Enantioselective Multicomponent Reaction for Rapid Construction of 1,2,5-Triol Derivatives with Vicinal Chiral Centers

Article abstract of DOI:10.1021/acs.joc.7b00473

1,2,5-Triol derivatives with vicinal chiral centers have been synthesized from simple starting materials by one-pot method in good yields and with an excellent enantioselectivity. This process was promoted by a chiral secondary amine and iridium(I) cocata

Full text of DOI:10.1021/acs.joc.7b00473

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Article
Enantioselective Multicomponent Reaction for Rapid
Construction of 1,2,5-Triol Derivatives with Vicinal Chiral Centers
Mingfeng Li, Xin Guo, Qing Zheng, Wenhao Hu, and Shunying Liu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017
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Enantioselective Multicomponent Reaction for Rapid
Construction of 1,2,5-Triol Derivatives with Vicinal Chiral
Centers
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Mingfeng Li, Xin Guo, Qing Zheng, Wenhao Hu and Shunying Liu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Molecular Engineering, East China Normal
University, Shanghai, China, 200062.
TOC:
1
. Ir(cod) BF (5 mol%)
2 4
-
N2
Ar2
Ar2
(
S)
4c
(20
(40
CH Cl , r.t. 4Å M.S.
mol%)
R
O
R
R
OH
O
Ar2
p-NBZA
mol%)
HO
HO
CO Me
2
+
+
2
2
Ar1
Ar1
OH
OH
o
2
. NaBH /MeOH, 40 C
H
H
Ar1
4
O
Ph
up to 80% yield
up to 99% ee for each isomer
N
H
(S)-
Ph
OTBS
4c
iminium ion
Ar1
*
enatioenriched
N
1,2,5-triol derivatives
with vicinal chiral centers
OMe
Ir] Ar2
H
O
[
R
O
MeO C
O
R
2
[Ir] Ar2
H
active oxonium ylide intermediate
ABSTRACT: 1,2,5-triol derivatives with vicinal chiral centers have been synthesized
from simple starting materials by one-pot method in good yields and with an excellent
enantioselectivity. This process was promoted by a chiral secondary amine and
iridium(I) co-catalyzed three-component reaction of aryldiazoacetates and alcohols
with enals as electrophiles followed by a reduction with NaBH .. Iridium(I)-associated
4
oxonium ylide intermediates were efficiently generated and successfully trapped by
the amine-activated enals via a selective 1,4-addtition manner, generating
enantioselective three-component coupling products.
Introduction
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Chiral 1,5-pentanediol scaffolds, including 1,2,5-triols, are important
1
1a
1b
substructures in natural products, such as caylobolide A, ripostatin B, sclerophytin
1
c
A (Scheme 1).They are also essential building blocks in medicinal chemistry and
2
0
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0
synthetic organic chemistry owing to their diverse functionalization. A variety of
elegant methods have been well-established for the preparation of enantiomerically
3
4
pure 1,5-pentanediols, including kinetic resolution,
substrate induction
and
asymmetric catalysis. 5 For instance, Zhou et al. developed a highly efficient and
practical method by kinetic resolution of racemic aliphatic alcohols via catalytic
hydrogenation of hydroxyl esters to prepare optically active δ-alkyl-δ-hydroxy esters
and δ-alkyl-1,5-diols. 3a However, the methods for rapid construction of 1,2,5-triol
derivatives are rarely developed. Herein, we reported an efficient chiral secondary
amine and iridium(I) complex co-catalyzed enantioselective three-component reaction
for rapid construction of enantiomerically pure 1,2,5-triol derivatives with two vicinal
chiral centers from simple starting materials under mild conditions.
Scheme 1. Selected bioactive natural and synthetic compounds containing chiral
1
,5-diols or 1,2,5-triols.
OH
OH
OH
O
∗
∗
∗
∗
O
∗
HO
HO
O
H
H
H
H
∗
CO
Ph
H
2
O
O
HO
HO
OH OH OH
OH
∗
OH
OH
HO
caylobolide A (cytotoxin)
ripostatin
OH
B
sclerophytin A
O
N
OH
OTBS
OTBS
OTBS
O
O
H
H
OH
TBSO
HO
OBn
OTBS
crotanecine
protected C
1-C25
of
Amphidinol
3
fragment
Asymmetric multi-component reaction (AMCR) is an efficient atom- and step-
economical fashion for the rapid construction of structurally complex chiral
6
compounds. Based on our continuing interest in developing new AMCRs by trapping
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of active intermediates in situ generated from diazo compounds with appropriately
activated electrophiles, several efficient co-catalyst systems have been developed.7-13
For example, the co-catalyst system of Rh
2
(OAc)
4
and chiral metal complexes afforded
an efficient asymmetric trapping of oxonium ylides by aldehydes or acyl imidazoles. 9
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
3
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3
4
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0
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0
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0
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0
The combination of Rh
2
(OAc) and chiral phosphoric acid (CPA) successfully
4
1
0
11
promoted an enantioselective trapping of oxonium ylides, ammonium ylides and
zwitterions with imines, respectively.12 Very recently, the co-catalytic strategy of
combining iridium complex and chiral secondary amine, which is a readily accessible
and inexpensive Lewis base co-catalyst, efficiently enabled the trapping of active
1
3
zwitterionic intermediates with enals in a 1,4-addition manner (Scheme 2a). Thus, we
envisioned that the combination of iridium complexes and chiral secondary amines
might present a compatible catalytic strategy to promote the trapping of active oxonium
ylides generated in situ from diazo compounds and alcohols with enals to rapidly
construct chiral 1,2,5-triol scaffolds (Scheme 2b). A possible challenge in this desired
trapping process is to obtain a matching generation rate between the active ylide and
the iminium-activated enals.
Scheme 2. AMCR of trapping active intermediates with enals.
(
a) Previous
work:
iminium co-catalysis promoting enals to trap zwitterionic intermediate
[Ir]/
Ar1
[Ir]
CO2R1
O
Ar1
R O C
Ar
N
N2
+
1
2
[
Ir]
Ar1
CO R
2
1
N
N
Ar
R2
R2
zwitterions ions
N
R2
(
b) This
work:
iminium co-catalysis promoting enals to trap oxonium
[Ir]/
ylides
Ar1
Ar
N
1
R2
O
N2
[Ir] Ph
R O C
R O2C
O
+
R2
[Ir]
OH
1
R2
ylides
Ar1
CO R1
O
2
2
H
one pot
Ar
H
oxonium
Ar1
R2
O
HO
NaBH4
Ar
OH
H
chiral triol derivatives
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6
The reaction of cinnamyl aldehyde 1a with methyl phenyldiazoacetate 2a and
benzyl alcohol 3a was chosen as the model system for our initial investigetion under
the conditions of Rh
diphenyl((trimethylsilyl)oxy)-methyl)pyrrolidine 4a as co-catalyst and benzoic acid as
additive in CH Cl . To our great delight, the desired 1,4-addition product 5a was
2
(OAc)
4
as the efficient diazo decompostion reagent, (S)-2-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
2
obtained in 70% yield within 2 hrs, although no diastereoselectivity was observed. The
resluting product 5a further gave 1,2,5-triol derivative 6a in a quantitative yield and
with a good ee value (88% ee for anti-6a, 91% ee for syn-6a) by a simple reduction
o
with NaBH
4
in methanol at 40 C (Table 1, entry1). The main side product was O˗H
insertion product 7a derived from reaction of 2a and 3a, and no three-component
,2˗addition product was observed. The starting materials of 2a and 3a were consumed
1
completely while 8% of cinnamyl aldehyde 1a was recovered even prolonging the
reaction time. These results indicate that the generation ratio of the (S)-4a-catalyzed
iminium didn’t match that of the Rh
2
(OAc) -catalyzed ylide very well. The further
4
screening of chiral secondary amine co-catalysts showed that (S)-4b and 4c with larger
steric triethylsilyl (TES) gave a similar yield and an improved enantioselectivity
(entries 2-3). Other co-catalysts (S)-4d-g were much less effective in promoting this
reaction, forming product 5a in lower yields of less than 10% (entries 4-7). To obtain a
more matching reactivity, other commonly used transition metal catalysts for the
decomposition of diazo compounds, including Ir(COD)
2
BF , were investigated. Most
4
3
of these catalysts, such as [PdCl(η -C
3
H
5
2
)] ,
Table 1. Reaction condition optimization for the enantioselective three-component
reaction of 1a, 2a, and 3a [a]
N2
OH
Ph
Ph
Ph
Ph
1
. [M] (5 mol%)
(
HOH
C
O
Ph HOH C
O
Ph
MeO C
O
Ph MeO
+
2
C
O
Ph
O
2
2
Ph
CO Me Ph
2
2
4
2. NaBH4
S)- (20 mol%)
2a
+
3a
+
additives (40 mol%)
CH Cl
, r.t. 4Å MS
o
Ph
O
Ph
MeOH, 40 C
Ph
OH
Ph
OH
Ph
O
2
2
H
-
H
-
H
-
H
-
1a
anti
anti 5a
syn 5a
6a
syn 6a
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[
[c]
[d]
t
yield
dr
ee (%,
entry
M
(S)-4
Additives
b]
(
hrs)
(%) (anti:syn) anti/syn)
1
2
3
4
5
6
7
8
9
Rh
Rh
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
2
2
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
4
4
4
4
4
4
4
(S)-4a PhCO
(S)-4b PhCO
(S)-4c PhCO
(S)-4d PhCO
(S)-4e PhCO
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
70
50:50
50:50
50:50
--
88/91
93/94
96/97
--
2
80
2
60
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
<10
<10
<10
<10
20
2
--
--
(S)-4f
PhCO
2
--
--
(OAc)
(S)-4g PhCO
(S)-4c PhCO
(S)-4c PhCO
2
--
--
3
[PdCl(η -C
3
H
5
)]
2
2
50:50
50:50
95/96
95/98
AgOTf
8
34
[
Ru(p-
1
1
0
1
(S)-4c PhCO
2
H
1
<10
--
--
cymene)Cl
2 2
]
Cu(hfacac)
2
(S)-4c PhCO
(S)-4c PhCO
(S)-4c PhCO
(S)-4c PhCO
(S)-4c PhCO
2
H
2
H
2
H
2
H
2
H
1
<10
80
--
--
12
Ir(COD)
[Ir(COD)OMe]
[Ir(COD)Cl]
Ir(COD)(hfacac)
2
BF
4
48
36
48
48
48
48
48
50:50
--
97/97
--
13
2
<10
75
14
2
50:50
50:50
50:50
50:50
93/94
93/95
98/98
96/96
94/96
15
32
16
Ir(COD)
Ir(COD)
Ir(COD)
2
2
2
BF
BF
BF
4
(S)-4c p-NBZA
(S)-4c p-ClPhCO
90
17
4
2
H
58
18
4
(S)-4c p-MeOPhCO
2
H
32
50:50
O
(S)
-
-
4a: R=TMS
(trimethylsilyl),
Ar=Ph
Ar=Ph
O
Ar
Ar
OR
(
(
(
S)
4b: R=TES
(triethylsilyl),
N
CO
2
H
N
H
t
Bu
N
H
N
S)-4c: R=TBS (tert-butyldimethylsilyl), Ar=Ph
NHPh
H
H
S)
-
4d: R=TMS, Ar=3,5-
(CF
3
)
2
C H
6
3
S -4e
S -4f
)
S -4g
(
)
(
(
)
[a]
General reaction conditions: M:(S)-4: additives:1a:2a:3a= 0.05:0.2:0.4:1:1.5:1.5. [b] Isolated total
yield of anti- and syn-6a. [c] Determined by H NMR analysis of the crude mixture of anti- and syn-
1
6a. [d] Determined by chiral HPLC analysis of anti- and syn-6a.
AgOTf, [Ru(p-cymene)Cl
entries 8-11 vs. 12). Compared to Rh
Ir(COD) BF decomposed diazo compounds more slowly and it took 48 hrs to consume
diazo compound 2a totally. Gratifyingly, Ir(COD) BF provided a higher yield of 80%
2
]
2
, and Cu(hfacac)
2
, failed to achieve a good yield
(
2
(OAc) , which finished the reaction within 2 hrs,
4
2
4
2
4
with an excellent ee value (97% ee for both anti-6a and syn-6a) and 50:50 dr (entry 12
vs. 3). In this case, cinnamyl aldehyde 1a was totally consumed within 48 hrs (detected
1
by H NMR). These results indicated the generation rate of oxonium ylides by
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
5
5
5
6
Ir(COD)
2
BF
4
was slow enough to match that of the formation of iminium ions which
derived from cinnamyl aldehyde 1a and co-catalysts (S)-4c. Varying the counter anions
or ligands in iridium complexes only afforded much lower yields but remaining a
similar enantioselectivity (entries 13-15). Considering that the acidity of the additives
might influence the formation rate of the iminium ions, the acids were screened in the
trapping process (entries 16-18). p-Nitrobenzoic acid (p-NBZA) with a stronger acidity
indeed improved both the reaction yield (from 80% to 90%) and the enantioselectivity
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(97% ee for anti-6a and 98% ee for syn-6a) than p-chlorobenzoic acid or p-
methoxybenzoic acid. Screening of other solvents and reaction temperature gave no
obvious improvement in the yield or in the stereoselectivity (see Supporting
Information, Table S1). Therefore, the optimal reaction conditions were established as
5
mol% of Ir(COD)
2
BF , 20 mol% of chiral secondary amine co-catalyst (S)-4c and 40
4
mol% of p-NBZA as additive in CH
2
Cl at room temperature in the presence of 4A
2
molecular sieve (entry 16).
We next explored the substrate scope of this three-component reaction with the
optimal reaction conditions and a series of 1,2,5-triol derivatives were obtained. The
reaction proceeded smoothly with a variety of substitutions on the aromatic enals 1
(Table 2, entries 1-7), diazo compounds 2 (entries 9-14) and alcohols 3 (entries 15-18).
In most cases, both a good yield (up to 95%) and an excellent enantioselectivity (up to
99% ee for anti-6 and up to 99% ee for syn-6) were obtained. But unfortunately, o-Me
substituted aromatic enal can’t be applied here and only O-H insertion side product was
obtained with a total recovery of cinnamaldehyde, indicating the reaction process might
be sensitive to steric effect (Table 2, entry 8). The developed reaction provides an
efficient approach for rapid access to chiral 1,2,5-triol derivatives under mild conditions
even though the diastereoselectivity is poor. By single crystal X-ray crystallography,
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absolute configurations of the isomer of anti-6n and the isomer of syn-6a were
determined as (2S, 3S) and (2R, 3S), respectively (Figure 1). That of other products
were then assigned by analogy.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Substrate scope of the Iridium/iminium co-catalyzed three-component
reaction [a]
N2
1. Ir(cod) BF
(5 mol%)
2 4
-
Ar2
Ar2
R
OH
(S) 4c (20 mol%)
p-NBZA (40 mol%)
CH Cl , r.t. 4Å M.S.
HOH C
O
R
HOH
2
C
O
R
2
Ar2
CO Me
3
2
+
2
+
2
2
Ar1
OH
Ar1
OH
o
2
. NaBH /MeOH, 40 C
H
H
4
Ar1
O
-
-
1
anti 6
syn 6
1
2
yield(%)[b] dr(anti:syn)[c]
ee(%,anti/syn)[d]
98/98
96/99
99/96
97/99
97/98
53/98
99/95
--
entry
1
Ar / Ar / R
6
Ph/ Ph/Ph
6a
6b
6c
6d
6e
6f
90
88
85
81
84
80
75
--
50:50
50:50
50:50
50:50
50:50
50:50
50:50
--
2
p-NO
p-ClC
p-BrC
p-MeOC
p-MeC
m-MeC
2
C
6
H
4
/ Ph/Ph
/ Ph/Ph
/ Ph/Ph
/ Ph/Ph
/ Ph/Ph
3
6
H
4
4
6
H
4
5
6
H
4
6
6
H
4
7
6
H
4
/ Ph/Ph
6g
--
8
o-MeC H
6
4
/ Ph/Ph
9
Ph/p-FC
6
H
4
/ Ph
/ Ph
/ Ph
/ Ph
/ Ph
/ Ph
6h
6i
59
62
66
50
81
68
75
74
75
95
50:50
50:50
50:50
50:50
50:50
37:63
50:50
50:50
50:50
50:50
98/98
97/97
96/98
96/98
96/97
92/98
98/99
98/99
87/99
94/95
10
11
Ph/p-BrC
Ph/p-MeC
Ph/p-MeOC
Ph/m-MeOC
Ph/o-BrC
Ph/Ph/p-BrC
Ph/Ph/p-MeOC
Ph/Ph/m-BrC
Ph/Ph/TMSCH
6
H
4
6
H
4
6j
1
1
2
3
6
H
4
6k
6l
6
H
4
1 [
4
e]
H
6m
6n
6o
6p
6q
6
4
15
6
H
4
6
1
6
H
4
17
18
6
H
4
2
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[a], [b], [c], [d]: Reaction conditions as performed in Table 1. [e]: LAH/THF was used for reduction
reaction instead of NaBH /MeOH.
4
Figure 1. Single Crystal X-ray Diffraction Data of (2S,3S)-anti-6n and (2R,3S)-syn-
a.
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
HOH
2
C
O
HOH
2
C
O
OH
OH
H
H
-
-
2S,3S)-
anti 6n
(2R,3S)-syn 6a
(
Due to the intriguing chiral 1,2,5-triol derivatives have been established through
this method, we then sought to explore its synthetic applications. By a deprotection
process of O-atom of anti-6q with BF ·Et O in CH Cl , chiral 1,2,5-pentane-triol
derivative anti-8 was obtained, which is an admirable chiral scaffold to construct
3
2
2
2
1
d
alkaloids (Scheme 3a). Furthermore, when 3-phenylpropargyl alcohol 3r was used as
starting material, the resulting product anti-5r (Scheme 3b) was performed by a simple
o
reduction to chiral mono alcohol anti-9 with NaBH
4
at 0 C (Scheme 3c), which further
afforded the corresponding chiral lactone anti-10 by an intramolecular
transesterification. Chiral lactones (five- and six-membered) are important building
blocks for the synthesis of natural products and biologically active compounds, such as
1
4
15
alkaloids, terpenoids, and antiviral agents. The mono alcohol anti-9 can be also
easily transferred into chiral 1,5-pentanediol derivative anti-6r by adding excess
o
NaBH
4
at 40 C (Scheme 3c).
Scheme 3. Synthetic application of the three-component products.
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9
(a)
Ph
Ph
HOH2C
Ph
O
HOH2C
Ph
OH
TMS
BF •Et O
3
2
CH2Cl2, r.t.
OH
OH
H
-
H-
anti 6q
anti 8
5
1% yield, 94% ee
(b)
OH
N2
Ph
Ph
Ph
Ph
MeO C
O
MeO2C
O
Ir(c -o d)2BF4 (5 mol%)
(S) 4c (20 mol%)
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
CO Me
2
Ph
+
2a
3r
+
Ph
O
Ph
O
p-NBZA (40 mol%)
CH2Cl2, r.t. 4Å M.S.
H
H
-
Ph
O
-
anti 5r
ee
syn 5r
1
a
81% yield
96%
97% ee
Ph
O
Ph
(c)
H
O
TsOH•H2O
CH2Cl2,
Ph
Ph
O
-
anti 10
Ph
O
r.t.
MeO C
NaBH4
2
-
anti 5r
60% yield, 98% ee
Ph
o
MeOH, 0 C
Ph
Ph
OH
H
-
NaBH4
HOH2C
O
o
anti 9
MeOH, 40 C
8
6% yield, 98% ee
Ph
OH
H
-
anti 6r
5% yield, 98% ee
9
Control experiments were then carried out to confirm the reaction pathway. The
reaction of O-H insertion product 7a with cinnamaldehyde 1a under the standard
conditions (Scheme 4a) can’t provide any three-component product 5a, excluding a
possible stepwise tandem process of the reaction. And only O-H insertion side product
7a was obtained together with a total recovery of cinnamaldehyde 1a without addition
of co-catalyst (S)-4c or additive p-NBZA under the standard conditions (Scheme 4b and
4
c). Additionally, iminium cation II generated from 1 and 4c was detected in the
reaction mixture solution by LC-MS spectra (see Supporting Information, Figure S1).
Scheme 4. Control experiments.
BF
(5 mol%)
mol%)
mol%)
Ph
Ph
Ir(cod)
2
c
4
(a)
O
Ph
-
MeO C
O
Ph MeO
+
2
C
O
Ph
O
(S)
4
(20
(40
2
+
Ph
O
p-NBZA
Ph
Ph
CO Me
2
1a
Ph
O
Ph
7
a
CH
2
Cl
2
, r.t. 4Å M.S.
H
-
H
-
anti 5a
syn 5a
0% yield
0
% yield
(b)
N
2
OH
Ir(cod)
2
BF
4
(5 mol%)
mol%)
O
Ph
CO Me
Ph
3a
2
p-NBZA
-
(40
+
+
+
anti/syn 5a
2a
Ph
CO Me
CH
2
Cl
2
, r.t. 4Å M.S.
2
7
a
Ph
+
O
1a
65%
0% yield
yield
Ir(cod)
2
BF
4
(5 mol%)
mol%)
-
(c)
(S)
4c
-
(20
, r.t. 4Å M.S.
1a
2a
+
3a
7a
anti/syn 5a
CH
2
Cl
2
62% yield
0% yield
According to the control experiments, a possible mechanism was proposed and
outlined in Scheme 5a. The reaction initially forms oxonium ylide intermediate Ia or
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1
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2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
enolate Ib from 2 and 3 catalyzed by iridium. The planar Ib is a favored intermediate.
On the other hand, chiral iminium ion II was formed from 1 and (S)-4c by the
acceleration of acid additive, which can enaltioselectively trap intermediate Ib to give
enamine III via transition states TS-1 and TS-2 (Scheme 5b). The addition of the planar
enolate Ib from both sides to chiral iminium ion II is possibly responsible for the poor
diastereoselectivity of the reaction. Three-component coupling product 5 would be
subsequently formed by acid-promoted hydrolysis of enamine III, and meanwhile,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chiral amine 4c was regenerated. The reduction of the resulting product 5 with NaBH
4
delivered chiral 1,2,5-triol derivatives 6.
Scheme 5. Proposed reaction mechanism of the iridium/iminium co-catalyzed
three-component reaction.
(a)
[Ir] Ar2
MeO C
N
O
R
O
R
2
H
OTBS
Ph Ph
Ia
Ar2
CO Me
Ar1
Ar2
MeO C
-
-
R
OH
(disfavored)
7
2
anti 6 +
syn
6
H O
2
3
R
OMe
O
H
H
2
NaBH4
III
O
R
O
-
-
anti 5 + syn 5
Ir] Ar2
[
ArCOOH
Ib
(
favored)
Ar2
Ph
N
H
(S)-4c
Ph
OTBS
[Ir]
ArCOOH
CO
2
Me
Ph
OTBS
Ph
Ar1
[Ir]
O
1
N
II
H O
2
Ar2
2
N2
Ar
1
CO
2
Me
(b)
MeO
H
O
[Ir]
Ar1
Ar2
MeO
H
O
[Ir]
Ar1
R
R
O
H
Ar
2
O
H
TBSO
Ph
TBSO
Ph
N
N
Ph
TS-1
TS-2
Ph
In conclusion, we have reported an enantioselective iridium complex/chiral amine
co-catalyzed three-component reaction of diazoacetates, alcohols and enals. The
established reaction provides a mild method to rapid access to enantiomerically pure
1
,2,5-triol derivatives with two vicinal chiral centers from simple starting materials in
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9
good yields and with an excellent enantioselectivity. The enantioselective trapping of
iridium (I)-associated oxonium ylide intermediates was promoted via selective 1,4-
addtition to the chiral amine-activated enals. The further research of using this strategy
in the improvement of the reaction diastereoselectivity and the synthetic application of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
,2,5-triol derivatives is currently underway in our lab.
EXPERIMENTAL SECTION
1
13
19
General. All H NMR (400 MHz) and C NMR (100 MHz) and F NMR (376
MHz) spectra were recorded on Brucker spectrometers in CDCl
3
. Tetramethylsilane
was used as
1
(
TMS) served as an internal standard (δ = 0) for H NMR, and CDCl
3
1
3
internal standard (δ = 77.0) for C NMR. Chemical shifts are reported in parts per
million as follows: chemical shift, multiplicity (s =singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad). High-resolution mass spectrometry (HRMS) was
performed on IonSpec FT-ICR or Waters Micromass Q-TOF micro Synapt High
Definition Mass Spectrometer. HPLC analysis was performed on Dalian Elite (UV230+
UV/Vis Detector and P230P High Pressure Pump). Chiralpak IC, IA, AD-H and OD-
H column was purchased from Daicel Chemical Industries, LTD. Single crystal X-ray
diffraction data were recorded on Bruker-AXS SMART APEX II single crystal X-ray
diffractometer. The racemic standards used in HPLC studies were prepared according
to the general procedure by using racemic (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)
pyrrolidine catalyst. Yields for all compounds were total yield of isolated anti and syn
products unless otherwise indicated.
All reactions and manipulations were carried out under an argon atmosphere in a
flame-dried or oven-dried flask containing magnetic stir bar. Dichloromethane (DCM),
1, 2-dichloroethane (DCE), CHCl and toluene was distilled over calcium hydride.
3
Cinnamaldehydes 3 were prepared from palladium-catalyzed synthesis of
cinnamaldehydes from acrolein diethyl acetal and aryl iodides according to the
literature method. Diarylprolinol silyl ethers 4a-d were prepared according to the
literature procedure. Solvents for the column chromatography were distilled before use.
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9
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
4
Å molecular sieves were dried in a Muffle furnace at 250 C over 5 hrs.
General Experimental Procedure for the Synthesis of Enantioselective Three-
component Products: A mixture of Ir(COD) BF (5 mol%), substituted
cinnamaldehydes 1(1.0 mmol), p-Nitrobenzoic acid (40 mol%), (S)-4c (20 mol%), and
Å MS (100 mg) in 1.0 mL of DCM under an argon atmosphere was stirred at room
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
temperaure. The mixture of diazo compounds 2 (1.5 mmol) and alcohols 3 (1.5 mmol)
in 1.0 mL of DCM was then added over 1.0 h via a syringe pump. After completion of
the addition, the reaction mixture was stirred for another 48 h at room temperaure. After
the completion of the reaction (monitored by TLC, until diazo compounds 2
disappeared), the reaction mixture was filtrated and evaporated in vacuo to give the
crude products. The crude products was purified by flash chromatography on silica gel
(
EtOAc/light petroleum ether = 1:50 ~ 1:20) to give the mixture of anti-5 and syn-5.
Then the mixture were reduced with excess NaBH (10.0 mmol) in batches in methanol
4
o
for another 3 h at 40 C. After the completion of the reaction (monitored by TLC, until
anti-5 and syn-5 disappeared), the reaction was then quenched with 10 mL water. The
aqueous layer was washed with DCM (2x40 mL) and the combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
resulting residue was purified by flash column chromatography on silica gel
(EtOAc/light petroleum ether = 1:20 ~ 1:10) to give the pure product of anti-6 and syn-
6
as a white solid.
Procedure for the Synthesis of anti-8: To a flask charged with (2S,3S)-anti-6q
(
0.17 mmol, 65 mg) in CH
mmol, 0.8 mL) was added. After the completion of the reaction (monitored by TLC),
the reaction mixture was quenched with saturated aqueous solution of NaHCO . Then
. The combined organic phases were washed by
SO . The product was then purified by flash
2
Cl
2
(2 mL) was stirred at room temperature. BF
3
·Et
2
O (6.4
3
the product was extracted with CH
2
Cl
2
water and brine, and dried over Na
2
4
chromatography (EtOAc/light petroleum ether = 1:50 ~ 1:10) to give the pure product
anti-8.
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Procedure for the Synthesis of anti-5r and syn-5r: A mixture of Ir(COD)
2
BF (5
4
mol%), cinnamaldehydes 1a(1.0 mmol), p-Nitrobenzoic acid (40 mol%), (S)-4c (20
mol%), and 4 Å MS (100 mg) in 1.0 mL of DCM under an argon atmosphere was stirred
at room temperaure. The mixture of diazo compounds 2a (1.5 mmol) and alcohols 3r
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1.5 mmol) in 1.0 mL of DCM was then added over 1.0 h via a syringe pump. After
completion of the addition, the reaction mixture was stirred for another 48 h at room
temperaure. After the completion of the reaction (monitored by TLC, until diazo
compounds 2a disappeared), the reaction mixture was filtrated and evaporated in vacuo
to give the crude products. The crude products was purified by flash chromatography
on silica gel (EtOAc/light petroleum ether = 1:50 ~ 1:20) to give the pure product of
anti-5r and syn-5r.
Procedure for the Synthesis of anti-9: To a flask charged with (2S,3S)-anti-5r (0.4
o
mmol) in methanol (1 mL) was stirred at 0 C. NaBH
4
(0.8 mmol) was added in batches
o
for another 3 h at 0 C. After the completion of the reaction (monitored by TLC), the
reaction was then quenched with 1 mL water. The aqueous layer was washed with
DCM (2x4 mL) and the combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash
column chromatography on silica gel (EtOAc/light petroleum ether = 1:20 ~ 1:10) to
give the pure product of anti-9.
Procedure for the Synthesis of anti-10: To a flask charged with anti-9 (0.1 mmol)
in DCM (0.3 mL) was stirred at room temperaure. Then TsOH·H
added. After the completion of the reaction (monitored by TLC), the reaction mixture
was extracted with water. The combined organic phases were dried over Na SO and
2
O (0.05 mmol) was
2
4
the solvent was evaporated in vacuo. The product was then purified by flash
chromatography (EtOAc/light petroleum ether = 1:50 ~ 1:10) to give the pure product
anti-10.
Procedure for the Synthesis of anti-6r: To a flask charged with anti-9 (0.1 mmol)
o
in methanol (0.3 mL) was stirred at 40 C. NaBH
4
(1.0 mmol) was added in batches.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
After the completion of the reaction (monitored by TLC), the reaction mixture was
quenched with 1 mL water. Then the product was extracted with DCM (2x3 mL). The
combined organic phases were washed by water and brine, and dried over Na
product was then purified by flash chromatography (EtOAc/light petroleum ether =
:10 ~ 1:5) to give the pure product anti-6r.
2
SO . The
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(2S,3S)-2-(benzyloxy)-2,3-diphenylpentane-1,5-diol (6a)
1
(
2S,3S)-anti-6a: white solid, 163.0 mg, 45% yield, 98% ee. H NMR (400 MHz, CDCl
.34 – 7.23 (m, 4H), 7.19 – 7.08 (m, 3H), 7.06 – 6.92 (m, 2H), 6.91 – 6.57 (m, 2H), 4.43 (s, 2H), 3.93 (s, 2H), 3.57
d, J = 9.8 Hz, 1H), 3.49 – 3.38 (m, 1H), 3.38 – 3.24 (m, 1H), 2.64 – 2.42 (m, 1H), 2.18 (s, 1H), 1.78 – 1.49 (m,
H).
13C NMR (100 MHz, CDCl
4.9, 62.0, 61.7, 47.9, 31.6.
HRMS(ESI): Calcd. for C24
3
) δ 7.56 – 7.35 (m, 4H),
7
(
2
3
) δ 139.3, 138.6, 137.3, 130.1, 128.6, 127.9, 127.7, 127.7, 127.6, 127.2, 126.9, 84.0,
6
+
H
26NaO
3
[M+Na] : 385.1780 , Found:385.1786.
HPLC (Chiral OD-H, λ= 220 nm, hexane/2-propanol = 4.7/1, Flow rate =0.8 mL/min), tmajor = 9.12 min, tminor
.59 min.
(2R,3S)-2-(benzyloxy)-2,3-diphenylpentane-1,5-diol (6a)
(2R,3S)-syn-6a: white solid, 163.0 mg, 45% yield, 98% ee. H NMR (400 MHz, CDCl
=
7
1
3
) δ 7.43 – 7.27 (m, 8H),
7.27 – 7.19 (m, 7H), 4.58 (q, J = 12.1 Hz, 2H), 4.19 – 3.97 (m, 2H), 3.35 (s, 1H), 3.24 – 3.04 (m, 2H), 2.21 – 2.01
(m, 1H), 2.01 – 1.87 (m, 1H), 1.83 – 1.47 (m, 2H).
13C NMR (100 MHz, CDCl
4.2, 65.6, 65.5, 61.1, 52.2, 32.8.
HRMS(ESI): Calcd. for C24
HPLC (Chiral OD-H, λ= 220 nm, hexane/2-propanol = 4.7/1, Flow rate =0.8 mL/min), tmajor = 9.67 min, tminor
.20 min.
) δ 140.2, 139.7, 139.3, 130.1, 128.5, 128.4, 128.0, 127.4, 127.2, 127.0, 126.9, 126.7,
3
8
+
H
3
26NaO [M+Na] : 385.1780 , Found:385.1786.
=
7
(2S,3S)- 2-(benzyloxy)-3-(4-nitrophenyl)-2-phenylpentane-1,5-diol (6b)
o
1
(2S,3S)-anti-6b: white solid, 175.0 mg, 43% yield, mp 126-127 C, 96% ee. H NMR (400 MHz, CDCl
3
) δ 7.91
(d, J = 8.1 Hz, 2H), 7.46 – 7.20 (m, 8H), 7.07 – 6.76 (m, 4H), 4.37 (q, J = 11.7 Hz, 2H), 4.07 – 3.91 (m, 1H), 3.90
3.75 (m, 1H), 3.67 (d, J = 9.6 Hz, 1H), 3.40 (s, 1H), 3.31 – 3.14 (m, 1H), 2.62 – 2.43 (m, 1H), 2.04 (d, J = 8.2
Hz, 1H), 1.83 – 1.66 (m, 1H), 1.32 (s, 1H).
–
13C NMR (100 MHz, CDCl
) δ 147.6, 146.9, 138.3, 137.0, 131.0, 128.7, 128.1, 127.8, 127.5, 127.1, 122.7, 83.8,
3
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7.3, 77.0, 76.7, 65.2, 62.4, 61.1, 48.3, 31.6.
+
5
HRMS(ESI): Calcd. for C24H25NNaO [M+Na] : 430.1630 , Found:430.1635.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 13.22 min, tminor = 10.01
min.
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(2R,3S)- 2-(benzyloxy)-3-(4-nitrophenyl)-2-phenylpentane-1,5-diol (6b)
1
(2R,3S)-syn-6b: white solid, 183.2 mg, 45% yield, 99% ee. H NMR (400 MHz, CDCl
3
) δ 8.00 (d, J = 8.4 Hz, 2H),
7
.38 – 7.25 (m, 7H), 7.20 (d, J = 7.4 Hz, 3H), 7.09 (d, J = 7.4 Hz, 2H), 4.44 (s, 2H), 4.04 (s, 2H), 3.52 – 3.28 (m,
H), 3.20 – 3.02 (m, 1H), 2.08 – 1.96 (m, 1H), 1.95 – 1.84 (m, 1H), 1.78 (s, 1H).
) δ 147.9, 146.9, 138.7, 138.5, 131.2, 128.6, 127.9, 127.5, 127.0, 126.7, 122.7, 84.4,
7.3, 77.0, 76.7, 65.6, 64.2, 60.5, 50.5, 32.6.
HRMS(ESI): Calcd. for C24 [M+Na] : 430.1630 , Found:430.1639.
2
13C NMR (100 MHz, CDCl
3
7
+
H25NNaO
5
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 8.93 min, tminor = 10.26
min.
(2S,3S)- 2-(benzyloxy)-3-(4-chlorophenyl)-2-phenylpentane-1,5-diol (6c)
o
1
3
(2S,3S)-anti-6c: white solid, 178.2 mg, 45% yield, mp 126-129 C, 99% ee. H NMR (400 MHz, CDCl ) δ 7.37 –
7.28 (m, 4H), 7.26 – 7.17 (m, 4H), 7.02 (d, J = 8.6 Hz, 2H), 6.98 – 6.89 (m, 2H), 6.61 (d, J = 7.2 Hz, 2H), 4.34 (s,
2H), 3.95 – 3.75 (m, 2H), 3.50 (dd, J = 11.6, 3.1 Hz, 1H), 3.42 – 3.28 (m, 1H), 3.28 – 3.15 (m, 1H), 2.56 – 2.37 (m,
1
H), 2.24 – 2.04 (m, 1H), 1.74 – 1.53 (m, 2H).
13C NMR (100 MHz, CDCl
) δ 138.4, 137.9, 137.0, 132.7, 131.4, 128.6, 128.5, 127.9, 127.8, 127.8, 127.7, 127.2,
3
8
3.9, 77.4, 77.0, 76.7, 65.0, 62.0, 61.4, 47.3, 31.5.
+
HRMS(ESI): Calcd. for C24
H
25ClNaO
3
[M+Na] : 419.1390 , Found:419.1407.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 10.02 min, tminor = 5.69
min.
(2R,3S)- 2-(benzyloxy)-3-(4-chlorophenyl)-2-phenylpentane-1,5-diol (6c)
1
(2R,3S)-syn-6c: white solid, 158.4 mg, 40% yield, 96% ee . H NMR (400 MHz, CDCl
3
) δ 7.43 – 7.25 (m, 8H),
7
.22 – 7.12 (m, 4H), 7.05 (d, J = 8.3 Hz, 2H), 4.63 – 4.39 (m, 2H), 4.07 (s, 2H), 3.45 – 3.30 (m, 1H), 3.29 – 3.09
m, 2H), 2.08 – 1.86 (m, 3H), 1.79 (brs, 1H).
13C NMR (100 MHz, CDCl
) δ 139.3, 139.1, 138.1, 132.6, 131.6, 128.5, 128.4, 127.9, 127.6, 127.3, 127.0, 126.7,
4.2, 77.4, 77.0, 76.7, 65.5, 64.6, 60.7, 50.5, 32.6.
(
3
8
+
HRMS(ESI): Calcd. for C24
H
25ClNaO
3
[M+Na] : 419.1390 , Found:419.1405.
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HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 5.54 min, tminor = 7.12
min.
(2S,3S)- 2-(benzyloxy)-3-(4-bromophenyl)-2-phenylpentane-1,5-diol (6d)
1
(
2S,3S)-anti-6d: white solid, 176.0 mg, 40% yield, 97% ee. H NMR (400 MHz, CDCl
3
) δ 7.44 – 7.35 (m, 4H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
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4
5
6
7
8
9
0
7
3
1
.35 – 7.26 (m, 5H), 7.23 (s, 1H), 7.09 – 6.90 (m, 2H), 6.62 (d, J = 6.8 Hz, 2H), 4.41 (s, 2H), 4.02 – 3.83 (m, 2H),
.56 (d, J = 10.8 Hz, 1H), 3.48 – 3.37 (m, 1H), 3.34 – 3.22 (m, 1H), 2.61 – 2.45 (m, 1H), 2.22 (brs, 1H), 1.82 –
.59 (m, 2H).
13C NMR (100 MHz, CDCl
3.8, 77.4, 77.0, 76.7, 65.0, 62.0, 61.3, 47.4, 31.5.
) δ 138.4, 138.4, 137.0, 131.8, 130.8, 128.6, 128.5, 127.9, 127.8, 127.7, 127.2, 120.8,
3
8
+
3
HRMS(ESI): Calcd. for C24H25BrNaO [M+Na] : 463.0885 , Found:463.0901.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 6.0/1, Flow rate =1.0 mL/min), tmajor = 10.25 min, tminor = 5.79
min.
(2R,3S)- 2-(benzyloxy)-3-(4-bromophenyl)-2-phenylpentane-1,5-diol (6d)
o
1
3
(2R,3S)-syn-6d: white solid, 180.4 mg, 41% yield, mp 99-100 C, 99% ee . H NMR (400 MHz, CDCl ) δ 7.41 –
7.27 (m, 10H), 7.20 (d, J = 7.4 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.53 (s, 2H), 4.12 – 3.98 (m, 2H), 3.43 – 3.31 (m,
1H), 3.25 – 3.09 (m, 2H), 2.07 – 1.90 (m, 2H), 1.77 (s, 1H), 1.62 (s, 1H).
13C NMR (100 MHz, CDCl
7.3, 77.0, 76.7, 65.6, 64.9, 60.8, 50.9, 32.6.
HRMS(ESI): Calcd. for C24 25BrNaO [M+Na] : 463.0885 , Found: 463.0896.
) δ 139.4, 139.1, 138.7, 131.9, 130.9, 128.5, 127.6, 127.3, 127.0, 126.7, 120.8, 84.1,
3
7
+
H
3
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 6.0/1, Flow rate =1.0 mL/min), tmajor = 6.40 min, tminor =8.99
min.
(2S,3R)- 2-(benzyloxy)-3-(4-methoxyphenyl)-2-phenylpentane-1,5-diol (6e)
o
1
(
2S,3R)-anti-6e: white solid, 160.8 mg, 41% yield, mp 121-122 C, 97% ee. H NMR (400 MHz, CDCl
3
) δ 7.48 –
7
.36 (m, 4H), 7.35 – 7.24 (m, 4H), 7.08 – 6.95 (m, 2H), 6.67 (s, 4H), 4.43 (s, 2H), 3.93 (s, 2H), 3.76 (s, 3H), 3.52
(
dd, J = 11.5, 2.6 Hz, 1H), 3.48 – 3.40 (m, 1H), 3.40 – 3.29 (m, 1H), 2.63 – 2.45 (m, 1H), 2.07 (brs, 1H), 1.80 –
.56 (m, 2H).
13C NMR (100 MHz, CDCl
4.2, 77.3, 77.0, 76.7, 64.9, 61.9, 61.8, 55.1, 47.1, 31.7.
1
3
) δ 158.5, 138.6, 137.3, 131.1, 131.0, 128.6, 127.9, 127.7, 127.7, 127.6, 127.1, 113.0,
8
+
4
HRMS(ESI): Calcd. for C25H28NaO [M+Na] : 415.1885 , Found: 415.1878.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 22.97 min, tminor = 8.82
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(2R,3R)- 2-(benzyloxy)-3-(4-methoxyphenyl)-2-phenylpentane-1,5-diol (6e)
o
1
(2R,3R)-syn-6e: white solid, 168.6 mg, 43% yield, mp 100-103 C, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.50 –
7
1
.26 (m, 8H), 7.24 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.60 (d, J = 12.1 Hz,
H), 4.54 (d, J = 12.1 Hz, 1H), 4.07 (s, 2H), 3.79 (s, 3H), 3.47 – 3.29 (m, 1H), 3.27 – 3.13 (m, 1H), 3.08 (dd, J =
1
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4
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
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0
1
2
3
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8
9
0
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2
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4
5
6
7
8
9
0
1
1.4, 2.9 Hz, 1H), 2.13 – 1.85 (m, 2H), 1.66 (brs, 2H).
13C NMR (100 MHz, CDCl
) δ 158.6, 140.3, 139.4, 131.6, 131.0, 128.4, 127.4, 127.2, 126.9, 126.7, 113.4, 84.2,
7.4, 77.0, 76.7, 65.6, 65.5, 61.1, 55.2, 51.4, 32.8.
3
7
+
4
HRMS(ESI): Calcd. for C25H28NaO [M+Na] : 415.1885 , Found: 415.1881.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 7.97 min, tminor = 12.59
min.
(2S,3S)- 2-(benzyloxy)-2-phenyl-3-(p-tolyl)pentane-1,5-diol (6f)
o
1
3
(2S,3S)-anti-6f: white solid, 150.0 mg, 40% yield, mp 123-125 C, 53% ee. H NMR (400 MHz, CDCl ) δ 7.40 –
7.27 (m, 4H), 7.27 – 7.16 (m, 4H), 7.00 – 6.82 (m, 4H), 6.59 – 6.30 (m, 2H), 4.37 (s, 2H), 3.86 (s, 2H), 3.44 (dd, J
= 11.6, 3.2 Hz, 1H), 3.41 – 3.32 (m, 1H), 3.32 – 3.23 (m, 1H), 2.52 – 2.37 (m, 1H), 2.11 (s, 3H), 1.98 (brs, 1H),
1.71 – 1.61 (m, 1H), 1.37 (brs, 1H).
13C NMR (100 MHz, CDCl
4.0, 77.3, 77.0, 76.7, 64.9, 62.0, 61.8, 47.9, 31.7, 21.3.
) δ 139.1, 138.6, 137.4, 137.0, 130.9, 128.6, 128.0, 127.7, 127.6, 127.6, 127.5, 127.2,
3
8
+
3
HRMS(ESI): Calcd. for C25H28NaO [M+Na] : 399.1936 , Found: 399.1928.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 17.58 min, tminor = 6.54
min.
(2R,3S)- 2-(benzyloxy)-2-phenyl-3-(p-tolyl)pentane-1,5-diol (6f)
1
(2R,3S)-syn-6f: white solid, 150.5 mg, 40% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.45 – 7.26 (m, 9H),
7
.25 – 7.23 (m, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 3H), 4.62 (d, J = 12.0 Hz, 1H), 4.55 (d, J = 12.0
Hz, 1H), 4.08 (s, 2H), 3.42 – 3.30 (m, 1H), 3.26 – 3.15 (m, 1H), 3.08 (dd, J = 11.6, 3.3 Hz, 1H), 2.29 (s, 3H), 2.13
2.01 (m, 1H), 1.98 – 1.85 (m, 1H), 1.35 (brs, 1H), 1.08 (brs, 1H).
13C NMR (100 MHz, CDCl
) δ 140.4, 139.6, 139.3, 137.4, 131.0, 128.4, 127.9, 127.7, 127.4, 127.2, 127.0, 126.9,
26.8, 84.2, 77.3, 77.2, 77.0, 76.7, 65.7, 65.6, 61.2, 52.3, 32.7, 21.4.
–
3
1
+
3
HRMS(ESI): Calcd. for C25H28NaO [M+Na] : 399.1936 , Found: 399.1938.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 7.46 min, tminor = 9.88
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o
1
(2S,3S)-anti-6g: white solid, 146.7 mg, 39% yield, mp 164-165 C, 99% ee. H NMR (400 MHz, CDCl
3
) δ 7.39 –
7
2
3
.28 (m, 4H), 7.26 – 7.20 (m, 3H), 7.19 (s, 1H), 7.00 – 6.92 (m, 2H), 6.87 (d, J = 7.0 Hz, 2H), 6.57 (d, J = 7.0 Hz,
0
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4
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6
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9
0
1
2
3
4
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6
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8
9
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9
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1
2
3
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8
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0
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0
H), 4.37 (s, 2H), 3.86 (s, 2H), 3.46 (dd, J = 11.6, 3.2 Hz, 1H), 3.40 – 3.23 (m, 2H), 2.52 – 2.39 (m, 1H), 2.21 (s,
H), 1.93 (brs, 1H), 1.71 – 1.56 (m, 1H).
13C NMR (100 MHz, CDCl
7.3, 77.0, 76.7, 64.8, 62.0, 61.8, 47.6, 31.7, 21.0.
) δ 138.6, 137.3, 136.5, 136.1, 129.9, 128.6, 128.4, 128.0, 127.7, 127.6, 127.1, 84.1,
3
7
+
3
HRMS(ESI) :Calcd. for C25H28NaO [M+Na] : 399.1936 , Found: 399.1936.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 33.13 min, tminor = 8.15
min.
(2R,3S)- 2-(benzyloxy)-2-phenyl-3-(m-tolyl)pentane-1,5-diol (6g)
1
(2R,3S)-syn-6g: white solid, 135.5 mg, 36% yield, 95% ee. H NMR (400 MHz, CDCl
3
) δ 7.39 – 7.25 (m, 6H),
7.20 (dd, J = 12.1, 4.5 Hz, 4H), 7.06 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 7.6 Hz, 2H), 4.55 (d, J = 12.1 Hz, 1H), 4.48
(d, J = 12.1 Hz, 1H), 4.07 – 3.90 (m, 2H), 3.34 – 3.22 (m, 1H), 3.18 – 3.05 (m, 1H), 2.99 (dd, J = 11.4, 2.7 Hz,
1H), 2.23 (s, 3H), 2.06 – 1.93 (m, 1H), 1.92 – 1.78 (m, 1H), 1.68 – 1.42 (m, 2H).
13C NMR (100 MHz, CDCl
4.1, 77.3, 77.0, 76.7, 65.7, 65.7, 61.2, 52.1, 32.8, 21.1.
) δ 140.5, 139.4, 136.6, 136.5, 129.9, 128.8, 128.4, 128.4, 127.3, 127.2, 126.9, 126.7,
3
8
+
3
HRMS(ESI) :Calcd. for C25H28NaO [M+Na] : 399.1936 , Found: 399.1928.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 7.39 min, tminor = 12.91
min.
(2S,3S)- 2-(benzyloxy)-2-(4-fluorophenyl)-3-phenylpentane-1,5-diol (6h)
1
(2S,3S)-anti-6h: white solid, 114.2 mg, 30% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.55 – 7.35 (m, 4H),
7
.34 – 7.27 (m, 1H), 7.21 – 7.09 (m, 3H), 7.07 – 6.89 (m, 4H), 6.86 – 6.61 (m, 2H), 4.42 (q, J = 11.7 Hz, 2H), 3.91
(
s, 2H), 3.55 (dd, J = 11.7, 2.9 Hz, 1H), 3.50 – 3.39 (m, 1H), 3.38 – 3.25 (m, 1H), 2.58 – 2.42 (m, 1H), 2.20 (brs,
H), 1.82 – 1.46 (m, 2H).
13C NMR (100 MHz, CDCl
1
3
) δ 162.2 (d, J = 246.9 Hz), 139.1, 138.4, 133.3 (d, J = 3.2 Hz), 130.1, 129.6 (d, J = 7.9
Hz), 128.6, 127.8, 127.7, 127.1, 127.0, 114.6 (d, J = 21.1 Hz), 83.7, 64.8, 62.2, 61.5, 47.8, 31.5.
+
HRMS(ESI) :Calcd. for C24
19F NMR (376 MHz, CDCl
H
25
O
3
NaF [M+Na] : 403.1685 , Found: 403.1695.
3
) δ -114.6.
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HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 8.02 min, tminor = 6.36
min.
(2R,3S)- 2-(benzyloxy)-2-(4-fluorophenyl)-3-phenylpentane-1,5-diol (6h)
1
(
2R,3S)-syn-6h: white solid, 110.3 mg, 29% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.42 – 7.33 (m, 4H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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0
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0
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0
7
4
.32 – 7.26 (m, 1H), 7.25 – 7.19 (m, 3H), 7.19 – 7.05 (m, 4H), 6.99 (t, J = 8.7 Hz, 2H), 4.56 (d, J = 12.1 Hz, 1H),
.45 (d, J = 12.1 Hz, 1H), 4.12 – 4.00 (m, 2H), 3.40 – 3.29 (m, 1H), 3.24 – 3.06 (m, 2H), 2.02 – 1.91 (m,2H), 1.86
(
brs, 1H), 1.28 – 1.20 (m, 1H).
13C NMR (100 MHz, CDCl
) δ 162.0 (d, J = 246.4 Hz), 139.4, 139.1, 135.8 (d, J = 3.2 Hz), 130.2, 128.8, 128.7 (d,
J = 7.9 Hz), 127.9, 127.3, 127.0, 126.6, 115.1 (d, J = 21.2 Hz), 83.9, 65.4, 64.8, 60.9, 51.6, 32.6.
19F NMR (376 MHz, CDCl
) δ -115.1.
HRMS(ESI) :Calcd. for C24 NaF [M+Na] : 403.1685, Found: 403.1669.
3
3
+
25 3
H O
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 5.47 min, tminor = 6.99
min.
(2S,3S)- 2-(benzyloxy)-2-(4-bromophenyl)-3-phenylpentane-1,5-diol (6i)
1
(2S,3S)-anti-6i: white solid, 132.4 mg, 30% yield, 97% ee. H NMR (400 MHz, CDCl
3
) δ 7.55 – 7.36 (m, 6H),
7.35 – 7.30 (m, 1H), 7.22 – 7.07 (m, 3H), 6.89 (d, J = 8.2 Hz,2H), 6.83 – 6.62 (m, 2H), 4.44 – 4.40 (m, 2H), 3.90
(s, 2H), 3.56 (dd, J = 11.7, 3.0 Hz, 1H), 3.51 – 3.39 (m, 1H), 3.39 – 3.25 (m, 1H), 2.58 – 2.40 (m, 1H), 2.11 (brs,
1
H), 1.78 – 1.65 (m, 1H), 1.42 (brs, 1H).
13C NMR (100 MHz, CDCl
4.9, 62.1, 61.5, 47.7, 31.5.
HRMS(ESI) :Calcd. for C24
) δ 138.9, 138.3, 136.7, 130.8, 130.0, 129.7, 128.6, 127.8, 127.7, 127.1, 121.9, 83.8,
3
6
+
H
25
O
3
NaBr [M+Na] : 463.0885 , Found: 463.0896.
HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 9.38 min, tminor =6.88
min.
(2R,3S)- 2-(benzyloxy)-2-(4-bromophenyl)-3-phenylpentane-1,5-diol (6i)
1
(
2R,3S)-syn-6i: white solid, 131.6 mg, 32% yield, 97% ee. H NMR (400 MHz, CDCl
3
) δ 7.52 – 7.43 (m, 2H), 7.42
–
7.34 (m, 4H), 7.34 – 7.28 (m, 1H), 7.27 – 7.19 (m, 5H), 7.13 (d, J = 8.5 Hz, 2H), 4.59 (d, J = 12.1 Hz, 1H), 4.48
d, J = 12.1 Hz, 1H), 4.05 (s, 2H), 3.46 – 3.32 (m, 1H), 3.28 – 3.15 (m, 1H), 3.13 (dd, J = 11.7, 3.3 Hz, 1H), 2.13 –
.99 (m, 1H), 1.98 – 1.86 (m, 1H), 1.61 (brs, 2H).
13C NMR (100 MHz, CDCl
) δ 139.5, 139.4, 139.0, 131.5, 130.1, 128.8, 128.5, 128.1, 127.3, 127.1, 126.7, 121.5,
4.0, 65.6, 65.2, 60.9, 51.8, 32.6.
(
1
3
8
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6
+
HRMS(ESI) :Calcd. for C24
H
25
O
3
NaBr [M+Na] : 463.0885 , Found: 463.0871.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 5.37 min, tminor =4.66
min.
(
2S,3S)- 2-(benzyloxy)-3-phenyl-2-(p-tolyl)pentane-1,5-diol (6j)
0
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0
1
(
2S,3S)-anti-6j: white solid, 124.2 mg, 33% yield, 96% ee. H NMR (400 MHz, CDCl
3
) δ 7.53 – 7.32 (m, 4H), 7.32
–
7.25 (m, 1H), 7.21 – 7.01 (m, 5H), 6.88 (d, J = 7.4 Hz, 2H), 6.83 – 6.52 (m, 2H), 4.40 (s, 2H), 3.88 (s, 2H), 3.54
(
(
dd, J = 11.3, 2.5 Hz, 1H), 3.48 – 3.35 (m, 1H), 3.35 – 3.21 (m, 1H), 2.64 – 2.44 (m, 1H), 2.34 (s, 3H), 2.31 – 2.10
m, 1H), 1.91 – 1.49 (m, 2H).
13C NMR (100 MHz, CDCl
) δ 139.5, 138.7, 137.3, 134.2, 130.2, 128.6, 128.4, 127.9, 127.7, 127.5, 127.2, 126.9,
3
8
3.9, 64.7, 62.1, 61.7, 47.9, 31.7, 21.1.
+
HRMS(ESI) :Calcd. for C25
H
28
O
3
Na [M+Na] : 399.1936 , Found: 399.1935.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 18.20 min, tminor =6.11
min.
(2R,3S)- 2-(benzyloxy)-3-phenyl-2-(p-tolyl)pentane-1,5-diol (6j)
1
(2R,3S)-syn-6j: white solid, 124.2 mg, 33% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.47 – 7.32 (m, 4H), 7.30
– 7.26 (m, 1H), 7.25 – 7.17 (m,5H), 7.15 – 7.01 (m, 4H), 4.56 (d, J = 12.2 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H), 4.02
(s, 2H), 3.46 – 3.26 (m, 1H), 3.12 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H), 2.10 – 1.84 (m, 3H), 1.69 (brs, 1H).
13C NMR (100 MHz, CDCl
) δ 139.8, 139.5, 137.0, 136.9, 130.3, 129.1, 128.4, 127.9, 127.1, 127.0, 126.9, 126.7,
3
8
4.1, 65.5, 65.3, 61.0, 51.7, 32.8, 21.1.
+
HRMS(ESI) :Calcd. for C25
H
28
O
3
Na [M+Na] : 399.1936 , Found: 399.1919.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 5.91 min, tminor =8.33
min.
(
2S,3S)-2-(benzyloxy)-2-(4-methoxyphenyl)-3-phenylpentane-1,5-diol (6k)
1
(
2S,3S)-anti-6k: white solid, 98.2 mg, 25% yield, 96% ee. H NMR (400 MHz, CDCl
3
) δ 7.48 – 7.32 (m, 4H), 7.31
–
7.25 (m, 1H), 7.18 – 7.04 (m, 3H), 7.00 – 6.86 (m, 2H), 6.84 – 6.65 (m, 4H), 4.38 (s, 2H), 3.85 (s, 2H), 3.79
s,3H), 3.54 (d, J = 11.1 Hz, 1H), 3.43 – 3.33 (m, 1H), 3.32 – 3.20 (m, 1H), 2.62 – 2.30 (m, 2H), 2.05 (brs, 1H),
.69 (s, 1H).
13C NMR (100 MHz, CDCl
(
1
3
) δ 159.0, 139.5, 138.7, 130.2, 129.3, 129.1, 128.6, 127.7, 127.5, 127.2, 126.8, 113.0,
8
3.7, 64.6, 62.1, 61.5, 55.2, 47.9, 31.7.
+
HRMS(ESI) :Calcd. for C25
H
28
O
4
Na [M+Na] : 415.1885 , Found: 415.1898.
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HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 13.59 min, tminor =7.80
min.
(2R,3S)- 2-(benzyloxy)-2-(4-methoxyphenyl)-3-phenylpentane-1,5-diol (6k)
1
(
2R,3S)-syn-6k: white solid, 98.1 mg, 25% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.55 – 7.31 (m, 4H), 7.31
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
7.26 (m, 1H), 7.25 – 7.19 (m, 3H), 7.15 (s, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 4.77 – 4.35
(
m, 2H), 4.14 – 3.91 (m, 2H), 3.78 (s, 3H), 3.41 – 3.26 (m, 1H), 3.25 – 2.93 (m, 2H), 2.18 – 1.91 (m, 3H), 1.71
brs, 1H).
(
13C NMR (100 MHz, CDCl
3.9, 65.3, 65.0, 61.0, 55.3, 51.7, 32.7.
HRMS(ESI) :Calcd. for C25 Na [M+Na] : 415.1885 , Found: 415.1866.
) δ 158.8, 139.8, 139.4, 131.7, 130.3, 128.4, 128.2, 127.8, 127.1, 126.8, 126.6, 113.7,
3
8
+
28 4
H O
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 7.47 min, tminor =10.55
min.
(2S,3S)- 2-(benzyloxy)-2-(3-methoxyphenyl)-3-phenylpentane-1,5-diol (6l)
1
(2S,3S)-anti-6l: white solid, 157.0 mg, 40% yield, 96% ee. H NMR (400 MHz, CDCl
3
) δ 7.46 – 7.27 (m, 4H), 7.26
– 7.19 (m, 1H), 7.16 – 6.96 (m, 4H), 6.81 – 6.62 (m, 3H), 6.58 – 6.39 (m, 2H), 4.38 (s, 2H), 3.93 – 3.76 (m, 2H),
3.59 (s, 3H), 3.48 (dd, J = 11.6, 3.1 Hz, 1H), 3.41 – 3.30 (m, 1H), 3.30 – 3.17 (m, 1H), 2.52 – 2.35 (m, 1H), 2.11
(brs, 1H), 1.79 – 1.65 (m, 1H), 1.53 (brs, 1H).
13C NMR (100 MHz, CDCl
) δ 158.0, 138.2, 138.1, 137.6, 129.1, 127.6, 127.5, 126.6, 126.5, 126.1, 125.9, 119.2,
3
112.7, 112.2, 83.0, 63.9, 61.2, 60.6, 54.1, 47.0, 30.6.
+
HRMS(ESI): Calcd. for C25
H
28
O
4
Na [M+Na] : 415.1885 , Found: 415.1870.
HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 9.22 min, tminor =8.06
min.
(2R,3S)- 2-(benzyloxy)-2-(3-methoxyphenyl)-3-phenylpentane-1,5-diol (6l)
1
(
2R,3S)-syn-6l: white solid, 160.9 mg, 41% yield, 97% ee. H NMR (400 MHz, CDCl
3
) δ 7.40 – 7.34 (m, 4H), 7.31
–
3
7.19 (m, 7H), 6.86 – 6.79 (m,2H), 6.77 (s, 1H), 4.58 (q, J = 12.2 Hz, 2H), 4.04 (q, J = 12.7 Hz, 2H), 3.64 (s, 3H),
.40 – 3.27 (m, 1H), 3.24 – 3.08 (m, 2H), 2.13 – 1.98 (m, 1H), 1.99 – 1.86 (m, 1H), 1.79 (brs, 1H), 1.42 (brs, 1H).
13C NMR (100 MHz, CDCl
) δ 159.7, 141.8, 139.7, 139.4, 130.2, 129.5, 128.4, 127.9, 127.2, 127.0, 126.6, 119.0,
3
113.0, 112.9, 84.3, 65.7, 65.4, 61.1, 55.1, 51.8, 32.7.
+
HRMS(ESI): Calcd. for C25
H
28
O
4
Na [M+Na] : 415.1885 , Found: 415.1881.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 6.61 min, tminor =10.59
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(2S,3S)- 2-(benzyloxy)-2-(2-bromophenyl)-3-phenylpentane-1,5-diol (6m)
1
(2S,3S)-anti-6m: white solid, 154.5 mg, 35% yield, 92% ee. H NMR (400 MHz, CDCl
3
) δ 7.54 – 7.36 (m, 4H),
7
.34 – 7.27 (m, 3H), 7.22 – 7.08 (m, 3H), 7.06 – 6.97 (m, 2H), 6.88 – 6.60 (m, 2H), 4.56 – 4.29 (m, 2H), 3.94 (d, J
4.8 Hz, 2H), 3.57 (dd, J = 11.6, 3.2 Hz, 1H), 3.49 – 3.26 (m, 2H), 2.63 – 2.46 (m, 1H), 2.15 – 2.00 (m, 1H), 1.82
1.67 (m, 1H), 1.36 (s, 1H). 13C NMR (100 MHz, CDCl
) δ 139.3, 138.6, 137.3, 130.1, 128.6, 127.9, 127.7, 127.7,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
–
3
1
27.6, 127.1, 126.9, 84.0, 64.9, 62.0, 61.7, 48.0, 31.7.
+
HRMS(ESI) :Calcd. for C24
H
25
O
3
NaBr [M+Na] : 463.0885 , Found: 463.0877.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 15.82 min, tminor =5.99
min.
(2R,3S)- 2-(benzyloxy)-2-(2-bromophenyl)-3-phenylpentane-1,5-diol (6m)
1
(2R,3S)-syn-6m: white solid, 145.7 mg, 33% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.45 – 7.35 (m, 5H), 7.34
– 7.26 (m, 4H), 7.25 – 7.18 (m, 5H), 4.59 (q, J = 12.2 Hz, 2H), 4.17 – 3.98 (m, 2H), 3.44 – 3.31 (m, 1H), 3.25 – 3.16
(m, 1H), 3.13 (dd, J = 11.6, 3.3 Hz, 1H), 2.14 – 2.03 (m, 1H), 2.01 – 1.90 (m, 1H), 1.09 (brs, 1H).
13C NMR (100 MHz, CDCl
84.2, 65.7, 65.5, 61.1, 52.3, 32.8.
25 3
HRMS(ESI) :Calcd. for C24H O NaBr [M+Na] : 463.0885 , Found: 463.0908.
) δ 140.2, 139.8, 139.3, 130.1, 128.5, 128.4, 128.0, 127.4, 127.2, 127.0, 126.9, 126.7,
3
+
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 5.77 min, tminor =8.11
min.
(2S,3S)- 2-((4-bromobenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6n)
o
1
(2S,3S)-anti-6n: white solid, 167.7 mg, 38% yield, mp 119-122 C, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.50
(d, J = 7.7 Hz, 1H), 7.39 – 7.24 (m, 3H), 7.22 – 7.06 (m, 2H), 7.03 – 6.89 (m, 1H), 6.88 – 6.61 (m, 1H), 4.52 –
4
2
.27 (m, 1H), 3.95 (s, 1H), 3.55 (d, J = 10.6 Hz, 1H), 3.43 (s, 1H), 3.33 (d, J = 6.6 Hz, 1H), 2.56 – 2.40 (m, 1H),
.12 (s, 1H), 1.87 – 1.60 (m, 1H).
13C NMR (100 MHz, CDCl
) δ 139.1, 137.6, 137.2, 131.6, 130.1, 128.8, 128.5, 128.0, 127.8, 127.7, 127.0, 126.1,
3
1
21.4, 84.1, 77.3, 77.0, 76.7, 64.2, 62.2, 61.5, 48.0, 31.6.
+
3
HRMS (ESI) calcd for C24H25BrNaO [M+Na] = 463.0885 found 463.0879.
HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 10/1, Flow rate =1.0 mL/min), tmajor = 26.81 min, tminor =13.34
min.
(2R,3S)- 2-((4-bromobenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6n)
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(
2R,3S)-syn-6n: white solid, 163.3 mg, 37% yield, 99% ee . H NMR (400 MHz, CDCl
3
) δ 7.50 (d, J = 7.9 Hz, 2H),
7
2
.43 – 7.14 (m, 12H), 4.52 – 4.54(m, 2H), 4.06 – 4.08 (m, 2H), 3.35 (d, J = 3.7 Hz, 1H), 3.25 – 3.07 (m, 2H),
.00 – 2.01 (m, 2H), 1.64 (s, 2H).
13C NMR (100 MHz, CDCl
) δ 139.9, 139.6, 138.3, 131.5, 130.1, 128.5, 128.4, 128.0, 127.5, 127.1, 126.8, 120.9,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
4.3, 77.3, 77.0, 76.7, 65.6, 65.0, 61.0, 52.0, 32.7.
+
3
HRMS (ESI) calcd for C24H25BrNaO [M+Na] = 463.0885 found 463.0887.
HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 8.0/1, Flow rate =1.0 mL/min), tmajor = 19.29 min, tminor =14.99
min.
(
2S,3S)- 2-((4-methoxybenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6o)
1
(
3
2S,3S)-anti-6o: white solid, 145.2 mg, 37% yield, 98% ee. H NMR (400 MHz, CDCl ) δ 7.36 – 7.28 (m, 5H),
7
2
.20 – 7.08 (m, 3H), 7.02 (d, J = 4.2 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 5.7 Hz, 2H), 4.44 – 4.28 (m,
H), 3.92 (s, 2H), 3.83 (s, 3H), 3.55 (dd, J = 11.3, 4.0 Hz, 1H), 3.43 (ddd, J = 11.3, 7.4, 4.0 Hz, 1H), 3.35 – 3.38
(m, 1H), 2.59 – 2.46 (m, 1H), 2.07 (s, 1H), 1.78 – 1.67 (m, 1H).
13C NMR (100 MHz, CDCl
) δ 159.2, 139.4, 137.3, 130.6, 130.1, 128.8, 128.0, 127.7, 127.3, 126.9, 114.0, 84.0,
3
77.3, 77.0, 76.7, 64.6, 61.9, 61.8, 55.3, 48.0, 31.7.
+
HRMS (ESI) calcd for C25
H28NaO
4
[M+Na] = 415.1885 found 415.1875.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 38.04 min, tminor =20.48
min.
(
2R,3S)- 2-((4-methoxybenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6o)
o
1
(
2R,3S)-syn-6o: white solid, 145.0 mg, 37% yield, mp 133-135 C, 99% ee. H NMR (400 MHz, CDCl
3
) δ 7.47 –
7
3
.28 (m, 6H), 7.27 – 7.13 (m, 6H), 6.93 (d, J = 8.5 Hz, 2H), 4.48 – 4.52 (m, 2H), 4.19 – 3.98 (m, 2H), 3.83 (s, 3H),
.45 – 3.28 (m, 1H), 3.24 – 3.14 (m, 1H), 3.11 (dd, J = 11.4, 3.3 Hz, 1H), 2.13 – 1.86 (m, 2H).
) δ 158.9, 140.3, 139.8, 131.4, 130.1, 128.4, 128.3, 128.0, 127.4, 126.9, 113.9, 84.1,
7.3, 77.0, 76.7, 65.4, 61.1, 55.3, 52.3, 32.8.
13C NMR (100 MHz, CDCl
3
7
+
4
HRMS (ESI) calcd for C25H28NaO [M+Na] = 415.1885 found 415.1890.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 22.18 min, tminor =38.56
min.
(
2S,3S)- 2-((3-bromobenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6p)
1
(
2S,3S)-anti-6p: white solid, 158.9 mg, 36% yield, 87% ee. H NMR (400 MHz, CDCl
3
) δ 7.56 (s, 1H), 7.43 (d, J
=
7.7 Hz, 1H), 7.34 (d, J = 5.0 Hz, 2H), 7.29 (s, 3H), 7.13 – 7.15 (m, 3H), 6.99 (d, J = 4.6 Hz, 2H), 6.76 (d, J = 5.7
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Hz, 2H), 4.40 – 4.42 (m, 2H), 3.96 (s, 2H), 3.55 (d, J = 10.3 Hz, 1H), 3.43 (d, J = 3.6 Hz, 1H), 3.38 – 3.22 (m,
1
H), 2.56 – 2.40 (m, 1H), 2.19 (s, 1H), 1.76 (s, 2H).
13C NMR (100 MHz, CDCl
) δ 141.0, 139.1, 137.3, 130.6, 130.1, 130.1, 128.5, 127.8, 127.8, 127.7, 127.0, 126.1,
25.6, 122.6, 84.1, 77.4, 77.0, 76.7, 64.1, 62.3, 61.5, 48.1, 31.6.
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0
+
3
HRMS (ESI) calcd for C24H25BrNaO [M+Na] = 463.0885 found 463.0877.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 6.15 min, tminor =9.43
min.
(2R,3S)- 2-((3-bromobenzyl)oxy)-2,3-diphenylpentane-1,5-diol (6p)
1
(
2R,3S)-syn-6p: white solid, 172.1 mg, 39% yield, 99% ee. H NMR (400 MHz, CDCl
3
) δ 7.54 (s, 1H), 7.42 (d, J =
7
1
1
.7 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.33 – 7.25 (m, 5H), 7.24 – 7.18 (m, 5H), 4.59 (d, J = 12.5 Hz, 1H), 4.51 (d, J =
2.5 Hz, 1H), 4.16 – 3.99 (m, 2H), 3.45 – 3.32 (m, 1H), 3.26 – 3.09 (m, 2H), 2.11 – 1.98 (m, 1H), 1.98 – 1.86 (m,
H), 1.61 (s, 1H), 1.14 (brs, J = 8.2 Hz, 1H).
13C NMR (100 MHz, CDCl
) δ 141.7, 139.8, 139.5, 130.22, 130.1, 129.9, 129.7, 128.5, 128.1, 127.5, 127.1, 126.8,
3
125.1, 122.6, 84.4, 77.3, 77.0, 76.7, 65.5, 64.9, 61.0, 51.8, 32.7.
+
HRMS (ESI) calcd for C24
H
25BrNaO
3
[M+Na] = 463.0885 found 463.0883.
HPLC (Chiral IA, λ= 220 nm, hexane/2-propanol = 20/1, Flow rate =1.0 mL/min), tmajor = 5.76 min, tminor =9.71
min.
(2S,3S)- 2,3-diphenyl-2-(2-(trimethylsilyl)ethoxy)pentane-1,5-diol (6q)
1
(
2S,3S)-anti-6q: white solid, 175.1 mg, 47% yield, 94% ee. H NMR (400 MHz, CDCl
3
) δ 7.41 – 7.00 (m, 10H),
3
1
.99 (s, 2H), 3.61 – 3.51 (m, 1H), 3.50 – 3.42 (m, 1H), 3.42 – 3.32 (m, 1H), 3.27 – 3.14 (m, 1H), 3.04 (dd, J =
0.5, 3.8 Hz, 1H), 2.12 – 1.89 (m, 2H), 1.58 (brs, 2H), 1.11 – 0.93 (m, 2H), -0.00 (s, 9H).
13C NMR (100 MHz, CDCl
4.3, 20.3, -0.0.
HRMS (ESI) calcd for C22
) δ 142.2, 141.4, 131.3, 129.5, 129.2, 128.5, 128.2, 128.1, 84.9, 66.3, 62.6, 62.2, 53.7,
3
3
+
H
32 SiNaO
3
[M+Na] = 395.2110 found 395.2111.
HPLC (Chiral AD-H, λ= 220 nm, hexane/2-propanol = 12.0/1, Flow rate =1.0 mL/min), tmajor = 20.23 min, tminor
.21 min.
=
8
(2R,3S)- 2,3-diphenyl-2-(2-(trimethylsilyl)ethoxy)pentane-1,5-diol (6q)
1
(
2R,3S)-syn-6q: white solid, 178.9 mg, 48% yield, 95% ee. H NMR (400 MHz, CDCl
3
) δ 7.38 – 7.24 (m, 3H),
7
2
.21 – 7.07 (m, 3H), 7.04 – 6.86 (m, 2H), 6.82 – 6.55 (m, 2H), 3.92 – 3.73 (m, 2H), 3.54 – 3.24 (m, 5H), 2.57 –
.41 (m, 1H), 2.13 (brs, 1H), 1.77 (brs, 1H), 1.70 – 1.54 (m, 1H), 1.18 – 0.94 (m, 2H), -0.00 (s, 9H).
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13C NMR (100 MHz, CDCl
3.2, 20.2, -0.0.
HRMS (ESI) calcd for C22
) δ 141.0, 138.7, 131.4, 129.2, 128.9, 128.8, 128.8, 128.1, 84.8, 63.2, 63.1, 61.2, 49.4,
3
3
+
H
32
O
3
NaSi [M+Na] = 395.2018, found 395.1989.
HPLC (Chiral AD-H, λ= 220 nm, hexane/2-propanol = 6.0/1, Flow rate =1.0 mL/min), tmajor = 8.37 min, tminor
12.36 min.
2S,3S)-2,3-diphenylpentane-1,2,5-triol (8)
2S,3S)-anti-8: white solid, 23.6 mg, 51% yield, 94%ee. H NMR (400 MHz, CDCl
.79 (m, 2H), 3.82 (q, J = 24.1, 11.2 Hz, 2H), 3.59 – 3.46 (m, 1H), 3.38 – 3.23 (m, 2H), 2.48 (brs, 1H), 2.35 – 2.08
m, 2H), 1.79 – 1.66 (m, 1H), 1.36 – 1.27 (m, 1H).
13C NMR (100 MHz, CDCl
) δ 141.0, 139.5, 130.0, 127.8, 127.6, 127.2, 127.0, 126.8, 78.6, 68.0, 61.2, 49.7, 32.0.
HRMS(ESI) :Calcd. for C17
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
(
1
(
3
) δ 7.35 – 7.02 (m, 8H), 6.96 –
6
(
3
+
20 3
H O Na [M+ Na] : 295.1310, Found: 295.1349.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 4.5/1, Flow rate =1.0 mL/min), tmajor = 13.72 min, tminor = 11.20
min.
(2S,3S)-methyl-5-oxo-2,3-diphenyl-2-((3-phenylprop-2-yn-1-yl)oxy)pentanoate (5r)
1
(2S,3S)-anti-5r: white solid, 165.0 mg, 40% yield, 96% ee. H NMR (400 MHz, CDCl
3
) δ 9.41 (s, 1H), 7.66 (d, J
= 7.2 Hz, 2H), 7.57 – 7.46 (m, 2H), 7.38 (ddd, J = 9.6, 6.4, 2.7 Hz, 6H), 7.26 – 7.18 (m, 5H), 4.73 (d, J = 15.6 Hz,
1H), 4.30 (d, J = 15.6 Hz, 1H), 3.88 (dd, J = 9.8, 4.6 Hz, 1H), 3.60 (s, 3H), 3.08 – 2.82 (m, 2H).
13C NMR (100 MHz, CDCl
27.3, 122.8, 88.6, 85.8, 85.8, 77.4, 77.0, 76.7, 56.4, 52.0, 51.0, 44.3.
) δ 200.9, 171.2, 138.6, 136.4, 131.8, 130.1, 128.5, 128.5, 128.40, 128.3, 127.9, 127.7,
3
1
+
24 4
HRMS(ESI) :Calcd. for C27H O Na [M+ Na] : 435.1572, Found: 435.1564.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 15/1, Flow rate =0.8 mL/min), tmajor = 13.34 min, tminor = 16.69
min.
(2R,3S)-methyl-5-oxo-2,3-diphenyl-2-((3-phenylprop-2-yn-1-yl)oxy)pentanoate (5r)
1
(2R,3S)-syn-5r: white solid, 169.1 mg, 41% yield, 97% ee. H NMR (400 MHz, CDCl
3
) δ 9.53 (t, J = 1.9 Hz, 1H),
7
.48 – 7.42 (m, 2H), 7.35 – 7.31 (m, 3H), 7.28 – 7.21 (m, 3H), 7.20 – 7.13 (m, 5H), 7.04 – 6.97 (m, 2H), 4.51 (d, J
=
15.5 Hz, 1H), 4.21 (d, J = 15.5 Hz, 1H), 4.13 (dd, J = 9.9, 4.6 Hz, 1H), 3.83 (s, 3H), 3.03 (ddd, J = 17.3, 9.9, 2.0
Hz, 1H), 2.86 (ddd, J = 17.3, 4.6, 2.0 Hz, 1H).
13C NMR (100 MHz, CDCl
) δ 200.9, 171.6, 137.6, 135.1, 131.7, 130.2, 128.4, 128.3, 128.3, 128.0, 127.8, 127.8,
27.4, 122.8, 88.9, 85.6, 85.6, 77.4, 77.0, 76.7, 55.9, 52.3, 49.4, 45.1.
3
1
+
HRMS(ESI) :Calcd. for C27
H
24
O
4
Na [M+ Na] : 435.1572, Found: 435.1564.
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6
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 15/1, Flow rate =0.8 mL/min), tmajor = 18.14 min, tminor = 17.11
min.
(2S,3S)-methyl--5-hydroxy-2,3-diphenyl-2-((3-phenylprop-2-yn-1-yl)oxy)pentanoate (9)
1
(
2S,3S)-anti-9: white solid, 142.6 mg, 86% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.70 – 7.57 (m, 2H), 7.51
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
2
7.44 (m, 2H), 7.40 – 7.29 (m, 6H), 7.21 (s, 5H), 4.67 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 4.11 (s,
H), 3.58 (s, 3H), 3.48 – 3.32 (m, 2H), 3.21 (dd, J = 15.8, 9.2 Hz, 1H), 2.33 (t, J = 7.6 Hz, 1H), 2.13 – 1.89 (m,
H), 1.17 (s, 1H).
13C NMR (100 MHz, CDCl
6.1, 85.6, 77.4, 77.1, 76.7, 61.0, 56.3, 52.9, 51.9, 32.3.
) δ 171.8, 139.0, 136.6, 131.8, 130.3, 128.4, 128.3, 128.0, 127.6, 127.0, 123.0, 89.2,
3
8
+
26 4
HRMS(ESI) :Calcd. for C27H O Na [M+ Na] : 437.1729, Found: 437.1725.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 15/1, Flow rate =0.8 mL/min), tmajor = 17.50 min, tminor = 16.62
min.
(3R,4S)-3,4-diphenyl-3-((3-phenylprop-2-yn-1-yl)oxy)tetrahydro-2H-pyran-2-one (10)
1
(3R,4S)-anti-10: white solid, 23.0 mg, 60% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.45 (dd, J = 6.6, 3.0 Hz,
2H), 7.38 – 7.29 (m, 3H), 7.24 – 7.10 (m, 6H), 6.89 (d, J = 7.6 Hz, 4H), 4.76 – 4.58 (m, 3H), 4.32 (d, J = 15.6 Hz,
1H), 3.70 (dd, J = 11.0, 4.4 Hz, 1H), 2.35 (dtd, J = 14.3, 11.0, 6.2 Hz, 1H), 2.15 (dtd, J = 14.3, 4.4, 2.2 Hz, 1H).
13C NMR (100 MHz, CDCl
22.9, 86.0, 85.8, 85.6, 77.4, 77.0, 76.7, 68.8, 55.8, 49.6, 26.4.
) δ 170.9, 138.1, 134.8, 131.7, 129.4, 128.5, 128.3, 128.3, 128.2, 127.6, 127.3, 127.2,
3
1
+
22 3
HRMS(ESI) :Calcd. for C26H O Na [M+ Na] : 405.1467, Found: 405.1482.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 15/1, Flow rate =0.8 mL/min), tmajor = 31.84 min, tminor = 25.32
min.
(2S,3S)-2,3-diphenyl-2-((3-phenylprop-2-yn-1-yl)oxy)pentane-1,5-diol (6r)
1
(
2S,3S)-anti-6r: white solid, 36.7 mg, 95% yield, 98% ee. H NMR (400 MHz, CDCl
3
) δ 7.46 (dd, J = 6.6, 3.1 Hz,
2
2
H), 7.39 – 7.28 (m, 6H), 7.24 – 7.17 (m, 5H), 7.13 (dd, J = 6.6, 2.8 Hz, 2H), 4.36 – 4.38 (m, 2H), 4.18 – 4.05 (m,
H), 3.40 (dt, J = 11.2, 5.7 Hz, 1H), 3.28 – 3.12 (m, 2H), 2.11 – 2.00 (m, 3H), 1.63 (s, 1H).
) δ 139.8, 139.5, 131.7, 130.2, 128.5, 128.4, 128.3, 127.8, 127.5, 127.0, 126.8, 122.5,
6.5, 85.5, 85.3, 77.3, 77.0, 76.7, 64.7, 61.2, 53.5, 52.0, 32.7.
13C NMR (100 MHz, CDCl
3
8
+
26 3
HRMS(ESI) :Calcd. for C26H O Na [M+ Na] : 409.1780, Found: 409.1774.
HPLC (Chiral IC, λ= 220 nm, hexane/2-propanol = 10/1, Flow rate =0.8 mL/min), tmajor = 15.77 min, tminor = 18.22
min.
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ASSOCIATED CONTENT
Supporting Information
1
13
H and C NMR spectra data and HPLC spectra data for compounds 6a–6r, 8-10, and X-ray crystal
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data for compound anti-6n and syn-6a.
The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*E-mail: syliu@sist.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Science Foundation of China (No. 21332003 and No. 21672066) and Science
and Technology Com-mission of Shanghai Municipality (No. 15ZR1411000) for financial support.
REFERENCES
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