Diastereoselective synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones via SmI2-mediated reductive coupling of 2-alkylacrylates of N,N-diisopropyl-2-hydroxybenzamide with aldehydes

Article abstract of DOI:10.1016/j.tet.2015.12.009

Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Ar^am) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Ar^am enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Ar^am and aliphatic aldehydes are provided.

Full text of DOI:10.1016/j.tet.2015.12.009

Tetrahedron 72 (2016) 664e673
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective synthesis of trans-3,5-disubstituted
dihydrofuran-2(3H)-ones via SmI -mediated reductive coupling of
2
2
-alkylacrylates of N,N-diisopropyl-2-hydroxybenzamide with
aldehydes
y
Yecai Lai, Lijie Sun , Man Ki Sit, Yan Wang, Wei-Min Dai *
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong Special Administrative Region
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2015
Received in revised form 27 November 2015
Accepted 2 December 2015
Available online 11 December 2015
Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety
of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-
ones (g-butyrolactones). Two major issues, concerning with self-dimerization of a-non-branched ali-
phatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive
coupling protocol in total synthesis of natural products. We report here on a novel type of substituted
am
acrylates derived from the 2-amido arenols (HO-Ar ) such as N,N-diisopropyl-2-hydroxybenzamide.
Keywords:
Acrylate
Aldehyde
Dihydrofuran-2(3H)-one
am
The acrylates of HO-Ar
enable: (a) preferential conjugate reduction of the acrylates than carbonyl
reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization
of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-
bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate
intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-
2-Hydroxybenzamide
Reductive coupling
Samarium diiodide
am
alkylacrylates of HO-Ar and aliphatic aldehydes are provided.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1). However, the diastereoselectivity of the products
varies from 70:30 to 95:5 in terms of the structures of both ac-
4
Samarium(II) diiodide (SmI
used as an efficient reductant in facilitating various organic
transformations.1 One major utility of the SmI
-mediated re-
actions is the reductive couplings for carbonecarbon bond for-
mation. Although the intramolecular reductive couplings
2
, Kagan’s reagent) has been widely
rylates and aldehydes. In 1997, Fukuzawa and co-workers re-
ported the first enantioselective reductive coupling reaction of
the N-methylephedrine-derived chiral crotonate 5a with aliphatic
aldehydes to produce chiral dihydrofuran-2(3H)-ones 6 in both
high cis:trans ratios and high enantioselectivity (93e97% ee)
(Scheme 2). However, the product yields as estimated by GC
2
2
mediated by SmI have enjoyed applications in total synthesis of
natural products,1
e,g,k
the intermolecular reductive cross-coupling
analysis are moderate (57e74%). Procter and co-workers dis-
5
of carbonyl compounds with conjugate alkenes using SmI
2
re-
closed the Wang resin-bound chiral crotonate 5b and the
fluorous-tagged chiral crotonate 5c for the reductive coupling
reactions with aliphatic aldehydes, obtaining the products 6 in
both high cis:trans ratios and high enantioselectivities (88e99%
ee) albeit in low to moderate isolated yields (43e82%). In our
mains challenging.1m In 1986, Fukuzawa and Inanaga in-
2
3
dependently reported the cross-coupling reactions of substituted
acrylates 1 and 3 with aldehydes in the presence of SmI
alcohol (as the proton source) to afford substituted dihydrofuran-
(3H)-ones ( -butyrolactones) 2a,b and 4a,b in 70e75% yields
2
and an
7
a
2
g
previous work, we developed a novel class of chiral crotonate
5
d, which was derived from the atropisomeric 2-hydroxy-8-
7
b
methoxy-1-naphthamide.
2
The SmI -mediated reductive cou-
pling of 5d with aliphatic aldehydes gave the chiral products 6 in
good cis:trans ratios (72:28e91:9) and high enantioselectivities
(97e99%). Moreover, the isolated product yields of 81e90% are
much higher than those obtained with the crotonates 5aec.
*
Corresponding author. Tel.: þ86 852 23587365; fax: þ86 852 23581594; e-mail
address: chdai@ust.hk (W.-M. Dai).
y
Current address: Shijiazhuang No. 4 Pharmaceutical Co., Ltd., 88 Xingye Street,
Shijiazhuang Economic & Technological Development Zone, Shijiazhuang, Hebei
52165, China.
0
http://dx.doi.org/10.1016/j.tet.2015.12.009
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
0

Y. Lai et al. / Tetrahedron 72 (2016) 664e673
665
2
Scheme 1. SmI -mediated reductive coupling of the substituted acrylates 1 and 3 with
aldehydes reported by Fukuzawa [a; Ref. 2] and Inanaga [b; Ref. 3].
Scheme 3. Reductive coupling of 7 with aldehydes reported by Dai.
results of the highly diastereoselective synthesis of trans-3,5-
disubstituted dihydrofuran-2(3H)-ones.
2. Results and discussion
In our previous work, as mentioned in Scheme 2, the reactions
of the chiral 1-amido-2-naphthol-derived crotonate 5d with ali-
phatic aldehydes afforded higher product yields. We attributed
the results to the electron-withdrawing nature of the 1-amido-2-
9
naphthol moiety, which might favor for conjugate reduction of
the crotonate over carbonyl reduction of the aldehyde. Conse-
quently, the undesired self-dimerization of the aldehyde partner
via the ketyl radical could be minimized. Therefore, we envi-
sioned that the crotonate 11 derived from a simpler 2-amido
arenol, i.e., N,N-diisopropyl-2-hydroxybenzamide (10) should be
a useful substrate for the synthesis of racemic cis-5-alkyl-4-
methyldihydrofuran-2(3H)-ones rac-2a,cee (Scheme 4). Starting
from salicylic acid (9), the 2-amido phenol 10 was prepared in
8
5% overall yield by treating 9 in refluxing SOCl
2
and subsequent
2
NH in PhMe at
amidation of the resultant acyl chloride with i-Pr
8
Et
crotonate 11 in 86% yield. Three aliphatic
hydes, n-hexanal, TBDPSOCH CH CHO, and PMBOCH
ꢀ
0
C. Reaction of 10 with crotonoyl chloride in the presence of
ꢀ
Scheme 2. Reductive coupling of the chiral crotonates 5 with aldehydes reported by
Fukuzawa [a; Ref. 4], Procter [b; Refs. 5 and 6], and Dai [c; Ref. 7].
N and catalytic DMAP in PhMe at 70 C for 12 h furnished the
-non-branched alde-
CH CHO,
3
a
2
2
2
2
Low product yields are the drawback for accessing the chiral
cis-4,5-disubstituted dihydrofuran-2(3H)-ones 6 from the N-
methylephedrine-derived chiral crotonate 5a and it hampered
general applications of this highly enantioselective reaction. In
our effort in synthesis of the 2,3,5-trisubstituted tetrahydrofuran
fragment8 of amphidinolide T family of congeners, the chiral
compound 8c was prepared from the reductive coupling of the N-
methylephedrine-derived chiral crotonate 7 with the corre-
were subjected to the SmI -mediated reductive coupling with 11
to afford the products rac-2a, rac-2c, and rac-2d in 85%, 74%, and
2
75% yields, respectively, and in diastereomeric ratios of
87:13e95:5. For comparison purpose, we repeated the reductive
coupling of ethyl crotonate (1, X¼OEt) with n-hexanal (Scheme
2
8
1). Under our conditions, the product rac-2a was isolated in
41% yield and in a cis:trans ratio of 84:16 along with the dimer
byproducts 12a (34%; dr¼81:19) (Scheme 4). These results are
different from those as originally reported by Fukuzawa in
sponding
a-non-branched aldehyde in 46% isolated yield on
2
a 3 mmol scale under the optimized conditions (Scheme 3).
Similarly, the reaction of 7 with n-octanal furnished the product
Scheme 1. Also, the product yields of rac-2a,c,d obtained from 11
are much better than the yields for the chiral compounds 6 and
8aec synthesized from the chiral crotonates 5aec and 7 derived
from N-methylephedrine and the related 1,2-amino alcohol or
8
a in 45% isolated yield. When cyclohexanecarboxaldehyde was
used, the product 8b was formed in a slightly higher yield (56%).
We found that the main byproduct in the reductive coupling re-
4
e6,8
1,2-diol (Schemes 2 and 3).
Therefore, it can be concluded
-non-branched
action of
dimers of the aldehyde. The undesired dimerization pathway
might be suppressed for the ketyl radical generated from
branched aliphatic aldehydes. In order to address both issues of
low product yield and low stereoselectivity associated with SmI
a
-non-branched aliphatic aldehydes with 7 was the
that the undesired dimerization of the aliphatic a
aldehydes in the SmI -mediated reductive coupling reactions
2
a
-
could be minimized or suppressed by using the crotonate 11
derived from the 2-amido arenol 10 via preferential
conjugate reduction of the crotonate 11. Another piece of evi-
dence was obtained from the reductive coupling of cyclo-
2
-
mediated reductive coupling of substituted acrylates with ali-
phatic aldehydes, we have introduced a novel class of substituted
propanecarboxaldehyde with 11. The expected product, cis-5-
am
6
acrylates derived from the 2-amido arenols (HO-Ar ) such as
cyclopropyl-4-methyldihydrofuran-2(3H)-one
(rac-2e),
was
N,N-diisopropyl-2-hydroxybenzamide. We report here on the
formed in 80% isolated yield as a 90:10 mixture of cis and trans

666
Y. Lai et al. / Tetrahedron 72 (2016) 664e673
Scheme 4. Reductive coupling of the crotonates with aldehydes.
isomers (Scheme 4). Therefore, the preferential conjugate re-
duction of the crotonate 11 has been confirmed.
Mikami and Yamaoka1 reported reductive coupling of methyl
0
methacrylate (3, X¼OMe) with methyl aryl ketones in the presence
ꢀ
of 2 equiv each of SmI
2
, (R)-BINAPO, and t-BuOH in THF at ꢁ78 C to
Scheme 5. Preparation of 2-alkylacrylates 13aec of the 2-amido phenol 10.
form the chiral 4,5,5-trisubstituted dihydrofuran-2(3H)-ones in
2e46% yields and in cis:trans ratios of 51:49e66:34 with 77e89%
4
11
ee for the major isomers. Lin and co-workers carried out exten-
sive studies on the reactions of chiral and achiral methacrylates
with ketones in the presence of a chiral proton source. High product
yields and high enantioselectivities were obtained for some cases
but the cis:trans ratios are generally low for the reactions of un-
symmetrical ketone substrates. In contrast to ketones, reductive
Reductive coupling reactions of 2-alkylacrylates 13aec were
examined with four representative aliphatic aldehydes and the
results are summarized in Table 1. For comparison purpose, we first
carried out the reaction of methyl methacrylate (3, X¼OMe) with
the non-enolizable trimethylacetaldehyde and the product rac-20a
was formed in 80% yield but in a non-diastereoselective fashion
(entry 1, Table 1). In a sharp contrast, the same aldehyde underwent
the reductive coupling reactions with the 2-alkylacrylates 13aec to
give the products rac-20aec in both high chemical yields and high
trans:cis ratios (entries 2e4, Table 1). Similar results were obtained
for the reactions of cyclohexanecarboxaldehyde with 13aec (en-
2
coupling of 2-alkylacrylates with aldehydes mediated by SmI has
not been well explored except for few cases using methacrylates 3
,3
(
Scheme 1).2
We decided to investigate the diastereoselectivity of the re-
ductive coupling reactions of 2-alkylacrylates of 10 with alde-
hydes. Three 2-alkylacrylates 13aec were prepared as depicted in
Scheme 5. The methacrylate 13a was obtained in 86% yield by the
0
tries 5e7, Table 1) except for that a minor aldol byproduct rac-20e
was obtained in 6% yield (entry 6, Table 1). As mentioned in Scheme
1, Inanaga and co-workers reported a diastereomeric ratio of 86:14
reaction of the 2-amido phenol 10 with methacryloyl chloride in
ꢀ
the presence of Et
3
N and catalytic DMAP in CH
2
Cl
2
at 0 C to
12
room temperature. The known 2-ethylacrylic acid (15), pre-
pared from ethylmalonic acid (14) under the Mannich reaction
conditions, was subjected to the esterification with 10 using
EDCIeDMAP in PhMe at 80 C for 9 h to form the 2-ethylacrylate
3b in 96% yield. Benzylmalonic acid (18) was prepared from
for the product rac-4b (70% yield) formed from the a-non-branched
3
aldehyde, PhCH CH CHO, and methyl methacrylate (3, X¼OMe).
2
2
We repeated the same reaction under our conditions and ob-
tained a much lower yield of rac-4b (27%) and a lower dr value of
74:26 (entry 8, Table 1). It should be emphasized that the dimers
ꢀ
1
diethyl malonate (16) via benzylation of 16 and subsequent sa-
ponification of diethyl benzylmalonate (17) in excellent overall
yield. The Mannich reaction of 18 in the presence of para-
12b (dr¼74:26) of the
30% combined yield, echoing with the same phenomenon observed
for the reductive coupling of the crotonate 1 with -non-branched
aldehydes (Scheme 4). By using the 2-amido arenol-derived
methacrylate 13a, the product rac-4b was produced in low iso-
lated yields of 30e37% in two parallel runs but with an excellent
trans:cis ratio of 96:4 (entry 9, Table 1). Although the diol
a-non-branched aldehyde were isolated in
a
formaldehyde and Et
2
NH in refluxing EtOAc gave benzylacrylic
acid (19) in 90% yield. Esterification of 19 with 10 under the same
EDCIeDMAP conditions afforded 2-benzylacrylate 13c in 95%
yield.

Y. Lai et al. / Tetrahedron 72 (2016) 664e673
667
Table 1
from the original 98:2 to 84:16, indicating that partial epimeriza-
tion occurred under the silylation conditions. Nevertheless, it is
pleased to find the excellent trans:cis ratio of 98:2 for rac-20g and
2
Results of SmI -mediated reductive coupling of 13aec with aldehydes
0
a single diastereomer for rac-20g . Therefore, the lack of the dimer
byproducts in the reaction of 13a suggests it is a superior substrate
2
favored for conjugate reduction by SmI as compared to the simple
1
m,7,9
methacrylates 3.
In order to confirm the assigned stereochemistry for the trans-
,5-disubstituted dihydrofuran-2(3H)-ones rac-20, an alternative
3
synthesis of trans isomer rac-20a was carried out (Scheme 7). The
SmI -mediated reductive coupling of methyl acrylate (21) with
trimethylacetaldehyde gave the dihydrofuran-2(3H)-one rac-22 in
0% isolated yield. Methylation of rac-22 afforded the trans product
2
5
13
rac-20a in 80% yield and in almost a single diastereoisomer.
Treatment of rac-20a with LDA and protonation of the resultant
enolate with 2,6-di-tert-butylphenol (23), as a bulky proton source,
Entry
2-Alkylacrylate
R2
Yield (%)a
trans:cisb
1
2
3
4
5
6
7
8
9
3 (X¼OMe)
t-Bu
t-Bu
t-Bu
t-Bu
c-C
c-C
c-C
PhCH
PhCH
5 11
n-C H
rac-20a: 80
rac-20a: 95
rac-20b: 82
rac-20c: 86
rac-20d: 80
rac-20e: 87c
rac-20f: 99
50:50
98:2
95:5
90:10
97:3
95:5
92:8
74:26
96:4
98:2
ꢀ
at ꢁ78 C to furnish the cis isomer rac-24 in 80% yield and in a dr
1
13a: R ¼Me
1
value of >98:2. Therefore, the assigned trans stereochemistry of
13b: R ¼Et
1
1
13c: R ¼Bn
rac-20a was confirmed unambiguously by comparison of its H and
1
13
13a: R ¼Me
6
6
6
H
H
H
11
11
11
C NMR spectral data with those of the authentic sample. In
1
13b: R ¼Et
a similar manner, treatment of rac-4b of trans:cis ratio of 96:4 with
LDA followed by protonation with 23 afforded the cis isomer rac-25
in 86% yield as a 15:85 mixture in favor of the cis-isomer.
1
13c: R ¼Bn
d
3 (X¼OMe)
2
CH
CH
2
2
rac-4b: 27
1
e
13a: R ¼Me
2
rac-4b: 30e37
1
rac-20g: 40f
10
13a: R ¼Me
a
b
c
Isolated yields based on amount of the aldehyde used.
Estimated by 1H NMR spectroscopic analysis of the crude product.
0
The aldol product rac-20e was isolated in 6% yield.
d
e
A 74:26 mixture of the dimers 12b was isolated in 30% yield.
A nearly equal amount of an aldol byproduct was found in the 1H NMR spectra of
the crude product. The aldol byproduct is inseparable from the regenerated 10.
f
0
The aldol byproduct rac-20g was isolated, after converting into its TES ether rac-
00
0g , in 30% yield as a single diastereomer.
2
byproducts 12b were not detected in the reaction of 13a with
PhCH CH CHO by TLC analysis of the reaction mixture an aldol
2
2
1
byproduct was found in the H NMR spectra of the crude product in
an analogous manner to the reaction given in the entry 10 of Table
1. Due to the fact that the aldol byproduct is not separable from the
regenerated 10, the structure of the assumed aldol byproduct has
not been fully confirmed.
The unsatisfactory results with hydrocinnamaldehyde promp-
ted us to conduct the reaction of 13a with another simple linear
aliphatic aldehyde (entry 10, Table 1). Under the same reductive
coupling conditions, the expected trans-3,5-disubstituted dihy-
Scheme 7. Alternative synthesis of rac-20a, rac-24 and rac-25.
drofuran-2(3H)-one rac-20g was formed from 13a and n-hexanal in
0
4
0% yield along with an aldol byproduct rac-20g in 30% yield as
We propose mechanisms for the SmI -mediated reductive
coupling of 2-alkylacrylates 13 with aldehydes as illustrated in
2
1
estimated by H NMR analysis. Because the compounds rac-20g
and rac-20g are inseparable the mixture was then treated with
(0 C to room temperature, 1 h) to
convert rac-20g into the corresponding TES ether rac-20g (90%
yield) for column chromatographic separation over silica gel
Scheme 6). We found that the trans:cis ratio for rac-20g changed
0
Scheme 8. Reduction of an aldehyde (via carbonyl reduction) and
the 2-alkylacrylate 13 (via conjugate reduction) should form the
ketyl radical 30 and the radical enolate 26, respectively. In view of
the primary radical nature of the radical enolate, carbonyl re-
duction of an aldehyde might compete with conjugate reduction as
in the case of the simple alkyl methacrylates 3. Dimerization of the
ꢀ
TESOTf-2,6-lutidine in CH
2
Cl
2
0
00
(
ketyl radical 30 could become a significant side reaction for a-non-
branched aldehydes (entry 8, Table 1). Addition of the radical
enolate 26 with an aldehyde is considered to involve a 7/8-bicyclic
transition state 27, after picking up an electron from SmI
2
, leading
to the -alkoxide-bound Sm(III) enolate 28 where the amide car-
g
bonyl oxygen atom is also coordinated to Sm(III) to form another
eight-membered ring. Alternatively, the same Sm(III) enolate 28
could be formed from 1,4-addition of the ketyl radical 30 with 13
via a similar 7/8-bicyclic transition state 27. Since the amide moiety
1
blocks the Re-face of the enolate 28 (assuming R has the least
priority), its protonation should be favored from the Si-face,
1
2
resulting in the anti-relationship for R and R in 29. Finally, lac-
tonization of 29 with cleavage of the 2-hydroxybenzamide 10
0
Scheme 6. Silylation of the mixture of 20g and 20g for separation.

668
Y. Lai et al. / Tetrahedron 72 (2016) 664e673
Table 2
Effect of proton source on SmI2-mediated reductive coupling of 13a
rac-20g (%)a,b
rac-20g (%)
0
a,c
Ratiod
Entry
Protone source
1e
2
3
4
5
t-BuOH
t-BuOH
i-PrOH
23
40
52
48
50
52
30
27
24
9
57:43
66:34
67:33
85:15
88:12
f
MeSO
2
NH
2
7
a
Yields calculated based on the 1H NMR spectrum of the isolated product
mixture.
b
c
d
e
f
The trans:cis ratio is 98:2 in all entries.
A single diastereomer was observed in the 1H NMR spectrum.
0
The ratio of rac-20g to rac-20g .
Data taken from the entry 10 of Table 1.
Freshly distilled.
It should be mentioned that the synthesized trans and cis
compounds rac-20a and rac-24 are the useful starting materials for
construction of the building blocks for naturally occurring
1
4,15
enamide-containing macrolides, (ꢁ)-palmyrolide A (30),
lain-
and madangolide (33) (Fig. 1).
16
17,18
17
golide (31), laingolide A (32),
We have completed diverted total synthesis of palmyrolide A and
laingolide A, and their stereoisomers via multimodule assembly
strategy based on the key structural modules derived from rac-20a
19
and rac-24 and the results will be disclosed elsewhere.
Scheme 8. Proposed mechanisms for the reactions of 13 with aldehydes.
affords the trans end product rac-20 in high diastereoselectivity.
Therefore, it can be concluded that high diastereoselectivity in the
SmI -mediated reductive coupling reactions of aliphatic aldehydes
2
could be achieved by using 2-alkylacrylates 13 derived from the 2-
amido arenol 10 via chelation of the amide carbonyl oxygen atom
within the Sm(III) enolate intermediate. As a minor reaction path-
way, the Sm(III) enolate 28 was found to undergo an aldol reaction
0
with linear aliphatic aldehydes to form 20 as a single diastereomer.
0
The stereochemistry of 20 is tentatively proposed according to the
stereochemical result of the protonation of 28.
0
0
Formation of the aldol byproducts such as 20e and 20g has not
been reported in the literature. We considered that the co-
ordination of the amido moiety in the Sm(III) enolate 28 as given in
Scheme 8 enhanced its stability and then the aldol side reaction
could compete with the protonation pathway. We envisioned that
the proton source should have an effect on the product distribution
and the reaction of 13a with n-hexanal in the presence of different
proton sources was performed and the results are summarized in
Table 2. Freshly distilled t-BuOH or replacement of t-BuOH by i-
PrOH has no significant effect on the product ratio (entries 1e3,
Table 2). However, use of much more acidic proton donors such as
Fig. 1. Structures of the macrolides possessing a 1,3-Me/t-Bu subunit.
3. Conclusion
In summary, we have developed a practically useful protocol for
SmI -mediated reductive coupling reactions of aliphatic aldehydes
2
2
2 2
,6-di-tert-butylphenol (23) and MeSO NH could suppress for-
with substituted acrylates derived from the 2-amido arenols (HO-
0
mation of the aldol byproduct rac-20g (entries 4 and 5, Table 2).
With a higher product ratio in the reaction of entry 5 of Table 2, it
became possible to isolate a pure sample of the product rac-20g
with a 98:2 ratio for the trans and cis isomers.
am
Ar ) such as the crotonate 11 and the 2-alkylacrylates 13aec.
These novel
a,b-unsaturated esters undergo preferential conjugate
reduction than aldehyde carbonyl reduction so that the

Y. Lai et al. / Tetrahedron 72 (2016) 664e673
669
dimerization of
a
-non-branched aldehydes could be suppressed,
chloride (0.19 mL, 2.0 mmol). The resultant mixture was heated at
70 C for 12 h and the reaction mixture was then quenched with
aqueous HCl (1.0 M, 2 mL). The reaction mixture was extracted with
ꢀ
leading to high yields for the desired dihydrofuran-2(3H)-ones.
Moreover, coordination of the amide group within the Sm(III)
enolate 28 forms the 7/8-bicyclic architecture, which enables high
diastereoselective protonation to furnish trans-3,5-disubstituted
dihydrofuran-2(3H)-ones in diastereoselectivity ranging from
EtOAc (10 mLꢂ3). The combined organic layer was washed with
2 4
brine, dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography over silica gel (16.7% EtOAc in hexane) to give 11
9
0:10 to 98:2 regardless the structures of the aliphatic aldehydes. It
is found that an aldol reaction of the Sm(III) enolate 28 competes
with protonation in the reactions of -non-branched aldehydes.
(225.0 mg, 86%) as a colorless oil. R
IR (film): 2969, 1737, 1635, 1440, 1341, 1207, 1154 cm
(400 MHz, CDCl
7.40e7.10 (m, 5H), 5.98 (d, J¼15.2 Hz, 1H),
3.74e3.69 (m, 1H), 3.40e3.41 (m, 1H), 1.91 (d, J¼6.4 Hz, 3H), 1.52 (d,
f
¼0.20 (16.7% EtOAc in hexane);
ꢁ
1 1
a
; H NMR
Future effort would be directed to searching for conditions favor-
able for protonation of the Sm(III) enolate 28. Therefore, the desired
dihydrofuran-2(3H)-ones could be prepared in high yields even in
3
) d
13
J¼6.4 Hz, 3H), 1.44 (d, J¼6.4 Hz, 3H), 1.05 (d, J¼5.6 Hz, 6H); C NMR
(100 MHz, CDCl 167.0, 164.3, 147.7, 146.5, 131.8, 129.3, 126.4,
the case of
a
-non-branched aldehydes.
3
) d
1
25.9,123.1,121.6, 50.9, 45.8, 20.9, 20.6, 20.5, 20.4,18.3; HRMS (þCI)
þ
4
4
. Experimental
calcd for C17
H24NO
3
290.1756 (MþH ), found 290.1761.
.1. General methods
1H and 13C NMR spectra were recorded in CDCl
or DMSO-d
6
3
4
.4. 2-(N,N-Diisopropylcarbamoyl)phenyl methacrylate (13a)
1
13
(
400 MHz for H and 100 MHz for C, respectively). Residual sol-
vent peaks are used as the internal reference; the signals at 7.26 and
To a solution of 10 (2.72 g, 12.3 mmol), DMAP (151.0 mg,
1
13
7
7.16 ppm are set for H and C NMR spectra, respectively, taken in
1.23 mmol), and Et
3
N (3.45 mL, 24.6 mmol) in dry CH
2
Cl
2
(123 mL)
1
13
CDCl
3
while the signals at 2.50 and 40.45 ppm are set for H and
. IR spectra were taken
on an FT-IR spectrophotometer. High resolution mass spectra
C
ꢀ
cooled in an iceewater bath (0 C) was added dropwise meth-
acryloyl chloride (2.53 mL, 24.6 mmol). The resultant reaction
mixture was stirred at 0 C for 1 h, and then at room temperature
for another 5 h. The reaction was quenched with aqueous HCl
NMR spectra, respectively, taken in DMSO-d
6
ꢀ
(
HRMS) were measured by TOF MS under the þCI or eCI conditions.
Silica gel plates pre-coated on glass were used for thin-layer
chromatography using UV light, or 7% ethanolic phosphomolyb-
dic acid and heating as the visualizing methods. Silica gel was used
for flash column chromatography. Yields refer to chromatographi-
(
(
1.0 M, 3 mL) and the reaction mixture was extracted with CH
100 mLꢂ3). The combined organic layer was washed with brine,
SO , filtered, and concentrated under
2 2
Cl
dried over anhydrous Na
2
4
reduced pressure. The residue was purified by flash column chro-
matography (silica gel, 16.7% EtOAc in hexane) to give 13a (3.38 g,
1
cally and spectroscopically ( H NMR) homogeneous materials. Re-
agents were obtained commercially and used as received unless
otherwise mentioned.
9
2
5%) as a colorless oil. R
969, 1738, 1636, 1439, 1340, 1207, 1131 cm ; H NMR (400 MHz,
7.35e7.30 (m, 1H), 7.21e7.15 (m, 3H), 6.31 (s, 1H),
.72e5.68 (m, 1H), 3.70 (septet, J¼6.8 Hz, 1H), 3.42 (septet,
J¼6.8 Hz, 1H), 1.99 (s, 3H), 1.49 (d, J¼6.8 Hz, 3H), 1.42 (d, J¼6.8 Hz,
f
¼0.33 (16.7% EtOAc in hexane); IR (film):
ꢁ
1 1
3
CDCl ) d
5
4
.2. N,N-Diisopropyl 2-hydroxybenzamide (10)
To the solid salicylic acid (9, 2.00 g, 14.48 mmol) in a dry round
bottom flask, the freshly distilled SOCl (23.0 mL, 317 mmol) was
2
13
3
H), 1.03 (d, J¼6.8 Hz, 3H), 1.02 (d, J¼6.8 Hz, 3H); C NMR
(100 MHz, CDCl 166.8, 165.4, 146.6, 135.4, 131.7, 129.2, 127.7,
3
) d
added dropwise. The resultant mixture was heated under refluxing
126.3, 125.8, 123.1, 50.8, 45.8, 20.8, 20.4, 20.4, 20.4, 18.2; HRMS
ꢀ
at 80 C for 4 h and then the excess SOCl
2
was removed through
þ
(þCI) calcd for C17
H24NO
3
290.1756 (MþH ), found 290.1753.
distillation under reduced pressure to give the corresponding acyl
chloride, which was used for the next step without further
purification.
To
2
a solution of freshly distilled (i-Pr) NH (10.15 mL,
7
2.40 mmol) in dry PhMe (145 mL) cooled in an iceewater bath
4.5. 2-(N,N-Diisopropylcarbamoyl)phenyl 2-
methylenebutanoate (13b)
ꢀ
(
0 C) was added dropwise the acyl chloride prepared above. After
ꢀ
heating at 80 C for 10 h, the reaction was quenched with aqueous
HCl (1.0 M, 5 mL) and the reaction mixture was extracted with
CH
A solution of 10 (300.0 mg, 1.36 mmol), 2-methylenebutanoic
(50 mLꢂ3). The combined organic layer was dried over
acid1 (15, 272.0 mg, 2.72 mmol), DMAP (16.6 mg, 0.14 mmol),
2
2
Cl
2
0
anhydrous Na
2
SO , filtered, and concentrated under reduced
4
and
N-ethyl-N -(3-dimethylaminopropyl)carbodiimide
(EDCI,
ꢀ
pressure. The residue was purified by flash column chromatogra-
782.0 mg, 4.08 mmol) in dry PhMe (14 mL) was heated at 80
C
phy (silica gel, 9.1% EtOAc in hexane) to give 10 (2.72 g, 85% for 2
with stirring for 9 h. The reaction was quenched by water and the
reaction mixture was extracted with EtOAc (10 mLꢂ3). The com-
bined organic layer was washed with brine, dried over anhydrous
Na SO , filtered, and concentrated under reduced pressure. The
2 4
residue was purified by flash column chromatography (silica gel,
16.7% EtOAc in hexane) to give 13b (396.0 mg, 96%) as a colorless
ꢀ
steps) as a white solid. Mp 154e155 C (CH
2
Cl
2
ehexane); R
f
¼0.30
(
16.7% EtOAc in hexane); IR (film): 3153 (br), 2970, 1591, 1447,
ꢁ
1 1
1
350 cm ; H NMR (400 MHz, CDCl
J¼8.2, 7.6, 1.6 Hz, 1H), 7.12 (dd, J¼7.6, 1.2 Hz, 1H), 6.90 (d, J¼8.4 Hz,
H), 6.79 (dd, J¼8.0, 7.6 Hz, 1H), 3.86 (br s, 2H), 1.35 (d, J¼6.8 Hz,
2H); 13C NMR (100 MHz, CDCl
171.0, 157.0, 131.2, 126.7, 121.5,
3
)
d
9.20 (br s, 1H), 7.21 (ddd,
1
1
3
)
d
oil. R
1439, 1340, 1207, 1132 cm ; H NMR (400 MHz, CDCl
(m, 1H), 7.22e7.18 (m, 3H), 6.37 (d, J¼0.4 Hz, 1H), 5.70 (d, J¼1.2 Hz,
H), 3.73 (septet, J¼6.8 Hz, 1H), 3.43 (septet, J¼6.8 Hz, 1H), 2.39 (q,
J¼7.2 Hz, 2H), 1.51 (d, J¼6.8 Hz, 3H), 1.43 (d, J¼6.8 Hz, 3H), 1.11 (t,
f
¼0.28 (16.7% EtOAc in hexane); IR (film): 2969, 1736, 1636,
ꢁ1 1
1
C
18.7, 117.7, 48.8 (br, ꢂ2), 20.9 (ꢂ4); HRMS (þCI) calcd for
3
) d 7.38e7.32
þ
13
H
20NO
2
222.1494 (MþH ), found 222.1494.
1
4
.3. (E)-2-(N,N-Diisopropylcarbamoyl)phenyl but-2-enoate (11)
13
J¼7.2 Hz, 3H), 1.06 (d, J¼6.8 Hz, 3H), 1.03 (d, J¼6.8 Hz, 3H); C NMR
To a solution of 10 (200.0 mg, 0.99 mmol), DMAP (12.0 mg,
(100 MHz, CDCl 166.9, 165.4, 146.8, 141.4, 131.9, 129.3, 126.4,
3
) d
0
.1 mmol), and Et
3
N (0.28 mL, 2.0 mmol) in dry PhMe (10 mL)
126.0,125.9,123.2, 50.9, 45.9, 24.8, 20.9, 20.5 (ꢂ2), 20.5,12.7; HRMS
ꢀ
þ
cooled in an iceewater bath (0 C) was added dropwise crotonoyl
(þCI) calcd for C18
H26NO
3
304.1913 (MþH ), found 304.1917.

670
Y. Lai et al. / Tetrahedron 72 (2016) 664e673
4
.6. 2-(N,N-Diisopropylcarbamoyl)phenyl 2-methylene-3-
2
dropwise Et NH (2.77 mL, 26.8 mmol) followed by addition of solid
phenylpropionate (13c)
paraformaldehyde (1.07 g, 35.8 mmol). The resultant mixture was
stirred under refluxing for 3 h. The reaction was quenched with
water and the reaction mixture was adjusted to ca. pH 1 with concn.
aqueous HCl. The resultant mixture was extracted with EtOAc
(200 mLꢂ3) and the combined organic layer was washed with
A
solution of 10 (1.00 g, 4.52 mmol), 2-methylene-3-
phenylpropionic acid (19, 1.47 g, 9.04 mmol), DMAP (55.0 mg,
0
.45 mmol), and EDCI (2.60 g, 13.5 mmol) in dry PhMe (45 mL) was
ꢀ
heated at 80 C with stirring for 9 h and quenched with water. The
reaction was quenched by water and the reaction mixture was
extracted with EtOAc (50 mLꢂ3). The combined organic layer was
2 4
brine, dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 50% EtOAc in hexane) to give 19 (2.63 g,
1
washed with brine, dried over anhydrous Na
2
SO
4
, filtered, and
90%) as a yellow oil. R
(400 MHz, CDCl
f
¼0.62 (50% EtOAc in hexane); H NMR
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 16.7% EtOAc in hexane) to
3
)
d
12.17 (br s,1H), 7.44e7.39 (m, 2H), 7.35e7.31 (m,
13
3H), 6.51 (d, J¼0.8 Hz, 1H), 5.68 (d, J¼1.6 Hz, 1H), 3.75 (s, 2H);
C
give 13c (1.57 g, 95%) as a colorless oil. R
ane); IR (film): 2969,1737,1635,1439,1341,1206,1100 cm ; H NMR
400 MHz, CDCl
f
¼0.40 (25% EtOAc in hex-
NMR (100 MHz, CDCl
3
)
d
172.9, 139.7, 138.5, 129.1 (ꢂ2), 128.8, 128.6
ꢁ
1
1
þ
(ꢂ2), 126.5, 37.6; HRMS (þCI) calcd for C10
H
10
O
2
162.0681 (M ),
(
3
)
d
7.36e7.20 (m, 8H), 7.14 (d, J¼8.0 Hz, 1H), 6.49 (s,
H), 5.64 (d, J¼0.8 Hz,1H), 3.76e3.66 (m, 3H), 3.44 (septet, J¼6.8 Hz,
H), 1.53 (d, J¼6.8 Hz, 3H), 1.44 (d, J¼6.8 Hz, 3H), 1.06 (d, J¼6.8 Hz,
found 162.0683.
1
1
3
1
1
2
4.9. General procedure for SmI -mediated reductive coupling
13
H), 0.95 (d, J¼6.4 Hz, 3H); C NMR (100 MHz, CDCl
3
) d 166.9,165.0,
of crotonates/acrylates with aldehydes
46.7, 139.5, 138.3, 131.7, 129.4, 129.3 (ꢂ2), 128.6 (ꢂ2), 128.5, 126.5,
26.4, 125.9, 123.2, 50.9, 45.9, 38.1, 20.9, 20.5, 20.4, 20.34; HRMS
To a solution of SmI
2
in dry THF (0.1 M in THF, 110 mL,11.0 mmol,
þ
ꢀ
(þCI) calcd for C23H28NO
3
366.2069 (MþH ), found 366.2073.
3 equiv) cooled at ꢁ20 C under an argon atmosphere was added
a solution of the methacrylate 13a (1.27 g, 4.38 mmol, 1.2 equiv), t-
BuOH (0.42 mL, 4.38 mmol, 1.2 equiv), and trimethylacetaldehyde
4
.7. 2-Methylenebutanoic acid (15)12
(
0.40 mL, 3.65 mmol, 1 equiv) in THF (10 mL, degassed by argon).
ꢀ
To a solution of 2-ethylmalonic acid (14, 1.50 g, 11.35 mmol) in
The mixture was stirred at ꢁ20 and ꢁ15 C for 4 h and quenched
with aqueous HCl (1.0 M, 10 mL). The reaction mixture was con-
densed under reduced pressure by removing THF and then
extracted with EtOAc (30 mLꢂ3). The combined organic layer was
ꢀ
EtOAc (114 mL) cooled in an iceewater bath (0 C) was added
2
dropwise Et NH (1.76 mL, 17.01 mmol) followed by addition of solid
paraformaldehyde (682.0 mg, 22.70 mmol). The resultant mixture
was stirred under refluxing for 4 h. The reaction was quenched with
water and the reaction mixture was adjusted to ca. pH 1 with concn.
aqueous HCl. The resultant mixture was extracted with EtOAc
2 4
washed with brine, dried over anhydrous Na SO , filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 6.3% EtOAc in hexane) to
give 20a (541.7 mg, 95%; entry 2, Table 1).
(
100 mLꢂ3) and the combined organic layer was washed with
brine, dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by flash column
2
4
4.9.1. cis-4-Methyl-5-pentyldihydrofuran-2(3H)-one (rac-2a) and
dodecane-6,7-diol (12a). Prepared from ethyl crotonate (1) and
hexanal in 41% yield as an 84:16 mixture of cis and trans isomers.
The dimer 12a of the aldehyde was also isolated in 34% yield as an
81:19 mixture of two diastereomers. Compound rac-2a: a pale-
1
2
chromatography (silica gel, 50% EtOAc in hexane) to give 15
(
1.08 g, 95%) as a yellow oil. R
f
¼0.60 (25% EtOAc in hexane); 1H
NMR (400 MHz, CDCl ) d 11.98 (br s, 1H), 6.25 (s, 1H), 5.61 (d,
3
1
3
J¼2.0 Hz, 1H), 2.29 (qd, J¼7.6, 0.8 Hz, 2H), 1.06 (t, J¼7.6 Hz, 3H);
C
NMR (100 MHz, CDCl
calcd for C
3
)
d
173.2, 141.8, 125.9, 24.4, 12.6; HRMS (þCI)
yellow oil; R
f
¼0.45 (25% EtOAc in hexane); IR (film): 2956, 2934,
þ
ꢁ1
1
5
H
9
O
2
101.0603 (MþH ), found 101.0607.
1776, 1169 cm ; H NMR (400 MHz, CDCl
4.43e4.38 (m,1H), 2.66 (dd, J¼17.2, 8.0 Hz,1H), 2.60e2.50 (m,1H),
2.16 (dd, J¼17.2, 4.0 Hz, 1H), 1.65e1.56 (m, 1H), 1.49e1.42 (m, 2H),
3
; for the major isomer)
d
4
.8. 2-Methylene-3-phenylpropionic acid (19)
13
1
.38e1.21 (m, 5H), 0.98 (d, J¼7.2 Hz, 3H), 0.86 (t, J¼6.0 Hz, 3H);
C
A solution of diethyl malonate (16) (200.0 mg, 1.25 mmol), K
345.0 mg, 2.50 mmol), tetrabutylammonium iodide (23.0 mg,
.06 mmol), and benzyl bromide (178 L, 1.50 mmol) in MeCN
13 mL) was stirred under refluxing for 10 h. The reaction was
2
CO
3
NMR (100 MHz, CDCl ; for the major isomer) 177.1, 83.8, 37.6, 33.1,
3
d
(
0
(
31.7, 29.9, 25.6, 22.5, 14.0, 13.9; HRMS (eCI) calcd for C10
169.1229 (MeH ), found 169.1226.
H
17
O
2
þ
m
Compound 12a: a pale-yellow oil; R
ane); IR (film): 3308 (br), 2919, 2854, 1467, 1075 cm
(400 MHz, CDCl
3.59 (t, J¼5.2 Hz, 0.38H for the minor isomer),
3.39 (d, J¼6.0 Hz, 1.62H for the major isomer), 2.64 (br s, 2H),
f
¼0.31 (25% EtOAc in hex-
ꢁ
1 1
quenched with aqueous 10% HCl and the reaction mixture was
; H NMR
extracted with EtOAc (30 mLꢂ3). The combined organic layer was
3
) d
2 4
washed with brine, dried over anhydrous Na SO , filtered, and con-
2
0
13
centrated under reduced pressure to afford a crude product of 17.
1.52e1.20 (m, 8H), 0.86 (t, J¼6.4 Hz, 3H); C NMR (100 MHz, CDCl
3
;
To a suspension of the above crude 17 in water (10 mL) was
added solid NaOH (100.0 mg, 2.50 mmol) followed by refluxing
with stirring for 5 h. The reaction mixture was adjusted to ca. pH 1
with concn. aqueous HCl and was then extracted with EtOAc
for the major isomer)
d
74.7 (ꢂ2), 33.7 (ꢂ2), 32.0 (ꢂ2), 25.5 (ꢂ2),
22.7 (ꢂ2), 14.2 (ꢂ2); HRMS (eCI) calcd for C12
25 2
H O 201.1855
þ
(MeH ), found 201.1847.
(
20 mLꢂ3). The combined organic layer was washed with brine,
4.9.2. cis-5-[2-(((tert-Butyldiphenyl)silyl)oxy)]-ethyl-4-
methyldihydrofuran-2(3H)-one (rac-2c). Prepared from the croto-
dried over anhydrous Na SO , filtered, and concentrated under
2
4
reduced pressure. The residue was purified by flash column chro-
matography (silica gel, 50% EtOAc in hexane) to give 2-
nate 11 and TBDPSOCH
cis and trans isomers. Compound rac-2c: a pale-yellow oil; R
(25% EtOAc in hexane); IR (film): 2960, 2930, 2857, 1780,1428,1165,
2 2
CH CHO in 74% yield as an 89:11 mixture of
f
¼0.62
benzylmalonic acid (18, 187.0 mg, 93% for 2 steps) as a yellow oil.
1
ꢁ1
1
R
d
f
¼0.30 (50% EtOAc in hexane); H NMR (400 MHz, DMSO-d
6
)
C
1091 cm
;
H NMR (400 MHz, CDCl
3
; for the major isomer)
1
3
7.30e7.18 (m, 5H), 3.56 (t, J¼7.6 Hz, 1H), 3.04 (d, J¼7.2 Hz, 2H);
d 7.68e7.65 (m, 4H), 7.46e7.37 (m, 6H), 4.75e4.69 (m, 1H),
NMR (100 MHz, DMSO-d
26.5, 53.4, 34.4.
6
)
d
170.6, 138.8, 128.9 (ꢂ2), 128.4 (ꢂ2),
3.88e3.79 (m, 2H), 2.71 (dd, J¼17.2, 8.0 Hz, 1H), 2.62e2.53 (m, 1H),
2.18 (dd, J¼16.8, 3.6 Hz, 1H), 1.85e1.79 (m, 2H), 1.07 (s, 9H), 1.00 (d,
1
1
3
To a solution of 2-benzylmalonic acid (18, 3.50 g, 17.9 mmol) in
J¼6.8 Hz, 3H); C NMR (100 MHz, CDCl
3
; for the major isomer)
ꢀ
EtOAc (180 mL) cooled in an iceewater bath (0 C) was added
d
176.9, 135.6 (ꢂ2), 135.6 (ꢂ2), 133.7, 133.5, 129.9 (ꢂ2), 127.9 (ꢂ4),

Y. Lai et al. / Tetrahedron 72 (2016) 664e673
671
(16.7% EtOAc in hexane); IR (film): 2964, 1771, 1184, 1002 cm 1; 1H
NMR (400 MHz, CDCl
4.16 (dd, J¼7.6, 6.8 Hz, 1H), 2.52e2.47 (m,
H), 2.15 (ddd, J¼13.6, 10.0, 6.8 Hz, 1H), 1.86 (ddd, J¼13.6, 8.4,
5.6 Hz, 1H), 1.85e1.76 (m, 1H), 1.57e1.51 (m, 1H), 1.00 (t, J¼7.6 Hz,
ꢁ
8
C
0.3, 60.5, 37.6, 33.1, 33.0, 27.0 (ꢂ3), 19.3, 14.2; HRMS (þCI) calcd for
þ
H
23 30
O
3
Si 382.1964 (M ), found 382.1941.
3
) d
1
4
2
.9.3. cis-5-[2-((4-Methoxybenzyl)oxy)]ethyl-4-methyldihydrofuran-
(3H)-one (rac-2d). Prepared from the crotonate 11 and
13
3
3H), 0.92 (s, 9H); C NMR (100 MHz, CDCl ) d 179.8, 86.3, 41.8, 34.3,
PMBOCH
isomers. Compound rac-2d: a pale-yellow oil; R
in hexane); IR (film): 2964, 2870, 1775, 1613, 1514, 1248, 1170, 1093,
2
CH
2
CHO in 75% yield as an 87:13 mixture of cis and trans
28.2, 25.0 (ꢂ3), 24.7, 11.8; HRMS (þCI) calcd for C10
H
19
O
2
171.1385
þ
f
¼0.20 (25% EtOAc
(MþH ), found 171.1385.
ꢁ
1 1
1033 cm ; H NMR (400 MHz, CDCl
3
; for the major isomer) 7.25
d
4.9.8. trans-3-Benzyl-5-tert-butyldihydrofuran-2(3H)-one
(rac-
(
4
d, J¼8.8 Hz, 2H), 6.84 (d, J¼8.8 Hz, 2H), 4.68e4.63 (m, 1H), 4.46 and
20c). Prepared from the 2-benzylacrylate 13c and trimethylace-
taldehyde in 86% yield as a 90:10 mixture of trans and cis isomers
.42 (ABq, J¼11.6 Hz, 2H), 3.79 (s, 3H), 3.63e3.56 (m, 2H), 2.69 (dd,
J¼17.2, 8.0 Hz, 1H), 2.61e2.54 (m, 1H), 2.18 (dd, J¼17.2, 4.0 Hz, 1H),
(entry 4, Table 1). Compound rac-20c: a pale-yellow oil; R
f
¼0.58
1
3
ꢁ1
1
1
.88e1.82 (m, 2H),1.00 (d, J¼7.2 Hz, 3H); C NMR (100 MHz, CDCl
3
;
(25% EtOAc in hexane); IR (film): 2961, 1769, 1177, 1002 cm
NMR (400 MHz, CDCl
; H
for the major isomer)
8
C
d
176.9, 159.3, 130.3, 129.4 (ꢂ2), 113.9 (ꢂ2),
3
)
d
7.33e7.19 (m, 5H), 4.00 (dd, J¼8.0, 6.8 Hz,
0.5, 73.0, 66.5, 55.3, 37.5, 33.0, 30.6, 14.1; HRMS (þCI) calcd for
1H), 3.17 (dd, J¼13.6, 4.0 Hz,1H), 2.93e2.88 (m,1H), 2.78 (dd, J¼13.6,
9.6 Hz, 1H), 2.04 (ddd, J¼13.6, 9.6, 6.4 Hz, 1H), 1.91 (ddd, J¼14.0, 8.0,
þ
H
15 20
O
4
264.1357 (M ), found 264.1357.
13
5
3
.6 Hz, 1H), 0.88 (s, 9H); C NMR (100 MHz, CDCl ) d 179.2, 138.4,
4
2
.9.4. cis-5-Cyclopropyl-4-methyldihydrofuran-2(3H)-one
e). Prepared from the crotonate 11 and cyclopropane-
(rac-
129.0 (ꢂ2), 128.8 (ꢂ2), 126.9, 86.3, 42.0, 37.1, 34.3, 27.6, 25.0 (ꢂ3);
6
þ
HRMS (eCI) calcd for C15
H
19
O
2
231.1385 (MeH ), found 231.1389.
carboxaldehyde in 85% yield as a 95:5 mixture of cis and trans
1
isomers. Compound rac-2e: a pale-yellow oil; H NMR (400 MHz,
4.9.9. trans-5-Cyclohexyl-3-methyldihydrofuran-2(3H)-one
(rac-
CDCl
3
)
d
3.74 (dd, J¼9.2, 6.4 Hz, 1H), 2.69e2.62 (m, 2H), 2.30e2.22
20d). Prepared from the methacrylate 13a and cyclo-
hexanecarboxaldehyde in 80% yield as a 97:3 mixture of trans and
cis isomers (entry 5, Table 1). Compound rac-20d: a pale-yellow oil;
(
m, 1H), 1.17 (d, J¼7.2 Hz, 3H), 1.02e0.94 (m, 1H), 0.72e0.59 (m, 2H),
13
0
3
.47e0.41 (m, 1H), 0.29e0.23 (m, 1H); C NMR (100 MHz, CDCl )
d
177.0, 88.8, 37.2, 33.7, 14.9, 10.4, 3.7, 1.9.
R
f
¼0.50 (16.7% EtOAc in hexane); IR (film): 2928, 1770, 1451,
ꢁ
1 1
1177 cm
;
3
H NMR (400 MHz, CDCl ) d 4.24e4.19 (m, 1H),
4
.9.5. trans-5-(2-Phenylethyl)-3-methyldihydro-furan-2(3H)-one
2.69e2.59 (m, 1H), 2.19 (ddd, J¼13.2, 9.2, 5.6 Hz, 1H), 1.93e1.86 (m,
(
rac-4b) and 1,6-diphenylhexane-3,4-diol (12b). Prepared from
CH CHO in 27% yield
2H), 1.78e1.73 (m, 2H), 1.69e1.61 (m, 2H), 1.52e1.42 (m, 1H), 1.26
13
methyl methacrylate (3: X¼OMe) and PhCH
2
2
(d, J¼7.6 Hz, 3H), 1.25e1.10 (m, 3H), 1.05e0.94 (m, 2H); C NMR
as a 74:26 mixture of trans and cis isomers along with 30% yield of
the aldehyde dimer 12b as a 74:26 mixture of diastereomers (entry
(100 MHz, CDCl
3
)
d
180.2, 82.5, 42.4, 34.3, 33.0, 28.7, 28.0, 26.2, 25.7,
þ
25.5, 16.2; HRMS (þCI) calcd for C11
H
19
O
2
183.1385 (MþH ), found
8
, Table 1). The compound rac-4b was also obtained in 30e37%
yields and in a 96:4 ratio of trans:cis isomers from the reaction of
3a with PhCH CH CHO (entry 9, Table 1). Compound rac-4b:
a pale-yellow oil; R
¼0.32 (16.7% EtOAc in hexane); IR (film): 2936,
183.1386.
1
2
2
4.9.10. trans-5-Cyclohexyl-3-ethyldihydrofuran-2(3H)-one (rac-20e)
0
f
and the aldol byproduct rac-20e . Prepared from the 2-ethylacrylate
ꢁ1
1
1770, 1455, 1186, 1161, 997 cm
;
H NMR (400 MHz, CDCl
3
)
13b and cyclohexanecarboxaldehyde in 87% yield as a 95:5 mixture
of trans and cis isomers along with 6% of the aldol byproduct rac-
d
7.32e7.18 (m, 5H), 4.53e4.46 (m, 1H), 2.86e2.65 (m, 3H),
.15e2.08 (m, 1H), 2.05e1.96 (m, 2H), 1.90e1.81 (m, 1H), 1.28 (d,
0
2
20e (entry 6, Table 1). Compound rac-20e: a pale-yellow oil;
13
J¼7.6 Hz, 3H); C NMR (100 MHz, CDCl
3
)
d
180.1, 140.9, 128.7 (ꢂ2),
R
f
¼0.53 (16.7% EtOAc in hexane); IR (film): 2929, 1769, 1451,
ꢁ
1 1
1
28.6 (ꢂ2), 126.3, 77.5, 37.4, 35.5, 34.1, 31.8, 16.0; HRMS (þCI) calcd
1178 cm
;
3
H NMR (400 MHz, CDCl ) d 4.20e4.14 (m, 1H),
þ
for C13
H
17
O
2
205.1229 (MþH ), found 205.1237.
2.51e2.43 (m, 1H), 2.10 (ddd, J¼13.2, 9.2, 6.0 Hz, 1H), 1.97e1.69 (m,
Compound 12b: a pale-yellow oil; R
f
¼0.17 (25% EtOAc in hex-
5H), 1.68e1.57 (m, 2H), 1.55e1.39 (m, 2H), 1.26e1.08 (m, 3H),
ꢁ
1
1
13
ane); IR (film): 3385 (br), 2943, 1496, 1455, 1062 cm
400 MHz, CDCl 7.31e7.18 (m, 10H), 3.63e3.60 (m, 0.52H),
.48e3.44 (m, 1.48H), 2.90e2.78 (m, 2H), 2.72e2.60 (m, 2H),
;
H NMR
1.04e0.60 (m, 2H), 0.97 (t, J¼7.6 Hz, 3H); C NMR (100 MHz, CDCl
3
)
(
3
2
3
)
d
d
179.6, 82.9, 42.7, 41.1, 30.7, 28.7, 28.1, 26.3, 25.7, 25.6, 24.3, 11.7;
þ
HRMS (þCI) calcd for C12
H
21
O
2
197.1542 (MþH ), found 197.1543.
13
0
.20e1.85 (br s, 2H), 1.83e1.70 (m, 4H); C NMR (100 MHz, CDCl
3
;
Compound rac-20e : a pale-yellow oil; R
f
¼0.48 (16.7% EtOAc in
for the major isomer)
d
141.9 (ꢂ2), 128.6 (ꢂ4), 128.6 (ꢂ4), 126.1
hexane); IR (film): 3489 (br), 2925, 2852, 1747, 1449, 1200,
1024 cm ; H NMR (400 MHz, CDCl ) d 4.09e4.03 (m, 1H), 3.84 (br
3
ꢁ1 1
(
2
ꢂ2), 74.0 (ꢂ2), 35.4 (ꢂ2), 32.0 (ꢂ2); HRMS (þCI) calcd for C18
23
H O
2
þ
71.1698 (MþH ), found 271.1695.
s, 1H), 2.38 (dd, J¼12.8, 10.0 Hz, 1H), 2.06e1.96 (m, 2H), 1.87 (dd,
J¼12.4, 6.8 Hz, 1H), 1.82e1.37 (m, 15H), 1.32e1.09 (m, 6H),
1
3
4.9.6. trans-5-tert-Butyl-3-methyldihydrofuran-2(3H)-one
(rac-
1.06e0.95 (m, 2H), 0.96 (t, J¼7.6 Hz, 3H); C NMR (100 MHz, CDCl
3
)
2
0a). Prepared from the methacrylate 13a and trimethylace-
d 181.5, 82.4, 76.3, 54.1, 43.4, 39.0, 32.9, 31.4, 29.3, 28.2, 27.9, 26.8,
taldehyde in 95% yield as a 98:2 mixture of trans and cis isomers
26.5, 26.4, 26.2, 25.9, 25.8, 25.6, 9.2; HRMS (þCI) calcd for C19
33 3
H O
þ
(
(
9
2
entry 2, Table 1). Compound rac-20a: a pale-yellow oil; R
f
¼0.33
309.2430 (MþH ), found 309.2443.
16.7% EtOAc in hexane); IR (film): 2966, 1772, 1479, 1368, 1189,
ꢁ
1 1
97 cm ; H NMR (400 MHz, CDCl
3
)
d
4.16 (dd, J¼7.6, 6.4 Hz, 1H),
4.9.11. trans-3-Benzyl-5-cyclohexyldihydrofuran-2(3H)-one
(rac-
.64e2.58 (m, 1H), 2.19 (ddd, J¼13.2, 9.6, 6.4 Hz, 1H), 1.77 (ddd,
20f). Prepared from the 2-benzylacrylate 13c and cyclo-
hexanecarboxaldehyde in 99% yield as a 92:8 mixture of trans and cis
isomers (entry 7, Table 1). Compound rac-20f: a pale-yellow oil;
1
3
J¼13.6, 8.0, 6.0 Hz, 1H), 1.23 (d, J¼7.6 Hz, 3H), 0.88 (s, 9H);
C
NMR (100 MHz, CDCl
3
)
d
180.5, 85.9, 35.0, 34.2, 30.6, 24.9 (ꢂ3),
þ
1
6.7; HRMS (þCI) calcd for C
9
H
17
O
2
157.1229 (MþH ), found
R
f
¼0.52 (16.7% EtOAc in hexane); IR (film): 2926, 1767, 1452, 1166,
ꢁ1 1
157.1234.
3
1010 cm ; H NMR (400 MHz, CDCl ) d 7.35e7.18 (m, 5H), 4.07e4.01
(
m, 1H), 3.18 (dd, J¼13.6, 4.4 Hz, 1H), 2.94e2.85 (m, 1H), 2.76 (dd,
4.9.7. trans-5-tert-Butyl-3-ethyldihydrofuran-2(3H)-one
(rac-
J¼13.6, 9.2 Hz, 1H), 2.01 (dd, J¼8.0, 7.2 Hz, 2H), 1.90e1.82 (m, 1H),
2
0b). Prepared from the 2-ethylacrylate 13b and trimethylace-
1.78e1.54 (m, 4H), 1.49e1.38 (m, 1H), 1.25e1.10 (m, 3H), 1.02e0.86
1
3
taldehyde in 82% yield as a 95:5 mixture of trans and cis isomers
entry 3, Table 1). Compound rac-20b: a pale-yellow oil; R
¼0.50
(m, 2H); C NMR (100 MHz, CDCl
3
)
d
178.9, 138.4, 129.0 (ꢂ2), 128.7
(
f

672
Y. Lai et al. / Tetrahedron 72 (2016) 664e673
(
ꢂ2), 126.8, 82.9, 42.5, 41.4, 36.8, 30.2, 28.6, 28.0, 26.2, 25.6, 25.5;
4.11. General for epimerization of trans isomer to cis isomer
of 3,5-disubstituted dihydrofuran-2(3H)-one
þ
HRMS (þCI) calcd for C17
H
23
O
2
259.1698 (MþH ), found 259.1696.
4
.9.12. trans-3-Methyl-5-n-pentyldihydrofuran-2(3H)-one (rac-20g)
To a solution of rac-20a (250.0 mg, 1.58 mmol) in anhydrous THF
0
0
ꢀ
and the aldol byproduct rac-20g . Prepared from the methacrylate
(10 mL) cooled in a dry iceeacetone bath (ꢁ78 C) was slowly
13a and n-hexanal in 40% yield as a 98:2 mixture of trans and cis
added a freshly prepared LDA solution (4.40 mmol) followed by
stirring at the same temperature for 1 h. To the resultant mixture at
0
isomers along with the aldol byproduct rac-20g in 30% yield as
estimated by H NMR analysis of the inseparable mixture (entry 10,
Table 1). The chemical shifts for C5eH are assigned as follows:
1
ꢀ
ꢁ78 C was added a solution of 2,6-di-tert-butylphenol (1.96 g,
9.48 mmol) in anhydrous THF (5 mL). The reaction mixture was
4
2
.50e4.44 for the major trans isomer of rac-20g, 4.43e4.26 for rac-
extracted with CH
was washed with brine, dried over anhydrous Na
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 16.7% EtOAc in hexane) to
give rac-24 (200.0 mg, 80%, dr>98:2).
2
Cl
2
(10 mLꢂ3) and the combined organic layer
0
0g , and 4.33e4.28 for the minor cis isomer of rac-20g, re-
2
SO , filtered, and
4
0
spectively. The inseparable mixture of rac-20g and rac-20g was
silylated (TESOTf-2,6-lutidine, CH
ꢀ
2
Cl
2
, 0 C to rt, 1 h, 90%) to form
0
0
the TES ether rac-20g and the recovered rac-20g. The latter was
found to undergo partial epimerization to give an 84:16 mixture of
trans and cis isomers. Compound rac-20g (trans:cis¼84:16): a pale-
4.11.1. cis-5-tert-Butyl-3-methyldihydrofuran-2(3H)-one
24). Compound rac-24: a pale-yellow oil; R
¼0.31 (16.7% EtOAc in
hexane); IR (film): 2966, 1772, 1479, 1368, 1189, 997 cm ; H NMR
(400 MHz, CDCl
4.06 (dd, J¼11.2, 6.0 Hz, 1H), 2.73e2.62 (m, 1H),
(rac-
yellow oil; R
f
¼0.60 (25% EtOAc in hexane); IR (film): 2934, 1772,
f
ꢁ1
1
ꢁ1 1
1
0
0
0
458, 1190, 1006 cm ; H NMR (400 MHz, CDCl ) d 4.51e4.44 (m,
3
.84H), 4.33e4.28 (m, 0.16H), 2.70e2.62 (m, 0.84H), 2.49e2.42 (m,
.16H), 2.12e2.05 (m, 1H), 2.01e1.93 (m, 1H), 1.72e1.21 (m, 11H),
3
) d
2.31e2.24 (m, 1H), 1.64e1.55 (m, 1H), 1.27 (d, J¼6.8 Hz, 3H), 0.95 (s,
13
13
.87 (t, J¼6.4 Hz, 3H); C NMR (100 MHz, CDCl
3
)
d
for the major
9H); C NMR (100 MHz, CDCl
3
)
d
179.9, 85.9, 36.2, 33.3, 32.2, 25.1
þ
isomer, 180.3, 78.6, 35.5, 35.5, 34.1, 31.6, 25.1, 22.6, 16.0, 14.0 and for
the minor isomer, 179.8, 78.8, 37.5, 36.0, 35.6, 31.6, 25.0, 22.6, 16.0,
(ꢂ3), 15.1; HRMS (þCI) calcd for C
9
H20NO
2
174.1494 (MþNH
4
),
found 174.1504.
þ
1
1
5.2; HRMS (eCI) calcd for C10
69.1230.
A sample of rac-20g with a trans:cis ratio of 98:2 was obtained
from the reaction of 13a with n-hexanal in the presence of MeS-
NH as the proton source (see entry 5, Table 2).
Compound rac-20g : a pale-yellow oil; R
hexane); IR (film): 2956, 2936, 1771, 1459, 1202, 1123, 1094,
17
H O
2
169.1229 (MeH ), found
4.11.2. cis-5-(2-Phenylethyl)-3-methyldihydro-furan-2(3H)-one (rac-
25). Prepared from rac-4b (trans:cis¼96:4) in 86% yield as a 15:85
mixture of trans and cis isomers. Compound rac-25: a pale-yellow
O
2
2
oil; R
f
¼0.32 (16.7% EtOAc in hexane); IR (film): 2934, 1770, 1455,
0
0
ꢁ1
1
f
¼0.80 (25% EtOAc in
1186, 1163, 1027 cm ; H NMR (400 MHz, CDCl ) d 7.32e7.19 (m,
3
5H), 4.53e4.46 (m, 0.15H), 4.35e4.28 (m, 0.85H), 2.88e2.62 (m,
3.15H), 2.50e2.43 (m, 0.85H), 2.12e1.87 (m, 2H), 1.57e1.48 (m, 1H),
ꢁ1
1
1
3
6
0
d
015 cm
;
H NMR (400 MHz, CDCl ) d 4.39e4.32 (m, 1H),
3
13
.95e3.92 (m, 1H), 2.27 (dd, J¼12.4, 10.8 Hz, 1H), 1.78 (dd, J¼12.4,
1.27 (d, J¼7.2 Hz, 3H); C NMR (100 MHz, CDCl
3
for the major
.4 Hz, 1H), 1.73e1.66 (m, 1H), 1.60e1.20 (m, 15H), 1.12 (s, 3H),
.97e0.85 (m, 15H), 0.65e0.50 (m, 6H); C NMR (100 MHz, CDCl
isomer)
d
179.6, 141.0, 128.7 (ꢂ2), 128.6 (ꢂ2), 126.3, 77.7, 37.4, 37.4,
13
þ
3
)
36.0, 31.8, 15.2; HRMS (þCI) calcd for C13
H
17
O
2
205.1229 (MþH ),
181.1, 77.6, 74.6, 51.0, 35.8, 35.3, 33.0, 32.3, 31.7, 25.6, 25.1, 22.7,
found 205.1232.
2
C
2.6, 20.6, 14.2, 14.1, 7.1 (ꢂ3), 5.3 (ꢂ3); HRMS (eCI) calcd for
þ
H
22 43
O
3
Si 383.2981 (MeH ), found 383.2997.
Acknowledgements
4
.9.13. 5-tert-Butyldihydrofuran-2(3H)-one (rac-22).4,21 Prepared
from methyl acrylate (21) and trimethylacetaldehyde in 50% yield
This work is supported in part by a General Research Fund grant
(601211) from the Research Grant Council, The Hong Kong Special
Administrative Region, P. R. China, The Hong Kong Chiu Chow
Chamber of Commerce HKUST Scholarship for Ph.D. Study (Y.L.),
and the Department of Chemistry, HKUST.
1
(
Scheme 7). Compound rac-22: a pale-yellow oil;
400 MHz, CDCl
4.17 (dd, J¼8.4, 7.2 Hz, 1H), 2.59e2.44 (m, 2H),
.15e2.06 (m, 1H), 2.00e1.89 (m, 1H), 0.93 (s, 9H); C NMR
100 MHz, CDCl
177.4, 88.2, 33.7, 29.3, 24.8 (ꢂ3), 22.9.
H NMR
(
2
(
3
) d
13
3
) d
4
.10. Methylation of rac-22
Supplementary data
1H and 13C NMR spectra for the compounds 2a,c,d, 4b, 10, 11,
12a,b, 13aec, 20aeg, 24, 25, and the related compounds are
available. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2015.12.009.
To a solution of diisopropylamine (0.66 mL, 4.74 mmol) in an-
ꢀ
hydrous THF (4 mL) cooled in a dry iceeacetone bath (ꢁ78 C)
under an argon atmosphere was added n-BuLi (2 M in cyclohexane,
2
.2 mL, 4.40 mmol) dropwise. After stirring at the same tempera-
ture for 10 min, the mixture was allowed to warm to room tem-
perature followed by stirring for 1 h to form the LDA solution for the
next step.
References and notes
To a solution of rac-22 (221.5 mg, 1.58 mmol) in anhydrous THF
1
. For recent reviews, see (a) Molander, G. A.; Harries, C. R. Chem. Rev. 1996, 96,
307e338; (b) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745e778; (c) Steel, P. G.
J. Chem. Soc. Perkin Trans. 1 2001, 2727e2751; (d) Kagan, H. B. Tetrahedron 2003,
ꢀ
(
10 mL) cooled in a dry iceeacetone bath (ꢁ78 C) was added the
above freshly prepared LDA solution (4.40 mmol) dropwise fol-
lowed by stirring at the same temperature for 40 min. To the re-
sultant solution was added MeI (0.30 mL, 4.74 mmol) dropwise.
59, 10351e10372; (e) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004,
104, 3371e3403; (f) Gopalaiah, K.; Kagan, H. B. New. J. Chem. 2008, 32, 607e637;
(g) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48,
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Chinese); (i) Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40,
ꢀ
After stirring at ꢁ78 C for 2 h, the reaction was quenched with
4
saturated aqueous NH Cl. The reaction mixture was extracted with
2199e2210; (j) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem. Commun.
EtOAc (10 mLꢂ3) and the combined organic layer was washed with
2012, 330e346; (k) Harb, H. Y.; Procter, D. J. Synlett 2012, 6e20; (l) Szostak, M.;
brine, dried over anhydrous Na SO , filtered, and concentrated
2
4
Spain, M.; Parmar, D.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155e9183; (m)
Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114,
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 16.7% EtOAc in hexane) to afford rac-
0a (197.5 mg, 80%) as almost a single diastereomer.
5
959e6039 Also, see: (n) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61,
0377e10441; (o) Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2012, 51,
9238e9256; (p) Streuff, J. Synthesis 2013, 45, 281e307.
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. Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 5763e5764.
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5
6
. For SmI2-mediated reductive coupling of a solid-supported chiral crotonate
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1876e11883.
. For SmI2-mediated reductive coupling of atropisomeric 1-naphthamide-de-
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-mediated reductive coupling of a fluorous-tagged chiral crotonate
1
7
rived chiral crotonates with aldehydes, see (a) Zhang, Y.; Wang, Y.; Dai, W.-M. J.
Org. Chem. 2006, 71, 2445e2455; (b) Dai, W.-M.; Zhang, Y.; Zhang, Y. Tetrahe-
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934e936.
8
9
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