Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations

Article abstract of DOI:10.1021/acs.joc.7b00491

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the unde

Full text of DOI:10.1021/acs.joc.7b00491

Subscriber access provided by UniSA Library
Note
Synthesis of P-Chiral Dihydrobenzooxaphosphole (BOP)
Core for BI Ligands in Asymmetric Transformations
Guisheng Li, XIAO-JUN WANG, Yongda Zhang, Zhulin Tan, Philomen DeCroos, Jon
C Lorenz, Xudong Wei, Nelu Grinberg, Nathan K. Yee, and Chris H. Senanayake
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 May 2017
Downloaded from http://pubs.acs.org on May 2, 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 12
The Journal of Organic Chemistry
1
2
3
4
5
6
Synthesis of P-Chiral Dihydrobenzooxaphosphole (BOP) Core for BI Ligands in
Asymmetric Transformations
7
8
9
Guisheng Li,* Xiaoꢀjun Wang,* Yongda Zhang, Zhulin Tan, Philomen DeCroos, Jon C. Lorenz,
Xudong Wei, Nelu Grinberg, Nathan K. Yee, Chris H. Senanayake
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
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877,
USA
xiaoꢀjun.wang@boehringerꢀingelheim.com
guishengli@yahoo.com
Abstract: An efficient and practical synthesis of enantiomerically pure Pꢀchiral
dihydrobenzooxaphosphole (BOP) core 1 is developed which is amendable for large scale
preparation of the related ligand series. The unique epimerization of Pꢀchiral center of the
undesired (R,R)ꢀdiastereomeric phosphine oxide 19 through chlorination followed by
crystallization makes this chemical resolution method achieve 65% yield of the desired (R,S)ꢀ
diastereomer 12.
In the past decades, metalꢀcatalyzed reactions with chiral phosphine ligands are widely
utilized and advanced for variety of asymmetric transformations.1 In 2010, our laboratories
discovered a new series of Pꢀchiral monoꢀ and bisꢀphosphine ligands2 containing a unique
dihydrobenzooxaphosphole (BOP) core 1 which are structurally rigid, electronically and
sterically tunable, and airꢀstable. These unique chiral BOP ligands have demonstrated superior
reactivity and selectivity for various asymmetric transformations (Scheme 1) including 1)
asymmetric SuzukiꢀMiyaura crossꢀcoupling reaction,3 2) asymmetric hydrogenation of
enamide,2,4 ketones,5 unfunctionalized alkenes,6 and substituted pyridine,7 3) asymmetric
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 12
1
2
proprogylation,2b,8 and allenylation,9,10 4) asymmetric addition to ketone,10 imine, and
nitroalkene, 5) asymmetric ringꢀopening,11 6) asymmetric hydroboration,12 7) asymmetric
dearomative and reductive alkynone cyclization,12 8) asymmetric hydroformylation,13 and 9)
asymmetric alkene oxyarylation.12 More significantly, these chiral BOP ligands were
successfully applied to the syntheses of complex chiral drug candidates for Cholesteryl Ester
Transfer Protein (CETP) inhibitor,5 HIV Integrase Inhibitor,3and 11ꢀbetaꢀHSDꢀ1 inhibitor7
programs at BoehringerꢀIngelheim (Figure 1). Also these ligands are effectively used for other
nonꢀasymmetric transformations such as sterically hindered Suzuki14 and Negishi15 crossꢀ
coupling, amination,16 and borylation.17
3
4
5
6
7
8
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
Scheme 1. Asymmetric transformations using the Pꢀchiral BOP ligand families
Figure 1.
O
O
O
OH
N
NC
N
O
N
F3C
NH
OH
N
O
O
N
11 -HSD1 inhibitor
CETP inhibitor
HIV integrase integrase inhibitor
Due to the versatile and important utilities of these Pꢀchiral BOP ligands for various
asymmetric transformations, it becomes very important to have an efficient, practical, and costꢀ
effective synthesis of this class of chiral ligands, particular for its applications on industrial scale.
While our original synthesis2b (Scheme 2) of BOP core 1 was already used to produce kilogram
ACS Paragon Plus Environment

Page 3 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
quantity of these ligands, there are some drawbacks hindering its further scale up. At first, the
deprotonation of phosphanate 9 with nꢀBuLi at low temperatures (ꢀ78 oC) followed by iodination
is not desirable because the good inꢀprocess controls of the reaction conditions are required to
achieve reproducible results. Secondly, excess boron tribromide (BBr3, 3 eq.) used in the
demethylation of iodide 10 is a hazardous reagent in its handling on scale. Also, large amount of
byꢀproduct HBr generated during the quenching and workup of this demethylation reaction are
very problematic. In addition, chemical resolution of the menthyl ester has its inherent limitation
because its potential maximum yield is 50%.
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
Scheme 2. Original Synthesis of Dihydrobenzooxaphosphole Core 1
Herein, we describe a greatly improved synthesis of Pꢀchiral 3ꢀtertꢀbutylꢀ2,3ꢀ
dihydrobenzo(d)[1,3]oxaphospholꢀ4ꢀol oxide 1 in terms of efficiency, practicality, and costꢀ
effectiveness. The preparation of racemic phenol 11 started from commercially available 1,3ꢀ
o
dimethoxybenzene (13) (Scheme 3). 1,3ꢀDimethoxybenzene was first lithiated (nꢀBuLi, ꢀ20 C
to 0 oC, THF) and then reacted with tꢀbutyl dichlorophosphine (ꢀ 20 oC to 0 oC). In the same pot,
the reaction mixture was quenched with water to give phosphinate 14. The crude 14 in aqueous
layer was directly treated with 25% aq. NaOH and aq. 37% formaline. The desired hydroxyl
phosphinate 15 was isolated as solids in 84% overall yield from 1,3ꢀdimethoxybenzene (13).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 12
1
2
3
4
5
6
Scheme 3. Improved Synthesis of Dihydrobenzooxaphosphole Core 1
7
8
9
OMe
1) n-BuLi, -20 o
OMe
OH
P
OMe
H
C
OH
OH
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
NaOH, HCHO
H2O, 70 oC
84% from 13
57% HI
92-100 oC
94%
THF
2) t-BuPCl2
3) H2O
P
P
O
O
O
OMe
OMe
OH
OMe
13
15
16
14
O
OMs
O
O
P
OMs
NaOH, H2O
MsCl, Et3N
THF
+
P
+
O
P
P
O
O
O
OH
94% from 16
OH
OMs
OMs
11
18
11
17
i) (COCl)2
ii) H2O
+
O
P
O
P
O
O
(+)-Menthyl
chloroformate
O
O
O
O
O
O
MeCN, i-Pr2NEt
12
d.r. ~ 99/1
19
~65% total
NaOH,MeOH
NaOH,MeOH
H2O, 65 o
C
H2O, 65 o
98%
C
O
O
P
P
O
O
OH
OH
20
1
>99.5% ee
>99.5% ee
Demethylation of hydroxymethylꢀphosphine oxide 15 was not trivial, a number of
reaction conditions was explored to avoid the use of BBr3 (Table 1). Treatment of 15 with 4 eq.
BBr3 in 1,2ꢀdichloroethane (DCE) from rt to 60 oC gave 16 as major product (~60% yield) along
with other minor products. Lithium benzenethiolate (PhSLi) in THF cleanly provided the
monodemethylated product 21 only. Other conditions such as aq. 48% HBr (entry 3), 85%
H3PO4/NaI (entry 4), and aq. 47% HI (entry 5) gave moderate yields (74ꢀ83%) of triol 16. In
these cases, monoꢀdemethylation occurred smoothly in a few hours, while the second
demethylation was slow and higher temperatures were required for complete conversion of 15 to
16. Eventually, the demethylation of hydroxymethylꢀphosphine oxide 15 was best accomplished
with aq. 57% HI at 92 to 100 oC to give triol 16 in 94% yield as crystalline solids on cooling and
neutralization with aq. NaOH.
ACS Paragon Plus Environment

Page 5 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Table 1: Demethylation of 15
OMe
OH
OMe
OH
OH
OH
8
9
P
P
P
O
O
O
OMe
OH
OH
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
15
16
21
Reagent/Solvent (eq)
BBr3/CH2Cl2 (3)
PhSLi/THF (3)
Temp (oC)
60
Time (h) Yield (%)
entry
1
2
3
4
5
6
1
60
0
74
75
83
94
0ꢀ40
17
37
38
24
24
48% HBr (10)
85% H3PO4/NaI (8/6)
47% HI (8)
92ꢀ100
92ꢀ100
92ꢀ100
92ꢀ100
57% HI (8)
Propylphosphonic anhydride (T3P) was first evaluated for dehydration of triol 16 to
produce dihydrobenzooxaphosphole 11. A mixture of 16 and 50% T3P in DMF was heated at
100 oC for 1.5 h followed by treatment with aq NaOH, the desired 11 was obtained in about 90%
which contaminated with 10% unidentified byꢀproducts. On the other hand, treatment of 16 with
methanesulfonyl chloride (MsCl) in presence of triethylamine (Et3N) at room temperature, triol
16 was completely converted to a mixture of the desired hydroxyl dihydrobenzooxaphosphole 11,
its monoꢀmesylate 17, and triꢀmesylate 18. Addition of aq. NaOH to this mixture led to selective
hydrolysis of phenol mesylate functional group in 17 and 18 with concurrent cyclization to give
exclusively dihydrobenzooxaphosphole 11 in 94% yield. Treatment of 11 with (+)ꢀmenthyl
chloroformate (98.5% ee) and diisopropylethylamine (iꢀPr2NEt) in MeCN gave a mixture of
diastereomers 12 and 19, in which the desired diastereomer 12 (d.r. = 99:1) was directly
crystallized from the reaction mixture in ~48% yield (>98% dr) while the undesired diastereomer
19 remained in the mother liquor, simply due to different solubility of these two diasteromers 12
and 19 in this solvent system. The diastereomerically pure (R,R)ꢀ12 was hydrolyzed by aq.
NaOH in MeOH to give enantiomerically pure hydroxylꢀdihydrobenzooxaphosphole 1 (>99.5%
ee) in 98% yield. On the other hand, simple concentration of the resulting mother liquor
containing the diastereomeric (R,S)ꢀ19 followed by hydrolysis and crystallization gave (R,S)ꢀ20
(>99% ee) in 95% yield.
If ones only desire to have single enantiomer for specific asymmetric transformation,
chemical resolution of a racemic mixture typically needs to sacrifice one of the enantiomer. In
this case, however, by taking the advantage of the observed solubility difference of these two
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 12
1
2
3
4
5
6
7
8
9
diastereomers 12/19 as described above, the possibility of converting the undesired
diastereomeric (R,S)ꢀ19 into desired (R,R)ꢀ12 via epimerization of phosphine oxide was
envisioned. Treatment of the undesired diastereomer 19 (d.r. ~98/2) with 1.5 eq of oxalyl
chloride18 in CH2Cl2 at rt for about 20 h followed by quenching with water give a 42:58 mixture
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
31
of 12 and 19 as indicated by P NMR. Crystallization of this resulting mixture from MeCN
provide additional ~17% of the desired 12 (d.r. = 99:1). Therefore, the combined yields of this
chemical resolution protocol were ~65%. One can repeat this epimerization/crystallization
protocol to obtain additional desired diastereomer if needed.
Scheme 4. Epimerization of 19
The syntheses of various monoꢀ and bisꢀphosphine ligands (2, 3, 4, 5, 6, and 7 in
Scheme 1) using this key building block 1 have been previously reported from our laboratories
and others.2ꢀ17
In summary, an efficient and practical synthesis of enantiomerically pure Pꢀchiral
dihydrobenzooxaphosphole core 1 is developed, which has been used to produce multikilogram
quantities of this ligand series for asymmetric transformations on large scale. These unique
chiral phosphine ligand families have been successfully applied to the asymmetric syntheses of
drug candidates3,5,7 on scale.
EXPERIMENTAL SECTION
General Method. All reactions were carried out under an atmosphere of argon or nitrogen in
dry glassware with magnetic stirring or magnetic stirring. All commercially available reagents
and solvents were used without further purification. 1H, 13C and 31P NMR spectra were recorded
on a Bruker DRX400 MHz spectrometer with solvent resonance as the internal standard (1H
ACS Paragon Plus Environment

Page 7 of 12
The Journal of Organic Chemistry
1
2
NMR: DMSOꢀd6 at 2.50 ppm, CDCl3 at 7.26 ppm, CD3OD at 3.31 ppm; 13C NMR: DMSOꢀd6 at
3
4
5
6
1
39.52 ppm, CDCl3 at 77.16 ppm, CD3OD at 49.00). H NMR data are reported as follows:
7
8
9
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad), coupling constant and integration. 31P NMR spectra were referenced to 85% H3PO4 in
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
D2O at 0.0 ppm as external standard and obtained with H decoupling. High resolution mass
spectra were obtained on Agilent 85 LCꢀTOF mass analyzer with electrospray ionization. Chiral
analyses were performed on an Agilent HP 1100 Series HPLC system.
tert-Butyl(2,6-dimethoxyphenyl)phosphine oxide (14). To a solution of 1,3ꢀdimethoxybenzene
(13) (25.00 g, 180.94 mmol) in anhydrous THF (25 mL) was charged 2.5 M nꢀBuLi in hexane
o
(52.67 g, 190.00 mol, 1.05 eq) over 0.5 h between −20 to −10 C. The resulting mixture was
o
warmed to 10 C and stirred for 1 h. The mixture was transferred into a solution of tꢀBuPCl2
(30.21 g, 190.00 mmol, 1.05 eq) in anhydrous THF (30.21 g) cooled at −20 oC while the internal
temperature was controlled below 5 oC. The mixture was stirred at 0 oC for about 1 h. Water (50
o
mL) was added below 20 C. The volatiles (~50 mL) were distilled under reduced pressure.
Hexane (50 mL) was added and the mixture was stirred for ~20 min. The aqueous phase was
separated and the organic phase was extracted with water (25 mL). The combined aqueous
extracts (~104 g, containing 41.64 g of product, 171.90 mmol, 95% yield) were used in the next
step without further purification. Analytical data for 14: 1H (400 MHz, CDCl3) δ = 7.52 [d, 1H, J (P,
H) = 487.7 Hz], 7.42ꢀ7.37 (m, 1H), 6.58ꢀ6.53 (m, 2H), 3.84ꢀ3.81 (m, 6H), 1.17 [d, 1H, J (P, H) = 17.4 Hz,
9H]. 13C NMR (125 MHz, CDCl3) δ =163.1, 134.6, 104.1, 104.1, 55.8, 33.1 [d, J (P, C) = 89.95 Hz], 24.5,
24.5. 31P (162 MHz, CDCl3) δ = 32.77.
tert-Butyl(2,6-dimethoxyphenyl)(hydroxymethyl)phosphine oxide (15). To the crude product
14 (41.64 g, 171.90 mmol) in water from previous step was added 6 M NaOH (42.97 mL, 257.82
o
mmol, 1.50 eq). The solution was heated to ~65 C and 37% formaline solution (69.76 g, 859.50
o
mmol, 5.00 eq) was added slowly to maintain the internal temperature between 65−75 C. The
mixture was stirred for 0.5 h at this temperature and cooled to room temperature. Concentrated
hydrochloric acid (22.20 mL, 266.43 mmol, 1.55 eq) was added below 30 oC to adjust pH to 3−4.
The mixture was extracted with CH2Cl2 (3 x 70 mL) and the combined extracts were
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 12
1
2
3
4
5
6
concentrated to remove ~170 mL of solvents. The residual mixture was diluted with MeOH (120
o
mL) and treated with 6 M HCl in 2ꢀpropanol (0.57 mL, 0.02 eq) for ~1 h at 55−60 C. Solvents
7
8
9
(120 mL) were removed under reduced pressure. 2ꢀButanone (120 mL) was charged and solvents
(120 mL) was removed under reduced pressure. This process was repeated twice. The mixture
was cooled to rt. Isopropyl acetate (80 mL) was charged over 0.5 h and the mixture was stirred
for at least 0.5 h. The solid was filtered, rinsed with a mixed solution of 2ꢀbutanone (40 mL) and
isopropyl acetate (80 mL), and dried to give white solid (32.33 g, 69%). Crystallization of the
concentrated filtrate from 2ꢀbutanone and isopropyl acetate (1/2, v/v) gave the 2nd crop as white
solid (9.48 g, 20%) with high purity similar to the first crop. Analytical data for 15: M.P. 116ꢀ
118 oC. 1H (400 MHz, CDCl3) δ = 7.45 (t, J = 8.4 Hz, 1H), 6.58 (dd, J = 4.0, 8.4 Hz, 2H), 5.36 (bs, 1H),
4.45 (d, J =14.2 Hz, 1H), 4.26 (dd, J = 3.0, 14.2 Hz, 1H), 3.83 (s, 6H), 1.21 [d, J (P, H) = 16.0 Hz, 9H] .
13C NMR (125 MHz, CDCl3) δ = 163.1, 135.3, 104.6, 104.5, 58.5 [d, J (P, C) = 82.4 Hz], 55.9, 3438 [d, J
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
(P, C) = 81.8 Hz], 24.3 [d, J (P,C) = 1.25 Hz]. P (162 MHz, CDCl3) δ = 58.84. HRMS (ESI+) calcd
31
for C13H21O4P+H, 273.1256; found, 273.1266.
tert-Butyl(2,6-dihydroxyphenyl)(hydroxymethyl)phosphine oxide (16). The mixture of 15
(14.60 g, 53.62 mmol) and 57% HI (96.26 g, 428.96 mmol, 8.00 eq) was stirred at ~92 oC for 5 h,
at ~95 oC for 5 h, and 97−100 oC for 14 h for complete demethylation. The resulting solution was
o
cooled to 0−5 C and stirred for 1 h. Dichloromethane (50 mL) was added and 50% NaOH
(25.31 g, 316.38 mmol, 5.90 eq) was added slowly to maintain the temperature below 15 oC. The
o
slurry was aged at 15−20 C for 2 h, filtered, rinsed with water (~100 mL) to pH ~7. The solid
was dried in a vacuum oven at 40 oC until water content was < 0.1% to give white solid (12.30 g,
o
1
94%). Analytical data for 16: M.P. 176ꢀ178 C. H NMR (400 MHz, DMSOꢀd6) δ 7.16 (t, J =
13
8.1 Hz, 1H), 6.25 (dd, J = 8.1, 3.6 Hz, 2H), 4.31 (s, 2H), 1.14 (d, J = 1.47 Hz, 9H); C NMR
(100 MHz, DMSOꢀd6) δ 134.5, 107.0 (br), 96.4 (d, J (P, C) = 81.6 Hz), 58.0 (d, J (P, C) = 73.7
31
Hz), 34.3 (d, J (P, C) = 63.2 Hz), 24.5; P NMR (162 MHz, DMSOꢀd6) δ 64.3; HRMS (ESI+)
calcd for C11H17O4P +H, 245.0943; found, 245.0934.
3-(tert-Butyl)-4-hydroxy-2H-benzo[d][1,3]oxaphosphole 3-oxide (11).2b To the suspension of
triol 16 (100.00 g, 0.41 mol) in THF (200 mL) was added Et3N (124.30 g, 1.23 mol, 3.00 eq) and
o
the resulting solution was cooled to −5 C. Methanesulfonyl chloride (107.88 g, 0.94 mol, 2.30
ACS Paragon Plus Environment

Page 9 of 12
The Journal of Organic Chemistry
1
2
eq) was added slowly to control the internal temperature below 20 oC. After addition, the mixture
was warmed up and stirred at 25 oC for 0.5 h. A solution of NaOH (98.27 g, 2.46 mol, 6.00 eq) in
water (500 mL) was charged. The mixture was heated to 60 oC, stirred for 1 h, then cooled to 25
oC and neutralized with a solution of concentrated HCl (201.71 g, 2.05 mol, 5.00 eq) in water
3
4
5
6
7
8
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
o
(170 mL) to pH <2. The mixture was distilled at ~50 C under reduced pressure to remove
o
volatiles (180 mL). MeOH (200 mL) was added and the mixture was distilled at ~50 C under
reduced pressure to remove solvents (220 mL). The suspension was cooled to 10 oC, rinsed with
o
water (200 mL) and heptane (100 mL). The wet cake was dried in a vacuum oven at ~40 C to
constant weight to give white solid (88.40 g, 95%). Analytical data are identical to those in the
literature.2b
(R)-3-(tert-Butyl)-3-oxido-2H-benzo[d][1,3]oxaphosphol-4-yl
methylcyclohexyl) carbonate (12).2b To the suspension of 11 (40.00 g, 176.83 mmol) in
((1S,2R,5S)-2-isopropyl-5-
CH3CN (120 mL) was added iꢀPr2NEt (29.71 g, 229.88 mmol, 1,30 eq), followed by (+)ꢀmenthyl
o
chloroformate (41.00 g, 187.44 mmol, 1.06 eq). The mixture was heated to 60 C in ~0.5 h and
o
held for ~1 h. The slurry was cooled to ~5 C in 1 h and held for 2 h. The solid was filtered,
rinsed with chilled MeCN (80 mL), and dried at ~40 oC under vacuum to give white solid (34.92
g, 48%). Chiral HPLC conditions for separation of the four diastereomers: Chiralcel IAꢀ3, 4.6 x
o
150 mm, 3 µm, nꢀheptane/isopropanol = 90/10, isocratic, 40 C, 1.2 mL/min; The ratio of the
four diastereomers was determined as follows: 3.2 min (19, 0.5%), 4.2 min (entꢀ12, 0.1%), 4.6
min (entꢀ19, 0.2%), 5.8 min (12, 99.2%). Analytical data of 12 are identical to those in the
literature.2b
(R)-3-(tert-Butyl)-3-oxido-2H-benzo[d][1,3]oxaphosphol-4-yl
((1S,2R,5S)-2-isopropyl-5-
methylcyclohexyl) carbonate (12) via epimerization of (19). The filtrate from previous
experiment was concentrated under reduced pressure. The residue was dissolved in EtOAc (200
mL) and extracted with 0.5 N HCl (100 mL). The organic layer was extracted with water (2 x 50
mL), dried over MgSO4, filtered and concentrated to give brownish oil (~40 g, ~97.93 mmol).
The ratio of the four diastereomers was determined by chiral HPLC (same conditions as above):
3.2 min (19, 97.8%), 4.2 min (entꢀ12, 0.9%), 4.6 min (entꢀ19, 0.2%), 5.8 min (12, 1.1%). The oil
was dissolved in CH2Cl2 (200 mL) and cooled to ~0 oC. Oxalyl chloride (18.64 g, 146.89 mmol,
1.50 eq) was added in ~15 min. The mixture was stirred at rt for 20 h. Solvents were removed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
1
2
3
4
5
6
o
under vacuum. MeCN (50 mL) and water (5 mL) were added. The mixture was stirred at 60 C
o
for 2 h, and the resulting suspension was cooled to ~3 C in an iceꢀwater bath for 1 h. The solid
7
8
9
was filtered, rinsed with chilled MeCN (10 mL) and dried to give 12 as white solid (11.86 g, 17%
based on 11) with 99.2% chiral purity. Another round of epimerization of 19 from the filtrate
provided additional amount of 12 (8.25 g, 11%) with chiral purity of 99.5%.
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
(R)-3-(tert-Butyl)-4-hydroxy-2H-benzo[d][1,3]oxaphosphole 3-oxide (1).2b To the suspension
of 12 (60.36 g, 144.49 mmol) in MeOH (240 mL) was added a solution of NaOH (11.56 g,
o
288.97, 2.00 eq) in water (60 mL). The mixture was heated to 65 C and stirred for 2 h. The
o
mixture was cooled to 30 C and acidified with a solution of 37% HCl (29.9 g, 303.42, 2.10 eq)
in water (25 mL) to pH <2. The mixture was distilled at normal pressure to remove volatiles (190
mL). Heptane (300 mL) was added and solvents (150 mL) were distilled at normal pressure. The
o
suspension was cooled to ~3 C and filtered. The solid was rinsed with water (120 mL), heptane
(120 mL), and dried to give 1 as white solid (32.15 g, 98%) with >99.5% ee (the enantiomer 20
was not detected). Chiral HPLC conditions for separation of enantiomers of 5: Chiralcel IAꢀ3,
o
4.6 x 150 mm, 3 µm, nꢀheptane/isopropanol = 90/10, isocratic, 40 C, 1.2 mL/min; 4.2 min (1),
5.8 min (20). Analytical data of 1 are identical to those in the literature.2b
Supporting Information
Copies of 1H, 13C NMR and/or 31P spectra of the compounds are available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
1. a) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver, C.; Pamies, O.; Diéguez, M. Chem.
Rev. 2011, 111, 2077. b) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem. Rev. 2007,
251, 25. c) Cui, X.; Burgess, K. Chem. Rev. 2005, 15, 3272. d) Guiry, P. J.; Saunders, C.
P. Adv. Synth. Catal. 2004, 346, 497. e) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry
2012, 23, 1. f) Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; WileyꢀVCH: Weinheim, Germany, 2000; Chapter 1. g) Busacca, C. A.;
Senanayake, C. H. In Comprehensive Chirality; Carreira, E., Yamamoto, H., Eds.;
Elsevier: Frankfurt, 2012, pp 167−216.
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2. a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. D.; Savoie, J.; Gao, J.
J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.;
Senanayake, C. H. Angew. Chem. Int. Ed. 2010, 49, 5879. b) Fandrick, D. R.; Fandrick,
K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee,
H.; Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600. c) For a recent
review, see: Yang, H.; Yang, X.; Tang, W. Tetrahetron, 2016, 72, 6143.
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
3. a) Haddad, N.; Mangunuru, H. P. R.; Fandrick, K. R.; Qu, B.; Sieber, J. D.; Rodriguez, S.;
Desrosiers, JꢀN; Patel, N. D.; Lee, H.; Kurouski, D.; Grinberg, N.; Yee, N. K.; Song, J. J.;
Senanayake, C. H. Adv. Synth. Catal. 2016, 358, 3522 and references cited therein.
4. a) Liu, G.; Liu, X.; Cai, Z.; Jiao, G.; Xu, G.; Tang, W. Angew. Chem. Int. Ed. 2013, 52,
4235. b) Reeves, J. T.; Tan, Z.; Fandrick, D. R.; Song, J. J.; Yee, N. K.; Senanayake, C.
H. Org. Proc. Res. Dev, 2014, 18, 904 and references cited therein.
5. Han, Z. S.; Xu, Y.; Fandrick, D. R.; Rodriguez, S.; Li, Z.; Qu, B.; Gonnella, N. C.;
Sanyal, S.; Reeves, J. T.; Ma, S.; Grinberg, N.; Haddad, N.; Krishnamurthy, D.; Song, J.
J.; Yee, N. K.; Pfrengle, W.; Ostermeier, M.; Schnaubelt, J.; Leuter, Z.; Steigmiller, S.;
Däubler, J. Stehle, E.; Neumann, L.; Trieselmann, T.; Buba, A.; Hamm, R.; Koch, G.;
Renner, S.; Dehli, J. R.; Schmelcher, F.; Stange, C.; Mack, J. Org. Lett. 2014, 16, 4142
and references cited therein.
6. Qu, B.; Samankumara, L. P.; Ma, S.; Fandrick, K. R.; Desrosiers, JꢀN.; Rodriguez, S.; Li,
Z.; Haddad, N.; Han, Z. S.; McKellop, K.; Pennino, S.; Grinberg, N.; Gonnella, N. C.;
Song, J. J.; and Senanayake. C. H. Angew. Chem., Int. Ed. 2014, 53, 14428 and
references cited therein.
7. Wei, X.; Qu, B.; Zeng, X.; Savoie, J.; Fandrick, K. R.; Desrosiers, JꢀN.; Tcyrulnikov, S.;
Marsini, M. A.; Buono, F. G.; Li, Z.; Yang, BꢀS.; Tang, W.; Haddad, N.; Gutierrez, O.;
Wang, J.; Lee, H.; Ma, S.; Campbell, S.; Lorenz, J. C.; Eckhardt, M.; Himmelsbach, F.;
Peters, S.; Patel, N. D.; Tan, Z.; Yee, N. K.; Song, J. J.; Roschangar, F.; Kozlowski, M.
C.; Senanayake, C. H. J. Am. Chem. Soc. 2016, 138, 15473 and references cited therein.
8. Sieber, J. D.; AngelesꢀDunham, V. V.; Chennamadhavuni, D.; Fandrick, D. R.; Haddad,
N.; Grinberg, N.; Kurouski, D.; Lee, H.; Song, J. J.; Yee, N. K.; Mattson, A. E.;
Senanayake, C. H. Adv. Synth. Catal. 2016, 358, 3062.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 12
1
2
3
4
5
6
9. Huang, L.; Zhu, J.; Jiao, G.; Wang, Z.; Yu, X.; Deng, WꢀP.; Tang, W. Angew. Chem, Int.
Ed. 2016, 55, 4527.
7
8
9
10. Sieber, J. D.; Chennamadhavuni, D.; Fandrick, K. R.; Qu, B.; Han, Z. S.; Savoie, J.; Ma,
S.; Samankumara, L. P.; Grinberg, N.; Lee, H.; Song, J. J.; Senanayake, C. H. Org. Lett.
2014, 16, 5494.
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
11. Luo, R.; Liao, J.; Xie, L.; Tang, W.; Chan, A. S. C. Chem. Comm. 2013, 49, 9959.
12. a) Zhao, G.; Xu,G.; Qian, C.; Tang, W. J. Am. Chem. Soc., 2017, 139, 3360. b) Hu, N.;
Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am. Chem. Soc., 2015, 137, 6746 and
references cited therein.
13. Tan, R.; Zheng, X.; Zhang, X.; Qi, B.; Sader, C. A.; Fandrick, K. R; Senanayake, C. H.
Org. Lett. 2016, 18, 3346
14. a) Li, G. Chen, T.; Li, B.; Xiao, G.; Tang, W. Angew. Chem. Int. Ed. 2015, 54, 3792. bc)
Qu, B.; Haddad, N.; Rodriguez, S.; Sieber, J. D.; Desrosiers, JꢀN; Patel, N. D.; Zhang, Y.;
Grinberg, N.; Lee, H.; Ma, S.; Ries, U. J.; Yee, N. K.; Senanayake, C. H. J. Org. Chem.
2016, 81, 745 and references cited therein.
15. Sieber, J. D.; Qu, B.; Rodriguez, S.; Haddad, N.; Grinberg, N.; Lee, H.; Song, J. J.; Yee,
N. K.; Senanayake, C. H. J. Org. Chem. 2016, 81, 729.
16. Rodriguez, S.; Qu, B.; Haddad, N.; Reeves, D. C.; Tang, W.; Lee, H.; Krishnamurthy, D.;
Senanayake, C. H. Adv. Syn. Catal. 2011, 353, 533.
17. Tang, W.; Keshipeddy, S.; Zhang, Y.; Wei, X.; Savoie, J.; Patel, N. D.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2011, 13, 1366.
18. Yano, T.; Hoshino, M.; Kuroboshi, M.; Tanaka, H. Synlett, 2010, 5, 801.
ACS Paragon Plus Environment