Diastereoselective Synthesis of Adjacent P,C-Stereogenic β-N-Glycosidic Linked α-Aminophosphinates

Article abstract of DOI:10.1021/acs.joc.6b02877

The diastereoselective formation of adjacent P,C-stereogenic β-N-glycosidic linked α-aminophosphinates is developed in high yields via a phospha-Mannich reaction. The reaction was performed by employing (R_p)-O-(?)-menthyl H-phenylphosphinate and O-pivaloylated N-galactosylimine for double stereodifferentiation and BF₃·Et₂O as a promoter in THF. O-Pivaloylated N-galactosylphenyl imine 2 and (R_p)-O-(?)-menthyl H-phenylphosphinate 1 were converted to N-galactosyl α-aminoalkylphosphinate 3 with ratios of diastereomers up to 20:1. The synthetic method of the conversion provides a rapid access to adjacent P,C-stereogenic chiral α-aminophosphinates.

Full text of DOI:10.1021/acs.joc.6b02877

Subscriber access provided by University of Newcastle, Australia
Article
Diastereoselective Synthesis of Adjacent P,C-Stereogenic
#-N-Glycosidic Linkaged #-Aminophosphinates
Shuang Liu, Yuming Li, Zhiyu Yin, Qiuli Yu, and Zhiwei Miao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02877 • Publication Date (Web): 04 Feb 2017
Downloaded from http://pubs.acs.org on February 6, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Diastereoselective Synthesis of Adjacent P,CꢀStereogenic
βꢀNꢀGlycosidic Linkaged αꢀAminophosphinates
Shuang Liu†, Yuming Li†, Zhiyu Yin†, Qiuli Yu† and Zhiwei Miao*,†,‡
†State Key Laboratory and Institute of ElementoꢀOrganic Chemistry, Nankai
University, Weijin Road 94, Tianjin 300071, China
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, China
Diastereoselective Synthesis of Adjacent P,CꢀStereogenic βꢀNꢀGlycosidic Linkaged
αꢀAminophosphinates
Shuang Liu, Yuming Li, Zhiyu Yin, Qiuli Yu, and Zhiwei Miao*
O
P
OPiv
PivO
OPiv
O
O
P
1.5eqv
.
PivO
PivO
O
H
H
S
O
Yield up to 91%
dr up to 20:1
Ph
N
S
PivO
O
N
OPiv
Ph
R
BF3 Et2O, THF
OPiv
R
O
R = Aryl, C6H5CH=CH, p-ClC6H4CH=CH,
S
OPiv
O
H2N
P
S
O
PivO
PivO
2-furyl, 2-naphthyl, CH3(CH2)3
1 M HCl
Ph
+
MeOH, r.t.
OH
OPiv
R
ABSTRACT:
The diastereoselective formation of adjacent P,Cꢀstereogenic βꢀNꢀglycosidic
linkaged αꢀaminophosphinates is developed in high yields via a phosphaꢀMannich
reaction. The reaction was performed by employing (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl
Hꢀphenylphosphinate
and
Oꢀpivaloylated
Nꢀgalactosylimine
as
double
stereodifferentiation and BF3·Et2O as a promoter in THF. Oꢀpivaloylated
Nꢀgalactosylphenyl imine 2 of aromatic and (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate
1 were transferred to Nꢀgalactosyl αꢀaminoalkylphosphinate 3 with ratios of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
diastereomers up to 20:1. The synthetic method of the conversion provides a rapid
access to adjacent P,Cꢀstereogenic chiral αꢀaminophosphinates.
7
8
9
INTRODUCTION:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pꢀstereogenic organophosphorus compounds have attracted great interest due to the
potential applications in the fields of pharmaceutical chemistry,1 material science,2
ligands for asymmetric catalysis3 and chiral reagents and organocatalyst.4 The
applications of Pꢀchirogenic derivatives in agrochemistry, biology and drugs
significantly increased in the recent past.5
Considering the growing interest for Pꢀchirogenic phosphorus compounds in
modern chemistry, the preparation of enantiomerically enriched phosphorus
compounds with Pꢀstereogenic centers has received considerable attention. The
stereoselective functionalized chiral phosphine oxides and phosphines possessing
chiral centers at phosphorus and/or carbon atoms are typically prepared using
enantiopure starting materials, chiral auxiliaries, organocatalytic asymmetric PꢀC
bond formation, or by recrystallization resolution of racemic phosphines.6 These
strategies corresponded to a variety of efficient ways to obtain versatile chiral
phosphorus compounds.
The addition of achiral PꢀH species ([R2PH]7, [R2P(O)H]8 and [(RO)2P(O)H]9) to
imines is a widely utilized method for the newly created PꢀC bond and the preparation
of chiral αꢀaminophosphonic acids.10 αꢀAminophosphorus compounds are structurally
analogous to natural αꢀamino acids, and therefore have biological and biochemical
properties in their role as enzyme inhibitors, agrochemicals, or pharmaceuticals.11
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Successful enantioselective approaches preparation of αꢀaminophosphinates
employed catalysts such as metal complexes,12 guanidinium salt,13 thiourea,14 and
chiral phosphoric acid.15 However, in those systems, efficient preparation of
αꢀaminophosphinates with Pꢀstereogenic centers still remains challenging. Especially,
controlling the stereochemistry of chiral αꢀaminophosphorus compounds with
adjacent P,Cꢀstereogenic center has been scarcely reported.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In 2008, Yuan and Zhang reported the nucleophilic addition of ethyl
diethoxymethylphosphinate to Nꢀ(S)ꢀ(tertꢀbutanesulfinyl) methylphenylketimine by
using Rb2CO3 as base. This procedure leads to the enantiomerically enriched
αꢀaminophosphinates with two stereogenic atoms, but with different configuration on
the phosphorus atom (Scheme 1, a).13a In 2009, Tan and coꢀworkers reported the
enantioselective phosphaꢀMannich reaction catalyzed by chiral guanidinium salt,
involving secondary phosphine oxides and Hꢀphosphinates as the Pꢀnucleophile. A
series of optically pure αꢀamino phosphine oxides, αꢀaminophosphinates, and
Hꢀphosphinates containing a Pꢀchiral center were prepared (Scheme 1, b).13b
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
Previous work:
O
S
O
4
5
6
7
8
9
S
tBu
O
tBu
O
O
HN
HN
O
P
O
HP
S
N
Rb2CO3
+
O
O
+
O
O
R
R
P
O
(a)
(b)
R
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Ss,Rc,Rp)
(Ss,Rc,Sp)
Ph
N
Ph
N
N
N
OBn
NTs
OBn
O
O
N
cat (10 mol%)
P
R
+
P R
H
Ar
CH2Cl2/toluene 1:1
N
H
K2CO3 (10 equiv), -40oC
Ar
NHTs
BArF
4
syn
cat
This work:
OPiv
O
PivO
PivO
OPiv
O
PivO
PivO
O
H
N
.
S
Et2O
BF3
(c)
P
S
+
O
O
P
N
O
THF
H
OPiv
Ph
R
OPiv
Ph
R
Scheme 1. Previous and proposed work.
In 2008, we demonstrated the asymmetric synthesis of βꢀNꢀglycosidically linked
αꢀaminophosphonic acids derivatives by glycosylationꢀinduced and Lewis
acidꢀcatalyzed.16 As a natural extension, we developed the enantioselective synthesis
of αꢀamino(phenyl)methyl(phenyl)phosphinic acids by Mannichꢀtype reactions
between Oꢀpivaloylated Dꢀgalactosylamines and ethyl phenylphosphinate.17
Continuing with our interest in the chemistry of aminophosphorus derivatives, here
we report the Lewis acidꢀcatalyzed double stereodifferentiation18 asymmetric
phosphaꢀMannich reaction between (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 and
Oꢀpivaloylated Nꢀgalactosylimine 2 (Scheme 1, c). This methodology provides chiral
αꢀaminophosphinates with rich stereochemistry at both phosphorus and αꢀcarbon
centers in high yields with high diastereoselectivities.
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION:
5
6
7
8
9
We initially investigated the reaction of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate
119 with Oꢀpivaloylated Nꢀgalactosylphenyl imine 2a16,20 in THF without the aid of
Lewis acid. Surprisingly, no desired product 3a was observed even prolonging the
reaction time to 24 hours (Table 1, entry 1). Since the nucleophilicity of chiral PꢀH
species was low and the electrophilicity of imines is only moderate, a Lewis acid was
required to active these compounds and drive the reaction to completion. In this sense,
various Lewis acids were screened in the reaction of the Nꢀgalactosylphenylimine 2a
with (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 in THF and the results were shown in
Table 1. The results revealed that CuCl, CuBr, CuI and ZnCl2·Et2O only caused
anomerization of the Schiff base 2a (Table 1, entries 2ꢀ5). Other Lewis acids tested
(e.g., SnCl4, AlCl3, and BF3·Et2O) were able to promote the desired reaction to afford
moderate yields and stereoselectivities (Table 1, entries 6ꢀ8).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compared with SnCl4 and AlCl3, BF3·Et2O gave the best result in THF at 0 °C to
room temperature. The desired product 3a was obtained in 60% yield with good
diastereoselectivity (d.r. = 14:1) (Table 1, entry 8). When the reactions performed in
THF with equimolar or higher than equimolar amounts of BF3·Et2O, within 12 hours
the reactions were finished in good yields and moderate to excellent
diastereoselectivities (Table 1, entries 8ꢀ10). The ratio of diastereomers 3a was
detected by 31P NMR in THF. From the stereochemical point of view, four
diastereoisomers could be formed in this reaction, because of the anomeric carbon and
one stereogenic center created at the αꢀposition of chiral phosphinate. The four
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
anomeric diastereomers have the βScRp, βRcRp, αScRp and αRcRp configurations. From
the stereochemical outcome of the reaction, it could state that the corresponding
αꢀanomer was not detected in this reaction. It was found that the configuration of
phosphorus was stable and maintained (Rp/Sp > 99:1) in all the tested reactions.
Solvent effect investigation indicated that the reaction could not work if CH2Cl2 or
Et2O is used as solvent (Table 1, entries 11ꢀ12). Toluene delivered the desired product
in a high conversion rate, but with a decrease in the diastereomeric ratio (Table 1,
entry 13). The screening of solvents identified THF as the optimal solvent for this
reaction (Table 1, entry 10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To further increase the reaction diastereoselectivity, the suitable amount of chiral
PꢀH species (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 was investigated by
performing the reaction in the presence of 2 equiv. of BF3·Et2O in THF at 0 °C for 1h,
followed by warming to room temperature. The reaction of imine 2a with equimolar
(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 gave the desired product 3a in 59% yield
with 7:1 diastereoselectivity (Table 1, entry 14). When 1.5 equiv. of
(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 was used, superior result was obtained in
terms of yield and diastereoselectivity of 3a (85% yield, >20:1 dr, Table 1, entry 10).
Further increase in the amount of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 had no
positive change in both yield and stereoselectivity (Table 1, entry 15). Thus, the
optimal reaction conditions for this transformation were determined to be 0.5 mmol of
2a, 1.5 equiv. of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1, 2 equiv. of BF3·Et2O in
THF as solvent at 0 °C to room temperature.
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
Table 1. Optimization of the Reaction Conditionsa
4
5
6
7
8
9
OPiv
PivO
PivO
OPiv
O
P
O
P
H
PivO
PivO
O
Lewis acid
solvent
N
O
O
+
H
O
N
OPiv
Ph
Ph
OPiv
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Rp)-1
2a
3a
Entry
Lewis Acid
(equiv.)
―
Solvent
Reaction
Yields
[%]b
n.r.d
n.r.
n.r.
n.r.
n.r.
48
d.r.c
Time (h)
48
1
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
Et2O
PhCH3
THF
THF
—
—
CuCl (1)
CuBr (1)
CuI (1)
48
3
48
—
4
48
—
5
ZnCl2 (1)
SnCl4 (1)
AlCl3 (1)
48
—
6
16
8:1
7:1
14:1
15:1
>20:1
—
7
24
14
8
BF3·Et2O (1)
BF3·Et2O (1.5)
BF3·Et2O (2)
BF3·Et2O (2)
BF3·Et2O (2)
BF3·Et2O (2)
BF3·Et2O (2)
BF3·Et2O (2)
12
60
9
12
70
10
11
12
13
14e
15f
12
85
48
n.r.
n.r.
60
48
—
24
6:1
7:1
>20:1
12
59
12
82
a
Unless otherwise specified, all reactions were carried out using (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl
Hꢀphenylphosphinate 1 (0.3 mmol, 1.5 equiv) and Oꢀpivaloylated Nꢀgalactosylphenylimine 2a
(0.2 mmol, 1 equiv) in 2 mL solvent at 0 °C to room temperature. b Yields of pure products after
c
purification by chromatography.
Diastereomeric ratio (d.r.) determined by 31P NMR
spectroscopic assay of unpurified products. d no reaction. 1 equiv. of (Rp)ꢀ1 was used. 2 equiv.
e
f
of (Rp)ꢀ1 was used.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
Under the optimum conditions, the phosphaꢀMannich reaction was investigated
with different imines (Table 2). It was found that the desired products 3aꢀ3p can be
successfully obtained in good to high yields and diastereoselectivities, irrespective the
electronic properties and position of the aryl substituents on Oꢀpivaloylated
Nꢀgalactosylimine 2. As for the aldimine in which R was a phenyl group, good yield
and stereoselectivity was realized under identical conditions (Table 1, entry 1).
Similar conclusions were drawn from the hydrophosphinylation of Oꢀpivaloylated
Nꢀgalactosylimine 2bꢀ2h, in which the yields of the process were only slightly
influenced by the substituents present in the aromatic ring (Table 2, entries 2ꢀ8). A
paraꢀmethoxyl substituent on benzene ring of imine 2i displayed good compatibility
with the standard reaction conditions, providing the desired product 3i in good yield
with relative low diastereoselectivity (Table 2, entry 9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The steric properties have remarkable effect on the yields and stereoselectivities.
Yields however were much lower for the imines derived from 2ꢀfluorobenzaldehyde,
2ꢀchlorobenzꢀaldehyde and 2ꢀbromobenzaldehyde respectively, afforded 3j, 3k and 3l
in lower yields and poor stereoselectivities (Table 2, entries 10ꢀ12). Particularly, this
process was efficient for cinnamaldehydes and afforded the desired products 3m and
3n in good yields with excellent diastereoselctivities (Table 2, entries 13ꢀ14). Notably,
heteroaromatic Oꢀpivaloylated Nꢀgalactosylimine 2o was reacted under optimized
reaction conditions with (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 and the desired
αꢀaminophosphinate 3o was obtained in 51% yield with poor stereoselectivity (Table
2, entry 15). The bulky 2ꢀnaphthyl imine 2p could also afford the corresponding
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
product 3p in high yield with good selectivity (Table 2, entry 16). Furthermore, the
reaction of aliphatic aldehyde derived Schiff base 2 with (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl
Hꢀphenylphosphinate 1 led to the product in very low yield, only anomerization and
decomposition occurred (Table 2, entry 17).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. The phosphaꢀMannich of
Nꢀ(2,3,4,6ꢀtetraꢀOꢀpivaloylatedꢀDꢀgalactosyl)aldimines 2aꢀ2q.
OPiv
PivO
OPiv
O
OPiv
O
O
R
O
P
PivO
PivO
PivO
PivO
H
R
O
O
N S P
S
N
H
BF3 Et2O
THF
PivO
S
O
+
H
O
N
R
O
OPiv
Ph
Ph
OPiv
OPiv
2a-2p
Ph
R
(Rp)-1
3a-3p
3r
Entry
Product
R
Time [h]
Yield (%)a
d.r.b
1
2
C6H5 (2a)
12
12
6
85
73
85
85
88
81
84
75
77
63
46
45
80
79
51
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>16:1
7:1
3a
3b
3c
3d
3e
3f
pꢀCH3C6H4 (2b)
pꢀFC6H4 (2c)
3
4
pꢀClC6H4 (2d)
pꢀBrC6H4 (2e)
pꢀNO2C6H4 (2f)
pꢀCNC6H4 (2g)
6
5
6
6
6
7
6
3g
3h
3i
8
mꢀCH3C6H4 (2h)
12
12
12
12
12
12
12
12
9
pꢀOCH3C6H4 (2i)
oꢀFC6H4 (2j)
10
11
12
13
14
15
7:1
3j
oꢀClC6H4 (2k)
7:1
3k
3l
oꢀBrC6H4 (2l)
9:1
C6H5CH=CH (2m)
pꢀClC6H4CH=CH (2n)
2ꢀfuryl (2o)
>20:1
>20:1
1:1
3m
3n
3o
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
16
17
2ꢀnaphthyl (2p)
CH3(CH2)3 (2q)
2ꢀnaphthyl (2p)
12
24
24
91
trace
67
>20:1
—
3p
3q
3r
18c
>20:1
9
a
b
Yields of pure products after purification by chromatography. Diastereomeric ratio (d.r.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
determined by 31P NMR spectroscopic assay of unpurified products.
(Sp)
Oꢀ(+)ꢀmenthylꢀHꢀphosphinate 1’ was used.
The absolute configuration at the phosphorus atom of the product 3d from
Oꢀpivaloylated Nꢀgalactosylꢀ4ꢀchlorophenyl imine 2d with (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl
Hꢀphenylphosphinate 1 was determined unambiguously by Xꢀray analysis (see the
details in Supporting Information),21 showing that this phosphaꢀMannich reaction
takes place with retention of the configuration at phosphorus. The structure shows that
the relative configuration of βꢀNꢀglycosideꢀαꢀaminophosphinate main product can be
assigned as GalaβScSpMenL. This illustrates that in this novel reaction high
diastereoselectivity of both αꢀC and P were realized simultaneously, and supporting
the stereogenic nature of phosphorus atom of αꢀaminophosphinates. To confirm the
efficient removal of the auxiliary, compound 3a was treated with a solution of
hydrochloric acid in methanol to give 4a in 86% yield, which maintains excellent
diastereoselectivity (Scheme 2).
OPiv
PivO
OPiv
O
O
P
O
PivO
PivO
H
O
S
N
1 M HCl
H2N
P
O
Ph
S
+
PivO
O
OH
OPiv
OPiv
MeOH, r.t.
Ph
3a
4a d.r. >20:1
Scheme 2. The removal of the chiral auxiliary of 3a.
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
To explore the mechanism, some control experiments were carried out. Under the
5
6
7
identified conditions, (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate
1
added to
8
9
Nꢀbenzylbenzylimine 5 to generate two diastereoisomers with a diastereomeric ratio
(d.r.) of 1:1 in 75% yield (Scheme 3, a). When the enantiomerically enriched
(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 was resubjected to the reaction conditions
in the absence of imine 5 for 24 hours, no racemization was observed. The treatment
of the diastereoisomeric mixture [(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1:
(Sp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 = 2.27:1] with 2ꢀnaphthyl imine 2p under
the standard reaction conditions provided two stereoisomers 3p and 3p’. On 31P NMR
spectra, the corresponding peaks were observed at 35.23 and 37.39 ppm, representing
GalaβScSpMenL and GalaβScRpMenL in the ratio of 1.48:1, respectively (Scheme 3, b).
In a separate experiment, (Sp)ꢀOꢀ(+)ꢀmenthyl Hꢀphenylphosphinate 1’ reacted with
2ꢀnaphthyl imine 2p and gave the desired product 3r in 67% yield with excellent
diastereoselectivity (Scheme 3, c and Table 2, entry 18). These results indicated that
the high diastereoselectivity was determined by the combination of
(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 and Oꢀpivaloylated Nꢀgalactosylimine 2.
The chiral imine 2 is the major controlling element in the phosphaꢀMannich reaction,
and the stereoselectivity could be modulated by double asymmetric induction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
O
O
P
H
S
.
P OMen(-)
N
BF3 Et2O
THF
N
Ph
OMen(-)
Ph
(a)
*
+
H
7
8
d.r. = 1:1
(Rp)-1
5
6
9
OPiv
O
PivO
PivO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
H
S
N S P
O
P
OMen(-)
Ph
OPiv
OMen(-)
Ph
OPiv
PivO
H
O
N
PivO
BF3 Et2O
+
(Rp)-1
OPiv
(b)
3p
THF
O
P
OPiv
PivO
PivO
O
OMen(-)
H
H
R
O
S
N
P
2p
OMen(-)
Ph
Ph
OPiv
(Sp)-1
3p'
OPiv
OPiv
PivO
PivO
PivO
PivO
O
O
S
P
O
H
R
O
N
P OMen(+)
N
H
BF3 Et2O
THF
OMen(+)
Ph
(c)
OPiv
+
OPiv
Ph
(Sp)-1'
d.r. > 20:1
yield: 67%
2p
3r
Scheme 3. Investigation of the mechanism of the phosphaꢀMannich.
According to these observations, we can propose the following models as an
explanation to the diastereoselectivity of the PꢀC bond formation as shown in Scheme
4. The diastereoselectivity of the GalaβScSpMenLꢀconfigured diastereomer of 3 at αꢀC
position of phosphinate is the result of the preferential formation of the transition state
corresponding to an attack of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 from the Si
side of (E)ꢀNꢀgalactosylaldimines 2. In the transition state, the boron atom has
tetraꢀcoordination to the front side coordinating the imine nitrogen and the carbonyl
oxygen (Cꢀ2) of the pivaloyloxy group, and one of the three fluorines may be
removed when (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 was introduced. It appears
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
that the imine·BF3 complex maintains the Hꢀeclipsed conformation being of the
chelation by the auxiliary’s pivaloyl group inhibits rotation along the NꢀC* bond. The
presence of the bulky pivaloyl group forces the SN2’ꢀtype attack of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl
Hꢀphenylphosphinate 1 from the back side of the imine to be initiated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is suggested that the OH moiety of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 is
important in determining the high diastereoselectivity, since the required tautomeric
equilibrium liberates P(III) phosphonous form from the P(V) phosphinic. From these
results, this hypothesis would explain the course of the main isomer synthesis. The
mechanism indicates that the Piv4Gala group has a significant role in controlling the
regio
and
stereoselectivity
of
(Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 to Nꢀgalactosylimines 2.
O
P
O
H
O
P
O
Ph
Ph
F
B
phosphite form
(reactive)
F
B
phosphite form
(reactive)
F
F
F
O
O
H
O
N
Ph
O
N
Ph
O
O
H
tBu
tBu
O
HP
O
Si side attack
Si side attack
O
HP
O
Ph
Ph
phosphonate form
(unreactive)
phosphonate form
(unreactive)
Scheme 4. Proposed reaction mechanism.
CONCLUSION:
In conclusion, we have described a convenient and efficient synthesis protocol for
preparation of adjacent P,Cꢀstereogenic βꢀNꢀglycosidic linkaged αꢀaminophosphinates
in high yields with high diastereoselectivities, employing BF3·Et2O as the promoter
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
9
and both of (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 and Oꢀpivaloylated
Nꢀgalactosylimine 2 as double stereodifferentiation by means of phosphaꢀMannich
reactions. OꢀPivaloylated Nꢀgalactosylimine 2 is an effective stereodifferentiating tool
in this reaction, and boron trifluoride presumably forms a tetraꢀcoordination
intermediate that induces the S configuration at the Cα center by attack at the
sterically less hindered the Si side of the imine. Further efforts on the application of
the Pꢀstereogenic phosphinate as a catalyst in asymmetric reactions are current
underway in our laboratory and will be reported in due course.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General. All reactions were carried out under an inert atmosphere of nitrogen and in ovenꢀdried
glassware with magnetic stirring. Anhydrous THF were distilled from sodium. Flash
1
chromatography was performed with silica gel (particle size 10ꢀ40 ꢁm). H, 13C and 31P NMR
1
spectra were obtained in CDCl3 using 300 MHz NMR instrument (300 MHz for H, 75 MHz for
1
13C, 100 MHz for 31P) and 400 MHz NMR instrument (400 MHz for H, 162 MHz for 13C, 121
MHz for 31P) spectrometers. Chemical shifts were reported in ppm downfield from internal
Si(CH3)4 and external 85% H3PO4, respectively. NMR data are reported as follows: chemical shift,
peak information (br = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constant (Hz) and integration. Data collections for crystal structure were
determined on an Xꢀray diffractometer. Highꢀresolution mass spectra (HRMS) were obtained using
an (ESI) mass spectrometer (TOF). Melting points were determined on a melting apparatus
without correction.
General procedure for the preparation of optically pure (Rp)ꢀ(ꢀ)ꢀmenthyl
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hꢀphenylphosphinate 1 and (Sp)ꢀ(+)ꢀmenthyl Hꢀphenylphosphinate 1’.19 The mixture of
(ꢀ)ꢀmenthol (20 g, 128 mmol) and pyridine (10.3 mL, 128 mmol) in Et2O (40 mL) was added
dropwise with stirring to a PhPCl2 (17.4 mL, 128 mmol) solution in Et2O (20 mL) at 0 and then
stirred at room temperature for overnight. Water (3 mL, 167 mmol) was added, and the reaction
mixture was washed with water and extracted with hexane. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization of the
mixture in hexane (twice) at ꢀ30 gave pure (Rp)ꢀ(ꢀ)ꢀmenthyl hydrogenophenylphosphinate 1 as a
white crystal (4.18 g, 23% yield, RP/SP > 99/1). (SP)ꢀ(+)ꢀmenthyl hydrogenophenylphosphinate 1’
was prepared similarly from PhPCl2 and (+)ꢀmenthol.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
(Rp)ꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1. [α]D = ꢀ35.6 (c = 2.0, CH2Cl2); 31P NMR (162 MHz,
CDCl3): δ 24.74; 1H NMR (400 MHz, CDCl3): δ 0.88 (dd, J = 13.7, 6.7 Hz, 6H), 0.96 (d, J = 7.0
Hz, 3H), 0.99ꢀ1.10 (m, 2H), 1.24 (dd, J = 23.3, 12.0 Hz, 1H), 1.43ꢀ1.49 (m, 2H), 1.66ꢀ1.72 (m,
2H), 2.17ꢀ2.24 (m, 2H), 4.29 (qd, J = 10.5, 4.5 Hz, 1H), 7.51 (td, J = 7.4, 3.5 Hz, 2H), 7.58ꢀ7.61
(m, 1H), 7.66 (d, J = 553.0 Hz, 1H), 7.76ꢀ7.81 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.8,
21.1, 21.9, 23.0, 25.8, 31.7, 34.0, 43.6, 48.7 (d, J = 6.1 Hz), 79.0 (d, J = 7.3 Hz), 128.7 (d, J = 14.0
Hz), 130.7 (d, J = 11.8 Hz), 133.0 (d, J = 2.4 Hz).
(Sp)ꢀ(+)ꢀmenthyl Hꢀphenylphosphinate 1’: [α]D25 = +35.3 (c = 2.0, CH2Cl2). 31P NMR (162 MHz,
CDCl3): δ 24.71; 1H NMR (400 MHz, CDCl3): δ 0.86 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H),
0.96 (d, J = 7.0 Hz, 3H), 0.99ꢀ1.10 (m, 2H), 1.20ꢀ1.29 (m, 1H), 1.43ꢀ1.49 (m, 2H), 1.66ꢀ1.72 (m,
2H), 2.17ꢀ2.24 (m, 2H), 4.29 (qd, J = 10.4, 4.3 Hz, 1H), 7.66 (d, J = 553.0 Hz, 1H), 7.50ꢀ7.61 (m,
3H), 7.78 (dd, J = 13.8, 7.5 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.8, 21.0, 21.9, 22.9,
25.8, 31.6, 33.9, 43.5, 48.7 (d, J = 6.2 Hz), 78.9 (d, J = 7.3 Hz), 128.7 (d, J = 14.0 Hz), 130.6 (d, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
= 11.7 Hz), 132.9 (d, J = 2.7 Hz).
5
6
7
8
9
General procedure for the preparation of Oꢀpivaloyiated NꢀGalactosylimines 2. To a stirred
solution of 2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalactopyranosylamine20 (0.515 g, 1 mmol) and aldehyde
(1.3 mmol) in 2ꢀpropanol (2.5 ml) were added 2ꢀ3 drops of acetic acid and the mixture was stirred
at room temperature for about 0.5 h. The appearance of a precipitate from the solution indicated
the formation of 2. The mixture was filtered off and the precipitate was washed with ice cold
2ꢀpropanol and dried under reduced pressure, Nꢀgalactosylaldimines 2 was isolated as a colorless
solid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of Nꢀgalactosyl αꢀaminoalkylphosphinate 3. To a
stirred solution of Nꢀgalactosylaldimines 2 (0.2 mmol) in THF (2 mL) were added
(Rp)ꢀ(ꢀ)ꢀmenthyl hydrogenophenylphosphinate 1 (0.084 g, 0.3 mmol) and BF3⋅Et2O (0.057 g, 0.4
mmol) at 0 °C, and the mixture was stirred at room temperature for 12 hours. After completion of
the reaction, the mixture was diluted with an aqueous saturated solution of sodium bicarbonate (25
mL) and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the crude products 3. The residue
was purified by column chromatography on silica gel [petroleum ether/ethyl acetate, 5:1 (V/V)] to
provided pure compounds 3.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](phenyl)phosphinate (3a). White Solid (149.6 mg, 85% yield); Mp
115ꢀ117 °C; 31P NMR (162 MHz, CDCl3): δ 35.38; 1H NMR (400 MHz, CDCl3): δ 0.76 (d, J = 6.5
Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 1.09 (s, 9H), 1.11 (s, 9H), 1.18 (s,
11H), 1.27 (s, 11H), 1.46 (dd, J = 19.4, 7.9 Hz, 1H), 1.57ꢀ1.73 (m, 2H), 1.79 (d, J = 11.8 Hz, 1H),
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.10ꢀ2.18 (m, 1H), 2.69 (dd, J = 12.5, 6.5 Hz, 1H), 3.66 (t, J = 6.5 Hz, 1H), 3.82 (dd, J = 12.5, 8.4
Hz, 1H), 3.95 (dd, J = 11.1, 6.5 Hz, 1H), 4.02 (dd, J = 11.1, 7.0 Hz, 1H), 4.42 (m, 1H), 4.69 (d, J =
19.7 Hz, 1H), 5.00 (dd, J = 10.2, 3.1 Hz, 1H), 5.02ꢀ5.09 (m, 1H), 5.32 (d, J = 2.5 Hz, 1H),
7.07ꢀ7.19 (m, 4H), 7.19ꢀ7.25 (m, 1H), 7.28ꢀ7.34 (m, 2H), 7.43ꢀ7.54 (m, 3H); 13C {1H} NMR (101
MHz, CDCl3): δ 15.9, 21.3, 21.9, 23.0, 25.9, 27.1, 27.3, 31.5, 34.1, 38.7, 38.8, 39.1, 43.1, 48.8 (d,
J = 5.4 Hz), 59.3 (d, J = 105.5 Hz), 61.7, 67.4, 68.8, 71.4, 71.7, 77.8 (d, J = 7.8 Hz), 85.4 (d, J =
14.6 Hz), 127.7, 127.8, 127.9, 129.3 (d, J = 5.2 Hz), 130.4, 132.1, 132.8 (d, J = 9.0 Hz,), 133.6 (d,
J = 5.7 Hz), 176.9, 177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for C49H75NO11P [M+H]+:
884.5072, found: 884.5069.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀmethylphenyl)phosphinate (3b). White Solid (130.2 mg, 73% yield); Mp
181ꢀ183 °C; 31P NMR (162 MHz, CDCl3): δ 35.50; 1H NMR (400 MHz, CDCl3) δ 0.76 (d, J = 6.5
Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 1.10 (m, 18H), 1.18 (s, 11H), 1.26 (s,
11H, 1.43ꢀ1.48 (m, 1H), 1.60ꢀ1.69 (m, 2H), 1.78 (d, J = 11.9 Hz, 1H), 2.09ꢀ2.13 (m, 1H), 2.30 (d,
J = 1.9 Hz, 3H), 2.65 (dd, J = 12.5, 6.2 Hz, 1H), 3.65 (t, J = 6.7 Hz, 1H), 3.81 (dd, J = 12.5, 8.4
Hz, 1H), 3.95 (dd, J = 11.1, 6.4 Hz, 1H), 4.01 (dd, J = 11.1, 7.1 Hz, 1H), 4.39ꢀ4.42 (m, 1H), 4.65
(d, J = 19.4 Hz, 1H), 4.99 (dd, J = 10.2, 3.2 Hz, 1H), 5.00ꢀ5.06 (m, 1H), 5.31 (d, J = 2.3 Hz, 1H),
6.97ꢀ7.01 (m, 4H), 7.29ꢀ7.35 (m, 2H), 7.44ꢀ7.53 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
15.9, 21.2 (d, J = 11.5 Hz), 21.9, 23.0, 25.9, 27.1, 27.1, 27.2, 29.7, 31.5, 34.1, 38.7, 38.8, 39.1,
43.1, 48.7 (d, J = 5.3 Hz), 59.1 (d, J = 106.8 Hz), 61.8, 67.3, 68.8, 71.3, 71.7, 77.7 (d, J = 7.5 Hz),
85.3 (d, J = 14.8 Hz), 127.7 (d, J = 12.7 Hz), 128.6, 129.2 (d, J = 5.4 Hz), 130.3 (d, J = 6.1 Hz),
132.0, 132.8 (d, J = 9.0 Hz), 137.6, 176.9, 177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
C50H77NO11P [M+H]+: 898.5229, found: 898.5227.
5
6
7
8
9
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀfluorophenyl)phosphinate (3c). White Solid (152.5 mg, 85% yield); Mp
176ꢀ178°C; 31P NMR (162 MHz, CDCl3): δ 35.16 (d, J = 4.7 Hz); 1H NMR (400 MHz, CDCl3): δ
0.76 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 6.7 Hz,
18H), 1.18 (s, 9H), 1.26ꢀ1.31 (m, 11H), 1.42ꢀ1.48 (m, 1H), 1.61ꢀ1.65 (m, 2H), 1.71ꢀ1.78 (m, 3H),
2.06ꢀ2.09 (m, 1H), 2.68 (dd, J = 12.5, 6.6 Hz, 1H), 3.66 (t, J = 6.6 Hz, 1H), 3.78 (dd, J = 12.4, 7.8
Hz, 1H), 3.94 (dd, J = 11.4, 6.9 Hz, 1H), 4.02 (dd, J = 11.1, 7.1 Hz, 1H), 4.39ꢀ4.42 (m, 1H), 4.66
(d, J = 19.3 Hz, 1H), 5.02ꢀ5.06 (m, 2H), 5.32 (s, 1H), 6.86 (t, J = 8.4 Hz, 2H), 7.08ꢀ7.09 (m, 2H),
7.27ꢀ7.34 (m, 2H), 7.46ꢀ7.51 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 16.0, 21.4, 22.0, 23.2,
26.0, 27.2, 27.4, 31.6, 34.1, 38.85, 38.89, 39.2, 43.2, 48.9, 58.6 (d, J = 106.7 Hz), 61.8, 67.4, 68.9,
71.4, 71.9, 78.1 (d, J = 6.7 Hz), 85.6 (d, J = 9.3 Hz), 115.1, 128.0 (d, J = 12.7 Hz), 130.8, 130.9,
131.0, 132.4, 132.9 (d, J = 9.0 Hz), 176.9, 177.2, 177.5, 178.0; HRMS (ESI): m/z calcd for
C49H74NO11PF [M+H]+: 902.4978, found: 902.4980.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀchlorophenyl)phosphinate (3d). White Solid (156.5 mg, 85% yield); Mp
233ꢀ235 °C;31P NMR (162 MHz, CDCl3): δ 34.83; 1H NMR (400 MHz, CDCl3): δ 0.76 (d, J = 6.5
Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 5.7 Hz, 18H), 1.18 (s,
11H), 1.26 (s, 11H), 1.43ꢀ1.45 (m, 1H), 1.61ꢀ1.78 (m, 3H), 2.03ꢀ2.08 (m, 1H), 2.69 (dd, J = 12.5,
6.7 Hz, 1H), 3.66 (t, J = 6.7 Hz, 1H), 3.77 (dd, J = 12.5, 7.8 Hz, 1H), 3.94 (dd, J = 11.1, 6.5 Hz,
1H), 4.01 (dd, J = 11.1, 7.0 Hz, 1H), 4.41 (dd, J = 6.8, 4.2 Hz, 1H), 4.65 (d, J = 19.7 Hz, 1H),
4.98ꢀ5.06 (m, 2H), 5.32 (d, J = 1.9 Hz, 1H), 7.03ꢀ7.04 (m, 2H), 7.05ꢀ7.06 (m, 2H), 7.14ꢀ7.16 (m,
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 7.47ꢀ7.51 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.2, 21.9, 23.0, 25.9, 27.1,
27.2, 31.5, 34.0, 38.7, 38.8, 39.1, 43.1, 48.7 (d, J = 5.8 Hz, CH), 58.7 (d, J = 105.4 Hz), 61.6, 67.2,
68.8, 71.3, 71.7, 78.0 (d, J = 7.6 Hz), 85.4 (d, J = 14.8 Hz), 127.8, 128.0, 128.1 (d, J = 2.5 Hz),
130.5 (d, J = 5.0 Hz), 132.3 (d, J = 6.0 Hz), 132.7 (d, J = 9.6 Hz), 133.8 (d, J = 4.0 Hz), 176.8,
177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for C49H74ClNO11P [M+H]+: 918.4683, found:
918.4687.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀbromophenyl)phosphinate (3e). White Solid (169.3 mg, 88% yield); Mp
193ꢀ195 °C; 31P NMR (162 MHz, CDCl3): δ 34.63; 1H NMR (400 MHz, CDCl3) δ 0.76 (d, J = 6.4
Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 7.6 Hz, 20H), 1.18 (s,
11H), 1.26 (s, 9H), 1.42 (s, 1H), 1.61ꢀ1.66 (m, 2H), 1.77 (d, J = 11.7 Hz, 1H), 2.04ꢀ2.07 (m, 1H),
2.69 (dd, J = 12.5, 6.8 Hz, 1H), 3.67 (t, J = 6.5 Hz, 1H), 3.78 (dd, J = 12.1, 7.4 Hz, 1H), 3.94 (dd,
J = 11.1, 6.4 Hz, 1H), 4.01 (dd, J = 11.1, 7.0 Hz, 1H), 4.41 (dd, J = 6.5, 4.3 Hz, 1H), 4.64 (d, J =
19.7 Hz, 1H), 5.02ꢀ5.06 (m, 2H), 5.33 (s, 1H), 6.99ꢀ7.01 (m, 2H), 7.29ꢀ7.35 (m, 4H), 7.48ꢀ7.52 (m,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.2, 21.9, 23.0, 25.9, 27.1, 27.2, 27.2, 31.5, 34.0,
38.7, 38.8, 39.0, 43.1, 48.7 (d, J = 5.4 Hz), 58.7 (d, J = 105.0 Hz), 61.6, 67.2, 68.8, 71.3, 71.8,
78.0 (d, J = 7.7 Hz), 85.4 (d, J = 14.3 Hz), 121.9 (d, J = 4.2 Hz), 127.9 (d, J = 12.7 Hz), 128.7,
130.0, 130.8 (d, J = 5.0 Hz), 131.1, 132.3, 132.7 (d, J = 9.0 Hz), 176.7, 177.0, 177.3, 177.8;
HRMS (ESI): m/z calcd for C49H74BrNO11P [M+H]+: 962.4177, found: 962.4175.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀnitrophenyl)phosphinate (3f). White Solid (151.1 mg, 81% yield); Mp
1
245ꢀ247 °C; 31P NMR (162 MHz, CDCl3): δ 33.98; H NMR (400 MHz, CDCl3): δ 0.77 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
6.4 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 13.3 Hz, 18H), 1.17 (s,
9H), 1.27 (s, 11H), 1.43ꢀ1.47 (m, 2H), 1.61ꢀ1.66 (m, 3H), 1.70ꢀ1.76 (m, 1H), 2.04 (s, 1H), 2.81
(dd, J = 12.5, 7.6 Hz, 1H), 3.66 (t, J = 6.6 Hz, 1H), 3.75 (dd, J = 12.5, 8.3 Hz, 1H), 3.93 (dd, J =
11.1, 6.5 Hz, 1H), 4.02 (dd, J = 11.1, 6.9 Hz, 1H), 4.42ꢀ4.45 (m, 1H), 4.81 (d, J = 21.2 Hz, 1H),
5.01 (dd, J = 10.2, 3.0 Hz, 1H), 5.03ꢀ5.06 (m, 1H), 5.33 (d, J = 3.0 Hz, 1H), 7.30ꢀ7.36 (m, 4H),
7.44ꢀ7.53 (m, 3H), 8.03ꢀ8.05 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.2, 21.9, 23.1,
26.0, 27.2, 27.3, 27.3, 31.6, 34.0, 38.8, 38.9, 39.1, 43.1, 48.7 (d, J = 5.3 Hz), 59.2 (d, J = 101.7
Hz), 61.6, 67.1, 68.9, 71.1, 71.9, 78.6 (d, J = 7.3 Hz), 85.7 (d, J = 13.6 Hz), 123.1 (d, J = 2.1 Hz),
128.1 (d, J = 12.8 Hz), 129.8 (d, J = 4.5 Hz), 132.7 (d, J = 8.7 Hz), 142.1 (d, J = 5.4 Hz), 147.6 (d,
J = 4.1 Hz), 176.8, 177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for C49H74N2O13P [M+H]+:
929.4923, found: 929.4933..
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀcyanophenyl)phosphinate (3g). White Solid (152.4 mg, 84% yield); Mp
231ꢀ233°C; 31P NMR (162 MHz, CDCl3): δ 34.12; 1H NMR (400 MHz, CDCl3): δ 0.77 (d, J = 6.5
Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 8.6 Hz, 18H), 1.17 (s,
11H), 1.26 (s, 9H), 1.43ꢀ1.45 (m, 2H), 1.61ꢀ1.68 (m, 3H), 1.76 (d, J = 11.9 Hz, 1H), 2.00ꢀ2.05 (m,
1H), 2.76 (dd, J = 12.5, 7.6 Hz, 1H), 3.66 (t, J = 6.8 Hz, 1H), 3.74 (dd, J = 12.5, 7.9 Hz, 1H), 3.92
(dd, J = 11.1, 6.6 Hz, 1H), 4.01 (dd, J = 11.1, 6.9 Hz, 1H), 4.42 (dd, J = 6.8, 4.1 Hz, 1H), 4.74 (d,
J = 20.8 Hz, 1H), 4.99ꢀ5.07 (m, 2H), 5.33 (d, J = 1.9 Hz, 1H, 7.23ꢀ7.25 (m, 2H), 7.32ꢀ7.37 (m,
2H), 7.46ꢀ7.53 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.2, 21.9, 23.0, 26.0, 27.1,
27.2, 31.5, 33.9, 38.7, 38.8, 39.1, 43.1, 48.7 (d, J = 5.5 Hz), 59.2 (d, J = 102.3 Hz), 61.5, 67.1,
68.8, 71.2, 71.8, 78.5 (d, J = 7.6 Hz), 85.6 (d, J = 13.6 Hz), 111.7, 118.7, 128.0 (d, J = 12.8 Hz),
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
129.7 (d, J = 5.0 Hz), 131.6, 132.6 (d, J = 9.1 Hz), 140.0, 176.8, 177.1, 177.4, 177.9; HRMS (ESI):
m/z calcd for C50H74N2O11P [M+H]+: 909.5025, found: 909.5022.
7
8
9
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](3ꢀmethylphenyl)phosphinate (3h). Yellow oil (135.1 mg, 75% yield); 31P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
NMR (162 MHz, CDCl3): δ 35.59 (s); H NMR (400 MHz, CDCl3): δ 0.77 (d, J = 6.5 Hz, 3H),
0.87 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 8.3 Hz, 18H), 1.18 (s, 9H),
1.23ꢀ1.31 (m, 11H), 1.31ꢀ1.43 (m, 2H), 1.59ꢀ1.66 (m, 3H), 1.69ꢀ1.70 (m, 1H), 2.11ꢀ2.14 (m, 1H),
2.18 (s, 3H), 2.67 (dd, J = 12.5, 6.4 Hz, 1H), 3.66 (t, J = 6.6 Hz, 1H), 3.82 (dd, J = 12.5, 8.3 Hz,
1H), 3.95 (dd, J = 11.1, 6.4 Hz, 1H), 4.01 (dd, J = 11.1, 7.1 Hz, 1H), 4.40ꢀ4.43 (m, 1H), 4.65 (d, J
= 19.6 Hz, 1H), 4.98ꢀ5.07 (m, 2H), 5.32 (d, J = 2.3 Hz, 1H), 6.88ꢀ6.93 (m, 2H), 7.03ꢀ7.05 (m, 2H),
7.32ꢀ7.33 (m, 2H), 7.45ꢀ7.50 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.3, 21.9, 23.0,
25.9, 27.1, 27.2, 29.7, 31.5, 34.1, 38.7, 38.8, 39.1, 43.1, 48.8 (d, J = 5.4 Hz), 59.3 (d, J = 104.4
Hz), 61.8, 67.4, 68.8, 71.4, 71.7, 77.7 (d, J = 8.4 Hz), 85.4 (d, J = 14.7 Hz), 126.5, 127.7 (d, J =
12.0 Hz), 128.7, 129.2, 129.9 (d, J = 6.0 Hz), 132.0, 132.8 (d, J = 9.3 Hz), 133.4 (d, J = 5.6 Hz),
137.4, 176.8, 177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for C50H77NO11P [M+H]+: 898.5229,
found: 898.5224.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀmethoxyphenyl)phosphinate (3i). Yellow oil (141.5 mg, 77% yield); 31P
NMR (162 MHz, CDCl3): δ 35.50; 1H NMR (400 MHz, CDCl3): δ 0.78 (d, J = 6.5 Hz, 3H), 0.88
(d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 1.11 (t, J = 7.1 Hz, 18H), 1.21 (d, J = 8.6 Hz, 11H),
1.28 (d, J = 2.7 Hz, 11H), 1.47 (dd, J = 18.2, 7.2 Hz, 1H), 1.62ꢀ1.71 (m, 2H), 1.80 (d, J = 7.3 Hz,
1H), 2.11ꢀ2.14 (m, 1H), 2.66 (dd, J = 12.5, 5.9 Hz, 1H), 3.67 (t, J = 6.6 Hz, 1H), 3.80 (s, 3H), 3.83
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
(dd, J = 8.5, 4.2 Hz, 1H), 3.97 (dd, J = 11.1, 6.4 Hz, 1H), 4.04 (dd, J = 11.1, 7.0 Hz, 1H),
4.41ꢀ4.42 (m, 1H), 4.64 (d, J = 18.9 Hz, 1H), 5.01 (dd, J = 10.2, 3.1 Hz, 1H), 5.03ꢀ5.08 (m, 1H),
5.34 (d, J = 2.2 Hz, 1H), 6.73 (t, J = 8.1 Hz, 2H), 7.01ꢀ7.03 (m, 2H), 7.35 (td, J = 7.8, 3.5 Hz, 2H),
7.48ꢀ7.54 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.3, 21.9, 23.0, 25.9, 27.10, 27.13,
27.2, 27.3, 31.5, 34.1, 38.7, 39.1, 43.1, 48.7 (d, J = 5.6 Hz), 55.2, 58.6 (d, J = 107.7 Hz), 61.7,
67.3, 68.8, 71.4, 71.8, 77.7 (d, J = 8.0 Hz), 85.3 (d, J = 14.9 Hz), 113.4, 125.2 (d, J = 6.2 Hz),
127.8 (d, J = 12.6 Hz), 129.2, 130.4 (d, J = 5.3 Hz), 132.0 (d, J = 2.7 Hz), 132.8 (d, J = 9.0 Hz),
176.9, 177.1, 177.4, 177.9; HRMS (ESI): m/z calcd for C50H77NO12P [M+H]+: 914.5178, found:
914.5174.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](2ꢀfluorophenyl)phosphinate (3j). White Solid (113.8 mg, 63% yield); Mp
1
86ꢀ88°C; 31P NMR (162 MHz, CDCl3): δ 34.70 (d, J = 4.7 Hz); H NMR (400 MHz, CDCl3): δ
0.68 (d, J = 6.9 Hz, 3H), 0.75 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 2.3 Hz,
18H), 1.20 (s, 9H), 1.25ꢀ1.27 (m, 11H), 1.27ꢀ1.29 (m, 2H), 1.60ꢀ1.63 (m, 2H), 1.70ꢀ1.73 (m, 3H),
2.64ꢀ2.69 (m, 1H), 3.67 (t, J = 6.7 Hz, 1H), 3.76ꢀ3.87 (m, 3H), 4.30 (dd, J = 6.8, 4.2 Hz, 1H),
4.96ꢀ5.07 (m, 3H), 5.30 (d, J = 1.9 Hz, 1H), 7.02 (dt, J = 15.2, 8.6 Hz, 2H), 7.04ꢀ7.07 (m, 2H),
7.22ꢀ7.25 (m, 2H), 7.44ꢀ7.46 (m, 1H), 7.69ꢀ7.74 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ
15.4, 21.2, 21.8, 22.7, 25.2, 27.1, 27.1, 27.2, 31.4, 33.9, 38.7, 39.0, 43.0, 48.7 (d, J = 5.5 Hz), 50.4
(d, J = 107.7 Hz), 61.5, 67.1, 68.6, 71.4, 71.5, 77.6 (d, J = 7.6 Hz), 86.3 (d, J = 12.3 Hz), 115.0 (d,
J = 22.4 Hz), 123.6, 128.0 (d, J = 12.7 Hz), 129.2, 130.7, 132.3, 132.7 (d, J = 9.3 Hz), 176.7,
177.1,177.2, 178.0; HRMS (ESI): m/z calcd for C49H74FNO11P [M+H]+: 902.4978, found:
902.4981.
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
5
6
7
topyranosyl)amino](2ꢀchlorophenyl)phosphinate (3k). Yellow oil (29.0 mg, 16% yield);31P NMR
8
9
1
(162 MHz, CDCl3): δ 32.88; H NMR (400 MHz, CDCl3): δ 0.56 (d, J = 6.9 Hz, 3H), 0.69ꢀ0.73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 6H), 1.06 (s, 9H), 1.17 (s, 9H), 1.21 (s, 9H), 1.26 (s, 11H), 1.42 (d, J = 7.8 Hz, 2H), 1.55 (d, J
= 11.0 Hz, 2H), 1.62 (d, J = 12.3 Hz, 1H), 1.78ꢀ1.86 (m, 2H), 2.73 (t, J = 9.3 Hz, 1H), 3.64 (t, J =
6.7 Hz, 1H), 3.67ꢀ3.71 (m, 1H), 3.72ꢀ3.76 (m, 1H), 3.93ꢀ4.03 (m, 1H), 4.15ꢀ4.25 (m, 1H), 4.44 (dd,
J = 32.7, 6.0 Hz, 1H), 4.86ꢀ4.99 (m, 2H), 5.26 (d, J = 2.7 Hz, 1H), 7.10ꢀ7.23 (m, 2H), 7.33ꢀ7.40
(m, 2H), 7.42ꢀ7.48 (m, 2H), 7.53ꢀ7.61 (m, 1H), 7.73ꢀ7.81 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3): δ 15.3, 21.2, 21.8, 22.6, 24.9, 27.06, 27.10, 27.12, 27.2, 31.4, 33.9, 38.7, 38.7, 38.7, 39.0,
42.9, 48.7 (d, J = 5.6 Hz), 54.0 (d, J = 106.6 Hz), 61.2, 67.0, 68.6, 71.3, 71.4, 77.5 (d, J = 7.8 Hz),
86.7 (d, J = 11.6 Hz), 126.4, 128.1 (d, J = 12.8 Hz), 128.8, 129.1, 130.2, 131.4, 132.4, 132.7 (d, J
= 9.4 Hz), 133.8 (d, J = 4.8 Hz), 135.0 (d, J = 7.0 Hz), 176.7, 177.1, 177.2, 177.9; HRMS (ESI):
m/z calcd for C49H74ClNO11P [M+H]+: 918.4683, found: 918.4682.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](2ꢀbromophenyl)phosphinate (3l). White Solid (48.3 mg, 25% yield); Mp
76ꢀ78 °C; 31P NMR (162 MHz, CDCl3): δ 34.88; 1H NMR (400 MHz, CDCl3): δ 0.56 (d, J = 6.9
Hz, 3H), 0.71ꢀ0.74 (m, 6H), 1.07ꢀ1.08 (m, 18H), 1.18ꢀ1.22 (m, 11H), 1.22 (s, 9H), 1.27ꢀ1.30 (m,
2H), 1.42ꢀ1.44 (m, 1H), 1.55ꢀ1.65 (m, 3H), 1.89ꢀ1.92 (m, 1H), 2.72ꢀ2.78 (m, 1H), 3.65ꢀ3.68 (m,
1H), 3.70ꢀ3.73 (m, 1H), 3.75ꢀ3.81 (m, 1H), 3.98ꢀ4.08 (m, 1H), 4.21ꢀ4.24 (m, 1H), 4.88ꢀ4.99 (m,
2H), 5.15ꢀ5.23 (m, 1H), 5.28 (d, J = 3.0 Hz, 1H), 7.12ꢀ7.22 (m, 2H), 7.40ꢀ7.42 (m, 1H), 7.45ꢀ7.50
(m, 2H), 7.54ꢀ7.61 (m, 2H), 7.79ꢀ7.83 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.3, 21.2,
21.8, 22.5, 24.9, 27.1, 27.1, 27.2, 31.4, 33.9, 38.7, 38.7, 39.0, 42.9, 48.7 (d, J = 5.4 Hz), 56.7 (d, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
= 107.4 Hz), 61.0, 66.9, 68.6, 71.2, 71.4, 77.4 (d, J = 8.1 Hz), 86.6 (d, J = 11.6 Hz), 125.7 (d, J =
7.5 Hz), 127.0, 128.1 (d, J = 12.7 Hz), 129.1, 130.2, 131.6 (d, J = 3.7 Hz), 132.4, 132.7 (d, J = 9.7
Hz), 135.5, 176.7, 177.1, 177.2, 177.9; HRMS (ESI): m/z calcd for C49H74BrNO11P [M+H]+:
962.4177, found: 962.4174.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](3ꢀphenylallyl)phosphinate (3m). White Solid (145.6 mg, 80% yield); Mp
118ꢀ120°C; 31P NMR (162 MHz, CDCl3): δ 34.77; 1H NMR (400 MHz, CDCl3): δ 0.83 (d, J = 6.3
Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H), 1.15 (s, 9H), 1.25 (s, 9H),
1.32ꢀ1.35 (m, 11H), 1.48ꢀ1.54 (m, 2H), 1.67ꢀ1.76 (m, 3H), 1.86ꢀ1.89 (m, 1H), 2.30ꢀ2.33 (m, 1H),
2.48ꢀ2.53 (m, 1H), 3.87 (t, J = 6.6 Hz, 1H), 4.04 (dd, J = 10.8, 7.0 Hz, 1H), 4.11ꢀ4.15 (m, 2H),
4.32 (dd, J = 20.0, 8.0 Hz, 1H), 4.49ꢀ4.52 (m, 1H), 5.04ꢀ5.16 (m, 2H), 5.43 (d, J = 1.6 Hz, 1H),
5.72ꢀ5.79 (m, 1H), 6.61 (dd, J = 15.9, 4.9 Hz, 1H), 7.26ꢀ7.37 (m, 5H), 7.48ꢀ7.49 (m, 2H),
7.57ꢀ7.59 (m, 1H), 7.80ꢀ7.82 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 21.2, 21.9, 22.7,
23.0, 26.0, 27.0, 27.07, 27.12, 27.2, 29.7, 31.5, 34.0, 38.7, 38.7, 39.1, 43.2, 48.7 (d, J = 5.5 Hz),
57.8 (d, J = 107.2 Hz), 61.5, 67.2, 68.6, 71.3, 71.7, 77.9 (d, J = 8.1 Hz), 85.7 (d, J = 14.9 Hz),
122.6 (d, J = 8.6 Hz), 126.4, 128.0 (d, J = 7.7 Hz), 128.1, 128.6, 129.7, 131.0, 132.2 (d, J = 2.0
Hz), 132.6 (d, J = 9.0 Hz), 135.3 (d, J = 12.4 Hz), 136.4, 176.8, 177.0, 177.2, 177.9; HRMS (ESI):
m/z calcd for C51H77NO11P [M+H]+: 910.5229, found: 910.5226.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](4ꢀchlorophenylallyl)phosphinate (3n). White Solid (148.3 mg, 79% yield);
Mp 125ꢀ127 °C; 31P NMR (162 MHz, CDCl3): δ 34.53; 1H NMR (400 MHz, CDCl3): δ 0.77 (d, J
= 6.5 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 1.03 (s, 9H), 1.09 (s, 9H), 1.19 (s,
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
9H), 1.26 (s, 9H), 1.42ꢀ1.47 (m, 4H), 1.67ꢀ1.72 (m, 4H), 2.23ꢀ2.25 (m, 1H), 2.44 (dd, J = 12.4, 7.1
Hz, 1H), 3.97 (dd, J = 10.4, 7.4 Hz, 2H), 4.07ꢀ4.09 (m, 2H), 4.30 (dd, J = 14.2, 7.4 Hz, 1H), 4.44
(dd, J = 6.7, 4.1 Hz, 1H), 5.04 (dt, J = 19.0, 8.6 Hz, 2H), 5.37 (d, J = 2.7 Hz, 1H), 5.69 (ddd, J =
15.8, 8.0, 5.5 Hz, 1H), 6.50 (dd, J = 16.0, 5.5 Hz, 1H), 7.12ꢀ7.14 (m, 2H), 7.42 (dt, J = 7.3, 3.7 Hz,
2H), 7.52ꢀ7.53 (m, 2H), 7.70ꢀ7.74 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.9, 19.2, 21.2,
21.8, 23.0, 25.6, 27.1, 27.2, 31.5, 34.0, 38.6, 38.7, 39.0, 43.2, 48.7 (d, J = 5.5 Hz), 64.3 (d, J =
129.0 Hz), 67.96, 68.02, 68.6, 71.3, 71.7, 78.0 (d, J = 5.3 Hz), 85.8 (d, J = 14.0 Hz), 123.5 (d, J =
6.5 Hz), 127.5, 128.0, 128.5 (d, J = 64.4 Hz), 129.7, 130.9, 132.3, 132.6 (d, J = 9.2 Hz), 133.6,
133.9 (d, J = 12.4 Hz), 134.9 (d, J = 3.7 Hz), 176.8, 177.0, 177.2, 177.9; HRMS (ESI): m/z calcd
for C51H76ClNO11P [M+H]+: 944.4839, found: 944.4836.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](furyl)phosphinate (3o). Yellow oil (88.8 mg, 51% yield); 31P NMR (162
MHz, CDCl3): δ 33.01, 33.94; 1H NMR (400 MHz, CDCl3): δ 0.80 (d, J = 6.5 Hz, 3H), 0.90ꢀ0.95
(m, 6H), 1.09ꢀ1.13 (m, 18H), 1.25 (d, J = 5.5 Hz, 11H), 1.30 (s, 11H), 1.46ꢀ1.53 (m, 1H),
1.64ꢀ1.73 (m, 2H), 1.85 (d, J = 11.5 Hz, 1H), 2.23ꢀ2.25 (m, 1H), 2.72ꢀ2.76 (m, 1H), 3.54 (t, J =
6.9 Hz, 1H), 3.74ꢀ3.78 (m, 1H), 3.83ꢀ3.88 (m, 1H), 4.00ꢀ4.14 (m, 1H), 4.18ꢀ4.22 (m, 1H),
4.40ꢀ4.43 (m, 1H), 4.72 (dd, J = 85.5, 11.7 Hz, 1H), 5.04ꢀ5.08 (m, 1H), 5.23ꢀ5.32 (m, 1H),
5.38ꢀ5.44 (m, 1H), 6.04ꢀ6.28 (m, 1H), 6.32 (s, 1H), 7.43ꢀ7.52 (m, 1H), 7.53ꢀ7.56 (m, 2H),
7.58ꢀ7.70 (m, 1H), 7.80ꢀ7.95 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.2,15.9, 21.3, 21.9,
22.5, 25.8, 27.01, 27.07, 27.12, 27.2, 31.5, 34.0, 38.6, 38.7, 38.8, 39.0, 43.2, 48.8 (d, J = 18.5 Hz),
52.5 (d, J = 117.4 Hz), 61.4, 65.8, 67.7, 68.1, 71.2, 77.6 (d, J = 7.6 Hz), 81.0 (d, J = 13.0 Hz),
109.8 (d, J = 6.3 Hz), 110.5 (d, J = 2.2 Hz), 110.6 (d, J = 7.0 Hz), 110.8, 127.8, 128.0 (d, J = 13.1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
6
Hz), 132.6 (d, J = 9.1 Hz), 142.5 (d, J = 10.3 Hz), 147.1, 176.6, 176.8, 177.3, 177.6; HRMS (ESI):
m/z calcd for C47H73NO12P [M+H]+: 874.4865, found: 874.4867.
7
8
9
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalac
topyranosyl)amino](2ꢀnaphthyl)phosphinate (3p). White Solid (169.5 mg, 91% yield); Mp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
93ꢀ95°C; 31P NMR (162 MHz, CDCl3): δ 35.30; H NMR (400 MHz, CDCl3): δ 0.81 (d, J = 6.9
Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 1.08 (s, 9H), 1.16 (s, 9H), 1.18 (s, 9H),
1.27ꢀ1.30 (m, 10H), 1.43ꢀ1.46 (m, 2H), 1.60ꢀ1.68 (m, 4H), 1.79 (d, J = 11.8 Hz, 1H), 2.05ꢀ2.09 (m,
1H), 2.77 (dd, J = 12.6, 6.5 Hz, 1H), 3.61 (t, J = 6.7 Hz, 1H), 3.85 (dd, J = 12.3, 9.0 Hz, 1H), 3.94
(dd, J = 11.2, 6.4 Hz, 1H, 4.02 (dd, J = 11.2, 7.0 Hz, 1H), 4.42ꢀ4.46 (m, 1H), 4.85 (d, J = 19.4 Hz,
1H), 4.96 (dd, J = 10.3, 3.4 Hz, 1H), 5.07 (dd, J = 10.1, 9.0 Hz, 1H), 5.30 (d, J = 2.6 Hz, 1H), 7.21
(d, J = 8.5 Hz, 1H), 7.30 (td, J = 7.7, 3.6 Hz, 2H), 7.43ꢀ7.46 (m, 3H), 7.48ꢀ7.51 (m, 2H), 7.58ꢀ7.65
(m, 3H), 7.78ꢀ7.80 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.8, 21.2, 21.8, 23.0, 25.9,
27.09, 27.14, 27.2, 27.3, 31.5, 34.0, 38.7, 38.8, 39.1, 43.1, 48.7 (d, J = 5.7 Hz), 59.5 (d, J = 105.6
Hz), 61.8, 67.4, 68.8, 71.3, 71.8, 77.9 (d, J = 7.7 Hz), 85.4 (d, J = 14.3 Hz), 126.0, 126.9 (d, J =
3.7 Hz), 127.4, 127.6, 127.7 (d, J = 5.5 Hz), 127.9, 128.6 (d, J = 6.5 Hz), 130.4, 131.3 (d, J = 5.7
Hz), 132.1, 132.8 (d, J = 9.3 Hz), 176.8, 177.0, 177.4, 177.9; HRMS (ESI): m/z calcd for
C53H77NO11P [M+H]+: 934.5229, found: 934.5226.
(((1S,2R,5S)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀ[(2,3,4,6ꢀtetraꢀOꢀpivaloylꢀβꢀDꢀgalact
opyranosyl)amino](2ꢀnaphthyl)phosphinate (3r). White Solid (126 mg, 67% yield); Mp 119
ꢀ121°C; 31P NMR (162 MHz, CDCl3): δ 37.32; 1H NMR (400 MHz, CDCl3): δ 0.67 (d, J = 6.5 Hz,
3H, 0.91 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 1.07 (s, 9H), 1.12 (s, 9H), 1.18 (s, 9H), 1.30
(s, 10H), 1.30ꢀ1.43 (m, 3H), 1.56ꢀ1.59 (m, 1H), 1.64ꢀ1.70 (m, 3H), 2.35ꢀ2.39 (m, 1H), 2.96ꢀ2.98
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(m, 1H), 3.54 (t, J = 6.7 Hz, 1H), 3.84 (t, J = 10.1 Hz, 1H), 3.95 (dd, J = 11.2, 6.2 Hz, 1H), 4.06
(dd, J = 11.2, 7.1 Hz, 1H), 4.38 (dd, J = 6.3, 4.4 Hz, 1H), 4.48ꢀ4.93 (m, 2H), 5.10ꢀ5.15 (m, 1H),
5.28 (d, J = 2.6 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.20ꢀ7.25 (m, 2H), 7.31ꢀ7.35 (m, 2H), 7.43ꢀ7.48
(m, 4H), 7.55ꢀ7.58 (m, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.80ꢀ7.82 (m, 1H); 13C{1H} NMR (101 MHz,
CDCl3): δ 15.6, 21.2, 21.8, 22.7, 25.8, 27.09, 27.13, 27.2, 27.3, 31.4, 33.9, 38.68, 38.72, 39.1, 43.2,
48.8 (d, J = 5.8 Hz), 59.5 (d, J = 109.2 Hz), 61.9, 67.4, 68.6, 71.5, 71.8, 77.8 (d, J = 7.6 Hz), 85.0
(d, J = 16.4 Hz), 126.1 (d, J = 3.0 Hz), 127.1 (d, J = 3.6 Hz), 127.3, 127.55 (d, J = 5.2 Hz), 127.64,
128.7 (d, J = 6.8 Hz), 130.0, 130.6, 131.4 (d, J = 7.4 Hz), 132.1, 133.0 (d, J = 20.3 Hz), 133.2 (d, J
= 9.1 Hz), 176.9, 177.0, 177.1, 177.8; HRMS (ESI): m/z calcd for C53H77NO11P [M+H]+:
934.5229, found: 934.5231.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General
procedure
for
the
preparation
of
(((1R,2S,5R)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀAmino(phenyl)phosphinate 4a. A
solution of compound 3a (0.40 mmol) in dry methanol (5 mL) was treated with freshly prepared
(1.0 M) solution of HCl (0.62 mL). The solution was stirred for 2 days (TLC control). Then the
mixture was filtered to give 4a as white solid in 86% yield.
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylꢀαꢀAmino(phenyl)phosphinate
(4a).
1
White Solid (132.3 mg, 86% yield); Mp 231ꢀ233°C; 31P NMR (162 MHz, DMSO): δ 30.92; H
NMR (400 MHz, DMSO): δ 0.34 (d, J = 6.6 Hz, 3H), 0.53 (d, J = 6.8 Hz, 3H), 0.62 (d, J = 6.4 Hz,
3H), 0.66ꢀ0.83 (m, 3H), 1.03 (s, 2H), 1.11ꢀ1.19 (m, 1H), 1.31 (d, J = 12.1 Hz, 1H), 1.44 (t, J =
11.3 Hz, 2H), 3.94 (d, J = 10.8 Hz, 1H), 5.12 (s, 1H), 7.44ꢀ7.45 (m, 2H), 7.61ꢀ7.62 (m, 3H), 7.73
(t, J = 7.2 Hz, 1H), 7.90ꢀ7.94 (m, 2H), 8.84 (s, 2H). HRMS (ESI): m/z calcd for C23H33NO2P
[M+H]+: 386.2243, found: 386.2241.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
General
procedure
for
the
preparation
of
5
6
7
8
9
(((1R,2S,5R)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylbenzylꢀαꢀamino(phenyl)phosphinate
(6). A solution of Nꢀbenzylideneꢀ1ꢀphenylmethanamine 5 (0.119 g, 0.2 mmol) in THF (2 mL) was
cooled to 0 °C, and (Rp)ꢀOꢀ(ꢀ)ꢀmenthyl Hꢀphenylphosphinate 1 (0.084 g, 0.3 mmol) was added.
The mixture was stirred for 12 hours at room temperature. Then an aqueous saturated solution of
sodium bicarbonate (25 mL) was added, and the mixture was stirred at room temperature for 5
min. Then the aqueous phase was extracted with CH2Cl2 (3 × 25 mL), and the organic layers were
dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the crude products 6,
which were purified by column chromatography on silica gel [petroleum ether/ethyl acetate, 6:1
(V/V)] to provided pure compounds 6.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2S,5R)ꢀ2ꢀIsopropylꢀ5ꢀmethylcyclohexyl)oxy)phenylbenzylꢀαꢀamino(phenyl)phosphinate
(6). White Solid (70.9 mg, 75% yield); Mp 101ꢀ103 °C; 31P NMR (162 MHz, CDCl3): δ 35.65,
37.23; 1H NMR (400 MHz, CDCl3): δ 0.76 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.98 (d, J
= 7.1 Hz, 3H), 1.02ꢀ1.04 (m, 2H), 1.28ꢀ1.33 (m, 2H), 1.44ꢀ1.46 (m, 1H), 1.61ꢀ1.70 (m, 2H), 1.83
(d, J = 11.9 Hz, 1H), 2.36ꢀ2.40 (m, 2H), 3.54 (d, J = 13.2 Hz, 1H), 3.79 (d, J = 13.2 Hz, 1H), 4.13
(d, J = 17.4 Hz, 1H), 4.41ꢀ4.44 (m, 1H), 7.14ꢀ7.15 (m, 2H), 7.20ꢀ7.25 (m, 5H), 7.27ꢀ7.31 (m, 5H),
7.43ꢀ7.51 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 15.5, 21.2, 21.9, 22.7, 25.5, 31.5, 34.1,
43.2, 49.0 (d, J = 5.3 Hz), 51.4 (d, J = 15.1 Hz), 63.4 (d, J = 108.0 Hz), 77.5, 127.0, 127.4 (d, J =
3.4 Hz), 127.6, 127.7, 128.0 (d, J = 2.2 Hz), 128.3 (d, J = 4.7 Hz), 128.8 (d, J = 5.3 Hz), 130.0,
131.3, 131.9, 132.6 (d, J = 8.9 Hz), 135.5, 139.6; HRMS (ESI): m/z calcd for C30H39NO2P
[M+H]+: 476.2713, found: 476.2719.
AUTHOR INFORMATION
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
Corresponding Author
5
6
7
*Eꢀmail: miaozhiwei@nankai.edu.cn.
8
9
Notes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21072102), the Committee of
Science and Technology of Tianjin (15JCYBJC20700) and State Key Laboratory of
ElementoꢀOrganic Chemistry in Nankai University for financial support. We also thank the
anonymous reviewer’s helpful suggestions improving our manuscript.
ASSOCIATED CONTENT
*Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
31P NMR, 1H and 13C NMR spectra for all products (PDF)
Xꢀray data for compound 3d (CIF)
REFERENCES
[1] For selected reviews see: (a) Montchamp, J. L. Acc. Chem. Res. 2014, 47, 77. (b) Dubrovina,
N. V.; Börner, A. Angew. Chem. Int. Ed. 2004, 43, 5883. (c) Organophosphorus Reagents in
Asymmetric Reactions (Eds.: Tang, C. C.; Zhou, Z. H.), Nankai University Press, Tianjin,
China, 2012. (d) New Aspects in Phosphorus Chemistry, Vols. 1ꢀ5 (Ed.: Majoral, J. P.),
Springer, Berlin, 2003. (e) Organophosphorus Reagents (Ed.: Murphy, P. J.), Oxford
University Press: Oxford, U.K., 2004. (f) Quin, L. D. A Guide to Organophosphorus
Chemistry, Wiley Interscience, New York, 2000.
ACS Paragon Plus Environment