Construction of multisubstituted tetrahydropyrans by a domino oxa-michael/tsujia-trost reaction

Article abstract of DOI:10.1021/jo302102x

Biologically significant tetrahydropyrans (THP) were synthesized by a Tandem oxa-Michael/Tsujia-Trost reaction. Different Michael acceptors were investigated, and optimal results in terms of diastereoselectivities and yields were obtained with nitro olefins. The influence of the reaction parameters, substrate patterns, and type of metal counterions on the yield and stereochemical outcome of this process is discussed, and an explanation for the observed stereoselectivities is proposed.

Full text of DOI:10.1021/jo302102x

Article
pubs.acs.org/joc
Construction of Multisubstituted Tetrahydropyrans by a Domino
Oxa-Michael/Tsuji−Trost Reaction
Liang Wang† and Dirk Menche*
Kekule-
́
Institut fur Organische Chemie und Biochemie der Rheinischen, Friedrich-Wilhelms-Universitat Bonn,
̈
̈
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
S
* Supporting Information
ABSTRACT: Biologically significant tetrahydropyrans (THP) were
synthesized by a Tandem oxa-Michael/Tsuji−Trost reaction. Differ-
ent Michael acceptors were investigated, and optimal results in terms
of diastereoselectivities and yields were obtained with nitro olefins.
The influence of the reaction parameters, substrate patterns, and type
of metal counterions on the yield and stereochemical outcome of this
process is discussed, and an explanation for the observed stereoselec-
tivities is proposed.
respect to convergence, brevity, and ready availability of the
starting materials, we desired a more direct sequence for THP
synthesis. Herein, we report in full detail17 the design and
development of a conceptually novel cascade reaction based
on an oxa-Michael-addition and an allylic substitution and suc-
cessfully implement this concept for the direct synthesis of poly-
substituted tetrahydropyrans.
INTRODUCTION
■
The development of efficient processes, that enable a rapid and
easy access to optically active building blocks is of great impor-
tance, particularly for the synthesis of complex molecules. The
metal-catalyzed asymmetric allylic substitution reaction, which
involves the addition of a range of diverse nucleophiles, such as
derivatives of malonate and tosyl amides, to an allyl metal inter-
mediate, is one of the most studied processes.1 In recent years,
the notion of combining several metal-mediated processes in
relay-type domino sequences has been attracting increasing
attention.2 Through the combination of several synthetic trans-
formations in a one-pot fashion, domino reactions efficiently
transform simple starting materials into products of structural
complexity. The addition of nucleophilic carbons to Michael
acceptors is a highly important C−C bond forming reaction in
organic synthesis. In marked contrast, the conjugate addition of
noncarbon nucleophiles such as alcohols3 (oxa-Michael addition)
has gained considerably less interest in the past decades. For a long
time, this reaction has suffered from major drawbacks such as low
reactivity and reversibility issues as well as a lack of stereoselectivity.
Consequently, reports concerning the oxa-Michael reaction have
remained quite scarce, and no general reaction protocols for this
transformation have been reported until quite recently.3e
RESULTS AND DISCUSSION
■
Since deprotonated hydroxy groups may react with Michael
acceptors to furnish carbon nucleophiles, we conceived a novel
type of domino reaction based on an oxa-Michael reaction and
palladium(0)-catalyzed asymmetric allylic alkylation (AAA) to
construct multisubstituted THPs. As shown in Scheme 1, our
Scheme 1
Tetrahydropyrans (THPs) are prevalent constitutional chemo-
types and underlying structural moieties in a variety of biologically
important natural products such as polyether antibiotics, marine
toxins, pheromones, and pharmaceutical agents, etc.4 As such, there
have been extensive efforts made toward the synthesis of tetra-
hydropyrans and tetrahydropyran-containing compounds using
various methods,5,6 including cyclizations involving oxocarbenium
ions7 and epoxides,8 hetero-Diels−Alder reactions,9,10 Prins cycli-
zations,11 intramolecular nucleophilic reactions,12 Michael reac-
tions,13 reductions of cyclic hemiacetals,14 cyclizations involving
nonactivated double bonds,15 and one-pot procedures based on
alkene−alkyne couplings followed by ether formation.16 Because
of certain limitations of these existing methods, in particular with
Received: October 1, 2012
Published: November 9, 2012
© 2012 American Chemical Society
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synthetic concept was based on a three-step sequential process
involving an oxa-Michael and a Tsuji−Trost coupling. The
deprotonated homoallylic alcohol can first add to an electrophilic
olefin resulting in a nucleophilic carbon-enolate center (step 1)3a,b,18
followed by palladium catalyzed π-allyl complex generation
(step 2); afterward, the nucleophilic carbon will be captured in
an intramolecular fashion through an allylic substitution reaction
leading to the desired multisubstituted THPs in a highly direct
and efficient fashion (step 3). In this process, three new stereo-
genic centers are generated. It should be noted that the synthetic
design is highly convergent (two components are combined
in one process) and flexible and may readily be adapted to vari-
ous other substrates enabling direct access to a broad range of
heterocycles.
Scheme 3
With respect to linear allylic carbonates, allylic substitution reac-
tions may result inproblems of regioselectivtiy because of so-called
memory effects.19 One efficient solution to this problem is to use a
combination of Feringa’s phosphoramidite ligand and iridium-
(I),20−22 and the groups of Hartwig,20 Helmchen,21 and Alexakis22
contributed much to iridium-catalyzed asymmetric allylic alkyl-
ation. They employed achiral linear allylic carbonates to get chiral
branched substitution products with the help of Feringa’s
phosphoramidite ligand and iridium(I). These reactions have led
to excellent results using C-, N-, and O-nucleophiles with good
enantioselectivity and regioselectivity. Although linear allylic
carbonates and palladium catalysts are used in our reaction, it
was conceived that no problems of regioselectivity would arise
because a six-membered THP ring would be expected as the
predominant product for sterical reasons. Subsequent to our
initial report on this type of relay process,17 related domino
sequences have been reported by us23 and others.24
step of conjugate addition was unsuccessful, not to mention the
subsequent allylic substitution. Afterward, we studied derivatives
of malonates as very classical substrates for Tsuji−Trost reac-
tions. Accordingly, dimethyl 2-benzylidenemalonate 13 was pre-
pared, but disappointingly again no oxa-Michael addition could
be observed. In a similar fashion, these types of substrates were
evaluated in the presence of both various bases and palladium
catalysts. However, only traces of the desired tetrahydropyran
products could be detected in some cases at best.
Subsequently, commercially available β-nitrostyrenes were
evaluated as electrophilic alkenes, and the coupling of 1 and 14
was studied. At the beginning, the oxa-Michael and Tsuji−Trost
reaction was studied as a stepwise process. We were pleased to
see that both of these steps were indeed successful; i.e., the oxa-
Michael addition to 15 and the ensuing allylic substitution to 16
proceeded. These two conversions were then combined to
investigate the feasibility of a domino oxa-Michael/Tsuji−Trost
reaction (Scheme 4). Gratifyingly, this relay process indeed
To initiate our study, the required homoallyl carbonate sub-
strates (1) could be conveniently prepared stereoselectively with
good yields (85%) by second-generation Grubbs catalyst mediated
cross-metathesis of an homoallylic alcohol, itself readily available
by allylation of the corresponding aldehyde and dicarbonate 8
(Scheme 2).
Scheme 4
Scheme 2
With substrate 1 in hand, different Michael acceptors were
then investigated in the presence of different bases and solvents.
First, methyl acrylate (11) was evaluated, but no desired adduct
product was obtained (Scheme 3). During this study, it was
accidently found that a combination of DBU and NaH would
result in the formation of desired adduct 9, while neither DBU
nor NaH alone could facilitate the reaction (Scheme 3). The
Tsuji−Trost reaction was then investigated, but disappointedly
no desired cyclized product could be obtained. In agreement with
seminal reviews by Trost,1c,d,f it was conceived that carboxylate
might not afford a carbon nucleophile that would be stabilized
enough for the subsequent allylic substitution, and only few
examples which use ketones as nucleophilic carbon sources have
been reported.18 With methyl vinyl ketone (12) as acceptor, the
worked, albeit initially in only low yields. However, the yield was
slightly higher in comparison to the stepwise process. In detail,
the coupling of 1 with 14 in the presence of KOtBu as base and
Pd2(dba)3 as catalyst resulted in the formation of two major
diastereomers, 16a and 16b, in a ratio of 1:1.5. The relative con-
figurations of these two diastereomers was elucidated by analysis
of the coupling constants, COSY and NOESY data (see Table 1).
Different conditions were then investigated to improve the
diastereoselectivity. First, a variety of ligands, including bidentate
ligands, such as DPPE, DPPB or DPPP, and chiral ligand like
(S)-BINAP, were tried, but disappointingly, only lower yields or
selectivities resulted (see Table 1, entries 4−7). When LHMDS
was used, it was surprising to find that a third diastereomer 16c
was obtained. The orientation of the nitro group was now found
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Table 1. Investigation of Different Ligands and Palladium
Sources
Table 2. Investigation of the Influence of Leaving Groups and
Different Substrates on the Diastereoselectivity
a
a
a
The reactions were carried out on a 0.2 mmol scale with 0.3 mmol of
b
c
nitroolefin in 3 mL of THF. Yield of isolated product. Ratio was
determined by 1H NMR analysis of the crude product.
c
yield
b
d
entry
Pd cat.
ligand
base
(%)
dr (a:b)
a
Table 3. Investigation of Different Substrates
1
2
3
4
5
6
7
8
Pd2(dba)3−CHCl3 PPh3
KOtBu
KOtBu
35 1:1.5 (trace of c)
14 1:1.5
Pd(PPh3)4
−/18-c-6
[Pd(C3H5)Cl]2
PPh3/18-c-6 KOtBu
14 1:1.9
Pd2(dba)3−CHCl3 DPPE
Pd2(dba)3−CHCl3 DPPB
Pd2(dba)3−CHCl3 DPPP
KOtBu
KOtBu
KOtBu
35 1:1.1
53 1:1.1
53 1:1
Pd2(dba)3−CHCl3 (S)-BINAP KOtBu
22 1:1.1
b
c
entry
R
yield (%)
dr (d1/d2)
1:0.8
Pd2(dba)3−CHCl3 PPh3
LiHMDS 27 1:2.2:2.6 (a/b/c)
a
1
2
3
4
5
6
4-methylbenzyl
4-methoxybenzyl
2-methoxybenzyl
2-furyl
56
51
40
50
40
40
The reactions were carried out on a 0.2 mmol scale with 0.3 mmol of
nitroolefin in 3 mL of THF. Commercially available solutions of the
bases in THF were used. Yield of isolated product. Ratio was deter-
mined by 1H NMR analysis of the crude product.
b
1:1
c
d
1:0.8
1:0.8
c-hexyl
five diastereomers
ethylbenzene
seven diastereomers
to be in an axial position (entry 8). This suggested that the
lithium cation might play a certain role in this reaction. When
[Pd(C3H5)Cl]2 was used, the diastereoselectivity was found to
be improved as compared to Pd2(dba)3 (entry 1, 3).
a
The reactions were carried out on a 0.2 mmol scale with 0.3 mmol of
nitroolefin in 3 mL of THF. Yield of isolated product. Ratio was
determined by 1H NMR analysis of the crude product.
b
c
Motivated by previous reports on the influence of the leaving
groups on the enantioselectivity of Tsuji−Trost reactions,1c
a
when Pd2(dba)3, PPh3, LiHMDS and methyl carbonate were
employed (Table 4). The relative configurations of these di-
astereomers 21a−c were again elucidated by analysis of coupling
constants and NOESY data.
An advantage of this transformation was that the major
product, diastereomer 21a, could be readily separated from the
other two diastereomers by flash chromatography, which under-
lines the efficiency of the overall process. As shown in Table 4,
various conditions and leaving groups were evaluated. It was
found that the best result could be achieved when Pd2(dba)3·CHCl3,
PPh3, LiOtBu, and Boc-carbonate as leaving group were used
(Table 4, entry 3).
In order to further analyze the influence of the β-substituent,
the linear nitroolefin 22 was then investigated under these opti-
mized conditions. Gratifyingly, good diastereoselectivities and
yields were again observed (Scheme 5).
Subsequently, these optimized conditions were applied to other
substrates, which resulted in good yields and diasteroselectivities, as
shown in Figure 1. While this reaction was routinely carried out with
0.2 mmol of homoallylic alcohol, similar yields and selectivities were
also obtained on larger scale reactions up to 2 mmol.
series of substrates (17−19) with different leaving groups were
prepared and subjected to our procedure. However, the
diasteroselectivities did not change significantly, and in contrast
to previous results, 4-methoxybenzoate (19) gave the lowest
selectivities. (Table 2, entry 3).
Other homoallylic alcohol analogues that were substituted with
Boc carbonates were also investigated, but again poor diastereo-
selectivities and poor to moderate yields were observed. It was
conceived that nitroolefins with aromatic substituents might
generally only afford moderate stereoselectivities. Diastereomer 16a
was observed as the major product. The observed diastereoselectivity
was opposite to the one observed above (Table 3, entries 1−4). No
stereoselectivity was found for substrates with aliphatic substituents
(entries 5 and 6).
Subsequently, we turned our attention to the investigation of
nitroolefins with aliphatic substituents at the β-carbon atom, in a
rational that this might have a beneficial effect on the stereo-
chemical outcome of the process. First, alkene 20 was studied as a
Michael acceptor. It could be readily prepared by base-catalyzed
condensation of nitromethane with isobutyraldehyde and sub-
sequent dehydration with trifluoroacetic anhydride.17 Three
diastereomers were observed (21a, 21b, 21c). However, in this
case, promising diastereoselectivities resulted (a/b/c = 5.8:2.5:1),
We then turned our attention to the synthesis of tetrahydro-
pyrans bearing a tetrasubstituted carbon center by coupling with
α-substituted nitroolefins. The reaction of 1 with 29 was studied
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in detail. As shown in Table 5, three diastereomers were formed,
i.e.m 30a−c, which could not be separated by flash chro-
Table 4. Domino Process with Nitroolefin 16 as Michael
Acceptor
a
a
Table 5. Domino Reaction with α-Substituted Nitroolefin 29
b
c
d
entry
1
substrate/PdLn/base
yield (%) dr a/b/c
R = Me; Pd2(dba)3 (5%)/PPh3 (20%)/
LiHMDS (1.5 equiv)
47
63
78
5.8:2.5:1
c
yield
R = Me; Pd2(dba)3 (5%)/PPh3 (20%)/KOtBu
(1.5 equiv)
4.4:1.4:1
b
d
2
3
entry
R
PdLn/base
(%)
dr a/b/c
1
2
3
4
5
6
7
8
9
OMe [Pd(C3H5)Cl]2/LiOtBu
OMe Pd2(dba)3/LiOtBu
24
14
17
39
71
43
44
62
9.1:6.9:1
10.4:12.3:1
12:11.7:1
4.8:3.4:1
R = tBu; Pd2(dba)3 (5%)/PPh3 (20%)/
5.2:1.4:1
LiOtBu (1.5 equiv)
a
OMe Pd2(dba)3/LiHMDS
The reactions were carried out on a 0.2 mmol scale with 0.3−0.4 mmol
b
OMe [Pd(C3H5)Cl]2/LiHMDS
OMe [Pd(C3H5)Cl]2/LiHMDS
PMB [Pd(C3H5)Cl]2/LiHMDS
tBu [Pd(C3H5)Cl]2/LiHMDS
tBuO [Pd(C3H5)Cl]2/LiHMDS
tBuO [Pd(C3H5)Cl]2/LiHMDS (10%)
of nitroolefin in 3 mL of THF. Commercially available solutions of the
bases in THF were used. Yield of isolated product. Ratio was deter-
mined by H NMR analysis of the crude product.
c
d
10.3:8:1
1
14.4:10.2:1
1.4:1.3:1
Scheme 5
1.6:1:<0.05
[e]
17 nd
44
10 tBuO [Pd(C3H5)Cl]2/PPh3 (20%)/LiHMDS
11 tBuO [Pd(C3H5)Cl]2/P(iOPr)3 (20%)/LiHMDS 44
12 tBuO [Pd(C3H5)Cl]2/P(OEt)3 (20%)/LiHMDS 44
13 tBuO [Pd(C3H5)Cl]2/dppf (10%)/LiHMDS
14 tBuO [Pd(C3H5)Cl]2/dppp (10%)/LiHMDS
1.4:1.3:1
1.4:1.3:1
1.4:1.3:1
1.4:1.3:1
1.4:1.3:1
44
44
a
The reactions were carried out in 2.5 mL of THF with 0.2 mmol of
homoallylic alcohol 6, 2 mmol of nitroolefin, 0.3 mmol of base, and
b
0.01 mmol (5 mol %) of catalyst. Commercially available solutions of
c
d
the bases in THF were used as supplied. Isolated yields. Ratio was
[e]
nd: not
1
determined by H NMR analysis of the crude product.
determined. PMB: p-methoxybenzyl.
matography column. The relative configuration of 30a and 30b
can be elucidated relatively easily, while it took some time to find
out the correct relative configuration of 30c because of con-
siderable signal overlaps in the NMR spectra. It was surprising to
find that the orientation of the phenyl group in 30c was axial.
Possibly, the phenyl group might be forced in an axial position to
avoid strong 1,3-axial interaction between the isopropyl and
the vinyl group, resulting in the depicted major conformer
30c. In this reaction, various conditions, including leaving
group, palladium catalysts and bases, were investigated. It was
found that the best result could be achieved when a com-
bination of allyl palladium chloride dimer, Boc-carbonate as
leaving group and LiHMDS as base were used (Table 5, entry 8).
Interestingly, the amount of diastereomer 30c decreased drasticly
when the equivalents of nitroalkene were increased (entries 8 and 10).
To further evaluate nitroolefin 29 a substrate with a furyl group
was evaluated, resulting, however, in only poor diastereoselectivities
(Scheme 6).
Figure 1. Selected tetrasubstituted THPs prepared by our method.
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Scheme 6
Table 6. Domino Reaction with Nitroolefin 31: Assembly of
THPs with a Tetrasubstituted Carbon Center
a
b
c
entry
R1
PdLn/base
yield (%) dr 38a/38b
1
2
3
4
OMe
OMe
OMe
tBuO
[Pd(C3H5)Cl]2/KOtBu
[Pd(C3H5)Cl]2/NaHMDS
[Pd(C3H5)Cl]2/LiHMDS
[Pd(C3H5)Cl]2/LiHMDS
16
12
17
62
2.5:1
4.4:1
8.8:1
8.8:1
a
The reactions were carried out on a 0.2 mmol scale with 0.4 mmol of
Presumably, the energy difference between the diastereomers of
the oxa-Michael adduct is too small to enable useful levels of asym-
metric induction, despite the reversibility of the process (vide infra).
In order to circumvent the inherent problem of the low selectivities of
the oxa-Michael reaction, we then considered nitro olefins without a
β-substituent. Consequently, nitroethylene 35 was chosen as the
Michael acceptor. As shown in Scheme 7 it may be conveniently
b
c
nitroolefin in 2.5 mL of THF. Yield of isolated product. Ratio was
determined by H NMR analysis of the crude product.
1
In addition, the use of different equivalents of the nitroolefin
was investigated. It was found that 2 equiv of nitroolefin 35
resulted in the highest yields, while more or less equivalents only
led to lower conversion or no product formation at all. The
selectivities increased in the order K, Na, Li, which corresponds
to the chelative ability of these alkali metals, in agreement with
our mechanistic proposal (vide infra).
Scheme 7
As shown in Figure 2, the method was applicable to various
aliphatic and aromatic substrates. Good diastereoselectivties (5:1
to 10:1) and moderate to good yields (25 −72%) were obtained.
obtained directly from 33. Alternatively, the precursor 34 can be
synthesized, which may then be transformed into 35 in situ by base.
We were delighted to find that coupling of 1 with 35 obtained
in situ in the presence of LiHMDS and [Pd(C3H5)Cl]2 resulted
in the formation of only one major diastereomer (36a) together
with minor amounts of 36b (Table 6). The relative configuration
of these two diastereomers 36a and 36b was again elucidated by
analysis of coupling constants and NOE data. Notably, the nitro
group and the vinyl group were syn in both diastereomers. In this
reaction, nitroolefin 35 could be prepared easily via dehydration
with phthalic anhydride or trifluoroacetic anhydride. Different
metal counterions were investigated in the domino coupling
with methyl carbonate 1 as the substrate. When KOtBu was used
as base, the lowest diastereoselectivity was observed (Table 6,
entry 1), moderate diastereoselectivity could be obtained with
NaHMDS (Table 6 entry 2), while LiHMDS gave the highest
diastereoselectivity (Table 6, entry 3). A higher yield could be
achieved with Boc carbonate 17 as substrate, and the observed
stereoselectivity was still good (Table 6, entry 4).
Figure 2. Investigation of the effectiveness of the methodology.
Similarly, a homologated α-substituted nitroethylene, i.e., the
ethyl analogue 45, was analyzed. It was prepared by base-mediated
coupling of nitropropane with paraformaldehyde and subsequent
dehydration, as described above. Coupling of 17 with 45 resulted in
similar good selectivities but decreased yields (Scheme 8).
Mechanistically, the observed selectivities in these domino cycli-
zations may be explicable if these reactions proceed via Traxler−
Zimmermann-type transition states. As shown in Scheme 9, the
homoallylic alcoholate 50 may first attack an electrophilic nitro
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states, viz. 49a, 49b, and 54a. In transition states 49a and 49b, the
substituents at C-2, C-5, and C-6 would be in equatorial positions
(in contrast to 49c and 49d as well as 54b, 54c and 54d) leading
to a stabilization of these pathways. Generation of the axial con-
figuration at C-5 in 55a, in turn, may be explained by a chelation
of the metal counterion to the ether oxygen and the nitro group,
which would be more favorable with an axial nitro group, as
shown in 54a. Alternatively, also minimization of dipole−dipole
interactions of the nitronate with the π-allyl complex would
be more favorable for 54a as compared to 49a and 49b. The
intermediate chelate complex 54a may also rationalize the observed
selectivity at C-6, as this substituent would reside in a pseudo-
equatorial position in this second 6-membered cycle. Depending on
the substitution pattern of the nitro-olefin (i.e., R1 and R2), subtle
difference in the relative stabilization of these pathways appear to
be present, leading to either 48a, 48b, or 48c. Presumably, a
Scheme 8
olefin of general type 51 from either side, resulting in inter-
mediates 52 or intermediate 53, leading to transition states 49a−
d and 54a−d, respectively. These transition states, i.e., 49a−d
and 54a−d, would be expected to be in an equilibrium via
η3−η1−η3 (or π−δ−π) processes. The observed stereochemical
outcome of these reactions, i.e., formation of the major products
48a, 48b, and 55a, may arise from the corresponding transition
Scheme 9
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sterically more demanding substituent R1 at C-6 (here Ph) leads
to formation of 48a and 48b, where both substituents at C-2 and
C-6 are in equatorial positions, while a smaller substituent at
this position (e.g., iPr, Pr,H) favors formation of 55a. This fine
balance might also be influenced by chelative effects of the
counterion. Importantly, the observed yields and selectivities of
these reactions may only be explained if the initial oxa-Michael
addition may not be stereodiscriminating. Intermediates 52
and 53 may be reversibly transformed into the more favorable
diastereomers leading to the major products as observed.25
water until the white precipitate disappeared. The mixture was then
extracted with ethyl acetate three times, and the combined organic
phases were washed with 1 N HCl, saturated aqueous NaHCO3 solu-
tion, and brine and dried over anhydrous Na2SO4. After filtration, the
solution was concentrated in vacuo, and the residue was purified by flash
chromatography and eluted with a gradient of petroleum ether and ethyl
acetate, from 12:1 to 6:1, to give 11.8 g of a colorless oil (96%): 1H NMR
(300 MHz, CDCl3) δ = 5.75 (t, J = 4.0 Hz, 2H), 4.70 (d, J = 4.6 Hz, 4H),
3.74 (s, 6H); 13C NMR (75 MHz, CDCl3) δ = 155.9, 128.3, 63.5, 55.2;
HRMS (ESI+) calcd for C8H12O6Na [M + Na]+ 227.0531, found
227.0527.
3-Nitro-2,6-diphenyl-4-vinyltetrahydro-2H-pyran (16). (E)-tert-
Butyl 5-hydroxy-5-phenylpent-2-enyl carbonate (55.7 mg, 0.2 mmol)
and β-trans-nitrostyrene (44.7 mg, 0.3 mmol) were dissolved in 1 mL of
anhydrous THF, and the solution was cooled to −78 °C. The solu-
tion was then treated with a suspension of Pd2(dba)3·CHCl3 (10.4 mg,
0.0100 mmol) and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of anhydrous
THF and a solution of potassium tert-butoxide (1 M in THF, 0.300 mL,
1.5 equiv, as commercially supplied). The mixture was then warmed to
room temperature and stirred until the alcohol was consumed. The
reaction was then cooled to −78 °C again and quenched with saturated
NH4Cl solution. After being warmed to room temperature, the mixture
was extracted with ethyl acetate three times. The combined organic
phases were washed with brine, dried (Na2SO4), and filtered. The
solution was concentrated in vacuo, and the residue was purified with
column of silica gel and eluted with the gradient of petroleum and ethyl
acetate, from 60:1 to 30:1, to afford 35.0 mg of 16a and 4-epi-16b as a
pale-yellow viscous oil with a diastereomeric ratio of 16:4-epi-16 = 1.5:1
(combined yield: 57%). The two diastereomers could be isolated by
preparative HPLC, eluted with isocratic eluent (hexane/EtOAc = 96:4).
CONCLUSION
■
We have developed a new method to synthesize biologically
significant multisubstituted THPs. This protocol combines an
oxa-Michael with a metal-catalyzed reaction in an efficient way
and generates up to three stereogenic centers resulting in a rapid
increase of molecular complexity. The high degree of selectivity
in this process is remarkable considering the stereochemical
complexity of the process. Moreover, the heterocyclic products
bear two functional handles (nitro and terminal olefin) which can
be further elaborated. It is expected that this novel domino
concept will be further explored and applied to the synthesis of
functional molecules.
EXPERIMENTAL SECTION
■
General Information. NMR data were acquired on 300, 400, and
600 MHz NMR spectrometers and use the following abbreviations: s =
singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets,
ddd = doublet of doublets of doublets, brm = broad multiplet, brs =
broad singlet. HRMS spectra were acquired using an MS spectrometer
with a Q-TOF mass analyzer. Flash chromatography was carried out by
column with silica gel Kieselgel S (grid size 32−62 μm). Solvents were
dried and kept air-free in a solvent purification unit and were evaporated
using a standard rotovapor and high vacuum. All reactions were carried
out in oven-dried glassware under an Ar atmosphere.
General Procedure for Oxa-Michael/Tsuji−Trost Cascade. A
solution of homoallylic alcohol and the nitroolefin in 1 mL of anhydrous
THF was treated at −78 °C with a suspension of the palladium catalyst
and phosphorus ligand in 1.5 mL of anhydrous THF and a solution of
the base. The mixture was then warmed to room temperature and stirred
until the alcohol was completely consumed (ca. 2 h). After being cooled
to −78 °C, the reaction was stopped by addition of satd aq NH4Cl
solution. After being warmed to room temperature, the mixture was
extracted three times with ethyl acetate. The combined organic phases
were washed with brine, dried (MgSO4), and filtered. Evaporation of the
solvent in vacuo and purification of the residue by column
chromatography on silica gel afforded the product.
(E)-5-Hydroxy-5-phenylpent-2-enyl Methyl Carbonate (1). 1-Phenyl-
but-3-en-1-ol (2.40 g, 16.2 mmol) and (Z)-but-2-ene-1,4-diyl dimethyl
dicarbonate (6.61 g, 32.4 mmol) were dissolved in 40 mL of anhydrous
CH2Cl2. A solution of second-generation Grubbs catalyst (0.275 g,
0.324 mmol) in 10 mL of anhydrous CH2Cl2 was added, and the mixture
was refluxed overnight. The solvent was then removed in vacuo, and the
residue was purified by flash chromatography and eluted with a gradient
of petroleum ether and ethyl acetate, from 10:1 to 7:1 to 3:1, to give
3.88 g of pale brown oil (85%): 1H NMR (300 MHz, CDCl3) δ = 7.25−
7.38 (m, 5H), 5.65−5.92 (m, 2H), 4.74 (t, J = 6.2 Hz, 1H), 4.58 (d, J =
5.8 Hz, 2H), 3.77 (s, 3H), 2.52 (t, J = 6.2 Hz, 2H), 2.12 (br, 1H); 13C
NMR (75 MHz, CDCl3) δ = 155.6, 143.7, 132.3, 128.4, 127.6, 127.6,
126.8, 125.7, 77.4, 76.6, 73.4, 68.1, 54.7, 42.1; HRMS (ESI+) calcd for
C13H16O4Na [M + Na]+ 259.0946, found 259.0942.
(Z)-But-2-ene-1,4-diyl Dimethyl Dicarbonate (8). Under argon, cis-
2-butene-1,4-diol (5.29 g, 60.0 mmol) and pyridine (11.9 g, 150 mmol)
were dissolved at room temperature in 120 mL of anhydrous THF,
the solution was cooled to 0 °C, and methyl chloroformate (14.2 g,
150 mmol) was added to this solution. The mixture was then warmed to
room temperature and stirred overnight. The reaction was diluted with
1
16a: H NMR (600 MHz, CDCl3) δ = 7.28−7.50(m, 10H), 6.45
(ddd, J = 9.5, 10.2, 16.8 Hz, 1H), 5.36(d, J = 10.3 Hz, 1H), 5.30 (d, J =
16.8 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.96 (dd, J = 3.0, 10.5 Hz, 1H),
4.95 (dd, J = 5.2, 10.4 Hz, 1H), 3.41 (dddd, J = 4.4, 4.4, 4.4, 8.5 Hz, 1H),
2.23 (ddd, J = 4.5, 14.1, 14.1 Hz, 1H), 2.20 (ddd, J = 3.3, 14.1 Hz, 1H);
13C NMR (151 MHz, CDCl3) δ = 140.8, 137.3, 132.6, 129.2, 129.0,
128.6, 128.5, 127.9, 127.8, 126.1, 126.1, 125.7, 120.2, 89.2, 77.2, 76.8,
75.9, 74.9, 42.6, 38.8; HRMS (ESI+) calcd for C19H19NO3Na [M + Na]+
332.1262, found 332.1258. 4-epi-16b: 1H NMR (600 MHz, CDCl3) δ =
7.27−7.39 (m, 10H), 5.67 (ddd, J = 8.3, 10.29, 17.5 Hz, 1H), 6.79−6.85
(d, J = 16.2 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.91 (d, J = 9.6 Hz, 1H),
4.79 (dd, J = 2.1, 11.6 Hz, 1H), 4.45 (d, J = 10.1 Hz, 1H), 3.25 (dddd, J =
4.1, 8.12, 11.8, 11,8 Hz, 1H), 2.22 (ddd, J = 2.4, 4.1, 14.1 Hz, 1H), 1.78
(ddd, J = 12.1, 12.1, 13.7 Hz, 1H); 13C NMR (151 MHz, CDCl3)
δ =140.6, 136.5, 135.2, 129.2, 128.7, 128.5, 128.0, 126.9, 125.7, 118.6,
92.7, 81.3, 79.4, 77.2, 76.8, 45.4, 38.1. 5-epi-16c: 1H NMR (600 MHz,
CDCl3) δ = 7.28−7.50 (m, 10H), 5.93 (ddd, J = 6.7, 10.2, 17.1 Hz, 1H),
5.70 (d, J = 1.3, 1H), 5.38 (dd, J = 2.6, 4.3 Hz, 1H), 5.27 (d, J = 10.4 Hz,
1H), 5.28 (d, J = 17.2 Hz, 1H), 4.81 (dd, J = 3.3, 11.4 Hz, 1H), 3.41
(dddd, J = 3.9, 4.8, 6.7, 11.9 Hz, 1H), 2.61 (ddd, J = 11.9, 11.9, 13.2 Hz,
1H), 1.90 (ddd, J = 3.9, 3.9, 13.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ =136.1 (C7), 117.7 (C8), 85.6 (C5), 75.9 (C6), 72.6 (C2), 37.7 (C4),
32.1 (C3) (only chemical shifts of carbons in the THP ring are given).
(E)-tert-Butyl 5-Hydroxy-5-phenylpent-2-enyl Carbonate (17).
1-Phenylbut-3-en-1-ol (1.05 g, 7.1 mmol) and (Z)-but-2-ene-1,4-diyl
tert-butyl dicarbonate (4.08 g, 14.2 mmol) were dissolved in 50 mL of
anhydrous dichloromethane. A solution of second-generation Grubbs
catalyst (0.301 g, 0.355 mmol) in 10 mL of anhydrous dichloromethane
was then added, and the reaction mixture was refluxed overnight. The
solvent was then removed in vacuo, and the residue was purified by
column chromatography on silica gel and eluted with a gradient of
petroleum ether and ethyl acetate, from 10:1 to 7:1 to 4:1, to afford 1.37 g
1
of a viscous pale-brown oil (69%): H NMR (300 MHz, CDCl3) δ =
7.21−7.35 (m, 5H), 4.62−5.81 (m, 2H), 4.69 (t, J = 6.2 Hz, 1H), 4.47 (d,
J = 5.5 Hz, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.17 (s, br, 1H), 1.45 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ = 153.3, 143.7, 131.8, 128.4, 127.6, 127.2,
125.7, 82.1, 77.4, 77.0, 76.6, 73.4, 67.2, 42.1, 27.7; HRMS (ESI+) calcd for
C16H22O4Na [M + Na]+ 301.1415, found 301.1411.
(E)-5-Hydroxy-5-phenylpent-2-enyl Acetate (18). 1-Phenylbut-3-en-
1-ol (1.40 g, 9.40 mmol) and (Z)-but-2-ene-1,4-diyl diacetate (3.25 g,
10817
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18.9 mmol) were dissolved in 50 mL of anhydrous toluene. A solution of
second-generation Grubbs catalyst (0.239 g, 0.15 mmol) in 10 mL of
anhydrous toluene was then added, and the reaction mixture was then
heated with stirring to 80 °C for 1.5 h. The solvent was then removed in
vacuo, and the residue was purified by column chromatography on silica
gel and eluted with a gradient of petroleum ether and ethyl acetate, from
8:1 to 4:1, to afford 1.27 g of a viscous pale-yellow oil (61%): 1H NMR
(300 MHz, CDCl3) δ = 7.25−7.38 (m, 5H), 5.63−5.82 (m, 2H), 4.74
(t, J = 6.2 Hz, 1H), 4.52 (d, J = 6.2 Hz, 2H), 2.52 (t, J = 6.2 Hz, 2H), 2.05
(s, 3H), 2.00 (s, 1H); 13C NMR (75 MHz, CDCl3) δ = 170.8, 143.7,
131.4, 128.4, 127.6, 127.4, 125.7, 77.4, 76.6, 73.4, 64.8, 42.1; HRMS
(ESI+) calcd for C13H16O3Na [M + Na]+ 243.0996, found 243.0994.
(E)-5-Hydroxy-5-phenylpent-2-enyl 4-Methoxybenzoate (19).
1-Phenylbut-3-en-1-ol (445 mg, 3 mmol) and (Z)-but-2-ene-1,4-diyl bis-
(4-methoxybenzoate) (2.14 g, 6 mmol) were dissolved in 20 mL of
anhydrous dichloromethane. A solution of second-generation Grubbs
catalyst (127 mg, 0.15 mmol) in 10 mL of anhydrous dichloromethane
was then added, and the reaction mixture was refluxed for 2 days. The
solvent was then removed in vacuo, and the residue was purified by column
chromatography on silica gel and eluted with a gradient of petroleum ether
and ethyl acetate, from 6:1 to 3:1, to afford 489 mg of a viscous pale-
yellow oil (52%): 1H NMR (300 MHz, CDCl3) δ = 7.98−8.02 (m, 2H),
7.25−7.39 (m, 5H), 6.91−6.95 (m, 2H), 5.75−5.91 (m, 2H), 4.75−4.79
(m, 3H), 3.87 (s, 3H), 2.55 (t, J = 6.2 Hz, 2H), 2.16 (s, br, 1H); 13C
NMR (75 MHz, CDCl3) δ = 166.5, 163.8, 144.2, 132.1, 131.5, 128.9,
128.3, 128.0, 126.2, 123.0, 114.0, 77.9, 77.0, 73.9, 65.4, 55.8, 42.7;
HRMS (ESI+) calcd for C38H40O8Na [2M + Na]+ 647.2621, found
647.2625.
2-Isopropyl-3-nitro-6-phenyl-4-vinyltetrahydro-2H-pyran (21).
(E)-5-Hydroxy-5-phenylpent-2-enyl methyl carbonate (59.1 mg,
0.250 mmol) and (E)-3-methyl-1-nitrobut-1-ene (43.2 mg, 0.380 mmol)
were dissolved in 1 mL of anhydrous THF, and the solution was cooled to
−78 °C. A suspension Pd2(dba)3·CHCl3 (12.9 mg, 0.0125 mmol) and
PPh3 (13.1 mg, 0.05 mmol) in 1.5 mL of anhydrous THF was then
added. Subsequently, a solution of potassium tert-butoxide (1 M in THF,
0.3 mL, 1.5 equiv) was added. The mixture was warmed to room
temperature and stirred until the alcohol was consumed. The reaction
was then cooled to −78 °C again and quenched with saturated NH4Cl
solution. After being warmed to room temperature, the mixture was
extracted with ethyl acetate three times. The combined organic phases
were washed with brine, dried (Na2SO4), and filtered. The solution was
then concentrated in vacuo, and the residue was purified by flash
chromatography and eluted with a gradient of petroleum and ethyl
acetate, from 60:1 to 30:1, to afford a mixture of diastereomers 21b and
21c and pure diastereomer 21a with a diastereomeric ratio of 21a:b:c =
5.2:1.4:1 as a viscous oil (combined yield: 43.0 mg; 78%).
(C5), 85.6, 84.5, 81.9 (C6), 78.2 (C2), 45.2 (C4), 38.6 (C3) (only the
chemical shifts of carbons in THP ring are reported);
3-Nitro-6-phenyl-2-propyl-4-vinyltetrahydro-2H-pyran (23).
(E)-tert-Butyl 5-hydroxy-5-phenylpent-2-enyl carbonate (55.7 mg,
0.200 mmol) and (E)-1-nitropent-1-ene (34.5 mg, 0.300 mmol) were
dissolved in 1 mL of anhydrous THF, and the solution was cooled
to −78 °C. A suspension of Pd2(dba)3·CHCl3 (10.4 mg, 0.0100 mmol)
and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of anhydrous THF was
then added. Subsequently, a solution of lithium tert-butoxide (1 M in
hexane, 0.3 mL, 1.5 equiv) was added. The mixture was then warmed to
room temperature and stirred until the alcohol was consumed. The
reaction mixture was cooled to −78 °C and quenched with saturated
NH4Cl solution. After being warmed to room temperature, the mixture
was extracted with ethyl acetate three times. The combined organic
phases were washed with brine, dried (Na2SO4), and filtered. The
solution was then concentrated in vacuo, and the residue was purified by
flash chromatography on silica gel and eluted with the gradient of
petroleum and ethyl acetate, from 60:1 to 30:1, to afford pure diaste-
reomer 23a together with minor amounts of the 5-epi,6-epi-23 (23b)
and 4-epi,5-epi,6-epi-23 (23c) with a diastereomeric ratio of 6.1:1:0.4 as a
viscous oil (combined yield: 39.0 mg, 71%).
23a: 1H NMR (400 MHz, CDCl3) δ = 7.26−7.43 (m,5H), 5.85 (ddd,
J = 6.4, 10.5, 17.1 Hz, 1H), 5.22 (d, J = 17.4 Hz, 1H), 5.20 (d, J = 10.3 Hz,
1H), 4.72 (dd, J = 3.1, 11.3 Hz, 1H), 4.58 (d, J = 4.1 Hz, 1H), 4.50 (dd,
J = 4.3, 9.6 Hz, 1H), 2.94 (dddd, J = 3.9, 4.5, 6.6, 12.7 Hz, 1H), 2.40 (ddd,
J = 12.7, 12.7, 12.7 Hz,1H), 2.01 (ddt, J = 4.8, 9.1, 13.8 Hz, 1H), 1.80
(ddd, J = 3.9, 3.9, 13.7 Hz,1H), 1.61−1.39 (m, 3H), 0.96 (t, J = 7.3 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ = 141.7, 136.2, 128.5, 127.8, 126.1,
117.6, 86.4, 77.4, 76.6, 75.3, 71.2, 37.2, 32.2, 32.1, 18.9, 13.7. 23b: 1H
NMR (400 MHz, CDCl3) δ = 7.30−7.47 (m, 5H), 5.63 (ddd, J = 8.0,
10.2, 17.2 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10.2 Hz, 1H),
4.56 (dd, J = 2.3, 10.3 Hz, 1H), 4.23 (dd, J = 9,5, 10.8 Hz, 1H), 3.88 (ddd,
J = 3.0, 7.3, 9.9 Hz, 1H), 3.06 (dddd, J = 3.9, 7.9, 11.8, 11.8 Hz, 1H), 2.12
(ddd, J = 2.3, 4.3, 13.8 Hz,1H), 1.56 (ddd, J = 13.9, 13.9, 13.9 Hz, 1H),
1.64−1.42 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ =135.6 (C7), 118.3 (C8), 91.0 (C5), 78.1 (C6), 78.4 (C2),
45.2 (C4), 37.9 (C3) (only the chemical shifts of carbons in THP ring
1
are reported). 23c: H NMR (400 MHz, CDCl3) δ = 7.30−7.47 (m,
5H), 6.26 (ddd, J = 9.5, 10.2, 16.7 Hz, 1H), 5.24 (d, J = 10.2 Hz, 1H),
5.19 (d, J = 16.7 Hz, 1H), 4.70 (dd, J = 3.0, 10.7 Hz, 1H), 4.53 (dd, J =
6.0, 9.9 Hz, 1H), 4.20 (d, J = 10.8 Hz, 1H), 3.24 (dddd, J = 3.9, 4.5, 6.0,
8.5 Hz, 1H), 1.99 (ddd, J = 4.5, 10.7, 13.8 Hz,1H), 1.84 (ddd, J = 3.9, 3.9,
13.7 Hz, 1H), 11.64−1.42 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ = 133.0 (C7), 119.7 (C8), 88.0 (C5), 73.9 (C2),
72.8 (C6), 42.4 (C4), 38.5 (C3) (only the chemical shifts of carbons
in THP ring are reported); HRMS (ESI+) calcd for C32H42N2O6 Na
[M + Na]+ 573.2939, found 573.2941.
21a: 1H NMR (300 MHz, CDCl3) δ = 7.28−7.44 (m, 5H), 6.31 (ddd,
J = 9.4, 10.2, 16.7 Hz, 1H), 5.27 (d, J = 10.2 Hz, 1H), 5.22 (d, J = 16.7 Hz,
1H), 4.75 (dd, J = 3.0, 8.0 Hz, 1H), 4.75 (dd, J = 5.1, 10.4 Hz, 1H), 4.09
(dd, J = 2.0, 10.1 Hz, 1H), 3.05 (dddd, J = 2.9, 5.3, 5.3, 9.4 Hz, 1H), 2.12
(ddd, J = 2.9, 2.9, 13.9 Hz, 1H), 1.94 (qd, J = 3.5, 6.9 Hz, 1H), 1.55 (ddd,
J = 12.3, 12.3, 13.8 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ = 133.2 (C7), 119.4 (C8), 81.9
(C6), 74.2 (C5), 73.7 (C2), 42.2 (C4), 29.2 (C3) (only chemical shifts
of carbons in THP ring are reported); HRMS (ESI+) calcd for
6-(Furan-2-yl)-3-nitro-2-propyl-4-vinyltetrahydro-2H-pyran (24).
(E)-tert-Butyl 5-(furan-2-yl)-5-hydroxypent-2-enyl carbonate (53.7 mg,
0.2 mmol) and (E)-1-nitropent-1-ene (46.0 mg, 0.4 mmol) were
dissolved in 1 mL of anhydrous THF, and the solution was cooled to
−78 °C. A suspension of Pd2(dba)3·CHCl3 (10.4 mg, 0.0100 mmol) and
PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of anhydrous THF was then
added. Subsequently, a solution of lithium tert-butoxide (1 M in THF,
0.3 mL, 1.5 equiv) was added. The mixture was then warmed to room
temperature and stirred until the alcohol was consumed. The reaction
mixture was cooled to −78 °C again and quenched with saturated
NH4Cl solution. After being warmed to room temperature, the mixture
was extracted with ethyl acetate three times. The combined organic
phases were washed with brine, dried (Na2SO4), and filtered. The
solution was concentrated in vacuo, and the residue was purified
with column chromatography on silica gel and eluted with the gradient
of petroleum and ethyl acetate, from 60:1 to 30:1, to afford pure
diastereomer 24a together with minor amounts of the 5-epi,6-epi-isomer
(24b) and the 4-epi,5-epi,6-epi-isomer (24c) with a diastereomeric ratio
of 5.2: 1: 0.8 as a viscous oil (combined yield: 50.7 mg, 78%). 24a: 1H
NMR (300 MHz, CDCl3) δ = 7.42 (s, 1H), 6.38 (s, 2H), 5.83 (ddd, J =
6.8, 10.3, 17.2 Hz, 1H), 5.23 (d, J = 18.3 Hz, 1H), 5.22 (d, J = 8.0 Hz,
1H), 4.84 (dd, J = 3.9, 11.1 Hz, 1H), 4.56 (dd, J = 3.5, 4.6 Hz, 1H), 4.39
(dt, J = 3.7, 9.5 Hz, 1H), 2.85−3.00 (m, 1H), 2.64 (ddd, J = 11.3, 12.1,
1
C16H21NO3Na [M + Na]+ 298.1418, found 298.1414. 21b: H NMR
(300 MHz, CDCl3) δ = 7.26−7.68 (m, 5H), 5.88 (ddd, J = 6.2, 10.2, 17.1
Hz, 1H), 5.22 (dd, J = 1.1, 16.1 Hz, 1H), 5.21 (dd, J = 1.0, 11.4 Hz, 1H),
4.79 (dd, J = 1.4, 4.2 Hz, 1H), 4.70 (dd, J = 3.3, 11.7 Hz, 1H), 3.98 (d, J =
10.3 Hz, 1H), 2.91 (dddd, J = 4.6, 4.6, 6.3, 12.2 Hz, 1H), 2.49 (ddd, J =
12.6, 12.6, 12.6 Hz, 1H), 2.29(dt, J = 17.6, 6.3 Hz, 1H)1.85 (ddd, J = 3.9,
3.9, 13.4 Hz, 1H), 1.07 (d, J = 6.5 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ = 141.7, 136.4, 128.5, 127.9, 126.1, 117.5, 84.6, 81.6, 77.3, 76.7, 71.8,
37.4, 31.8, 27.3, 19.4, 18.9. 21c: 1H NMR (300 MHz, CDCl3) δ = 7.28−
7.44 (m, 5H), 5.63(ddd, J = 8.2, 10.3, 16.8 Hz, 1H), 5.18 (d, J = 16.8 Hz,
1H), 5.13 (dd, J = 10.3 Hz, 1H), 4.59 (dd, J = 2.3, 11.5 Hz, 1H), 4.42 (dd,
J = 9.8, 10.7 Hz, 1H), 3.78 (dd, J = 2.1, 9.7 Hz, 1H), 3.05 (dddd, J = 4.0,
4.0, 7.6, 11.7 Hz, 1H), 2.13 (ddd, J = 2.4, 3.9, 13.8 Hz, 1H), 1.94 (qd, J =
3.5, 6.9 Hz, 1H), 1.55 (ddd, J = 12.3, 12.3, 13.8 Hz, 1H), 1.06 (d, J = 6.7
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ =136.3 (C7), 118.2 (C8), 88.4
10818
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13.4 Hz, 1H), 1.89−1.98 (m, 2H), 1.49−1.63 (m, 3H), 0.98 (t, J =
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 153.7, 142.5, 135.5, 118.0,
110.2, 107.2, 87.2, 77.4, 76.6, 74.2, 65.7, 37.4, 33.0, 28.0, 18.7, 13.6;
HRMS (ESI+) calcd for C14H19NO4 Na [M + Na]+ 288.1211, found
288.1207. 24b: 1H NMR (300 MHz, CDCl3) δ = 7.40 (s, 1H), 6.36 (dt,
J = 1.9, 3.4 Hz, 1H), 6.31 (dd, J = 3.5, 4.0 Hz, 1H), 5.68 (ddd, J = 8.1,
10.1, 17.2 Hz, 1H), 5.19 (d, J = 17.0 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H),
4.62 (dd, J = 2.1, 11.6 Hz, 1H), 4.23 (dd, J = 9.5, 10.8 Hz, 1H), 3.87 (ddd,
J = 2.7, 8.0, 9.5 Hz, 1H), 3.03 (dddd, J = 4.2, 8.2, 12.0, 12.0 Hz, 1H), 2.13
(ddd, J = 2.4, 4.4, 13.9 Hz, 1H), 1.89 (ddd, J = 12.2, 12.2, 13.7 Hz, 1H),
1.27−1.61 (m, 4H), 0.90 (t, J = 8.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ = 135.4 (C7), 118.5 (C8), 78.2 (C6), 72.3 (C2), 68.1 (C5),
44.8 (C4), 33.8 (C3) (only the chemical shifts of carbons in THP ring
are reported); HRMS (ESI+) calcd for C14H19NO4 Na [M + Na]+
288.1211, found 288.1207. 24c: 1H NMR (300 MHz, CDCl3) δ = 7.40
(s, 1H), 6.36 (dt, J = 1.9, 3.4 Hz, 1H), 6.31 (dd, J = 3.5, 4.0 Hz, 1H), 6.20
(ddd, J = 9.4, 10.3, 16.6 Hz, 1H), 5.25 (d, J = 10.1 Hz, 1H), 5.21 (d, J =
16.6 Hz, 1H), 4.76 (dd, J = 2.4, 11.9 Hz, 1H), 4.53 (dd, J = 5.4, 10.2 Hz,
1H), 4.14 (ddd, J = 1.8, 8.2, 10.1 Hz, 1H), 3.25−3.33 (m, 1H), 2.31
(ddd, J = 4.8, 11.7, 13.7 Hz, 1H), 2.11 (ddd, J = 2.6, 2.6, 11.2 Hz, 1H),
1.27−1.61 (m, 4H), 0.90 (t, J = 8.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ = 132.6 (C7), 119.9 (C8), 87.9 (C5), 73.0 (C6), 68.1 (C2),
41.7 (C4), 34.7 (C3) (only the chemical shifts of carbons in THP ring
are reported); HRMS (ESI+) calcd for C14H19NO4 Na [M + Na]+
288.1211, found 288.1207.
6-(2-Methoxyphenyl)-3-nitro-2-propyl-4-vinyltetrahydro-2H-
pyran (25). Under argon, (E)-tert-butyl-5-hydroxy-5-(2-methoxyphenyl)-
pent-2-enyl carbonate (53.2 mg, 0.200 mmol) and (E)-1-nitropent-1-ene
(46.0 mg, 0.400 mmol) were dissolved in 1 mL of anhydrous THF, and
the solution was cooled to −78 °C. A suspension of Pd2(dba)3·CHCl3
(10.4 mg, 0.0100 mmol) and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL
of anhydrous THF was then added. Subsequently, a solution of lithium
tert-butoxide (1 M in THF, 0.3 mL, 1.5 equiv) was added. The mixture
was then warmed to room temperature and stirred until the alcohol
was consumed. The reaction mixture was cooled to −78 °C again and
quenched with saturated NH4Cl solution. After being warmed to room
temperature, the mixture was extracted with ethyl acetate three times.
The combined organic phases were washed with brine, dried (Na2SO4),
and filtered. The solution was concentrated in vacuo, and the residue
was purified by column chromatography on silica gel and eluted with the
gradient of petroleum and ethyl acetate, from 40:1 to 20:1, to afford
diastereomer 25a together with minor amounts of the 5-epi,6-epi-com-
pound (25b) and the 4-epi,5-epi,6-epi-isomer (25c) with a diastereo-
meric ratio of 5.2:1:0.6 as a viscous oil (combined yield: 42 mg, 70%).
25a: 1H NMR (500 MHz, CDCl3) δ = 7.57 (dd, J = 1.6, 8.5 Hz, 1H),
7.27 (d, J = 1.6, 15.6 Hz, 1H), 7.01 (ddd, J = 0.7, 7.5, 7.5 Hz, 1H), 6.87
(d, J = 8.2 Hz, 1H), 5.85 (ddd, J = 6.4, 10.4, 17.0 Hz, 1H), 5.20 (ddd, J =
1.2, 1.2, 17.2 Hz, 1H), 5.18 (ddd, J = 1.2, 1.2, 10.2 Hz, 1H), 5.12 (dd, J =
2.7, 11.6 Hz, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.47 (dd, J = 5.1, 9.5 Hz, 1H),
3.84 (s, 3H), 2.99 (dddd, J = 4.76.0, 6.0, 10.8 Hz, 1H), 2.27 (ddd, J =
12.0, 12.0, 12.9 Hz, 1H), 2.02−2.15 (m, 1H), 1.80 (ddd, J = 3.7, 3.7, 13.5
Hz, 1H), 1.52−1.62 (m, 2H), 1.41−1.49 (m, 1H), 0.99 (t, J = 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ = 156.1, 137.0, 130.7, 128.8, 127.2,
121.4, 117.7, 110.5, 86.9, 76.0, 65.5, 55.7, 37.7, 32.7, 31.3, 19.4, 14.1;
HRMS (ESI+) calcd for C34H46N2O8Na [2M + Na]+ 633.3151, found
633.3149. 25b: 1H NMR (500 MHz, CDCl3) δ = 7.45 (ddd, J = 2.1, 2.1,
7.5 Hz, 1H), 7.27 (ddd, J = 1.6, 1.6, 15.7 Hz, 1H), 6.99 (ddd, J = 0.7,
7.5, 7.5 Hz, 1H), 6.87 (dd, J = 3.3, 8.2 Hz, 1H), 5.64 (ddd, J = 8.1, 10.3,
17.2 Hz, 1H), 5.17 (ddd, J = 0.8, 0.8, 17.0 Hz, 1H), 5.11 (d, J = 11.3 Hz,
1H), 4.91 (dd, J = 1.8, 11.0 Hz, 1H), 4.26 (dd, J = 9.5, 10.8 Hz, 1H), 3.92
(ddd, J = 2.9, 8.1, 9.5 Hz, 1H), 3.84 (s, 3H), 3.12 (dddd, J = 4.2, 8.2, 11.9,
11.9 Hz, 1H), 2.22 (ddd, J = 2.0, 4.2, 13.7 Hz, 1H), 1.42 (ddd, J = 10.8,
13.2, 13.2 Hz, 1H), 1.27−1.62 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ = 135.9 (7), 117.9 (8), 91.3 (5), 78.1 (6),
73.3 (2), 45.2 (4), 36.6 (3), (only the chemical shifts of carbons in THP
ring are reported); HRMS (ESI+) calcd for C34H46N2O8Na [2M + Na]+
633.3151, found 633.3149. 25c: 1H NMR (500 MHz, CDCl3) δ = 7.45
(ddd, J = 2.1, 2.1, 7.5 Hz, 1H), 7.27 (ddd, J = 1.6, 1.6, 15.7 Hz, 1H), 6.99
(ddd, J = 0.7, 7.5, 7.5 Hz, 1H), 6.87 (dd, J = 3.3, 8.2 Hz, 1H), 6.25 (ddd,
J = 8.8, 11.0, 16.5 Hz, 1H), 5.28 (d, J = 10.3 Hz, 1H), 5.27 (d, J = 17.4 Hz,
1H), 5.06 (dd, J = 1.6, 11.3 Hz, 1H), 457 (dd, J = 5.3, 10.2 Hz, 1H), 4.16
(ddd, J = 2.0, 7.5, 9.9 Hz, 1H), 3.85 (s, 3H), 3.919−3.28 (m, 1H), 2.10
(ddd, J = 2.4, 2.4, 11.6 Hz, 1H), 1.79 (ddd, J = 4.8, 11.3, 13.9 Hz, 1H),
1.27- 1.62(m, 4H), 0.91 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ = 133.2 (7), 119.2 (8), 88.3 (5), 73.3 (6), 69.0 (2), 42.2 (4),
36.6 (3) (only the chemical shifts of carbons in THP ring are reported);
HRMS (ESI+) calcd for C34H46N2O8Na [2M + Na]+ 633.3151, found
633.3149.
3-Nitro-2-propyl-6-p-tolyl-4-vinyltetrahydro-2H-pyran (26).
Under argon, (E)-tert-butyl-5-hydroxy-5-(4-methylphenyl)pent-2-enyl
carbonate (50.1 mg, 0.200 mmol) and (E)-1-nitropent-1-ene (46.0 mg,
0.400 mmol) were dissolved in 1 mL of anhydrous THF, and the solu-
tion was cooled to −78 °C. A suspension of Pd2(dba)3·CHCl3 (10.4 mg,
0.0100 mmol) and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of
anhydrous THF was then added. Subsequently, a solution of lithium tert-
butoxide (1 M in THF, 0.3 mL, 1.5 equiv) was added. The mixture was
then warmed to room temperature and stirred until the alcohol was
consumed. The reaction mixture was cooled to −78 °C and quenched
with saturated NH4Cl solution. After being warmed to room tem-
perature, the mixture was extracted with ethyl acetate three times. The
combined organic phases were washed with brine, dried (Na2SO4), and
filtered. The solution was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel and eluted with the
gradient of petroleum and ethyl acetate, from 40:1 to 20:1, to afford
diastereomer 26a together with minor amounts of the 5-epi,6-epi-isomer
(26b) and the 4-epi,5-epi,6-epi-isomer (26c) with a diastereomeric ratio
of 6.2:1:0.5 as a viscous oil (75%). 26a: 1H NMR (300 MHz, CDCl3) δ =
7.16−7.33 (m, 4H), 5.86 (ddd, J = 6.4, 10.4, 17.0 Hz, 1H), 5.21 (d, J =
17.0 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 4.69 (dd, J = 3.0, 11.6 Hz, 1H),
4.57 (dd, J = 1.3, 4.6 Hz, 1H), 4.18 (ddd, J = 1.6, 9.7, 12.1 Hz, 1H), 2.93−
3.02 (m, 1H), 2.44 (ddd, J = 2.8, 12.8, 12.8 Hz, 1H), 2.30 (s, 3H), 1.82
(ddd, J = 3.8, 3.8, 13.5 Hz, 1H), 1.43−1.67 (m, 4H), 1.00 (t, J = 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ = 136.3 (C7), 117.5 (C8), 91.0
(C6), 86.5 (C5), 71.1 (C2), 37.3 (C4), 32.1 (C3) (only the chemical
shifts of carbons in THP ring are reported); HRMS (ESI+) calcd for
C34H46N2O6 Na [2M + Na]+ 601.3253, found 601.3252. 26b: 1H NMR
(300 MHz, CDCl3) δ = 7.16−7.33 (m, 4H), 5.66 (ddd, J = 8.0, 10.2,
17.2 Hz, 1H), 5.18 (d, J = 17.2 Hz, 1H), 5.13 (d, J = 10.8 Hz, 1H),
4.49(dd, J = 4.0, 9.7 Hz, 1H), 4.25 (dd, J = 9.3, 11.0 Hz, 1H), 3.91 (ddd,
J = 2.7, 3.7, 9.8 Hz, 1H), 3.09 (dddd, J = 4.2, 8.2, 11.8, 11.8 Hz, 1H), 2.12
(ddd, J = 2.0, 2.0, 13.5 Hz, 1H), 2.30 (s, 3H), 1.61 (ddd, J = 11.9, 11.9,
13.7 Hz, 1H), 1.43−1.67 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz,CDCl3) δ =135.7 (C7), 118.2 (C8), 78.4 (C6), 75.3 (C2),
68.1 (C5), 45.1 (C4), 37.8 (C3) (only the chemical shifts of carbons
in THP ring are reported); HRMS (ESI+) calcd for C34H46N2O6 Na
1
[2M + Na]+ 601.3253, found 601.3252. 26c: H NMR (300 MHz,
CDCl3) δ = 7.16−7.33 (m, 4H), 6.29 (ddd, J = 9.5, 10.1, 16.8 Hz, 1H),
5.25 (d, J = 17.6 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 5.12 (dd, J = 2.6, 11.6
Hz, 1H), 4.55 (dd, J = 4.0, 8.6 Hz, 1H), 4.18 (ddd, J = 2.2, 8.0, 9.7 Hz,
1H), 3.23−3.30 (m, 1H), 2.30(s, 3H), 1.97−2.12 (m, 2H), 1.43−1.67
(m, 4H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 133.1
(C7), 119.6 (C8), 88.1 (C5), 73.8 (C2), 72.8 (C6), 42.4 (C4), 38.5
(C3) (only the chemical shifts of carbons in THP ring are reported);
HRMS (ESI+) calcd for C34H46N2O6 Na [2M + Na]+ 601.3253, found
601.3252.
6-(4-Methoxyphenyl)-3-nitro-2-propyl-4-vinyltetrahydro-2H-
pyran (27). (E)-tert-Butyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-enyl
carbonate (53.2 mg, 0.200 mmol) and (E)-1-nitropent-1-ene (46.0 mg,
0.400 mmol) were dissolved in 1 mL of anhydrous THF, and the solu-
tion was cooled to −78 °C. A suspension of Pd2(dba)3·CHCl3 (10.4 mg,
0.0100 mmol) and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of anhydrous
THF were then added. Subsequently the solution of lithium tert-butoxide
(1 M in THF, 0.3 mL, 1.5 equiv) was added. The mixture was then
warmed to room temperature and stirred until the alcohol was con-
sumed. The reaction mixture was cooled to −78 °C again and quenched
with saturated NH4Cl solution. After being warmed to room
temperature, the mixture was extracted with ethyl acetate three times.
The combined organic phases were washed with brine, dried (Na2SO4),
and filtered. The solution was then concentrated in vacuo, and the
residue was purified by column chromatography on silica gel and eluted
10819
dx.doi.org/10.1021/jo302102x | J. Org. Chem. 2012, 77, 10811−10823

The Journal of Organic Chemistry
Article
with the gradient of petroleum and ethyl acetate, from 40:1 to 20:1, to
afford diastereomer 27a together with minor amounts of the 5-epi,6-epi-
isomer (27b) and the 4-epi,5-epi,6-epi-isomer (27c) with a diastereo-
meric ratio of 5.4:1:0.8 as a viscous oil (combined yield: 47 mg, 77%).
27a: 1H NMR (500 MHz, CDCl3) δ = 7.34 (d, J = 8.5 Hz, 2H), 6.90 (d,
J = 8.5 Hz, 2H), 5.66 (ddd, J = 8.2, 10.2, 17.2 Hz, 1H), 5.25 (d, J = 10.0
Hz, 1H), 5.21 (d, J = 16.8 Hz, 1H), 4.67 (dd, J = 2.9, 11.7 Hz, 1H), 4.56
(d, J = 4.1 Hz, 1H), 4.47 (dd, J = 4.7, 9.9 Hz, 1H), 3.82 (s, 3H), 2.96
(dddd, J = 3.8, 4.7, 9.3, 13.7 Hz, 1H), 2.45 (ddd, J = 12.6, 12.6, 12.6 Hz,
1H), 2.00−2.11 (m, 1H), 1.80 (ddd, J = 3.8, 3.8, 13.7 Hz, 1H), 1.52−
1.62 (m, 2H), 1.41−1.49 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ = 159.3, 136.3, 134.0, 127.5, 117.5, 113.9, 86.4,
77.3, 76.7, 75.3, 70.9, 55.3, 37.3, 32.3, 32.1, 18.9, 13.7; HRMS (ESI+)
calcd for C34H46N2O8Na [2M + Na]+ 633.3151, found 633.3149. 27b:
1H NMR (500 MHz, CDCl3) δ = 7.34 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 8.5
Hz, 1H), 5.85 (ddd, J = 6.3, 10.4, 17.0 Hz, 1H), 5.21 (d, J = 18.4 Hz, 1H),
5.20 (d, J = 9.3 Hz, 1H), 4.54 (dd, J = 2.1, 11.4 Hz, 1H), 4.24 (dd, J = 9.6,
10.7 Hz, 1H), 3.90 (ddd, J = 2.5, 8.0, 10.5 Hz, 1H), 3.81 (s, 3H), 3.08
(dddd, J = 4.1, 8.2, 11.6, 11.6 Hz, 1H), 2.10 (ddd, J = 2.2, 4.1, 13.7 Hz,
1H), 1.61 (ddd, J = 12.4, 12.4, 14.0 Hz, 1H), 1.27−1.62 (m, 4H), 0.91 (t,
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 135.7 (C7), 118.2
(C8), 91.0 (C7), 78.2 (C6), 73.6 (C2), 45.1 (C4), 37.7 (C3) (only the
chemical shifts of carbons in THP ring are reported); HRMS (ESI+)
calcd for C34H46N2O8Na [2M + Na]+ 633.3151, found 633.3149. 27c:
1H NMR (500 MHz, CDCl3) δ = 7.34 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5
carbons in THP ring are reported); HRMS (ESI+) calcd for
C40H46N2O6Na [M + Na]+ 673.3253, found 673.3251. 28c: 1H NMR
(300 MHz, CDCl3) δ = 7.81−7.86 (m, 4H), 7.43−7.51 (m, 3H), 5.88
(ddd, J = 9.5, 10.1, 16.6 Hz, 1H), 5.30 (d, J = 9.9 Hz, 1H), 5.25 (d, J =
16.6 Hz, 1H), 4.90 (dd, J = 2.3, 11.6 Hz, 1H), 4.61 (dd, J = 5.3, 10.2 Hz,
1H), 4.24 (ddd, J = 3.8, 3.8, 9.5 Hz, 1H), 3.27−3.35 (m, 1H), 2.06−2.23
(m, 2H), 1.27−1.77 (m, 4H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ = 133.2 (C7), 119.8 (C8), 88.1 (C5), 74.1 (C2), 68.1
(C6), 42.4 (C4), 38.6 (C3) (only the chemical shifts of carbons in THP
ring are reported); HRMS (ESI+) calcd for C40H46N2O6Na [M + Na]+
673.3253, found 673.3251.
2-Isopropyl-3-methyl-3-nitro-6-phenyl-4-vinyltetrahydro-2H-
pyran (30). (E)-tert-Butyl 5-hydroxy-5-p-tolylpent-2-enyl carbonate
(55.7 mg, 0.2 mmol) and (Z)-4-methyl-2-nitropent-2-ene (0.2583 mg,
2 mmol) were dissolved in 1 mL of anhydrous THF, and the solution
was cooled to −78 °C. A suspension of allylpalladium(II) chloride dimer
(7.3 mg, 0.0200 mmol) and PPh3 (15.7 mg, 0.0600 mmol) in 1.5 mL of
anhydrous THF were added. Subsequently, a solution of LHMDS (1 M
in THF, 0.3 mL, 1.5 equiv) was added. The mixture was then warmed to
room temperature and stirred until the alcohol was consumed. The
reaction mixture was cooled to −78 °C and quenched with saturated
aqueous NH4Cl solution. After being warmed to room temperature, the
mixture was extracted with ethyl acetate three times. The combined
organic phases were washed with brine, dried (Na2SO4), and filtered.
The solution was then concentrated in vacuo, and the residue was
purified by column chromatography on silica gel and eluted with the
gradient of petroleum and ethyl acetate, from 60:1 to 30:1, to afford
36.1 mg (0.124 μmol, 62%) of the three diastereomers 30a−c with a
diastereomeric ratio of 1.6:1:<0.05 as a viscous oil. 30a: 1H NMR (400
MHz, CDCl3) δ = 7.30−7.50 (m, 5H), 5.60 (ddd, J = 7.4, 10.3, 17.3 Hz,
1H), 5.16 (d, J = 10.4 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H), 4.66 (dd, J =
2.6, 11.6 Hz, 1H), 3.90 (d, J = 6.9 Hz, 1H), 3.24 (ddd, J = 4.2, 7.4, 12.8
Hz, 1H), 2.05 (ddd, J = 3.6, 6.8, 13.9 Hz, 1H), 1.65 (ddd, J = 12.6, 12.6,
12.6 Hz, 1H), 1.57 (s, 3H), 1.75 (ttd, J = 6.6, 6.9, 8.4 Hz, 1H), 1.06 (d, J =
6.6 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ =134.1 (C7), 118.8 (C8), 110.6, 93.1, 92.1 (C5), 86.5 (C6), 79.1 (C2),
50.3 (C4), 35.5 (C3) (only the chemical shifts of carbons in THP ring
are reported); HRMS (ESI+) calcd for C17H23NO3 Na [M + Na]+
312.1575, found 312.1572. 30b: 1H NMR (400 MHz, CDCl3) δ = 7.30−
7.50 (m, 5H), 5.62 (ddd, J = 6.9, 10.0, 17.2 Hz, 1H), 5.26 (d, J = 11.7 Hz,
1H), 5.21 (d, J = 6.0 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H), 3.68 (d, J = 7.2
Hz, 1H), 3.14 (ddd, J = 4.0, 7.6, 12.9 Hz, 1H), 2.44 (dd, J = 3.9, 14.7 Hz,
1H), 2.09 (ddd, J = 6.2, 13.7, 13.7 Hz, 1H), 1.59 (s, 3H), 1.73 (dtt, J =
7.2, 7.2, 6.8 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 7.2 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ = 134.3 (C7), 118.8 (C8), 93.1 (C5),
78.5 (C6), 72.7 (C2), 45.5 (C4), 27.8 (C3) (only the chemical shifts of
carbons in THP ring are reported). 30c: 1H NMR (400 MHz, CDCl3)
δ = 7.30−7.50 (m, 5H), 5.61 (ddd, J = 7.7, 10.0, 17.1 Hz, 1H), 5.26 (d,
J = 11.7 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H), 4.94 (dd, J = 6.3, 11.0 Hz,
1H), 4.08 (d, J = 9.7 Hz, 1H), 2.66 (ddd, J = 11.1, 13.2, 13.2 Hz, 1H),
2.51 (ddd, J = 2.3, 7.9, 12.8 Hz, 1H), 184 (dtt, J = 8.3, 6.5, 6.9 Hz, 1H),
2.00 (ddd, J = 2.4, 6.2, 13.4 Hz, 1H), 1.59 (s, 3H), 0.91 (d, J = 6.5 Hz,
3H), 0.86 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ = 134.0
(C7), 118.8 (C8), 92.0 (C5), 79.9 (C6), 75.6 (C2), 48.1 (C4), 28.5
(C3) (only the chemical shifts of carbons in THP ring are reported).
(E)-tert-Butyl 5-(Furan-2-yl)-5-hydroxypent-2-enyl carbonate (31).
1-(Furan-2-yl)but-3-en-1-ol (1.38 g, 10 mmol) (1.38 g, 10 mmol) and
(Z)-but-2-ene-1,4-diyl tert-butyl dicarbonate (2.88 g, 10 mmol) were
dissolved in 40 mL of anhydrous dichloromethane. A solution of
second-generation Grubbs catalyst (0.170 g, 0.2 mmol) in 10 mL of
anhydrous dichloromethane was then added, and the reaction mixture
was refluxed overnight. The solvent was removed in vacuo and the
residue was purified by column chromatography on silica gel and eluted
with the gradient of petroleum ether and ethyl acetate, from 12:1 to 8:1
to 4:1, to afford 1.78 g of a viscous pale-brown oil (66%): 1H NMR 300
MHz, CDCl3) δ = 7.40−7.41 (m, 1H), 6.35−6.37 (m, 1H), 6.27(d, J =
3.3 Hz, 1H), 5.70−5.88 (m, 2H), 4.77 (t, J = 6.4 Hz, 1H), 4.54 (d, J = 5.0
Hz, 2H), 2.66 (t, J = 5.4 Hz, 2H), 2.11 (s, br, 1H), 1.50(s, 9H); 13C NMR
(75 MHz, CDCl3) = 155.8, 153.3, 142.0, 131.1, 127.5, 110.1, 106.2, 82.1,
Hz, 2H), 5.85 (ddd, J = 9.9, 9.9, 16.8 Hz, 1H), 5.25 (d, J = 10.0 Hz, 1H),
5.21 (d, J = 16.8 Hz, 1H), 4.68 (dd, J = 2.7, 10.7 Hz, 1H), 4.54 (dd, J =
2.1, 11.4 Hz, 1H), 4.47 (ddd, J = 1.6, 8.5, 10.0 Hz, 1H), 3.85 (s, 3H),
3.23−3.30 (m, 1H), 1.99 −2.07(m, 2H), 1.27−1.62 (m, 4H), 0.89 (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ = 133.1 (C7), 119.6 (C8),
78.2 (C5), 73.6 (C2), 72.9 (C6), 42.4 (C4), 27.4 (C3) (only the
chemical shifts of carbons in THP ring are reported); HRMS (ESI+)
calcd for C34H46N2O8Na [2M + Na]+ 633.3151, found 633.3149.
6-(Naphthalen-2-yl)-3-nitro-2-propyl-4-vinyltetrahydro-2H-
pyran (28). (E)-tert-Butyl 5-hydroxy-5-(naphthalen-2-yl)pent-2-enyl
carbonate (65.7 mg, 0.2 mmol) and (E)-1-nitropent-1-ene (46.0 mg,
0.400 mmol) were dissolved in 1 mL of anhydrous THF, and the solu-
tion was cooled to −78 °C. A suspension of Pd2(dba)3·CHCl3 (10.4 mg,
0.0100 mmol) and PPh3 (10.5 mg, 0.0400 mmol) in 1.5 mL of
anhydrous THF was then added. Subsequently, a solution of lithium tert-
butoxide (1 M in THF, 0.3 mL, 1.5 equiv) was added. The mixture was
then warmed to room temperature and stirred until the alcohol was con-
sumed. The reaction mixture was cooled to −78 °C again and quenched
with saturated NH4Cl solution. After being warmed to room tem-
perature, the mixture was extracted with ethyl acetate three times. The
combined organic phases were washed with brine, dried (Na2SO4), and
filtered. The solution was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel and eluted with the
gradient of petroleum and ethyl acetate, from 60:1 to 30:1, to afford pure
diastereomer 28a together with minor amounts of the 5-epi,6-epi-isomer
(28b) and the 4-epi,5-epi,6-epi-isomer (28c) with a diastereomeric ratio
1
of 6.3:1:0.7 as a viscous oil (combined yield: 50.7 mg, 78%). 28a: H
NMR (300 MHz, CDCl3) δ =7.84−7.88 (m, 4H), 7.57 (d, J = 8.8 Hz,
1H), 7.47−7.52 (m, 2H), 5.88 (ddd, J = 6.4, 10.5, 17.1 Hz, 1H), 5.24 (d,
J = 17.3 Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.90 (dd, J = 2.7, 11.8 Hz,
1H), 4.61 (d, J = 3.6 Hz, 1H), 4.56 (dd, J = 4.5, 9.5 Hz, 1H), 3.02−
3.05(m, 1H), 2.55 (ddd, J = 12.4, 12.4, 12.4 Hz, 1H), 1.88−1.97 (m,
1H), 1.93 (ddd, J = 3.6, 3.6, 13.4 Hz, 1H), 1.55−1.68 (m, 3H), 1.03 (t,
J = 7.14 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 139.2, 136.2, 133.2,
133.1, 128.3, 128.0, 127.7, 126.1, 125.9, 124.8, 124.2, 117.6, 86.5, 77.3,
76.7, 75.4, 71.4, 37.3, 32.3, 32.2, 18.9, 13.7; HRMS (ESI+) calcd for
C40H46N2O6Na [M + Na]+ 673.3253, found 673.3251. 28b: 1H NMR
(300 MHz, CDCl3) δ =7.81−7.86 (m, 4H), 7.43−7.51 (m, 3H), 5.68
(ddd, J = 8.2, 10.2, 17.1 Hz, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.15 (d, J =
10.43 Hz, 1H), 4.75 (dd, J = 1.9, 11.4 Hz, 1H), 4.30 (dd, J = 9.5, 10.8 Hz,
1H), 3.98 (ddd, J = 2.9, 7.8, 9.5 Hz, 1H), 3.15 (dddd, J = 4.0, 8.0, 11.9,
11.9 Hz, 1H), 2.24 (ddd, J = 2.2, 4.2, 13.9 Hz, 1H), 1.70 (ddd, J = 12.1,
12.1, 13.7 Hz, 1H), 1.27−1.77 (m, 4H), 0.94 (t, J = 7.14 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ = 135.6 (C7), 118.3 (C8), 91.0 (C5), 78.6
(C2), 78.3 (C6), 45.2 (C4), 37.9 (C3) (only the chemical shifts of
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77.4, 76.6, 67.2, 66.9, 38.5, 27.7; HRMS (ESI+) calcd for C28H40O10Na
[2M + Na]+ 559.2519, found 559.2518.
over anhydrous Na2SO4, and filtered. The solvent was removed in vacuo,
and residue was purified by flash chromatography on silica gel and eluted
with the gradient of petroleum ether and ethyl acetate, from 60:1, 30:1,
to give 19.0 mg of a colorless viscous oil afford a mixture of the major
diastereomer (37a) together with the 4-epi,5-epi-isomer (37b) as a
colorless oil with a diastereomeric ratio of 8:1 (combined yield: 27.0 mg;
51%). 37a: 1H NMR (300 MHz, CDCl3) δ = 7.26 (d, J = 8.0 Hz, 2H),
7.19 (d, J = 8.0 Hz, 2H), 5.68 (ddd, J = 7.1, 10.4, 17.2 Hz, 1H), 5.18 (d,
J = 10.4 Hz, 1H), 5.12 (d, J = 17.0 Hz, 1H) 4.56 (dd, J = 2.6, 11.7 Hz,
1H), 4.11 (d, J = 10.8 Hz, 1H), 4.04 (d, J = 10.6 Hz, 1H), 3.38 (ddd, J =
4.6, 7.1, 12.1 Hz, 1H), 2.38 (s, 3H), 2.04 (ddd, J = 2.7, 4.2, 13.9 Hz, 1H),
1.69 (s, 3H), 1.73 (ddd, J = 12.1, 12.1, 13.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ = 137.8, 134.5, 129.2, 125.6, 118.6, 89.0, 79.8, 75.2,
46.5, 35.7, 21.1, 15.5; HRMS (ESI+) calcd for C15H19NO3Na [M + Na]+
284.1262, found 284.1258.
2-(4-Methoxyphenyl)-5-methyl-5-nitro-4-vinyltetrahydro-2H-
pyran (38). (E)-tert-Butyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-enyl
carbonate (61.7 mg, 0.2 mmol) and 2-nitroprop-1-ene (34.8 mg,
0.4 mmol,) were dissolved in 1 mL of anhydrous THF, and the solution
was cooled to −78 °C. A solution of allyl palladium(II) chloride dimer
(7.3 mg, 0.0200 mmol) and PPh3 (15.7 mg, 0.0600 mmol) in 1.5 mL
of anhydrous THF was then added. Subsequently, 0.3 mL of LiHMDS
(1 M in THF, 0.3 mmol) in THF was added. The mixture was then
warmed to room temperature and stirred until the alcohol was con-
sumed. The mixture was cooled to −78 °C again and quenched with
saturated NH4Cl solution. After being warmed to room temperature, the
mixture was extracted with ethyl acetate three times. The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
and filtered. The solvent was removed in vacuo, and the residue was
purified by flash chromatography on silica gel and eluted with the
gradient of petroleum ether and ethyl acetate, from 40:1, 20:1, to afford a
mixture of the major diastereomers (38a) and the 4-epi,5-epi-isomer
(38b) as a colorless oil with a diastereomeric ratio of 8:1 (combined
yield: 31.7 mg, 57%). 38a: 1H NMR (300 MHz, CDCl3) δ = 7.18−7.24
(m, 2H), 6.79−6.85 (m, 2H), 5.59 (ddd, J = 7.3, 10.4, 17.4 Hz, 1H),
5.01−5.19 (m, 2H), 4.47 (dd, J = 2.6, 11.5 Hz, 1H), 3.95(d, J = 10.8 Hz,
1H), 3.82 (s, 3H), 3.29 (ddd, J = 4.4, 7.1, 12.1 Hz, 1H), 1.94 (ddd, J =
2.6, 4.21, 13.9 Hz, 1H), 1.71 (s, 3H), 1.66 (ddd, J = 12.3, 12.3, 13.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ =15.9, 36.0, 47.0, 55.7, 75.6, 77.9,
80.1, 89.4, 114.3, 119.0, 127.4, 133.4, 134.9; HRMS (ESI+) calcd for
C15H19NO4Na [M + Na]+ 300.1211, found 300.1207.
2-(2-Methoxyphenyl)-5-methyl-5-nitro-4-vinyltetrahydro-2H-
pyran (39). According to the procedure described above for compound
36, (E)-tert-butyl 5-hydroxy-5-(2-methoxyphenyl)pent-2-enyl carbo-
nate (61.7 mg, 0.2 mmol) was treated with 2-nitroprop-1-ene (34.8 mg,
0.4 mmol), allylpalladium(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3
(15.7 mg, 0.06 mmol), and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol)
in anhydrous THF to give after an analogous workup and purification
the major diastereomer 39a together with the 4-epi,5-epi-isomer (39b)
as a colorless oil with a diastereomeric ratio of 6:1 (combined yield: 32.8
mg, 59%). 39a: 1H NMR (300 MHz, CDCl3) δ = 7.45 (dd, J = 1.4, 7.6
Hz, 1H), 7.25−7.32 (m, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.4 Hz,
1H), 5.66 (ddd, J = 7.1, 10.4, 17.4 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H),
5.11 (td, J = 1.1, 17.2 Hz, 1H), 4.95 (dd, J = 2.5, 11.4 Hz, 1H), 4.13 (d, J =
10.6 Hz, 1H), 4.05 (d, J = 10.6 Hz, 1H), 3.85 (s, 3H), 3.40 (ddd, J = 4.4,
7.1, 11.9 Hz, 1H), 2.13 (ddd, J = 2.7, 4.2, 13.9 Hz, 1H), 1.72 (s, 3H), 1.58
(ddd, J = 11.7, 11.7, 14.3 Hz, 1H); 13C NMR (75 MHz, CHCl3) δ=
135.1, 129.1, 126.2, 121.2, 118.8, 110.7, 89.6, 77.8, 77.6, 75.7, 75.1, 55.7,
47.0, 34.6, 30.1, 15.9; HRMS (ESI+) calcd for C15H19NO4Na [M + Na]+
300.1211, found 300.1208.
6-(Furan-2-yl)-2-isopropyl-3-nitro-4-vinyltetrahydro-2H-pyran
(32). After an analogous procedure, workup, and purification as
described above, the major diastereomer a together with b and c was
a colorless oil with a ratio of 6.4:10.4:1 (combined yield: 43.5 mg, 78%).
32a: 1H NMR (500 MHz, CDCl3) δ = 7.41 (s, 1H), 6.36 (dd, J = 1.9, 3.3
Hz, 1H), 6.31 (d, J = 3.3 Hz, 2H), 5.62 (ddd, J = 7.5, 10.2, 17.5 Hz, 1H),
5.17 (d, J = 10.4 Hz, 1H), 5.10 (d, J = 17.0 Hz, 1H), 4.67 (dd, J = 2.5, 11.8
Hz, 1H), 3.84 (d, J = 7.4 Hz, 1H), 3.16 (ddd, J = 4.3, 7.5, 12.3 Hz, 1H),
2.03 (ddd, J = 2.7, 4.1, 13.7 1H), 1.92 (ddd, J = 12.3, 12.3, 13.7 Hz, 1H),
1.69−1.78 (m, 1H), 1.55 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.9
Hz, 7H); 13C NMR (126 MHz, CDCl3) δ = 153.4, 142.3, 110.1, 106.8,
118.9; 119.0, 91.9, 86.6, 73.1, 50.1, 31.5, 30.2, 19.9, 18.6, 11.0; HRMS
(ESI+) calcd for C15H21NO4 Na [M + Na]+ 302.1369, found 302.1366.
32b: 1H NMR (500 MHz, CDCl3) δ = 7.47 (s, 1H), 6.49 (d, J = 3.3 Hz,
1H), 6.39 (dd, J = 1.8, 3.2 Hz, 1H), 5.55 (ddd, J = 7.7, 10.0, 17.2 Hz, 1H),
5.24 (d, J = 17.0 Hz, 1H), 5.22 (d, J = 9.9 Hz, 1H), 4.96 (dd, J = 7.3, 11.1
Hz, 1H), 4.01 (d, J = 9.6 Hz, 1H), 2.66 (ddd, J = 11.2, 13.2, 13.2 Hz,1H),
2.48 (ddd, J = 2.8, 8.0, 12.8 Hz, 1H), 1.92 (ddd, J = 3.2, 7.1, 14.0 Hz, 1H),
1.61 (s, 3H), 1.66−1.77 (m, 1H), 0.75 (d, J = 6.3 Hz, 3H), 0.68 (d, J = 6.6
Hz, 1H); 13C NMR (126 MHz, CDCl3) δ = 153.6, 142.9, 119.8; 119.8;
110.0, 107.8, 91.7, 78.9, 69.7, 47.8; 29.4, 26.0, 19.9, 17.8, 17.7; HRMS
(ESI+) calcd for C15H21NO4 Na [M + Na]+ 302.1369, found 302.1366.
5-Methyl-5-nitro-2-phenyl-4-vinyltetrahydro-2H-pyran (36).
(E)-tert-Butyl 5-hydroxy-5-phenylpent-2-enyl carbonate (55.7 mg, 0.2 mmol)
and (E)-1-nitropent-1-ene (34.8 mg, 0.4 mmol) were dissolved in 1 mL of
anhydrous THF, and the solution was cooled to −78 °C. A suspension
of allylpalladium(II) chloride dimer (7.3 mg, 0.0200 mmol) and PPh3
(15.7 mg, 0.0600 mmol) in 1.5 mL of anhydrous THF was added.
Subsequently, a solution of LHMDS (1 M in THF, 0.3 mL, 1.5 equiv)
was added. The mixture was then warmed to room temperature and
stirred until the alcohol was consumed. The reaction was then cooled
to −78 °C and quenched with saturated NH4Cl solution. After being
warmed to room temperature, the mixture was extracted with ethyl
acetate three times. The combined organic phases were washed with
brine, dried (Na2SO4), and filtered. The solution was concentrated in
vacuo, and the residue was purified with column of silica gel, eluted with
the gradient of petroleum and ethyl acetate, from 60:1 to 30:1, to afford a
mixture of diastereomers 36a and the 4-epi,5-epi-isomer (36b) as a
colorless oil with a diastereomeric ratio of 8.8:1 (combined yield: 31.0
mg; 62%). 36a: 1H NMR (400 MHz, CDCl3) δ = 7.31−7.41 (m, 5H),
5.67 (ddd, J = 7.3, 10.4, 17.4 Hz, 1H), 5.18 (dt, J = 1.0, 10.5 Hz, 1H),
5.13 (dt, J = 1.1, 17.1 Hz, 1H), 4.60 (dd, J = 2.6, 11.7 Hz, 1H), 4.12 (d, J =
10.8 Hz, 1H), 4.06 (d, J = 10.8 Hz, 1H), 3.39 (ddd, J = 4.4, 7.2, 12.2 Hz,
1H), 2.06 (ddd, J = 2.8, 4.3, 14.0 Hz, 1H), 1.74 (ddd, J = 12.3, 12.3, 13.9
Hz, 1H), 1.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ = 134.4, 128.6,
128.0, 125.7, 125.6, 118.7, 88.9, 79.9, 76.7, 75.1, 46.5, 35.7, 15.5; HRMS
1
(FAB+) calcd for (C14H17NO3) 247.1208, found 247.1203. 36b: H
NMR (400 MHz, CDCl3) δ =7.31−7.41 (m, 5H), 6.13 (ddd, J = 9.0,
10.7, 16.6 Hz, 1H), 5.27 (d, J = 10.0 Hz, 1H), 5.26 (d, J = 17.4 Hz, 1H),
4.70 (dd, J = 2.9, 11.3 Hz, 1H), 4.01 (dd, J = 1.5, 11.9 Hz, 1H), 4.06 (d,
J = 10.8 Hz, 1H), 3.39 (ddd, J = 3.0, 4.8, 9.0 Hz, 1H), 2.20 (ddd, J = 4.8,
11.4, 14.2 Hz, 1H), 2.01 (ddd, J = 3.0, 3.0, 14.3 Hz, 1H), 1.88 (s, 3H);
13C NMR (101 MHz, CDCl3) δ = 133.5 (C7), 120.1 (C8), 85.8 (C5)
74.9 (C2), 67.5 (C6), 46.4 (C4), 35.7 (C3), 23.6 (C9) (only the
chemical shifts of carbons in THP ring are reported); HRMS (FAB+)
calcd for (C14H17NO3) 247.1208, found 247.1203.
5-Methyl-5-nitro-2-p-tolyl-4-vinyltetrahydro-2H-pyran (37).
(E)-tert-Butyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-enyl carbonate
(58.5 mg, 0.2 mmol) and 2-nitroprop-1-ene (34.8 mg, 0.4 mmol,)
were dissolved in 1 mL of anhydrous THF, and the solution was cooled
to −78 °C. A solution of allylic palladium(II) chloride dimer (7.3 mg,
0.0200 mmol) and PPh3 (15.7 mg, 0.0600 mmol) in 1.5 mL of anhydrous
THF were then added. Subsequently, LiHMDS (1 M in THF, 0.3 mL) in
THF was added. The mixture was then warmed to room temperature
and stirred until the alcohol was consumed. The mixture was then cooled
to −78 °C again and quenched with saturated NH4Cl solution. After being
warmed to room temperature, the mixture was extracted with ethyl acetate
three times. The combined organic phases were washed with brine, dried
2-(Furan-2-yl)-5-methyl-5-nitro-4-vinyltetrahydro-2H-pyran (40).
According to the procedure described above for compound 36, (E)-tert-
butyl 5-(furan-2-yl)-5-hydroxypent-2-enyl carbonate(53.7 mg, 0.2 mmol)
was treated with 2-nitroprop-1-ene (34.8 mg, 0.4 mmol), allylpalladium-
(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3 (15.7 mg, 0.06 mmol),
and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol) in anhydrous THF to
give after an analogous workup and purification the major diastereomer
40a together with the 4-epi,5-epi-isomer (40b) as a colorless oil with a
1
diastereomeric ratio of 7:1 (combined yield: 14.2 mg, 30%). 40a: H
NMR (300 MHz, CDCl3) δ = 7.43 (dd, J = 0.7, 1.8 Hz, 1H), 6.33−6.40
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(m, 2H), 5.70 (ddd, J = 7.3, 10.6, 17.6 Hz, 1H), 5.21 (d, J = 0.8, 10.3 Hz,
1H), 5.16 (ddd, J = 1.2, 1.2, 17.2 Hz, 1H), 4.65 (dd, J = 3.8, 10.8 Hz, 1H),
4.10 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.6 Hz, 1H), 3.33 (ddd, J = 6.2,
7.0, 11.3 Hz, 1H), 2.06 (ddd, J = 4.8, 4.8, 8.8 Hz, 1H), 1.69 (s, 3H), 2.00
(ddd, J = 11.7, 13.9, 13.9 Hz, 1H); 13C NMR (75 MHz, CHCl3) δ =
152.7, 142.7, 134.2, 118.9, 110.3, 107.4, 88.9, 74.9, 73.1, 46.1, 31.4, 15.4;
HRMS (ESI+) calcd for C12H15NO4Na [M + Na]+ 260.0899, found
260.0896.
2-Cyclohexyl-5-methyl-5-nitro-4-vinyltetrahydro-2H-pyran (41).
According to the procedure described above for compound 36,
(E)-tert-butyl 5-cyclohexyl-5-hydroxypent-2-enyl carbonate (51.6 mg,
0.2 mmol) was treated with 2-nitroprop-1-ene (34.8 mg, 0.4 mmol),
allylpalladium(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3 (15.7 mg,
0.06 mmol), and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol) in
anhydrous THF to give after an analogous workup and purification the
major diastereomer 41a together with the 4-epi,5-epi-isomer (41b) as a
colorless oil with a diastereomeric ratio of 5:1 (combined yield: 36.4 mg,
72%). 41a: 1H NMR (500 MHz, CHCl3) δ = 5.64 (ddd, J = 7.4, 10.4,
17.3 Hz, 1H), 5.14 (d, J = 10.7 Hz, 1H), 5.09 (dt, J = 1.10, 17.0 Hz, 1H),
3.87 (s, 2H), 3.26 (ddd, J = 2.5, 6.3, 11.8 Hz, 1H), 3.15 (ddd, J = 4.7, 7.4,
12.1 Hz, 1H), 1.77 (ddd, J = 2.7, 4.4, 13.8 Hz, 1H), 1.58 (s, 3H), 1.43
(ddd, J = 12.6, 12.6, 12.6 Hz, 1H), 1.79−1.67 (m, 3H), 1.29−0.97 (m,
8H); 13C NMR (125 MHz, CHCl3) δ = 135.1, 118.3, 82.3, 76.8, 75.1,
46.4, 42.5, 30.6, 28.8, 28.6, 26.5, 26.1, 26.0, 15.3; HRMS (ESI+) calcd for
C14H23NO3 [M + Na]+ 276.1575, found 276.1570.
(combined yield: 39.1 mg, 67%). 44a: 1H NMR (300 MHz, CDCl3) δ =
8.24 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 5.67 (ddd, J = 7.3, 10.4,
17.4 Hz, 1H), 5.21 (td, J = 1.0, 10.4 Hz, 1H), 5.14 (td, J = 1.0, 10.2 Hz,
1H), 4.71 (dd, J = 2.6, 11.7 Hz, 1H), 4.14 (d, J = 11.3 Hz, 1H), 4.09(d, J =
10.8 Hz, 1H), 3.41 (ddd, J = 4.4, 7.3, 12.1 Hz, 1H), 2.11 (ddd, J = 2.7, 4.2,
13.9 Hz, 1H), 1.71 (S, 3H), 1.66 (ddd, J = 12.4, 12.4, 13.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ= 15.5, 35.8, 46.4, 75.0, 76.6, 77.4, 78.7, 88.5,
119.1, 123.8, 133.9, 147.9.
5-Ethyl-5-nitro-2-phenyl-4-vinyltetrahydro-2H-pyran (46). (E)-
tert-Butyl 5-hydroxy-5-phenylpent-2-enyl carbonate (55.7 mg, 0.2 mmol)
and 2-nitrobut-1-ene (40.4 mg, 0.4 mmol) were dissolved in 1 mL of
anhydrous THF, and the solution was cooled to −78 °C. A solution of
allylpalladium(II) chloride dimer (7.3 mg, 0.02 mmol) and PPh3 (15.7
mg, 0.06 mmol) in 1.5 mL of anhydrous THF was added. Subsequently,
LHMDS (1 M in THF, 0.3 mL) was added. The mixture was then
warmed to room temperature and stirred until the alcohol was con-
sumed. The mixture was then cooled to −78 °C and quenched with
saturated NH4Cl solution. After being warmed to room temperature, the
mixture was extracted with ethyl acetate three times. The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
and filtered. The solvent was removed in vacuo, and the residue was
purified by flash chromatography on silica gel and eluted with the
gradient of petroleum ether and ethyl acetate, from 60:1, 30:1, to give
the major diastereomer 46a together with the 4-epi,5-epi-isomer (46b)
as a colorless oil with a diastereomeric ratio of 7:1 (combined yield: 13.1
mg, 25%). 46a: 1H NMR (500 MHz, CHCl3) δ = 7.31−7.39 (m, 5H),
5.80 (ddd, J = 7.8, 10.4, 17.3 Hz, 1H), 5.17 (dt, J = 1.1, 10.4 Hz, 1H),
5.09 (dt, J = 1.1, 17.1 Hz, 1H), 4.60 (dd, J = 2.9, 11.6 Hz, 1H), 4.37 (d, J =
11.5 Hz, 1H), 4.11 (dd, J = 1.5, 11.6 Hz, 1H), 3.13 (ddd, J = 4.4,
7.5, 12.2 Hz, 1H), 2.27 (ddt, J = 1.2, 7.4, 14.7 Hz, 1H), 2.09 (dt, J = 7.3,
14.7 Hz, 1H), 2.04 (ddd, J = 3.1, 4.5, 14.0 Hz, 1H), 1.82 (ddd, J = 12.0,
12.0, 14.0 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,
CHCl3) δ = 134.5, 130.9, 128.8, 128.5, 128.0, 125.7, 125.6, 118.4, 79.8,
69.7, 48.6, 36.2, 28.9, 20.7, 7.8; HRMS (ESI+) calcd for C15H19NO3Na
[M + Na]+ 284.1262, found 284.1259.
5-Ethyl-2-(4-methoxyphenyl)-5-nitro-4-vinyltetrahydro-2H-pyran
(47). According to the procedure described above for compound 36,
(E)-tert-butyl (5-hydroxy-5-(4-methoxyphenyl)pent-2-en-1-yl) carbo-
nate (61.7 mg, 0.2 mmol) was treated with 2-nitrobut-1-ene (40.4 mg,
0.4 mmol), allylpalladium(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3
(15.7 mg, 0.06 mmol), and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol)
in anhydrous THF to give after an analogous workup and purification
the major diastereomer 47a together with the 4-epi,5-epi-isomer b as a
colorless oil with a diastereomeric ratio of 6:1 (combined yield: 11.6 mg,
20%). 47a: 1H NMR (500 MHz, CDCl3) δ = 7.29 (d, J = 8.5 Hz, 2H),
6.91 (d, J = 8.8 Hz, 2H), 5.80 (ddd, J = 7.7, 10.4, 17.3 Hz, 1H), 5.17 (d,
J = 10.4 Hz, 1H), 5.09 (d, J = 17.3 Hz, 1H), 4.54 (dd, J = 2.7, 11.5 Hz,
1H), 4.35 (d, J = 11.5 Hz, 1H), 4.10 (dd, J = 1.4, 11.5 Hz, 1H), 3.82 (s,
3H), 3.11 (ddd, J = 4.7, 7.7, 12.3 Hz, 1H), 2.26 (qd, J = 7.1, 14.6 Hz, 1H),
2.09 (qd, J = 7.1,14.6 Hz, 1H), 2.00 (ddd, J = 3.0, 4.4, 14.0 Hz, 1H), 1.82
(ddd, J = 12.1, 12.1, 14.0 Hz, 1H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ = 159.3, 134.5, 133.0, 127.0, 118.3, 113.9, 91.1,
79.5, 76.7, 69.7, 55.3, 48.6, 36.0, 20.6, 7.74; HRMS (ESI+) calcd for
C32H41N2O8Na [2M + Na]+ 605.2839, found 605.2850.
5-Methyl-5-nitro-2-phenethyl-4-vinyltetrahydro-2H-pyran (42).
According to the procedure described above for compound 36,
(E)-tert-butyl 5-hydroxy-7-phenylhept-2-enyl carbonate (55 mg, 0.2 mmol)
was treated with 2-nitroprop-1-ene (34.8 mg, 0.4 mmol), allylpalladium-
(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3 (15.7 mg, 0.06 mmol),
and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol) in anhydrous THF to
give after an analogous workup and purification the major diastereomer
42a together with the 4-epi,5-epi-isomer (42b) as a colorless oil with a
1
diastereomeric ratio of 7:1 (combined yield: 26.4 mg, 48%). 42a: H
NMR (500 MHz, CDCl3) δ = 7.19−7.32 (m, 5H), 5.63 (ddd, J = 7.4,
10.4, 17.6 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 5.08 (dt, J = 1.1, 17.0 Hz,
1H), 3.92 (d, J = 10.7 Hz, 1H), 3.89 (d, J = 11.0 Hz, 1H), 3.48 (dddd, J =
2.5, 4.1, 8.2, 11.4 Hz, 1H), 3.16 (ddd, J = 4.4, 7.1, 12.4 Hz, 1H), 2.64−
2.83 (m, 2H), 1.73−1.94 (m, 2H), 1.76 (ddd, J = 2.5, 4.4, 13.7 Hz, 1H),
1.62 (s, 3H), 1.58 (ddd, J = 12.1, 12.3, 13.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ = 141.5, 134.7, 128.4, 126.0, 118.4, 89.3, 76.9,
76.8, 74.9, 46.2, 37.2, 33.7, 31.5; HRMS (ESI+) calcd for C16H21NO3Na
[M + Na]+ 298.1418, found 298.1418.
5-Methyl-2-(naphthalen-2-yl)-5-nitro-4-vinyltetrahydro-2H-
pyran (43). According to the procedure described above for compound
36, (E)-tert-butyl 5-hydroxy-5-(naphthalen-2-yl)pent-2-enyl carbonate
(65.6 mg, 0.2 mmol) was treated with 2-nitroprop-1-ene (34.8 mg,
0.4 mmol), allylpalladium(II) chloride dimer (7.3 mg, 0.02 mmol), PPh3
(15.7 mg, 0.06 mmol), and 0.3 mL of LiHMDS (1 M in THF, 0.3 mmol)
in anhydrous THF to give after an analogous workup and purification
the major diastereomer 43a together with the 4-epi,5-epi-isomer (43b)
as a colorless oil with a diastereomeric ratio of 10:1 (combined yield:
39.8 mg, 67%). 43a: 1H NMR (300 MHz, CDCl3) δ = 7.84−7.88 (m,
4H), 7.46−7.52 (m, 3H), 5.70 (ddd, J = 7.3, 10.6, 17.5 Hz, 1H), 5.20 (d,
J = 10.4 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 4.77 (dd, J = 2.6, 11.7 Hz,
1H), 4.19 (d, J = 11.2 Hz, 1H), 4.12 (d, J = 10.8 Hz, 1H), 3.44 (ddd, J =
4.4, 7.1, 12.1 Hz, 1H), 2.15 (ddd, J = 2.7, 4.4, 14.1 Hz, 1H), 1.82 (ddd, J =
12.3, 12.3, 13.9 Hz, 1H), 1.77 (s, 3H); 13C NMR (75 MHz, CHCl3) δ =
138.2, 134.4, 133.2, 133.1, 128.4, 128.0, 127.7, 126.3, 126.1, 124.4, 123.6,
118.7, 89.0, 80.0, 75.2, 46.6, 35.8, 15.6; HRMS (FAB+) calcd for
(C18H19NO3) 297.1365, found 297.1356.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(2S,4R,5R)-5-Methyl-5-nitro-2-(4-nitrophenyl)-4-vinyltetrahydro-
2H-pyran (44). According to the procedure described above for
compound 36, (E)-tert-butyl (5-hydroxy-5-(4-nitrophenyl)pent-2-en-1-yl)
carbonate (64.6 mg, 0.2 mmol) was treated with 2-nitroprop-1-ene
(34.8 mg, 0.4 mmol), allylpalladium(II) chloride dimer (7.3 mg,
0.02 mmol), PPh3 (15.7 mg, 0.06 mmol), and 0.3 mL of LiHMDS (1 M
in THF, 0.3 mmol) in anhydrous THF to give after an analogous workup
and purification the major diastereomer 44a together with the 4-epi,5-
epi-isomer (44b) as a colorless oil with a diastereomeric ratio of 5:1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dirk.menche@uni-bonn.de.
Present Address
†Department of Chemistry, University Basel.
Notes
The authors declare no competing financial interest.
10822
dx.doi.org/10.1021/jo302102x | J. Org. Chem. 2012, 77, 10811−10823

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
Generous financial support from the Deutsche Forschungsge-
meinschaft (SFB 623 “Molekulare Katalysatoren: Struktur und
Funktionsdesign”) is gratefully acknowledged. We thank Prof.
G. Helmchen for helpful discussions and suggestions.
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