Chiral aminocyclopentene-based cycloaddition strategies to bicyclic [3.3.0] rings

Article abstract of DOI:10.1016/j.tetasy.2013.04.014

Two cycloaddition methods were applied to chiral protected aminocyclopentenes 2 and 9 and provided novel bicyclic products 3 and 4 in good yields. The explanation for the observed stereochemistry was based on the sterically encumbered β-face forcing the c

Full text of DOI:10.1016/j.tetasy.2013.04.014

Tetrahedron: Asymmetry 24 (2013) 651–656
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Tetrahedron: Asymmetry
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Chiral aminocyclopentene-based cycloaddition strategies to bicyclic [3.3.0] rings
Chaozhong Cai a, Fu-An Kang a, Derek A. Beauchamp b, Zhihua Sui a, Ronald K. Russell b,
Christopher A. Teleha b,
⇑
a Metabolic Diseases Research, Janssen Pharmaceutical Research and Development, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA
b CREATe, High Output Synthesis Team (HOPS), Janssen Pharmaceutical Research and Development, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 March 2013
Accepted 19 April 2013
Two cycloaddition methods were applied to chiral protected aminocyclopentenes 2 and 9 and provided
novel bicyclic products 3 and 4 in good yields. The explanation for the observed stereochemistry was
based on the sterically encumbered b-face forcing the cycloadditions to occur on the a-face of the cyclo-
pentene ring. The stereochemistry of 4 was confirmed by X-ray of the fumarate salt 10 and showed the
trans-relationship between the newly formed ring and the chiral –NHBoc group.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
and 4. Elaboration of cycloaddition products 3 and 4 has been fea-
tured as CC-Chemokine receptor-2 (CCR-2) antagonists, generally
The formation of bicyclic rings from cyclic
a
,b-unsaturated esters
depicted as 1b, when decorated with a key functionality that im-
allows for quick entry into fused ring systems. Pseudo-symmetric
ring annulations typically employ methods that allow for ring for-
mation with a symmetry element for the newly attached ring. Trost
developed a palladium-catalyzed trimethylenemethane method
that provided for an all-carbon ring annulation with an exo-methy-
lene group at the locus of the three-atom attachment.1 Padwa et al.
pioneered the development of azomethine-ylide cycloaddition
methodology that provided three-atom annulations with an N-ben-
zyl at the center of the newly formed attachment.2 Clearly these
methodologies allow for entry into bicyclic ring systems in one step
that otherwise required multistep synthesis. However, in both cases,
the simplicity of the annulations has not been evaluated when the
starting acrylates had more diverse substitutions. Cycloadditions
of these types have seen little exploration in the literature, although
several are reported in patents3 (see Fig. 1).
parted biological activity.6
2. Results and discussion
While the preparation of acrylate 2 has been generally de-
scribed by several groups,5 our procedure provided some addi-
tional optimization of an otherwise acceptable procedure
(Scheme 1). Opening of the strained [2.2.1] lactam 5 was a facile
reaction, accomplished by the action of HCl in an alcoholic solvent
that would ultimately result in the corresponding carboxylic ester.
Our initial procedure, which used AcCl/MeOH, was a suitable
method for the generation of stoichiometric amounts of HCl, but
we chose the conventional procedure (SOCl2/MeOH), which al-
lowed for the isolation of hydrochloride salt 6 by direct precipita-
tion upon dilution of the reaction with IPAc. The Boc protection of
the amino group was carried out by using typical conditions
(Boc2O/TEA/DCM), but we found that work-up using non-aqueous
removal of Et3NꢀHCl provided 7, a low-melting solid in high chem-
ical purity and mass yield. As a benefit, 7 readily crystallized upon
standing, making for easy weighing in the next reaction. Conjuga-
tion of the double bond in 7 was affected using DBU/DCM at rt and,
after aqueous work-up, provided acrylate 2. We discovered that
crude 2 could be recrystallized from heptane and provided pure
product in 95% yield. As an aside, an attempt was made to convert
6 into 2 in a one-pot operation using DBU as a base for both reac-
tions; this resulted in the isolation of product 2 which was contam-
inated with an impurity (identified by LCMS) that appeared to
result from the direct reaction of DBU with Boc2O.7 The overall pro-
cedure for the conversion of 5 into 2 was 76% overall yield, and was
performed on multi-hundred gram scale.
We were inspired by the recent publication of an azomethine-
ylide cycloaddition reaction applied to chiral 4-substituted-2,3-
dihydrothiophene1,1-dioxides, as a means to obtain non-planar,
saturated bicycles 1a.4 In the case of 1a, the R-substituent was a
directing group for the diastereoselective formation of the product.
Chiral acrylate 2 has been featured as an intermediate in the syn-
theses of many nucleosides that were found to be inhibitors of Re-
verse Transcriptase.5 We were unaware of its use as
cycloaddition partner for entry into bicyclic ring systems. Our work
described herein focuses on the use of 2 in both cycloaddition
strategies as a means to construct novel bicyclic ring products 3
a
⇑
Corresponding author. Tel.: +1 215 628 5225; fax: +1 215 540 4611.
E-mail addresses: caich@hotmail.com (C. Cai), cteleha@its.jnj.com (C.A. Teleha).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.014

652
C. Cai et al. / Tetrahedron: Asymmetry 24 (2013) 651–656
O
R
O
S
Boc
Boc
Boc
N
R
NH
N
Boc
NH
CO2Me
Ph
CO2Me
1a
O
N
CO2Me
NH
Ph
2
3a
3b
3c
R = CH2
R = O
R = H,OH
4
O
O
N
1b
CF3
Figure 1. Retrosynthesis of bicycles using a chiral aminocyclopentene.
HCl
O
O
OCH3
O
H
SOCl2
MeOH, 0 °C
H2N
Boc2O, TEA
CH2Cl2, rt
N
OCH3
Boc
NH
7
5
6
Boc
O
O
H
N
DBU
CH2Cl2, rt
Boc2O, DMAP
THF, 56 °C
N
Boc
OCH3
Boc
OCH3
2
10
TMS
OMe
8
X
Pd(OAc)2, P(OiPr)3
PhH, 100 °C
Boc
CO2Me
CO2Me
N
H
*
*
N
Boc
Boc
H
3a (* - as a 6:1 mixture
9
of isomers)
Scheme 1.
With acrylate 2 in hand, we were ready to test the cycloaddition
preference for the diastereoselectivity away from the Boc-amino
group that blocked one side of the extended enolate.8
strategies and evaluate the effect of the chiral Boc-amino group on
the diastereoselectivity. The reaction of acrylate 2 under the reac-
tion conditions of Trost for the formation of TMM (8/Pd(OAc)2/
P(OiPr)3/100 °C) in toluene failed to give any 9, most likely due
to the competing reaction of the electrophilic reagent with the
NHBoc group. Blocking this reactive NH group of 2 by addition of
a second Boc group was affected by using more forcing conditions
(10 mol % DMAP/Boc2O/refluxing THF) and provided bis-Boc 10 in
90% yield. Despite a melting point similar in range to 2, bis-Boc
10 did not succumb to crystallization from heptane and instead
was isolated in pure form by chromatography. The reaction of 10
under the TMM cycloaddition conditions provided 3a as an insep-
arable mixture of isomers, with the ratio being determined by NMR
to be ꢁ6:1 (as drawn). The diastereoselectivity of 3a was consis-
tent with the cycloaddition having occurred opposite to the hin-
dered top face of the cyclopentene ring. The trans-relationship of
the new carbon skeleton relative to the NHBoc group was also ob-
served to control the alkylation of the anion of 6, which gave a
Characterization of the exo-olefin product 3a was accomplished
by oxidative cleavage using catalytic osmylation in a one-pot
method and gave 3b in 54% yield (Scheme 2). This reaction method
was more convenient than the typical two-step procedure, where-
by the dihydroxylation product was isolated and the periodate
cleavage would be performed as a separate operation.
Furthering the chemistry around the [3.3.0] core, 3b was re-
duced using NaBH4 in MeOH and provided 3c in 97% yield. The
NMR of 3c indicated the diastereoselection as drawn, with the ex-
pected multiplicities for key signals consistent with earlier work
reported for a similar [3.3.0] series lacking the –NHBoc group.9
More importantly our work revealed the sensitivity of the ester
group to the excess of reducing agent, since any amount over
0.5 M equiv of borohydride also reduced the ester to the alcohol.
Having demonstrated that the cycloadditions of the acrylate
portion of 2 provided the all-carbon containing core 3a along with
derivatives 3b and 3c, we turned our attention to the azomethine-

C. Cai et al. / Tetrahedron: Asymmetry 24 (2013) 651–656
Boc
653
Boc
CO2Me
CO2Me
N
N
K O O 2H2O
s
2
4
*
*
*
Boc
Boc
NaBH4
MeOH
NaIO4
*
3a
O
OH
H
H
3b
3c
Scheme 2.
ylide cycloaddition reaction. The reaction of 2 under acid-catalyzed
conditions (11/cat. TFA/CH2Cl2) provided 4 as a thick oil in 80%
yield (Scheme 3).
used as received and correction factors for purity are used where
indicated. Elemental Analyses and Karl Fisher determinations were
performed by Intertek.
We found that 4 formed a 1:1 fumarate salt 12 and readily crys-
tallized from acetone. The X-ray crystal structure (Fig. 2) confirmed
the relative stereochemistry of the newly formed pyrrolidine ring
to be in a trans-relationship to the encumbering NHBoc group.
While searching for an explanation for the exclusive formation of
the single diastereomer 4 considering the earlier observed 6:1 ratio
seen for 3a, it is postulated that the azomethine-ylide from 11,
with the associated N-benzyl group, is sterically more sensitive
to directing groups close to the reacting center. In this case, the
NHBoc is sufficient to induce exclusive cyclization with acrylate
2, leading to the observed product.
4.2. (1R,4S)-Methyl 4-aminocyclopent-2-enecarboxylate
hydrochloride 6
A 22-L 4-neck round bottomed flask equipped with an overhead
mechanical stirrer, nitrogen inlet, temperature controller, and a
500-mL addition funnel with a nitrogen outlet was charged with
MeOH (2.1 L) and 5 (702.1 g, 6.43 mol). The mixture was stirred
at 2 °C until the mixture dissolved. Thionyl chloride (282 mL,
3.87 mol) was charged to the addition funnel and added portion-
wise at a rate not to exceed 12 °C. After 30 min stirring, the reac-
tion was allowed to warm to 8 °C for 1 h. Isopropyl acetate (IPAc,
15.5 L) was added rapidly and the slurry was stirred for 1 h. The so-
lid was filtered and washed with IPAc (1 L) and the resulting white
solid was air-dried for a few hours and afforded 6 (1084 g) in 95%
yield. 1H NMR (400 MHz, DMSO-d6) d 8.46 (3H, br s), 6.07 (1H, dt,
J = 6, 2 Hz), 5.82–5.96 (1H, m), 4.17 (1H, tt, J = 6 and 2 Hz), 3.66–
3.75 (1H, m), 2.44–2.67 (1H, m), 1.83–2.06 (1H, m). 13C NMR
(100 MHz, d6-DMSO) d 172.61, 134.10, 139.38, 55.10, 51.83,
3. Conclusion
We have described two cycloaddition reactions of acrylates 2
and 10 which provided novel bicyclic ring products 3a and 4 in fair
to good yields. We have provided a preliminary explanation for the
degree of diastereoselection seen in the reactions; in the TMM
reaction with 10, the 6:1 ratio seen suggests that the smaller
[3+2] cycloaddition partner gives some amount of control but not
exclusive. In the case of the azomethine-ylide reaction with 2,
we observed a high degree of stereoselectivity with this reagent
on our substrate. We have also characterized novel products 3b
and 3c, which were prepared to support the characterization of
the cycloaddition product 3a.
48.86, 31.15. ½a D25
¼ þ85:52 (c 1.0, EtOH). MS (ESI) m/z (%) 142
ꢂ
(M+H, 100). Anal. Calcd for C7H12ClNO2 C 47.33, H 6.81, Cl 19.96,
N 7.89. Found: C 47.34, H 6.72, Cl 20.01, N 7.76. Karl Fisher 0.92.
4.3. (1R,4S)-Methyl 4-(tert-butoxycarbonylamino) cyclopent-2-
encarboxylate 7
To a 22-L 4-neck round bottomed flask equipped with a temper-
ature controller, nitrogen inlet, mechanical stirrer, and 500-mL
addition funnel with nitrogen outlet was charged 6 (343.3 g,
1.93 mol), dichloromethane (9.6 L), and di-tert-butyldicarbonate
(426 g, 1.93). The suspension was cooled to 1 °C with an ice bath.
Et3N (270 mL, 1.93 mol) was added via an addition funnel slowly
over 50 min not to exceed 2 °C. The resulting clear solution was
stirred for 2 h. The volatiles were then evaporated on a rotary
evaporator and afforded a crude product, which was contaminated
with Et3NHCl. Et3NHCl was removed by eluting the crude product
through silica gel (500 g) with 50% EtOAc/heptane (500 mL), fol-
lowed by additional washes (4 ꢃ 2 L). The organic filtrates were
evaporated to a colorless oil, which slowly crystallized and affor-
ded 7 (650 g) in 96% yield. Mp 48 °C. 1H NMR (400 MHz, CDCl3) d
5.87 (2H, q, J = 6 Hz), 4.79 (2H, br d), 3.72 (3H, s), 3.48 (1H, dd,
J = 8 and 4 Hz), 2.51 (1H, dt, J = 14 and 9 Hz), 1.86 (1H, dt, J = 14
and 4 Hz), 1.44 (9H, s). 13C NMR (100 MHz, CDCl3) d 174.96,
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker 400 MHz for 1H,
100 MHz for 13C. Chemical shifts are given in ppm relative to the
internal reference. Coupling constants (J values) are reported in
Hertz (Hz), and multiplicities are indicated by the following sym-
bols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
and b (broad). The MS spectra were recorded on a Varian LCMS
apparatus and molecular ions are reported in nominal mass units.
Optical rotation values were measured on a Perkin Elmer 341 and
concentrations are given in g/100 mL. Melting points were deter-
mined either by Differential Scanning Calorimeter (DSC) versus a
blank pan or a Buchi melting point apparatus and are uncorrected.
Flash chromatography separations were performed using Merck 60
40–63 lm silica and technical grade solvents. All reagents were
TMS
N
OMe
11
CO2Me
H
CO2Me
Ph
H
N
N
funaric acid
2
Boc
Ph
HO2C
Boc
N
TFA, MeOH
Ph
acetone
N
CO2H
H
H
12
4
Scheme 3.

654
C. Cai et al. / Tetrahedron: Asymmetry 24 (2013) 651–656
O7
C25
O8
C21
C24
C23
O4
O3
C22
C20
O6
O5
C13
C12
C14
C8
C17
N1
C11
N2
C15
O2
C9
C7
C19
C10
C5
C4
C16
O1
C8
C18
C1
C3
C2
Figure 2. X-ray of fumarate 12.
155.15/147.00, 134.89, 131.13, 85.18/79.30, 55.81, 52.19, 49.20,
34.58, 28.45/27.44 (rotomers found).
MeOH). Anal. Calcd for C12H19NO4 C 59.73, H 7.94, N 5.81. Found:
(130.2 g, 0.596 mol), and DMAP (4.6 g, 0.037 mol). The reaction
was heated to 60 °C for 18 h. Additional di-tert-butyldicarbonate
(17.9 g, 0.082 mol) and THF (100 mL) were added and heating con-
tinued for 5 h. The reaction was transferred to a round bottomed
flask and the volatiles were removed under reduced pressure.
The crude was loaded onto silica gel (800 g) and eluted with a gra-
dient of EtOAc in heptane (1 L heptane, 4 L of 10%, 4 L of 20%). The
product fractions were collected and provided 10 (114.1 g) in 90%
yield. Mp 86.6 °C. tlc of 10 (20% EtOAc in heptane, KMnO4 stain to
visualize): 0.25. 1H NMR (400 MHz, CDCl3) d 6.70 (1H, s), 4.87–5.14
(1H, m), 3.73 (3H, s), 2.76–2.94 (4H, m), 1.43–1.54 (18H, m). 13C
NMR (100 MHz, CDCl3) d 165.11, 152.81, 141.29, 134.40, 82.57,
½
a 2D5
ꢂ
¼ þ59:57 (c 1.05,
C 59.60, H 8.04, N 5.43.
4.4. (R)-Methyl 4-(tert-butoxycarbonylamino)cyclopent-1-enecarb-
oxylate 2
To a 20-L rotary evaporator flask was charged 7 (368.3 g,
1.53 mol), dichloromethane (2.7 L), and DBU (325 mL, 2.14 mol)
at rt and the flask swirled for 66 h. The flask was chilled in an
ice-bath, poured into a 22-L separatory funnel containing ice-cold
aqueous HCl (0.5 M, 4.2 L) and the contents were gently swirled (to
prevent emulsification). The layers were separated and the aque-
ous layer was back-extracted with dichloromethane (300 mL).
The combined organic layers were washed with water (600 mL),
dried over Na2SO4, filtered, and concentrated under reduced vac-
uum. The crude product was recrystallized from heptane
(900 mL) in a round bottomed flask and heated until all of the solid
dissolved. The heat was turned off and the flask swirled as it was
allowed to return to rt. The product precipitated as yellow prills,
and was collected by filtration and washed with heptane
(2 ꢃ 150 mL). The collected solid was dried in a vacuum oven
(26 °C, 30 in Hg) and provided 2 (341 g) in 93% isolated yield. Mp
88.5 °C. 1H NMR (400 MHz, CDCl3) d 6.69–6.74 (2H, m), 4.74 (1H,
br s), 4.36 (1H, br s), 3.73 (3H, s), 2.86–3.01 (1H, m), 2.34–2.48
(1H, m), 1.44 (9H, s). 13C NMR (100 MHz, CDCl3) d 165.11,
155.51, 141.20, 134.43, 79.5, 51.57, 50.2, 41.18, 39.17, 28.42.
54.20, 51.43, 38.43, 36.22, 28.04. ½a D25
¼ ꢄ6:3 (c 1.19, MeOH). MS
ꢂ
(ESI) 364 (M+Na, 15), 705 (2 M+Na, 100). Anal. Calcd for
C17H27NO6: C 59.81, H 7.97, N 4.10. Found C 60.12, H 8.03, N
3.95. Karl Fisher 0.2.
4.6. (2R,3aR,6aR)-Methyl 2-(bis(tert-butoxycarbonyl) amino)-5-
methyleneoctahydropentalene-3a-carboxylate 3a
To a 1-L 4-neck round bottomed flask equipped with a mechan-
ical stirrer, reflux condenser with nitrogen outlet, a temperature
controller, and nitrogen inlet was charged 10 (64.1 g, 0.188 mol),
toluene (320 mL), 2-(acetoxymethyl)-3-allyltrimethylsilane
8
(70 g, 0.376 mol), and Pd(OAc)2 (2.95 g, 0.013 mol). The deep red
solution was degassed with nitrogen through the solution for
15 min. Triisopropylphosphite (26.4 mL, 0.112 mol) was then
added via syringe and the greenish yellow solution was heated to
100 °C for 20 h. The reaction was loaded directly onto silica gel
(2.5 kg, prewetted with 4 L heptane) and eluted with a gradient
of EtOAc in heptane (4 L heptane, 8 L of 5%, 12 L of 10%). The prod-
uct fractions were collected and provided 3a (64.4 g) in 87% yield
as a clear oil (data below for the major isomer, ratio based on inte-
gration of the 4.83 ppm [major] versus 4.87 ppm [minor] of the exo
olefin). 1H NMR (400 MHz, CDCl3) d 4.79–4.92 (m, 2H), 4.62 (tt,
J = 7.3, 11 Hz, 1H), 3.65–3.73 (s, 3H), 2.83–2.99 (m, 2H), 2.51–
2.74 (m, 2H), 2.21–2.38 (m, 2H), 2.01–2.16 (m, 1H), 1.87–1.99
(m, 1H), 1.57–1.78 (m, 1H), 1.49 (s, 18H). 13C NMR (100 MHz,
½
a 2D5
ꢂ
¼ ꢄ10:28 (c 1.13, MeOH). Anal. Calcd for C12H19NO4 C 59.73,
H 7.94, N 5.81. Found: C 59.97, H 8.04, N 6.03.
4.5. (R)-Methyl 4-(bis(tert-butoxycarbonyl)amino) cyclopent-1-
enecarboxylate 10
To a 3-L 4-neck round bottomed flask equipped with a mechan-
ical stirrer, reflux condenser with nitrogen outlet, and a Claisen
head with a temperature controller and nitrogen inlet was charged
2
(90 g, 0.373 mol), THF (900 mL), di-tert-butyldicarbonate

C. Cai et al. / Tetrahedron: Asymmetry 24 (2013) 651–656
655
CDCl3) d 177.5, 153.0, 150.8, 106.2, 82.3, 82.2, 57.2, 55.6, 52.1, 45.0,
trimethylsilylmethyl)benzylamine 11 (263 g, 1.11 mol). The solu-
tion was cooled in an ice bath to 2 °C, TFA (4.1 mL, 0.0542 mol)
was charged to the addition funnel and added to the reaction drop-
wise over 3–5 min. The reaction was stirred for 2 h. The reaction
was quenched at 2 °C by the addition of aqueous saturated sodium
bicarbonate (500 mL) and stirred for 30 min. The layers were sep-
arated and the aqueous layer back-extracted with dichlorometh-
ane (2 ꢃ 200 mL). The combined organics were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was split into two even portions and purified on sil-
ica gel (5 kg, prewetted with 8 L of 20% EtOAc in heptane) and
eluted with 72 L of 20% EtOAc in heptane. The product fractions
from both runs were collected and provided 4 (167.1 g) in 80%
yield as a thick yellow oil.
44.5, 40.8, 40.2, 36.3, 28.0. ½a D25
¼ ꢄ5:4 (c 1.14, MeOH). A satisfac-
ꢂ
tory elemental analysis could not be obtained for this compound.
4.7. (2R,3aS,6aS)-Methyl 2-(bis(tert-butoxycarbonyl) amino)-5-
oxooctahydropentalene-3a-carboxylate 3b
To a 12-L 4-neck round bottomed flask equipped with a
mechanical stirrer, reflux condenser with nitrogen outlet, a tem-
perature controller, and nitrogen inlet was charged 3a (100.3 g,
0.253 mol) and THF (3.5 L). Water (1.8 L) was then added, followed
by NaIO4 (220 g, 1.028 mol) and potassium osmate (VI) hydrate
(4.70 g, 0.0127 mol). The reaction exothermed from 24 to 34 °C
over the course of 20 min, and the reaction was stirred at rt over-
night. The reaction was quenched by the addition of aq sodium
thiosulfate (satd, 350 mL) and after stirring was found to be nega-
tive with starch–iodide paper. The reaction was diluted with water
and EtOAc (2.5 L each), the layers were separated and the aqueous
layer extracted with EtOAc (1 L). The combined organics were
washed with brine (1 L), dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified
on silica gel (2.5 kg, prewetted with 4 L heptanes, loaded in
DCM) and eluted with a gradient of EtOAc in heptane (4 L of 10%,
16 L of 20%, 8 L of 30%). The product fractions were collected and
provided 3b (87.7 g) in 54% yield as a clear oil. (data reported for
major isomer) 1H NMR (400 MHz, CDCl3) d 5.30 (s, 1H), 4.65–
4.84 (m, 2H), 3.66–3.77 (m, 3H), 3.12–3.26 (m, 2H), 2.72–2.87
(m, 2H), 2.54–2.71 (m, 1H), 2.47 (ddd, J = 8.3, 9.9, 13.6 Hz, 1H),
2.16–2.28 (m, 2H), 2.04–2.16 (m, 2H), 1.66–1.79 (m, 1H), 1.45–
1.54 (m, 18H). 13C NMR (100 MHz, CDCl3) d 216.8, 176.0, 153.0,
82.7, 55.3, 54.9, 52.5, 46.8, 44.6, 42.4, 38.9, 36.5, 28.0.
4.10. (3aR,5R,6aR)-Methyl 2-benzyl-5-(tert-butoxycarbonylamino)-
octahydrocyclopenta[c]pyrrole-3a-carboxylate fumarate 12
To a 3-L 3-neck round bottomed flask equipped with a heating
mantle, mechanical stirrer, reflux condenser with nitrogen outlet,
and Claisen adapter with a temperature controller and nitrogen in-
let was charged fumaric acid (50.3 g, 0.433 mol) and a small
amount of acetone. A solution of 4 (162.7 g, 0.433 mol) in acetone
(1.62 L) was prepared by swirling until completely dissolved. The
solution of 4 was quickly poured into the reaction flask, and
washed with a small amount of acetone. The mixture was stirred,
and may or may not be clear at this point. A white precipitate
started to form at rt, but the mixture was heated to 50 °C for 1 h.
The heating was stopped and allowed to cool to rt over 1 h. The
mixture was immersed in an ice bath, stirred until reasonably cold,
and the solid was filtered and washed with ice-cold acetone
(300 mL). The white solid was dried in a vacuum oven (30 in Hg,
29 °C) and provided 12 (159.8 g) in 75% yield as a white solid.
Mp 175.3–176.4 °C. 1H NMR (400 MHz, DMSO-d6) d = 13.01–
13.32 (m, 1H), 7.17–7.42 (m, 5H), 6.84 (d, J = 7.6 Hz, 1H), 6.62 (s,
2H), 3.98–4.21 (m, 1H), 3.61 (s, 3H), 2.76–2.95 (m, 2H), 2.64 (t,
J = 8.4 Hz, 1H), 2.44 (d, J = 9.3 Hz, 1H), 2.27 (dd, J = 4.4, 8.8 Hz,
1H), 1.76–1.96 (m, 2H), 1.56–1.73 (m, 2H), 1.37 (s, 9H).
½
a 2D5
ꢂ
¼ ꢄ31:14 (c 1.55, MeOH) MS (ESI) 420 (M+Na, 40), 817
(2 M+Na, 100). Anal. Calcd for C20H31NO7: C 60.44, H 7.86, N
3.52; found C 60.16, H 7.59, N 3.42.
4.8. (2R,3aS,5R,6aS)-Methyl 2-(bis(tert-butoxycarbonyl) amino)-
5-hydroxyoctahydropentalene-3a-carboxylate 3c
½
a 2D5
ꢂ
¼ þ11:3 (c 1.03, MeOH). MS (ESI) 375 (M+H for free-base,
To a 3-L 4-neck round bottomed flask equipped with a mechan-
ical stirrer, nitrogen outlet, a temperature controller, and nitrogen
inlet was charged 3b (72.6 g, 0.182 mol) and MeOH (1.8 L) and the
solution was chilled to ꢄ70 °C with a CO2/acetone bath. NaBH4
(3.46 g, 0.091 mol) was added in one portion and the reaction
was stirred for 2 h at ꢄ70 °C. The bath was removed and the reac-
tion was allowed to warm to ꢄ6 °C over the course of 2 h. Water
(6.6 mL) was then added and the reaction was transferred to a
one-neck flask and the volatiles were removed on a rotary evapo-
rator. The resulting yellow oil was partitioned between water
(450 mL) and EtOAc (900 mL). The combined organics were dried
with Na2SO4, filtered, and evaporated under reduced pressure to
give 3c (71 g) in 97% yield as a clear oil. 1H NMR (400 MHz, CDCl3)
d 4.72 (tt, J = 6.3, 12.3 Hz, 1H), 4.22 (td, J = 4.8, 9.1 Hz, 1H), 3.64–
3.70 (m, 3H), 2.69 (q, J = 9.0 Hz, 1H), 2.48–2.61 (m, 2H), 2.19–
2.32 (m, 2H), 1.87 (dd, J = 6.4, 12.2 Hz, 1H), 1.59–1.73 (m, 4H),
100), 397 (M+Na for free-base, 20%). Anal. Calcd for C25H34N2O8:
C 61.21, H 6.99, N 5.71; found C 61.13, H 6.99, N 5.65. Karl Fisher
0.59.
Full crystallographic data for this structure have been deposited
with the Cambridge Crystallographic Data Centre as supplemen-
tary publications CCDC 931521. These data can be obtained free
of charge on application to CCDC, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033; or e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgments
The coauthors would like to thank Mr. Shawn Branum for the
preparation of some early intermediates in support for this work.
1.47–1.52 (m, 18H), 1.34 (dt, J = 8.9, 12.7 Hz, 1H). ½a D25
¼ ꢄ3:29 (c
ꢂ
References
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C
20H33NO7: C 60.13, H 8.33, N 3.51; found C 59.78, H 8.53, N
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