A cross-metathesis-conjugate addition route to enantiopure γ-butyrolactams and γ-lactones from a C2-symmetric precursor

Article abstract of DOI:10.1002/ejoc.201001528

A protected derivative of (3R,4R)-hexa-1,5-diene-3,4-diol, a conveniently accessible C₂-symmetric building block, undergoes single or double cross metathesis with methyl acrylate. The cross metathesis products are amenable to stereoselective co

Full text of DOI:10.1002/ejoc.201001528

FULL PAPER
DOI: 10.1002/ejoc.201001528
A Cross-Metathesis–Conjugate Addition Route to Enantiopure
γ-Butyrolactams and γ-Lactones from a C2-Symmetric Precursor
Bernd Schmidt,*[a] Lucia Staude,[a] Alexandra Kelling,[b] and Uwe Schilde[b]
Keywords: Lactams / Lactones / Oxygen heterocycles / Metathesis / Desymmetrization
A protected derivative of (3R,4R)-hexa-1,5-diene-3,4-diol, a
conveniently accessible C2-symmetric building block, un-
dergoes single or double cross metathesis with methyl acryl-
ate. The cross metathesis products are amenable to stereo-
selective conjugate addition reactions and can be converted
into either γ-butyrolactones or γ-lactams.
depending on the nucleophile used, cyclization to oxa- or
azacycles may occur (Scheme 1). Results obtained along
these lines are presented in this contribution.
Introduction
Two-directional chain elongation emerged in the 1990s
as a powerful strategy in the synthesis of natural products.[1]
C2-Symmetric building blocks are particularly useful be-
cause they have homotopic functional groups and can be
desymmetrized by selective monofunctionalization.[2] Ac-
cordingly, (3R,4R)-hexa-1,5-diene-3,4-diol (1), which is
available from d-mannitol in a few steps,[3–6] is a very useful
ex-chiral-pool starting material. Diol 1 has been used in
target molecule synthesis,[7–19] as a chiral diene ligand in
asymmetric catalysis,[20] and as a probe for catalyst directing
effects by hydroxy groups in ring-closing metathesis (RCM)
reactions.[6,21,22] The enantiomer, ent-1, has been synthe-
sized by Blechert and co-workers from d-(–)-tartrate and
employed in the total synthesis of phomopsolide by using
cross metathesis and a subsequent RCM step.[23] In this and
many other cases, desymmetrization of 1 or ent-1 is
achieved by monofunctionalization of one OH group, often
with a bulky protecting group. This allows differentiation of
the two C–C double bonds on the basis of steric hindrance.
Recently, Chou and Hou synthesized (+)-cladospolide C by
using the cross-metathesis[24] reaction of an acetonide-pro-
tected derivative of 1 as the actual desymmetrization step.[8]
We became intrigued by the opportunity to monofunc-
tionalize 1 or a protected derivative of 1 by using cross me-
tathesis with an electron-deficient alkene, thereby activating
one C–C double bond for a conjugate addition. During this
addition, a new stereogenic center would be created and,
Scheme 1. Envisaged stereoselective conjugate addition–cycliza-
tion.
Results and Discussion
Monofunctionalization by Cross Metathesis
At the beginning of our work, we attempted cross me-
tathesis of diol 1 with methyl acrylate. This resulted in the
formation of complex mixtures, and no conditions for the
selective synthesis of either single or double cross-metathe-
sis products could be identified. We therefore decided to
start from benzylidene acetal 2a,[20] synthesized from 1 and
benzaldehyde (Scheme 2). One advantage of benzylidene
acetals is that they can be cleaved reductively in the pres-
ence of a Lewis acid to furnish a monoprotected diol.[25]
In an initial experiment, we applied conditions described
by Chou and Hou for a cross-metathesis reaction of the
analogous acetonide.[8] The results were rather disappoint-
ing, because undesired double cross-metathesis product 2c
was the major product, and desired 2b was isolated in only
16% yield. Due to the pseudo-C2 symmetry of 2a, mono-
[a] Universität Potsdam, Institut für Chemie, Organische
Synthesechemie,
Karl-Liebknecht-Straße 24-25, Haus 25, 14476 Golm, Germany
Fax: +49-331-9775059
E-mail: bernd.schmidt@uni-potsdam.de
[b] Universität Potsdam, Institut für Chemie, Anorganische
Chemie,
Karl-Liebknecht-Straße 24-25, Haus 26, 14476 Golm, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001528.
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B. Schmidt, L. Staude, A. Kelling, U. Schilde
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Table 1. Optimization of cross metathesis of 3a and methyl acryl-
ate.[a]
Entry[a] Catalyst
(mol-%) [molL–1][b]
c
Isolated yield [%][c]
3a
3b
3c
3d
1[d]
2
A (5.0)
A (5.0)
B (3.3)
B (2.5)
B (5.0)
B (8.0)
B (6.0)
B (5.0)
B (5.0)
B (4.0)
B (5.0)
B (4.0)
B (10.0)
C (10.0)
C (4.0)
C (4.0)
C (5.0)
D (5.0)
0.5
0.1
0.1
0.1
0.1
0.1
0.06
0.2
0.5
1.0
neat
1.0
1.0
0.1
0.05
0.1
0.2
0.2
67
n.d.
43
12
10
41
19
25
39
58
70
68
22
39
22
32
39
49
54
60
51
n.d.
n.d.
8
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Ͻ5
3[d]
4
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
26
26
26
20
22
17
19
29
20
29
n.d.
5
5
6
7
8
9
Ͻ3
10[e]
11
12[e]
13[d]
14[d]
15
16
17
18
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Scheme 2. Initial cross metathesis experiments with benzylidene
acetal 2a.
functionalized product 2b was obtained as an inseparable
1:1 mixture of diastereomers, resulting in complicated
NMR spectra (Scheme 2). The disadvantages associated
with 2a prompted us to consider the use of acetonide 3a.
The application of previously published conditions[8] for the
cross metathesis of 3a and methyl acrylate afforded 3b, as
described by Chou and Hou.[8] However, we also isolated
considerable amounts of double cross-metathesis product
3c, and in certain cases, very small amounts of dimer 3d.
Motivated by the ability to produce 3b, we investigated this
reaction in detail, with the objective of suppressing forma-
tion of undesired double cross-metathesis product 3c
(Scheme 3 and Table 1).
n.d.
n.d.
n.d.
n.d.
40
21
34
31
[a] General conditions: toluene, 110 °C, methyl acrylate (10 equiv.),
phenol (50 mol-%, unless otherwise stated). [b] Initial concentra-
tion of 3a. [c] n.d., not detected. [d] Without addition of phenol.
[e] With addition of phenol (30 mol-%).
Figure 1. Catalysts used for cross-metathesis reactions.
In all experiments, methyl acrylate (10 equiv.) was used
along with toluene as the solvent at a temperature of
110 °C. Variable parameters included the catalyst, the cata-
lyst loading, the concentration, and the presence or absence
of phenol as an additive. The beneficial effect of phenol in
cross-metathesis reactions had previously been established
by Forman and co-workers[34] and was also corroborated
by Chou and Hou in their study.[8] More recently, our group
discovered a beneficial effect of added phenol in RCM and
enyne metathesis reactions.[22] Phenol is believed to promote
catalyst initiation and to stabilize the catalytically active
species. The following conclusions can be drawn from the
results summarized in Table 1: (i) First-generation catalyst
A (Table 1, Entries 1 and 2) is not sufficiently active for this
cross-metathesis reaction. (ii) The addition of phenol im-
proves the conversion significantly (Table 1, Entries 3 and
4). (iii) High initial substrate concentrations (Ͼ1.0 m) ap-
Scheme 3. Cross metathesis of 3a with methyl acrylate.
Catalysts tested for this task were first- and second-gen- pear to be detrimental for reaction selectivity and overall
eration Grubbs catalysts A and B, respectively,[26,27] and in- yield. Good results were obtained with initial substrate con-
denylidene catalysts C[28,29] and D (Figure 1).[30] We re- centrations ranging from 0.05 to 0.5 m in most cases. (iv) In-
frained from investigating phosphane-free metathesis cata- denylidene catalyst C (Table 1, Entries 14–17) seems to be
lysts containing a hemilabile benzylidene ligand,[31–33] be- slightly more active than benzylidene catalyst B, because
cause these are reported to be active in cross-metathesis re- significantly higher amounts of double cross-metathesis
actions and we feared that the presence of phosphanes product 3c were obtained (Table 1, Entries 7 vs. 16 and 8
might preferentially induce deleterious double cross metath- vs. 17). (v) In two cases (Table 1, Entries 8 and 9) dimeriza-
esis.
tion of 3b to triene 3d was observed. However, this result
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Enantiopure γ-Butyrolactams and γ-Lactones from a C2-Symmetric Precursor
was somewhat difficult to reproduce. Eventually, we discov-
ered that 3d was only formed if the catalyst had been freshly
synthesized; formation of 3d was not observed with com-
mercially available catalysts. (vi) All cross-metathesis reac-
tions proceed with very high E selectivity. No Z isomers
1
could be detected in the H NMR spectra. (vii) The effec-
tiveness of pyridine-containing catalyst D (Table 1, En-
try 18) is comparable to that of catalyst C, which is in agree-
ment with our recently published results, suggesting that D
shows some preference for cross metathesis.[35] (viii) Most
importantly, these results show that it is possible to obtain
monofunctionalized cross-metathesis product 3b reproduci-
Figure 2. Three-dimensional representation of 3b and preferred
side of nucleophilic attack.
bly and in a preparatively useful yield of 70% (Table 1, En-
tries 8 and 9).
be ruled out on the basis of vicinal coupling between the
olefinic hydrogen and the proton CH(OH). The assigned
relative cis configuration of 5 was substantiated by a strong
NOE between 4-H and 5-H (Scheme 4).
To demonstrate that the remaining C–C double bond in
lactone 5 can indeed participate in olefin metathesis reac-
tions, it was subjected to a cross-metathesis reaction with
methyl acrylate in the presence of phenol, as described
above (Scheme 5).
1,4-Addition of Nitromethane to 3b and Subsequent
Cyclization
The conjugate addition of nitroalkanes to enoates, fol-
lowed by reduction of the nitro group, is a useful method
for the synthesis of substituted γ-aminobutyric acids and γ-
lactams.[36–39] These compounds are very important, be-
cause γ-aminobutyric acid (GABA) is a significant inhibi-
tory neurotransmitter in the central nervous system and a
number of drugs such as pregabalin,[40] baclofen,[41] and ro-
lipram[42] are derived from this structure.[43] We achieved
conjugate addition of nitromethane to enoate 3b by using
DBU (1 equiv.) as a base. Resulting nitroalkane 4 was iso-
lated as a single diastereomer in nearly quantitative yield
(Scheme 4). Previous reports on the addition of nitro-
alkanes to 2,2-dimethyl-1,3-dioxolane-substituted en-
oates[44–47] suggest that, in our case, the nucleophilic attack
should occur preferentially from the Si face of the electron-
deficient C–C double bond due to minimization of 1,3-al-
lylic strain (Figure 2). Correia and co-workers have pre-
viously applied similar reasoning to understand reactions
involving an enoate derived from glyceraldehyde.[44]
Scheme 5. Cross metathesis and subsequent conjugate addition–
cyclization sequence.
The reaction of 5 and methyl acrylate appeared, at first,
to be surprisingly sluggish on the basis of TLC and 1H
NMR spectroscopic analyses of the crude reaction. Chro-
matographic purification gave a fraction from which com-
pound 7 could be isolated in moderate yield by crystalli-
zation. X-ray crystal structure analysis of 7 revealed a
pseudo C2-symmetric structure with two γ-butyrolactone
rings annulated to a cyclopentane core (Figure 3).[48]
Tricycle 7 results from cross metathesis and subsequent
intramolecular conjugate addition, followed by lacton-
ization. Characteristic signals for desired cross-metathesis
Scheme 4. Conjugate addition of nitromethane to 3b.
1
product 6 were found in the H NMR spectrum, but this
product could not be isolated.
Based on these stereoelectronic considerations, the R
Next, different conditions for a reduction of the nitro
configuration was expected for the newly generated group in compound 4 and subsequent lactam formation
stereocenter. Confirmation of this hypothesis came from 2D were investigated. Hydrogenation with Pd/C under an at-
NMR spectroscopic investigations of cyclization product γ- mosphere of hydrogen (1 bar) gave a mixture of γ-amino
butyrolactone 5, which was obtained after cleavage of the ester 8 and its corresponding γ-lactam 9. Both compounds
acetal. Formation of the alternative δ-valerolactone could are separable, and subsequent conversion of 8 into 9 was
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B. Schmidt, L. Staude, A. Kelling, U. Schilde
FULL PAPER
reaction.[51] Nitromethyl-substituted bislactone 14 was ob-
tained by twofold addition of nitromethane to 3c and sub-
sequent cleavage of acetal 13 (Scheme 7).
Figure 3. X-ray crystal structure analysis of compound 7. Molecu-
lar structure with thermal ellipsoids drawn at the 50% probability
level.
achieved by treatment with aqueous NaOH in methanol.
Reduction of the nitro group with conservation of the C–C
double bond was achieved with zinc in acetic acid. Under
these conditions, only γ-lactam 10 was detected and isolated
(Scheme 6).
Scheme 7. C2-Symmetric bislactones from double cross metathesis
product 3c.
The C2 symmetry of lactones 12 and 14 is evident from
1
a half set of signals in the H and 13C NMR spectra. The
relative configuration of 14 is supported by a coupling con-
stant of 8.0 Hz for the two protons highlighted in the struc-
ture of 14 in Scheme 7, which is in agreement with a cis
orientation. For a trans orientation, a coupling constant of
3 to 4 Hz would have been expected.[52]
Scheme 6. Nitro group reduction of 4.
Functionalization of 3c with Conservation of C2 Symmetry
Conclusions
Double cross-metathesis product 3c was obtained under
our standard conditions in yields up to 40%, preferably by
using indenylidene catalysts C and D. As higher amounts
of methyl acrylate and longer reaction times did not in-
crease the amount of 3c formed, we investigated a second
cross metathesis of isolated 3b with methyl acrylate. Using
the standard conditions established previously along with
benzylidene complex B as a catalyst, 57% of 3c and 6%
of dimer 3d were isolated. C2-Symmetric bislactones were
accessed by two different routes: through hydrogenation of
3c, followed by acid-catalyzed cleavage of the acetal to give
bis-γ-butyrolactone 12, which was previously synthesized
from ascorbic acid,[49] or through asymmetric dihydrox-
ylation.[50] Very recently, a synthesis of 12 was described
starting from the ethyl ester analogue of 3c, which was, in
In conclusion, we showed that a conveniently available
C2-symmetric building block can be efficiently monofunc-
tionalized by cross metathesis and that subsequent highly
stereoselective addition of nitromethane yields enantiomer-
ically pure γ-butyrolactones or γ-lactams.
Experimental Section
General Remarks: All experiments were conducted in dry reaction
vessels under an atmosphere of dry Ar. Solvents were purified by
standard procedures. 1H NMR spectra were obtained with a
Bruker DRX 300 spectrometer at 300 MHz in CDCl3 with CHCl3
(δ = 7.26 ppm) as an internal standard, in [D6]DMSO with [D5]-
DMSO (δ = 2.50 ppm) as an internal standard, in [D4]methanol
with CD2HOD (δ = 3.31 ppm) as an internal standard, or in [D6]-
turn, synthesized from d-(–)tartrate by using an olefination acetone with [D5]acetone (δ = 2.05 ppm) as an internal standard.
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Enantiopure γ-Butyrolactams and γ-Lactones from a C2-Symmetric Precursor
Signal assignments refer to numbering schemes which are detailed
in the Supporting Information 13C NMR spectra were recorded at
75 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm) as an internal stan-
dard, in [D6]DMSO with [D6]DMSO (δ = 39.5 ppm) as an internal
standard, in [D4]methanol with CD3OD (δ = 49.2 ppm) as an in-
hydrofuran (11 mL) and conc. H2SO4 (10 drops) was added. The
reaction mixture was stirred under reflux for 12 h and then cooled
to ambient temperature. It was diluted with water and extracted
with ethyl acetate. The organic phase was washed with saturated
aqueous NaHCO3 solution and dried with MgSO4.The solids were
filtered, and the solvents were evaporated. The residue was purified
ternal standard, or in [D6]acetone with CD3C(O)CD3 (δ
=
1
29.9 ppm) as an internal standard. IR spectra were recorded with
by column chromatography on silica to give 5 (204 mg, 92%). H
a Nicolet Impact 400 D as films on NaCl or KBr plates or as KBr NMR (600 MHz, CDCl3): δ = 5.99 (ddd, J = 17.1, 10.4, 6.6 Hz, 1
discs. Mass spectra were obtained at 70 eV with a GC-TOF mass
spectrometer (Micromass Manchester Waters Inc.) for EI. ESI
mass spectra were obtained with a Q-TOF micromass spectrometer
(Micromass Manchester Waters Inc.). X-ray analysis was per-
formed with an Imaging Plate Diffraction System IPDS-2 (Stoe).
H, 2Ј-H), 5.34 (ddd, J = 17.2, 1.2, 1.1 Hz, 1 H, 3Ј-Htrans), 5.28 (ddd,
J = 10.4, 1.1, 1.0 Hz, 1 H, 3Ј-Hcis), 4.91 (dd, J = 14.9, 8.3 Hz, 1 H,
4Ј-Ha), 4.73 (dd, J = 14.8, 6.7 Hz, 1 H, 4Ј-Hb), 4.69 (dd, J = 8.1,
1.5 Hz, 1 H, 5-H), 4.23 (d, J = 6.3 Hz, 1 H, 1Ј-H), 3.49 (ddtd, J =
11.0, 9.6, 8.2, 6.7 Hz, 1 H, 4-H), 2.81 (br. s, 1 H, -OH), 2.65 (dd,
J = 17.3, 11.1 Hz, 1 H, 3-Ha), 2.59 (dd, J = 17.3, 9.7 Hz, 1 H, 3-
Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.1, 135.5, 118.6,
Selective Cross Metathesis of Acetonide 3a and Methyl Acrylate: To
a solution of 3a (6.5 mmol, 1.00 g), methyl acrylate (64.9 mmol,
5.90 mL), and phenol (3.3 mmol, 310 mg) in toluene (32 mL) was
added catalyst B (5 mol-%, 0.3 mmol, 308 mg). The reaction mix-
ture was stirred at 110 °C for 3 h, and all volatiles were evaporated.
The residue was purified by column chromatography on silica to
give 3b (963 mg, 70%), 3c (298 mg, 17%), and 3d (129 mg, 5%).
Analytical data of 3b[8] and 3c[53] match those reported in the litera-
ture. Analytical data for (2E,2ЈE)-Dimethyl-3,3Ј-{(4R,4ЈR,5R,5ЈR)-
5,5Ј-[(E)-ethene-1,2-diyl]bis(2,2-dimethyl-1,3-dioxolane-5,4-diyl)}-
diacrylate (3d): 1H NMR (300 MHz, CDCl3): δ = 6.84 (dd, J =
15.7, 5.3 Hz, 2 H, 3-H), 6.12 (dd, J = 15.6, 1.1 Hz, 2 H, 2-H), 5.87
(dd, J = 3.2, 1.8 Hz, 2 H, 5-H), 4.28–4.12 (4 H, -CH-O-), 3.76 (s,
6 H, 4-H), 1.51–1.39 (12 H, -CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.2, 142.7, 129.7, 122.6, 110.3, 80.6, 80.0, 51.7, 27.0,
81.5, 72.6, 74.1, 35.7, 32.0 ppm. IR: ν = 3438 (br., m), 1762 (s),
˜
1549 (s), 1373 (m), 1176 (s) cm–1. LRMS (ES): m/z (%) = 202 (20)
[M + H]+, 175 (25). HRMS (ESI): calcd. for C8H12NO5 [M + H]+
202.0715; found 202.0714. [α]2D5
= –26.4 (c = 0.68, THF).
C8H11NO5 (201.18): calcd. C 47.8, H 5.5, N 7.0; found C 47.6, H
5.4, N 7.2.
(3aR,4aR,7aR,7bR)-4-Nitrohexahydrocyclopenta[2.1-b;3.4-bЈ]-
difuran-2,6-dione (7): To a solution of 5 (450 mg, 2.2 mmol), methyl
acrylate (22.4 mmol, 2.0 mL), and phenol (1.1 mmol, 105 mg) in
toluene (4.4 mL) was added catalyst B (5 mol-%, 0.1 mmol, 95 mg).
The solution was stirred for 4 h at 110 °C, all volatiles were evapo-
rated, and the residue was filtered through a small pad of silica.
Crystallization from acetone afforded 7 (180 mg, 35%) as colorless
1
26.7 ppm. IR: ν = 2987 (br., w), 2953 (w), 1724 (s), 1663 (m), 1436
˜
crystals (m.p. 179 °C). H NMR (300 MHz, [D6]DMSO): δ = 5.47
(m), 1372 (m), 1236 (s), 1164 (s), 1047 (s) cm–1. LRMS (ES): m/z
(%) = 396 (5) [M]+, 156 (20), 98 (100). HRMS (EI): calcd. for
C20H28O8 [M]+ 396.1784; found 396.1808. [α]3D0 = 28.2 (c = 0.76,
CH2Cl2). C20H28O8 (396.43): calcd. C 60.6, H 7.1; found C 60.3,
H 7.0.
(dd, J = 7.4, 7.4 Hz, 1 H, 4-H), 5.01 (dd, J = 7.2, 2.3 Hz, 2 H, 8-
H, 9-H), 3.94–3.78 (2 H, 3-H, 5-H), 2.91 (dd, J = 18.2, 9.4 Hz, 1
H, -CH2-), 2.79–2.65 (2 H, -CH2-), 2.45 (dd, J = 9.3, 7.0 Hz, 1 H, -
CH2-) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 174.8, 174.7,
89.9, 86.1, 84.9, 41.6, 41.4, 32.1, 29.3 ppm. IR: ν = 3536 (w), 3446
˜
Synthesis of 3c by Cross Metathesis of 3b and Methyl Acrylate: To
a solution of 3b (3.8 mmol, 800 mg), methyl acrylate (37.7 mmol,
3.40 mL), and phenol (1.9 mmol, 177 mg) in toluene (19 mL) was
added catalyst B (5 mol-%, 0.2 mmol, 160 mg). The reaction mix-
ture was stirred at 110 °C for 3 h, and all volatiles were evaporated.
The residue was purified by column chromatography on silica to
give 3c (582 mg, 57%) and 3d (90 mg, 6%).
(w), 2992 (w), 1774 (br., s), 1550 (s), 1410 (m), 1388 (m), 1366 (m),
1314 (m), 1158 (s), 1037 (s), 1018 (s) cm–1. LRMS (EI): m/z (%) =
228 (48) [M + H]+, 181 (45) [M – NO2], 95 (78), 67 (100). HRMS
(ESI): calcd. for C9H10NO6 [M + H]+ 228.0508; found 228.0514.
[α]2D6 = 9.0 (c = 0.62, acetone). C9H9NO6 (227.17): calcd. C 47.6,
H 4.0, N 6.2; found C 47.4, H 3.8, N 6.0.
Hydrogenation of Nitromethane Addition Product 4: To a solution
of 4 (585 mg, 2.1 mmol) in methanol (21 mL) was added Pd/C
(10 wt.-% Pd, 59 mg). The solution was degassed, saturated with
hydrogen, and then stirred under an atmosphere of H2 (1 bar) at
ambient temperature for 12 h. The mixture was filtered through a
small pad of Celite and then washed with ethyl acetate and meth-
anol. Chromatography on silica and subsequent crystallization
yielded amine 8 (188 mg, 24%) and lactam 9 (309 mg, 45%).
(R)-Methyl 3-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-4-ni-
trobutanoate (4): Ester 3b (4.2 mmol, 900 mg) was dissolved in ni-
tromethane (11 mL) and DBU (4.2 mmol, 633 μL) was added at
room temperature. Stirring was continued for 12 h. After this time,
all volatiles were evaporated, and the residue was purified by col-
umn chromatography to give 4 (1.10 g, 98%). 1H NMR (300 MHz,
CDCl3): δ = 5.81 (ddd, J = 17.1, 10.2, 7.6 Hz, 1 H, 6Ј-H), 5.42
(ddd, J = 17.1, 1.1, 0.9 Hz, 1 H, 7Ј-Htrans), 5.32 (ddd, J = 10.2, 0.6,
0.5 Hz, 1 H, 7Ј-Hcis), 4.77 (dd, J = 13.5, 4.9 Hz, 1 H, 4-Ha), 4.57
(dd, J = 13.5, 6.8 Hz, 1 H, 4-Hb), 4.17 (dd, J = 7.9, 7.9 Hz, 1 H,
-CH-O-), 3.82 (dd, J = 8.1, 6.3 Hz, 1 H, -CH-O-), 3.68 (s, 3 H, 5-
H), 2.90 (ddm, J = 12.1, 6.1 Hz, 1 H, 3-H), 2.54 (dd, J = 8.1,
Base-Mediated Cyclization of 8 to Lactam 9. To a solution of amine
8 (0.5 mmol, 120 mg) in methanol (5 mL) was added aq. NaOH
(0.5 mmol, 22 mg, in 100 μL H2O). The solution was stirred at am-
bient temperature for 2 d and then carefully evaporated. The resi-
due was dissolved in ethyl acetate, washed with sat. NH4Cl solution
and brine, dried with MgSO4, filtered, and concentrated. Column
chromatography gave lactam 9 (50 mg, 48%).
5.8 Hz, 2 H, 2-H), 1.39 (s, 3 H, 8Ј-H), 1.38 (s, 3 H, 8Ј-H) ppm. 13
NMR (75 MHz, CDCl3): δ = 171.3, 135.0, 120.4, 109.4, 80.9, 79.8,
C
75.3, 52.0, 36.1, 33.4, 26.8 ppm. IR: ν = 2988 (m), 1734 (s), 1552
˜
(s), 1436 (m), 1372 (s), 1211 (br., s), 1169 (br., s) cm–1. LRMS (ES):
m/z (%) = 296 (35) [M + Na], 274 (20) [M + H]+, 137 (100). HRMS
(ESI): calcd. for C12H20NO6 [M + H]+ 274.1291; found 274.1292.
[α]2D6 = –0.73 (c = 0.92, CH2Cl2). C12H19NO6 (273.28): calcd. C
52.7, H 7.0, N 5.1; found C 52.3, H 8,1; N 5.6.
(R)-Methyl 4-Amino-3-[(4R,5R)-5-ethyl-2,2-dimethyl-1,3-dioxolan-
4-yl]butanoate (8): M.p. 152–153 °C. 1H NMR (300 MHz,
CD3OD): δ = 3.84 (td, J = 7.8, 3.7 Hz, 1 H, -CH-O-), 3.77 (dm, J
= 7.8 Hz, 1 H, -CH-O-), 3.71 (s, 3 H, 5-H), 3.20 (dd, J = 13.3,
6.3 Hz, 1 H, -CH2-), 3.10 (dd, J = 13.4, 5.7 Hz, 1 H, -CH2-), 2.56
(dd, J = 6.4, 2.8 Hz, 2 H, 2-H), 2.35 (quint., J = 6.2 Hz, 1 H, 3-
H), 1.67 (ddd, J = 10.7, 7.5, 3.3 Hz, 1 H, 6Ј-Ha), 1.55 (sept., J =
(4R,5R)-5-[(R)-1-Hydroxyallyl]-4-(nitromethyl)-dihydrofuran-2(3H)-
one (5): Compound 4 (1.10 mmol, 300 mg) was dissolved in tetra-
Eur. J. Org. Chem. 2011, 1721–1727
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1725

B. Schmidt, L. Staude, A. Kelling, U. Schilde
FULL PAPER
7.4 Hz, 1 H, 6Ј-Hb), 1.39 (s, 3 H, 8-H), 1.37 (s, 3 H, 8-H), 1.02 (t, (2R,2ЈR,3R,3ЈR)-3,3Ј-Bis(nitromethyl)tetrahydro-2,2Ј-bifuran-5,5Ј-
J = 7.4 Hz, 3 H, 7-H) ppm. 13C NMR (75 MHz, CD3OD): δ =
(2H,2ЈH)-dione (14): To a solution of 13 (0.6 mmol, 250 mg) in
173.7, 110.3, 83.4, 82.1, 52.7, 42.6, 34.7, 28.0, 37.7, 27.6, 27.4, THF (3.2 mL, 0.2 m) was added conc. H2SO4 (5 drops). The reac-
10.6 ppm. IR: ν = 2984 (br., s), 2240 (m), 1728 (s), 1489 (m), 1465 tion was heated to 65 °C and stirred at this temperature for 12 h.
˜
(m), 1438 (m), 1416 (m), 1379 (s), 1246 (m), 1203 (s), 1049 (m), After cooling to ambient temperature, the solution was diluted with
1000 (m), 874 (m) cm–1. LRMS (EI): m/z (%) = 246 (77) [M +
H]+, 230 (43) [M – NH2], 187 (44), 156 (85), 59 (98), 43 (100).
HRMS (ESI): calcd. for C12H24NO4 [M + H]+ 246.1705; found
246.1695. [α]2D4 = 20.0 (c = 0.56, MeOH). C12H23NO4 (245.32):
calcd. C 58.8, H 9.5, N 5.7; found C 58.5, H 9.6, N 6.4.
water, and extracted with ethyl acetate. The combined organic
phases were washed with sat. NaHCO3 solution, dried with
MgSO4, solids filtered, and the solvents evaporated. The residue
was purified by crystallization from MeOtBu (MTBE) to give 14
(151 mg, 82%) as a waxy solid with a melting point slightly above
1
ambient temperature. H NMR (300 MHz, [D6]acetone): δ = 5.16
(R)-4-[(4R,5R)-5-Ethyl-2,2-dimethyl-1,3-dioxolan-4-yl]pyrrolidin-2-
one (9): 1H NMR (300 MHz, CDCl3): δ = 3.65 (dd, J = 7.5, 6.5 Hz,
1 H, -CH-O-), 3.58 (ddd, J = 11.5, 7.4, 4.0 Hz, 1 H, -CH-O-), 3.46
(dd, J = 9.5, 8.5 Hz, 1 H, -CH2-), 3.36 (ddm, J = 9.8, 8.3 Hz, 1
H, -CH2-), 2.59 (dddm, J = 15.4, 7.2, 1.7 Hz, 1 H, 4-H), 2.33 (dd,
J = 16.6, 9.0 Hz, 1 H, -CH2-), 2.18 (dd, J = 16.6, 9.0 Hz, 1 H,
-CH2-), 1.55 (dq, J = 7.0, 4.0 Hz, 2 H, 6Ј-H), 1.35 (s, 6 H, 8Ј-H),
0.99 (t, J = 7.3 Hz, 3 H, 7Ј-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 177.6, 108.4, 81.6, 80.8, 44.3, 33.1, 26.3, 37.3, 27.3, 27.2,
(d, J = 8.0 Hz, 2 H, 2-H), 5.02 (dd, J = 15.0, 7.7 Hz, 2 H, 6-Ha),
4.92 (dd, J = 15.0, 7.3 Hz, 2 H, 6-Hb), 3.79 (dddm, J = 10.6, 9.5,
7.7 Hz, 2 H, 3-H), 2.77 (dd, J = 17.6, 9.5 Hz, 2 H, 4-Ha), 2.56 (dd,
J = 17.6, 10.7 Hz, 2 H, 4-Hb) ppm. 13C NMR (75 MHz, [D6]ace-
tone): δ = 174.1, 78.8, 75.2, 36.5, 32.1 ppm. IR: ν = 2956 (br., m),
˜
1790 (m), 1729 (s), 1550 (s), 1437 (m), 1375 (s), 1211 (m) cm–1.
LRMS (EI): m/z (%) = 288 (25)[M]+, 129 (75), 43 (93), 59 (100).
HRMS (EI): calcd. for C10H12N2O8 [M]+ 288.0594; found
288.0583. [α]2D5 = 1.6 (c = 0.57, acetone).
10.1 ppm. IR: ν = 3225 (br., w), 2982 (w), 2934 (m), 2876 (w), 1692
˜
(s), 1490 (w), 1456 (w), 1369 (m), 1238 (m), 1170 (m) cm–1. LRMS
(ES): m/z (%) = 214 (100) [M + H]+, 156 (25). HRMS (ESI): calcd.
for C11H20NO3 [M + H]+ 214.1443; found 214.1444. [α]2D3 = 24.0 (c
= 0.81, THF).
Supporting Information (see footnote on the first page of this arti-
cle). Full experimental details, analytical data, and copies of the
1H and 13C NMR spectra for compounds 2a–c, 3a–d, 4, 5, and 7–
14; details concerning the single-crystal X-ray structure determi-
nation of 7.
(R)-4-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]pyrrolidin-2-
one (10): To a solution of 4 (400 mg, 1.5 mmol) in ethanol (7 mL)
was added Zn powder (478 mg, 7.3 mmol), followed by acetic acid
(407 μL, 7.3 mmol). The mixture was stirred for 3 h at ambient
temperature. After evaporation of all volatiles, the residue was dis-
solved in hydrochloric acid (1 m) and extracted with ethyl acetate.
The organic phase was washed with sat. NaHCO3 solution and
brine, dried with MgSO4, solids filtered, and the solvents evapo-
rated. Column chromatography on silica gave lactam 10 (145 mg,
Acknowledgments
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG grant 1095/3–4). We thank Evonik Oxeno for
generous donation of solvents and Umicore, Hanau (Germany),
for a generous donation of the Umicore M2 and M31 catalysts.
1
47%). H NMR (300 MHz, CDCl3): δ = 6.85 (s, 1 H, -NH), 5.79
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(dddm, J = 17.4, 10.1, 7.1 Hz, 1 H, 6Ј-H), 5.37 (dm, J = 17.0 Hz,
1 H, =CH2trans), 5.28 (dm, J = 10.2 Hz, 1 H, =CH2cis), 4.02 (dd, J
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˜
3208 (br., w), 2985 (w), 2934 (w), 2872 (w), 1691 (s), 1490 (w), 1371
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C11H17NO3 [M]+ 211.1203; found 211.1209. [α]2D9 = 1.6 (c = 0.73,
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(3R,3ЈR)-Dimethyl 3,3Ј-[(4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-di-
yl]bis(4-nitrobutanoate) (13): To a solution of 3c (270 mg,
1.0 mmol) in CH3NO2 (0.2 m, 5 mL) was added DBU (2.2 mmol,
0.3 mL), and the mixture was stirred for 12 h at ambient tempera-
ture. Column chromatography on silica gave 13 (390 mg, quant.).
1H NMR (300 MHz, CDCl3): δ = 4.62 (dd, J = 13.6, 4.4 Hz, 2 H,
4-Ha), 4.51 (dd, J = 13.6, 7.7 Hz, 2 H, 4-Hb), 4.01 (dd, J = 3.2,
1.4 Hz, 2 H, 4Ј-H, 5Ј-H), 3.72 (s, 6 H, 5-H), 2.87 (m, 2 H, 3-H),
2.67 (dd, J = 6.4, 2.0 Hz, 4 H, 2-H), 1.33 (s, 6 H, 6Ј-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.5, 110.0, 78.5, 74.9, 52.2, 36.8,
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Received: November 12, 2010
Published Online: February 3, 2011
Eur. J. Org. Chem. 2011, 1721–1727
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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