Propellane as a conformational device for the stabilization of the β-lactone of salinosporamide A

Article abstract of DOI:10.1016/j.tet.2009.05.085

The synthesis of a propellane derivative of salinosporamide A having increased stability under physiological-like conditions is reported. The synthesis took advantage of a substrate-controlled stereoselective Ugi 4-center 3-component reaction to construct

Full text of DOI:10.1016/j.tet.2009.05.085

Tetrahedron 65 (2009) 5899–5903
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Propellane as a conformational device for the stabilization of the
of salinosporamide A
b-lactone
*
Mitchell Vamos, Yoshihisa Kobayashi
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343, La Jolla, CA 92093-0343, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a propellane derivative of salinosporamide A having increased stability under physio-
logical-like conditions is reported. The synthesis took advantage of a substrate-controlled stereoselective
Ugi 4-center 3-component reaction to construct the required syn-bicyclic pyroglutamic acid framework.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 April 2009
Received in revised form 27 May 2009
Accepted 28 May 2009
Available online 6 June 2009
1. Introduction
difficult, except for when the necessary orientation is achieved in
the protein complex.4 Second, the conformational change of the
Naturally occurring salinosporamide A exhibits potent and se-
lective inhibition of proteasome activity similar to that of the
clinically used pharmaceutical VelcadeÒ.1 Despite its efficacy as an
irreversible inhibitor of the 20S proteasome and possible clinical
utility in the treatment of certain types of cancer, salinosporamide
A still suffers from a lack of stability that could limit its viability or
cyclohexane ring in going from the boat to chair conformation5
upon b-lactone opening could be a means to render the proteaso-
mal binding irreversible, similar to the chloroethyl trapping of the
resulting alkoxide of salinosporamide A.6 By these two structural
designs, it is expected that we should see increased b-lactone sta-
bility, hopefully coinciding with retention of irreversible protea-
some complexation.
shelf life.2 Degradation of the
b-lactone through nucleophilic ring-
opening of the strained four-membered ring is an issue, especially if
it is to be viable in vivo.3 We were interested in designing an analog
which preserves the main structural feature of salinosporamide A,
2. Results and discussion
the fused b-lactone-g-lactam, and thus its biological activity, while
enhancing its stability (Fig. 1).
We were also interested in designing a substrate-controlled
stereoselective Ugi 4-center 3-component reaction (4C-3CR) for the
synthesis of pyroglutamic acid derivatives (Scheme 1, B/A).
g
-Ketoacid B seemed like a logical choice to fit these qualifications;
O
O
O
the restricted conformational freedom imposed by the ring could
allow for stereoselective kinetic attack of the isocyanide to the
putative iminium ion, thus a diastereoselective Ugi reaction.
H
O
7
HN
HN
CH3
OH
O
O
H
O
Ugi 4C-3C
1
β-Lactonization
Reaction
R1
O
Cl
Salinosporamide A
O
O
O
O
[4.3.2]-Propellane
HN
HO
β-lactone
HO
O
N
O
R1
R2
Figure 1. Structures of propellane 1 and salinosporamide A.
O
1
Boat
A
Chair
B
The salinosporamide A analog that interested us, [4.3.2]-pro-
pellane b-lactone 1, did so for two reasons. First, we anticipated that
Scheme 1. Retrosynthetic analysis of propellane 1.
introduction of the fused six-membered ring to give the propellane
structure could make nucleophilic attack to the lactone more
We envisioned that access to the pyroglutamic acid portion of
[4.3.2]-propellane -lactone 1 could come through the Ugi 4C-3CR
with -ketoacid B and a convertible isocyanide, as shown in
b
g
Scheme 1. Usage of an appropriate convertible isocyanide would
allow for selective hydrolysis of the desired amide to the
* Corresponding author.
E-mail address: ykoba@chem.ucsd.edu (Y. Kobayashi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.085

5900
M. Vamos, Y. Kobayashi / Tetrahedron 65 (2009) 5899–5903
pyroglutamic acid A. In order to eventually form the
b
-lactone, it
protected with the methoxymethyl (MOM) group (7a), the diaster-
eoselectivity dropped to 3.5:1 syn/anti. Without protection (7b)
there was a 1.5:1 ratio in favor of the anti-isomer.
was necessary that the syn-diastereomer be formed as the major
product in the Ugi 4C-3CR. Besides the use of the Ugi 4C-3CR as
a means to build up the pyroglutamic acid core, it also proved to be
a useful method to access the functionalized [4.3.2]-propellane
structure.7
During our studies on the racemic synthesis of pyroglutamic
acid A (R1¼H, R2¼PMB), we encountered two limitations in using
the synthetic route for the synthesis of 1.8 First, negligible (1.5:1
anti/syn) stereoselectivity was observed in the Ugi 4C-3CR, in favor
of the undesired anti-isomer of 2 (Scheme 2). Second, we observed
loss of the required syn-isomer of 2 as the N,O-acetal 4 during
formation of N-acylindole 3. As a solution to both problems, we
Ar
Ar
O
N
NH
O
N
NH
PMB
O
PMB
O
PMB-NH2
O
HO
isocyanide 8
TFE, 80 °C
O
O
O
O
R
R
R
7-7b
9-9b
γ-Ketoacid
Yield (%) Syn
Anti
7
R = -CH2SCH3
R = -CH2OCH3
R = -H
:
:
:
80
66
83
7.0
3.5
1.0
1.0
1.0
1.5
sought an O-protected g-ketoacid B.
7a
7b
OMe
OMe
Scheme 4. Stereocontrolled Ugi 4C-3CR of cyclic levulinic acid derivatives.
O
N
NH
O
N
N
O
N
N
O
PMB
O
PMB
O
PMB
O
CSA
The anilide 9 was converted to N-acylindole 10 in 73% yield by
treatment with a 5:1 mixture of acetic acid and trifluoroacetic acid.
The conditions for indole formation were important as it was found
that stronger acids like CSA induced deprotection of the MTM
group and formation of the aforementioned N,O-acetal 4 from the
major syn-isomer. Attempts to convert 4 to the desired unprotected
N-acylindole were unsuccessful.14 Alkaline hydrolysis of 10 occurs
readily to afford acid 11 in 81% yield under relatively mild condi-
tions due to the lower bond order of the C–N amide bond.
H
PhH
60 °C
OH
OH
2
3
4
5 : 1
1.5 : 1
68%
26%
anti / syn
anti / syn
Scheme 2. Loss of syn-Ugi product 2 as N,O-acetal 4.
Due to the steric congestion around the tertiary alcohol of B, our
options for protecting groups were limited. However, the methyl-
thiomethyl (MTM) protecting group was feasible due to its previous
usage in this realm.9 It was expected that this protecting group
would be stable under acidic conditions, preventing formation of
the undesired N,O-acetal 4.
This special N-acylindole reactivity is important because
strongly basic conditions caused elimination of the protected
b-alcohol. Deprotection of the MTM group with trityl tetra-
fluoroborate occurred in 81% yield, followed by -lactone formation
b
of hydroxyacid 12 with bromotripyrrolidinophosphonium hexa-
fluorophosphate (PyBroP) and triethylamine to give 13 in 67%
yield.15 Subsequent oxidative deprotection of the PMB group with
The Ugi precursor, g-ketoacid 7, was synthesized as described in
Scheme 3. The starting ketone 5 was prepared enantioselectively as
described previously.10 Introduction of the MTM protecting group
to the tertiary alcohol was efficiently accomplished using DMSO
and acetic anhydride. Hydrogenation of the benzyl ester 6 proved
difficult; palladium poisoning from the MTM-sulfur greatly di-
minished the reaction rate. However, a simple alkaline hydrolysis
with sodium hydroxide posed no problem and 7 was obtained in
quantitative yield.11
ceric ammonium nitrate (CAN) furnished the propellane b-lactone
1 in 78% yield. The relative stereochemistry of the final compound
was unambiguously confirmed by single crystal X-ray analysis as
shown below (Fig. 2).16 As anticipated, the cyclohexane ring adopts
the boat conformation, causing the pseudo-axial C(7)-H bond to
cover the corresponding side of the
the space-filling diagrams).
b-lactone carbonyl (as seen in
With g-ketoacid 7 in hand, the Ugi 4C-3CR was used with para-
Shown in Scheme 5 is our proposed rationale for the observed
trend of stereoselectivity in the Ugi 4C-3CR with the three -keto-
methoxybenzylamine and convertible isocyanide 812 to give the
pyroglutamic acid amide 9 in 80% yield as a 7:1 ratio of diastereomers
with syn as the major isomer.13 The MTM protecting group was es-
sential for diastereoselectivity in the Ugi 4C-3CR with convertible
isocyanide 8 and para-methoxybenzylamine (Scheme 4). When
g
acids 7, 7a, and 7b. The direction of attack of the isocyanide to the two
possible chair conformations C and D of the iminium salt (E-geom-
etry) is what determines the syn/anti diastereoselectivity. As the size
of the R-group increases (H/MOM/MTM), this should shift the
OMe
O
O
O
PMB-NH2
BnO
O
BnO
O
HO
OMe
Ac2O
NaOH, H2O
THF, quant.
TFA, AcOH
PhH, 50 °C
73%
isocyanide 8
O
N
NH
PMB
O
O
TFE, 80 °C
80%
DMSO
60 °C
OH
O
O
MTM
MTM
7:1
syn/anti
5
6
7
quant.
O
9
OMe
MTM
MTM = -CH2SCH3
OMe
PMB = 4-MeOC6H4CH2-
NC
8
O
O
PMB
PMB
CAN
PyBroP
O
N
CO2H
OH
CO2H
O
PMB
Et3N
Ph3C•BF4
H2O
O
N
N
NaOH
O
N
O
PMB
O
O
O
HN
N
MeCN
DCM
67%
DCM
81%
THF, H2O
70 °C
0 °C
78%
[α]D23 -39
81%
O
O
MTM
1
13
12
11
10
MTM
Scheme 3. Stereocontrolled asymmetric synthesis of [4.3.2]-propellane b-lactone 1.

M. Vamos, Y. Kobayashi / Tetrahedron 65 (2009) 5899–5903
5901
Figure 2. X-ray crystal structure of propellane
b-lactone 1 and the space-filling models (gray: carbon; green: hydrogen; red: oxygen; blue: nitrogen) from an aerial view (A), from an
anterior view (B) and from a right lateral view (C).
protection of the tertiary alcohol in ketoacid 7 led to good dia-
stereocontrol in the Ugi 4C-3CR, as well as a successful trans-
formation to N-acylindole without formation of N,O-acetal side
product. The synthesis took advantage of mild hydrolysis of the
sterically hindered N-acylindole amide 9. The boat conformation of
propellane 1 is important for its enhanced stability compared to
salinosporamide A, which could allow for better viability in vivo as
a therapeutic agent. Biological testing of [4.3.2]-propellane b-lac-
tone 1 as a potential selective and irreversible proteasome inhibitor
will be reported in due course.
H
N
Iminium
R
O
PMB
of 7
O
R
PMB
N
H
CO2
Conformation C
CO2
Conformation D
:C=N-Ar
:C=N-Ar
R
R
O
PMB
O
HN
HN
O2C
PMB
CO2
:C=N-Ar
anti-9 (minor)
E
F
syn-9
syn-9
4. Experimental section
4.1. General
Scheme 5. Analysis of Ugi 4C-3CR stereochemical output.
conformational equilibrium towards C, which places the ether in the
less encumbered equatorial position. Attack of the isocyanide to C for
7 and 7a should occur from the axial direction (in blue) so as to avoid
the eclipsing interaction between the PMB-amine and R-group that
occurs upon movement of the PMB-amine to the axial position after
equatorial attack (see structure E of conformation C). The torsional
strain incurred in the transition state resulting from equatorial ap-
proach and leading to the anti diastereomer should become more
prominent as the size of the R-group increases.17 Thus, attack of the
isocyanide from the axial direction is favored and the syn product
is obtained as the major diastereomer for 9 and 9a. For unprotected
All solvents were used as purchased from commercial sources or
dried over 4 Å molecular sieves prior to use in the case of moisture
sensitive reactions. Thin-layer chromatography (TLC) was performed
using silica gel 60 F254 pre-coated plates (0.25 mm). Flash chroma-
tography was performed using silica gel (32–63 mm particle size). All
products were purified to homogeneity by TLC analysis (single spot),
using a UV lamp and/or iodine and/or CAM or basic KMnO4 for de-
tection purposes. NMR spectra were recorded on 300 MHz,
400 MHz, and 500 MHz spectrometers. 1H and 13C NMR chemical
shifts are reported as d using residual solvent as an internal standard.
g
-ketoacid 7b (R¼H) the amount of conformational bias (C vs D), as
4.2. Benzyl (1S)-{1-[(methylsulfanyl)methoxy]-2-
oxocyclohexyl}acetate (6)
well as the eclipsing interaction, is diminished, leading to a 1.0:1.5
mixture of diastereomers 9b.8 Attack of the isocyanide to confor-
mation D (structure F) requires the seemingly more hindered
equatorial approach (in blue) to give the syn product. Therefore,
more anti product may result from this minor conformer. However,
the coulombic attraction between the iminium and carboxylate ions
present in both conformations could be important and would tend to
give the syn product for each.
To a solution of 5 (86 mg, 0.328 mmol, 1.0 equiv) in DMSO
(1.5 mL) was added Ac2O (1.5 mL). Heated to 50 ꢀC and periodically
added 1 equiv DMSO and Ac2O until TLC showed completion. After
2 h of heating the reaction was partitioned between 1 M NaOH
(25 mL) and EtOAc (20 mL), washed with saturated aqueous so-
dium chloride (15 mL), dried over sodium sulfate, filtered and
concentrated in vacuo. Prior to chromatography, any sulfide by-
products were removed by heating under hi-vacuum. The resultant
oil was purified by flash chromatography on silica gel (7:1 hexanes/
Propellane b-lactone 1 was subjected to buffered alkaline con-
ditions identical to those previously reported in the salinospor-
amide A stability study by Stella et al.3,18 Treatment of a 25 mM
acetonitrile solution of 1 to pH 7.5 phosphate buffer for the
reported salinosporamide A half-life time of 87 min gave no de-
tectable decomposition by TLC (thin-layer chromatography) and 1H
NMR analysis of the crude product. At pH 8.07 the reported half-life
time of salinosporamide A is 50 min, and treatment of 1 to this
higher pH under the same reaction conditions resulted in less than
EtOAc) to yield 6 as a colorless oil (105 mg, 99%). Rf¼0.42 (3:1
23
hexanes/EtOAc); [
a
]
ꢁ55.9 (c 1.3, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
: 7.40–7.30 (m, 5H), 5.12 (s, 2H), 4.64 (d, 1H, J¼11.0 Hz), 4.30
(d, 1H, J¼11.0 Hz), 2.91 (d, 1H, J¼16.0 Hz), 2.78 (td, 1H, J¼13.0,
6.0 Hz), 2.68 (d, 1H, J¼16.0 Hz), 2.42–2.32 (m, 2H), 2.18 (s, 3H),
2.08–1.95 (m, 2H), 1.89–1.79 (m, 1H), 1.74–1.57 (m, 2H); 13C NMR
5% decomposition. As anticipated, the b-lactone showed improved
stability under physiological-like conditions.
(75 MHz, CDCl3) d: 210.0, 170.4, 135.9, 128.8, 128.5, 81.9, 69.0, 66.8,
39.6, 38.4, 37.5, 27.8, 20.7, 15.2; HRMS calcd for C17H22O4S:
322.1233, found: 322.1241.
3. Conclusions
4.3. (1S)-[1-[(Methylsulfanyl)methoxy]-2-
We have demonstrated the feasibility and applicability of the
Ugi 4C-3CR to the synthesis of an interesting structural analog of
the proteasome inhibitor salinosporamide A by preparation of
oxocyclohexyl]acetic acid (7)
To a solution of 6 (289 mg, 0.896 mmol, 1.0 equiv) in THF (5 mL)
[4.3.2]-propellane
b
-lactone 1 in enantiomerically pure form. The
was added NaOH (36 mg, 0.896 mmol,1.0 equiv) in H2O (1 mL). After

5902
M. Vamos, Y. Kobayashi / Tetrahedron 65 (2009) 5899–5903
stirring for 1 h, EtOAc (10 mL) was added and the organic layer re-
moved. The aqueous layer was acidified with concd HCl to pHꢂ2 and
then extracted with EtOAc (3ꢃ10 mL), dried over sodium sulfate,
159.1, 137.1, 130.3, 129.9, 129.8, 128.4, 125.0, 124.0, 120.8, 116.7,
114.0, 108.2, 80.9, 76.8, 68.9, 55.4, 45.3, 40.0, 30.7, 21.4, 21.0,
20.4, 14.9; HRMS calcd for
478.1925.
C27H30N2O4S: 478.1921, found:
filtered and concentrated in vacuo to yield 7 as a colorless oil
23
(205 mg, 98%). [
d
a
]
ꢁ16.1 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3)
D
: 4.69 (d, 1H, J¼11.2 Hz), 4.63 (d, 1H, J¼11.2 Hz), 2.98 (d, 1H,
4.6. (3aS,7aR)-1-(4-Methoxybenzyl)-3a-[(methylsulfanyl)-
methoxy]-2-oxooctahydro-7aH-indole-7a-carboxylic
acid (11)
J¼17.2 Hz), 2.72 (d, 1H, J¼17.6 Hz), 2.38–2.28 (m, 1H), 2.20 (s, 3H),
2.03–1.96 (m,1H),1.90–1.76 (m, 2H),1.75–1.61 (m, 2H),1.60–1.49 (m,
1H),1.43–1.32 (m,1H); 13C NMR (75 MHz, CDCl3)
d: 172.0,106.6, 81.4,
68.4, 37.4, 34.5, 29.1, 21.7, 21.5, 14.4; HRMS calcd for C10H16O4S:
232.0764, found: 232.0767.
To a solution of 10 (355 mg, 0.742 mmol, 1.0 equiv) in 3:1 THF/
H2O (12 mL) was added 1 M NaOH (1.19 mL, 1.19 mmol, 1.6 equiv).
The mixture was heated to 70 ꢀC for 5 h, then EtOAc (10 mL) and
1 M NaOH (10 mL) were added and the layers separated. The
aqueous layer was acidified with concd HCl to a pHꢂ2, then
extracted with EtOAc (3ꢃ10 mL), dried over sodium sulfate, filtered
4.4. (3aS,7aR)-N-[2-(2,2-Dimethoxyethyl)phenyl]-1-(4-
methoxybenzyl)-3a-[(methylsulfanyl)methoxy]-2-
oxooctahydro-7aH-indole-7a-carboxamide (9)
and concentrated in vacuo to yield 11 as an orange solid (215 mg,
23
To a solution of 7 (111 mg, 0.478 mmol, 1.0 equiv) in 2,2,2-tri-
fluoroethanol (8 mL) was added 4-methoxybenzylamine (62 mL,
0.478 mmol, 1.0 equiv) and isocyanide 8 (91 mg, 0.478 mmol,
1.0 equiv) in 2,2,2-trifluoroethanol (2 mL). Reaction progress can be
monitored by TLC using isocyanide 8 as a reference. The mixture
was heated to 70 ꢀC for 3 h, then saturated aqueous sodium chlo-
ride (20 mL) was added and the organics extracted with EtOAc
(25 mL). The organics were dried over sodium sulfate, filtered and
concentrated in vacuo. The resultant viscous oil was purified by
flash chromatography on silica gel (3:1/2:1 hexanes/EtOAc) to
yield 9 as an off-white solid (206 mg, 80%, 7:1 syn/anti). A small
amount of 9 already may have converted to the aldehyde (from
dimethyl acetal deprotection) during the reaction and/or during
77%). Rf¼0.13 (100% EtOAc); mp¼70–72 ꢀC; [
a
]
ꢁ28.9 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.22 (d, 2H, J¼8.8 Hz), 6.79 (d,
2H, J¼8.8 Hz), 4.57 (d, 1H, J¼11.2 Hz), 4.49 (d, 1H, J¼15.2 Hz), 4.47
(d, 1H, J¼11.2 Hz), 4.18 (d, 1H, J¼15.2 Hz), 3.76 (s, 3H), 3.17 (d, 1H,
J¼15.2 Hz), 2.36 (d, 1H, J¼15.6 Hz), 2.24 (td, 1H, J¼12.8, 4.4 Hz), 2.10
(m, 1H), 2.06 (s, 3H), 1.91 (m, 1H), 1.40 (m, 4H), 0.76 (m, 1H); 13C
NMR (100 MHz, CDCl3) d: 176.4, 175.6, 159.1, 130.3, 129.1, 113.9, 79.7,
72.3, 69.4, 55.4, 46.3, 44.0, 42.0, 32.1, 25.9, 20.9, 20.3, 20.0, 14.4, 8.9;
HRMS calcd for C19H25NO5S: 379.1448, found: 379.1455.
4.7. (3aS,7aR)-3a-Hydroxy-1-(4-methoxybenzyl)-2-
oxooctahydro-7aH-indole-7a-carboxylic acid (12)
chromatography and can be taken into the next reaction. Rf¼0.32
To a solution of 11 (70 mg, 0.184 mmol, 1.0 equiv) in CH2Cl2
(7 mL) under N2 gas was added trityl tetrafluoroborate (73 mg,
0.221 mmol, 1.2 equiv). The mixture was stirred for 14 h, then 1 M
NaOH (8 mL) was added and the layers separated. The aqueous
layer was acidified with concd HCl to pHꢂ2 and then extracted
with EtOAc (3ꢃ5 mL). The organics were dried over sodium sul-
fate, filtered and concentrated in vacuo to yield 12 as an off-white
23
(1:1 hexanes/EtOAc); [
a
]
þ7.5 (c 1.6, CHCl3). Data for the major
D
syn-isomer: 1H NMR (400 MHz, CDCl3)
d: 9.00 (s, 1H), 7.60 (d, 1H,
J¼8.0 Hz), 7.27 (d, 2H, J¼8.4 Hz), 7.24–7.18 (m, 1H), 7.18–7.14 (m,
1H), 7.10–7.04 (m, 1H), 6.80 (d, 2H, J¼8.8 Hz), 4.81 (d, 1H,
J¼15.6 Hz), 4.58 (d,1H, J¼10.8 Hz), 4.46 (t,1H, J¼5.2 Hz), 4.45 (d,1H,
J¼10.8 Hz), 3.99 (d, 1H, J¼15.6 Hz), 3.76 (s, 3H), 3.43 (s, 3H), 3.40 (s,
3H), 3.08 (dd, 1H, J¼14.0, 6.0 Hz), 3.04 (d, 1H, J¼14.8 Hz), 2.82 (dd,
1H, J¼14.0, 4.8 Hz), 2.34 (d, 1H, J¼15.2 Hz), 2.24–2.08 (m, 2H), 2.04–
1.96 (m, 1H), 1.96 (s, 3H), 1.52–1.41 (m, 4H), 0.89–0.76 (m, 1H); 13C
solid (50 mg, 85%). Rf¼0.14 (4:1 EtOAc/methanol); mp¼62–64 ꢀC;
23
[
a
]
ꢁ30.3 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
d: 7.23 (d, 2H,
D
J¼8.5 Hz), 6.80 (d, 2H, J¼8.0 Hz), 4.66 (d, 1H, J¼15.5 Hz), 4.24 (d,
2H, J¼15.5 Hz), 3.78 (s, 3H), 2.77 (d, 1H, J¼16.0 Hz), 2.46 (d, 1H,
J¼16.5 Hz), 2.14 (m, 2H), 1.81 (m, 2H), 1.67 (td, 1H, J¼14.5, 4.0 Hz),
NMR (100 MHz, CDCl3) d: 175.0, 169.2, 158.7, 136.7, 130.8, 129.9,
128.3, 127.3, 124.9, 124.2, 113.6, 106.7, 79.4, 77.3, 77.0, 76.7, 73.5,
69.2, 44.3, 41.5, 36.8, 31.7, 26.8, 20.7, 20.2, 14.2; HRMS calcd for
C29H38N2O6S: 542.2445, found: 542.2444.
1.53 (m, 1H), 1.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 175.7,
175.4, 158.8, 130.0, 129.2, 113.8, 74.1, 72.1, 55.2, 44.3, 44.2, 35.8,
27.7, 20.3, 20.1; HRMS calcd for C17H21NO5: 319.1414, found:
319.1417.
4.5. (3aS,7aR)-1-(4-Methoxybenzyl)-3a-[(methylsulfanyl)-
methoxy]-7a-(1H-indol-1-ylcarbonyl)octahydro-
2H-indol-2-one (10)
4.8. (3aS,7aR)-1-(4-Methoxybenzyl)-2-methylenehexahydro-
1H-3a,7a-(epoxymethano)indol-8-one (13)
To a solution of 9 (572 mg, 1.05 mmol, 1.0 equiv) in benzene
(20 mL) was added AcOH (1.51 mL, 26.4 mmol, 25.0 equiv) and
trifluoroacetic acid (390 mL, 5.27 mmol, 5.0 equiv). The mixture
was heated to 50 ꢀC for 4 h, then saturated aqueous sodium
bicarbonate (50 mL) was added and the mixture extracted with
EtOAc (30 mL). The organics were dried over sodium sulfate,
filtered and concentrated in vacuo. The resultant oil was puri-
fied by flash chromatography on silica gel (3:1/2:1/1:1
hexanes/EtOAc) to yield 10 as a yellow solid (370 mg, 73%,
To a solution of 12 (127 mg, 0.398 mmol, 1.0 equiv) in CH2Cl2
(5 mL) was added bromotripyrrolidinophosphonium hexa-
fluorophosphate (PyBroP) (278 mg, 0.597 mmol, 1.5 equiv) and
Et3N (83 mL, 0.597 mmol, 1.5 equiv). The mixture was stirred for
2 h, then water (20 mL) was added and it was extracted with
CH2Cl2 (2ꢃ15 mL), dried over sodium sulfate, filtered and con-
centrated in vacuo. The resultant oil was purified by flash
chromatography on silica gel (1:1 hexanes/EtOAc) to yield 13
single diastereomer). Rf¼0.41 (1:1 hexanes/EtOAc); mp¼102–
(80 mg, 67%) as a colorless oil. Rf¼0.29 (1:1 hexanes/EtOAc);
23
23
105 ꢀC; [
a
]
þ6.4 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
:
[
a
]
ꢁ30.5 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 7.23 (d,
D
D
8.21 (d, 1H, J¼5.6 Hz), 7.95 (s, 1H), 7.55 (d, 1H, J¼8.4 Hz), 7.36–
7.23 (m, 2H), 7.17 (d, 2H, J¼8.4 Hz), 6.75 (d, 2H, J¼8.8 Hz), 6.56
(d, 1H, J¼4.0 Hz), 5.00 (d, 1H, J¼14.8 Hz), 4.56 (d, 1H, J¼11.2 Hz),
4.48 (d, 1H, J¼10.8 Hz), 3.76 (s, 3H), 3.66 (d, 1H, J¼15.6 Hz), 2.87
(d, 1H, J¼16.0 Hz), 2.60–2.47 (m, 1H), 2.52 (d, 1H, J¼15.2 Hz),
2.15–2.03 (m, 1H), 1.83 (s, 3H), 1.78–1.55 (m, 4H), 1.47–1.35 (m,
2H, J¼8.8 Hz), 6.83 (d, 2H, J¼8.8 Hz), 4.70 (d, 1H, J¼15.2 Hz), 4.33
(d, 2H, J¼15.2 Hz), 3.79 (s, 3H), 3.07 (d, 1H, J¼18.8 Hz), 2.67 (d,
1H, J¼19.2 Hz), 2.26–2.14 (m, 2H), 1.98–1.92 (m, 1H), 1.78–1.72
(m, 1H), 1.68–1.62 (m, 1H), 1.60–1.44 (m, 2H), 1.42–1.34 (m, 1H);
13C NMR (100 MHz, CDCl3)
d: 171.6, 168.9, 159.3, 129.7, 129.0,
114.1, 79.3, 55.4, 44.4, 41.0, 29.9, 24.2, 17.7, 17.5; HRMS calcd for
C17H19NO4: 301.1309, found: 301.1311.
1H), 1.08–0.84 (m, 1H); 13C NMR (75 MHz, CDCl3)
d: 174.2, 171.6,

M. Vamos, Y. Kobayashi / Tetrahedron 65 (2009) 5899–5903
5903
4.9. (3aS,7aR)-Tetrahydro-1H-3a,7a-(epoxymethano)indole-
References and notes
2,8-dione (1)
1. (a) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.;
Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355–357; (b) Chauhan, D.; Catley,
L.; Li, G.; Podar, K.; Hideshima, T.; Velankar, M.; Mitsiades, C.; Mitsiades, N.;
Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T. H.; Neu-
teboom, S.; Richardson, P.; Palladino, M. A.; Anderson, K. C. Cancer Cell 2005,
8, 407–419.
2. (a) Williams, P. G.; Buchanan, G. O.; Feling, R. H.; Kauffman, C. A.; Jensen, P. R.;
Fenical, W. J. Org. Chem. 2005, 70, 6196–6203; (b) Hogan, P. C.; Corey, E. J. J. Am.
Chem. Soc. 2005, 127, 15386–15387.
3. Denora, N.; Potts, B. C. M.; Stella, V. J. J. Pharm. Sci. 2007, 96, 2037–2047.
4. Based on ab initio calculations using the MM2 force field, we expected either
the boat or half-chair conformation for the cyclohexane ring in 1. From either of
these two conformations, the hydrogen on C7 of Figure 1 could block attack of
a nucleophile from the Bu¨rgi–Dunitz angle.
To a solution of 13 (15 mg, 0.05 mmol, 1.0 equiv) in CH3CN
(0.8 mL), and H2O (0.2 mL) was added cerium ammonium nitrate
(109 mg, 0.199 mmol, 4.0 equiv). The mixture stirred for 1 h, then
saturated sodium chloride was added and it was extracted with
EtOAc (3ꢃ5 mL), dried over sodium sulfate, filtered and concentrated
in vacuo. The resultant residuewas purified by flash chromatography
on silica gel (1:1/1:2 hexanes/EtOAc) to yield 1 as a colorless solid
23
(7 mg, 78%). Rf¼0.12 (1:1 hexanes/EtOAc); mp¼106–108 ꢀC; [
a]
D
ꢁ38.7 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 7.02 (br s,1H), 3.00
(d, 1H, J¼19.2 Hz), 2.60 (d, 1H, J¼18.8 Hz), 2.31–2.25 (m, 2H), 1.99–
5. The X-ray crystal structure for the pyroglutamic acid A (R1¼H, R2¼PMB in
1.91 (m, 1H), 1.78–1.53 (m, 5H); 13C NMR (100 MHz, CDCl3)
d: 174.3,
Scheme 1, also racemic 12 in Scheme 3) resulting from b-lactone hydrolysis is
reported in Ref. 8.
170.2, 81.5, 72.3, 41.0, 30.3, 25.2, 18.1, 17.9; HRMS calcd for C9H11NO3
(MþHþ): 182.0812, found: 182.0814.
6. Groll, M.; Huber, R.; Potts, B. C. M. J. Am. Chem. Soc. 2006, 128, 5136–5141.
7. Dodziuk, H. J. Comput. Chem. 1984, 5, 571–575. A literature search revealed no
known compounds possessing this interesting propellane structure in-
corporating both a lactam and a lactone.
Acknowledgements
8. Vamos, M.; Ozboya, K.; Kobayashi, Y. Synlett 2007, 1595–1599.
9. Yamada, K.; Kato, K.; Nagase, H.; Hirata, Y. Tetrahedron Lett. 1976, 17, 65–66.
10. Vamos, M.; Kobayashi, Y. J. Org. Chem. 2008, 73, 3938–3941. Compound 5 is
readily prepared in enantiopure form in 5 steps in 30% overall yield from
cyclohexanone.
Financial support of the National Science Foundation (in-
strumentation grants CHE-9709183, CHE-0116662 and CHE-
0741968) are gratefully acknowledged. We thank the University of
California for financial support of this research. We acknowledge
Professor Arnold Rheingold (UCSD) and Dr. Antonio DiPasquale
(UCSD) for X-ray crystal analysis, Dr. Yongxuan Su (UCSD) for Mass
Spectroscopy, and Kerem Ozboya (UCSD undergraduate student)
11. Hydrolysis of 5 under acidic or basic conditions led to elimination of the
alcohol; See Ref. 10.
12. Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631–3634. Compound
8 is readily prepared in 5 steps in 88% overall yield from 2-nitrotoluene.
13. The stereochemistry of 9 was confirmed by conversion of the unprotected Ugi
adduct 9b (syn/anti mixture) to 9 (same conditions as for 5/6); See Ref. 8.
14. Surprisingly, N,O-acetal 4 was stable to both acidic and basic conditions. This
disregard for rearomatization may be due to extra stability in the extended
cyclic framework.
for a racemic synthesis of propellane b-lactone 13.
Supplementary data
´
15. Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967–1970.
16. Crystallographic data for propellane
-lactone 1 are deposited as CCDC 728305.
b
Experimental procedures for stability tests of 1 and copies of 1H
NMR and 13C NMR spectra for 6–7, 9–13 and 1 (20 pages). Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.05.085.
The data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/re-
trieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033, e-mail deposit@ccdc.cam.ac.uk).
´
17. Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 18, 2205–2208.
18. See Supplementary data for experimental details.