A Practical and Scalable Synthesis of (S)- and (R)-1-(Dimethoxyphosphoryl)allyl Methyl Carbonates

Article abstract of DOI:10.1055/s-0035-1560487

The preparation of (S)- and (R)-1-(dimethoxyphosphoryl)allyl methyl carbonates is achieved on multigram scale from commercially available dimethyl phosphite and acrolein in three steps. The key steps involve an asymmetric Pudovik reaction and enzyme-catal

Full text of DOI:10.1055/s-0035-1560487

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3669–3672
psp
3669
S. Roy et al.
PSP
Synthesis
A Practical and Scalable Synthesis of (S)- and (R)-1-(Dimethoxy-
phosphoryl)allyl Methyl Carbonates
Sudeshna Roy
O
P
O
P
O
P
Nongnuch Sutivisedsak
Bruce C. Hamper
MeO
MeO
MeO
MeO
MeO
MeO
S
S
S
OCO2Me
OCO2Me
OH
Alexander M. Lyss
CHO
60–70% ee
60–70% ee
Christopher D. Spilling*
catalyst
~95% ee
O
enzyme
(MeO)2P(O)H
ClCO2Me
O
O
MeO
MeO
MeO
MeO
MeO
MeO
Department of Chemistry and Biochemistry,
University of Missouri–St. Louis, One University
Boulevard, St. Louis, MO 63121, USA
cspill@umsl.edu
R
R
R
P
P
P
OCO2Me
OCO2Me
OH
60–70% ee
60–70% ee
>98% ee
Received: 04.08.2015
Accepted after revision: 11.09.2015
Published online: 21.10.2015
O
MeO
P
O
R
2
MeO
P
R
MeO
1
Grubbs II, CuI
CH2Cl2, reflux
DOI: 10.1055/s-0035-1560487; Art ID: ss-2015-m0469-psp
MeO
3
OCO2Me
OCO2Me
2
3
Abstract The preparation of (S)- and (R)-1-(dimethoxyphosphoryl)al-
lyl methyl carbonates is achieved on multigram scale from commercial-
ly available dimethyl phosphite and acrolein in three steps. The key
steps involve an asymmetric Pudovik reaction and enzyme-catalyzed ki-
netic resolution.
O
MeO
P
NuH, Pd(PPh3)4
THF
R
MeO
4
Nu
Scheme 2 Synthesis of phosphono allylic carbonates via alkene cross-
metathesis and subsequent palladium-catalyzed substitution reactions
Key words cross-metathesis, enzymatic amplification, α-hydroxy
phosphonates, natural products, phosphonoallylic carbonates
Allylic hydroxyphosphonates (1) and their carbonate
derivatives (2 and 3) (Scheme 1 and Scheme 2) in particu-
lar, are useful building blocks for the synthesis of interest-
ing biologically active molecules.1–7 More complex phos-
phonate homologs (3) can be prepared (Scheme 2) by an
alkene cross-metathesis reaction of the parent 1-(dimeth-
oxyphosphoryl)allyl methyl carbonate (2) using the Grubbs
second-generation catalyst.8
The substituted phosphono allylic carbonates (3) are
useful substrates for palladium π-allyl chemistry (Scheme
2).1–7,9 The steric and electronic influence of the phospho-
nate moiety dictates the stereochemical and regiochemical
outcomes of the reaction. Addition of nucleophiles always
takes place at the 3-position resulting in formation of a vi-
nyl phosphonate (4), while relaying and preserving the chi-
ral information from the starting material to the product.
O
P
O
P
O
MeO
P
MeO
MeO
MeO
MeO
i
MeO
iv
v
OCO2Me
OCO2Me
OH
(S)-1
CHO
(S)-2
(S)-2
iii
60–70% ee
60–70% ee
~95% ee
(MeO)2P(O)H
O
O
O
ii
MeO
MeO
MeO
MeO
MeO
MeO
P
P
P
OCO2Me
OCO2Me
OH
60–70% ee
(R)-2
(R)-1
(R)-2
60–70% ee
>98% ee
Scheme 1 Synthesis of (S)-phosphono allylic carbonate (S)-2 and (R)-phosphono allylic carbonate (R)-2. Reagents and conditions: (i) Ti(Oi-Pr)4, D-di-
methyl tartrate, THF, –15 °C, 24 h (quant.); (ii) Ti(Oi-Pr)4, L-dimethyl tartrate, THF, –15 °C, 24 h (quant.); (iii) ClCO2Me, DMAP, py, CH2Cl2, 0 °C to r.t., 18
h [(S)-2: 80%]; (iv) immobilized lipase AYS, MTBE, pH 7 phosphate buffer, r.t. (42%); (v) Candida antarctica lipase B (CALB), MTBE, pH 7 phosphate buffer,
r.t. (62%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3669–3672

3670
S. Roy et al.
PSP
Synthesis
Intramolecular reactions of pendent nucleophiles result in
the formation of cyclic products.4,5,7a
antiopurity.12 The minor carbonate enantiomer was hydro-
lyzed, leaving the major enantiomer with increased enan-
tiomeric excess. Amongst the different lipases that were
screened, R-selective Amano lipase AYS and S-selective
Candida antarctica lipase B (CALB) gave excellent enanti-
oselectivity. In fact, treatment of the S- and R-carbonates of
60–70% ee with immobilized lipase AYS13 and CALB, respec-
tively, in a biphasic solution of methyl tert-butyl ether
(MTBE) and pH 7 phosphate buffer yielded the respective
carbonates in very high enantiomeric excess (usually ≥95%).
The hydroxy phosphonate (1) is formed in low enantiomer-
ic excess (see ref. 12 for details) and is usually discarded.
The enantiomeric purity of the carbonates 2 was deter-
mined directly by HPLC with an amylose-based AD-H chiral
stationary phase. Carbonates 2 lack a sufficient chromo-
phore for UV detection even at lower than 205 nm wave-
lengths, however, the enantiomers can be detected using a
combination of polarimetric and refractive index detec-
tors.14 Alternatively, the enantiomeric excess can be deter-
mined indirectly by conversion of 2 into UV-absorbing
phosphono cinnamyl carbonate (11) via alkene cross-
metathesis with an excess of styrene using Grubbs’ second-
generation catalyst (Scheme 3).8 The enantiomers of 11 can
be resolved by HPLC using either an AD-H or Whelk-O 12
chiral stationary phase. The absolute configurations of the
carbonates (R)-2 and (S)-2 were unambiguously assigned
by conversion of the (–)-(R)-2 enantiomer (~95% ee by
HPLC) into (R)-11-(+). The rotation and HPLC elution order
were in agreement with a sample of (+)-(R)-11 prepared
from configurationally known α-hydroxy phenylallyl phos-
phonate (+)-(R)-12.15
CO2Me
O
O
O
P
O
R
MeO
O
5 (ref. 1)
7 (ref. 3)
MeO
HO
6 (ref. 2)
O
6
OMe
H
H
HO
OH
8a (ref. 4)
Me
O
6
H
H
OH
8b (ref. 4)
OPMB
O
OMe
9 (ref. 5)
OMe
OMe
O
P
H
HO
H
O
O
10 (ref. 6)
Figure 1 Examples of natural and biologically active compounds pre-
pared from phosphono allylic carbonates
Phosphono allylic carbonates have been used extensive-
ly by us as chiral building blocks for the syntheses of natu-
ral products and biologically active compounds (Figure 1).
The reaction of phosphono allylic carbonates with various
nucleophiles has been used for the synthesis of tumerone
(5) (aryl stannane),1 enterolactone (6) (malonate),2 cyclic
enolphosphonate lipase inhibitors (7) (acetoacetate),3 the
tetrahydrofuran containing diastereoisomeric oxylipids (8a
and 8b),4 centrolobine (9),5 and the tetrahydrofuran-con-
taining fragment of amphidinolides C and F (10) (intramo-
lecular hydroxy),6 amongst others.7 Consequently, methods
for obtaining both the (R)-2 and (S)-2 enantiomers of phos-
phono allylic carbonates are particularly useful.
O
O
MeO
MeO
MeO
P
P
MeO
Grubbs II, CuI
CH2Cl2, reflux
OCO2Me
OCO2Me
(+)-(R)-11
(–)-(R)-2
MeOCOCl
DMAP, pyridine
CH2Cl2, r.t.
The α-hydroxy phosphonates (R)-1 and (S)-1 (Scheme
1) were prepared by catalytic asymmetric phosphonylation
using dimethyl tartrate and titanium(IV) isopropoxide
[Ti(Oi-Pr)4] as the catalyst.10 The enantiomeric excess of the
O
MeO
MeO
P
OH
(+)-(R)-12
99.7% ee
non-racemic hydroxy phosphonates was determined by 31
P
NMR spectroscopy with quinine as a shift reagent.11 L-Di-
methyl tartrate and D-dimethyl tartrate delivered the (R)-
and (S)-hydroxy phosphonate enantiomers, respectively,
typically with modest enantiomeric excess (60–70% ee).
The hydroxy phosphonates were treated with methyl chlo-
roformate and pyridine to give the corresponding carbon-
ates (R)-2 and (S)-2. At this point, high enantiopurities of
the phosphono allylic carbonates were desired because of
their envisaged application in palladium π-allyl chemistry.
An increase in the enantiopurity was achieved by enzyme-
mediated kinetic resolution of carbonates of moderate en-
Scheme 3 Conversion of carbonate (–)-(R)-2 into the configurationally
known (+)-(R)-11 derivative via alkene cross-metathesis
In summary, we have developed an efficient and reliable
three-step procedure for the production of multigram
quantities of (R)- and (S)-phosphono allylic carbonates 2.
The key transformations include an asymmetric Pudovik
reaction, formation of the carbonate, and enzyme-mediated
kinetic resolution. The individual steps are high yielding,
highly reproducible, and overall have wide application in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3669–3672

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S. Roy et al.
PSP
Synthesis
the synthesis of biologically active natural products and
could be useful in medicinal chemistry for the synthesis of
heterocyclic compounds.
(2 × 20 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO2, 50% EtOAc–hexanes) to
give the carbonate (S)-2.
Yield: 2.87 g (80%); colorless oil; Rf = 0.58 (100% EtOAc).
IR (neat, NaCl): 2960, 2856, 1757, 1642 cm–1
1H NMR (300 MHz, CDCl3): δ = 6.04–5.88 (m, 1 H), 5.57–5.45 (m, 2 H),
5.43–5.38 (m, 1 H), 3.85 (s, 3 H), 3.83 (d, JH–P = 10.5 Hz, 6 H).
.
All reactions were carried out in oven-dried glassware under an at-
mosphere of argon unless otherwise noted. Tetrahydrofuran (THF)
was dried by passing through activated alumina columns and then
heated at reflux over Na/benzophenone and distilled. Dichlorometh-
ane (CH2Cl2) was dried over calcium hydride (CaH2). Commercial re-
agents of high purity were purchased and used without further puri-
fication, unless otherwise noted. Ti(Oi-Pr)4 and dimethyl phosphite
were distilled before use. Dimethyl tartrate was dried by azeotropic
removal of water by toluene, followed by drying under vacuum. Li-
pase AYS was obtained from Amano and CALB was purchased from
Sigma Aldrich. Reactions were monitored by thin-layer chromatogra-
phy (TLC) using TLC silica gel plates (60 Å 254 nM) and visualizing
with UV light or KMnO4 stain. Silica gel (Natland International Corp,
230–400 mesh) was used for flash column chromatography. Optical
rotations were recorded using a Jasco P-1010 polarimeter. IR spectra
were obtained using a Thermo Nicolet Avatar 360 FT-IR spectropho-
tometer. NMR spectra were recorded in CDCl3 at 300 or 500 (1H), 75
or 125 (13C) and 121 (31P) MHz, respectively. 1H NMR spectra were
referenced to residual CHCl3 (7.27 ppm), 13C NMR spectra were refer-
enced to the center line of CDCl3 (77.23 ppm), and 31P NMR spectra
were referenced to external 85% H3PO4 (0 ppm). Coupling constants, J,
are reported in Hz.
31P NMR (121 MHz, CDCl3): δ = 19.48.
To the S-carbonate (S)-2 (3.09 g, 70% ee) was added MTBE (61 mL) and
pH 7.0 phosphate buffer (61 mL), followed by the immobilized lipase
AYS (4.43 g). The reaction mixture was agitated using a rotary shaker
for 24 h, after which another batch of immobilized lipase AYS (4.43 g)
was added. The mixture was stirred for an additional 48 h and then
filtered through a pad of Celite. After the addition of brine, the aq
mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organ-
ic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy (SiO2, 50% EtOAc–hexanes) to give the carbonate (S)-2.
Yield: 1.29 g (42%); a colorless oil; 95% ee; [α]D +16.7 (c 1, CHCl3).
The enantiomeric excess was measured either directly or indirectly
by HPLC (see the Supporting Information).
Dimethyl (R)-1-Hydroxyallylphosphonate [(R)-1]
The title compound was prepared using the same procedure as that
described for the synthesis of (S)-hydroxy phosphonate (S)-1, using L-
dimethyl tartrate instead of D-dimethyl tartrate.
Dimethyl (S)-(1-Hydroxyallyl)phosphonate [(S)-1]
To a solution of dry D-dimethyl tartrate (3.18 g, 89.3 mmol, 20 mol%)
in anhydrous THF (135 mL) at –15 °C was added freshly distilled
Ti(Oi-Pr)4 (5.23 mL, 17.8 mmol, 20 mol%), and the resulting mixture
was stirred for 0.5 h. Freshly distilled dimethyl phosphite (16.36 mL,
178.6 mmol, 2 equiv) was added followed, after 10 min, by the addi-
tion of acrolein (5.95 mL, 89.3 mmol, 1 equiv). The flask containing
the reaction mixture was placed in a freezer at a temperature of
–15 °C for a period of 24 h. The reaction was quenched by dropwise
addition of H2O to precipitate the TiO2, which was removed by filtra-
tion through Celite. The organic solution was washed with brine (50
mL) and the aq layer re-extracted with CH2Cl2 (2 × 100 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by column
chromatography (SiO2, 50% EtOAc–hexanes) to give the hydroxy phos-
phonate (S)-1.
(R)-1-(Dimethoxyphosphoryl)allyl Methyl Carbonate [(R)-2]
A solution of the R-carbonate (R)-2 (0.5 g, 72% ee) in MTBE (5 mL) was
added to a solution of CALB (0.6 g) in pH 7.0 phosphate buffer (5 mL).
The flask containing the mixture was placed in an oil bath set to 40 °C
and the contents stirred. The progress of the reaction was monitored
by taking an aliquot from the organic and aq layers (0.1 mL from each
layer). The aliquot was drawn out from the mixture by syringe and
evaporated in vacuo before checking by 31P NMR spectroscopy. The
reaction was stopped at 24% conversion and the CALB was removed
by filtration. The CALB was washed several times with MTBE to rinse
off the reaction mixture which was coated on the enzyme-polymer
surface. The CALB was dried in air and kept in a freezer for subse-
quent reuse. The reaction mixture was extracted with CH2Cl2 (2 × 10
mL). The combined organic layer was dried over Na2SO4 and concen-
trated in vacuo to afford the carbonate (R)-2.
Yield: 10.15 g (100%); colorless oil; Rf = 0.25 (100% EtOAc); 70% ee
(measured by 31P NMR spectroscopy after the addition of quinine as a
chemical shift reagent).
Yield: 0.26 g (68%); colorless oil; >98% ee.
Enzyme Recycling
IR (neat, NaCl): 3298, 2959, 2855, 1638 cm–1
.
The CALB can be used up to five times in the hydrolysis of the R-car-
bonate (R)-2 under the same reaction conditions to give products
with similar ee values, but with diminishing reaction rates. Recycling
of the immobilized lipase AYS was not examined.
1H NMR (300 MHz, CDCl3): δ = 6.09–5.92 (m, 1 H), 5.68–5.46 (m, 1 H),
5.41–5.30 (m, 1 H), 4.60–4.50 (m, 1 H), 3.82 (d, JH–P = 11.3 Hz, 6 H).
31P NMR (121 MHz, CDCl3): δ = 24.2.
(S)-1-(Dimethoxyphosphoryl)allyl Methyl Carbonate [(S)-2]
To a solution of hydroxy phosphonate (S)-1 (1.86 g, 16.05 mmol, 1
equiv) in CH2Cl2 (15.6 mL) was added DMAP (0.392 g, 3.21 mmol, 20
mol%) followed by py (1.94 mL, 24.1 mmol, 1.5 equiv) and then
ClCO2Me (3.3 g, 2.47 mL, 2 equiv) at 0 °C. The reaction mixture was
allowed to warm to r.t. and was stirred for 16 h. The reaction was
quenched with HCl (1 M) and the aq layer was extracted with CH2Cl2
Acknowledgment
We thank the Graduate School of University of Missouri–St. Louis for
the Dissertation Fellowship to S.R. We also thank Amano Enzyme USA
for a generous gift of lipase AYS and other enzymes.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3669–3672

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Supporting Information
(7) (a) De la Cruz, A.; He, A.; Thanavaro, A.; Yan, B.; Spilling, C. D.;
Rath, N. P. J. Organomet. Chem. 2005, 690, 2577. (b) Yan, B.;
Spilling, C. D. J. Org. Chem. 2008, 73, 5385.
(8) He, A.; Yan, B.; Thanavaro, A.; Spilling, C. D.; Rath, N. P. J. Org.
Chem. 2004, 69, 8643.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560487.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3669–3672