Stereoselective addition of Grignard reagents to (2-methyl-5-tert-butyl)phenyl 1-thio-β-D-ribopentodialdo-1,4-furanoside derivative

Article abstract of DOI:10.1016/j.tet.2017.03.013

Addition of a wide range of Grignard reagents to acetone protected (2-methyl-5-tert-butyl)phenyl 1-thio-β-D-ribopentodialdo-1,4-furanoside 3b produced useful 5(R)[sbnd]C-substituted products with moderate to good yields, and moderate to perfect stereoselectivities, with no need of additives. n.O.e. Analysis of 3b showed that 1-S-aryl group could contribute to the stereoselectivity of addition reaction. The stereochemistry of 4 representative 5-C-substituted ribofuranoside products was further confirmed by NMR study of corresponding Mosher esters, by chemical derivatization, or by single crystal study.

Full text of DOI:10.1016/j.tet.2017.03.013

Tetrahedron 73 (2017) 2290e2304
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective addition of Grignard reagents to (2-methyl-5-tert-
butyl)phenyl 1-thio-b-D-ribopentodialdo-1,4-furanoside derivative
,
,
,
,
, **
Huanming Ren a b, Wuchen Xie a b, Bing Xiong b c, Jingkang Shen b c, Guohua Chen a
,
, c, *
Yue-Lei Chen b
a School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR
China
c University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Addition of a wide range of Grignard reagents to acetone protected (2-methyl-5-tert-butyl)phenyl 1-thio-
Received 3 January 2017
Received in revised form
4 March 2017
Accepted 6 March 2017
Available online 9 March 2017
Dedicated to Prof. Dr. Weiyong Ma
b
-D-ribopentodialdo-1,4-furanoside 3b produced useful 5(R)eC-substituted products with moderate to
good yields, and moderate to perfect stereoselectivities, with no need of additives. n.O.e. Analysis of 3b
showed that 1-S-aryl group could contribute to the stereoselectivity of addition reaction. The stereo-
chemistry of 4 representative 5-C-substituted ribofuranoside products was further confirmed by NMR
study of corresponding Mosher esters, by chemical derivatization, or by single crystal study.
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Nucleophilic addition
Stereoselective reaction
Grignard reagents
5-C-Substituted ribofuranoside
Mosher ester
1. Introduction
Interestingly, the attack of the arylzinc reagents was on the Si-face
of the aldehyde (according to the conformation in structure 2), and
Enantiomerically pure 5-C-substituted ribofuranoside (Scheme
1, structure 1) is useful building block for organic synthesis.1 This
type of compounds is often prepared from the addition reaction
between ribopentodialdo-1,4-furanosides (Scheme 1, structure 2)
and organolithium,2a organomagnesium,2a-f or organotin
reagents.2g,h These organometallic reagents often attack from the
Re-face (according to the conformation in structure 2) of the 5-
aldehyde, yielding unsatisfactory enatioselectivity for most of
the ribose substrates and organometallic reagents. Recently,
arylzincs were found good nucleophile to ribopentodialdo-1,4-
furanosides,1d,3 and constantly produced good to excellent stereo-
selectivity in the addition reaction. Because the organozinc re-
agents were prepared by metal exchange reaction using organic
boronic acids, the nucleophile is reportedly limited to aryl groups.
the stereochemistry was explained by the Zn-chelation model.1d
Clearly, there was a lack of general method to prepare 5-C-
substituted ribofuranoside 1 from structure 2 with both features of
broad nucleophile scope and good stereoselectivity.
During our study of carbohydrate chemisty, 5-C-substituted
ribofuranosides were required, too. Instead of using the known
substrate 3a for the addition reaction, we prepared compound 3b
as the substrate, initially because odorless 5-(tert-butyl)-2-
methylbenzenethiol is a preferred reagent. After several experi-
mentations, compound 3b appeared to be a great substrate for the
enantioselective addition reactions with a wide range of Grignard
reagents, with no need of additives. The yield and enantiose-
lectivity were generally satisfying, especially with alkyl magnesium
reagents. The stereochemistry of 4 representative 5-C-substituted
ribofuranoside products was further confirmed by NMR study of
corresponding Mosher esters, by chemical derivatization, or by
single crystal study. It was found that in all cases, the Grignard
reagents approaches from the Re-face of the 5-aldehyde group
(according to the conformation in structure 2). The details of the
work will be reported herein.
* Corresponding author. State Key Laboratory of Drug Research, Shanghai Insti-
tute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, PR China.
** Corresponding author.
E-mail address: chenyuelei@gmail.com (Y.-L. Chen).
http://dx.doi.org/10.1016/j.tet.2017.03.013
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2291
phenylmagnesium bromide and p-fluorophenylmagnesium bro-
mide were reacted with 3b to give good yields and moderate
stereoselectivity for products 13a/b and 14a/b respectively. With
the increase of steric hindrance at the nucleophilic center (Table 1,
Entry 10), o-tolylmagnesium bromide again showed perfect ster-
eoselectivity, without sacrificing the yield of product 15 too much.
For most cases, the nucleophilic addition on compound 3a gave
yields above 60% and stereoselectivity above 1:4.0, with a broad
spectrum of Grignard reagents and very simple experimental
setting, as no additives was needed. Meanwhile, in all cases, the
yields and stereoselectivities were weakly affected by the temper-
ature change. Thus, the internal factors in compound 3b that con-
trol the course of stereoselective addition must be strong.
To understand the robust factors in compound 3b that domi-
nated the addition reactions, n.O.e. effect was measured at room
temperature in CDCl3. As shown in Fig. 1, interactions between H-50
and H-5, as well as interactions between 20eCH3 and H-1 indicated
the close contact between 1-S-phenyl group and 4-formyl group.
Meanwhile, one of the acetonide methyl groups showed correlation
with H-2 and H-3, and another one interacted with H-1 and H-4. A
simple modeling study5 (Fig. 1) further visualized the n.O.e.. As
shown in Fig. 1, the Si-face of the 4-formyl group (according to the
conformation in this image) has been shielded by t-Bu group,
rendering the nucleophilic attack from this side difficult. Also, the
Re-face attack agreed with polar Felkin-Ahn model, as the nucleo-
Scheme 1. Typically, 5-C-substituted ribofuranoside (1) was prepared from ribo-
pentodialdo-1,4-furanosides (2) and organometallic reagents.
2. Results and discussion
From compound 4, compound 3b was prepared through 3
consecutive steps, including S-glycosylation, deacylation, and ace-
tonide protection, without purification of intermediates. The yield
of the beta-anomer 54 was 45% for 3 steps, demonstrating that both
the stereoelectivity of glycosylation step, and the conversion of
each step were good. Next, the free 5-OH on compound 5 was
oxidized with Dess-Martin reagent to the desired aldehyde sub-
strate 3b with 77% yield (Scheme 2).
Substrate 3b was reacted in THF with methylmagnesium bro-
mide at ꢀ78 ꢁC, and it was found that the yield of 5(R)-isomer 6b
was good and the stereoselectivity excellent (The stereochemistry
of the addition product was hypothesized at the stage, and
confirmed later in this work by different studies). To separate the
minor 5(S)-isomer 6a, we performed another addition reaction at
0 ꢁC. The stereochemical outcome decreased to 1:8.0, but was still
good enough for synthetic purpose (Table 1, Entry 1). Next, ethyl
and isopropyl Grignard reagents were tested and showed for both
cases reduced yields, although which were compensated by the
perfect stereoselectivity observed for products 7 and 8, even at 0 ꢁC
(Table 1, Entry 2 and 3). In the case of entry 3, the compromised
yield was partially due to the reduction of 3b to 5. From vinyl-
magnesium bromide (Table 1, Entry 4), the diastereomeric ratio of
products 9a and 9b was 1:10.1 at ꢀ78 ꢁC, and 1:5.3 at 0 ꢁC. Although
the stereoselectivity was lower than that of the alkyl cases, it was
still synthetically useful. Using isopropenylmagnesium bromide
(Table 1, Entry 5) as nucleophile, the stereoselectivity decreased
significantly, but the yields of 10a and 10b were similar to that in
vinyl cases. Next, 1-propynylmagnesium bromide showed very low
reactivity in the addition reaction (Table 1, Entry 6). Even at 0 ꢁC,
large amount of remaining starting material 3b was recovered.
Meanwhile, the highly reactive allylmagnesium chloride gave
moderate results in terms of both yields and stereoselectivity, to
products 12a and 12b (Table 1, Entry 7). In entries 8 and 9,
phile should approach from a direction close to C4eO6 s* bond.
The experimental setting of the addition reaction was already
very simple, the spectrum of Grignard reagent was broad, the yield
of most products was good, and the stereoselectivity was generally
suitable for preparation purpose. Therefore, we did not continue
optimize the addition reaction condition. Instead, since the ste-
reochemistry of most products was not clarified in history, we feel
the necessity to undertake this task.
Thus, Mosher esters6,7 were prepared from representative sub-
strates, including methyl diastereomeric pair 6a/b, vinyl diaste-
reomeric pair 9a/b, allyl diastereomeric pair 13a/b, and phenyl
diastereomeric pair 14a/b, via Mosher acid chlorides 16a/b.
As shown in Table 2: From compound 6a, esters 6aR and 6aS
were prepared with (R)-Mosher acid chloride (16a) and (S)-Mosher
acid chloride (16b) respectively. From compound 6b, esters 6bR
and 6bS were prepared with (R)-Mosher acid chloride (16a) and
(S)-Mosher acid chloride (16b) respectively, too. In Table 2, equa-
tion 1, H3 in 6aR was shielded by the phenyl ring on C-200 and
shifted upfield relative to that in 6aS. Due to a similar shielding
effect, 5-CH3 in 6aS shifted upfield relative to that in 6aS. The
chemical shift difference of H4 in 6aR and of H4 in 6aS is too small to
be considered. Since the sugar (as the larger group C-5) -phenyl (as
the larger group on C-200) interaction was more energetically dis-
favored, CF3 in 6aR was forced into the shielding zone of the
carbonyl group, thus showing an upfield shift in 19F NMR relative to
that in 6aS. Meanwhile, when being compared with the yield of 6aS
in the esterification step, the particularly low yield of 6aR could
reflect the disfavored interaction between the sugar and phenyl
ring on C-200), too. Analogously, as demonstrated in Table 2, equa-
tion 2, H3 and H4 in 6bS were shielded by the phenyl ring on C-200
and shifted upfield relative to that in 6bR. Due to the similar
shielding effect, 5-CH3 in 6bR shifted upfield relative to that in 6bS.
Because of the energetically disfavored interaction between the
sugar (as the larger group C-5) and phenyl ring (as the larger group
on C-200), CF3 in 6bS was forced into the shielding zone of the
carbonyl group, thus showing an upfield shift in 19F NMR relative to
that of 6bR. Thus, all major chemical shift value change supported
the proposed stereochemistry of 6a and 6b.
Scheme 2. Preparations of aldehyde substrate 3b. Reaction conditions: a) 2-methyl-5-
tert-butyl-thiophenol, BF3 etherate, DCM; then methanolic ammonia; then
Me2C(OMe)2, acetone, p-TsOH hydrate, 45% from compound 4. b) Dess-Martin peri-
odinane, DCM, 77%.
As shown in Table 3: From compound 9a, esters 9aR and 9aS
were prepared with (R)-Mosher acid chloride (16a) and (S)-Mosher

2292
H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
Table 1
Addition of Grignard reagents to aldehyde 7.a
No
1
RMgx
Productsb
Yieldc
Yieldc
@ ꢀ78 ꢁC (5-S:5-R)d
@ 0 ꢁC (5-S:5-R)d
MeMgBr
in ether
92% (1:14.3)
92% (1:8.0)
2
3
EtMgBr
in THF
65% (only 5-R isomer)
59%e (only 5-R isomer)
68% (only 5-R isomer)
61%f (only 5-R isomer)
i-PrMgBr
in THF
4
5
6
76% (1:10.1)
71% (1:5.3)
76% (1:2.9)
78% (1:1.5)
No product isolated.g
No product isolated.g
7
62% (1:5.0)
83% (1:5.3)

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2293
Table 1 (continued )
No
RMgx
Productsb
Yieldc
Yieldc
@ ꢀ78 ꢁC (5-S:5-R)d
@ 0 ꢁC (5-S:5-R)d
8
PhMgBr
in THF
84% (1:4.0)
79% (1:2.1)
9
89% (1:2.2)
87% (1:3.5)
10
73% (only 5-R isomer)
79% (only 5-R isomer)
a
Reaction conditions: a) Grignard reagents (3 equiv.), THF.
b
c
d
e
f
The suffix “a” or “b” in product numbers are in accordance with the order of chromatography peaks. Thus, “a” or “b” does not correspond to the stereodescriptor “R-” or “S-”.
Chromatography separation yields.
All diastereoisomers were separated by flash chromatography, and the ratio was based on separation yield.
With 9% of reduction product 6 separated.
With 19% of reduction product 6 separated.
g
Unreacted starting material 3b was recovered.
considered. Since the sugar (as the larger group C-5) -phenyl (as the
larger group on C-200) interaction is more energetically disfavored,
CF3 in 9aR was forced into the shielding zone of the carbonyl group,
and should give an upfield shift in 19F NMR relative to that in 9aS.
However, inversed shift change was observed one more time.
Analogously, as demonstrated in Table 3, equation 2, all major shift
difference for H,3 CH2]CH, CH2]CH, and CF3 in 9bR and 9bS were
inconsistent (red values in Table 3) to the proposed structure and
conformation. Only the chemical shift difference of H4 in 9bR and
9bS was in accord with prediction. In addition, comparison of H5 in
9bR and 9bS revealed significant change of ꢀ0.36 ~ ꢀ0.23, indi-
cating that the conformations of 9bR and 9bS may not be ideal for
Mosher ester analysis.
As NMR analysis of Mosher ester derivatives 9aR, 9aS, 9bR, and
9bS questioned the proposed stereochemistry of 9a and 9b, we had
to seek other method to validate the structure of 9a and 9b. To this
end, major diastereomer 9b was subjected to regular hydrogena-
tion condition at RT and 1 atm with excessive 10% Pd/C. Interest-
ingly, 1-sulfide remained intact while the vinyl susbstitution was
reduced to ethyl group (Scheme 3). The proton NMR of the product
Fig. 1. n.O.e. observed for compound 3b.
was found identical to that of compound 7. As the hydrogenation
acid chloride (16b) respectively. From compound 9b, esters 9bR
and 9bS were prepared with (R)-Mosher acid chloride (16a) and
(S)-Mosher acid chloride (16b) respectively, too. In Table 3, equa-
tion 1, according to the proposed structure and conformation, H3 in
9aR was shielded by the phenyl ring on C-200 and should shift up-
field relative to that in 9aS, nevertheless opposite result was
recorded. Due to a similar shielding effect, CH2]CH and CH2]CH
in 9aS should shift upfield relative to that in 9aS. However, opposite
result was recorded again for CH2]CH, while the shift change for
CH2]CH was too small to be considered. Also, the chemical shift
difference of H4 in 9aR and of H4 in 9aS is too small to be
condition was neutral on pH scale, epimerization of 5-OH at the
allylic position was not likely. Thus, we concluded that the pro-
posed structure of 9a and 9b were correct and Mosher ester anal-
ysis was not applicable on these two compounds.
As shown in Table 4: From compound 12a, esters 12aR and 12aS
were prepared with (R)-Mosher acid chloride (16a) and (S)-Mosher
acid chloride (16b) respectively. From compound 12b, esters 12bR
and 12bS were prepared with (R)-Mosher acid chloride (16a) and
(S)-Mosher acid chloride (16b) respectively, too. In Table 4, equa-
tion 1, H3 and H4 in 12aR were shielded by the phenyl ring on C-200
and shifted upfield relative to that in 12aS. Due to a similar

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H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
Table 2
shifted upfield relative to that in 13aS. The chemical shift difference
of H4 in 13aR and of H4 in 13aS was too small to be considered. The
proton signals of 200-phenyl group and 5-phenyl group could not be
assigned due to overlapping. In Table 5, equation 1, according to the
proposed structure and conformation, we considered that chemical
shift of 200eCH3O could be used to probe the C5 stereochemistry as
it should be affected by 5-phenyl group. Unfortunately, the chem-
ical shift difference of CH3O in 13aR and of H4 in 13aS was too small
to be considered useful. Since the sugar (as the larger group C-5)-
phenyl (as the larger group on C-200) interaction was more ener-
getically disfavored, CF3 in 13aR was forced into the shielding zone
of the carbonyl group, and should give an upfield shift in 19F NMR
relative to that in 13aS. However, inversed shift change was
observed (red values in Table 5). In Table 5, equation 2, H3 in 13bR
was shielded by the phenyl ring on C-200 and shifted upfield relative
to that in 13bS. Although according to the proposed structure and
conformation, H4 in 13bR was also shielded by the phenyl ring on
C-200 and should shift upfield relative to that in 13bS, opposite result
was recorded (red values in Table 5). Chemical shift of CH3O in 13bR
indeed moved downfield relative to the chemical shift of CH3O in
13bS, presumably because of the shielding of 5-phenyl ring. Due to
the energetically disfavored interaction between the sugar (as the
larger group C-5) and phenyl ring (as the larger group on C-200), CF3
in 13bS was forced into the shielding zone of the carbonyl group,
thus showing an upfield shift in 19F NMR relative to that of 13bR.
Nevertheless, inversed shift change was recorded again (red values
in Table 5). Thus, Mosher ester analysis for compounds 13a and 13b
was inconclusive.
Determination of absolute stereochemistry on Mosher's acid derivatives 6aR, 6aS,
6bR, and 6bS.a
Selected NMR data (d) of 6a derivatives
6aR (38% from 6a)b
H3 ¼ 4.13
6aS (88% from 6a)b
Dd
H3 ¼ 4.51
ꢀ0.38
þ0.04
H4 ¼ 4.17
H4 ¼ 4.13
H5 ¼ 5.30
H5 ¼ 5.19
ꢀ0.11
5-CH3 ¼ 1.45
CF3 ¼ ꢀ71.92
5-CH3 ¼ 1.35
CF3 ¼ ꢀ71.40
þ0.10
ꢀ0.52
Selected NMR data (d) of 6b derivatives
To validate the proposed stereochemistry of 13a and 13b, major
diastereomer 13b was oxidized with mCPBA first to sulfoxide,
which was an oil if separated, and then to sulfone 17 in one pot.
Compound 17 was a solid and could be converted into single crystal
in TBME and petroleum ether. X-Ray analysis of crystalline 178
showed that the absolute stereochemistry of C5 was R unambigu-
ously (Scheme 4), further indicated that Mosher ester analysis was
not applicable on compounds 13a and 13b.
It is known that sterically congested system could render
Mosher ester analysis less effective.9 In this work, through the data
collected for the vinyl substituted 9aR, 9aS, 9bR, and 9bS, as well as
for the phenyl substituted 13aR, 13aS, 13bR, and 13bS, we have
found that the group with pi-electrons directly connected to the
chiral center in question could interrupt Mosher ester analysis, too.
6bR (50% from 6b)b
H3 ¼ 4.74e4.65
H4 ¼ 4.08
H5 ¼ 5.47
6bS (82% from 6b)b
H3 ¼ 4.50
Dd
þ0.24 ~ þ0.15
þ0.05
H4 ¼ 4.03
H5 ¼ 5.47e5.39
0 ~ þ0.08
5-CH3 ¼ 1.29
CF3 ¼ ꢀ71.43
5-CH3 ¼ 1.37
CF3 ¼ ꢀ71.50
ꢀ0.08
þ0.07
a
Reaction conditions: a) (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl
(16a), pyridine, MeCN; b) (S)-3,3,3-trifluoro-2-methoxy-2-
chloride
phenylpropanoyl chloride (16b), pyridine, MeCN.
b
Chromatography separation yields.
shielding effect, CH2]CHeCH2, CH2]CHeCH2, and CH2]CHeCH2
in 12aS shifted upfield relative to that in 12aS. Since the sugar (as
the larger group C-5) -phenyl (as the larger group on C-200) inter-
action was more energetically disfavored, CF3 in 12aR was forced
into the shielding zone of the carbonyl group, thus showing an
upfield shift in 19F NMR relative to that in 12aS. Meanwhile, the
particularly low yield of 12aR in the esterification step relative to
the yield of 12aS could reflect the disfavored interaction between
the sugar and phenyl ring on C-200), too. Analogously, as demon-
strated in Table 4, equation 2, H3 and H4 in 12bS were shielded by
the phenyl ring on C-200 and shifted upfield relative to that in 12bR.
Due to a similar shielding effect, CH2]CHeCH2, CH2]CHeCH2, and
CH2]CHeCH2 in 12bR shifted upfield relative to that in 12bS.
Because of the energetically disfavored interaction between the
sugar (as the larger group C-5) and phenyl ring (as the larger group
on C-200), CF3 in 12bS was forced into the shielding zone of the
carbonyl group, thus showing an upfield shift in 19F NMR relative to
that of 12bR. Thus, all major chemical shift change supported the
proposed stereochemistry of 12a and 12b.
3. Conclusion
Addition of alkyl, vinyl, allyl, and aryl Grignard reagents to
acetone protected (2-methyl-5-tert-butyl)phenyl 1-thio-b-D-ribo-
pentodialdo-1,4-furanoside 3b produced useful 5(R)eC-substituted
products with moderate to good yields, and moderate to perfect
stereoselectivities. As the addition reaction was carried out in THF
with no need of additives, the high stereoselectivity was attributed
to the conformation arrangement of 3b. The stereochemistry of 4
representative 5-C-substituted ribofuranoside products was further
confirmed by NMR study of corresponding Mosher esters, by
chemical derivatization, or by single crystal study. During the study
of the C5-stereochemistry, the group with pi-electrons directly
connected to the chiral center in question was found interrupting
Mosher ester analysis. This suggests that Mosher ester analysis of
other allylic or benzylic alcohols should be made with caution, too.
As shown in Table 5: From compound 13a, esters 13aR and 13aS
were prepared with (R)-Mosher acid chloride (16a) and (S)-Mosher
acid chloride (16b) respectively. From compound 13b, esters 13bR
and 13bS were prepared with (R)-Mosher acid chloride (16a) and
(S)-Mosher acid chloride (16b) respectively, too. In Table 5, equa-
tion 1, H3 in 13aR was shielded by the phenyl ring on C-200 and
4. Experimental section
4.1. General
All solvents were dried and purified prior to use: Et2O and THF

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2295
Table 3
Determination of absolute stereochemistry on Mosher's acid derivatives 9aR, 9aS, 9bR, and 9bS.a
Melting points were measured on an uncorrected SGW X-4 micro
melting point apparatus. HPLC analysis was performed on a Gilson
HPLC system (306 pump, UV/vis-156 Detector, 215 liquid handle)
with a YMC-ODS column (4.6 ꢂ 50 mm, 5
mm). HPLC conditions:
solvent A ¼ H2O containing 0.1% (v/v) TFA, solvent B ¼ MeCN
containing 0.1% (v/v) TFA; flow rate ¼ 2.5 mL/min; Gradient (B%):
0e0.5 min (4% isostatic), 0.5e4.5 min (4%e95%), 4.5e6.1 min (95%
isostatic), 6.1e6.3 min (95%e4%), 6.3e8.0 min (4% isostatic); peaks
were identified at 254 nm and 214 nm.
Scheme 3. Hydrogenation of compound 9b yielded compound 7. Reaction conditions:
a) H2, MeOH, excessive 10% Pd/C, 1 atm, RT, 8 h, 80%.
were distilled from potassium, and DCM was distilled from CaH2.
All other commercially available reagents were used as received. All
moisture sensitive reactions were performed under N2
(ca. þ1.1 bar) in heating-gun (500e600 ꢁC)/vacuum dried glassware
sealed with rubber septa. Flash chromatography was performed on
silica gel (300e400 mesh ASTM), and monitored by thin layer
4.2. Experimental
4.2.1. ((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)thio)-
2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (5)
A solution of commercially available compound 4 (20 g,
62.8 mmol, 1 equiv.) in DCM (150 mL) was treated with 5-(tert-
butyl)-2-methylbenzenethiol (10.76 g, 59.7 mmol, 0.95 equiv.) and
BF3 etherate (9.8 g, 62.8 mmol, 1 equiv.), and stirred at RT for 4 h.
The reaction was quenched with sat. aq. NaHCO3 and extracted
with DCM. Combined organic phases were washed with brine and
concentrated to give a light yellow oil (34.0 g).
chromatography (TLC) on HSGF-254 (10e40 mm) TLC plates. NMR
data were collected on a Varian Mercury-300 High Performance
Digital FT-NMR, a Varian Mercury-400 High Performance Digital FT-
NMR, a Bruker Ultrashield 500 NMR, or an Agilent 1260 Prospekt 2
Bruker Ascend 600 NMR. Spectra from solutions in CDCl3
(
dC ¼ 77.0 ppm) are calibrated relative to TMS (dH ¼ 0.00 ppm).
A solution of above-mentioned light yellow oil (34.0 g) in MeOH
(200 mL) was treated with NaOMe (2 g, 37 mmol) and stirred at RT
for 2 h. The reaction was quenched by sat. aq. NH4Cl, concentrated,
HRMS were carried out on a Thermo Finnigan MAT-95 spectrometer
(for EI), or on a Waters, Q-Tof Ultima Global spectrometer (for ESI).

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H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
Table 4
4.6 Hz, 1H, H-5), 2.43 (s, 3H, thiophenol-CH3), 1.56 (s, 3H, iso-
propylidene-CH3), 1.39 (s, 3H, isopropylidene-CH3), 1.34 (d,
J ¼ 0.7 Hz, 9H, thiophenol-C(CH3)3), hydroxyl proton was not
Determination of absolute stereochemistry on Mosher's acid derivatives 12aR, 12aS,
12bR, and 12bS.a
found; 13C NMR (126 MHz, Chloroform-d) 149.76 (C5-thiophenol),
d
136.51 (C1-thiophenol), 131.78 (C2-thiophenol), 130.17 (C3-thio-
phenol), 129.62 (C6-thiophenol), 125.16 (C4-thiophenol), 113.40
(quaternary-C), 92.29 (C-1), 87.78 (C-4), 86.19 (C-2), 81.89 (C-3),
63.37 (C-5), 34.49 (thiophenol-C(CH3)3), 31.30 (3C, thiophenol-
C(CH3)3), 26.91 (isopropylidene-CH3), 25.21 (isopropylidene-CH3),
20.31(thiophenol-CH3); HRMS (ESIþ) calcd. for Chemical Formula:
C
19H28 NaO4Sþ 375.1601, found 375.1611.
4.2.2. (3aR,4S,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)thio)-
2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde (3b)
A solution of Dess-Martin periodinane (9 g, 22.1 mmol, 1.3
equiv.) in DCM (100 mL) was treated dropwise with another solu-
tion of compound 5 (6 g, 17.0 mmol, 1 equiv.) in DCM (50 mL). The
mixture was stirred at RT for 4 h. The reaction was quenched by sat.
aq. NaHCO3 and sat. aq. Na2S2O3, and extracted with DCM. The
organic phase was washed with brine, concentrated, and purified
with flash chromatography (on silica gel with 60e90 ꢁC petroleum
ether: EtOAc ¼ 10:1e5:1) to give product 3b (colorless oil, 4.6 g,
13.1 mmol, 77%). Compound 7: Rf 0.30e0.80 (ethyl acetate:
Selected NMR data (d) of 12a derivatives
12aR (19% from 12a)b
H3 ¼ 4.05
12aS (62% from 12a)b
Dd
H3 ¼ 4.48
ꢀ0.43
ꢀ0.28
60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.44 min; [
a]
¼ ꢀ36
D
d
H4 ¼ 3.92
H4 ¼ 4.20
H5 ¼ 5.34e5.25
(20 ꢁC, c ¼ 0.29, CHCl3); 1H NMR (600 MHz, Chloroform-d)
9.73 (s,
1H, eCHO), 7.62 (m, 1H, H6-thiophenol), 7.21 (m, 1H, H3-thio-
phenol), 7.13 (m, 1H, H4-thiophenol), 5.87 (s, 1H, H-1), 5.21 (d,
J ¼ 6.0 Hz, 1H, H-3), 4.74 (d, J ¼ 6.0 Hz, 1H, H-2), 4.48 (t, J ¼ 0.9 Hz,
1H, H-4), 2.32 (s, 3H, thiophenol-CH3), 1.53 (s, 3H, isopropylidene-
CH3), 1.36 (s, 3H, isopropylidene-CH3), 1.33 (s, 9H, thiophenol-
H5 ¼ 5.14
ꢀ0.20 ~ ꢀ0.11
CH2]CHeCH2-a ¼ 2.68
CH2]CHeCH2-b ¼ 2.57
CH2]CHeCH2 ¼ 5.79
CH2]CHeCH2 ¼ 5.18
CF3 ¼ ꢀ71.66
CH2]CHeCH2-a ¼ 2.56
CH2]CHeCH2-b ¼ 2.39
CH2]CHeCH2 ¼ 5.66
CH2]CHeCH2e ¼ 5.07
CF3 ¼ ꢀ71.10
þ0.12
þ0.18
þ0.13
þ0.11
ꢀ0.56
C(CH3)3); 13C NMR (126 MHz, Chloroform-d)
d 200.51 (eCHO),
149.80 (C5-thiophenol), 135.46 (C1-thiophenol), 131.47 (C2-thio-
phenol),130.25 (C3-thiophenol),127.31 (C6-thiophenol),124.57 (C4-
thiophenol), 113.33 (quaternary-C), 91.23 (C-1), 90.06 (C-4), 85.00
(C-2), 81.76 (C-3), 34.60 (thiophenol-C(CH3)3), 31.34 (3C, thio-
phenol-C(CH3)3), 26.31 (isopropylidene-CH3), 25.05 (iso-
propylidene-CH3), 19.93 (thiophenol-CH3); HRMS (ESIþ) calcd. for
Selected NMR data (d) of 12b derivatives
12bR (31% from 12b)b
H3 ¼ 4.74e4.65
H4 ¼ 4.16
H5 ¼ 5.51
12bS (19% from 12b)b
H3 ¼ 4.51
Dd
þ0.23 ~ þ0.14
þ0.05
H4 ¼ 4.11
H5 ¼ 5.52
ꢀ0.01
CH2]CHeCH2-a ¼ 2.47
CH2]CHeCH2-b ¼ 2.34
CH2]CHeCH2 ¼ 5.60
CH2]CHeCH2e ¼ 4.96
CF3 ¼ ꢀ71.14
CH2]CHeCH2-a ¼ 2.58
CH2]CHeCH2-b ¼ 2.39
CH2]CHeCH2 ¼ 5.72
CH2]CHeCH2e ¼ 5.07
CF3 ¼ ꢀ71.25
ꢀ0.11
ꢀ0.15
ꢀ0.12
ꢀ0.11
þ0.11
C
20H30NaO5Sþ 405.1706 (MþMeOHþNaþ), found 405.1723.
4.2.3. General procedure A
A solution of compound 3b (50 mg, 0.14 mmol, 1 equiv.) in THF
(3 mL) was cooled to ꢀ78 ꢁC and treated with Grignard reagent
(0.43 mmol, 3 equiv.). The mixture was stirred at this temperature
for 2 h. The reaction was quenched by sat. aq. NH4Cl, concentrated,
and extracted TBME. The organic phase was washed with brine,
concentrated, and purified with flash chromatography (on silica gel
on silica gel with 60e90 ꢁC petroleum ether: EtOAc ¼ 20:1e10:1) to
give products 6a,b through 15.
a
Reaction conditions: a) (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl
(16a), pyridine, MeCN; b) (S)-3,3,3-trifluoro-2-methoxy-2-
chloride
phenylpropanoyl chloride (16b), pyridine, MeCN.
b
Chromatography separation yields.
and extracted with
a mixture of DCM and MeOH (DCM:
MeOH ¼ 10:1, v/v). The organic phase was washed with sat. aq.
NaHCO3 and brine and concentrated to give a light yellow oil
(22.0 g).
4.2.4. General procedure B
A solution of above-mentioned light yellow oil (22.0 g) in
acetone (160 mL) was treated with Me2C(OMe)2 (40 mL,
325.3 mmol) and p-TSA hydrate (2 g, 11.6 mmol) and stirred at RT
for 4 h. The reaction was quenched by sat. aq. NaHCO3, concen-
trated, and extracted with DCM. The organic phase was washed
with brine, concentrated, and purified with flash chromatography
(on silica gel with 60e90 ꢁC petroleum ether: EtOAc ¼ 10:1e5:1) to
give product 5 (colorless oil, 10 g, 28.4 mmol, 45% based on com-
pound 4). Compound 5: Rf 0.36 (ethyl acetate: 60e90 ꢁC petroleum
A solution of compound 3b (200 mg, 0.57 mmol, 1 equiv.) in THF
(10 mL) was cooled to 0 ꢁC and treated with Grignard reagent
(1.71 mmol, 3 equiv.). The mixture was stirred at this temperature
for 5 h. The reaction was quenched by sat. aq. NH4Cl, concentrated,
and extracted TBME. The organic phase was washed with brine,
concentrated, and purified with flash chromatography (on silica gel
on silica gel with 60e90 ꢁC petroleum ether: EtOAc ¼ 20:1e10:1) to
give products 6a,b through 15.
ether, 1/5); HPLC tR 4.07 min; [
a
]
D
¼ ꢀ76 (20 ꢁC, c ¼ 0.71, CDCl3); 1H
4.2.5. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol
(6a) and (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol
(6b)
NMR (400 MHz, Chloroform-d)
d
7.60 (m, 1H, H6-thiophenol),
7.28e7.22 (m, 1H, H3-thiophenol), 7.18 (d, J ¼ 8.0 Hz, 1H, H4-thio-
phenol), 5.54 (d, J ¼ 2.4 Hz, 1H, H-1), 4.84 (dd, J ¼ 6.3, 1.6 Hz, 1H, H-
3), 4.80 (dd, J ¼ 6.2, 2.5 Hz, 1H, H-2), 4.39 (ddd, J ¼ 4.8, 3.4, 1.6 Hz,
1H, H-4), 3.85 (dd, J ¼ 12.4, 3.4 Hz, 1H, H-5), 3.77 (dd, J ¼ 12.3,
According to general procedure A, MeMgBr (3 M in Et2O) yielded

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2297
Table 5
Determination of absolute stereochemistry on Mosher's acid derivatives 13aR, 13aS, 13bR, and 13bS.a
(colorless oil, 22 mg, 0.06 mmol, 11%) and compound 6b (colorless
oil, 170 mg, 0.46 mmol, 82%). Compound 6a: Rf 0.60 (ethyl acetate:
60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.31 min; [
a
]
¼ ꢀ30
D
(20 ꢁC, c ¼ 0.25, CHCl3); 1H NMR (400 MHz, Chloroform-d)
d 7.62
(m, 1H, H6-thiophenol), 7.23 (m, 1H, H3-thiophenol), 7.15 (m, 1H,
H4-thiophenol), 5.56 (d, J ¼ 2.4 Hz, 1H, H-1), 4.79 (dd, J ¼ 6.1, 2.4 Hz,
1H, H-2), 4.72 (dd, J ¼ 6.2, 1.9 Hz, 1H, H-3), 4.07 (dd, J ¼ 5.7, 1.9 Hz,
1H, H-4), 3.89 (m, 1H, H-5), 2.39 (s, 3H, thiophenol-CH3), 1.53 (m,
3H, isopropylidene-CH3), 1.36 (m, 3H, isopropylidene-CH3), 1.31 (s,
9H, thiophenol-C(CH3)3), 1.26 (d, J ¼ 6.4 Hz, 3H, eCH3), hydroxyl
proton was not found; 13C NMR (126 MHz, Chloroform-d)
d149.83
(C5-thiophenol), 136.17 (C1-thiophenol), 132.02 (C2-thiophenol),
130.21 (C3-thiophenol), 128.96 (C6-thiophenol), 124.96 (C4-thio-
phenol), 113.46 (quaternary-C), 91.82 (C-1), 91.58 (C-4), 86.18 (C-2),
82.43 (C-3), 68.01 (C-5), 34.53 (thiophenol-C(CH3)3), 31.31 (3C,
thiophenol-C(CH3)3), 26.92 (isopropylidene-CH3), 25.24 (iso-
propylidene-CH3), 20.22 (thiophenol-CH3), 19.24 (eCH3); HRMS
(ESIþ) calcd. for C20H30NaO4Sþ 389.1757, found 389.1766. Com-
pound 6b: Rf 0.42 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/5);
HPLC tR 4.26 min; [
(400 MHz, Chloroform-d)
a
]
¼ ꢀ59 (20 ꢁC, c ¼ 0.69, CHCl3); 1H NMR
Scheme 4. Oxidation of compound 13b yielded compound 17. Reaction conditions: a)
mCPBA, DCM, RT, over night, 67%.
D
d
7.58 (m, 1H, H6-thiophenol), 7.23 (m,
1H, H3-thiophenol), 7.15 (m, 1H, H4-thiophenol), 5.45 (d, J ¼ 3.0 Hz,
1H, H-1), 4.88 (dd, J ¼ 6.4, 2.1 Hz, 1H, H-3), 4.71 (dd, J ¼ 6.4, 3.0 Hz,
1H, H-2), 4.08 (dd, J ¼ 3.3, 2.2 Hz,1H, H-4), 4.04 (m,1H, H-5), 2.40 (s,
3H, thiophenol eCH3), 1.53 (s, 3H, isopropylidene-CH3), 1.37 (s, 3H,
isopropylidene-CH3), 1.31 (s, 9H, thiophenol eC(CH3)3), 1.24 (d,
compound 6a (colorless oil, 3 mg, 8.5 mmol, 6%) and compound 6b
(colorless oil, 45 mg, 0.12 mmol, 86%). Alternatively, according to
general procedure B, MeMgBr (3 M in Et2O) yielded compound 6a

2298
H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
J ¼ 6.4 Hz, 3H, eCH3), hydroxyl proton was not found; 13C NMR
129.41 (C6-thiophenol), 124.99 (C4-thiophenol), 113.57 (quater-
nary-C), 91.59 (C-1), 88.68 (C-4), 85.99 (C-2), 80.68 (C-3), 76.45 (C-
5), 34.52 (thiophenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3),
30.08 (eCH(CH3)2), 27.05 (isopropylidene-CH3), 25.26 (iso-
propylidene-CH3), 20.33 (thiophenol-CH3), 19.21 (eCH(CH3)2),
18.09 (eCH(CH3)2); HRMS (ESIþ) calcd. for C22H34NaO4Sþ 417.2070,
found 417.2079.
(126 MHz, Chloroform-d)
d
149.72 (C5-thiophenol), 136.53 (C1-
thiophenol), 131.70 (C2-thiophenol), 130.12 (C3-thiophenol), 129.73
(C6-thiophenol), 125.15 (C4-thiophenol), 113.60(quaternary-C),
91.86 (C-1), 91.53 (C-4), 85.89 (C-2), 80.06 (C-3), 67.59 (C-5), 34.50
(thiophenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 27.01 (iso-
propylidene-CH3), 25.24 (isopropylidene-CH3), 20.33 (thiophenol-
CH3), 18.34 (eCH3); HRMS (ESIþ) calcd. for C20H30NaO4Sþ 389.1757,
found 389.1759.
4.2.8. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)prop-2-en-
1-ol (9a) and (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-
methylphenyl)thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-
4-yl)prop-2-en-1-ol (9b)
4.2.6. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)propan-1-
ol (7)
According to general procedure A, vinylmagnesium bromide
a) According to general procedure A, EtMgBr (1 M in THF) yielded
(1 M in THF) yielded compound 9a (colorless oil, 4 mg, 9.7
mmol,
compound 7 (colorless oil, 35 mg, 92
mmol, 65%). Alternatively,
6.8%) and compound 9b (colorless oil, 37 mg, 98 mol, 69%).
m
according to general procedure B, EtMgBr (1 M in THF) yielded
compound 7 (colorless oil, 148 mg, 0.39 mmol, 68%). Compound
7: Rf 0.57 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR
Alternatively, according to general procedure B, vinylmagnesium
bromide (1 M in THF) yielded compound 9a (colorless oil, 24 mg,
63 mmol, 11%) and compound 9b (colorless oil, 130 mg, 0.34 mmol,
4.45 min; [
Chloroform-d)
a
]
¼ ꢀ47 (20 ꢁC, c ¼ 0.34, CHCl3); 1H NMR (400 MHz,
60%). Compound 9a: Rf 0.63 (ethyl acetate: 60e90 ꢁC petroleum
D
d
7.58 (m, 1H, H6-thiophenol), 7.25e7.20 (m, 1H,
ether, 1/5); HPLC tR 4.41 min; [
NMR (400 MHz, Chloroform-d)
a
]
d
¼ ꢀ18 (20 ꢁC, c ¼ 0.45, CHCl3); 1H
D
H3-thiophenol), 7.15 (m, 1H, H4-thiophenol), 5.44 (d, J ¼ 3.0 Hz,
1H, H-1), 4.87 (dd, J ¼ 6.3, 2.2 Hz, 1H, H-3), 4.71 (dd, J ¼ 6.4,
3.0 Hz,1H, H-2), 4.15 (dd, J ¼ 3.4, 2.2 Hz,1H, H-4), 3.76 (m, 1H, H-
5), 2.39 (s, 3H thiophenol-CH3), 1.58 (m, 1H, eCH2CH3), 1.53 (s,
3H, isopropylidene-CH3), 1.36 (s, 3H, isopropylidene-CH3), 1.31
(s, 9H, thiophenol-C(CH3)3), 1.01 (t, J ¼ 7.4 Hz, 3H, eCH2CH3),
hydroxyl proton was not found; 13C NMR (151 MHz, Chloroform-
7.60 (m, 1H, H6-thiophenol), 7.23
(m, 1H, H4-thiophenol), 7.15 (m, 1H, H3-thiophenol), 5.87 (m, 1H,
eCH]CH2); 5.55 (d, J ¼ 1.9 Hz, 1H, H-1), 5.42 (m, 1H, eCH]CH2),
5.29 (m, 1H, eCH]CH2), 4.85e4.77 (m, 2H, H-2, H-3), 4.27 (m, 1H,
H-5), 4.22 (dd, J ¼ 5.9, 1.4 Hz, 1H, H-4), 2.40 (s, 3H, thiophenol-CH3),
1.52 (s, 3H, isopropylidene-CH3), 1.36 (s, 3H, isopropylidene-CH3),
1.30 (s, 9H, thiophenol-C(CH3)3), hydroxyl proton was not found;
d)
d
149.71 (C5-thiophenol), 136.49 (C1-thiophenol), 131.81 (C2-
13C NMR (126 MHz, Chloroform-d) 149.83 (C5-thiophenol), 136.39
d
thiophenol), 130.12 (C3-thiophenol), 129.63 (C6-thiophenol),
125.12 (C4-thiophenol), 113.54(quaternary-C), 91.84 (C-1), 90.33
(C-4), 85.96 (C-2), 80.37 (C-3), 73.03 (C-5), 34.51 (thiophenol-
C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 27.02 (isopropylidene-
CH3), 25.56 (eCH2CH3), 25.23 (isopropylidene-CH3), 20.36 (thi-
ophenol-CH3), 10.21 (eCH2CH3); HRMS (ESIþ) calcd. for
(C1-thiophenol), 136.33 (eCH]CH2), 131.85 (C2-thiophenol), 130.19
(C3-thiophenol), 129.40 (C6-thiophenol), 125.10 (C4-thiophenol),
117.87 (eCH]CH2), 113.51 (quaternary-C), 92.19 (C-1), 90.13 (C-4),
86.13 (C-2), 82.07 (C-3), 73.13 (C-5), 34.53 (thiophenol-C(CH3)3),
31.31 (3C, thiophenol-C(CH3)3), 26.89 (isopropylidene-CH3), 25.26
(isopropylidene-CH3), 20.28 (thiophenol-CH3); HRMS (ESIþ) calcd.
for C21H30NaO4Sþ 401.1757, found 401.1768. Compound 9b: Rf 0.53
(ethyl acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.40 min;
C
21H32NaO4Sþ 403.1914, found 403.1920.
b) Compound 9b (30 mg, 72 mol, 1 equiv.), prepared in section
m
4.2.8, was dissolved in MeOH (10 mL), treated with 10% Pd/C
(100 mg), and subjected to hydrogenation condition at 1 atm
and RT for 8 h. The reaction mixture was filtered, dried and
purified with flash chromatography (on silica gel on silica gel
with 60e90 ꢁC petroleum ether: EtOAc ¼ 10:1e5:1) to give
[
d)
a
]
d
¼ ꢀ47 (20 ꢁC, c ¼ 0.26, CHCl3); 1H NMR (400 MHz, Chloroform-
D
7.59 (m, 1H, H6-thiophenol), 7.23 (m, 1H, H4-thiophenol), 7.16
(m, 1H, H3-thiophenol), 5.89 (ddd, J ¼ 17.2, 10.7, 4.6 Hz, 1H, eCH]
CH2), 5.46 (m, 2H, eCH]CH2, H-1), 5.30 (m, 1H, eCH]CH2), 4.85
(dd, J ¼ 6.3, 2.0 Hz, 1H, H-2), 4.73 (dd, J ¼ 6.3, 2.9 Hz, 1H, H-3), 4.45
(m, 1H, H-5), 4.25 (m, 1H, H-4), 2.40 (s, 3H, thiophenol-CH3), 1.52 (s,
3H, isopropylidene-CH3), 1.35 (s, 3H, isopropylidene-CH3), 1.31 (s,
9H, thiophenol-C(CH3)3), hydroxyl proton was not found; 13C NMR
product 7 (colorless oil, 24 mg, 63 mmol, 80%), which showed
parallel proton NMR to that produced above.
(126 MHz, Chloroform-d)
d
149.77 (C5-thiophenol), 136.53 (C1-
4.2.7. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-
methylpropan-1-ol (8)
thiophenol), 135.03 (eCH]CH2), 131.71 (C2-thiophenol), 130.15
(C3-thiophenol), 129.74 (C6-thiophenol), 125.21 (C4-thiophenol),
117.08 (eCH]CH2), 113.49 (quaternary-C), 92.57 (C-1), 90.36 (C-4),
85.92 (C-2), 80.17 (C-3), 72.12 (C-5), 34.51 (thiophenol-C(CH3)3),
31.31 (3C, thiophenol-C(CH3)3), 27.00 (isopropylidene-CH3), 25.26
(isopropylidene-CH3), 20.36 (thiophenol-CH3); HRMS (ESIþ) calcd.
for C21H30NaO4Sþ 401.1757, found 401.1762.
According to general procedure A, i-PrMgBr (1 M in THF) yielded
compound 8 (colorless oil, 33 mg, 84
mmol, 59%). Alternatively,
according to general procedure B, i-PrMgBr (1 M in THF) yielded
compound 8 (colorless oil, 138 mg, 0.35 mmol, 61%). Compound 8:
Rf 0.63 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR
4.65 min; [
Chloroform-d)
a
]
¼ ꢀ31 (20 ꢁC, c ¼ 0.35, CHCl3); 1H NMR (400 MHz,
4.2.9. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-
methylprop-2-en-1-ol (10a) and (S)-1-((3aR,4R,6S,6aR)-6-((5-
(tert-butyl)-2-methylphenyl)thio)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)-2-methylprop-2-en-1-ol (10b)
According to general procedure A, isopropenylmagnesium bro-
mide (1 M in THF) yielded compound 10a (colorless oil, 11 mg,
28 mmol, 19%) and compound 10b (colorless oil, 32 mg, 82 mmol,
D
d
7.58 (m, 1H, H6-thiophenol), 7.22 (m, 1H, H3-thi-
ophenol), 7.14 (m, 1H, H4-thiophenol), 5.44 (d, J ¼ 3.0 Hz, 1H, H-1),
4.88 (dd, J ¼ 6.4, 2.3 Hz, 1H, H-3), 4.70 (dd, J ¼ 6.4, 3.0 Hz, 1H, H-2),
4.28 (dd, J ¼ 4.0, 2.3 Hz, 1H, H-4), 3.57e3.49 (m, 1H, H-5), 2.39 (s,
3H, thiophenol-CH3), 1.53 (s, 3H, isopropylidene-CH3), 1.84 (m, 1H,
eCH(CH3)2), 1.36 (s, 3H, isopropylidene-CH3), 1.31 (s, 9H, thio-
phenol-C(CH3)3), 1.01 (d, J ¼ 6.7 Hz, 3H, eCH(CH3)2), 0.96 (d,
J ¼ 6.8 Hz, 3H, eCH(CH3)2), hydroxyl proton was not found; 13C
57%). Alternatively, according to general procedure B, vinyl-
magnesium bromide (1 M in THF) yielded compound 10a (colorless
oil, 69 mg, 0.18 mmol, 31%) and compound 10b (colorless oil,
NMR (151 MHz, Chloroform-d)
(C1-thiophenol), 131.97 (C2-thiophenol), 130.10(C3-thiophenol),
d
149.69 (C5-thiophenol), 136.35

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2299
105 mg, 0.27 mmol, 47%). Compound 10a: Rf 0.63 (ethyl acetate:
found 415.1915. Compound 12b: Rf 0.71 (ethyl acetate: 60e90 ꢁC
60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.61 min; [
a
]
¼ ꢀ62
petroleum ether,1/5); HPLC tR 4.52 min; [
a]
¼ ꢀ44 (20 ꢁC, c ¼ 0.34,
D
D
d
(20 ꢁC, c ¼ 0.35, CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.60
CHCl3); 1H NMR (400 MHz, Chloroform-d) 7.58 (m, 1H, H6-thio-
(m, 1H, H6-thiophenol), 7.21 (m, 1H, H4-thiophenol), 7.14 (m, 1H,
H3-thiophenol), 5.54 (d, J ¼ 2.0 Hz, 1H, H-1), 5.08 (m, 1H, ¼CH2),
5.01 (m, 1H, ¼CH2), 4.80 (m, 2H, H-2, H-3), 4.39 (dd, J ¼ 5.8, 1.6 Hz,
1H, H-4), 4.19 (d, J ¼ 5.7 Hz, 1H, H-5), 2.39 (s, 3H, thiophenol-CH3),
1.80 (s, 3H, eCH3), 1.53 (s, 3H, isopropylidene-CH3), 1.36 (s, 3H,
isopropylidene-CH3), 1.30 (s, 9H, thiophenol-C(CH3)3), hydroxyl
proton was not found; 13C NMR (126 MHz, Chloroform-d)
phenol), 7.22 (m, 1H, H4-thiophenol), 7.13 (m, 1H, H3-thiophenol),
5.84 (m, 1H, eCH2CH]CH2), 5.49 (d, J ¼ 2.6 Hz, 1H, H-1), 5.15 (m,
2H, eCH2CH]CH2), 4.92 (dd, J ¼ 6.3, 2.2 Hz, 1H, H-3), 4.74 (dd,
J ¼ 6.3, 2.7 Hz, 1H, H-2), 4.12 (dd, J ¼ 4.7, 2.2 Hz, 1H, H-4), 3.92 (m,
1H, H-5), 2.32 (m, 5H, eCH2CH]CH2, thiophenol-CH3), 1.53 (s, 3H,
isopropylidene-CH3), 1.36 (s, 3H, isopropylidene-CH3), 1.31 (s, 9H,
thiophenol-C(CH3)3), hydroxyl proton was not found; 13C NMR
d
149.78(C5-thiophenol), 143.49 (-C(CH3) ¼ CH2), 136.28 (C1-thio-
(126 MHz, Chloroform-d) d
149.71 (C5-thiophenol), 136.23 (C1-
phenol), 132.01 (C2-thiophenol), 130.11 (C3-thiophenol), 129.33 (C6-
thiophenol), 124.99 (C4-thiophenol), 113.71 (-C(CH3) ¼ CH2), 113.43
(quaternary-C), 92.36 (C-1), 88.76 (C-4), 86.23 (C-2), 82.56 (C-3),
75.52 (C-5), 34.52 (thiophenol-C(CH3)3), 31.29 (3C, thiophenol-
C(CH3)3), 26.91 (isopropylidene-CH3), 25.24 (isopropylidene-CH3),
20.27 (thiophenol-CH3), 18.63 (-C(CH3) ¼ CH2); HRMS (ESIþ) calcd.
for C22H32NaO4Sþ 415.1914, found 415.1923. Compound 10b: Rf 0.53
(ethyl acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.58 min;
thiophenol),133.82 (eCH2CH]CH2),131.99 (C2-thiophenol),130.09
(C3-thiophenol), 129.23 (C6-thiophenol), 124.93 (C4-thiophenol),
118.41 (eCH2CH]CH2), 113.55 (quaternary-C), 91.80 (C-1), 89.86
(C-4), 86.02 (C-2), 80.79 (C-3), 70.76 (C-5), 37.33 (eCH2CH]CH2),
34.51 (thiophenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 26.97
(isopropylidene-CH3), 25.24 (isopropylidene-CH3), 20.29 (thio-
phenol-CH3); HRMS (ESIþ) calcd. for C22H32NaO4Sþ 415.1914, found
415.1919.
[
a]
¼ ꢀ92 (20 ꢁC, c ¼ 0.44, CHCl3); 1H NMR (400 MHz, Chloroform-
D
d)
d
7.59 (m, 1H, H6-thiophenol), 7.23 (m, 1H, H4-thiophenol), 7.15
4.2.11. (S)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)
methanol (13a) and (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-
methylphenyl)thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-
4-yl)(phenyl)methanol (13b)
(m, 1H, H3-thiophenol), 5.48 (d, J ¼ 2.9 Hz, 1H, H-1), 5.21 (m,
1H, ¼CH2), 5.03 (m, 1H, ¼CH2), 4.84 (dd, J ¼ 6.3, 2.1 Hz, 1H, H-3),
4.73 (dd, J ¼ 6.3, 2.9 Hz, 1H, H-2), 4.37 (dd, J ¼ 3.4, 2.2 Hz, 1H, H-4),
4.30 (d, J ¼ 3.4 Hz,1H, H-5), 2.40 (s, 3H, thiophenol-CH3),1.79 (s, 3H,
eCH3), 1.52 (s, 3H, isopropylidene-CH3), 1.35 (s, 3H, isopropylidene-
CH3), 1.31 (s, 9H, thiophenol-C(CH3)3), hydroxyl proton was not
According to general procedure A, phenylmagnesium bromide
(1 M in THF) yielded compound 13a (colorless oil, 11 mg, 25
mmol,
found; 13C NMR (126 MHz, Chloroform-d)
d
149.74 (C5-thiophenol),
17%) and compound 13b (colorless oil, 41 mg, 96 mol, 67%).
m
142.11 (-C(CH3) ¼ CH2), 136.45 (C1-thiophenol), 131.88 (C2-thio-
phenol), 130.11 (C3-thiophenol), 129.67 (C6-thiophenol), 125.13 (C4-
thiophenol), 113.44 (quaternary-C), 112.86 (-C(CH3) ¼ CH2), 92.57
(C-1), 88.91 (C-4), 85.98 (C-2), 80.21 (C-3), 74.39 (C-5), 34.51 (thi-
ophenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 27.05 (iso-
propylidene-CH3), 25.29 (isopropylidene-CH3), 20.36 (thiophenol-
CH3), 19.81 (-C(CH3) ¼ CH2); HRMS (ESIþ) calcd. for C22H32NaO4Sþ
415.1914, found 415.1920.
Alternatively, according to general procedure B, phenylmagnesium
bromide (1 M in THF) yielded compound 13a (colorless oil, 61 mg,
0.14 mmol, 25%) and compound 13b (colorless oil, 133 mg,
0.31 mmol, 54%). Compound 13a: Rf 0.63 (ethyl acetate: 60e90 ꢁC
petroleum ether,1/5); HPLC tR 4.65 min; [
a
]
¼ ꢀ46 (20 ꢁC, c ¼ 0.45,
D
d
CHCl3); 1H NMR (400 MHz, Chloroform-d)
7.58 (m, 1H, H6-thio-
phenol), 7.35 (m, 5H, Ph), 7.22 (m, 1H, H4-thiophenol), 7.15 (m, 1H,
H3-thiophenol), 5.62 (d, J ¼ 2.2 Hz, 1H, H-1), 4.87 (m, 2H, H-2, H-5),
4.78 (dd, J ¼ 6.1, 1.8 Hz, 1H, H-3), 4.46 (dd, J ¼ 6.7, 1.8 Hz, 1H, H-4),
2.40 (s, 3H, thiophenol-CH3), 1.50 (s, 3H, isopropylidene-CH3), 1.31
(s, 3H, isopropylidene-CH3), 1.27 (s, 9H, thiophenol-C(CH3)3), hy-
droxyl proton was not found; 13C NMR (126 MHz, Chloroform-d)
4.2.10. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-
1-ol (12a) and (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-
methylphenyl)thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-
4-yl)but-3-en-1-ol (12b)
d
149.93 (C5-thiophenol), 139.58 (1C, Ph), 136.07 (C1-thiophenol),
132.16 (C2-thiophenol), 130.22 (C3-thiophenol), 128.71 (C6-thio-
phenol), 128.63 (2C, Ph), 128.19 (1C, Ph), 127.05 (2C, Ph), 124.92 (C4-
thiophenol), 113.44 (quaternary-C), 92.19 (C-1), 91.41 (C-4), 86.27
(C-2), 82.01 (C-3), 74.20 (C-5), 34.51 (thiophenol-C(CH3)3), 31.31
(3C, thiophenol-C(CH3)3), 26.85 (isopropylidene-CH3), 25.24 (iso-
propylidene-CH3), 20.21 (thiophenol-CH3); HRMS (ESIþ) calcd. for
According to general procedure A, allylmagnesium chloride (1 M
in THF) yielded compound 12a (colorless oil, 6 mg, 15
and compound 12b (colorless oil, 29 mg, 74 mol, 52%). Alterna-
tively, according to general procedure B, allylmagnesium chloride
(1 M in THF) yielded compound 12a (colorless oil, 30 mg, 76 mol,
mmol, 10%)
m
m
13%) and compound 12b (colorless oil, 157 mg, 0.40 mmol, 70%).
C
25H32NaO4Sþ 451.1914, found 451.1921. Compound 13b: Rf 0.58
Compound 12a: Rf 0.65 (ethyl acetate: 60e90 ꢁC petroleum ether,1/
(ethyl acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.64 min;
5); HPLC tR 4.62 min; [
(400 MHz, Chloroform-d)
a
]
¼ ꢀ46 (20 ꢁC, c ¼ 0.22, CHCl3); 1H NMR
[
a
]
d
¼ ꢀ35 (20 ꢁC, c ¼ 0.47, CHCl3); 1H NMR (400 MHz, Chloroform-
D
D
d
7.63 (m, 1H, H6-thiophenol), 7.22 (m,
d)
7.57 (m, 1H, H6-thiophenol), 7.35 (m, 5H, Ph), 7.24 (m, 1H, H4-
1H, H4-thiophenol), 7.15 (m, 1H, H3-thiophenol), 5.85 (m, 1H,
eCH2CH]CH2), 5.53 (d, J ¼ 2.4 Hz, 1H, H-1), 5.12 (m, 2H, eCH2CH]
CH2), 4.79 (m, 2H, H-2, H-3), 4.24 (dd, J ¼ 4.2, 1.7 Hz, 1H, H-4), 3.73
(m, 1H, H-5), 2.43e2.31 (m, 5H, eCH2CH]CH2, thiophenol-CH3),
1.52 (s, 3H, isopropylidene-CH3), 1.36 (s, 3H, isopropylidene-CH3),
1.31 (s, 9H, thiophenol-C(CH3)3), hydroxyl proton was not found;
thiophenol), 7.16 (m, 1H, H3-thiophenol), 5.52 (d, J ¼ 2.8 Hz, 1H, H-
1), 5.02 (m, 1H, H-5), 4.88 (dd, J ¼ 6.2, 1.6 Hz, 1H, H-3), 4.79 (dd,
J ¼ 6.2, 2.9 Hz,1H, H-2), 4.50 (dd, J ¼ 4.0,1.6 Hz,1H, H-4), 2.42 (s, 3H,
thiophenol-CH3), 1.47 (s, 3H, isopropylidene-CH3), 1.29 (m, 12H,
isopropylidene-CH3, thiophenol-C(CH3)3), hydroxyl proton was not
found; 13C NMR (126 MHz, Chloroform-d) 149.80 (C5-thiophenol),
d
13C NMR (126 MHz, Chloroform-d)
d
149.81 (C5-thiophenol), 136.03
139.04 (1C, Ph), 136.31 (C1-thiophenol), 131.91 (C2-thiophenol),
130.13 (C3-thiophenol), 129.46 (C6-thiophenol), 128.55 (2C, Ph),
127.72 (1C, Ph), 126.12 (2C, Ph), 125.11 (C4-thiophenol), 113.30
(quaternary-C), 92.90 (C-1), 91.92 (C-4), 86.05 (C-2), 80.36 (C-3),
73.58 (C-5), 34.50 (thiophenol-C(CH3)3), 31.31 (3C, thiophenol-
C(CH3)3), 26.98 (isopropylidene-CH3), 25.25 (isopropylidene-CH3),
20.36 (thiophenol-CH3); HRMS (ESIþ) calcd. for C25H32NaO4Sþ
451.1914, found 451.1920.
(C1-thiophenol), 133.98 (eCH2CH]CH2), 132.12 (C2-thiophenol),
130.16 (C3-thiophenol), 128.77 (C6-thiophenol), 124.90 (C4-thio-
phenol), 117.85 (eCH2CH]CH2), 113.44 (quaternary-C), 92.23 (C-1),
89.30 (C-4), 86.08 (C-2), 82.62 (C-3), 71.56 (C-5), 38.40 (eCH2CH]
CH2), 34.54 (thiophenol-C(CH3)3), 31.32 (3C, thiophenol-C(CH3)3),
26.96 (isopropylidene-CH3), 25.21 (isopropylidene-CH3), 20.23
(thiophenol-CH3); HRMS (ESIþ) calcd. for C22H32NaO4Sþ 415.1914,

2300
H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
4.2.12. (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(4-
fluorophenyl)methanol (14a) and (S)-((3aR,4R,6S,6aR)-6-((5-(tert-
butyl)-2-methylphenyl)thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]
dioxol-4-yl)(4-fluorophenyl)methanol (14b)
4.81 (dd, J ¼ 6.2, 3.0 Hz, 1H, H-2), 4.45 (dd, J ¼ 2.9, 1.6 Hz, 1H, H-4),
2.43 (s, 3H, thiophenol-CH3), 2.33 (s, 3H, toluene-CH3), 1.47 (s, 3H,
isopropylidene-CH3), 1.30 (m, 12H, isopropylidene-CH3, thio-
phenol-C(CH3)3), hydroxyl proton was not found; 13C NMR
(126 MHz, Chloroform-d)
d
149.78 (C5-thiophenol), 136.91
According to general procedure A, 4-fluorophenylmagnesium
bromide (1 M in THF) yielded compound 14a (colorless oil,
(toluene), 136.63 (C1-thiophenol), 134.93 (toluene), 131.67 (C2-thi-
ophenol), 130.57 (toluene), 130.18 (C3-thiophenol), 130.02
(toluene), 127.72 (C6-thiophenol), 126.34 (toluene), 125.49
(toluene), 125.30 (C4-thiophenol), 113.22 (quaternary-C), 92.99 (C-
1), 90.01 (C-4), 86.07 (C-2), 80.12 (C-3), 71.09 (C-5), 34.50 (thio-
phenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 27.00 (iso-
propylidene-CH3), 25.23 (isopropylidene-CH3), 20.38 (thiophenol-
CH3), 19.18 (toluene-CH3); HRMS (ESIþ) calcd. for C26H34NaO4Sþ
465.2070, found 465.2081.
39 mg, 87
mmol, 61%) and compound 14b (colorless oil, 18 mg,
40 mol, 28%). Alternatively, according to general procedure B, 4-
m
fluorophenylmagnesium bromide (1 M in THF) yielded compound
14a (colorless oil, 173 mg, 0.39 mmol, 68%) and compound 14b
(colorless oil, 49 mg, 0.11 mmol, 19%). Compound 14a: Rf 0.52 (ethyl
acetate: 60e90 ꢁC petroleum ether, 1/5); HPLC tR 4.64 min;
[
d)
a
]
d
¼ ꢀ52 (20 ꢁC, c ¼ 0.34, CHCl3); 1H NMR (400 MHz, Chloroform-
D
7.56 (m, 1H, H6-thiophenol), 7.37 (m, 2H, H-fluobenzene), 7.23
(m, 1H, H4-thiophenol), 7.15 (m, 1H, H3-thiophenol), 7.03 (m, 2H, H-
fluobenzene), 5.63 (d, J ¼ 2.1 Hz, 1H, H-1), 4.86 (m, 2H, H-2, H-5),
4.75 (dd, J ¼ 6.2, 1.8 Hz, 1H, H-3), 4.41 (dd, J ¼ 6.7, 1.9 Hz, 1H, H-4),
2.39 (s, 3H, thiophenol-CH3), 1.50 (s, 3H, isopropylidene-CH3), 1.32
(s, 3H, isopropylidene-CH3), 1.27 (s, 9H, thiophenol-C(CH3)3), hy-
droxyl proton was not found; 13C NMR (126 MHz, Chloroform-d)
4.2.14. (R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl chloride
(16a)
The method was adapted from literature.7 A solution of DMF
(93.6 mg,1.28 mmol, 3 equiv.) and (R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoic acid (100 mg, 0.43 mmol,1 equiv.) in MeCN (5 mL)
was cooled to 0 ꢁC and treated with oxalyl chloride (366.2 mg,
2.56 mmol, 6 equiv.). The mixture was stirred at this temperature
for 2 h, evaporated to dryness at 45 ꢁC, co-evaporated with toluene
at 45 ꢁC to remove the excessive oxalyl chloride, and yield com-
pound 16a (brown oil, 98 mg, 0.38 mmol, 90%), which was used
without further purification.
d
162.55 (d, J ¼ 246.5 Hz, C-fluobenzene), 149.96 (C5-thiophenol),
136.04 (C1-thiophenol), 135.42 (C-fluobenzene), 131.99 (C2-thio-
phenol), 130.27 (C3-thiophenol), 128.78 (2C, d, J ¼ 8.1 Hz, C-fluo-
benzene), 128.61 (C6-thiophenol), 124.96 (C4-thiophenol), 115.54
(2C, d, J ¼ 21.6 Hz, C-fluobenzene), 113.54 (quaternary-C), 92.03 (C-
1), 91.38 (C-4), 86.23 (C-2), 81.91 (C-3), 73.58 (C-5), 34.51 (thio-
phenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 26.83 (iso-
propylidene-CH3), 25.21 (isopropylidene-CH3), 20.18 (thiophenol-
4.2.15. (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl chloride
(16b)
CH3); 19F NMR (471 MHz, Chloroform-d)
d
ꢀ114.11 (m), HRMS
The method was adapted from literature.7 A solution of DMF
(93.6 mg, 1.28 mmol, 3 equiv.) and (S)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoic acid (100 mg, 0.43 mmol,1 equiv.) in MeCN (5 mL)
was cooled to 0 ꢁC and treated with oxalyl chloride (366.2 mg,
2.56 mmol, 6 equiv.). The mixture was stirred at this temperature
for 2 h, evaporated to dryness at 45 ꢁC, co-evaporated with toluene
at 45 ꢁC to remove the excessive oxalyl chloride, and yield com-
pound 16b (brown oil, 101 mg, 0.40 mmol, 93%), which was used
without further purification.
(ESIþ) calcd. for C25H31FNaO4Sþ 469.1819, found 469.1827. Com-
pound 14b: Rf 0.46 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/5);
HPLC tR 4.66 min; [
(400 MHz, Chloroform-d)
a
]
¼ ꢀ42 (20 ꢁC, c ¼ 0.29, CHCl3); 1H NMR
D
d
7.54 (m, 1H, H6-thiophenol), 7.42e7.34
(m, 2H, H-fluobenzene), 7.24 (m, 1H, H4-thiophenol), 7.16 (m, 1H,
H3-thiophenol), 7.03 (m, 2H, H-fluobenzene), 5.53 (d, J ¼ 2.7 Hz, 1H,
H-1), 4.99 (d, J ¼ 4.1 Hz, 1H, H-5), 4.86 (dt, J ¼ 6.2, 1.4 Hz, 1H, H-3),
4.79 (dd, J ¼ 6.3, 2.7 Hz, 1H, H-2), 4.44 (dd, J ¼ 4.1, 1.8 Hz, 1H, H-4),
2.41 (s, 3H, thiophenol-CH3), 1.48 (s, 3H, isopropylidene-CH3), 1.30
(s, 3H, isopropylidene-CH3), 1.28 (s, 9H, thiophenol-C(CH3)3), hy-
droxyl proton was not found; 13C NMR (126 MHz, Chloroform-d)
4.2.16. General procedure C
The method was adapted from literature.7 A solution of com-
d
162.24 (d, J ¼ 245.7 Hz, C-fluobenzene), 149.83 (C5-thiophenol),
pound 16a or 16b (10 mg, 40
treated dropwise with another solution of compound 6a/b, 9a/b,
12a/b, 13a/b (26 mol, 1 equiv.) and pyridine (5 mg, 63 mol, 2.4
mmol, 1.5 equiv.) in MeCN (0.5 mL) was
136.16 (C1-thiophenol), 134.90 (C-fluobenzene), 131.88 (C2-thio-
phenol), 130.14 (C3-thiophenol), 129.22 (C6-thiophenol), 127.81 (2C,
d, J ¼ 8.1 Hz, C-fluobenzene), 125.07 (C4-thiophenol), 115.53 (2C, d,
J ¼ 21.4 Hz, C-fluobenzene), 113.43 (quaternary-C), 92.67 (C-1),
91.81 (C-4), 86.02 (C-2), 80.36 (C-3), 72.99 (C-5), 34.50 (thiophenol-
C(CH3)3), 31.29 (3C, thiophenol-C(CH3)3), 26.95 (isopropylidene-
CH3), 25.23 (isopropylidene-CH3), 20.33 (thiophenol-CH3); 19F NMR
m
m
equiv.) in MeCN (0.5 mL). The mixture was stirred at RT for 2 h and
subjected directly to preparative TLC (on silica gel with 60e90 ꢁC
petroleum ether: EtOAc ¼ 10:1) to give Mosher's acid derivatives in
Tables 2e5.
(471 MHz, Chloroform-d)
C
d
ꢀ114.76 (m), HRMS (ESIþ) calcd. for
4.2.17. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl (R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (6aR)
25H31FNaO4Sþ 469.1819, found 469.1823.
4.2.13. (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(o-tolyl)
methanol (15)
According to general procedure C, compound 6a (10 mg,
27
10
mmol, 1 equiv.) yielded compound 6aR (colorless oil, 6 mg,
m
mol, 38%). Compound 6aR: Rf 0.63 (ethyl acetate: 60e90 ꢁC
According to general procedure A, 2-methylphenylmagnesium
bromide (0.9 M in THF) yielded compound 15 (colorless oil,
46 mg, 0.10 mmol, 73%). Alternatively, according to general pro-
cedure B, 2-methylphenylmagnesium bromide (0.9 M in THF)
yielded compound 15 (colorless oil, 199 mg, 0.45 mmol, 79%).
Compound 15: Rf 0.67 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/
petroleum ether, 1/5); HPLC tR 5.32 min; [
a]
¼ ꢀ11 (20 ꢁC, c ¼ 0.34,
7.63e7.57 (m, 2H, Ar),
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.54 (m, H6-thiophenol), 7.42e7.34 (m, 3H, Ar), 7.18 (m, 1H, H3-
thiophenol), 7.10 (m, 1H, H4-thiophenol), 5.24 (d, J ¼ 3.8 Hz, 1H, H-
1), 5.19 (m, 1H, H-5), 4.17 (dd, J ¼ 4.6, 2.1 Hz, 1H, H-4), 4.13 (dd,
J ¼ 6.1, 2.2 Hz, 1H, H-3), 4.07 (dd, J ¼ 6.1, 3.8 Hz, 1H, H-2), 3.59 (s, 3H,
eOCH3), 2.37 (s, 3H, thiophenol-CH3), 1.45 (m, 6H, isopropylidene-
CH3, eCH3), 1.28 (s, 9H, thiophenol-C(CH3)3), 1.17 (s, 3H, iso-
5); HPLC tR 4.78 min; [
(400 MHz, Chloroform-d)
a
]
¼ ꢀ53 (20 ꢁC, c ¼ 0.56, CHCl3); 1H NMR
D
d
7.60 (m, 2H, H6-thiophenol, H-toluene),
7.20 (m, 5H, 2H-thiophenol, 3H-toluene), 5.49 (d, J ¼ 3.0 Hz, 1H, H-
propylidene-CH3); 13C NMR (151 MHz, Chloroform-d)
O), 149.61 (C5-thiophenol), 135.96 (C1-thiophenol), 133.63 (C2-
d 165.98 (C]
1), 5.18 (d, J ¼ 2.9 Hz, 1H, H-5), 4.99 (dd, J ¼ 6.2, 1.6 Hz, 1H, H-3),

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2301
thiophenol), 132.66 (Ph-MTPA), 129.85 (C3-thiophenol), 129.58 (Ph-
MTPA), 128.63 (C6-thiophenol), 128.40 (2C, Ph-MTPA), 127.11 (2C,
Ph-MTPA), 124.41 (C4-thiophenol), 113.82 (quaternary-C), 92.68 (C-
1), 86.63 (C-4), 85.30 (C-2), 81.67 (C-3), 73.42 (C-5), 55.93 (eOCH3),
34.50 (thiophenol-C(CH3)3), 31.31 (3C, thiophenol-C(CH3)3), 27.14
(isopropylidene-CH3), 25.12 (isopropylidene-CH3), 20.29 (thio-
phenol-CH3), 15.93 (eCH3), CF3 and CCF3 were not found; 19F NMR
27
22
mmol, 1 equiv.) yielded compound 6bS (colorless oil, 13 mg,
m
mol, 82%). Compound 6bS: Rf 0.70 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.39 min; [
a]
¼ ꢀ61 (20 ꢁC, c ¼ 0.31,
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.57 (m, 3H, Ar),
7.44e7.39 (m, 3H, Ar), 7.20 (m, 1H, H3-thiophenol), 7.12 (m, 1H, H4-
thiophenol), 5.47e5.39 (m, 2H, H-1, H-5), 4.65 (dd, J ¼ 6.4, 2.9 Hz,
1H, H-2), 4.50 (dd, J ¼ 6.4, 2.2 Hz, 1H, H-3), 4.03 (dd, J ¼ 8.2, 2.2 Hz,
1H, H-4), 3.57 (s, 3H, eOCH3), 2.36 (s, 3H, thiophenol-CH3), 1.46 (s,
3H, isopropylidene-CH3), 1.37 (d, J ¼ 6.3 Hz, 3H, eCH3), 1.30 (s, 9H,
thiophenol-C(CH3)3), 1.26 (s, 3H, isopropylidene-CH3); 13C NMR
(471 MHz, Chloroform-d)
C
d
ꢀ71.92; HRMS (ESIþ) calcd. for
30H37F3NaO6Sþ 605.2155, found 605.2161.
4.2.18. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl (S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (6aS)
(151 MHz, Chloroform-d) d
165.81 (C]O), 149.67 (C5-thiophenol),
135.77 (C1-thiophenol), 132.67 (Ph-MTPA), 132.18 (C2-thiophenol),
129.99 (C3-thiophenol), 129.64 (Ph-MTPA), 128.49 (2C, Ph-MTPA),
128.32 (C6-thiophenol), 127.34 (2C, Ph-MTPA), 124.48 (C4-thio-
phenol), 113.92 (quaternary-C), 91.19 (C-1), 87.70 (C-4), 85.44 (C-2),
81.47 (C-3), 72.06 (C-5), 55.54 (eOCH3), 34.54 (thiophenol-
C(CH3)3), 31.33 (3C, thiophenol-C(CH3)3), 26.80 (isopropylidene-
CH3), 25.02 (isopropylidene-CH3), 20.17 (thiophenol-CH3), 17.15
(eCH3), CF3 and CCF3 were not found; 19F NMR (471 MHz, Chlo-
According to general procedure C, compound 6a (10 mg,
27
24
mmol, 1 equiv.) yielded compound 6aS (colorless oil, 14 mg,
m
mol, 88%). Compound 6aS: Rf 0.67 (ethyl acetate: 60e90 ꢁC
petroleum ether,1/5); HPLC tR 5.32 min; [
a
]
D
¼ ꢀ19 (20 ꢁC, c ¼ 0.39,
7.60e7.55 (m, 2H, Ar),
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.53 (m, 1H, H6-thiophenol), 7.35 (m, 3H, Ar), 7.22 (m, 1H, H3-thi-
ophenol), 7.14 (m, 1H, H4-thiophenol), 5.44 (d, J ¼ 3.4 Hz, 1H, H-1),
5.30 (m, 1H, H-5), 4.67 (dd, J ¼ 6.4, 3.4 Hz, 1H, H-2), 4.51 (dd, J ¼ 6.4,
3.5 Hz, 1H, H-3), 4.13 (dd, J ¼ 7.7, 3.5 Hz, 1H, H-4), 3.46 (s, 3H,
eOCH3), 2.38 (s, 3H, thiophenol-CH3), 1.55 (s, 3H, isopropylidene-
CH3), 1.35 (m, 6H, isopropylidene-CH3, eCH3), 1.30 (s, 9H, thio-
roform-d)
605.2155, found 605.2160.
d
ꢀ71.50; HRMS (ESIþ) calcd. for C30H37F3NaO6Sþ
4.2.21. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)allyl (R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (9aR)
phenol-C(CH3)3); 13C NMR (151 MHz, Chloroform-d)
d 165.90 (C]
O), 149.64 (C5-thiophenol), 136.53 (C1-thiophenol), 132.20 (C2-thi-
ophenol), 132.16 (Ph-MTPA), 130.10 (C3-thiophenol), 129.51 (Ph-
MTPA), 128.75 (C6-thiophenol), 128.41 (2C, Ph-MTPA), 127.38 (2C,
Ph-MTPA), 124.78 (C4-thiophenol), 114.59 (quaternary-C), 90.67 (C-
1), 86.97 (C-4), 85.34 (C-2), 81.34 (C-3), 73.16 (C-5), 55.51 (eOCH3),
34.49 (thiophenol-C(CH3)3), 31.29 (3C, thiophenol-C(CH3)3), 27.20
(isopropylidene-CH3), 25.40 (isopropylidene-CH3), 20.29 (thio-
phenol-CH3), 15.60 (eCH3), CF3 and CCF3 were not found; 19F NMR
According to general procedure C, compound 9a (10 mg,
27
8.4
mmol, 1 equiv.) yielded compound 9aR (colorless oil, 5 mg,
m
mol, 32%). Compound 9aR: Rf 0.69 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.49 min; [
a
]
¼ ꢀ13 (20 ꢁC, c ¼ 0.23,
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.59 (m, 3H, Ar, H6-
thiophenol), 7.46e7.37 (m, 3H, Ar), 7.20 (m,1H, H3-thiophenol), 7.13
(m, 1H, H4-thiophenol), 5.84e5.72 (m, 2H, H-5, eCH]CH2), 5.34 (d,
J ¼ 3.8 Hz, 1H, H-1), 5.28 (m, 2H, eCH]CH2), 4.69 (dd, J ¼ 6.6,
2.8 Hz, 1H, H-3), 4.63 (dd, J ¼ 6.6, 3.8 Hz, 1H, H-2), 4.19 (dd, J ¼ 6.1,
2.8 Hz, 1H, H-4), 3.61 (s, 3H, eOCH3), 2.37 (s, 3H, thiophenol-CH3),
1.51 (s, 3H, isopropylidene-CH3), 1.32 (s, 3H, isopropylidene-CH3),
1.29 (s, 9H, thiophenol-C(CH3)3); 13C NMR (151 MHz, Chloroform-d)
(471 MHz, Chloroform-d)
C
d
ꢀ71.40; HRMS (ESIþ) calcd. for
30H37F3NaO6Sþ 605.2155, found 605.2147.
4.2.19. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl (R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (6bR)
d
165.55 (C]O), 149.68 (C5-thiophenol), 135.96 (C1-thiophenol),
132.65 (Ph-MTPA), 132.00 (C2-thiophenol), 131.35 (C3-thiophenol),
129.92 (Ph-MTPA), 129.67 (eCH]CH2), 128.81 (C6-thiophenol),
128.47 (2C, Ph-MTPA), 127.45 (2C, Ph-MTPA), 124.64 (C4-thio-
phenol), 120.33 (eCH]CH2), 114.63 (quaternary-C), 91.09 (C-1),
86.05 (C-4), 85.11 (C-2), 80.85 (C-3), 75.36 (C-5), 55.75 (eOCH3),
34.52 (thiophenol-C(CH3)3), 31.30 (3C, thiophenol-C(CH3)3), 27.07
(isopropylidene-CH3), 25.27 (isopropylidene-CH3), 20.24 (thio-
phenol-CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz,
According to general procedure C, compound 6b (10 mg,
27
14
mmol, 1 equiv.) yielded compound 6bR (colorless oil, 8 mg,
m
mol, 50%). Compound 6bR: Rf 0.73 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.45 min; [
a
]
¼ ꢀ28 (20 ꢁC, c ¼ 0.19,
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.61 (m, 3H, Ar), 7.44
(m, 3H, Ar), 7.23 (m, 1H, H3-thiophenol), 7.16 (m, 1H, H4-thio-
phenol), 5.47 (m, 1H, H-5), 5.42 (d, J ¼ 3.0 Hz, 1H, H-1), 4.74e4.65
(m, 2H, H-2, H-3), 4.08 (dd, J ¼ 7.1, 2.3 Hz, 1H, H-4), 3.62 (s, 3H,
eOCH3), 2.35 (s, 3H, thiophenol-CH3), 1.52 (s, 3H, isopropylidene-
CH3), 1.34 (s, 3H, isopropylidene-CH3), 1.32 (s, 9H, thiophenol-
C(CH3)3), 1.29 (d, J ¼ 8.1 Hz, 3H, eCH3); 13C NMR (151 MHz, Chlo-
Chloroform-d)
d
ꢀ71.34 (m, 2H, Ar); HRMS (ESIþ) calcd. for
C
31H37F3NaO6Sþ 617.2155, found 617.2165.
4.2.22. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)allyl (S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (9aS)
roform-d)
d
165.88 (C]O), 149.71 (C5-thiophenol), 135.88 (C1-thi-
ophenol), 132.63 (Ph-MTPA), 132.02 (C2-thiophenol), 129.99 (C3-
thiophenol), 129.66 (Ph-MTPA), 128.53 (2C, Ph-MTPA), 128.51 (C6-
thiophenol), 127.44 (2C, Ph-MTPA), 124.59 (C4-thiophenol), 114.42
(quaternary-C), 90.87 (C-1), 87.31 (C-4), 85.30 (C-2), 81.24 (C-3),
72.28 (C-5), 55.61 (eOCH3), 34.54 (thiophenol-C(CH3)3), 31.32 (3C,
thiophenol-C(CH3)3), 27.01 (isopropylidene-CH3), 25.22 (iso-
propylidene-CH3), 20.21 (thiophenol-CH3), 16.65 (eCH3), CF3 and
According to general procedure C, compound 9a (10 mg,
27
15
mmol, 1 equiv.) yielded compound 9aS (colorless oil, 9 mg,
m
mol, 57%). Compound 9aS: Rf 0.56 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.39 min; [
a
]
¼ ꢀ26 (20 ꢁC, c ¼ 0.31,
7.53e7.46 (m, 3H, Ar,
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
H6-thiophenol), 7.39e7.27 (m, 3H, Ar), 7.19 (m, 1H, H3-thiophenol),
7.13 (m, 1H, H4-thiophenol), 5.74 (m, 1H, eCH]CH2), 5.63 (m, 1H,
H-5), 5.53 (d, J ¼ 2.8 Hz, 1H, H-1), 5.43 (m, 2H, eCH]CH2), 4.73 (dd,
J ¼ 6.3, 2.8 Hz, 1H, H-2), 4.58 (dd, J ¼ 6.3, 3.1 Hz, 1H, H-3), 4.23 (dd,
J ¼ 8.5, 3.1 Hz,1H, H-4), 3.41 (s, 3H, eOCH3), 2.36 (s, 3H, thiophenol-
CH3), 1.51 (s, 3H, isopropylidene-CH3), 1.32 (s, 3H, isopropylidene-
CH3), 1.28 (s, 9H, thiophenol-C(CH3)3); 13C NMR (126 MHz, Chlo-
CCF3 were not found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.43;
HRMS (ESIþ) calcd. for C30H37F3NaO6Sþ 605.2155, found 605.2149.
4.2.20. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl (S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (6bS)
According to general procedure C, compound 6b (10 mg,
roform-d) d
165.40 (C]O), 149.62 (C5-thiophenol), 136.34 (C1-

2302
H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
thiophenol), 132.27 (Ph-MTPA), 131.97 (C2-thiophenol), 130.56 (C3-
thiophenol), 130.16 (eCH]CH2), 129.45 (Ph-MTPA), 128.26 (2C, Ph-
MTPA), 128.21 (C6-thiophenol), 127.29 (2C, Ph-MTPA), 124.67 (C4-
thiophenol), 122.23 (eCH]CH2), 114.29 (quaternary-C), 90.84 (C-
1), 86.23 (C-4), 85.50 (C-2), 81.15 (C-3), 76.91 (C-5), 55.62 (eOCH3),
34.47 (thiophenol-C(CH3)3), 31.27 (3C, thiophenol-C(CH3)3), 27.06
(isopropylidene-CH3), 25.35 (isopropylidene-CH3), 20.21 (thio-
phenol-CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz,
4.2.25. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-
1-yl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12aR)
According to general procedure C, compound 12a (10 mg,
27
4.9
mmol, 1 equiv.) yielded compound 12aR (colorless oil, 3 mg,
m
mol, 19%). Compound 12aR: Rf 0.59 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.62 min; [
a
]
¼ ꢀ6.6 (20 ꢁC,
D
c ¼ 0.23, CHCl3); 1H NMR (400 MHz, Chloroform-d)
d 7.68e7.58 (m,
Chloroform-d)
d
ꢀ71.52; HRMS (ESIþ) calcd. for C31H37F3NaO6Sþ
2H, Ar), 7.56 (m, 1H, H6-thiophenol), 7.39 (m, 3H, Ar), 7.18 (m, 1H,
H3-thiophenol), 7.11 (m, 1H, H4-thiophenol), 5.79 (m, 1H,
eCH2CH]CH2), 5.21 (d, J ¼ 4.3 Hz, 1H, H-1), 5.18 (m, 2H, eCH2CH]
CH2), 5.14 (m, 1H, H-5), 4.30 (dd, J ¼ 3.8, 2.0 Hz, 1H, H-2), 4.05 (dd,
J ¼ 6.1, 2.0 Hz,1H, H-3), 3.92 (dd, J ¼ 6.1, 4.2 Hz,1H, H-4), 3.64 (s, 3H,
eOCH3), 2.68 (m, 1H, eCH2CH]CH2), 2.57 (m, 1H, eCH2CH]CH2),
2.38 (s, 3H, thiophenol-CH3), 1.43 (s, 3H, isopropylidene-CH3), 1.29
(s, 9H, thiophenol-C(CH3)3), 1.12 (s, 3H, isopropylidene-CH3); 13C
617.2155, found 617.2163.
4.2.23. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)allyl (R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (9bR)
According to general procedure C, compound 9b (10 mg,
27
17
mmol, 1 equiv.) yielded compound 9bR (colorless oil, 10 mg,
NMR (126 MHz, Chloroform-d)
d
165.69 (C]O), 149.14 (C5-thio-
m
mol, 64%). Compound 9bR: Rf 0.58 (ethyl acetate: 60e90 ꢁC
phenol), 135.28 (C1-thiophenol), 133.48 (Ph-MTPA), 132.17 (C2-thi-
ophenol), 131.51 (C3-thiophenol), 129.33 (Ph-MTPA), 129.15
(eCH2CH]CH2), 127.93 (3C, Ph-MTPA; C6-thiophenol), 126.57 (2C,
Ph-MTPA), 123.80 (C4-thiophenol), 118.97 (eCH2CH]CH2), 113.27
(quaternary-C), 92.44 (C-1), 84.75 (C-4), 83.90 (C-2), 81.18 (C-3),
75.55 (C-5), 55.68 (eOCH3), 34.27 (eCH2CH]CH2), 34.01 (thio-
phenol-C(CH3)3), 30.83 (3C, thiophenol-C(CH3)3), 26.65 (iso-
propylidene-CH3), 24.59 (isopropylidene-CH3), 19.75 (thiophenol-
CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz, Chloro-
petroleum ether, 1/5); HPLC tR 5.71 min; [
a
]
¼ ꢀ40 (20 ꢁC,
D
c ¼ 0.25, CHCl3); 1H NMR (400 MHz, Chloroform-d)
d 7.60e7.53 (m,
2H, Ar), 7.51 (m, 1H, H6-thiophenol), 7.41e7.31 (m, 3H, Ar), 7.18 (m,
1H, H3-thiophenol), 7.11 (m, 1H, H4-thiophenol), 5.94 (m, 1H,
eCH]CH2), 5.58 (m, 2H, eCH]CH2), 5.45 (m, 1H, H-5), 5.34 (d,
J ¼ 3.3 Hz, 1H, H-1), 4.33 (dd, J ¼ 6.2, 2.3 Hz, 1H, H-3), 4.29 (m, 2H,
H-2, H-4), 3.51 (s, 3H, eOCH3), 2.37 (s, 3H, thiophenol-CH3), 1.47 (s,
3H, isopropylidene-CH3), 1.28 (s, 9H, thiophenol-C(CH3)3), 1.22 (s,
3H, isopropylidene-CH3); 13C NMR (151 MHz, Chloroform-d)
form-d)
found 631.2317.
d
ꢀ71.66; HRMS (ESIþ) calcd. for C32H39F3NaO6Sþ 631.2312,
d
165.67 (C]O), 149.64 (C5-thiophenol), 136.00 (C1-thiophenol),
133.10 (C2-thiophenol), 132.33 (Ph-MTPA), 131.03 (C3-thiophenol),
129.93 (eCH]CH2), 129.56 (Ph-MTPA), 128.43 (C6-thiophenol),
128.35 (2C, Ph-MTPA), 127.36 (2C, Ph-MTPA), 124.49 (C4-thio-
phenol), 122.28 (eCH]CH2), 113.94 (quaternary-C), 92.18 (C-1),
86.10 (C-4), 85.43 (C-2), 81.38 (C-3), 77.15 (C-5), 55.77 (eOCH3),
34.49 (thiophenol-C(CH3)3), 31.28 (3C, thiophenol-C(CH3)3), 27.07
(isopropylidene-CH3), 25.19 (isopropylidene-CH3), 20.26 (thio-
phenol-CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz,
4.2.26. (S)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-
1-yl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12aS)
According to general procedure C, compound 12a (10 mg,
27
16
mmol, 1 equiv.) yielded compound 12aS (colorless oil, 10 mg,
m
mol, 62%). Compound 12aS: Rf 0.54 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.56 min; [
a
]
¼ ꢀ10 (20 ꢁC, c ¼ 0.28,
7.62e7.54 (m, 2H, Ar),
D
Chloroform-d)
617.2155, found 617.2169.
d
ꢀ71.96; HRMS (ESIþ) calcd. for C31H37F3NaO6Sþ
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.52 (m, 1H, H6-thiophenol), 7.44e7.39 (m, 1H, Ar), 7.37e7.32 (m,
2H, Ar), 7.20 (m, 1H, H3-thiophenol), 7.12 (m, 1H, H4-thiophenol),
5.66 (m, 1H, eCH2CH]CH2), 5.34e5.25 (m, 2H, H-1, H-5), 5.07 (m,
1H, eCH2CH]CH2), 5.02 (m, 1H, eCH2CH]CH2), 4.55 (dd, J ¼ 6.4,
3.9 Hz, 1H, H-2), 4.48 (dd, J ¼ 6.4, 3.5 Hz, 1H, H-3), 4.20 (dd, J ¼ 6.6,
3.5 Hz, 1H, H-4), 3.45 (s, 3H, eOCH3), 2.56 (m, 1H, eCH2CH]CH2),
2.39 (m, 4H, eCH2CH]CH2, thiophenol-CH3), 1.51 (s, 3H, iso-
propylidene-CH3), 1.31 (s, 3H, isopropylidene-CH3), 1.27 (s, 9H,
4.2.24. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)allyl (S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (9bS)
According to general procedure C, compound 9b (10 mg,
27
13
mmol, 1 equiv.) yielded compound 9bS (colorless oil, 8 mg,
m
mol, 51%). Compound 9bS: Rf 0.61 (ethyl acetate: 60e90 ꢁC
petroleum ether, 1/5); HPLC tR 5.42 min; [
a
]
¼ ꢀ25 (20 ꢁC, c ¼ 0.31,
thiophenol-C(CH3)3); 13C NMR (126 MHz, Chloroform-d)
d 165.56
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.56 (m, 3H, Ar, H6-
(C]O), 149.16 (C5-thiophenol), 136.07 (C1-thiophenol), 131.93 (Ph-
MTPA), 131.51 (C2-thiophenol), 131.27 (C3-thiophenol), 129.54 (Ph-
MTPA), 129.06 (eCH2CH]CH2), 128.50 (C6-thiophenol), 127.88 (2C,
Ph-MTPA), 127.13 (2C, Ph-MTPA), 124.28 (C4-thiophenol), 118.80
(eCH2CH]CH2), 114.17 (quaternary-C), 90.39 (C-1), 84.63 (C-4),
84.47 (C-2), 80.72 (C-3), 74.98 (C-5), 55.02 (eOCH3), 34.20
(eCH2CH]CH2), 33.99 (thiophenol-C(CH3)3), 30.80 (3C, thio-
phenol-C(CH3)3), 26.77 (isopropylidene-CH3), 24.89 (iso-
propylidene-CH3), 19.80 (thiophenol-CH3), CF3 and CCF3 were not
thiophenol), 7.41 (m, 3H, Ar), 7.19 (m, 1H, H3-thiophenol), 7.11 (m,
1H, H4-thiophenol), 5.91e5.78 (m, 2H, H-5, eCH]CH2), 5.41 (m,
1H, eCH]CH2), 5.37 (d, J ¼ 3.3 Hz, 1H, H-1), 5.33 (m, 1H, eCH]
CH2), 4.63 (dd, J ¼ 6.5, 3.3 Hz, 1H, H-2), 4.56 (dd, J ¼ 6.4, 2.5 Hz, 1H,
H-3), 4.17 (dd, J ¼ 7.0, 2.5 Hz, 1H, H-4), 3.56 (s, 3H, eOCH3), 2.36 (s,
3H, thiophenol-CH3), 1.48 (s, 3H, isopropylidene-CH3), 1.29 (s, 9H,
thiophenol-C(CH3)3), 1.28 (s, 3H, isopropylidene-CH3); 13C NMR
(126 MHz, Chloroform-d)
d
165.57 (C]O), 149.62 (C5-thiophenol),
135.81 (C1-thiophenol), 132.76 (Ph-MTPA), 132.06 (C2-thiophenol),
131.73 (C3-thiophenol), 129.86 (Ph-MTPA), 129.63 (eCH]CH2),
128.68 (C6-thiophenol), 128.45 (2C, Ph-MTPA), 127.47 (2C, Ph-
MTPA), 124.47 (C4-thiophenol), 121.19 (eCH]CH2), 114.20 (qua-
ternary-C), 91.40 (C-1), 86.34 (C-4), 85.28 (C-2), 81.07 (C-3), 75.23
(C-5), 55.57 (eOCH3), 34.50 (thiophenol-C(CH3)3), 31.29 (3C, thio-
phenol-C(CH3)3), 26.89 (isopropylidene-CH3), 25.10 (iso-
propylidene-CH3), 20.19 (thiophenol-CH3), CF3 and CCF3 were not
found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.10; HRMS (ESIþ)
calcd. for C32H39F3NaO6Sþ 631.2312, found 631.2321.
4.2.27. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl (R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12bR)
According to general procedure C, compound 12b (10 mg,
27
8.2
mmol, 1 equiv.) yielded compound 12bR (colorless oil, 5 mg,
found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.38; HRMS (ESIþ)
m
mol, 31%). Compound 12bR: Rf 0.67 (ethyl acetate: 60e90 ꢁC
calcd. for C31H37F3NaO6Sþ 617.2155, found 617.2156.
petroleum ether, 1/5); HPLC tR 5.71 min; [
a]
¼ ꢀ18 (20 ꢁC, c ¼ 0.33,
D

H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
2303
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.61 (m, 2H, Ar), 7.57
(C]O), 149.72 (C5-thiophenol), 135.44 (C1-thiophenol), 135.18 (Ph),
133.47 (Ph-MTPA), 132.38 (C2-thiophenol), 129.92 (Ph-MTPA),
129.51 (C3-thiophenol), 129.20 (Ph), 128.73 (2C, Ph-MTPA), 128.31
(2C, Ph), 128.29 (2C, Ph), 127.57 (C6-thiophenol), 127.43 (2C, Ph-
MTPA), 124.21 (C4-thiophenol), 113.76 (quaternary-C), 92.22 (C-1),
87.43 (C-4), 85.67 (C-2), 81.54 (C-3), 78.21 (C-5), 55.74 (eOCH3),
34.52 (thiophenol-C(CH3)3), 31.29 (3C, thiophenol-C(CH3)3), 26.99
(isopropylidene-CH3), 25.19 (isopropylidene-CH3), 20.21 (thio-
phenol-CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz,
(m, 1H, H6-thiophenol), 7.44e7.37 (m, 3H, Ar), 7.20 (m, 1H, H3-
thiophenol), 7.13 (m, 1H, H4-thiophenol), 5.60 (m, 1H, eCH2CH]
CH2), 5.51 (m, 1H, H-5), 5.46 (d, J ¼ 2.5 Hz, 1H, H-1), 4.96 (m, 2H,
eCH2CH]CH2), 4.74e4.65 (m, 2H, H-2, H-3), 4.16 (dd, J ¼ 7.9,
2.1 Hz, 1H, H-4), 3.59 (s, 3H, eOCH3), 2.47 (m, 1H, eCH2CH]CH2),
2.34 (m, 4H, eCH2CH]CH2, thiophenol-CH3), 1.52 (s, 3H, iso-
propylidene-CH3), 1.31 (s, 3H, isopropylidene-CH3), 1.30 (s, 9H,
thiophenol-C(CH3)3); 13C NMR (126 MHz, Chloroform-d)
d 165.54
(C]O), 149.24 (C5-thiophenol), 135.18 (C1-thiophenol), 132.11 (Ph-
MTPA), 131.61 (C2-thiophenol), 131.16 (C3-thiophenol), 129.52 (Ph-
MTPA), 129.13 (eCH2CH]CH2), 127.94 (2C, Ph-MTPA), 127.64 (C6-
thiophenol), 126.97 (2C, Ph-MTPA), 123.99 (C4-thiophenol), 118.72
(eCH2CH]CH2), 113.82 (quaternary-C), 90.31 (C-1), 85.17 (C-4),
85.02 (C-2), 80.97 (C-3), 73.96 (C-5), 55.19 (eOCH3), 34.77
(eCH2CH]CH2), 34.05 (thiophenol-C(CH3)3), 30.83 (3C, thio-
phenol-C(CH3)3), 26.42 (isopropylidene-CH3), 24.65 (iso-
propylidene-CH3), 19.67 (thiophenol-CH3), CF3 and CCF3 were not
Chloroform-d)
d
ꢀ71.72; HRMS (ESIþ) calcd. for C35H39F3NaO6Sþ
667.2312, found 667.2319.
4.2.30. (S)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)
methyl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (13aS)
According to general procedure C, compound 13a (9.5 mg,
26
22
mmol, 1 equiv.) yielded compound 13aS (colorless oil, 14 mg,
m
mol, 93%). Compound 13aS: Rf 0.54 (ethyl acetate: 60e90 ꢁC
found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.14; HRMS (ESIþ)
petroleum ether,1/5); HPLC tR 5.49 min; [
a]
¼ ꢀ42 (20 ꢁC, c ¼ 0.34,
D
d
calcd. for C32H39F3NaO6Sþ 631.2312, found 631.2323.
CHCl3); 1H NMR (400 MHz, Chloroform-d)
7.53 (m, 1H, H6-thio-
phenol), 7.41e7.31 (m, 4H, Ar), 7.31e7.25 (m, 4H, Ar), 7.24e7.14 (m,
4H, Ar, H3-thiophenol, H4-thiophenol), 6.15 (d, J ¼ 9.3 Hz, 1H, H-5),
5.72 (d, J ¼ 2.2 Hz, 1H, H-1), 4.81 (dd, J ¼ 6.1, 2.2 Hz, 1H, H-2), 4.57
(dd, J ¼ 9.4, 2.5 Hz, 1H, H-4), 4.50 (dd, J ¼ 6.2, 2.5 Hz, 1H, H-3), 3.37
(s, 3H, eOCH3), 2.41 (s, 3H, thiophenol-CH3), 1.49 (s, 3H, iso-
propylidene-CH3), 1.31 (s, 9H, thiophenol-C(CH3)3), 1.24 (s, 3H,
4.2.28. (R)-1-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-
1-yl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (12bS)
According to general procedure C, compound 12b (10 mg,
27
mmol, 1 equiv.) yielded compound 12bS (colorless oil, 3 mg,
4.9 m
mol, 19%). Compound 12bS: Rf 0.65 (ethyl acetate: 60e90 ꢁC
isopropylidene-CH3); 13C NMR (151 MHz, Chloroform-d)
d 165.32
petroleum ether, 1/5); HPLC tR 5.65 min; [
a]
¼ ꢀ10 (20 ꢁC,
D
(C]O), 149.66 (C5-thiophenol), 135.84 (C1-thiophenol), 134.72 (Ph),
132.30 (C2-thiophenol), 132.20 (Ph-MTPA), 130.25 (C3-thiophenol),
129.29 (2C, Ph-MTPA; Ph), 128.77 (2C, Ph-MTPA), 128.20 (2C, Ph),
128.14 (2C, Ph), 127.26 (C6-thiophenol), 127.18 (2C, Ph-MTPA),
124.41 (C4-thiophenol), 113.82 (quaternary-C), 91.16 (C-1), 87.83
(C-4), 85.80 (C-2), 81.32 (C-3), 78.67 (C-5), 55.71 (eOCH3), 34.55
(thiophenol-C(CH3)3), 31.32 (3C, thiophenol-C(CH3)3), 26.92 (iso-
propylidene-CH3), 25.28 (isopropylidene-CH3), 20.20 (thiophenol-
CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz, Chloro-
c ¼ 0.23, CHCl3); 1H NMR (400 MHz, Chloroform-d)
d 7.64e7.50 (m,
3H, Ar, H6-thiophenol), 7.45e7.34 (m, 3H, Ar), 7.19 (m, 1H, H3-thi-
ophenol), 7.12 (m, 1H, H4-thiophenol), 5.72 (m, 1H, eCH2CH]CH2),
5.52 (m, 1H, H-5), 5.46 (d, J ¼ 2.8 Hz, 1H, H-1), 5.07 (m, 2H,
eCH2CH]CH2), 4.67 (dd, J ¼ 6.4, 2.8 Hz, 1H, H-2), 4.51 (dd, J ¼ 6.4,
2.2 Hz, 1H, H-3), 4.11 (dd, J ¼ 8.4, 2.3 Hz, 1H, H-4), 3.55 (s, 3H,
eOCH3), 2.58 (m, 1H, eCH2CH]CH2), 2.39 (m, 4H, eCH2CH]CH2,
thiophenol eCH3), 1.47 (s, 3H, isopropylidene-CH3), 1.30 (s, 9H,
thiophenol-C(CH3)3), 1.29 (s, 3H, isopropylidene-CH3); 13C NMR
form-d)
found 667.2321.
d
ꢀ71.77; HRMS (ESIþ) calcd. for C35H39F3NaO6Sþ 667.2312,
(151 MHz, Chloroform-d)
d
166.09 (C]O), 149.70 (C5-thiophenol),
135.53 (C1-thiophenol), 132.73 (Ph-MTPA), 132.06 (C2-thiophenol),
131.98 (C3-thiophenol), 129.99 (Ph-MTPA), 129.64 (eCH2CH]CH2),
128.42 (2C, Ph-MTPA), 127.88 (C6-thiophenol), 127.50 (2C, Ph-
MTPA), 124.36 (C4-thiophenol), 119.23 (eCH2CH]CH2), 113.94
(quaternary-C), 91.05 (C-1), 85.68 (C-4), 85.50 (C-2), 81.49 (C-3),
74.25 (C-5), 55.70 (eOCH3), 35.38 (eCH2CH]CH2), 34.55 (thio-
phenol-C(CH3)3), 31.33 (3C, thiophenol-C(CH3)3), 26.75 (iso-
propylidene-CH3), 24.97 (isopropylidene-CH3), 20.15 (thiophenol-
CH3), CF3 and CCF3 were not found; 19F NMR (471 MHz, Chloro-
4.2.31. (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)
methyl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (13bR)
According to general procedure C, compound 13b (10 mg,
27
20
mmol, 1 equiv.) yielded compound 13bR (colorless oil, 13 mg,
m
mol, 86%). Compound 13bR: Rf 0.64 (ethyl acetate: 60e90 ꢁC
petroleum ether,1/5); HPLC tR 5.64 min; [
a]
¼ ꢀ33 (20 ꢁC, c ¼ 0.49,
7.44e7.27 (m, 6H, Ar),
D
form-d)
found 631.2310.
d
ꢀ71.25; HRMS (ESIþ) calcd. for C32H39F3NaO6Sþ 631.2312,
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.27e7.17 (m, 5H, Ar), 7.15 (m, 1H, H3-thiophenol), 7.11 (m, 1H, H4-
thiophenol), 6.22 (d, J ¼ 8.3 Hz, 1H, H-5), 5.42 (d, J ¼ 3.0 Hz, 1H, H-
1), 4.84 (dd, J ¼ 6.3, 2.3 Hz, 1H, H-3), 4.77 (dd, J ¼ 6.3, 3.0 Hz, 1H, H-
2), 4.47 (dd, J ¼ 8.3, 2.3 Hz,1H, H-4), 3.58 (s, 3H, eOCH3), 2.35 (s, 3H,
thiophenol-CH3), 1.49 (s, 3H, isopropylidene-CH3), 1.33 (s, 3H, iso-
propylidene-CH3), 1.16 (s, 9H, thiophenol-C(CH3)3); 13C NMR
4.2.29. (S)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)
methyl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (13aR)
According to general procedure C, compound 13a (10 mg,
26
7.7
m
m
mol, 1 equiv.) yielded compound 13aR (colorless oil, 5 mg,
(151 MHz, Chloroform-d) d
165.38 (C]O), 149.65 (C5-thiophenol),
mol, 33%). Compound 13aR: Rf 0.52 (ethyl acetate: 60e90 ꢁC
135.52 (C1-thiophenol), 135.05 (Ph), 133.06 (C2-thiophenol), 131.75
(Ph-MTPA), 129.77 (C3-thiophenol), 129.56 (Ph-MTPA), 128.64 (Ph),
128.32 (2C, Ph-MTPA; 2C, Ph), 127.81 (2C, Ph), 127.53 (C6-thio-
phenol), 127.40 (2C, Ph-MTPA), 124.16 (C4-thiophenol), 114.22
(quaternary-C), 91.08 (C-1), 87.45 (C-4), 85.65 (C-2), 81.76 (C-3),
76.93 (C-5), 55.79 (eOCH3), 34.40 (thiophenol-C(CH3)3), 31.20 (3C,
thiophenol-C(CH3)3), 26.92 (isopropylidene-CH3), 25.21 (iso-
propylidene-CH3), 20.14 (thiophenol-CH3), CF3 and CCF3 were not
petroleum ether,1/5); HPLC tR 5.48 min; [
a
]
¼ ꢀ12 (20 ꢁC, c ¼ 0.23,
7.56e7.45 (m, 5H, Ar),
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
7.43e7.35 (m, 4H, Ar), 7.35e7.30 (m, 2H, Ar), 7.19 (m, 1H, H3-thio-
phenol), 7.13 (m, 1H, H4-thiophenol), 6.15 (d, J ¼ 6.8 Hz, 1H, H-5),
5.47 (d, J ¼ 2.9 Hz, 1H, H-1), 4.56 (dd, J ¼ 6.8, 2.1 Hz, 1H, H-4), 4.40
(dd, J ¼ 6.2, 3.0 Hz, 1H, H-2), 4.34 (dd, J ¼ 6.2, 2.1 Hz, 1H, H-3), 3.41
(s, 3H, eOCH3), 2.41 (s, 3H, thiophenol-CH3), 1.47 (s, 3H, iso-
propylidene-CH3), 1.28 (s, 9H, thiophenol-C(CH3)3), 1.21 (s, 3H,
found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.55; HRMS (ESIþ)
isopropylidene-CH3); 13C NMR (151 MHz, Chloroform-d)
d
165.79
calcd. for C35H39F3NaO6Sþ 667.2312, found 667.2310.

2304
H. Ren et al. / Tetrahedron 73 (2017) 2290e2304
4.2.32. (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
thio)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)
methyl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (13bS)
According to general procedure C, compound 13b (10 mg,
(thiophenol-C(CH3)3), 31.31 (thiophenol-C(CH3)3), 27.42 (iso-
propylidene-CH3), 25.27 (isopropylidene-CH3), 20.55 (thiophenol-
CH3); HRMS (ESIþ) calcd. for C25H32O6SNaþ 483.1817, found
483.1810.
27
16
mmol, 1 equiv.) yielded compound 13bS (colorless oil, 10 mg,
m
mol, 66%). Compound 13bS: Rf 0.63 (ethyl acetate: 60e90 ꢁC
Acknowledgements
petroleum ether, 1/5); HPLC tR 5.59 min; [
a
]
¼ ꢀ29 (20 ꢁC, c ¼ 0.47,
7.48e7.43 (m, 2H, Ar),
D
CHCl3); 1H NMR (400 MHz, Chloroform-d)
d
This work was supported by the National Natural Science
Foundation of China (81673309, 81273368), National Science &
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2014ZX09507-002), and
"Personalized Medicines - Molecular Signature-based Drug Dis-
covery and Development", Strategic Priority Research Program of
the Chinese Academy of Sciences, Grant No. XDA12020310.
7.42e7.31 (m, 6H, Ar), 7.28e7.24 (m, 3H, Ar), 7.19e7.09 (m, 2H, H3-
thiophenol, H4-thiophenol), 6.29 (d, J ¼ 9.2 Hz, 1H, H-5), 5.46 (d,
J ¼ 2.6 Hz, 1H, H-1), 4.78 (dd, J ¼ 6.3, 2.5 Hz, 1H, H-2), 4.65 (dd,
J ¼ 6.3, 1.9 Hz, 1H, H-3), 4.53 (dd, J ¼ 9.1, 1.9 Hz, 1H, H-4), 3.46 (s, 3H,
eOCH3), 2.37 (s, 3H, thiophenol-CH3), 1.46 (s, 3H, isopropylidene-
CH3), 1.29 (s, 3H, isopropylidene-CH3), 1.16 (s, 9H, thiophenol-
C(CH3)3); 13C NMR (151 MHz, Chloroform-d)
d 165.68 (C]O),149.61
(C5-thiophenol), 135.85 (C1-thiophenol), 134.90 (C, Ph), 133.19 (Ph-
MTPA), 132.09 (C2-thiophenol), 129.72 (Ph-MTPA), 129.62 (C3-thi-
ophenol), 128.81 (C6-thiophenol), 128.46 (2C, Ph-MTPA), 128.42
(2C, Ph), 128.23 (2C, Ph), 127.39 (2C, Ph-MTPA; C, Ph), 124.03 (C4-
thiophenol), 113.78 (quaternary-C), 91.48 (C-1), 87.53 (C-4), 85.78
(C-2), 81.84 (C-3), 76.35 (C-5), 55.56 (eOCH3), 34.39 (thiophenol-
C(CH3)3), 31.20 (thiophenol-C(CH3)3), 26.72 (isopropylidene-CH3),
24.98 (isopropylidene-CH3), 20.14 (thiophenol-CH3), CF3 and CCF3
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.03.013.
References
were not found; 19F NMR (471 MHz, Chloroform-d)
d
ꢀ71.27; HRMS
1. For some recent examples: (a) Sabbavarapu NM, Shavit M, Degani Y, Smolkin B,
Belakhov V, Baasov T. ACS Med Chem Lett. 2016;7:418e423;
(b) Kandasamy J, Atia-Glikin D, Shulman E, et al.
(ESIþ) calcd. for C35H39F3NaO6Sþ 667.2312, found 667.2319.
J Med Chem. 2012;55:
10630e10643;
4.2.33. (R)-((3aR,4R,6S,6aR)-6-((5-(tert-butyl)-2-methylphenyl)
sulfonyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl)(phenyl)methanol (17)
(c) Kandasamy J, Atia-Glikin D, Belakhov V, Baasov T. MedChemComm. 2011;2:
165e171;
(d) Wouters AD, Bessa AB, Sachini M, Wessjohann LA, Ludtke DS. Synthesis.
2013;45:2222e2233.
Compound 13b (50 mg,117
(1 mL), cooled with ice bath, and treated with a solution of mCPBA
(60 mg, 350 mol, 3 equiv.) in DCM (1 mL). The reaction mixture
mmol,1 equiv.) was dissolved in DCM
2. (a) Boyd Jr FL, Baker DC. J Carbohydr Chem. 1986;5:257e269, 5’-Aldo nucleosides
or carbanucleosides were often reacted with Grignard reagents, too. But
generally poor selectivity and yields were obtained. For example;
(b) Hai TT, Picker D, Abo M, Hampton A. J Med Chem. 1982;25:806e812;
c) Kappler F, Hampton A. J Med Chem. 1990;33(9):2545e2551;
(d) Ciuffreda P, Loseto A, Santaniello E. Tetrahedron asymmetr. 2004;15:203e206;
e) Verma VA, Rossman R, Bennett F, et al. Bioorg Med Chem Lett. 2012;22:
6967e6973;
(f) Kel’in AV, Zlatev I, Harp J, et al. J Org Chem. 2016;81:2261e2279;
(g) Henry Jr KJ, Grieco PA, Jagoe CT. Tetrahedron Lett. 1992;33:1817e1820;
(h) Trost BM, Bonk PJ. J Am Chem Soc. 1985;107:8277e8279.
3. Wouters AD, Lüdtke DS. Org Lett. 2012;14:3962e3965.
4. Anomeric mixture of this compound was mentioned in Sugimura H, Nitta D.
Tetrahedron Lett. 2012;53:4460e4463 (No analytical data was presented
therein).
m
was then stirred overnight at RT, quenched with sat. aq. NaHCO3
and sat. aq. Na2S2O3. The organic phase was washed with brine,
concentrated, and purified with flash chromatography (on silica gel
with 60e90 ꢁC petroleum ether: EtOAc ¼ 10:1) to give product 17
(white solid, 36 mg, 78 mmol, 67%). Crystal of 17 suitable for X-ray
analysis was obtained from TBME and 60e90 ꢁC petroleum ether.
Compound 17: Rf 0.63 (ethyl acetate: 60e90 ꢁC petroleum ether, 1/
5); mp. 126.5e128.8 ꢁC (TBME/60e90 ꢁC petroleum ether); HPLC tR
4.28 min; [
Chloroform-d)
a
]
¼ ꢀ39 (20 ꢁC, c ¼ 0.38, CHCl3); 1H NMR (500 MHz,
D
€
5. The conformation of compound 3b was generated by Schrodinger 2015. To refine
d
8.01 (m, 1H, H6-thiophenol), 7.59 (m, 1H, H4-thi-
the conformation, the force field of OPLS3 was applied to the molecule. The
calculation consisted of 200 steps of Polak-Ribier conjugate gradient (PRCG)
minimization with default parameters implemented in macromodel program of
ophenol), 7.42 (m, 2H, Ph), 7.38 (m, 2H, Ph), 7.33e7.27 (m, 2H, Ph,
H3-thiophenol), 5.41 (dd, J ¼ 6.0, 3.7 Hz, 1H, H-2), 5.05 (m, 1H, H-5),
4.98 (d, J ¼ 3.8 Hz,1H, H-1), 4.87 (dd, J ¼ 6.0,1.4 Hz,1H, H-3), 4.67 (t,
J ¼ 1.7 Hz, 1H, H-4), 2.70 (s, 3H, thiophenol-CH3), 1.47 (s, 3H, iso-
propylidene-CH3), 1.34 (s, 9H, isopropylidene-(CH3)3), 1.29 (s, 3H,
isopropylidene-CH3), CF3 and CCF3 were not found; 13C NMR
€
Schrodinger 2015.
6. (a) Dale JA, Dull DL, Mosher HS. J Org Chem. 1969;34:2543e2549;
(b) Dale JA, Mosher HS. Nuclear magnetic resonance enantiomer regents. J Am
Chem Soc. 1973;95:512e519;
(c) Sullivan GR, Dale JA, Mosher HS. J Org Chem. 1973;38:2143e2147;
(d) Hoye TR, Jeffrey CS, Shao F. Nat Protoc. 2007;2:2451e2458.
7. Trost BM, Belletire JL, Godleski S, et al. J Org Chem. 1986;51:2370e2374.
8. CCDC 1524481 contains the supplementary crystallographic data for compound
17 in this paper. Details can be found in supporting information.
9. (a) Ohtani I, Kusumi T, Kashman Y, Kakisawa H. J Org Chem. 1991;56:1296e1298;
(b) Paterson I, Dalby SM, Roberts JC, et al. Angew Chem, Int Ed. 2011;50:
3219e3223.
(126 MHz, Chloroform-d) d
150.44 (C5-thiophenol), 138.69 (1C, Ph),
136.32 (C1-thiophenol), 134.48 (C2-thiophenol), 133.05 (C3-thio-
phenol), 131.89 (C6-thiophenol), 128.80 (2C, Ph), 128.11 (1C, Ph),
127.91 (C4-thiophenol), 126.00 (2C, Ph), 114.04 (quaternary-C),
100.23 (C-1), 93.90 (C-4), 80.89 (C-2), 80.05 (C-3), 73.57 (C-5), 34.95