Enantioselective synthesis of H -phosphinic acids bearing natural amino acid residues

Article abstract of DOI:10.1021/jo400798f

The first systematic study on the asymmetric synthesis of H-phosphinic acids bearing natural protein amino acid residues was reported on the basis of the asymmetric addition of ethyl diethoxymethylphosphinate to N-tert-butanesulfinyl imines. Good yields a

Full text of DOI:10.1021/jo400798f

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Article
Enantioselective Synthesis of H-Phosphinic
Acids Bearing Natural Amino Acids Residues
Qiuli Yao, and Chengye Yuan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400798f • Publication Date (Web): 17 Jun 2013
Downloaded from http://pubs.acs.org on June 25, 2013
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Enantioselective Synthesis of H-Phosphinic Acids Bearing Natural Amino Acids Residues
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Qiuli Yao and Chengye Yuan*
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State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
yuancy@mail.sioc.ac.cn
Abstract
32 The first systematic study on the asymmetric synthesis of H-phosphinic acids bearing natural protein amino acids residues was
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reported based on the asymmetric addition of ethyl diethoxymethylphosphinate to N-tert-butanesulfinyl imines. Good yields and
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moderate to high enantioselectivities were obtained. Reliable methods were developed for the elucidation of the stereochemistry of
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these phosphinic acids and derivatives thereof. The transformation of the side chains of these analogs was studied. Methods for the
conversion of the α-aminophosphinates to oligopetides were reported.
Introduction
As a phosphoru analogue of natural α-aminocarboxylic acid, α-aminophosphonic acid is of great interest to chemists (Scheme 1).
Many procedures have been developed for their preparation in both racemic and optically pure forms,1 and their biological studies
have revealed diverse activities.2
However, direct comparison of α-aminophosphonic acids with α-aminocarboxylic acids is not reasonable, since the former
belongs to dibasic acids while the latter are monobasic acids in nature. From this structural point of view, α-amino-H-phosphinic
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acids are much closer to natural α-aminocarboxylic acids (Scheme 1). It is well documented that optically active α-aminocarboxylic
acids play an irreplaceable role in the biological metabolism. Consequently, it is reasonable to assume that better bioactivities can
be expected for H-phosphinic analogs of α-amino acids than for corresponding phosphonic acids. Previous work by George et al
demonstrates that N-methyl-N-amidinoaminomethylphosphinic acid is much more reactive as analog of creatine in the creatine
kinase reaction than the corresponding phosphonic acid or its monoester.3a Similar effects were found for inhibitors of nitric oxide
synthase (NOS).3b In fact, derivatives of H-phosphinic acids have already demonstrated varieties of activities,4 also, the precursor
of α-amino phosphinates are excellent synthons for the preparation of various organophosphorus compounds.5
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Scheme 1. α-Amino Acid and ts Phosphorus Analogs
Unfortunately, probably due to the unique structure, it is difficult to synthesize chiral α-amino-H-phosphinic acids. Most of the
available methods only lead to racemates.6 Thus, almost all current literature data recordings used racemic H-phosphinic acids
directly in their biological studies. As far as we know, only five α-amino-H-phosphinic acids have been described in the literature
for their asymmetric syntheses.7 This might be due to three reasons. Firstly, the high reactivity of P−H group usually makes the
preparation of H-phosphinic acid difficult. Secondly, the stereochemistry for organophosphorus compounds is complex because of
43 the delocalization of P=O bond due to d-p π bond. To be specific, reliable methods to elucidate the stereochemistry of H-phosphinic
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acids or phosphinates are lacked. Finally, additional functionalization of amino acids emphasizes the difficulty toward the
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asymmetric syntheses of H-phosphinic analogs of the natural α-amino acids. For these reasons, studies on the asymmetric synthesis
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51 and biological studies of this type of compounds are challenging.
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Recently, a convenient procedure for the preparation of optically active α-aminophosphinates by using N-tertbutanesulfinyl
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imines as chiral auxiliaries was described.8 Rb2CO3 was found to have suitable basicity in the asymmetric synthesis of
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phosphinates. Also, a procedure describing a one-pot transformation of protected P−H group into P−O or P−N group by bromine,
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which provides a convenient method to elucidate the absolute configuration and d.r. values of α-aminophosphinates, was
developed.5 Herein, as a part of our systematic efforts in the study of H-phosphinic acids and their derivatives, we describe the first
systematic stereoselective synthesis of H-phosphinic isosteres of α-amino acids (Scheme 2). Nucleophilic attack of ethyl
diethoxymethylphosphinate on sulfinamide 1 bearing a side chain of a natural amino acid gave phosphinate 2, which was then
subsequently converted to α-amino-H-phosphinate 3 or α-amino-H-phosphinic acid 4.
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Scheme 2. Asymmetric Syntheses of α-Amino-H-phosphinic Acids
Results and Discussion
Amino acids can be catalogued as: (i) nonfunctionalized amino acids (alanine, glycine, phenylalanine, valine, and leucine); (ii)
amino acids with additional functionalities, including hydroxyl (serine, tyrosine, and threonine), sulfanyl (methionine and cysteine),
amino (tryptophan, arginine, and proline), and amide linkage (asparagines, pyroglutamic acid, and glutamine); (iii) dicarboxylic
acids (aspartic acid and glutamic acid); and (iv) amino acids containing two amino groups (lysine). In order to achieve the
asymmetric synthesis of their phosphinic analogs, protection of additional function group is neccessary.
Consequently, (S)-sulfinamide 1 was firstly prepared by condensation of (S)-2-methylpropane-2-sulfinamide and
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corresponding aldehyde by Ti(OPri)4 or CuSO4 , followed by a nucleophilic reaction with diethoxymethylphosphinate to give
phosphinates 2 with Rb2CO3 as a base at room temperature (Table 1). For most of substrates 1 with side chains of natural amino
51 acids, the reactions proceeded successfully and gave good to high yields. Except for 1k (entry 11), the product 2k underwent
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debromination and decomposed, so it was directly subjected to the next reaction without further purification. (R)-sulfinamide (-)-1l
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was used in this reaction as well (entry 13).
Table 1. Preparation of Phosphinates 2a
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Entry
1
2
R
Time (h) Yield%b
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2a
2b
2c
2d
2e
2f
Me
30
17
10
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24
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15
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72
17
84
92
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90
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2
PhtN(CH2)3
BnSCH2
FmSCH2
MeOCO(CH2)2
(S)-sec-Bu
i-Bu
3
4
5
6
7
2g
2h
2i
8
PhtN(CH2)4
MeS(CH2)2
Bn
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2j
c
2k
2l
Br(CH2)3
-
BnOCH2
50
88
92
96
93
70
d
(-)-2l BnOCH2
2m
2n
2o
(R)-MeCH(OBn) 17
3’-indolyl-CH2 36
4-MeOC6H4CH2 36
i-Pr 24
2p
aThe reaction was carried out with 1 (5 mmol), ethyl diethoxymethylphosphinate (4 mmol) and Rb2CO3 (25 mmol) in 50 mL of
b
c
DCM at room temperature. Separated yield after column chromatography. The product was unstable, and debromination was
detected, so it was subjected to the next reaction without further purification. d(R)-sulfinamide was used as substrate instead of
(S)-sulfinamide.
The removal of the protecting groups of phosphinate 2 was attempted. The conditions of 4 M HCl in the solvent of methanol at
room temperature was found to be suitable to remove the tert-butylsulfinyl group to give phosphinate 3 with good to excellent
yields (Table 2). This mild condition does not affect the phosphinate group at all, but side chains with a methyl ester group (2e,
entry 4) would undergo transesterification to give an ethyl ester group when the reaction was performed with 1 M HCl in EtOH.
When prolonging the reaction of 2e with 1 M HCl in EtOH, partial hydrolysis was detected as well (entry 4). Phosphinate 2k with a
bromine-substituted side chain underwent cyclization to give phosphinate 3k under the acidic condition (entry 10).
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Table 2. Removal of tert-Butylsulfinyl Group of 2 to Phosphinates 3a
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Entry
1
3
R1
Yield%b
quant.
90
3b
3c
3d
3e
3f
3g
3h
3i
PhtN(CH2)3
BnSCH2
FmSCH2
EtOCO(CH2)2
(S)-sec-Bu
i-Bu
2
3
83
65c,d
4
5
82
6
90
7
PhtN(CH2)4
MeS(CH2)2
Bn
94
8
99
9
3j
3k
3l
quant.
80 f
e
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12
13
14
15
-
BnOCH2
quant.
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(-)-3l BnOCH2
3m
3n
3p
(R)-MeCH(OBn) 96
3’-indolyl-CH2
i-Pr
93
98
aThe reaction was carried out with 2 (0.5 mmol) in 2.5 mL of 4 M HCl in MeOH at room temperature for 75 minutes. Separated
b
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c
d
yield after column chromatography. The reaction was carried out for 20 hours with 1 M HCl in EtOH. When the reaction was
carried out for 33 hours in 1 M HCl in EtOH, 16% 3e and 29% product with conversion of the ester group to carboxylic group (R1 =
CH2CH2COOH) were given. eThe structure of product 3k is
. fSeparated yield for 2 steps from 1k.
Next, the removal of the protecting groups leading to final product 4 was investigated. Our initial study showed that when
phosphinate 2 was directly treated with 4 M HCl by heating to reflux for 15 hours, H-phosphinic acid 4 was obtained for specific
substrates without any additional functional group (Table 3, entries 1, 4, 9, 10). However, this procedure often led to byproducts
that may be caused by the sulfinamide group, especially for functionalized substrates. After an exploration of the reaction
conditions, simply by the reaction of phosphinate 3 in 4 M aqueous HCl by heating to reflux for 1.5 hours, the formation of
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byproducts was excluded (Table 3, entries 2, 3, 5−8).
Table 3. Preparation of Phosphinic Acids 4
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Entry Substrate
4
R1
Yield%
80a
1
2a
3c
3f
4a Me
2
4c BnSCH2
4f (S)-sec-Bu
4g i-Bu
95b
3
97b
4
2g
3h
3i
33a
5
4h PhtN(CH2)4
4i MeS(CH2)2
49b
6
84b
7
3j
4j Bn
86b
c
8
3k
2o
2p
4k
-
63b
9
4o 4-MeOC6H4CH2 60a
10
4p i-Pr
40a
aProcedure A: 2 (0.2 mmol) in 4 M aqueous HCl (4 mL) was heated to reflux for 15 hours, then treated with 20 mL of propylene
b
oxide. Procedure B: 3 (0.5 mmol) in 4 M aqueous HCl (2.5 mL) was heated to reflux for 1.5 hours, then treated with 20 mL of
propylene oxide. cThe structure of product 4k is
.
Finally, the stereochemistry of these addition reactions was studied. 31P NMR analysis indicates that phosphinate 2 has two
isomers as major products and additional two as minor products. However, it is difficult to separate these isomers by
chromatography for most substrates except 2c and 2m, and the chirality at the phosphorus center increased the difficulty. Thus to
discriminate the absolute configuration of each isomer is almost impossible. Nevertheless, N-tert-butanesulfinyl imines do not have
asymmetric inductive effect to the phosphinates group,8 so just confirming the stereochemistry of the α-substituent is adequate and
realizable. For phosphinate 2 and 3, although its dr value can be detected by 31P NMR spectrum, we can not know the relative value
between the isomer of (Rc) and (Sc), which actually reflects the enantioselectivities of these reactions.
Thus, methods to determine of the constituents of the α-carbon were studied (Scheme 3). To achieve this, phosphinate 3 was
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transferred to the diethyl phosphonate 5 by our previously developed one-pot procedure (Scheme 3, Eq. 1),5 then analysis of the
NMR spectra of the Mosher’s derivative 6 reflected its dr value. Also, oxidation and subsequent transformation of phosphinic acid
4 give phosphonate 7 (Eq. 2). Further determination of the er value of compound 4 can be achieved by analysis of the HPLC
spectrum of compound 7. Direct conversion of 4 to its Mosher’s derivative 8 provides another procedure to determine the er value
of 4 (Eq. 3) in the condition that diastereoisomers of 8 are distinguishable in their NMR or HPLC spectra. By the above procedures,
the relative ratio of (Rc) and (Sc) isomers of 3 and 4 was determined (Table 4).
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Scheme 3. Methods to Determine the Ratio of (Rc)/(Sc)
Table 4. The Ratio of (Rc)/(Sc) for 3 or 4
Entry Substrate R1
Procedurea Ratio of (Rc)/(Sc)
1
2
3
4
4a
3b
3c
3e
B
A
-
90:10
Me
PhtN(CH2)3
90:10
BnSCH2
Single isomer separated
88:12
EtOCO(CH2)2
A
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4f
(S)-sec-Bu
i-Bu
B
B
B
C
B
B
A
A
-
Ab
B
A
B
97:3
6
4g
4h
4i
88:12
7
PhtN(CH2)4
MeS(CH2)2
Bn
89:11
8
81:19
9
4j
90:10
10
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17
4k
3l
-
79:21
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BnOCH2
BnOCH2
(R)-MeCH(OBn)
66:34
(-)-3l
3m
3n
4o
3p
4p
69:31
Single isomer separated
c
95:5
3’-indolyl-CH2
4-MeOC6H4CH2
88:12
>95:5
>99:1
i-Pr
i-Pr
aProcedure A: Ratio of (Rc)/(Sc) was measured by NMR spectra of 6; Procedure B: Ratio of (Rc)/(Sc) was determined by chiral
HPLC analysis of 7; Procedure C: Ratio of (Rc)/(Sc) was estimated by NMR spectra and HPLC spectrum of 8. bThe indolyl group of
3n was dibrominated.
For sterically hindered substrates such as 4f (entry 5), 3n (entry 14), and 3p (entry 16, 17), excellent enantioselectivities were
31 obtained, while less sterically hindered substrates (entry 1, 2, 4, 6−9, 15) provide good enantioselectivities. For 3l or (-)-3l with a
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side chain of benzyloxy methyl group, relative low dr values resulted for both (S) and (R)-sulfinamide (entry 11, 12), indicating that
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the asymmetric inductive effect of these two isomers was similar. Similar ratios were measured by both procedure A (entry 16) and
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procedure B (entry 17), indicating that both these two methods are liable to elucidate the enantioseletivity of these reactions. The
major isomer of 2c and 2m were separated in yields of 48% and 45% respectively. Subsequently they were subjected to the reaction
providing single isomer of 3c and 3m respectively (entry 3, 13).
1
Next, the absolute configuration of the α-carbon atom was investigated by analyses of H NMR spectra of Mosher’s
derivatives 6p, which are single isomers, and it can be confirmed to be R (Table 5, Figure 1). Similar analyses of the derivatives of
the Mosher’s derivatives of the major isomer of 3m go to the same conclusion.10 These results indicate that the major isomer of 3
or 4 has the absolute configuration of R at the α-carbon atom.
Table 5. 1H NMR Data of (S) and (R)-Mosher’s Derivative 6p
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δ1 (CH3)2 δ2 CH δ3 CH δ4 CH2*2 δ5 CH3*2
(R)-MTPA
(S)-MTPA
△δ(S)-(R)
1.06
0.93
-0.13
< 0
2.31 4.35
2.25 4.35
4.06
4.14
0.08
> 0
1.26
1.33
0.07
> 0
-0.06
< 0
0
△δ(S)-(R)
= 0
Figure 1. Absolute Configuration of 3p Elucidated by Mosher’s Method
Further conversion of the side chains of the compounds 3 was studied. Transformation of the ester group of 2e to amide group
proceeded successfully in aqueous ammonia or BnNH2leading to 2q (Eq. 4) or 2r (Eq. 5), respectively. Quite interestingly, when
2q was reacted with 4 M HCl in MeOH, intramolecular amidation took place and 3q was obtained in 66% yield. As we know, 3q is
the intermediate toward the analog of L-pyroglutamic acid. Also, 3q can be transferred to 3k, the intermediate of the analog of
42 L-proline. 3e was converted to 3q by aqueous ammonia in quantitative yield too (Eq. 6), so the intramolecular amidation could take
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place under either acidic or basic conditions.
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Scheme 4. Transformation of Ester Group to Amide Group
Trying to remove the benzyl group of 3l, (-)-3l or 3m by Pd/C and hydrogen failed. However, under the conditions of
Pd(OH)2/C and hydrogen this group could be deprotected successfully to give corresponding alcohols (Scheme 5).
Scheme 5. Removal of Benzyl Group
The β-hydroxyl group of phosphinate 3s or (-)-3s can be transferred into amide group or carboxylic group via a cyano
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intermediate 9a or (-)-9a (Scheme 6). Firstly, 3s or (-)-3s was converted to 9a or (-)-9a. Then in hydrogen peroxide, 9a was
converted to 9b, after removal of the Boc group of which, 3u, which is the intermediate of asparagine, was obtained in quantitative
yield. The cyano group of (-)-9a was transferred to carboxylic group when refluxed in 4 M HCl giving the analog of D-aspartic acid
(-)-4v.
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Scheme 6. Transformation of the Analogs of Serine to Asparagine and Aspartic Acid
As demonstrated in our previous work,5 the P–H group of phosphinate 3 can be transferred to different groups such as P–O or
P–N group. Also, condensation of phosphinate 3 with N-protected amino acids or dipeptides (Table 6) leads to
phosphorus-oligopeptide 10 in moderate to quantitative yields by EDCI and HOBt.
Table 6. Preparation of Oligopeptide 10 from Phosphinate 3a
Entry
3
R1
Carboxylic component 10
Yield%b
10a 79
10b quant.
1
2
3
4
3f (S)-sec-Bu
3f (S)-sec-Bu
3j Bn
Boc-Phe-OH
Boc-Val-OH
Boc-Val-OH
Fmoc-Ala-OH
10c 81
3g i-Bu
10d quant.
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3h PhtN(CH2)4
Cbz-Gly-OH
10e 93
10f 76
6
3f (S)-sec-Bu
3g i-Bu
3j Bn
Boc-Phe-Val-OH
Boc-Phe-Val-OH
Boc-Phe-Val-OH
Boc-Phe-Val-OH
Boc-Phe-OH
7
10g 49
10h 35
8
9
3p i-Pr
10i
10j
67
98
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13
3p i-Pr
10
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3g i-Bu
Boc-Phe-OH
10k 82
10l 44
10m 78
3r BnNHCO(CH2)2 Boc-Phe-OH
3f (S)-sec-Bu Boc-Trp-OH
aThe reaction was carried out with 0.55 mmol carboxylic compound, 0.6 mmol HOBt, 0.6 mmol EDCI and 0.5 mmol 3 in 5.5 mL
of DCM at 0 °C and then room temperature. bSeparated yield after column chromatography.
These phosphorus-oligopeptides could be functioned as peptidomimetics for natural peptides. Previous studies have revealed
their diverse bioactivity.4 Initiate study on the bioactivity of these compounds indicates that compound 10a may have inhibitive
effect towards cell division cycle 25 homolog B (S. pombe) (CDC25B) which has oncogenic properties11.
Conclusions
31 The first systematic enantioselective preparation of H-phosphinic analogs of α-amino acids has been studied based on the
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asymmetric addition of phosphinates to N-tert-butanesulfinyl imines. Good yields and moderate to excellent enantioselectivities
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have been obtained for 17 substrates with side chains of natural α-amino acids. The transformation of the analog of glutamic acid to
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glutamine and pyroglutamic acid, and transformation of the analog of serine to asparagine and aspartic acid-analogs are studied as
well. This study provides guidelines for the investigation of the stereochemistry of organophosphorus compounds in future studies.
Furthermore, phosphorus-contain peptides are prepared from α-amino phosphinates, and their potent biological activities as
peptidomimetics could be expected in the future.
Experimental Section
General Methods: Reactions were performed under nitrogen unless otherwise stated. Materials were obtained from commercial
suppliers and used without further purification unless otherwise indicated. Preparative thin-layer chromatography (TLC) was
performed with plates precoated with silica gel G.F. Flash chromatography was performed using silica gel (300–400 mesh). HRMS
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were detected by FT-ICR MS.
Procedure for preparation of 1:7
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Procedure A: To a solution of (S)-2-methylpropane-2-sulfinamide (1820 mg, 15 mmol) in 30 mL of DCM, CuSO4 (4849 mg, 30
mmol) and 20 mmol aldehyde were added at room temperature. After completion of the reaction monitored by TLC, the solution
was filtered by celite, washed by EtOAc, and then purified by silica gel column chromatography with petroleum ether/ethyl acetate
(1:15 to 1:7) to give 1a, 1e, 1j or 1p. Data for compounds 1a,12 1j,9b and 1p9b were in accordance with reported data. Compounds 1
are mainly in E form, but at times Z form can be detected by NMR. Most of them were unstable at room temperature. So they
should be used as soon as they were purified.
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Procedure B: To (S)-2-methylpropane-2-sulfinamide (623 mg, 5 mmol), Ti(OPri)4 (2840 mg, 10 mmol), 6 mmol aldehyde and 1.5
mL of THF were added at room temperature. After completion of the reaction monitored by TLC, the solution was quenched by 1
mL of water with stirring, 100 mL of ethyl acetate added and then filtered by celite. The solid was washed by 30 mL of ethyl
acetate. The combined ethyl acetate phases were dried over anhydrous Mg2SO4 and then purified by silica gel column
chromatography with petroleum ether/ethyl acetate (1:15 to 1:7) to give 1b, 1c, 1d, 1f, 1g, 1h, 1i, 1k, 1l, (-)-1l, 1m, 1n, and 1o.
Data for compounds 1g13 and (-)-1l14 were in accordance with reported data.
Compound 1b. Yield 86%, 1.38 g; white solid; m.p. 77 °C; [α]2D1 158.6 (c 1.0, CHCl3); IR (film) 2957, 2925, 1712, 1396, 1083,
43 720 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.09 (t, J = 3.6 Hz, 1H), 7.85 (dd, J1 = 2.8 Hz, J2 = 5.2 Hz, 2H), 7.72 (dd, J1 = 3.2 Hz, J2 =
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5.2 Hz, 2H), 3.79 (t, J = 6.8 Hz, 2H), 2.60 (m, 2H), 2.05 (m, 2H), 1.19 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 168.4, 167.9, 134.0,
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132.1, 123.3, 56.7, 37.4, 33.5, 24.2, 22.3; MS (ESI) m/z (%) 343.1 [M + Na]+; HRMS (ESI) Calcd for C16H20N2O3SNa 343.1087,
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51 found 343.1101; Elemental analysis (%) calcd for C16H20N2O3S: C 59.98, H 6.29, N 8.74. Found: C 59.96, H 6.36, N 8.54.
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Compound 1c. Yield 63%, 0.85 g; colorless oil; [α]2D2 265.7 (c 1.0, CHCl3); IR (film) 3028, 2977, 2959, 2924, 1611, 1454, 1087,
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701 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.98 (t, J = 5.2 Hz, 1H), 7.35−7.24 (m, 5H), 3.70 (s, 2H), 3.35 (t, J = 5.6 Hz, 2H), 1.23 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 164.1, 137.3, 129.2, 128.7, 127.4, 57.0, 35.6, 34.4, 22.4; MS (ESI) m/z (%) 270.1 [M + H]+;
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HRMS (ESI) Calcd for C13H19NNaOS2 292.0800, found 292.0801.
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Compound 1d. Yield 71%, 1.27 g; yellow solid; m.p. 72−73 °C; [α]2D2 191.4 (c 1.0, CHCl3); IR (film) 3064, 2959, 2923, 2863,
1610, 1450, 1086, 743 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.96 (t, J = 5.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 7.6 Hz,
1H), 7.60 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 4.11 (t, J = 6.4 Hz, 1H), 3.48−3.34 (m, 1H),
3.39−3.34 (m, 1H), 3.13−2.98 (m, 1H), 3.03−2.98 (m, 1H), 1.20 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 164.0, 145.6, 141.1, 127.7,
127.1, 124.8, 120.0, 57.0, 46.6, 36.1, 35.6, 22.4; MS (ESI) m/z (%) 358.1 [M + H]+; Elemental analysis (%) calcd for C20H23NOS2:
C 67.19, H 6.48, N 3.92. Found: C 66.79, H 6.55, N 3.73.
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Compound 1e. Yield 44%, 1.44 g; colorless oil; E/Z≈5.2:1; [α]2D6 187.8 (c 1.1, CHCl3); IR (film) 2954, 2870, 1739, 1625, 1475,
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1438, 1365, 1213, 1169, 1085, 998, 583 cm−1; H NMR (CDCl3, 400 MHz) δ 8.13 (t, J = 2.8 Hz, 1H), 3.68 (s, 3H), 2.84 (m, 2H),
2.68 (m, 2H), 1.17 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 172.7, 167.2, 56.8, 51.8, 31.0, 29.1, 22.2; MS (ESI) m/z (%) 220.1 [M +
H]+; HRMS (EI) Calcd for C9H17NO3S 219.0929, found 219.0933.
Compound 1f. Yield 38%, 0.36 g; colorless oil; [α]2D7 208.7 (c 1.0, CHCl3); IR (film) 2964, 2929, 2875, 1620, 1458, 1363, 1087,
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1016, 725, 586 cm−1; H NMR (CDCl3, 300 MHz) δ 7.97 (d, J = 5.1 Hz, 1H), 2.55 (m, 1H), 1.66 (m, 1H), 1.50 (m, 1H), 1.20 (s,
9H), 1.14 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 173.3, 56.4, 41.6, 26.7, 22.3, 16.4, 11.5; MS
(ESI) m/z (%) 190.1 [M + H]+; HRMS (ESI) Calcd for C9H20NOS 190.1266, found 190.1265.
43 Compound 1h. Yield 72%, 1.21 g; colorless oil; [α]2D8 154.5 (c 1.4, CHCl3); IR (film) 3466, 2947, 1771, 1712, 1622, 1467, 1397,
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1364, 1081, 1047, 721 cm−1; H NMR (CDCl3, 400 MHz) δ 8.06 (t, J = 4.8 Hz, 1H), 7.84 (dd, J1 = 3.2 Hz, J2 = 5.6 Hz, 2H), 7.72
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(dd, J1 = 3.2 Hz, J2 = 5.6 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 2.59 (m, 2H), 1.77 (m, 2H), 1.71 (m, 2H), 1.18 (s, 9H); 13C NMR
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51 (CDCl3, 100 MHz) δ 168.8, 168.3, 134.0, 132.1, 123.2, 56.5, 37.5, 35.4, 28.1, 22.6, 22.3; MS (ESI) m/z (%) 335.2 [M + H]+;
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HRMS (ESI) Calcd for C17H22N2O3SNa 357.1243, found 357.1255.
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Compound 1i. Yield 80%, 0.83 g; colorless oil; [α]2D5 69.4 (c 2.0, CHCl3); IR (film) 2960, 2917, 2867, 1623, 1428, 1363, 1184,
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1087, 1018, 687, 582 cm−1; H NMR (CDCl3, 400 MHz) δ 8.09 (t, J = 2.8 Hz, 1H), 2.84−2.80 (m, 4H), 2.13 (s, 3H), 1.21 (s, 9H);
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13C NMR (CDCl3, 100 MHz) δ 167.4, 56.7, 35.6, 29.5, 22.3, 15.5; MS (ESI) m/z (%) 208.1 [M + H]+; HRMS (ESI) Calcd for
C8H17NOS2Na 230.0644, found 230.0646.
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Compound 1k. Yield 70%, 0.89 g; colorless oil; [α]2D8 187.3 (c 1.0, CHCl3); IR (film) 3480, 2964, 2926, 1629, 1455, 1363, 1247,
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1081, 583 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.11 (t, J = 4.0 Hz, 1H), 3.50 (m, 2H), 2.72 (m, 2H), 2.23 (m, 2H), 1.20 (s, 9H); 13
C
NMR (CDCl3, 100 MHz) δ 167.8, 56.7, 34.4, 32.6, 28.1, 22.4; MS (ESI) m/z (%) 254.0 [M + H]+; HRMS (EI) Calcd for
C8H16NOSBr 253.0136, found 253.0137.
Compound 1l. Yield 56%, 0.71 g; colorless oil; [α]2D3 220.6 (c 0.8, CHCl3); IR (film) 3063, 3031, 2960, 2926, 2866, 1632, 1274,
1455, 1363, 1085, 739, 699 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.13 (t, J = 3.2 Hz, 1H), 7.37−7.31 (m, 5H), 4.64 (s, 2H), 4.41 (t, J
= 2.4 Hz, 2H), 1.22 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 137.2, 128.6, 128.1, 127.9, 73.3, 71.3, 57.0, 22.4; MS (ESI) m/z
(%) 254.1 [M + H]+; HRMS (EI) Calcd for C13H19NO2S 253.1137, found 253.1140.
Compound 1m. Yield 79%, 1.06 g; colorless oil; [α]2D7 327.4 (c 1.0, CHCl3); IR (film) 3031, 2929, 2868, 1624, 1455, 1365, 1088,
699 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.06 (d, J = 4.4 Hz, 1H), 7.36−7.26 (m, 5H), 4.65 (d, J = 11.6 Hz, 1H), 4.53 (d, J = 11.6
Hz, 1H), 4.34 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 170.6, 137.6, 128.5, 127.9, 127.8,
76.3, 71.7, 57.0, 22.4, 18.7; MS (ESI) m/z (%) 268.1 [M + H]+; HRMS (ESI) Calcd for C14H21NO2SNa 290.1185, found 290.1197.
Compound 1n. Yield 48%, 0.63 g; yellow oil; [α]2D6 205.3 (c 1.0, CHCl3); IR (film) 3290, 3059, 2960, 1620, 1457, 1064, 742 cm−1;
43 1H NMR (CDCl3, 400 MHz) δ 8.32 (br, 1H), 8.16 (t, J = 5.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (dt, J1
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= 1.2 Hz, J2 = 8.0 Hz, 1H), 7.12 (dt, J1 = 0.8 Hz, J2 = 8.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 3.95 (d, J = 5.2 Hz, 2H), 1.19 (s, 9H);
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13C NMR (CDCl3, 100 MHz) δ 167.7, 136.3, 127.2, 122.7, 122.4, 119.7, 118.7, 111.3, 109.0, 56.8, 32.5, 22.4; MS (ESI) m/z (%)
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51 263.0 [M + H]+; HRMS (ESI) Calcd for C14H19N2OS 263.1213, found 263.1220.
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Compound 1o. Yield 66%, 0.84 g; yellow oil; [α]2D4 267.0 (c 2.0, CHCl3); IR (film) 2958, 2835, 1620, 1512, 1248, 1177, 1086, 831,
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667 cm−1; H NMR (CDCl3, 400 MHz) δ 8.10 (t, J = 4.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H),
3.76 (m, 2H), 1.18 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 167.7, 158.7, 130.3, 126.7, 114.3, 56.8, 55.3, 41.8, 22.4; MS (ESI) m/z
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(%) 254.1 [M + H]+; HRMS (ESI) Calcd for C13H20NO2S 254.1209, found 254.1209.
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Procedure for preparation of 2.
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To Rb2CO3 (5770 mg, 25 mmol), ethyl diethoxymethylphosphinate (3920 mg, 20 mmol), and 50 mL of DCM were added at room
temperature. After 15 minutes, compound 1 (5 mmol) was added to the solution. After completion of the reaction monitored by
TLC, the reaction was quenched by 30 mL of water and then extracted with ethyl acetate (50 mL×3), and washed with 30 mL of
brine. The combined organic phases were dried over anhydrous Na2SO4 and then purified by silica gel column chromatography
with petroleum ether/ethyl acetate (2:3 to 1:5) to give 2.
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Compound 2a. Yield 84%, 1.44 g; colorless oil; [α]2D5 64.1 (c 2.0, CHCl3); IR (film) 3465, 3184, 2978, 2931, 1740, 1653, 1476,
1391, 1365, 1296, 1216, 1061, 959, 557 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.97 (m, 1H), 4.27 (m, 2H), 4.12 (m, 1H), 3.93−3.73
(m, 5H), 1.50−1.41 (m, 3H), 1.39−1.34 (m, 3H), 1.29−1.27 (m, 6H), 1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ for the major
isomer: 100.3 (d, J = 140.3 Hz), 66.1 (d, J = 9.3 Hz), 65.4 (d, J = 8.8 Hz), 62.3 (d, J = 7.4 Hz), 55.8 (d, J = 0.9 Hz), 46.8 (d, J =
95.4 Hz), 22.3 (s), 16.5 (d, J = 5.1 Hz), 15.1 (d, J = 7.5 Hz), 14.5 (d, J = 0.9 Hz); 31P NMR (CDCl3, 162 MHz) δ 39.11, 38.89,
38.72, 38.24; MS (ESI) m/z (%) 344.2 [M + H]+, 366.3 [M + Na]+; HRMS (MALDI) Calcd for C13H31NO5PS 344.1655, found
344.1648.
Compound 2b. Yield 92%, 1.46 g; colorless oil; [α]2D6 33.6 (c 1.0, CHCl3); IR (film) 3471, 3198, 2977, 1713, 1396, 1060, 722 cm−1;
43 1H NMR (CDCl3, 400 MHz) δ 7.83 (m, 2H), 7.72 (m, 2H), 5.07 (m, 1H), 4.26 (m, 2H), 3.95−3.75 (m, 4H), 3.70 (m, 4H), 2.0 (m,
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2H), 1.83−1.64 (m, 2H), 1.26−1.22 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 168.3 (s), 133.9 (s), 132.1 (s),
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123.2 (s), 99.6 (d, J = 139.3 Hz), 66.1 (d, J = 10.2 Hz) and 65.2 (d, J = 9.5 Hz), 62.7 (d, J = 6.6 Hz), 56.8 (s), 52.0 (d, J = 89.0 Hz),
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51 37.6 (s), 27.2 (s), 25.0 (d, J = 9.5 Hz), 22.7 (s), 16.7 (d, J = 5.1 Hz), 15.3 (m); 31P NMR (CDCl3, 121 MHz) δ 40.11, 39.59, 39.07,
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38.70; MS (ESI) m/z (%) 517.4 [M + H]+ ; HRMS (ESI) Calcd for C23H37N2O7PSNa 539.1951, found 539.1972; Elemental analysis
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(%) calcd for C23H37N2O7PS: C 53.48, H 7.22, N 5.42. Found: C 53.67, H 7.45, N 5.37.
Compound 2c. Yield 91%, 2.12 g; colorless oil; data for the major isomer (yield approximately 48%): [α]2D3 -14.2 (c 1.0, CHCl3);
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IR (film) 3187, 2977, 2927, 2360, 1495, 1221, 1061, 1031, 702 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.33−7.21 (m, 5H), 5.06 (d, J
= 9.6 Hz, 1H), 4.27 (m, 2H), 3.94−3.76 (m, 5H), 3.74 (s, 2H), 3.69 (m, 1H), 3.06 (m, 1H), 2.74 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H),
1.29−1.21 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ 138.0 (s), 129.0 (s), 128.6 (s), 127.2 (s), 99.7 (d, J = 140.7 Hz), 66.2 (d, J =
10.9 Hz) and 65.2 (d, J = 8.8 Hz), 62.9 (d, J = 6.5 Hz), 57.3 (s), 52.2 (d, J = 86.1 Hz), 36.8 (s), 33.0 (d, J = 4.4 Hz), 22.8 (s), 16.7 (d,
J = 4.3 Hz), 15.4 (d, J = 6.6 Hz); 31P NMR (CDCl3, 162 MHz) δ 36.59; MS (ESI) m/z (%) 466.1 [M + H]+ ; HRMS (ESI) Calcd for
C20H36NO5PS2Na 488.1665, found 488.1667; Elemental analysis (%) calcd for C20H36NO5PS2: C 51.59, H 7.79, N 3.01. Found: C
51.25, H 7.89, N 3.03.
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Compound 2d. Yield 90%, 2.49 g; light yellow oil; [α]2D3 3.1 (c 1.0, CHCl3); IR (film) 3190, 2977, 2927, 2863, 1476, 1448, 1218,
1060, 1033, 743 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.73 (m, 2H), 7.67 (m, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.30 (m, 2H), 5.11−4.75
(m, 1H), 4.27 (m, 2H), 4.12 (t, J = 5.6 Hz, 1H), 3.96−3.53 (m, 6H), 3.22−2.78 (m, 4H), 1.34 (t, J = 6.8 Hz, 3H), 1.29−1.24 (m, 6H),
1.22−1.21 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ 145.9 (m), 141.2 (m), 127.6 (s), 127.0 (s), 124.9 (m), 119.9 (m), 100.3 (m), 66.3
(m) and 65.3 (m), 62.9 (m), 57.4 (m), 52.3 (m), 46.8 (m), 37.0 (m), 34.5 (m), 22.7 (m), 16.7 (m), 15.4 (m); 31P NMR (CDCl3, 162
MHz) δ 37.22, 37.16, 36.95, 36.69; MS (ESI) m/z (%) 554.3 [M + H]+; HRMS (ESI) Calcd for C27H40NO5PS2Na 576.1978, found
576.1979.
Compound 2e. Yield 87%, 1.81 g; colorless oil; [α]2D7 37.5 (c 1.0, CHCl3); IR (film) 3459, 3203, 2978, 1737, 1440, 1390, 1366,
43 1302, 1213, 1163, 1061, 959, 838, 593 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.10 (m, 1H), 4.29 (m, 2H), 4.0−3.72 (m, 6H), 3.68 (s,
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3H), 2.78−2.45 (m, 2H), 2.29 (m, 1H), 1.98 (m, 1H), 1.37 (t, J = 6.8 Hz, 3H), 1.30−1.25 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ
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for the major isomer: 173.0 (s), 99.7 (d, J = 140.0 Hz), 66.5 (d, J = 9.5 Hz) and 65.2 (d, J = 9.5 Hz), 62.7 (d, J = 7.3 Hz), 56.7 (s),
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51 51.5 (s), 51.4 (d, J = 89.7 Hz), 30.2 (d, J = 8.8 Hz), 25.3 (d, J = 2.9 Hz), 22.6 (s) 16.5 (d, J = 5.1 Hz), 15.2 (m); 31P NMR (CDCl3,
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121 MHz) δ 39.94, 39.41, 38.89, 38.64; ESI (m/z) 416.5 [M + H]+ ; HRMS (ESI) Calcd for C16H34NO7PSNa 438.1686, found
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438.1707; Elemental analysis (%) calcd for C16H34NO7PS: C 46.25; H 8.25; N 3.37. Found: C 46.04; H 8.37; N 3.22.
Compound 2f. Yield 59%, 1.14 g; colorless oil; [α]2D7 76.5 (c 1.1, CHCl3); IR (film) 3479, 3334, 2974, 2931, 2876, 1644, 1462,
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1390, 1365, 1216, 1061, 958, 870, 559, 497 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.16 (d, J = 7.2 Hz, 1H), 4.28 (m, 2H), 3.96−3.65
(m, 6H), 2.11 (m, 1H), 1.70 (m, 1H), 1.35 (m, 3H), 1.31−1.25 (m, 15H), 1.21 (m, 1H), 1.01 (m, 3H), 0.92 (m, 3H); 13C NMR
(CDCl3, 100 MHz) δ 99.0 (d, J = 137.8 Hz), 65.9 (d, J = 11 Hz) and 64.8 (d, J = 8.0 Hz), 62.4 (d, J = 7.3 Hz), 57.2 (d, J = 86.0 Hz),
57.0 (s), 35.9 (d, J = 2.1 Hz), 24.3 (d, J = 1.4 Hz), 22.9 (s), 16.7 (d, J = 18.9 Hz), 16.6 (d, J = 5.1 Hz), 15.4 (d, J =3.7 Hz), 11.9 (s);
31P NMR (CDCl3, 162 MHz) δ 40.23, 39.10, 39.06, 37.90; ESI (m/z) 386.3 [M + H]+; HRMS (MALDI) Calcd for C16H37NO5PS
386.2125, found 386.2123.
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Compound 2g. Yield 90%, 1.73 g; colorless oil; [α]2D5 33.8 (c 1.2 , CHCl3); IR (film) 3466, 3188, 2957, 2870, 1500, 1387, 1366,
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1294, 1215, 1062, 958, 795, 561 cm−1; H NMR (CDCl3, 300 MHz) δ 5.06 (d, J = 7.5 Hz, 1H), 4.18 (m, 2H), 3.87−3.58 (m, 6H),
1.78 (m, 1H), 1.52 (m, 2H), 1.28−1.08 (m, 18H), 0.84 (dd, J1 = 4.5 Hz, J2 = 19.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 99.4 (d, J
= 137.1 Hz), 65.9 (d, J = 9.4 Hz) and 64.9 (d, J = 8.8 Hz), 62.5 (d, J = 7.3 Hz), 56.9 (s), 50.7 (d, J = 89.7 Hz), 38.3 (d, J = 2.2 Hz),
23.8 (d, J = 10.2 Hz), 23.4 (s), 22.7 (s), 20.5 (s), 16.6 (d, J = 5.1 Hz), 15.3 (d, J = 6.6 Hz); 31P NMR (CDCl3, 162 MHz) δ 39.92,
39.24, 38.70, 38.66; ESI (m/z) 386.3 [M + H]+; HRMS (ESI) Calcd for C16H37NO5PS 386.2125, found 386.2109.
Compound 2h. Yield 94%, 2.49 g; colorless oil; [α]2D8 20.8 (c 1.0, CHCl3); IR (film) 3466, 3195, 2977, 2932, 1771, 1713, 1438,
1396, 1366, 1216, 1060, 958, 872, 722 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.76 (m, 2H), 7.64 (m, 2H), 5.03 (m, 1H), 4.19 (m, 2H),
3.80 (m, 4H), 3.67−3.53 (m, 4H), 1.88 (m, 1H), 1.61 (m, 4H), 1.35 (m, 1H), 1.27 (t, J = 6.8 Hz, 3H), 1.23−1.11 (m, 15H); 13C NMR
43 (CDCl3, 100 MHz) δ 168.3 (s), 133.9 (s), 132.1 (s), 123.2 (s), 99.6 (d, J = 138.6 Hz), 66.1 (d, J = 10.2 Hz) and 65.2 (d, J = 8.7 Hz),
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62.6 (d, J = 7.3 Hz), 56.8 (s), 52.3 (d, J = 89.0 Hz), 37.6 (s), 29.3 (s), 28.2 (s), 23.3 (d, J = 9.5 Hz ), 22.6 (s), 16.6 (d, J = 4.3 Hz),
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15.4 (m); 31P NMR (CDCl3, 162 MHz) δ 39.27, 38.92, 38.39, 38.0; ESI (m/z) 531.5 [M + H]+; HRMS (ESI) Calcd for
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51 C24H39N2O7PSNa 553.2108, found 553.2104.
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Compound 2i. Yield 98%, 1.49 g; colorless oil; [α]2D5 23.5 (c 2.0, CHCl3); IR (film) 3448, 3192, 2978, 2919, 1475, 1443, 1390,
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1296, 1216, 1163, 1060, 960, 562 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.10 (d, J = 9.6 Hz, 1H), 4.28 (m, 2H), 3.95−3.72 (m, 6H),
2.72 (m, 2H), 2.09 (m, 1H), 2.09 (s, 3H), 1.91 (m, 1H), 1.36 (t, J = 6.8 Hz, 3H), 1.29 (m, 6H), 1.25 (s, 9H); 13C NMR (CDCl3, 100
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MHz) δ 99.7 (d, J = 139.2 Hz), 66.1 (d, J = 9.5 Hz) and 65.1 (d, J = 8.7 Hz), 62.7 (d, J = 7.2 Hz), 56.8 (s), 51.0 (d, J = 89.7 Hz),
30.2 (d, J = 10.9 Hz), 29.6 (d, J = 2.1 Hz), 22.7 (s), 16.7 (d, J = 5.1 Hz), 15.3 (d, J =3.7 Hz), 15.0 (s); 31P NMR (CDCl3, 162 MHz)
δ 39.12, 38.80, 38.29, 37.95; ESI (m/z) 404.3 [M + H]+; Elemental analysis (%) calcd for C15H34NO5PS2: C 44.65; H 8.49; N 3.47.
Found: C 44.21; H 8.72; N 3.34.
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Compound 2j. Yield 64%, 1.34 g; colorless oil; [α]2D6 3.9 (c 1.0 , CHCl3); IR (film) 3446, 3184, 3063, 2978, 2929, 1475, 1214,
1166, 1060, 959, 598 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.44−7.19 (m, 5H), 5.03 (m, 1H), 4.28 (m, 2H), 4.10−3.64 (m, 6H), 3.09
(m, 2H), 1.39−0.92 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ 137.4 (d, J = 11.7 Hz ), 129.5 (m), 128.4 (m), 126.7 (m), 99.7 (d, J =
137.8 Hz), 66.2 (m) and 65.2 (d, J = 8.7 Hz), 62.9 (m), 56.7 (m), 53.9 (m), 36.0 (d, J = 4.4 Hz ), 22.4 (m), 16.7 (m), 15.3 (m); 31P
NMR (CDCl3, 162 MHz) δ 66.34, 65.24, 64.93, 64.84; ESI (m/z) 420.3 [ M+ H]+; Elemental analysis (%) calcd for C19H34NO5PS:
C 54.40; H 8.17; N 3.34. Found C 54.51; H 8.26; N 2.94.
Compound 2l. Yield 50%, 1.12 g; colorless oil; [α]2D1 36.4 (c 1.0 , CHCl3); IR (film) 3177, 2978, 2929, 2869, 1476, 1455, 1364,
1217, 1108, 1060, 958, 738, 700 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.40−7.28 (m, 5H), 5.0 (m, 1H), 4.54 (m, 2H), 4.39−3.94 (m,
4H), 3.93−3.72 (m, 5H), 3.60 (m, 1H), 1.35−1.21 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 137.6 (s), 128.4
(s), 128.0 (s), 127.8 (s), 99.8 (d, J = 145.2 Hz), 73.5 (s), 69.0 (s), 66.0 (d, J = 10.9 Hz) and 65.5 (d, J = 8.7 Hz), 62.6 (d, J = 7.3 Hz),
56.6 (s), 52.3 (d, J = 88.2 Hz), 22.5 (s), 16.6 (m), 15.4 (m); 31P NMR (CDCl3, 121 MHz) δ 38.26, 38.21, 37.89, 37.33; ESI (m/z)
43 450.3 [M + H]+; HRMS (ESI) calcd for C20H37NO6PS 450.2074, found 450.2072.
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Compound (-)-2l. Yield 88%, 1.98 g; colorless oil; [α]2D7 -34.4 (c 1.0 , CHCl3); IR (film) 3486, 3182, 2978, 2870, 1641, 1476, 1455,
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1364, 1301, 1218, 1106, 1058, 959, 739, 700, 560 cm−1; H NMR (CDCl3, 400 MHz) δ 7.38−7.28 (m, 5H), 5.0 (m, 1H), 4.54 (m,
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51 2H), 4.22 (m, 2H), 4.15−3.71 (m, 7H), 3.60 (m, 1H), 1.35−1.21 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer:
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137.6 (s), 128.3 (s), 127.9 (s), 127.8 (s), 99.7 (d, J = 145.1 Hz), 73.4 (s), 68.9 (s), 65.9 (d, J = 10.2 Hz) and 65.4 (d, J = 8.8 Hz),
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62.5 (d, J = 7.3 Hz), 56.5 (s), 52.3 (d, J = 88.3 Hz), 22.4 (s), 16.5 (m), 15.3 (m); 31P NMR (CDCl3, 162 MHz) δ 37.03, 36.68, 36.13;
ESI (m/z) 450.5 [M + H]+; HRMS (ESI) calcd for C20H36NO6PSNa 472.1893, found 472.1896.
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Compound 2m. Yield 92%, 2.13 g; colorless oil; [α]2D6 29.1 (c 1.0 , CHCl3); IR (film) 3478, 2977, 2929, 1455, 1390, 1217, 1060
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cm−1; H NMR (CDCl3, 400 MHz) δ 7.40−7.26 (m, 5H), 5.27−4.67 (m, 1H), 4.62 (m, 1H), 4.48 (m, 1H), 4.31 (m, 1H), 4.26−2.84
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(m, 8H), 1.53−1.12 (m, 21H); 13C NMR (CDCl3, 100 MHz) δ 138.0 (m), 128.1 (m), 127.7 (m), 127.3 (m), 100.6 (m), 77.1 (m), 72.1
(m), 67.3 (m), 64.8 (m), 62.3 (m), 57.1 (m), 22.7 (m), 16.8 (m), 16.3 (m), 15.2 (m); 31P NMR (CDCl3, 162 MHz) δ 38.37, 37.12,
36.53, 35.58; ESI (m/z) 464.4 [M + H]+; HRMS (MALDI) calcd for C21H38NO6PSNa 486.2050, found 486.2035.
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Compound 2n. Yield 93%, 2.13 g; sticky yellow oil; [α]2D6 4.7 (c 1.0 , CHCl3); IR (film) 3244, 2978, 2929, 1456, 1206, 1058, 960,
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742 cm−1; H NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.65 (m, 1H), 7.35 (d, J = 8.0 Hz , 1H), 7.17 (dt, J1 = 0.4 Hz, J2 = 7.2 Hz,
1H), 7.13−7.07 (m, 2H), 4.79 (d, J = 10.4 Hz, 1H), 4.28 (m, 2H), 4.15 (m, 1H), 3.95−3.65 (m, 4H), 3.43 (m, 2H), 3.14 (m, 1H),
1.38−1.24 (m, 6H), 1.18 (t, J = 7.2 Hz , 3H), 0.97 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 136.3 (s), 127.6 (s),
123.6 (s), 122.0 (s), 119.5 (s), 118.9 (s), 111.2 (s), 111.0 (s), 100.2 (d, J = 137.9 Hz), 66.3 (d, J = 8.8 Hz) and 65.3 (d, J = 10.3 Hz),
62.8 (d, J = 7.3 Hz), 56.6 (s), 52.7 (d, J = 88.2 Hz), 26.1 (d, J = 3.7 Hz), 22.3 (s), 16.6 (d, J = 5.1 Hz), 15.3 (d, J = 14.6 Hz); 31P
NMR (CDCl3, 121 MHz) δ 39.54, 38.72; ESI (m/z) 459.2 [M + H]+; HRMS (ESI) Calcd for C21H35N2O5PSNa 481.1897, found
481.1913; Elemental analysis (%) calcd for C21H35N2O5PS: C 55.00; H 7.69; N 6.11. Found C 54.68; H 7.92; N 5.93.
Compound 2o. Yield 96%, 2.16 g; colorless oil; [α]2D6 1.4 (c 1.3 , CHCl3); IR (film) 3184, 2978, 2931, 1613, 1514, 1456, 1391,
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1248, 1060, 960, 831 cm−1; H NMR (CDCl3, 400 MHz) δ 7.14 (m, 2H), 6.83 (m, 2H), 5.01 (d, J = 10.4 Hz, 1H), 4.26 (m, 2H),
43 4.2−3.6 (m, 6H), 3.78 (s, 3H), 3.34−2.76 (m, 2H), 1.39−0.96 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 158.5
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(s), 130.7 (s), 129.2 (d, J = 11.6 Hz), 113.8 (s), 99.7 (d, J = 138.6 Hz), 66.2 (d, J = 10.3 Hz) and 65.1 (d, J = 8.7 Hz), 62.7 (d, J =
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7.3 Hz), 56.6 (s), 55.3 (s), 54.1 (d, J = 87.5 Hz), 35.0 (d, J = 3.6 Hz ), 22.3 (s), 16.6 (d, J = 5.1 Hz), 15.4 (d, J = 5.9 Hz); 31P NMR
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51 (CDCl3, 162 MHz) δ 36.52, 35.46, 35.25, 35.02; ESI (m/z) 450.4 [M + H]+ ; HRMS (ESI) Calcd for C20H36NO6PSNa 472.1893,
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found 472.1915; Elemental analysis (%) calcd for C20H36NO6PS: C 53.44; H 8.07; N 3.12. Found C 53.12; H 8.18; N 2.97.
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Compound 2p. Yield 70%, 1.30 g; colorless oil; [α]2D5 44.5 (c 0.67, CHCl3); IR (film) 3480, 3000, 2931, 2875, 1653, 1475, 1390,
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1366, 1213, 1059, 952, 599 cm−1; H NMR (CDCl3, 300 MHz) δ 5.22−4.74 (m, 1H), 4.76−3.50 (m, 8H), 2.5−2.2 (m, 1H),
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1.38−1.26 (m, 24H); 13C NMR (CDCl3, 75 MHz) δ 99.6 (m), 67.7−64.8 (m), 63.4−62.3 (m), 58.4−55.2 (m), 57.2 (s), 30.3−28.2 (m),
23.0−22.9 (m), 20.8 (m), 16.9 (m), 15.4 (m); 31P NMR (CDCl3, 162 MHz) δ 39.87, 38.95, 38.86, 37.70; ESI (m/z) 372.1 [M + H]+;
HRMS (MALDI) Calcd for C15H35NO5PS 372.1968, found 372.1954.
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Compound 2q. 2q was prepared from 2e: To 2e (420 mg, 1mmol) was added 10 mL of aqueous ammonia and stirred overnight.
The reaction was extracted by chloroform (20 mL×5), washed with brine and then dried over anhydrous Na2SO4. The crude product
was purified by column chromatography giving 267 mg colorless oil in 67% yield. [α]2D5 40.8 (c 1.0, CHCl3); IR (film) 3369, 3196,
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2978, 1673, 1213, 1057, 594 cm−1; H NMR (CDCl3, 400 MHz) δ 6.80 (br, 1H), 6.28 (br, 1H), 5.03 (m, 1H), 4.69−4.41 (m, 1H),
4.27 (m, 2H), 3.90 (m, 2H), 3.83−3.65 (m, 3H), 2.52 (m, 1H), 2.42 (m, 1H), 2.25 (m, 1H), 2.05 (m, 1H), 1.38−1.25 (m, 18H); 13C
NMR (CDCl3, 100 MHz) δ for the major isomer: 175.2 (s), 99.7 (d, J = 139.3 Hz), 66.3 (d, J = 9.5 Hz) and 65.7 (d, J = 9.5 Hz),
62.9 (d, J = 7.3 Hz), 55.8 (s), 51.6 (d, J = 91.1 Hz), 31.9 (d, J = 8.0 Hz), 26.1 (s), 22.6 (s), 16.6 (m), 15.3 (m); 31P NMR (CDCl3,
162 MHz) δ 39.22, 38.60, 38.44, 38.15; ESI (m/z) 401.4 [M + H]+; HRMS (ESI) Calcd for C15H34N2O6PS 401.1870, found
401.1878.
Compound 2r. 2r was prepared from 2e: To 2e (414 mg, 1mmol) in 5 mL of MeOH, 5 mL of BnNH2 was added and stirred for 2
days. The solution was concentrated and then purified by column chromatography with DCM: MeOH (NH3) (50:1), giving 467 mg
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colorless oil in 95% yield. [α]2D5 33.9 (c 1.0, CHCl3); IR (film) 3281, 2977, 1655, 1546, 1215, 1058, 699 cm−1; H NMR (CDCl3,
43 400 MHz) δ 7.33−7.23 (m, 5H), 6.89−6.70 (m, 1H), 5.03 (m, 1H), 4.41 (m, 2H), 4.23 (m, 2H), 4.11 (m, 1H), 3.87 (m, 2H),
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3.80−3.56 (m, 3H), 2.52 (m, 1H), 2.42 (m, 1H), 2.26 (m, 1H), 2.09 (m, 1H), 1.35−1.22 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ
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for the major isomer: 172.1 (s), 138.5 (s), 128.6 (s), 127.7 (s), 127.3 (s), 99.9 (d, J = 140.0 Hz), 66.3 (d, J = 9.5 Hz) and 65.7 (d, J =
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51 9.5 Hz), 62.8 (d, J = 7.3 Hz), 56.8 (s), 51.4 (d, J = 91.2 Hz), 43.4 (s), 32.8 (d, J = 7.3 Hz), 26.8 (s), 22.6 (s), 16.6 (d, J = 5.1 Hz),
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15.3 (d, J = 5.8 Hz); 31P NMR (CDCl3, 162 MHz) δ 38.97, 38.30, 38.25, 37.64; ESI (m/z) 491.5 [M + H]+; HRMS (ESI) Calcd for
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C22H40N2O6PS 491.2339, found 491.2347.
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To 0.5 mmol phosphinate 2, 2.5 mL of 4 M HCl in MeOH was added at room temperature. After 75 minutes, the reaction
monitored by TLC was completed. The solution was concentrated under vacuum, and then dissolved in DCM. MeOH saturated
with ammonia was added to neutralize the residual acid. The crude product was purified by silica gel column chromatography with
DCM/MeOH (NH3) (50:1) to give phosphinate 3.
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Compound 3b. Yield >99%, 206 mg; colorless oil; [α]3D0 1.0 (c 0.97, CHCl3); IR (film) 3595, 3462, 3384, 2977, 2932, 1771, 1716,
1440, 1397, 1370, 1213, 1034, 722 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.83 (m, 2H), 7.72 (m, 2H), 4.88 (d, J = 7.2 Hz, 1H), 4.21
(m, 2H), 3.87 (m, 2H), 3.71 (m, 4H), 3.10 (m, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.82 (m, 1H), 1.53 (m, 1H), 1.42 (m, 2H), 1.33 (m,
3H), 1.24 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 168.2 (s), 133.8 (s), 132.0 (s), 123.0 (s), 100.6 (d, J =
132.0 Hz), 65.4 (m), 61.7 (m), 48.6 (d, J = 91.1 Hz), 37.5 (s), 27.3 (d, J = 9.5 Hz), 25.2 (d, J = 11.7 Hz), 16.6 (m), 15.1 (m); 31P
NMR (CDCl3, 162 MHz) δ 41.44, 41.14; MS (ESI) m/z (%) 413.3 [M + H]+; HRMS (ESI) Calcd for C19H30N2O6P 413.1836, found
413.1852. Analysis of 31P NMR and HPLC spectra of (S)-Mosher’s derivate 6b: retention time=148.6 min, 170.6 min (89.9:10.1).
Compound 3c. Yield 90%, 162 mg; colorless oil; [α]3D0 -50.3 (c 1.0, CHCl3); IR (film) 3370, 3292, 1221, 1109, 1057, 1035, 701
cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.34−7.22 (m, 5H), 4.87 (d, J = 7.2 Hz, 1H), 4.21 (m, 2H), 3.85 (m, 2H), 3.74 (s, 2H), 3.66 (m,
2H), 3.19 (m, 1H), 3.06 (m, 1H), 2.56 (m, 1H), 1.31 (t, J = 6.8 Hz, 3H), 1.23 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 138.2 (s),
128.9 (s), 128.6 (s), 127.1 (s), 100.4 (d, J = 136.4 Hz), 65.7 (d, J = 8.0 Hz) and 65.4 (d, J = 8.7 Hz), 62.1 (d, J = 7.3 Hz), 48.8 (d, J
43 = 93.3 Hz), 36.5 (s), 33.6 (d, J = 3.7 Hz), 16.7 (d, J = 4.3 Hz), 15.3 (d, J = 5.1 Hz); 31P NMR (CDCl3, 162 MHz) δ 39.84; MS (ESI)
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m/z (%) 362.1 [M + H]+; HRMS (ESI) Calcd for C16H28NO4PSNa 384.1369, found 384.1383; Elemental analysis (%) calcd for
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C16H28NO4PS: C 53.17, H 7.81, N 3.88. Found C 52.88, H 7.79, N 3.95.
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51 Compound 3d. Yield 82%, 184 mg; colorless oil; [α]2D4 -16.5 (c 1, CHCl3); IR (film) 3063, 3039, 2977, 2928, 1477, 1448, 1295,
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1216, 1108, 1057, 1034, 955, 744, 540 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.66
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(d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 4.89 (t, J = 7.6 Hz, 1H), 4.22 (m, 2H), 4.13 (t, J = 6.0 Hz, 1H),
3.86 (m, 2H), 3.68 (m, 2H), 3.27−3.02 (m, 4H), 2.65 (m, 1H), 1.70 (s, 2H), 1.32 (m, 3H), 1.23 (m, 6H); 13C NMR (CDCl3, 100
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MHz) δ for the major isomer: 145.9 (s), 141.1 (d, J = 3.6 Hz), 127.6 (s), 127.1 (s), 124.8 (d, J = 18.3 Hz), 119.9 (s), 100.5 (d, J =
137.1 Hz), 65.8 (m), 62.3 (m), 48.6 (d, J = 93.3 Hz), 46.9 (s), 36.7 (s), 35.2 (s), 16.8 (d, J = 5.1 Hz), 15.3 (s); 31P NMR (CDCl3, 162
MHz) δ 40.28, 39.89; MS (ESI) m/z (%) 450.3 [M + H]+; HRMS (ESI) Calcd for C23H33NO4PS 450.1862, found 450.1845.
Compound 3e. Yield 65%, 106 mg; colorless oil; [α]2D4 -2.5 (c 1.0, CHCl3); IR (film) 3389, 2979, 2933, 2904, 1732, 1446, 1208,
1056, 1034, 956 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.86 (d, J = 7.2 Hz, 1H), 4.23 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.88 (m, 2H),
3.71 (m, 2H), 3.08 (m, 1H), 2.62 (m, 1H), 2.51 (m, 1H), 2.20 (m, 1H), 1.80 (m, 1H), 1.64 (br, 2H), 1.35 (t, J = 6.8 Hz, 3H), 1.26 (m,
9H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 173.4 (s), 101.0 (d, J = 131.2 Hz), 65.8 (d, J = 8.0 Hz) and 65.6 (d, J =
9.7 Hz), 61.9 (d, J = 7.3 Hz), 60.4 (s), 48.6 (d, J = 89.7 Hz), 31.0 (d, J = 11.7 Hz), 25.5 (d, J = 3.6 Hz), 16.7 (d, J = 5.1 Hz), 15.2 (d,
J = 2.9 Hz), 14.2 (s); 31P NMR (CDCl3, 121 MHz) δ 42.32, 42.03; MS (ESI) m/z (%) 326.2 [M + H]+; HRMS (ESI) Calcd for
C13H29NO6P 326.1727, found 326.1717. Analysis of the 31P NMR and 19F NMR spectra of the (S)-Mosher’s derivate 6e: dr = 88:12.
Compound 3f. Yield 82%, 115 mg; colorless oil; [α]2D4 10.4 (c 1.0, CHCl3); IR (film) 3391, 2974, 2932, 2876, 1213, 1112, 1058,
953 cm−1; 1H NMR (CD3OD, 400 MHz) δ 4.99 (d, J = 6.8 Hz, 1H), 4.24 (m, 2H), 4.92 (m, 2H), 3.74 (m, 2H), 3.13 (dd, J1 = 4.0 Hz,
J2 = 6.8 Hz, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.28 (m, 7H), 1.07 (d, J = 36.4 Hz, 3H), 0.96 (t, J = 7.2 Hz,
3H); 13C NMR (CD3OD, 100 MHz) δ 100.7 (d, J = 181.2 Hz), 66.0 (d, J = 12.1 Hz) and 65.8 (d, J = 11.6 Hz), 62.0 (d, J = 10.2 Hz),
52.4 (d, J = 121.5 Hz), 35.6 (s), 24.1 (s), 15.6 (s), 15.5 (d, J = 5.9 Hz), 14.1 (d, J = 20.0 Hz), 10.8 (s); 31P NMR (CD3OD, 121 MHz)
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Compound 3g. Yield 90%, 126 mg; colorless oil; [α]2D6 -5.8 (c 1.0, CHCl3); IR (film) 3380, 2957, 2931, 1389, 1204, 1113, 1057,
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825 cm−1; 1H NMR (CDCl 3, 400 MHz) δ 4.88 (d, J = 7.6 Hz, 1H), 4.23 (m, 2H), 3.89 (m, 2H), 3.71 (m, 2H), 3.16 (m, 1H), 1.96 (m,
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51 1H), 1.56 (m, 1H), 1.46 (m, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 6H), 0.97 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H);
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13C NMR (CDCl 3, 100 MHz) δ 100.7 (d, J = 131.3 Hz), 65.7 (d, J = 7.3 Hz) and 65.3 (d, J = 8.8 Hz), 61.8 (d, J = 7.3 Hz), 46.8 (d,
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J = 91.9 Hz), 38.5 (s), 23.9 (d, J = 12.4 Hz), 23.6 (s) and 20.8 (s), 16.7 (d, J = 4.4 Hz), 15.2 (d, J = 5.8 Hz); 31P NMR (CDCl 3, 162
MHz) δ 42.05; MS (ESI) m/z (%) 282.3 [M + H]+; HRMS (ESI) Calcd for C12H29NO4P 282.1829, found 282.1831.
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Compound 3h. Yield 79%, 168 mg; colorless oil; [α]2D6 -10.9 (c 1.8, CHCl3); IR (film) 3237, 2976, 2931, 2866, 1771, 1713, 1397,
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1120, 1056, 722 cm−1; H NMR (CDCl3, 400 MHz) δ 7.84 (dd, J1 = 3.2 Hz, J2 = 5.2 Hz, 2H), 7.71 (dd, J1 = 2.8 Hz, J2 = 5.2 Hz,
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2H), 4.86 (d, J = 7.2 Hz, 1H), 4.21 (m, 2H), 3.87 (m, 2H), 3.71 (m, 4H), 3.04 (m, 1H), 1.89 (m, 1H), 1.78−1.68 (m, 3H), 1.47 (m,
2H), 1.33 (m, 3H), 1.26 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 168.4 (s), 133.9 (s), 132.2 (s), 123.2 (s),
100.9 (d, J = 131.2 Hz), 65.7 (d, J = 8.1 Hz) and 65.6 (d, J = 8.8 Hz), 61.8 (m), 48.9 (d, J = 91.1 Hz), 37.8 (s), 29.6 (d, J = 6.6 Hz),
28.4 (s), 23.6 (d, J = 11.6 Hz), 16.7 (d, J = 4.4 Hz), 15.3 (m); 31P NMR (CDCl3, 162 MHz) δ 40.96, 40.26; MS (ESI) m/z (%) 427.5
[M + H]+; HRMS (ESI) Calcd for C20H32N2O6P 427.1992, found 427.2012.
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Compound 3i. Yield 79%, 118 mg; colorless oil; [α]2D6 -8.8 (c 1.0, CHCl3); IR (film) 3983, 2977, 2919, 1633, 1444, 1205, 1109,
1058, 957 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.87 (m, 1H), 4.23 (m, 2H), 3.88 (m, 2H), 3.70 (m, 2H), 3.38 (m, 1H), 2.80 (m, 1H),
2.68 (m, 1H), 2.16 (m, 1H), 2.11 (s, 3H), 1.76 (m, 1H), 1.35 (m, 3H), 1.27 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ for
the major isomer: 101.0 (d, J = 132.0 Hz), 65.8 (d, J = 8.0 Hz) and 65.6 (d, J = 8.8 Hz), 61.9 (d, J = 8.0 Hz), 47.7 (d, J = 90.4 Hz),
30.8 (d, J = 13.1 Hz), 29.40 (s), 29.37 (s), 16.8 (d, J = 5.1 Hz), 15.2 (m); 31P NMR (CDCl3, 121 MHz) δ 42.78, 42.55; MS (ESI) m/z
(%) 300.3 [M + H]+; HRMS (MALDI) Calcd for C11H26NO4PSNa 322.1212, found 322.1212.
Compound 3j. Yield >99%, 158 mg; light yellow oil; [α]2D6 -9.6 (c 1.0, CHCl3); IR (film) 3378, 2977, 2929, 1454, 1217, 1111,
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1057, 953, 700 cm−1; H NMR (CDCl3, 400 MHz) δ 7.32 (m, 2H), 7.27−7.22 (m, 3H), 4.84 (m, 1H), 4.26 (m, 2H), 3.89 (m, 2H),
43 3.69 (m, 2H), 3.34 (m, 1H), 3.29 (m, 1H), 2.69 (m, 1H), 2.68 (m, 1H), 1.35 (t, J = 6.8 Hz, 3H), 1.27 (m, 6H); 13C NMR (CDCl3,
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100 MHz) δ for the major isomer: 138.2 (d, J = 13.2 Hz), 129.4 (s), 128.6 (s), 126.6 (s), 100.7 (d, J = 136.3 Hz), 66.1 (d, J = 8.0 Hz)
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and 65.6 (d, J = 9.4 Hz), 62.1 (d, J = 7.3 Hz), 50.2 (d, J = 98.4 Hz), 36.6 (s), 16.8 (d, J = 5.1 Hz), 15.3 (d, J = 2.9 Hz); 31P NMR
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51 (CDCl3, 162 MHz) δ 41.62, 41.22; MS (ESI) m/z (%) 316.3 [M + H]+; HRMS (ESI) Calcd for C15H27NO4P 316.1672, found
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316.1673.
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Compound 3k. Yield 80%, 106 mg; colorless oil; [α]2D5 -1.8 (c 1.0, CHCl3); IR (film) 3444, 2976, 2932, 2876, 1445, 1210, 1108,
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1059, 958, 540 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.87 (m, 1H), 4.24 (m, 2H), 3.88 (m, 2H), 3.72 (m, 2H), 3.43 (m, 1H), 3.03 (m,
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1H), 2.91 (m, 1H), 2.10−2.01 (m, 3H), 1.85 (m, 1H), 1.73 (m, 1H), 1.34 (t, J = 6.8 Hz, 3H), 1.26 (t, J = 7.2 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) δ for the major isomer: 100.3 (d, J = 140.1 Hz), 65.5 (m), 62.5 (d, J = 7.3 Hz), 53.6 (d, J = 101.3 Hz), 47.4 (d, J
= 7.3 Hz), 25.6 (s), 25.5 (m), 16.6 (d, J = 5.1 Hz), 15.2 (d, J = 5.8 Hz); 31P NMR (CDCl3, 121 MHz) δ 43.38, 42.90; MS (ESI) m/z
(%) 266.6 [M + H]+; HRMS (ESI) Calcd for C11H25NO4P 266.1516, found 266.1528.
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Compound 3l. Yield >99%, 173 mg; light yellow oil; [α]2D6 0.44 (c 1.0, CHCl3); IR (film) 3453, 2977, 2929, 2870, 1478, 1454,
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1212, 1106, 1068, 1035, 956, 740, 700, 556 cm−1; H NMR (CDCl3, 400 MHz) δ 7.34−7.27 (m, 5H), 4.83 (m, 1H), 4.55 (m, 2H),
4.21 (m, 2H), 3.80 (m, 4H), 3.62 (m, 2H), 3.40 (m, 1H), 1.30 (m, 3H), 1.22 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ for the major
isomer: 137.8 (s), 128.4 (s), 127.9 (s), 127.8 (s), 101.0 (d, J = 137.1 Hz), 73.5 (s), 70.0 (d, J = 19.6 Hz), 65.8 (m), 62.2 (m), 49.8 (d,
J = 91.1 Hz), 16.7 (m), 15.2 (m); 31P NMR (CDCl3, 162 MHz) δ 40.18, 39.95; MS (ESI) m/z (%) 346.3 [M + H]+; HRMS (MALDI)
Calcd for C16H29NO5P 346.1775, found 346.1773. Analysis of the 19F NMR and 31P NMR spectra of the (S)-Mosher’s derivative 6l:
dr = 66.0:34.0.
Compound (-)-3l. Yield >99%, 173 mg; light yellow oil; [α]D27 0.21 (c 1.0, CHCl3); IR (film) 3453, 3385, 2988, 2871, 1641, 1604,
1454, 1212, 1106, 1058, 1034, 740, 700 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.33−7.28 (m, 5H), 4.83 (m, 1H), 4.54 (m, 2H), 4.21
(m, 2H), 3.80 (m, 4H), 3.60 (m, 2H), 3.40 (m, 1H), 1.29 (m, 3H), 1.21 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ for the major
isomer: 137.8 (s), 128.3 (s), 127.8 (s), 127.7 (s), 100.9 (d, J = 136.4 Hz), 73.4 (s), 69.9 (d, J = 2.9 Hz), 65.6 (m), 61.9 (d, J = 6.6
43 Hz), 49.7 (d, J = 91.9 Hz), 16.6 (m), 15.1 (m); 31P NMR (CDCl3, 162 MHz) δ 40.05, 39.80 (1:0.8); MS (ESI) m/z (%) 346.3 [M +
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H]+; HRMS (MALDI) Calcd for C16H29NO5P 346.1778, found 346.1787. Analysis of the 19F NMR and 31P NMR spectra of the
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(S)-Mosher’s derivative (-)-6l: dr = 68.7:31.2.
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51 Compound 3m. Yield 96%, 172 mg; colorless oil; the major isomer had a yield of about 45%, and it could be separated as single
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isomer with the following data: [α]2D3 -5.9 (c 1.0, CHCl3); IR (film) 3455, 3389, 3310, 2977, 2930, 2898, 1606, 1454, 1392, 1219,
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1034, 557 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38−7.26 (m, 5H), 4.82 (d, J = 7.2 Hz, 1H), 4.64 (d, J = 10.8 Hz, 1H), 4.49 (d, J =
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10.8 Hz, 1H), 4.16 (m, 1H), 4.08 (m, 2H), 3.85 (m, 2H), 3.64 (m, 2H), 3.15 (dd, J1 = 7.2 Hz, J2 = 3.2 Hz, 1H), 1.36 (dd, J1 = 6.0 Hz,
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J2 = 0.8 Hz, 3H), 1.23 (dt, J1 = 2.8 Hz, J2= 7.2 Hz, 6H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.4 (s), 128.3 (s),
128.0 (s), 127.6 (s), 100.8 (d, J = 137.8 Hz), 72.9 (s), 71.0 (s), 65.5 (d, J = 8.8 Hz) and 65.3 (d, J = 8.7 Hz), 61.8 (d, J = 6.6 Hz),
54.4 (d, J = 91.1 Hz), 16.5 (d, J = 5.1 Hz), 16.3 (d, J = 8.8 Hz), 15.3 (s); 31P NMR (CDCl3, 162 MHz) δ 40.14; MS (ESI) m/z (%)
360.2 [M + H]+; HRMS (MALDI) Calcd for C17H30NO5PNa 382.1754, found 382.1746. Analysis of the 1H NMR spectra of the
(S)-Mosher’s and (R)-Mosher’s derivatives of 5m indicated the absolute configuration of (1R). But the configuration of the
phosphorus atom could not be confirmed.
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Compound 3n. Yield 74%, 131 mg; light yellow oil; [α]2D5 -13.7 (c 0.56, CHCl3); IR (film) 3399, 3241, 2977, 1633, 1205, 1102,
1056, 1034, 742 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.45 (br, 1H), 7.64 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.17 (m, 2H), 7.11 (m,
1H), 4.90−4.77 (m, 1H), 4.27 (m, 2H), 3.85 (m, 2H), 3.77−3.49 (m, 3H), 3.41 (m, 1H), 2.95 (m, 1H), 2.39 (br, 2H), 1.36 (m, 3H),
1.28−1.21 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 136.5 (s), 133.9 (s), 127.5 (d, J = 37.9 Hz), 123.6 (s), 122.1 (s), 119.5 (s), 118.9
(s), 111.4 (s), 100.7 (d, J = 134.9 Hz), 65.9 (d, J = 8.0 Hz) and 65.5 (d, J = 8.8 Hz), 62.3 (d, J = 7.3 Hz), 49.1 (d, J = 94.8 Hz), 26.2
(s), 16.8 (m), 15.3 (m); 31P NMR (CDCl3, 162 MHz) δ 41.23, 40.89; MS (ESI) m/z (%) 355.1 [M + H]+; HRMS (MALDI) Calcd for
C17H27N2O4PNa 377.1601, found 377.1599. Analysis of the 19F NMR and 31P NMR spectra of the (S)-Mosher’s derivative 6n
indicated the dr value was 94.8:5.2.
Compound 3p. Yield 98%, 131 mg; colorless oil; [α]2D6 3.9 (c 1.2, CHCl3); IR (film) 3390, 2975, 2931, 1208, 1113, 1057, 952, 551
43 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.87 (m, 1H), 4.23 (m, 2H), 3.89 (m, 2H), 3.71 (m, 2H), 3.0 (m, 1H), 2.25 (m, 1H), 1.34 (t, J =
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6.8 Hz, 3H), 1.26 (m, 6H), 1.08−1.0 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 100.9 (d, J = 131.3 Hz), 65.6 (m), 61.6 (d, J = 7.3 Hz),
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53.4 (d, J = 90.4 Hz), 27.7 (m), 20.8 (m), 17.0 (m), 15.3 (m); 31P NMR (CDCl3, 162 MHz) δ 42.32, 41.82; MS (ESI) m/z (%) 268.3
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51 [M + H]+; HRMS (ESI) Calcd for C11H27NO4P 268.1672, found 268.1674. Analysis of the 1H NMR, 19F NMR and 31P NMR
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spectra of the (S)-Mosher’s derivative 6p indicated the dr value was >95:5.
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Compound 3q. 3q was prepared from 2q by the conditions of 4 M HCl/MeOH in a yield of 66% or from 3e as the following
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procedure: 3e (34 mg, 0.1 mmol) dissolved in 10 mL of MeOH which was previously saturated with NH3 at room temperature. The
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reaction was stirred overnight. Then the solution was concentrated to give 30 mg colorless oil in quantitative yield. [α]2D8 10.4 (c 1.0,
CHCl3); IR (film) 3434, 3234, 2979, 1699, 1209, 1106, 1056, 544 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.12−6.05 (m, 1H), 4.81 (m,
1H), 4.23 (m, 2H), 3.98 (m, 1H), 3.87 (m, 2H), 3.71 (m, 2H), 2.55−2.30 (m, 4H), 1.35 (m, 3H), 1.28 (m, 6H); 13C NMR (CDCl3,
100 MHz) δ for the major isomer: 177.9 (d, J = 3.7 Hz), 101.2 (d, J = 140.0 Hz), 66.2 (m), 62.6 (d, J = 7.3 Hz), 49.6 (d, J = 100.6
Hz), 29.2 (d, J = 2.2 Hz), 20.4 (d, J = 3.7 Hz), 16.7 (d, J = 5.1 Hz), 15.2 (d, J = 4.4 Hz); 31P NMR (CDCl3, 162 MHz) δ 38.28,
39.10; MS (ESI) m/z (%) 302.2 [M + Na]+; HRMS (ESI) Calcd for C11H22NO5PNa 302.1128, found 302.1134.
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Compound 3r. 3r was prepared by the reaction of 2r with 2.3 M HCl in EtOAc instead of 4 M HCl in MeOH. Yield 39%, 73 mg;
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colorless oil; [α]D26 2.6 (c 1.0, CHCl3); IR (film) 3282, 2977, 2930, 1657, 1548, 1206, 1056, 956, 699 cm−1; H NMR (CDCl3, 400
MHz) δ 7.33−7.23 (m, 5H), 6.80 (br, 1H), 4.84 (m, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.18 (m, 2H), 3.85 (m, 2H), 3.68 (m, 2H), 3.08 (m,
1H), 2.53 (m, 1H), 2.44 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.32 (t, J = 6.8 Hz, 3H), 1.24 (t, J = 6.8 Hz, 6H); 13C NMR (CDCl3,
100 MHz) δ 172.5 (d, J = 3.6 Hz), 138.5 (s), 128.6 (s), 127.7 (s), 127.3 (s), 100.8 (d, J = 133.4 Hz), 65.8 (m), 62.0 (m), 48.4 (d, J =
90.4 Hz), 43.5 (s), 33.2 (d, J = 10.2 Hz), 26.6 (d, J = 3.0 Hz), 16.7 (d, J = 4.4 Hz), 15.3 (d, J = 3.7 Hz); 31P NMR (CDCl3, 162 MHz)
δ 41.3; MS (ESI) m/z (%) 387.5 [M + H]+; HRMS (ESI) Calcd for C18H32N2O5P 387.2043, found 387.2025.
Compound 3s. The product was obtained after the removal of the benzyl group of 3l according to the following procedure: 3l (37
mg, 0.1 mmol) was dissolved in 3.8 mL of EtOH and 1.2 mL of THF, Pd(OH)2/C (37 mg, 20%, moisture) and TFA (41 µL, 0.5
43 mmol) were added subsequently. The reaction was stirred under hydrogen at 27 °C overnight. After the completion of the reaction,
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the mixture was filtered through celite and washed by ethyl acetate. The solution was concentrated, and then purified by silica gel
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column chromatography with DCM/MeOH (NH3) (30:1) to give 23 mg colorless oil in a yield of 90%; [α]2D7 2.2 (c 1.0, CHCl3); IR
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2H), 3.88 (m, 4H), 3.72 (m, 2H), 3.25 (m, 1H), 2.36 (br, 3H), 1.36 (m, 3H), 1.27 (t, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ
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101.2 (d, J = 137.1 Hz), 66.2 (m), 62.3 (m), 61.9 (m), 50.9 (d, J = 89.7 Hz), 16.7 (s), 15.2 (s); 31P NMR (CDCl3, 162 MHz) δ 41.36,
40.82; MS (ESI) m/z (%) 256.1 [M + H]+; HRMS (ESI) Calcd for C9H23NO5P 256.1308, found 256.1309.
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Compound (-)-3s. The product was obtained similar to that for 3s as a colorless oil; Yield 76%, 19 mg; colorless oil; [α]2D7 -2.4 (c
1.0, CHCl3); IR (film) 3370, 2977, 2931, 1393, 1203, 1107, 1056, 957 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.85 (m, 1H), 4.24 (m,
2H), 3.88 (m, 4H), 3.72 (m, 2H), 3.27 (m, 1H), 2.73 (br, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3,
100 MHz) δ 101.2 (d, J = 137.1 Hz), 66.2 (m), 62.3 (m), 61.7 (m), 50.9 (d, J = 87.5 Hz), 16.7 (s), 15.2 (s); 31P NMR (CDCl3, 162
MHz) δ 41.14, 40.71; the rest data are the same as compound 3s.
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Compound 3t. The product was obtained after the removal of the benzyl group from the single isomer of 3m similar to that of 3s.
Yield 87%, 23 mg; colorless oil; [α]2D1 4.1 (c 0.44, CHCl3); IR (film) 3378, 2976, 2931, 1446, 1393, 1204, 1104, 1058, 669 cm−1;
1H NMR (CDCl3, 400 MHz) δ 4.83 (d, J = 6.4 Hz, 1H), 4.32−4.18 (m, 3H), 3.89 (m, 2H), 4.16 (m, 1H), 3.72 (m, 2H), 3.06 (dd, J1 =
4.8 Hz, J2 = 8.0 Hz, 1H), 1.38−1.33 (m, 6H), 1.27 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 101.3 (d, J = 135.3 Hz), 66.3
(d, J = 8.6 Hz) and 66.0 (d, J = 8.6 Hz), 65.6 (d, J = 2.0 Hz), 62.3 (d, J = 7.5 Hz), 54.0 (d, J = 87.5 Hz), 19.8 (d, J = 9.1 Hz), 16.7 (d,
J = 4.9 Hz), 15.2 (d, J = 2.9 Hz); 31P NMR (CDCl3, 162 MHz) δ 40.61; MS (ESI) m/z (%) 270.1 [M + H]+; HRMS (ESI) Calcd for
C10H25NO5P 270.1465, found 270.1471.
Compound 9a. 9a was prepared from 3s according to the following procedure: 3s (93 mg, 0.36 mmol) dissolved in 2 mL of THF at
0 °C, then NEt3 (0.1 mL, 0.72 mmol) was added. Boc2O (0.17 mL, 0.72 mmol) in 0.8 mL of THF was added dropwise to the
solution. After the reaction was stirred at 0 °C for 3 hours, it was warmed to room temperature and stirred overnight. Then the
43 solution was concentrated to give the crude product, which was directly subjected to next reaction. The crude product was dissolved
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in 6 mL of DCM, cooled to -15 °C, and then NEt3 (0.15 mL, 1.08 mmol) and DMAP (44 mg, 0.36 mmol) were added. Then MsCl
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(0.14 mL, 1.8 mmol) in 1 mL of DCM was added dropwise. After about 3 hours, the reaction was completed as indicated by TLC.
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51 Then 2 mL of diluted NaHCO3 was added to quench the reaction. The aqueous phase was extracted with 10 mL×3 EtOAc. The
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combined organic phase were washed with brine and then dried over anhydrous Na2SO4. The crude product passed through a short
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silica gel column to remove byproducts, and gave 119 mg colorless oil in 76% yield. The product (119 mg, 0.268 mmol) was
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dissolved in 5 mL of DMF, and NaCN (131 mg, 2.68 mmol) was added. The reaction was warmed to 40 °C. After 2 hours, the
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solution turned yellow. The reaction was completed as indicated by TLC. 20 mL of EtOAc was added. The solution was washed by
sat. FeSO4 untilled the color of the organic phase remained. The organic phase was dried over anhydrous Na2SO4, and then purified
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by silica gel column chromatography with petroleum ether/ethyl acetate (1:1 to 1:5) to give 49 mg light yellow oil in 54% yield. [α]
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3.2 (c 1.0, CHCl3); IR (film) 3244, 2979, 2933, 2248, 1717, 1522, 1367, 1167, 1059, 1033, 561 cm−1; H NMR (CDCl3, 400
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MHz) δ 5.56−5.27 (m, 1H), 4.80 (m, 1H), 4.43 (m, 1H), 4.27 (m, 2H), 3.87 (m, 2H), 3.71 (m, 2H), 2.92 (m, 2H), 1.46 (s, 9H), 1.37
(m, 3H), 1.28 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ for the major isomer: 155.0 (d, J = 7.3 Hz), 116.7 (d, J = 11.0 Hz), 101.7 (d,
J = 146.6 Hz), 80.7 (s), 67.1 (d, J = 8.1 Hz) and 66.6 (d, J = 10.2 Hz), 63.3 (m), 44.4 (d, J = 97.7 Hz), 28.2 (s), 19.4 (d, J = 5.9 Hz),
16.6 (m), 15.2 (m); 31P NMR (CDCl3, 162 MHz) δ 35.20, 34.73; MS (ESI) m/z (%) 387.1 [M + Na]+; HRMS (ESI) Calcd for
C15H30N2O6P 365.1836, found 365.1847.
Compound 9b. 9b was prepared from 9a according to the following procedure: To 9a (25 mg, 0.068 mmol), a mixture of 1.6 mL
of acetone, 0.13 mL of sat. Na2CO3, and 0.66 mL of H2O2 was added. After the reaction was stirred at room temperature for 2 days,
the reaction was completed as indicated by TLC. The solution was concentrated, and the crude product was purified by silica gel
column chromatography with DCM/MeOH(NH3) (40:1) to give 22 mg white sticky oil in 84% yield. [α]2D1 1.6 (c 1.0, CHCl3); IR
(film) 3418, 3292, 3202, 2978, 1673, 1516, 1308, 1167, 1058, 545 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.84 (s, 1H), 5.86 (s, 1H),
5.79−5.70 (m, 1H), 4.81 (m, 1H), 4.52 (m, 1H), 4.24 (m, 2H), 3.86 (m, 2H), 3.70 (m, 2H), 2.74 (m, 2H), 1.44 (s, 9H), 1.34 (t, J =
43 6.8 Hz, 3H), 1.27 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 172.5 (m), 155.6 (m), 100.8 (m), 80.3 (s), 66.7−66.2 (m), 62.9 (m), 45.0
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(m), 35.7 (m), 20.2 (s), 16.6 (m), 15.2 (m); 31P NMR (CDCl3, 162 MHz) δ 38.44, 37.97; MS (ESI) m/z (%) 405.1 [M + Na]+;
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HRMS (ESI) Calcd for C15H32N2O7P 383.1942, found 383.1948.
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51 Compound 3u. 3u was prepared from 9b as the following procedure: 9b (7.8 mg, 0.02 mmol) dissolved in 0.4 mL of chloroform,
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and 0.2 mL of TFA was added. After the reaction was stirred at room temperature for 1 hour, the reaction was completed as
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indicated by TLC. The solution was concentrated to give 8 mg light yellow oil in quantitative yield. [α]2D3 3.8 (c 0.5, MeOH); IR
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(film) 3350, 3187, 2983, 1677, 1421, 1204, 1057, 1028, 800, 722 cm−1; 1H NMR (CD3OD, 400 MHz) δ 5.00−4.96 (m, 1H), 4.22 (m,
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