ray
crystallography study of the related diol 5d was performed,
revealing a syn-relationship between the epoxide and the α-
protons, characteristic of having arisen from the exo Diels−
Alder adduct (Figure 1).18
Benzene oxide can be chemically accessed in a stepwise
fashion, starting from commercially available 1,4-cyclohex-
adiene. This method, developed initially by Gunther, has
̈
allowed access to benzene oxide for mechanistic and kinetic
studies.11,10b We modified this procedure in order to obtain an
operationally simple route that does not require heat or
purification (Experimental Section). From this point, meso
tetracycles 3a−3f were accessed from the Diels−Alder reaction
of benzene oxide with maleic anhydride and a number of N-
substituted maleimides (Table 1). These meso compounds
bearing six contiguous stereocenters have not been employed in
organic synthesis prior to this study; conformational studies
have been performed with 3c.10b The bicyclic products 3a, 3b,
and 3e have been previously synthesized by Gunther,11
̈
Gillard,10b and Golding,10d respectively. The N-benzyl
maleimide adduct 3c (entry 3) was synthesized in 53% yield,
and N-octyl maleimide adduct 3d (entry 4) was obtained in
61% yield. Furthermore, the indane derived tricyclic compound
3f (entry 6) could be afforded in 57% yield. At this point, an
oxidative cleavage reaction was employed to access substituted
meso fused cyclohexanes with six contiguous stereocenters.
Ozonolysis of anhydride 3a resulted in a mixture of starting
material and decomposition as the compound was highly
insoluble under the reaction conditions. Fortunately, Diels−
Alder adduct 3b was tolerant of the reaction conditions,
providing diol 4b in 98% yield after a NaBH4 workup (Scheme
2). Using Me2S for the workup conditions rendered a labile
putative dialdehyde that decomposed readily. Unexpectedly, the
conditions by which the NaBH4 was quenched had an effect in
the stereoselectivity of the reaction. Addition of water to
quench the remaining NaBH4 resulted in the expected endo
product 4b; however, if acetone was added instead and the
solution was concentrated and allowed to stir overnight, the
thermodynamically favored exo product 5b was obtained in a
9:1 dr.
Figure 1. X-ray structure of succinimide 5d. The n-octyl chain was
truncated for better visualization.
In contrast, an NOE correlation was observed between the
epoxide C−H methine and the proximal succinimide C−H
methine in cycloadduct 3d, thus showing that the initial Diels−
Alder adduct is endo selective. In order to rule out an unlikely
retro-Diels−Alder/Diels−Alder pathway where the exo Diels−
Alder adduct would be trapped at the lower temperatures
required by the ozonolysis reaction, we performed a crossover
experiment using N-octyl adduct 3d and N-benzyl maleimide;
however, as expected, only N-octyl maleimide adduct 3d was
observed, ruling out the retro-Diels−Alder pathway (Scheme
3a).
B
DOI: 10.1021/acs.joc.8b00523
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The Journal of Organic Chemistry
Note
Scheme 3. Experiments Probing the Mechanism of
Diastereomerization
Figure 2. Scope of the ozonolysis reaction of meso bicyclic
compounds. Footnote a represents the compound after DBU stir.
(Scheme 4a).20 Employing the opposite imide diastereoisomer
(5d) or changing the N-substituent resulted in lower
Alternatively, we considered the possibility that the exo
product 5b could form directly from endo diol 4b through a
double epimerization pathway. Addition of DBU to 4b resulted
in complete conversion to 5b after 16 h (Scheme 3b). Double
epimerization reactions of N-substituted maleimides are
unusual;19 it is possible that the presence of the diol increases
the acidity of the α-protons via formation of a hydrogen bond
with the carbonyl oxygen. To ensure that a double
epimerization was occurring under our ozonolysis conditions
with the acetone workup, we subjected the endo diol 4b to the
reductive conditions and aqueous or acetone workups. Using
the aqueous workup, only the endo diol 4b was observed,
whereas the acetone workup provided the exo diol 5b with 55%
conversion after only 1 h. Thus, addition of acetone in the
presence of NaBH4 results in the formation of a base
sufficiently potent to promote the double epimerization
reaction.
Scheme 4. Enantioselective Desymmetrization of meso
Products
We next sought to expand the scope of the oxidative cleavage
(Figure 2). Ozonolysis of the N-phenyl adduct 3c using the
aqueous workup resulted in 46% yield of the endo product 4c;
however, application of the acetone workup proved difficult and
resulted mainly in an inseparable mixture of products.
Pleasingly, when utilizing the N-octyl adduct 3d, both the
endo and exo products could be obtained. While endo product
4d was obtained selectively, the corresponding exo diol 5d was
obtained in a 1.4:1 dr; the diastereoselectivity could be
improved to >20:1 if the diol was stirred with DBU overnight.
Using the adduct derived from the indane benzene oxide 3f,
both diols were obtained selectively; the exo diol 5f was
obtained directly from the acetone workup and did not require
further manipulation. Finally, ozonolysis of the tetracyclic
dihydrotriazolopyridazinedione 3e resulted in the derived diol
4e in 65% yield. These products are sensitive to silica gel; a
reduction in diastereoselectivity was observed in various cases
after column chromatography (Experimental Section).
enantiomeric ratios. Enantioselective diol monofunctionaliza-
tion could be achieved using Birman’s acylation catalyst and
propionic anhydride.21 The endo diol 4b was monoacylated to
obtain propionate 7 in 44% yield and 80:20 er. Finally,
subjecting the meso diacetate 8 to enzymatic deacylating
conditions using porcine pancreatic lipase yielded monoacetate
9 in 69% yield and 88:12 er.22,23
In conclusion, we have disclosed the synthesis of meso diols
derived from the benzene oxide/oxepin equilibrium. These
compounds have not been previously accessed through other
synthetic methods, and similar compounds are still challenging
to obtain. Fully substituted chiral compounds were acquired
With these meso diols in hand, we sought to carry out initial
explorations of desymmetrizing transformations that would
provide access to fully substituted, chiral cyclohexanes with six
contiguous stereocenters. The use of a chiral phosphoric acid
catalyst and 2-mercaptothiazole resulted in the opening of the
epoxide 4d, providing alcohol 6 in 63% yield and 90:10 er
C
DOI: 10.1021/acs.joc.8b00523
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The Journal of Organic Chemistry
Note
temperature, and the solution was concentrated under reduced
pressure to yield a yellow oil. The oil was crystallized from pentanes
at −20 °C to obtain the product as clear crystals (722 mg, 2.44 mmol,
66% yield). Spectroscopic data was identical to those previously
reported:10b 1H NMR (400 MHz, CDCl3) δ 4.41 (q, J = 5.4 Hz, 1H),
4.29 (q, J = 5.9 Hz, 1H), 3.01 (dd, J = 15.9, 4.4 Hz, 1H), 2.82 (dd, J =
16.4, 6.3 Hz, 1H), 2.68 (dd, J = 16.4, 4.9 Hz, 1H), 2.42 (dd, J = 15.9,
5.4 Hz, 1H), 2.05 (dt, J = 12.4, 8.9 Hz, 2H), 1.55 (m, 4H).
General Procedure A for the Preparation of Diels−Alder
Adducts (3a−3d). Benzene Oxide/Oxepin. DBU (4 equiv) was
added to a solution of 3,4-dibromo-7-oxabicyclo[4.1.0]heptane (1
equiv) in Et2O (10 mL) at room temperature. The reaction was
allowed to stir for 24 h at that temperature and then a saturated aq
solution of NaHCO3 was added until all of the precipitate was
dissolved. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 5 mL). The organic layers were combined
and washed with brine. (Note that, if the organics are not washed with
brine, lower yields result in Diels−Alder reactions.) The organic
extracts were dried with sodium sulfate, filtered, and concentrated
under a stream of air. The yellow liquid was used immediately to avoid
decomposition. The same procedure was used for the substituted
benzene oxide, where R = CH2CH2CH2.
The crude benzene oxide/oxepin was redissolved in approximately
10 mL of ether, and the dienophile (1 equiv) was added as a solid. The
reaction was allowed to stir at room temperature for the required time.
The resulting precipitate was collected and washed with cold ether.
Only products 3d and 3f required further purification.
1a,2,2a,5a,6,6a-Hexahydro-2,6-ethenooxireno[2,3-f ]-
isobenzofuran-3,5-dione (3a). The title compound was prepared
according to general procedure A using benzene oxide (7.8 mmol),
maleic anhydride (766 mg, 7.8 mmol), and Et2O (20 mL) and was
stirred for 72 h. The product was obtained as a white powder (1.06 g,
7.81 mmol, 71% yield). Spectroscopic data were identical to those
previously reported:11 1H NMR (400 MHz, CDCl3) δ 5.97 (dd, J =
4.7, 3.5 Hz, 2H), 3.73−3.66 (m, 2H), 3.40 (dd, J = 4.0, 2.2 Hz, 2H),
3.27 (t, 1.8 Hz, 2H).
4-Benzyl-1a,2,2a,5a,6,6a-hexahydro-3H-2,6-ethenooxireno[2,3-
f ]isoindole-3,5(4H)-dione (3b). The title compound was prepared
according to general procedure A using benzene oxide (4.12 mmol),
benzyl maleimide (771 mg, 4.12 mmol), and Et2O (10 mL) and was
stirred for 24 h. The product was obtained as a white powder (263 mg,
0.935 mmol, 48% yield). Analytical data: 1H NMR (400 MHz, CDCl3)
δ 7.32−7.24 (m, 5H), 5.71 (dd, J = 4.8, 3.4 Hz, 2H), 4.57 (s, 2H),
3.65−3.57 (m, 2H), 3.40−3.35 (m, 2H), 2.97 (t, J = 1.8 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 176.7, 137.1, 123.3, 48.6, 31.1. IR (thin
film, cm−1): 3433, 1769, 1698, 1396, 1266, 1173, 1054. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H15NO3Na, 304.0944; found,
304.0947. Mp: 180−185 °C.
4-Phenyl-1a,2,2a,5a,6,6a-hexahydro-3H-2,6-ethenooxireno[2,3-
f ]isoindole-3,5(4H)-dione (3c). The title compound was prepared
according to general procedure A using benzene oxide (4.12 mmol),
phenyl maleimide (771 mg, 4.12 mmol), and Et2O (10 mL) and was
stirred for 24 h. The product was obtained as a white powder (277 mg,
1.04 mmol, 53% yield). Spectroscopic data were identical to those
previously reported:10b 1H NMR (400 MHz, CDCl3) δ 7.48−7.35 (m,
3H), 7.19−7.11 (m, 2H), 5.95 (dd, J = 4.7, 3.4 Hz, 2H), 3.76−3.66
(m, 2H), 3.47−3.39 (m, 2H), 3.13 (t, J = 1.8 Hz, 2H).
through desymmetrizing epoxide opening and acylation
reactions. This work provides further support to the notion
that the synthesis of complex, chiral molecules can be achieved
using benzene oxide as a building block.
EXPERIMENTAL SECTION
■
General Comments. Nuclear magnetic resonance spectra (1H
NMR, 13C NMR, 19F NMR) were recorded at the following
1
frequencies: H NMR at 400 or 600 MHz, 13C NMR at 101 or 151
MHz with solvent resonance as the internal standard (1H NMR
CDCl3 at 7.26 ppm and 13C NMR CDCl3 at 77.0 ppm). 1H NMR data
are reported as follows: chemical shift, multiplicity (abbreviations s =
singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, ddd
= doublet of doublet of doublets, dt = doublet of triplets, t = triplet, td
= triplet of doublets, tt = triplet of triplets, qt = quintet, and m =
multiplet), coupling constant (Hz), and integration. High resolution
mass spectra were obtained using a linear trap quadrupole Fourier
transform (LTQ-FT) spectrometer. TLC visualization was accom-
plished using UV light, phosphomolybdic acid in ethanol, or an
aqueous ceric ammonium nitrate solution. High performance liquid
chromatography (HPLC) analyses were carried out using Diacel
Chiralpak IA and IC columns. Samples were prepared using 90:10
HPLC grade iPrOH/hexanes and eluted with HPLC grade hexanes
with the indicated percentage of iPrOH with an oven temperature of
40 °C. Yields and diastereomeric ratios (dr’s) are reported herein for a
specific experiment and as a result may differ slightly from those found
in the schemes, which are averages of at least two experiments.
Nitrogen was dried by passage through anhydrous calcium sulfate with
3% cobalt chloride as an indicator. N-Benzylmaleimide,24 N-
octylmaleimide,25 N-phenylmaleimide,26 and 4-phenyl-1,2,4-triazo-
line-3,5-dione (PTAD)27 were prepared according to known literature
procedures. Birman’s catalyst21 and the phosphoric acid catalyst
(TiPSY)28 were prepared according to known literature procedures.
The benzene oxides were prepared by modifying a literature
procedure.10b All other reagents and solvents were purchased from
commercial sources and used as received.
Modified Procedure for the Synthesis of 3,4-Dibromo-7-
oxabicyclo[4.1.0]heptane. A solution of Br2 (2.05 mL, 40 mmol) in
hexanes (20 mL) was added dropwise to a solution of 1,4-
cyclohexadiene (3.78 mL, 40 mmol) in hexanes (45 mL) that had
been cooled to −45 °C using a dry ice/acetonitrile bath. (Note that
the reaction turns yellow upon addition of bromine and should not be
allowed to turn completely orange; lower yields resulted when this
occurred.) After the addition was complete, the yellow solution was
allowed to reach room temperature and then filtered. The solution was
concentrated under reduced pressure. The resulting oil solidified upon
cooling, and it was dissolved in dichloromethane (20 mL). This
solution was added to a solution of mCPBA (13.4 g, 58 mmol) in
dichloromethane (330 mL) at room temperature. The reaction was
allowed to stir at that temperature for 72 h. A 20% aq solution of
Na2S2O5 (100 mL) was added, and the solution was allowed to stir for
20 min. The layers were then separated, and the organic layer was
washed with a saturated aq NaHCO3 solution (2 × 100 mL) and brine
(100 mL × 1). The organic layer was dried with sodium sulfate,
filtered, and concentrated under a vacuum to yield the clean product as
an off white crystalline solid (6.85 g, 26.8 mmol, 68% yield over two
steps). The product was carried on to the next step without further
purification. Spectroscopic data was identical to those previously
reported:10b 1H NMR (400 MHz, CDCl3) δ 4.30 (td, J = 7.1, 4.6 Hz,
1H), 4.19 (q, J = 6.7 Hz, 1H), 3.17 (m, 2H), 3.00 (dd, J = 16.0, 4.6 Hz,
1H), 2.90 (ddd, J = 16.5, 6.4, 3.6 Hz, 1H), 2.65 (dd, J = 16.6, 6.3 Hz,
1H), 2.46 (ddd, J = 16.1, 6.7, 3.4 Hz, 1H).
4-Octyl-1a,2,2a,5a,6,6a-hexahydro-3H-2,6-ethenooxireno[2,3-f]-
isoindole-3,5(4H)-dione (3d). The title compound was prepared
according to general procedure A using benzene oxide (4.12 mmol),
octyl maleimide (771 mg, 4.12 mmol), and Et2O (10 mL) and was
stirred for 72 h. The solution was concentrated, and the crude was
purified using column chromatography with hexanes/ethyl acetate
(gradient, 5:1 to 1:1) to yield the product as a white solid (380 mg,
Synthesis of 5,6-Dibromohexahydro-1H-3a,7a-epoxyin-
dene. A solution of Br2 (0.19 mL, 3.67 mmol) in dichloromethane
(6 mL) was added over a period of 30 min to a solution of 2,3,4,7-
tetrahydro-1H-3a,7a-epoxyindene9 (1.0 g, 3.67 mmol) in dichloro-
methane (30 mL) cooled to −78 °C. The addition was stopped when
the orange color persisted. (Note that the bromine solution was not
added completely.) The reaction was allowed to reach room
1
1.25 mmol, 64% yield). Analytical data: H NMR (400 MHz, CDCl3)
δ 5.80 (dd, J = 4.7, 3.4 Hz, 2H), 3.66−3.55 (m, 2H), 3.43−3.32 (m,
4H), 2.93 (t, J = 1.8 Hz, 2H), 1.50−1.39 (m, 2H), 1.32−1.15 (m,
10H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 177.1,
126.6, 47.4, 42.0, 38.8, 35.5, 31.7, 29.1, 27.6, 26.7, 22.6, 14.1. IR (thin
film, cm−1): 2928, 2855, 1772, 1698, 1402, 1266, 1171. HRMS (ESI-
D
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The Journal of Organic Chemistry
Note
TOF) m/z: [M + H]+ calcd for C18H26NO3, 304.1907; found,
304.1912. Mp: 110−114 °C. TLC (1:1 hexanes/ethyl acetate): Rf =
0.4.
(50 mg, 0.18 mmol), NaBH4 (13.4 mg, 0.36 mmol), and 2:1 DCM/
MeOH (1.5 mL) and was obtained as a white solid (55 mg, 0.17
mmol, 98% yield, 9:1 dr). Analytical data: 1H NMR (400 MHz,
CDCl3) δ 7.38−7.27 (m, 5H), 4.65 (s, 2H), 4.15−4.05 (m, 2H),
4.04−3.95 (m, 2H), 3.29 (s, 2H), 2.94−2.85 (m, 2H), 2.85−2.78 (m,
2H), 2.30−2.20 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 179.6,
135.2, 128.8, 128.6, 128.2, 65.2, 51.6, 42.6, 38.6, 37.1. IR (thin film,
cm−1): 3420, 1697, 1558, 1402, 1340, 1175, 1030. HRMS (ES-TOF)
m/z: [M + H]+ calcd for C17H20NO5, 318.1336; found, 318.1334. Mp:
96−98 °C.
5-Phenyl-1a,2,8,8a-tetrahydro-4H-2,8-ethenooxireno[2,3-d]-
[1,2,4]triazolo[1,2-a]pyridazine-4,6(5H)-dione (3e). The title com-
pound was made according to a literature procedure10d using benzene
oxide (1.95 mmol) and 4-phenyl-1,2,4-triazole-3,5-dione (171 mg,
0.977 mmol). The product was purified using column chromatography
with 1:1 hexanes/ethyl acetate to obtain 3e as a white solid (171 mg,
0.635 mmol, 65% yield). Spectroscopic data were identical to those
previously reported:10d 1H NMR (400 MHz, CDCl3) δ 7.54−7.29 (m,
5H), 6.17 (t, J = 3.8 Hz, 2H), 5.31 (d, J = 3.9 Hz, 2H), 3.79−3.61 (m,
2H).
(1aR,2S,2aS,5aR,6R,6aS)-2,6-Bis(hydroxymethyl)-4-phenylhexa-
hydro-3H-oxireno[2,3-f ]isoindole-3,5(4H)-dione (4c). The title com-
pound was prepared according to general procedure B using 3c (50.0
mg, 0.19 mmol), NaBH4 (14.2 mg, 0.37 mmol), and 2:1 DCM/
MeOH (1.5 mL) and was obtained as a white amorphous solid (42
2-Benzyl-3a,4,6,7,8,8a-hexahydro-1H,5H-4a,7a-epoxy-4,8-
ethenocyclopenta[f ]isoindole-1,3(2H)-dione (3f). The title com-
pound was prepared according to general procedure A using 2,3-
dihydro-1H-3a,7a-epoxyindene (1.69 mmol), benzyl maleimide (316
mg, 1.69 mmol), and Et2O (8.5 mL) and stirred for 24 h. The solution
was concentrated, and the crude was purified using column
chromatography with hexanes/ethyl acetate (gradient, 5:1 to 1:1) to
yield the product as a white solid (331 mg, 1.03 mmol, 61% yield).
1
mg, 0.14 mmol, 74% yield, >20:1 dr). Analytical data: H NMR (600
MHz, CDCl3) δ 7.52−7.47 (m, 2H), 7.45−7.41 (m, 1H), 7.30−7.27
(m, 2H), 4.15 (dd, J = 11.9, 9.4 Hz, 2H), 4.03 (dd, J = 11.9, 5.6 Hz,
2H), 3.31−3.26 (m, 2H), 3.22 (s, 2H), 2.76−2.70 (m, 2H); 13C NMR
(150 MHz, CDCl3) δ 178.7, 129.3, 129.0, 126.7, 62.7, 52.4, 39.2, 37.7.
IR (thin film, cm−1): 3446, 1698, 1497, 1396, 1201, 1042. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C16H17NO5Na, 326.0999;
found, 326.0990.
1
Analytical data: H NMR (600 MHz, CDCl3) δ 7.34−7.20 (m, 5H),
5.76 (dd, J = 4.7, 3.2 Hz, 2H), 4.56 (s, 2H), 3.58−3.44 (m, 2H), 3.08−
3.01 (m, 2H), 2.02−1.95 (m, 2H), 1.86−1.78 (m, 1H), 1.75−1.67 (m,
3H); 13C NMR (150 MHz, CDCl3) δ 177.1, 135.5, 128.6, 128.5,
127.8, 64.3, 42.4, 42.3, 37.2, 25.4, 25.1. IR (thin film, cm−1): 2953,
1699, 1396, 1340, 1174, 916. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C20H19NO3Na, 344.1257; found, 344.1265. Mp: 179−181
°C. TLC (1:1 hexanes/ethyl acetate): Rf = 0.4.
(1R,2S,5R,6R,6S)-2,6-Bis(hydroxymethyl)-4-octylhexahydro-3H-
oxireno[2,3-f ]isoindole-3,5(4H)-dione (4d). The title compound was
prepared according to general procedure B using 3d (50 mg, 0.17
mmol), NaBH4 (12.5 mg, 0.33 mmol), and 2:1 DCM/MeOH (1.5
mL) and was obtained as a white solid (53 mg, 0.16 mmol, 95% yield).
1
Analytical data: H NMR (400 MHz, CDCl3) δ 4.13−4.02 (m, 2H),
General Procedure B for the Preparation of Diols (4a−4f). The
Diels−Alder adduct (1 equiv) was dissolved in a 2:1 mixture of DCM/
MeOH (0.11 M) and cooled to −78 °C in a dry ice/acetone bath.
Ozone was bubbled through the solution until the reaction turned
light blue, at which point the ozone bubbling was stopped, and the
solution was sparged with nitrogen to purge excess ozone. Solid
NaBH4 (2 equiv) was added, and the reaction was moved to an ice
bath. The reaction was allowed to stir for 1 h, and then 1 mL of water
was added. The layers were separated, and the aqueous layer was
extracted with DCM (2 mL × 3). The organic extracts were combined
and dried with sodium sulfate, filtered, and concentrated to obtain the
desired diol.
General Procedure C for the Preparation of Diols (5a−5f). The
Diels−Alder adduct (1 equiv) was dissolved in a 2:1 mixture of DCM/
MeOH (0.11 M) and cooled to −78 °C in a dry ice/acetone bath.
Ozone was bubbled through the solution until the reaction turned
light blue, at which point the ozone bubbling was stopped, and the
solution was purged with nitrogen to get rid of excess ozone. Solid
NaBH4 (2 equiv) was added, and the reaction was moved to an ice
bath. After stirring for 1 h, 1 mL of acetone was added and the reaction
was stirred for 5 min. The solvent was removed in vacuo, and the
residue was stirred overnight. Water (1 mL) and EtOAc (1 mL) were
then added, and the layers were separated. The aqueous layer was
extracted with EtOAc (3 × 2 mL), and the organics were combined,
dried with sodium sulfate, and concentrated to yield the crude diol.
(1R,2S,5R,6R,6S)-4-Benzyl-2,6-bis(hydroxymethyl)hexahydro-3H-
oxireno[2,3-f ]isoindole-3,5(4H)-dione (4b). The title compound was
prepared according to general procedure B using 3b (50 mg, 0.18
mmol), NaBH4 (13.4 mg, 0.36 mmol), and 2:1 DCM/MeOH (1.5
mL) and was obtained as a clear amorphous solid (56 mg, 0.18 mmol,
>98% yield, >20:1 dr). Analytical data: 1H NMR (600 MHz, CDCl3) δ
7.35 (d, J = 7.1 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.29−7.25 (m, 1H),
4.66 (s, 2H), 4.07 (dd, J = 11.9, 9.3 Hz, 2H), 3.97 (dd, J = 11.9, 5.5
Hz, 2H), 3.12 (s, 2H), 3.11−3.07 (m, 2H), 2.66−2.59 (m, 2H); 13C
NMR (150 MHz, CDCl3) δ 179.2, 138.6, 121.6, 64.1, 32.9. IR (thin
film, cm−1): 3417, 2939, 2885, 1769, 1683, 1405, 1186, 1029. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C17H20NO5, 318.1336; found,
318.1333.
4.02−3.92 (m, 2H), 3.60−3.50 (m, 2H), 3.47 (t, J = 7.4 Hz, 2H), 3.12
(s, 2H), 3.09−3.00 (m, 2H), 2.67−2.54 (m, 2H), 1.62−1.47 (m, 2H),
1.35−1.16 (m, 10H), 0.85 (t, J = 6.7 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 179.6, 62.7, 52.2, 39.0, 37.3, 31.7, 29.1, 29.0, 27.1, 26.7, 22.5,
14.1. IR (thin film, cm−1): 3420 (b), 2927, 2856, 1684, 1439, 1353,
1034. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H29NO5Na,
362.1938; found, 362.1938. Mp: 65−69 °C.
(1aR,2S,2aR,5aS,6R,6aS)-2,6-Bis(hydroxymethyl)-4-octylhexahy-
dro-3H-oxireno[2,3-f ]isoindole-3,5(4H)-dione (5d). The title com-
pound was prepared according to general procedure C using 3d (50
mg, 0.17 mmol), NaBH4 (12.5 mg, 0.33 mmol), and 2:1 DCM/
MeOH (1.5 mL) and was obtained with a 1.4:1 dr. To obtain the
product in >20:1 dr, a DCM (0.7 mL) solution of the diastereomeric
mixture was stirred with DBU (44 μL, 0.29 mmol) at room
temperature for 16 h. A saturated aq NaHCO3 solution (2 mL) was
added, and the layers were separated. The aqueous layer was extracted
with DCM (3 × 2 mL), and the organics were combined, dried with
sodium sulfate, and concentrated to afford the product as a white solid
(47 mg, 0.14 mmol, 97% yield). Analytical data: 1H NMR (400 MHz,
CDCl3) δ 4.15−4.06 (m, 2H), 4.06−3.94 (m, 2H), 3.49 (t, J = 11.3
Hz, 2H), 3.30 (s, 2H), 2.99−2.81 (m, 4H), 2.32−2.19 (m, 2H), 1.71−
1.47 (m, 3H), 1.34−1.16 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 180.0, 65.4, 65.4, 51.6, 39.1, 38.7, 38.7,
37.2, 31.7, 29.1, 29.0, 27.5, 26.7, 22.6, 14.1. IR (thin film, cm−1): 3420
(b), 2926, 2856, 1769, 1694, 1406, 1065. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C18H30NO5, 340.2118; found, 340.2111. Mp: 78−81
°C.
(1aR,2S,8R,8aS)-2,8-Bis(hydroxymethyl)-5-phenyltetrahydro-4H-
oxireno[2,3-d][1,2,4]triazolo[1,2-a]pyridazine-4,6(5H)-dione (4e).
The title compound was prepared according to general procedure B
using 3e (50 mg, 0.19 mmol), NaBH4 (14.1 mg, 0.37 mmol), and 2:1
DCM/MeOH (1.5 mL). The product was purified using silica gel
column chromatography with DCM/MeOH 20:1 and was obtained as
1
a white solid (34.0 mg, 0.11 mmol, 60% yield). Analytical data: H
NMR (600 MHz, CDCl3) δ 7.51−7.44 (m, 4H), 7.43−7.39 (m, 1H),
4.32−4.26 (m, 2H), 4.20−4.08 (m, 4H), 3.64 (dd, J = 2.3, 1.0 Hz,
2H), 3.49 (dd, J = 9.4, 4.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
153.4, 130.4, 129.3, 128.8, 125.7, 61.5, 55.9, 51.4. IR (thin film, cm−1):
3419, 2894, 1769, 1698, 1430, 1292, 1077, 768. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C14H15N3O5Na, 328.0904; found, 328.0893.
Mp: 119−122 °C. TLC (20:1 DCM/MeOH): Rf = 0.2.
(1aR,2S,2aR,5aS,6R,6aS)-4-Benzyl-2,6-bis(hydroxymethyl)-
hexahydro-3H-oxireno[2,3-f ]isoindole-3,5(4H)-dione (5b). The title
compound was prepared according to general procedure C using 3b
E
DOI: 10.1021/acs.joc.8b00523
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(3R,4R,4S,7R,8S,8S)-2-Benzyl-4,8-bis(hydroxymethyl)hexahydro-
1H,5H-4a,7a-epoxycyclopenta[f ]isoindole-1,3(2H)-dione (4f). The
title compound was prepared according to general procedure B using
3f (50 mg, 0.16 mmol), NaBH4 (11.8 mg, 0.31 mmol), and 2:1 DCM/
MeOH (1.5 mL). The crude was purified using column chromatog-
raphy with DCM/MeOH 20:1 and was obtained as a white
amorphous solid (53 mg, 0.15 mmol, 95% yield). Analytical data:
1H NMR (600 MHz, CDCl3) δ 7.38−7.33 (m, 2H), 7.33−7.29 (m,
37.0, 35.1, 27.5, 9.0. IR (thin film, cm−1): 3444, 2943, 1694, 1353,
1187, 1082, 1018, 881. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C20H23NO6Na, 396.1418; found, 396.1418. HPLC (65:35 hexa-
ne/iPrOH, Daicel CHIRALPAK IC): 82:18 er, tR (major) 16.5 min,
tR (minor) 29.6 min. [α]D = −5.08 (c 0.01, CHCl3). TLC (1:2
hexanes/ethyl acetate): Rf = 0.1.
Procedure for the Preparation of 8. Acetic anhydride (34 μL, 0.36
mmol) was added to a dichloromethane (0.8 mL) solution of 5b (52.0
mg, 0.16 mmol) and DMAP (2.0 mg, 0.02 mmol) at room
temperature, and the reaction was allowed to stir overnight. The
solvent was subsequently removed under reduced pressure, and the
crude material was purified using column chromatography (1:1
hexanes/ethyl acetate) to obtain 8 as a clear oil (50.0 mg, 0.13 mmol,
76% yield). Analytical data: 1H NMR (600 MHz, CDCl3) δ 7.35−7.26
(m, 5H), 4.70 (ddd, J = 11.1, 3.9, 1.2 Hz, 2H), 4.62 (s, 2H), 4.37 (ddd,
J = 11.1, 6.8, 1.1 Hz, 2H), 3.28 (s, 2H), 2.84−2.77 (m, 2H), 2.40−2.33
(m, 2H), 2.10 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 177.8, 170.7,
135.4, 128.7, 128.1, 64.6, 51.2, 42.4, 36.8, 34.7, 20.8. IR (thin film,
cm−1): 3648, 3456, 2951, 2359, 1698, 1401, 1235, 1040. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C21H23NO7Na, 424.1367; found,
424.1349. TLC (1:1 hexanes/ethyl acetate): Rf = 0.4.
Procedure for the Preparation of 9. A mixture of 8 (50 mg, 0.13
mmol), porcine pancreatic lipase (100 mg), acetone (2.5 mL), and pH
6.5 phosphate buffer (5 mL) was stirred for 5 days at room
temperature. Ethyl acetate (5 mL) was added, and the layers were
separated. The aqueous layer was extracted with ethyl acetate (3 × 5
mL). The organics were combined, dried with sodium sulfate, and
concentrated under reduced pressure. Purification via column
chromatography using hexanes/ethyl acetate 1:1 to 1:2 afforded 9 as
a clear oil (31.0 mg, 0.09 mmol, 69% yield, 88:12 er). The absolute
configuration is unassigned. Analytical data: 1H NMR (600 MHz,
CDCl3) δ 7.36−7.24 (m, 5H), 4.72 (ddd, J = 11.1, 3.9, 1.9 Hz, 1H),
4.63 (d, J = 1.9 Hz, 2H), 4.42−4.34 (m, 1H), 4.11−4.03 (m, 1H),
4.03−3.94 (m, 1H), 3.29 (q, J = 4.6 Hz, 2H), 2.92−2.77 (m, 3H),
2.40−2.33 (m, 1H), 2.28−2.21 (m, 1H), 2.10 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 179.4, 178.0, 170.8, 135.3, 128.8, 128.1, 65.2, 64.6,
51.7, 51.2, 42.5, 38.4, 37.1, 36.9, 36.6, 34.8, 20.8. IR (thin film, cm−1):
3502, 2926, 1697, 1400, 1241, 1176, 1037. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C19H21NO6Na, 382.1261; found, 382.1251.
HPLC (65:35 hexane/iPrOH, Daicel CHIRALPAK IC): 88:12 er, tR
(major) 23.1 min, tR (minor) 34.6 min. [α]D = +20.9 (c 0.01, CHCl3).
TLC (1:1 hexanes/ethyl acetate): Rf = 0.2.
2H), 7.29−7.27 (m, 1H), 4.67 (s, 2H), 4.09 (ddd, J = 12.0, 9.8, 6.8 Hz,
2H), 3.98 (ddd, J = 12.3, 7.9, 4.8 Hz, 2H), 3.58 (dd, J = 7.9, 6.9 Hz,
2H), 3.20−3.14 (m, 2H), 2.66−2.59 (m, 2H), 2.11−2.02 (m, 2H),
1.63−1.53 (m, 4H), 1.36−1.27 (m, 1H); 13C NMR (150 MHz,
CDCl3): 179.6, 135.3, 128.6, 128.4, 127.9, 66.6, 61.6, 42.7, 40.2, 39.3,
28.2, 19.5. IR (thin film, cm−1): 3446, 2952, 1685, 1431, 1350, 1169,
1054. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H23NO5Na,
380.1468; found, 380.1467. TLC (20:1 DCM/MeOH): Rf = 0.3.
(3aR,4S,4aR,7aS,8R,8aS)-2-Benzyl-4,8-bis(hydroxymethyl)-
hexahydro-1H,5H-4a,7a-epoxycyclopenta[f ]isoindole-1,3(2H)-
dione (5f). The title compound was prepared according to general
procedure C using 3f (50 mg, 0.16 mmol), NaBH4 (11.8 mg, 0.31
mmol), and 2:1 DCM/MeOH (1.5 mL) and was obtained as a light
pink solid (51.6 mg, 0.14 mmol, 93% yield). Analytical data: 1H NMR
(400 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 4.65 (s, 2H), 4.16−4.07 (m,
2H), 3.96 (dd, J = 11.1, 5.9 Hz, 2H), 3.14−3.07 (m, 2H), 2.91−2.83
(m, 2H), 2.29−2.23 (m, 2H), 2.18−2.11 (m, 2H), 1.67−1.55 (m, 5H),
1.46−1.36 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 180.0, 135.3,
128.8, 128.7, 128.2, 66.2, 63.9, 42.6, 40.3, 39.0, 29.1, 19.5. IR (thin
film, cm−1): 3445, 2953, 1696, 1430, 1174, 1071, 733. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C20H23NO5Na, 380.1468; found,
380.1488. Mp: 151−155 °C.
Procedure for the Preparation of 6. Under an inert atmosphere, 4d
(17.0 mg, 0.05 mmol), the phosphoric acid (1.1 mg, 0.0012 mmol),
and 2-mercaptobenzothiazole (10.0 mg, 0.06 mmol) were dissolved in
anhydrous tetrahydrofuran (0.1 mL), and the mixture was stirred at
room temperature for 72 h. The reaction was stopped by removal of
the solvent under reduced pressure. Purification with column
chromatography using 40:1 to 20:1 DCM/MeOH yielded 6 as a
clear oil (16.0 mg, 0.032 mmol, 63% yield, 90:10 er). The absolute
configuration is unassigned. Analytical data: 1H NMR (600 MHz,
CDCl3) δ 7.78−7.70 (m, 2H), 7.43−7.36 (m, 1H), 7.34−7.27 (m,
1H), 4.24 (d, J = 2.7 Hz, 1H), 4.17−4.01 (m, 3H), 3.99−3.81 (m,
4H), 3.52 (td, J = 7.2, 2.2 Hz, 2H), 3.39 (dd, J = 9.8, 5.1 Hz, 1H), 3.31
(dd, J = 9.8, 7.1 Hz, 1H), 2.99−2.88 (m, 1H), 2.53−2.43 (m, 1H),
2.21−2.11 (m, 1H), 1.78−1.68 (m, 1H), 1.64−1.53 (m, 2H), 1.38−
1.17 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 179.6, 179.4, 166.2, 152.5, 134.9, 126.2, 124.7, 121.2, 121.1, 74.6,
74.5, 62.5, 61.7, 50.2, 42.6, 39.4, 39.3, 37.9, 36.9, 31.8, 29.2, 27.09,
27.06, 22.6, 14.1. IR (thin film, cm−1): 3392, 2926, 2855, 1681, 1426,
1353, 999, 756, 728. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C25H34N2O5S2Na, 529.1801; found, 529.1798. HPLC (45:55
hexane/iPrOH, Daicel CHIRALPAK IA): 91:9 er, tR (minor) 4.4
min, tR (major) 6.6 min. [α]D = −65.2 (c 0.007, CHCl3). TLC (20:1
DCM/MeOH): Rf = 0.5.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00523.
Crystallographic data for 5d (CIF)
Mechanistic experiments and spectral data for all
compounds (PDF)
Procedure for the Preparation of 7. To a CHCl3 (0.7 mL) solution
of 4b (50.0 mg, 0.16 mmol), the catalyst (3.9 mg, 0.02 mmol), and
Na2SO4 (78.3 mg, 0.55 mmol) was added propionic anhydride (22 μL,
0.17 mmol) at room temperature. The reaction was allowed to stir for
5 days and stopped by removal of the solvent under reduced pressure.
Purification via column chromatography using a gradient from 1:1 to
1:2 hexanes/ethyl acetate afforded 7 as a clear oil (26.0 mg, 0.07
mmol, 44% yield, 14:1 dr, 80:20 er). The absolute configuration is
unassigned. Note that some epimerization was observed after column
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsj@unc.edu.
ORCID
Jeffrey S. Johnson: 0000-0001-8882-9881
Notes
The authors declare no competing financial interest.
1
chromatography, resulting in the 14:1 dr. Analytical data: H NMR
(600 MHz, CDCl3) δ 7.39−7.35 (m, 2H), 7.33−7.29 (m, 2H), 7.29−
7.25 (m, 1H), 4.81 (dd, J = 11.4, 6.2 Hz, 1H), 4.65 (s, 2H), 4.58 (dd, J
= 11.4, 8.8 Hz, 1H), 4.05−3.99 (m, 1H), 3.96−3.89 (m, 1H), 3.48−
3.41 (m, 1H), 3.28 (d, J = 4.8 Hz, 1H), 3.14−3.08 (m, 2H), 3.00 (dd, J
= 10.0, 6.4 Hz, 1H), 2.67−2.60 (m, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.15
(t, J = 7.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 178.9, 177.1,
174.1, 135.3, 128.5, 128.4, 127.8, 63.7, 62.8, 52.4, 51.9, 42.5, 38.9, 38.3,
ACKNOWLEDGMENTS
■
We acknowledge the National Science Foundation (CHE-
1402917 and CHE-1665008) for financial support. D.M.M.
acknowledges an NSF Graduate Research Fellowship. X-ray
crystallography was performed by Dr. Peter White (UNC).
F
DOI: 10.1021/acs.joc.8b00523
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Chem. Rev. 2005, 105, 313. (b) Díaz de Villegas, M. D.; Gal
́
vez, J. A.;
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