Ireland-Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones

Article abstract of DOI:10.1002/ejoc.201500918

The Ireland-Claisen rearrangement of 6-methylene-1,4-oxazepan-2-one-derived boron enolates leads to stereochemically defined, synthetically useful 4-(E)-ethylidene prolines. Detailed computational and experimental studies explain the stereochemical outcome of this transformation and suggest an unusual double-chelated transition state that involves two boron atoms. The scope of the method is also explored.

Full text of DOI:10.1002/ejoc.201500918

FULL PAPER
DOI: 10.1002/ejoc.201500918
Ireland–Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones
Gints Smits,[a] Artis Kinens,[a] and Ronalds Zemribo*[a]
Keywords: Natural products / Sigmatropic rearrangement / Boron / Amino acids / Density functional calculations /
Transition states
The Ireland–Claisen rearrangement of 6-methylene-1,4-ox-
azepan-2-one-derived boron enolates leads to stereochemi-
cally defined, synthetically useful 4-(E)-ethylidene prolines.
Detailed computational and experimental studies explain the
stereochemical outcome of this transformation and suggest
an unusual double-chelated transition state that involves two
boron atoms. The scope of the method is also explored.
covalently bind to the minor groove of DNA.[6] The crucial
building block for the synthesis of all of these natural prod-
ucts is the proline fragment, which contains a C-4 ethyl-
idene substituent in the (E) configuration relative to the
nitrogen atom of the pyrrolidine ring. Although the total
syntheses of several of these natural products have been re-
ported, the stereoselective introduction of the double bond
into these systems is still a considerable challenge. The clas-
sical Wittig olefination predominantly gives the undesired
(Z) configuration of the double bond as shown in the total
synthesis of prothracarcin (2) and tomaymycin (3),[7] and
four extra steps were needed to invert its geometry. A Julia–
Kocienski olefination reaction was employed in the total
synthesis of barmumycin[1] (1), but the product was af-
forded in moderate yield with only slight selectivity (E/Z,
2:1) towards the desired (E) double bond isomer. Finally,
the (E)-4-ethylidene proline fragment in lucentamycin A (5)
was obtained by a long linear sequence, and the pyrrolidine
ring was formed from an acyclic substrate that contained
the ethylidene substituent.[8]
Introduction
A broad number of biologically active natural products,
such as barmumycin (1),[1] limazepine E (4),[2] lucenta-
mycin A (5),[3] eleganine A (6),[4] and many others (Fig-
ure 1), contain an (E)-4-ethylidene substituted proline frag-
ment.
As a result of the preferred chair-like transition state, the
Ireland–Claisen[9] rearrangement is known to be a reliable
method for the stereoselective introduction of chiral centers
and double bonds that have the desired configuration. The
original method involved the enolization of an ester sub-
strate by treatment with a strong base followed by trapping
with a silyl chloride to give the intermediate silyl ketene
acetal, which further underwent a [3,3] sigmatropic re-
arrangement.[10] Currently, soft enolization protocols are
also known for the generation of ketene acetals by using a
reactive Lewis acid in combination with a tertiary amine
base.[11] Reports of this approach usually focus on Ireland–
Claisen rearrangements of silyl ketene acetals, but phos-
phorus,[12] boron,[13] and several metal (Zn, Mg, and
Al)[14] ketene acetals have also been successfully used in this
transformation.
Figure 1. Examples of natural products that contain the 4-ethyl-
idene proline fragment.
These types of natural products have interesting bio-
logical activities. For example, barmumycin (1) and lu-
centamycin A were found to be cytotoxic against various
human tumor cell lines. Prothracarcin (2), tomaymycin (3),
and limazepine E (4) belong to the pyrrolo[1,4]benzodi-
azepine (PBD) class[5] of natural products, the antitumor
antibiotic properties of which are a result of their ability to
[a] Latvian Institute of Organic Synthesis,
Aizkraukles 21, Riga, Latvia
E-mail: ronalds@osi.lv
http://www.osi.lv
The high stereoselectivity and mild conditions of the Ire-
land–Claisen rearrangement prompted us to examine its
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500918.
Eur. J. Org. Chem. 2015, 6701–6709
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6701

G. Smits, A. Kinens, R. Zemribo
FULL PAPER
potential to solve the problems related to the introduction
of an (E)-configured double bond in the synthesis of the 4-
ethylidene proline derivatives. Recently, we developed a new
approach to control the geometry of the exocyclic double
bond by using a boron enolate in the Ireland–Claisen re-
arrangement, and this strategy was applied to the total syn-
theses of several natural products.[15] Herein, on the basis
of our most recent experimental and computational studies,
we report a revised stereochemical model for this transfor-
mation, which suggests the involvement of two boron atoms
and an unusual double-chelated transition state.
Scheme 2. Synthesis of lactone 13 (DIPEA = N,N-diisopropylethyl-
amine, THF = tetrahydrofuran, TFA = trifluoroacetic acid, DCM
= dichloromethane, EDC = 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide, HOBt = N-hydroxybenzotriazole).[15]
Results and Discussion
The retrosynthetic analysis of some natural products that
contain a 4-ethylidene proline fragment is outlined in
Scheme 1.[15a] The common building block for the total syn-
theses of barmumycin (1) and PBDs 2–4 is 4-ethylidene pro-
line 7, which is accessible by employing an Ireland–Claisen
rearrangement of ketene acetal 8, which is derived from
lactone 9. The necessary lactone 9 is easily constructed from
glycine derivative 11 and allylic bromide 10.
Table 1. Optimization of the Ireland–Claisen rearrangement of
lactone 13 (LiHMDS = lithium hexamethyldisilazide).
Entry
X
Method
E/Z[a]
Isolated yield of 16
1
2
3
4
5
TMS[b]
TBS[b]
TIPS[b]
(nBu)2B
Zn
A
A
A
A
B
1:2
1:1
–
Ͼ95:5[c]
–
18
15
–
85
–
[a] The E/Z ratio was determined by using the integration of the
1
signals in the H NMR spectrum, and the geometry of the double
bond of each isomer was assigned by NOE experiments. [b] TMS
= trimethylsilyl, TBS = tert-butyldimethylsilyl, TIPS = triisoprop-
ylsilyl. [c] The minor isomer was not observed by NMR analysis.
Scheme 1. Retrosynthetic analysis of some natural products (i.e.,
1–4) that contain a 4-ethylidene proline fragment (PG = protecting
group).
block 16 was then successfully converted into the two natu-
ral products – barmumycin (1) and limazepine E (4;
Scheme 3).[15]
Lactone 13 was prepared by starting from known allyl
bromide 10[16] and PMB-protected (PMB = para-meth-
oxybenzyl) glycine tert-butyl ester[17] (Scheme 2).[15] The
alkylation of this glycine derivative with bromide 10 gave
tertiary amine 12, which was further converted into lactone
13 through a deprotection–macrolactonization sequence.
With lactone 13 in hand, we further investigated the Ire-
land–Claisen rearrangement, the results of which are shown
in Table 1.
The use of silyl triflates resulted in either poor E/Z selec-
tivity and low yields of the rearrangement products[18] or
no reaction in the case of using TIPS triflate (Table 1, En-
tries 1–3). Employing the Kazmaier protocol[19] also failed
(Table 1, Entry 5). On the other hand, the use of dibut-
ylboron triflate [(nBu)2BOTf] resulted in excellent selectivity
and a high product yield (Table 1, Entry 4). Remarkably,
additional experiments showed that the Ireland–Claisen re-
arrangement proceeded to full conversion at temperatures
as low as 10 °C. To facilitate the product isolation, the re-
Scheme 3. The total synthesis of barmumycin (1) and limazepine E
(4).[15]
We further proposed that the excellent E/Z stereoselecti-
sulting carboxylic acid boron or silicon esters were con- vity observed in the Ireland–Claisen rearrangement of
verted in situ into the corresponding methyl ester. Building boron enolates 14 (Table 1, Entry 4) could arise from the
6702
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6701–6709

Ireland–Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones
chelation of the boron atom with the nitrogen and oxygen
atoms, which would stabilize the boat-like transition state
(Scheme 4). This transition state would give the desired
ethylidene proline 21. In contrast, this stabilizing chelation
is not possible with the silyl ketene acetals, and hence,
(R,Z)-17, the undesired isomer, would be predominantly
formed through the chair-like transition state (Scheme 4).
Scheme 4. Suggested stereochemical model.
The relative energies of the two plausible transition states
were determined by DFT calculations using the B3LYP/6-
311++g(3dpf,2p)//B3LYP/6-31+g(d,p) method. The calcu-
lations confirmed the hypothesis that the nature of the
Lewis acid used in the rearrangement has great impact on
the transition-state geometry. Single coordinating Lewis
acids (LA), such as those derived from TMS-OTf, bind to
the exocyclic oxygen atom of the enolate (Scheme 5). This
coordination has little influence on the stabilization of the
transition state. Thus, both possible chair-like transition
states 18a and 18b have similar energies and lead to a re-
arrangement with low selectivity. Similarly, DFT calcula-
tions predicted that the rearrangement of the corresponding
dimethyl borane enolate, with the boron atom attached to
the exocyclic oxygen atom, also occurred with low selectiv-
ity. In this case, the rearrangement led to two chair-like
transition states 18a and 18b with a 0.5 kcal/mol relative
enthalpy difference (Scheme 5, Path A).
Scheme 5. DFT analysis of transition states.
second equivalent of dibutylboron triflate, which resulted in
the formation of the desired (E)-ethylidene proline 21. Ke-
tene acetal 20 was further treated with isobutyraldehyde to
give aldol product 22.
However, dimethyl borane can also bind to two Lewis
basic atoms and form a bridge between the endocyclic oxy-
gen and nitrogen atoms. A second equivalent of dimeth-
ylborane would coordinate in this fashion to result in sig-
nificant steric hindrance between the bridging dimethyl bor-
ane and the exocyclic methyl group in chair-like transition
state 19b as opposed to that found in boat-like transition
state 19a. As a result of the large energy difference between
transition states 19a and 19b (ΔΔH = 7 kcal/mol), the Ire-
land–Claisen rearrangement must proceed with high selec-
Scheme 6. Studies of ketene acetal 20 formation (brsm = based on
recovered starting material).
The formation of ketene acetal 20 was also observed in
1
tivity and yield only 21(Scheme 5, Path B) These computa- the H NMR spectrum of the crude reaction mixture (Fig-
tional results are in line with the experimental data reported ure 2).[20] Here, we observed an upfield shift of the signals
in Table 1. The presence of two borane species in the transi- that correspond to protons Ha, Hb, and He after treating
tion state was confirmed experimentally. Hence, the ad- lactone 13 with 1 equiv. of dibutylboron triflate. A new sig-
dition of 1 equiv. of dibutylboron triflate to lactone 13 led nal Hg also appeared, which corresponds to the newly
to formation of boron enolate 20, which did not undergo formed double bond in ketene acetal 20. After treatment
the rearrangement to give proline derivative 21 (Scheme 6). of intermediate 20 with another equivalent of dibutylboron
The rearrangement took place only after the addition of the triflate, the characteristic proton signals Ha, Hb, He, and Hg
Eur. J. Org. Chem. 2015, 6701–6709
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6703

G. Smits, A. Kinens, R. Zemribo
FULL PAPER
disappeared, and a multiplet for proton Hk in the double case, the selectivity may be lower, as the energy difference
bond of ethylidene proline 21 appeared. These experimental between transition states 30a and 30b is 4 kcalmol–1. The
results are in good agreement with those proposed as a re- higher energy of transition state 30b over 28b can be attrib-
sult of the in silico calculations.
uted to the presence of three axial substituents in the former
compared to two axial substituents in the latter.
1
Figure 2. H NMR spectrum (400 MHz, CDCl3) of crude reaction
mixture.
Next we turned our attention to the total synthesis of
lucentamycin A (5). Our retrosynthetic analysis is outlined
in Scheme 7. The crucial building block of this strategy is
ethylidene proline 23, which may be accessible by em-
ploying an Ireland–Claisen rearrangement of ketene acetal
24, which is derived from lactone 25. The necessary lactone
25 could be synthesized form two simple building blocks –
glycine and allyl bromide 26.
Scheme 8. Theoretical model for stereochemical control in the for-
mation of proline 29.
To support the theoretical model, both double-bond iso-
mers of lactone 27 were synthesized. First, lactone (E)-27
was prepared by starting from known acrylate 31[21]
(Scheme 9). Ester 31 was converted into the desired allyl
bromide by using a DIBAL-H reduction/Appel reaction se-
quence. The resulting bromide 32 was further used in the
alkylation of PMB-protected glycine tert-butyl ester.[22]
Alcohol and carboxylic acid protecting groups were sub-
sequently cleaved, and the intermediate hydroxy acid under-
Scheme 7. Retrosynthetic analysis of lucentamycin A (5).
By using our theoretical model, we hypothesized that the
stereochemistry at the β-carbon of proline derivative 29
would be determined by the double-bond geometry of lact-
one 27 (Scheme 8). Thus, treatment of (E)-27 with dimeth-
ylboron triflate leads to (anti,Z)-29. This reaction should
proceed with high selectivity, as there is an energy difference
of 7 kcalmol–1 between the favored transition state 28b and
unfavorable 28a. On the other hand, the treatment of (Z)-
Scheme 9. Synthesis of lactone (E)-27 [TBDPS = tert-butyldiphen-
ylsilyl, DIBAL-H = diisobutylaluminum hydride, TBAF = tetra-n-
butylammonium fluoride, HBTU
=
O-(benzotriazol-1-yl)-
N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate, DMAP = 4-
27 with dimethylboron triflate leads to (syn,Z)-29. In this (dimethylamino)pyridine].
6704
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6701–6709

Ireland–Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones
went a macrolactonization under high dilution to give Interestingly, the rearrangement was sensitive to the base
the desired product (E)-27. With lactone (E)-27 in hand, that was used, and only Et3N in combination with sterically
we then examined the Ireland–Claisen rearrangement small boron triflates (Table 2, Entries 2 and 5) could be
(Scheme 10).
used to isolate significant amounts of the desired ethylidene
proline 34. Again in this case, the product that resulted
from the less favorable transition state 30a [corresponding
to (syn,E)-29; Scheme 8] was not formed. Instead, a mixture
of isomers (syn,Z)-34 and (anti,Z)-34 was formed. The iso-
mers could be separated by using semipreparative chiral
HPLC. The relative stereochemistry of (syn,Z)-34 was de-
termined by a 2D NOESY experiment (Figure 4), whereas
the spectrum of (anti,Z)-34 was identical to that of 34
(Scheme 10).
Scheme 10. Ireland–Claisen rearrangement of lactone (E)-27.
By using our previously determined conditions,[11] we
were able to isolate the Ireland–Claisen rearrangement
product (anti,Z)-34 in moderate yield as a single dia-
stereomer. The relative anti stereochemistry of the obtained
4-ethylidene proline derivative was unambiguously deter-
mined by a NOESY experiment (Figure 3), and this was
in full agreement with our theoretical model (Scheme 8).
Although the obtained proline (anti,Z)-34 could not be
used in the total synthesis of lucentamycin A (5), it could
successfully be used in the synthesis of the C-3 and C-4
anti-ethylidene proline fragments found, for example, in ele-
ganine A (6, Figure 1). The Ireland–Claisen rearrangement
allows the generation of three out of the four stereochemi-
cal elements in a single step.
Table 2. Optimization of the Ireland–Claisen rearrangement of
lactone (Z)-27.
Entry Triflate
Base
(anti,Z)-34/(syn,Z)-34[a]
% Yield
1
2
3
4
5
6
7
8
9
Et2BOTf
Et2BOTf
Et2BOTf
Bu2BOTf
Bu2BOTf
Bu2BOTf
Bu2BOTf
Bu2BOTf
Me2NEt
Et3N
–
3:2
–
–
1:2
–
–
–
–
trace
23
trace
trace
40
trace
trace
trace
trace
DIPEA
Me2NEt
Et3N
NMM[b]
2,6-lut[b]
DIPEA
Cy2BOTf[b] Et3N
[a] The syn/anti ratio was determined by the integration of the sig-
1
nals in the H NMR spectrum. [b] NMM = N-methylmorpholine,
2,6-lut = 2,6-lutidine, Cy = cyclohexyl.
Figure 3. Overhauser effects of proline (anti,Z)-34 2D NOESY
spectrum.
Next, lactone (Z)-27 was prepared in a similar manner
as (E)-27 (Scheme 11). The known acrylate 35[23] was first
protected and then converted into the corresponding allyl
bromide 36, which was needed for the alkylation of the
PMB-protected glycine tert-butyl ester. Finally, the protect-
ing group cleavage–macrolactonization sequence gave the
desired lactone (Z)-27 in high yield.
Figure 4. Overhauser effects of proline (syn,Z)-34 2D NOESY
spectrum.
We speculate that the rearrangement of lactone (Z)-27
still proceeds through the favored boron-chelated transition
state 30b (Scheme 8). However, under the reaction condi-
tions, the chiral center at the C-2 position of ethylidene
proline (syn,Z)-34 partially epimerizes to form the more
stable isomer (anti,Z)-34.
Scheme 11. Synthesis of lactone (Z)-27 (DMF = N,N-dimethyl-
formamide).
To expand the scope of this transformation, we also syn-
thesized lactone 39, which has an additional methyl group
With lactone (Z)-27 in hand, we turned our attention at its C-3 position (Scheme 12). The Ireland–Claisen re-
toward the Ireland–Claisen rearrangement. A series of rea- arrangement of this substrate would provide a proline de-
gents were first screened to optimize this reaction (Table 2). rivative that has a chiral quaternary carbon.
Eur. J. Org. Chem. 2015, 6701–6709
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6705

G. Smits, A. Kinens, R. Zemribo
FULL PAPER
3 and C-4 anti- ethylidene proline fragments that are found,
for example, in eleganine A (6).
Experimental Section
General Methods: Reagents and starting materials were obtained
from commercial sources and used as received. The solvents were
purified and dried by standard procedures prior to use. Petroleum
ether with a boiling range 60–80 °C was used. Flash chromatog-
raphy was carried out by using Merck Kieselgel (230–400 mesh).
Thin layer chromatography was performed on Merck Kieselgel
60F254. The NMR spectroscopic data were recorded with Bruker
Fourier (300 MHz), Varian Mercury (400 MHz), and Varian Unity
Inova (600 MHz) spectrometers. Chemical shift values are refer-
Scheme 12. Synthesis of lactone 39.
We began the synthesis with the alkylation of commer-
cially available PMB-protected alanine tert-butyl ester with enced against the residual proton in the deuterated solvents for 1H
NMR and the deuterated solvent for 13C NMR. The multiplicities
of the signals are described as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), and br. (broad). Infrared spectra were
recorded as films in the range 4000–600 cm–1. HRMS was per-
formed on a Micromass AutoSpec Ultima Magnetic sector mass
spectrometer. Optical rotations were measured by using a Rudolph
Research Analytical Autopol VI polarimeter. LC–MS analyses
were performed on a Shimadzu Prominence chromatograph con-
nected to an Applied Biosystems API 2000 mass spectrometer [col-
umn: Phenomenex Gemini 5 μm C18, 50ϫ2 mm; eluent: MeCN
(+ 0.1% HCOOH)/H2O (+ 0.1% HCOOH)]. Preparative LC–MS
purification was performed by using a Waters 600 chromatograph
connected to a Waters 3100 mass spectrometer [column: Xterra
10 μm C18, 10ϫ150 mm; eluent: MeOH (+ 0.1% HCOOH)/H2O
(+ 0.1% HCOOH)].
known allyl bromide 10.[16] The obtained intermediate 38
was further converted into the desired lactone 39 in a sim-
ilar manner as described for 13 (Scheme 2). With lactone
39 in hand, we investigated the Ireland–Claisen rearrange-
ment as summarized in Table 3.
Table 3. Optimization of the Ireland–Claisen rearrangement of
lactone 39.
Entry
Triflate
Base
E/Z[a]
% Yield
NMR Experiment: Lactone 13 (100 mg, 0.383 mmol) was placed in
a microwave tube and dried overnight over P2O5 in a vacuum dry-
ing chamber. The tube was tightly sealed and purged with argon
(3ϫ). Dry CDCl3 (2 mL) and DIPEA (445 mg, 3.444 mmol), which
was freshly distilled from sodium, were added, and the resulting
mixture was then cooled to –78 °C, treated with dibutylboron tri-
flate (104 mg, 0.383 mmol), and then warmed to room temp. A few
drops of the reaction mixture were removed with a dry syringe,
placed in an NMR tube (sealed with a rubber septum and purged
with Ar), and diluted with dry CDCl3. The spectra, which were
recorded after 15 min and 3 h, looked very similar. The reaction
mixture was again cooled to –78 °C and treated with dibutylboron
triflate (104 mg, 0.383 mmol). The resulting mixture was warmed
to room temp., and an NMR sample was then prepared as de-
scribed above.
1
2
3
4
Bu2BOTf
Bu2BOTf
Cy2BOTf
Cy2BOTf
Et3N
DIPEA
Et3N
1:2
–
1:2
–
43
trace
47
DIPEA
trace
[a] The E/Z ratio was determined by the integration of the signals
in the H NMR spectrum.
1
Et3N was determined to be the preferred base (Table 3,
Entries 1 and 4), However, all attempts of the rearrange-
ment led to the formation of an inseparable mixture of (E)
and (Z) isomers in moderate yields. Understanding the
reasons for the poor stereocontrol in the Ireland–Claisen
rearrangement of lactone 39 is a topic of ongoing investiga-
tion, and the results of these studies will be reported in due
course.
(7S)-3-(1-Hydroxy-2-methylpropyl)-4-(4-methoxybenzyl)-7-methyl-
6-methylene-1,4-oxazepan-2-one (22): Lactone 13 (100 mg,
0.383 mmol) was placed in a microwave tube and dried overnight
over P2O5 in a vacuum drying chamber. The tube was tightly sealed
and purged with argon (3ϫ). Dry DCM (2 mL) and DIPEA
Conclusions
We have developed an efficient method for the fully (445 mg, 3.444 mmol), which was freshly distilled from sodium,
were added, and the mixture was cooled to –78 °C and treated with
dibutylboron triflate (104 mg, 0.383 mmol). The mixture was
placed in an ice bath, stirred for 10 min, and then recooled to
–78 °C. Then, freshly distilled isobutyraldehyde (82 mg,
1.148 mmol) was added, and the mixture was warmed to ambient
temperature, stirred overnight, and then diluted with brine. The
resulting solution was extracted with DCM (2ϫ). The combined
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography [petroleum ether (Pet)/EtOAc, 9:1 to 1:1) to give
stereoselective and high yielding synthesis of (E)-4-ethyl-
idene proline by using an Ireland–Claisen rearrangement.
The computational and experimental studies suggest an un-
usual mechanistic pathway, in which two molecules of
boron triflate are involved in the preferred transition state.
The obtained (E)-4-ethylidene proline was used in the total
syntheses of barmumycin (1) and limazepine E (4). Al-
though the method has some limitations when applied to
the synthesis of more complex (E)-4-ethylidene proline de-
rivatives, it has a good potential for the synthesis of the C- 22 (72 mg, 56 %, 63 % brsm) as a pale yellow oil. 1H NMR
6706
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6701–6709

Ireland–Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones
(400 MHz, CDCl3): δ = 7.11 (d, J = 8.6 Hz, 2 H), 6.83 (d, J =
1 H), 2.95 (2 H, AB m), 1.64 (d, J = 7.0 Hz, 3 H), 1.43 (s, 9 H),
8.6 Hz, 2 H), 5.42 (s, 1 H), 5.04 (q, J = 6.4 Hz, 1 H), 4.95 (s, 1 H), 1.06 (d, J = 6.3 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR (100 MHz,
4.05–4.00 (m, 1 H), 3.86 (d, J = 8.8 Hz, 1 H), 3.78 (s, 3 H), 3.55 CDCl3): δ = 171.14, 158.48, 140.28, 135.87, 134.85, 134.69, 134.31,
(d, J = 13.3 Hz, 1 H), 3.36 (2 H, AB m), 3.20 (d, J = 13.5 Hz, 1 131.51, 130.01, 129.38, 127.36, 127.31, 122.42, 113.41, 80.40, 71.36,
H), 2.63 (d, J = 3.5 Hz, 1 H), 2.35, (septet, J = 6.6 Hz), 1.54 (d, J
57.12, 55.19, 53.53, 49.34, 28.18, 27.06, 23.90, 19.30, 13.05 ppm.
= 6.54 Hz, 3 H), 1.07 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 [α]D = –19.16 (c = 1, CHCl3 ). HRMS (ESI): calcd. for
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.01, 158.80, 138.58,
C36H50SiNO4 [M + H]+ 588.3519; found 588.3495. IR (film): ν =
˜
129.72, 129.65, 117.79, 113.82, 75.04, 72.53, 65.89, 59.65, 55.19, 2962, 1734, 1661, 1512, 1247, 1144 cm–1.
50.33, 28.21, 20.25, 17.83, 14.57 ppm. HRMS (ESI): calcd. for
tert-Butyl (S,E)-2-{[2-(1-Hydroxyethyl)but-2-en-1-yl](4-meth-
oxybenzyl)amino}acetate (SI-2): A mixture containing ester 33
(100 mg, 0.170 mmol) and TBAF·3H2O (80 mg, 0.255 mmol) in
C19H28NO4 [M + H]+ 334.2016; found 334.2018. IR (film): ν =
˜
3503, 2958, 1717, 1612, 1512, 1245 cm–1.
(S,E)-2-{1-[(tert-Butyldiphenylsilyl)oxy]ethyl}but-2-en-1-ol (SI-1): dry THF (1 mL) was stirred in a sealed tube for 5 d under argon.
To a stirred solution of ester 31 (2.860 g, 7.476 mmol) in dry DCM The reaction mixture was concentrated in vacuo, and the residue
(25 mL) was slowly added DIBAL-H (1.2 m in toluene, 3.23 g, was purified by flash column chromatography (Pet/EtOAc, 20:1) to
1
22.427 mmol) at –78 °C. After 4 h, the mixture was quenched by
adding MeOH, and the resulting mixture was warmed to room
temp. and diluted with a saturated Rochelle salt solution. The mix-
ture was extracted with DCM (2ϫ). The combined organic layers
were dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
give SI-2 (55 mg, 93%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): δ = 7.25 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H),
5.70 (q, J = 6.6 Hz, 1 H), 5.41 (br. s, 1 H), 4.26 (q, J = 7.04 Hz, 1
H), 3.80 (s, 3 H), 3.76 (d, J = 12.9 Hz, 1 H), 3.55 (d, J = 12.5 Hz,
1 H), 3.36 (2 H, AB m), 3.15 (2 H, AB m), 1.66 (d, J = 7.0 Hz, 3
H), 1.46 (s, 9 H), 1.17 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.34, 158.98, 137.88, 130.55, 129.77,
(Pet/EtOAc, 10:1) to give alcohol SI-1 (2.170 g, 82%) as a pale
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.70–7.64 (m, 4 H), 124.51, 113.79, 81.31, 73.25, 57.67, 55.21, 54.06, 50.12, 28.10,
7.46–7.34 (m, 6 H), 5.31 (q, J = 7.0 Hz, 1 H), 4.35 (q, J = 6.3 Hz, 22.00, 12.93 ppm. HRMS (ESI): calcd. for C20H31NO4 [M + H]
1 H), 4.29 (d, J = 5.5 Hz, 2 H), 2.44 (t, J = 5.5 Hz, 1 H), 1.61 (d,
350.2337; found 250.2320. [α]D = 9.60 (c = 1, CHCl ). IR (film): ν
˜
3
J = 7.0 Hz, 3 H), 1.20 (d, J = 6.3 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C = 3070, 2962, 1734, 1247 cm–1.
NMR (100 MHz, CDCl3): δ = 140.57, 135.94, 135.89, 133.78,
(S,E)-6-Ethylidene-4-(4-methoxybenzyl)-7-methyl-1,4-oxazepan-2-
133.39, 129.74, 129.69, 127.55, 127.47, 124.01, 75.61, 57.83, 26.97,
23.27, 19.10, 12.88 ppm. [α]D = –26.50 (c = 1, CHCl3). HRMS
(ESI): calcd. for C22H31SiO2 [M + H]+ 355.2106; found 355.2089.
one [(E)-27]: To a stirred solution of ester SI-2 (1.330 g,
3.344 mmol) in DCM (20 mL) was added TFA (20 mL), and the
dark reaction mixture was stirred for 4 h and then concentrated in
vacuo. The residue was dissolved in dry DCM (10 mL), and over a
IR (film): ν = 3418, 3071, 1669 cm–1.
˜
(S,Z)-{[3-(Bromomethyl)pent-3-en-2-yl]oxy}(tert-butyl)diphenyl- period of approximately 1 h, the solution was added to a vigorously
silane (32): To a stirred solution of alcohol SI-1 (2.17 g,
6.120 mmol) and PPh3 (1.76 g, 6.732 mmol) in dry DCM under
argon was added CBr4 (2.23 g, 6.732 mmol) at 0 °C, and the re-
sulting mixture was warmed to ambient temperature. The reaction
mixture was stirred for 2 h and then concentrated in vacuo. The
residue was purified by flash column chromatography (Pet/EtOAc,
10:1) to give 32 (2.550 g, 87 %) as a pale yellow oil. 1H NMR
stirred slurry that contained O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-
tetramethyluronium hexafluorophosphate (HBTU, 3.804 g,
10.033 mmol) and DMAP (2.451 g, 20.065 mmol) in dry DCM
(150 mL). The resulting mixture was stirred overnight and then di-
luted with brine. The mixture was extracted with DCM (2ϫ) and
the combined organic layers were dried with anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
(400 MHz, CDCl3): δ = 7.69–7.61 (m, 4 H), 7.45–7.33 (m, 6 H), flash column chromatography (Pet/EtOAc 4:1 to 1:1) to give (E)-
5.57 (q, J = 7.0 Hz, 1 H), 4.36 (q, J = 6.4 Hz, 1 H), 4.02 (2 H, AB
m), 1.63 (d, J = 7.0 Hz, 3 H), 1.28 (d, J = 6.4 Hz, 3 H), 1.06 (s, 9
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.52, 135.87, 135.82,
27 (880 mg, 96 % in two steps) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2 H), 6.86 (d, J =
8.4 Hz, 2 H), 5.93 (q, J = 6.8 Hz, 1 H), 5.18 (q, J = 6.6 Hz, 1 H),
134.24, 133.79, 129.57, 129.55, 127.47, 127.41, 127.12, 72.80, 26.98, 3.80 (s, 3 H), 3.73 (d, J = 16.6 Hz, 1 H), 3.57 (2 H, AB m), 3.51
26.10, 23.68, 19.25, 13.20 ppm. [α]D = 65.84 (c = 1, CHCl3). HRMS
(ESI): calcd. for C22H30SiO79Br [M + H]+ 417.1244; found
417.1243; calcd. for C22H30SiO81Br [M + H]+ 419.1223; found
(d, J = 15.1 Hz, 1 H), 3.44 (d, J = 16.6 Hz, 1 H), 3.28 (d, J =
14.3 Hz, 1 H), 1.61 (d, J = 6.8 Hz, 3 H), 1.51 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.34, 158.94, 133.66,
129.89, 129.68, 126.68, 113.79, 77.18, 58.32, 58.14, 55.22, 54.37,
18.64, 13.31 ppm. [α]D = 58.4 (c = 1, CHCl3). HRMS (ESI): calcd.
419.1224. IR (film): ν = 2961, 1662 cm–1.
˜
tert-Butyl (S,E)-2-[(2-{1-[(tert-Butyldiphenylsilyl)oxy]ethyl}but-2-
en-1-yl)(4-methoxybenzyl)amino]acetate (33): A mixture containing
2-[(4-methoxybenzyl)amino]acetate (361 mg, 1.437 mmol), bromide
32 (400 mg, 0.958 mmol), and DIPEA (247 mg, 1.916 mmol) in dry
THF (3 mL) was stirred in a sealed tube for 7 d under argon. The
reaction mixture was concentrated in vacuo, and the residue was
diluted with a saturated aqueous NaHCO3 solution. The resulting
mixture was extracted with DCM (2ϫ). The combined organic lay-
ers were dried with anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy (Pet/EtOAc, 20:1) to give 33 (3.240 g, 98%) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 7.67–7.59 (m, 4 H), 7.41–
7.28 (m, 6 H), 7.06 (d, J = 8.6 Hz, 2 H), 6.73 (d, J = 8.6 Hz, 2 H),
5.85 (q, J = 7.0 Hz, 1 H), 4.35 (q, J = 6.6 Hz, 1 H), 3.77 (s, 3 H),
3.58 (2 H, AB m), 3.26 (d, J = 13.3 Hz, 1 H), 3.03 (d, J = 11.7 Hz,
for C16H22NO3 [M + H]+ 276.1594; found 276.1607. IR (film): ν =
˜
2934, 1717, 1513, 1247 cm–1.
Benzyl (2S,3S,E)-4-Ethylidene-1-(4-methoxybenzyl)-3-methyl-
pyrrolidine-2-carboxylate [(anti,Z)-34]: Lactone (E)-27 (50 mg,
0.182 mmol) was placed in a MW tube and dried overnight over
P2O5 in a vacuum drying chamber. The tube was tightly sealed and
purged with argon (3ϫ). Dry DCM (0.5 mL) and DIPEA (140 mg,
1.090 mmol), which was freshly distilled from sodium, were added,
and the mixture was cooled in an ice bath and then treated with
dibutylboron triflate (149 mg, 0.545 mmol). The mixture was
warmed to ambient temperature over 3 h, and then benzyl alcohol
(196 mg, 1.816 mmol) was added followed by HBTU (206 mg,
0.545 mmol). The obtained mixture was stirred for 16 h and then
diluted with a saturated aqueous sodium hydrogen carbonate solu-
Eur. J. Org. Chem. 2015, 6701–6709
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6707

G. Smits, A. Kinens, R. Zemribo
FULL PAPER
tion. The mixture was extracted with DCM (2ϫ). The combined
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by preparative
HPLC–MS to give (anti,Z)-34 (30 mg, 45%) as a pale yellow oil.
(400 MHz, CDCl3): δ = 7.67–7.65 (m, 2 H), 7.58–7.56 (m, 2 H),
7.43–7.28 (m, 6 H), 7.21 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz,
2 H), 5.47 (q, J = 7.4 Hz, 1 H), 4.64 (q, J = 6.3 Hz, 1 H), 3.78 (s,
3 H), 3.67 (2 H, AB m), 3.36 (d, J = 14.0 Hz, 1 H), 3.12–3.09 (m,
1H NMR (600 MHz, CDCl3): δ = 7.37–7.32 (m, 5 H), 7.21 (d, J = 3 H), 1.45 (s, 9 H), 1.43 (d, J = 7.4 Hz, 3 H), 1.18 (d, J = 6.3 Hz,
8.4 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 5.31 (q, J = 7.4 Hz, 1 H), 3 H), 1.00 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.19,
3.85 (d, J = 12.4 Hz, 1 H), 3.79 (s, 3 H), 3.46 (2 H, AB m), 3.14
(d, J = 12.0 Hz, 1 H), 3.11 (d, J = 5.7 Hz, 1 H), 2.96–2.93 (m, 1
H), 1.56 (d, J = 6.7 Hz, 3 H), 1.23 (d, J = 7.4 Hz, 3 H) ppm. 13C
158.50, 139.53, 135.83, 135.77, 134.59, 134.03, 131.28, 130.01,
129.41, 129.36, 127.40, 127.34, 121.59, 113.49, 80.39, 67.72, 57.38,
55.48, 55.19, 54.02, 28.23, 26.94, 22.75, 19.21, 12.97 ppm. [α]D
=
NMR (125 MHz, CDCl3): δ = 169.66, 158.88, 140.70, 135.80, 1.64 (c = 1, CHCl3). HRMS (ESI): calcd. for C36H50SiNO4 [M +
130.35, 128.53, 128.26, 116.53, 113.62, 73.43, 66.45, 57.68, 57.61,
H]+ 588.3504; found 588.3506. IR (film): ν = 2930, 1733, 1612,
˜
55.23, 39.89, 19.13, 13.84 ppm. HRMS (ESI): calcd. for 1145, 1111 cm–1.
C23H28NO3 [M + H]+ 376.2031; found 376.2096. [α]D = –13.5 (c =
tert-Butyl (S,Z)-2-{[2-(1-Hydroxyethyl)but-2-en-1-yl](4-meth-
1, CHCl ). IR (film): ν = 2927, 1730, 1248 cm–1.
˜
3
oxybenzyl)amino}acetate (SI-5): Compound SI-5 was obtained in a
similar manner as that described for the preparation of SI-2. Pale
tert-Butyl (S,E)-2-{1-[(tert-Butyldiphenylsilyl)oxy]ethyl}but-2-eno-
ate (SI-3): A mixture of alcohol 35 (4.016 g, 21.567 mmol),
TBDPS-Cl (8.892 g, 32.351 mmol), and imidazole (4.404 g,
64.702 mmol) in dry DMF (20 mL) in a sealed tube was stirred for
4 d under argon. The reaction mixture was concentrated in vacuo,
and the residue was diluted with a saturated aqueous NaHCO3
solution. The mixture was extracted with DCM (2ϫ). The com-
bined organic layers were dried with anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (Pet/EtOAc, 10:1 to 5:1). The fractions that
contained the desired product were concentrated in vacuo and used
1
yellow oil (1.180 g, 93%). H NMR (400 MHz, CDCl3): δ = 7.23
(d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.73 (br. s, 1 H),
5.35 (q, J = 7.0 Hz, 1 H), 4.77 (q, J = 6.3 Hz, 1 H), 3.85 (d, J =
12.9 Hz, 1 H), 3.80 (s, 3 H), 3.50 (2 H, AB m), 3.25 (d, J = 16.4 Hz,
1 H), 3.03–2.97 (m, 2 H), 1.64 (d, J = 7.0 Hz, 3 H), 1.46 (s, 9 H),
1.16 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.17, 158.94, 137.97, 130.57, 129.48, 124.98, 113.75, 81.22, 66.38,
58.42, 57.42, 55.22, 53.93, 28.09, 22.67, 13.05 ppm. [α]D = –23.56
(c = 1, CHCl3). HRMS (ESI): calcd. for C20H32NO4 [M + H]+
350.2326; found 350.2359. IR (film): ν = 3446, 2974, 1734, 1612,
˜
1
in the next step. H NMR (400 MHz, CDCl3): δ = 7.70–7.68 (m, 2
1157 cm–1.
H), 7.63–7.60 (m, 2 H), 7.44–7.30 (m, 6 H), 6.63 (q, J = 7.4 Hz, 1
H), 4.85 (q, J = 6.6 Hz, 1 H), 1.80 (d, J = 7.4 Hz, 3 H), 1.42 (s, 9
H), 1.30 (d, J = 6.6 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.41, 137.88, 137.19, 135.82, 134.34,
133.83, 129.49, 129.45, 127.46, 127.40, 79.96, 66.46, 28.12, 26.92,
23.23, 19.21, 14.30 ppm. [α]D = –8.64 (c = 1, CHCl3). HRMS (ESI):
calcd. for C26H36SiNaO3 [M + Na]+ 447.2326; found 447.2317. IR
(S,Z)-6-Ethylidene-4-(4-methoxybenzyl)-7-methyl-1,4-oxazepan-2-
one [(Z)-27]: Compound (Z)-27 was obtained in a similar manner
as that described for the preparation of (E)-27. Pale yellow oil
1
(730 mg, 90% over two steps). H NMR (400 MHz, CDCl3): δ =
7.24 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.64 (q, J =
7.0 Hz, 1 H), 5.29 (q, J = 6.6 Hz, 1 H), 3.80 (s, 3 H), 3.57 (s, 2 H),
3.47–3.40 (m, 3 H), 3.12 (d, J = 12.5 Hz, 1 H), 1.72 (d, J = 7.0 Hz,
3 H), 1.58 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
(film): ν = 2973, 1703, 1648, 1274, 1092 cm–1.
˜
(S,Z)-2-{1-[(tert-Butyldiphenylsilyl)oxy]ethyl}but-2-en-1-ol (SI-4): δ = 171.31, 158.92, 134.45, 130.20, 129.87, 129.51, 127.87, 113.77,
Compound SI-4 was obtained in a similar manner as that described 74.23, 58.54, 57.76, 55.26, 55.19, 19.88, 13.17 ppm. [α]D = 9.20 (c
for the preparation of SI-1. Pale yellow oil (4.740 g, 62% over two = 1, CHCl3). HRMS (ESI): calcd. for C16H22NO3 [M + Na]+
steps). 1H NMR (400 MHz, CDCl3): δ = 7.72–7.70 (m, 2 H), 7.67– 276.1594; found 276.1599. IR (film): ν = 2934, 1718, 1611, 1247,
˜
7.64 (m, 2 H), 7.47–7.35 (m, 6 H), 5.43 (q, J = 6.65 Hz, 1 H), 4.86 1078 cm–1.
(q, J = 7.0 Hz, 1 H), 4.40 (d, J = 12.5 Hz, 1 H), 4.13 (d, J =
Benzyl (2S,3R,E)-4-Ethylidene-1-(4-methoxybenzyl)-3-methyl-
12.5 Hz, 1 H), 2.64 (br. s, 1 H), 1.35 (d, J = 7.0 Hz, 3 H), 1.16 (d,
pyrrolidine-2-carboxylate [(syn,Z)-34]: Compound (syn,Z)-34 was
J = 6.5 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3):
obtained in a similar manner as that described for the preparation
δ = 139.83, 135.82, 135.72, 134.14, 133.71, 129.63, 127.53, 127.40,
of (anti,Z)-34 by starting from (Z)-27. Et3N was used instead of
67.33, 33.58, 26.96, 23.47, 19.23, 13.24 ppm. [α]D = –10.82 (c = 1,
DIPEA. After purification of the isomeric mixture by preparative
CHCl3). HRMS (ESI): calcd. for C22H29SiNaO2 [M + Na]+
HPLC–MS, the syn and anti isomers were successfully separated
377.1907; found 377.1930. IR (film): ν = 3411, 2930, 1589, 1111,
˜
by using semipreparative chiral HPLC. The product was obtained
1073 cm–1.
as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.32
(S,E)-{[3-(Bromomethyl)pent-3-en-2-yl]oxy}(tert-butyl)diphenyl- (m, 5 H), 7.21 (d, J = 8.6 Hz, 2 H), 6.81 (d, J = 8.6 Hz, 2 H), 5.24–
silane (36): Compound 36 was obtained in a similar manner as that
5.16 (m, 3 H), 3.99 (d, J = 12.5 Hz, 1 H), 3.79 (s, 3 H), 3.56 (d, J
= 13.7 Hz, 1 H), 3.42 (J = 6.6 Hz, 1 H), 3.25 (d, J = 12.5 Hz, 1
described for the preparation of 32 and used in the next step with-
1
out full purification. H NMR (400 MHz, CDCl3): δ = 7.70–7.68 H), 3.12–3.06 (m, 1 H), 2.88 (d, 1 H), 1.58 (d, J = 7.4 Hz, 3 H),
(m, 2 H), 7.63–7.60 (m, 2 H), 7.45–7.32 (m, 6 H), 5.65 (q, J = 1.00 (d, J = 7.0 Hz, 3 H) ppm.
7.0 Hz, 1 H), 4.74 (q, J = 6.6 Hz, 1 H), 4.35 (d, J = 9.8 Hz, 1 H),
tert-Butyl (S)-2-{[(S)-3-Hydroxy-2-methylenebutyl](4-meth-
3.90 (d, J = 9.8 Hz, 1 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.31 (d, J =
oxybenzyl)amino}propanoate (38): Compound 38 was obtained in a
6.6 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
similar manner as that described for the preparation of 33. Pale
= 139.98, 135.97, 135.87, 134.30, 133.87, 129.78, 127.67, 127.55,
1
yellow oil (710 mg, 71%). H NMR (300 MHz, CDCl3): δ = 7.25
67.49, 67.42, 27.10, 23.61, 19.39, 13.42 ppm. [α]D = –34.28 (c = 1,
(d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.10 (s, 2 H), 4.98
(s, 1 H), 4.30 (q, J = 6.3 Hz, 1 H), 3.80 (s, 3 H), 3.64–3.52 (m, 3
CHCl ). IR (film): ν = 2961, 1652, 1111 cm–1.
˜
3
tert-Butyl (S,Z)-2-[(2-{1-[(tert-Butyldiphenylsilyl)oxy]ethyl}but-2- H), 3.30 (2 H, AB m), 1.50 (s, 9 H), 1.24 (d, J = 7.1 Hz, 3 H), 1.19
en-1-yl)(4-methoxybenzyl)amino]acetate (37): Compound 37 was
(d, J = 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
obtained in a similar manner as that described for the preparation
172.51, 158.85, 147.81, 130.33, 130.28, 114.17, 113.78, 81.23, 70.23,
of 33. Pale yellow oil (1.070 g, 59 % over two steps). 1H NMR 56.22, 55.17, 54.55, 53.68, 28.17, 21.20, 12.16 ppm. [α]D = –65.80
6708
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6701–6709

Ireland–Claisen Rearrangement of 6-Methylene-1,4-oxazepan-2-ones
(c = 1, CHCl3). HRMS (ESI): calcd. for C20H32NO4 [M + H]+
[8] S. Ranatunga, C.-H. A. Tang, C.-C. A. Hu, J. R. Del Valle, J.
Org. Chem. 2012, 77, 9859–9864.
350.2331; found 350.2336. IR (film): ν = 3440, 2977, 1724, 1612,
˜
[9] For reviews of the Ireland–Claisen rearrangement, see: a)
A. M. M. Castro, Chem. Rev. 2004, 104, 2939–3002; b) Y. Chai,
S. Hong, H. A. Lindsay, C. McFarland, M. C. McIntosh, Tet-
rahedron 2002, 58, 2905–2928; c) M. Hiersemann, U. Nub-
bemeyer, The Claisen Rearrangement, Wiley-VCH, Weinheim,
Germany, 2007; d) E. A. Ilardi, C. E. Stivala, A. Zakarian,
Chem. Soc. Rev. 2009, 38, 3133–3148; for application of the
Ireland–Claisen rearrangement, see: e) C. He, C. Zhu, B. Wang,
H. Ding, Chem. Eur. J. 2014, 20, 15053–15060; f) Q. Xiao, J. J.
Jackson, A. Basak, J. M. Bowler, B. G. Miller, A. Zakarian,
Nature Chem. 2013, 5, 410–416; g) T. K. Kuilya, S. Chatterjee,
R. K. Goswami, Tetrahedron 2014, 70, 2905–2918; h) N. Kina-
shi, K. Fujiwara, T. Tsunoda, R. Katoono, H. Kawai, T. Su-
zuki, Tetrahedron Lett. 2013, 54, 4564.
1513, 1252 cm–1.
(3S,7S)-4-(4-Methoxybenzyl)-3,7-dimethyl-6-methylene-1,4-
oxazepan-2-one (39): Compound 39 was obtained in a similar man-
ner as that described for the preparation of (E)-27. Pale yellow oil
1
(140 mg, 37% over two steps). H NMR (300 MHz, CDCl3): δ =
7.19 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.42 (s, 1 H),
5.02–4.96 (m, 2 H), 4.08 (q, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 3.65
(d, J = 13.5 Hz, 1 H), 3.37 (2 H, AB m), 3.17 (d, J = 13.4 Hz, 1
H), 1.54 (d, J = 6.5 Hz, 3 H), 1.44 (d, J = 6.7 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.54, 158.74, 139.73, 130.44,
129.83, 116.83, 113.73, 74.49, 58.81, 58.77, 55.23, 49.27, 18.06,
16.39 ppm. [α]D = –146.70 (c = 1, CHCl3). HRMS (ESI): calcd. for
C16H22NO3 [M + H]+ 276.1600; found 176.1597.
[10] R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94,
5897–5898.
Methyl (S,E)-4-Ethylidene-1-(4-methoxybenzyl)-2-methylpyrrol-
idine-2-carboxylate and Methyl (S,Z)-4-Ethylidene-1-(4-meth-
oxybenzyl)-2-methylpyrrolidine-2-carboxylate (40): Compounds 40
were obtained in a similar manner as that described for the prepa-
ration of (anti,Z)-34 by starting from 39. The separation of isomers
was not successful. The product was obtained as a pale yellow oil.
1H NMR (400 MHz, CDCl3, mixture of isomers): δ = 7.28–7.24
(m, 2 H), 6.87–6.83 (m, 2 H), 5.23 (br. s), 3.81–3.71 (m, 7 H), 3.54–
3.31 (m, 3 H), 2.87–2.80 (m, 1 H), 2.49–2.40 (m, 1 H), 1.54 (d, 2
H, J = 7.0 Hz), 1.48–1.43 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, mixture of isomers): δ = 175.21, 158.58, 135.96, 131.64,
129.54, 129.45, 114.84, 113.61, 67.65, 56.34, 55.24, 53.88, 53.14,
53.02, 51.44, 44.84, 41.29, 20.89, 20.55, 14.50, 14.39 ppm.
[11] M. Kobayashi, K. Masumoto, E. Nakai, T. Nakai, Tetrahedron
Lett. 1996, 37, 3005–3008.
[12] R. L. Funk, J. B. Stallman, J. A. Wos, J. Am. Chem. Soc. 1993,
115, 8847–8848.
[13] For examples of the use of boron triflates in the Ireland–
Claisen rearrangement, see: a) T. Oh, Z. Wrobel, P. N. Devine,
Synlett 1992, 1, 81–83; b) E. J. Corey, B. E. Roberts, B. R. Di-
xon, J. Am. Chem. Soc. 1995, 117, 193–196; c) C. A. Seizert,
E. M. Ferreira, Chem. Eur. J. 2014, 20, 4460–4468.
[14] U. Kazmaier, Tetrahedron 1994, 50, 12895–12902.
[15] a) G. Smits, R. Zemribo, Org. Lett. 2013, 15, 4406–4409; b) G.
Sakaine, G. Smits, R. Zemribo, Tetrahedron Lett. 2015, in
press; DOI: 10.1016/j.tetlet.2015.06.051.
[16] O. G. Kulinkovich, Y. Y. Kozyrkov, A. V. Bekish, E. A. Matiu-
shenkov, I. L. Lysenko, Synthesis 2004, 10, 1713–1717.
[17] G. Arnott, J. Clayden, S. D. Hamilton, Org. Lett. 2006, 8,
5325–5328.
[18] Analysis of the crude reaction mixture by HPLC–MS showed
the formation of a number of byproducts, predominantly an
acyclic diene, which was formed by elimination of the starting
lactone 7.
[19] a) U. Kazmaier, Angew. Chem. Int. Ed. Engl. 1994, 33, 998–
999; Angew. Chem. 1994, 106, 1046–1047; b) U. Kazmeier, Lie-
bigs Ann./Recl. 1997, 285–295; c) U. Kazmeier, Org. Lett. 1999,
1, 1763–1766; d) U. Kazmeier, H. Mues, A. Krebs, Chem. Eur.
J. 2002, 8, 1850–1855; e) U. Kazmeier, C. Schneider, Synlett
1996, 975–977; f) U. Kazmeier, C. Schneider, Synthesis 1998,
1321–1329.
Acknowledgments
The authors thank Prof. Edvards Liepins for assistance with the
advanced NMR experiments and the European Social Fund (ESF)
for financial support (project no. 1DP/1.1.1.2.0/13/APIA/VIAA/
003).
[1] A. Lorente, D. Pla, L. M. Canedo, F. Albericio, M. Alvarez, J.
Org. Chem. 2010, 75, 8508–8515.
[2] S. Fotso, T. M. Zabriskie, P. J. Proteau, P. M. Flatt, D. A. San-
tosa, S. Mahmud, T. Mahmud, J. Nat. Prod. 2009, 72, 690–
695.
[3] J. Y. Cho, P. G. Williams, H. C. Kwon, P. R. Jensen, W. Fenical,
J. Nat. Prod. 2007, 70, 1321–1328.
[4] T. A. Mansoor, R. M. Ramalho, S. Mulhovo, C. M. P. Rodrig-
[20] The experiment was performed in CDCl3 instead of CD2Cl2.
Signals in the shift range δ = 4.60–5.60 ppm were analyzed.
[21] U. Pal, S. Ranatunga, Y. Ariyarathna, J. R. Del Valle, Org.
Lett. 2009, 11, 5298–5301.
ues, M. J. U. Ferreira, Bioorg. Med. Chem. Lett. 2009, 19, [22] G. Arnott, J. Clayden, S. D. Hamilton, Org. Lett. 2006, 8,
4255–4258.
5325–5328.
[5] For a recent review, see: D. Antonow, D. E. Thurston, Chem.
Rev. 2011, 111, 2815.
[6] For a review, see: L. Cipolla, A. C. Araujo, C. Airoldi, D. Bini,
Anti-Cancer Agents Med. Chem. 2009, 9, 1–31.
[7] a) M. Mori, Y. Uozumi, M. Kimura, Y. Ban, Tetrahedron 1986,
42, 3793–3806; b) D. R. Langley, D. E. Thurson, J. Org. Chem.
1987, 52, 91–97.
[23] a) A. Chernega, S. G. Davies, D. L. Elend, C. A. P. Smethurst,
P. M. Roberts, A. D. Smith, G. D. Smyth, Tetrahedron 2007, 63,
7036–7046; b) S. G. Davies, D. L. Elend, S. Jones, P. M. Rob-
erts, E. D. Savory, A. D. Smith, J. E. Thomson, Tetrahedron
2009, 65, 7837–7851.
Received: July 9, 2015
Published Online: September 23, 2015
Eur. J. Org. Chem. 2015, 6701–6709
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6709