Synthesis of Phostones via the Palladium-Catalyzed Ring Opening of Epoxy Vinyl Phosphonates

Article abstract of DOI:10.1021/acs.joc.9b00905

The reaction of epoxy aldehydes with tetraethyl methylenediphosphonate gave γ,δ-epoxy vinyl phosphonates. The palladium-catalyzed addition of primary alcohols gave the monoprotected diols as single diastereoisomers. The trans- and cis-epoxides lead to opp

Full text of DOI:10.1021/acs.joc.9b00905

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Note
Synthesis of Phostones via the Palladium-Catalyzed
Ring Opening of Epoxy vinyl phosphonates
Giri Raj Gnawali, Nigam P. Rath, and Christopher D. Spilling
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00905 • Publication Date (Web): 29 May 2019
Downloaded from http://pubs.acs.org on May 31, 2019
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Page 1 of 11
The Journal of Organic Chemistry
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Synthesis of Phostones via the Palladium-Catalyzed Ring Opening of
Epoxy vinyl phosphonates
7
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Giri Raj Gnawali, Nigam P. Rath and Christopher D. Spilling*
Department of Chemistry and Biochemistry, University of Missouri-St. Louis, One University
Boulevard, St. Louis, Missouri 63121, USA
Supporting Information
1
. ROH, B(OPh) , THF
R1
3
O
P
O
R1
O
Pd (dba) , dppe
2
3
O
EtO
EtO
P
R2
R2
EtO
2
. H , Pd/C, Py, MeOH
2
OR
3
. NaH, THF
ABSTRACT: Reaction of epoxy aldehydes with tetraethyl methylenediphosphonate gave ,-epoxy vinyl phosphonates. The
palladium-catalyzed addition of primary alcohols gave the monoprotected diols as single diastereoisomers. The trans and cis
epoxides lead to opposite (syn and anti) diastereoisomers of the addition products. The alkene of the vinyl phosphonates was
subjected to hydrogenation and the resulting saturated phosphonates underwent base catalyzed cyclization to give phostones with
very high diastereoselectivity in the formation of the new chiral center at phosphorus.
Phostones and phostines are 5- and 6-
membered cyclic phosphonates and phosphinates,
respectively, which contain a P-O bond within
proposed an alternative approach to phostone
synthesis employing ,-epoxy vinyl
phosphonate chemistry.
the
heterocyclic
ring.
These
Scheme 1. Palladium-catalyzed reactions of  and 
hetraphosphacyclanes are more formally called
oxaphospholanes and oxaphosphorinanes. Of
particular interest are the carbohydrate-based
phostones (or phosphonosugars). There are a
growing number of examples of carbohydrate-
based phostones and phostines that show
interesting biological activity.
based phostones are typically prepared by the
addition of trialkyl phosphites or dialkyl
phosphites to carbohydrate-derived aldehydes.
phosphono allylic carbonates
1
O
MeO
MeO
P
R
O
2-5
O
P
1
CO Me
2
CO2Me
MeO
MeO
R
or
O
P
Pd2(dba)3, dppe, THF
3
CO Me
MeO
MeO
2
R
2
,5b
O
Carbohydrate-
2
OCO Me
2
Scheme 2. Palladium-catalyzed reactions of ,-epoxy
unsaturated esters
3
,4
More recent methods for the synthesis of these
phostones include the application of a ring
closing metathesis strategy. Although phostones
OH
O
CO2R2
2 BnOH, B(OPh)3
CO R
R1
R1
2
5
Pd2(dba)3, dppe, THF
4
5
OBn
were first synthesized more than four decades
ago, there has recently been renewed interest in
their synthesis utilizing alternative modern
In a retrosynthetic analysis (Scheme 3), opening
the internal ring P-O bond of the phostones (A)
reveals -hydroxy phosphonates (B). Similar
phosphonates are known to undergo base
4
,5
synthetic methods.
9
Based on our experience with the chemistry of
catalyzed cyclization to give the phostones. The
6
,7
1
2
phosphono allylic carbonates (1 and 2) and the
known chemistry of ,-epoxy unsaturated
substituents A and A can be installed by an
alkene addition reaction on the vinyl phosphonate
8
10-13
carboxylate esters 4 (Scheme 1 and 2), we
moiety (C).
For example, the alkene of the
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vinyl phosphonates can be subjected to
Reaction of epoxy aldehydes (6)15 with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
asymmetric dihydroxylation (AD), selective -
tetraethyl methylenediphosphonate (7) gave ,-
epoxy vinyl phosphonates (8) in good yield
(Scheme 4). The initial attempts to add benzyl
alcohol to the epoxide 8a using palladium
catalysis resulted in formation of the unsaturated
ketone 10a (Scheme 5). It is believed that the
ketone 10a is formed from elimination (of proton
and palladium) from the -allyl intermediate 11,
which may occur faster than the competing
reaction of the alcohol nucleophile. It is probable
that the presence of the phenyl contributes to the
facile proton loss due to conjugation with the
resulting dienolate. Therefore switching from a
phenyl substituent to alkyl group adjacent to the
-allyl may reduce the propensity for elimination.
Scheme 4. Preparation of ,-epoxy vinyl phosphonates
7
h,11
7a,12
hydroboration,
-hydroboration,
or simple
7
b,7d,13
hydrogentation.
This leads to the critical
reaction involving the regioselective and
stereospecific ring opening of an ,-epoxy vinyl
phosphonates (D), which are in turn prepared in a
straight forward manner from the large array of
readily available non racemic epoxy aldehydes
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4,15
(and epoxy alcohols).
Scheme 3. A retro synthetic analysis for the synthesis
carbohydrate-based phostones
O
R1
R2
O
2
O
P
A HO
alkene
P
cyclization
R1
R2
EtO
EtO
EtO
A1
addition
Nu
A1 Nu
O
A2
A
B
R1
O
HO
R1
Pd(0)
EtO
EtO
O
EtO
EtO
P
P
R2
O
P
O
P
R2 NuH
EtO
EtO
OEt
OEt
Nu
D
C
R1
O
P
R1
7
O
EtO
EtO
O
R2
o
R2
By analogy with the reactions of ,-epoxy
NaH, THF, 0 C, 2h
O
8
6
8
unsaturated carboxylate esters, the palladium-
1
2
8
a R = H, R = Ph 90%
8b R = H, R = nC5H11 77%
8c R = H, R = CH OBn (trans) 81%
d R = CH OBn, R = H (cis) 87%
1
2
catalyzed addition of nucleophiles (e.g. benzyl
alcohol) to ,-epoxy vinyl phosphonates is
expected to give the monoprotected diols as
single diastereoisomers. The trans and cis
epoxides lead to opposite (syn and anti) isomers
of the addition products. Furthermore, we have
demonstrated that both  and  phosphono allylic
carbonates (1 and 2) undergo palladium-
catalyzed reactions with methyl acetoacetate
leading to the same vinyl phosphonate product 3,
1
2
2
2
1
8
2
Consequently, three additional epoxy vinyl
phosphonates 8b-d were investigated (Scheme
). We were pleased to find that palladium-
catalyzed reaction of these epoxy vinyl
phosphonate with benzyl alcohol gave the
addition product 9b-d in in good yields. As
anticipated, the ring opening reactions are
stereospecific with the trans epoxide 8c giving
mono protected syn diol 9c, and the cis epoxide
6
6
presumably via a common -allylintermediate.
Interestingly, the vinyl phosphonate ( carbonate)
8
d the anti diastereoisomer 9d. In a single
experiment with epoxide 8c, omission of the
2
converts to product about 6 times faster than
the -carbonate 1. This precedent gave us high
confidence that the proposed approach to
phostones would be successful.
B(OPh) from the reaction mixture resulted in
3
ketone 10c formation.
Scheme 5. A possible reaction mechanism to account for the competitive formation of the unsaturated ketone.
O
P
O
P
OH
Ph
BnOH, B(OPh)3
O
P
O
O
EtO
EtO
EtO
EtO
EtO
EtO
Ph
Pd (dba) , dppe, THF
Ph
2
3
8a
9a
OBn
10a
BnO
OBn
O
Addition of BnOH
slow)
BnO
B
OBn
(
O BnO
B
EtO
EtO
O BnO
P
O
P
Ph
EtO
EtO
Proton loss
fast)
H
Ph
(
1
1
Pd
Pd
12
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The Journal of Organic Chemistry
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2
Hydrogenation of the vinyl phosphonates 9
using hydrogen over palladium on carbon,
poisoned with 5-50 mol% of pyridine (Scheme
), gave the saturated phosphonate 13 without
over reduction and loss of the benzyl protecting
group. Treatment of the saturated phosphonates
When using methanol as a nucleophile, B(OMe)3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was used as the co-catalyst.
Again,
hydrogenation
of
the
vinyl
6
phosphonates 15a-d using hydrogen over
palladium on carbon, poisoned with pyridine,
gave the saturated phosphonates 16a-d.
Treatment of the saturated phosphonates 16a-d
with sodium hydride in THF resulted in
cyclization and the formation of phostones 17a-d
as single diastereoisomers (Scheme 7).
1
3 with sodium hydride in THF resulted in
cyclization and the formation of phostones 14 as
single diastereoisomers. The stereochemistry at
the phosphorus atom was elucidated via X-ray
crystallography with phostone 14b (details in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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3
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9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Palladium-catalyzed addition of alcohols to a
,-epoxy vinyl phosphonates
supporting
information).
The
highly
diastereoselective nature of the cyclization was
somewhat surprising. However, a review of the
published literature indicated that other
substituted -hydroxy phosphonates also undergo
O
EtO
EtO
O
P
CH OBn
2
14c
3
O
P
OH
CH OBn
R OH, B(OPh)
3
EtO
16
Pd2(dba)3, dppe, THF EtO
C to room temp., 3-4 h
highly diastereoselective cyclizations.
2
o
0
OR3
Scheme 6. Palladium-catalyzed addition of benzyl alcohol
to ,-epoxy vinyl phosphonates
3
1
5a R = nC15H31, 41%
3
15b R = pMeOC H CH , 85%
6
4
2
3
15c R = cC H CH , 56%
O
P
O
6
11
2
EtO
EtO
3
1
1
1
5d R = CH , 66%
O
P
R1
R2
OBn
3
EtO
EtO
O
3
5e R = Ph, 36% (iPrOH as nucleophile)
10c
3
5f R = cC H11, complex mixture
6
8b-d
HO R1
R2
O
P
BnOH, B(OPh)3
O
P
OH
CH OBn
EtO
H , Pd/C
2
EtO
EtO
Pd (dba) , dppe, THF EtO
2
3
MeOH, Py,
room temp. 4-6 h
2
o
0
C to room temp., 3-4 h
OBn
OR3
1
6a-d
1
2
9
9
9
b R = H, R = nC H 61%
O
5
11
O
CH OBn
NaH, THF
0 C to room temp., 2-3 h
2
1
2
c R = H, R = CH OBn (trans) 69%
P
2
EtO
1
2
o
d R = CH OBn, R = H (cis) 74%
2
OR3
HO R1
17a
3
O
P
R = nC15H31, 67% (2 steps)
H , Pd/C
2
EtO
EtO
1
3
1
1
1
7b R = pMeOC H CH , 65% (2 steps)
6 4 2
MeOH, Py,
room temp. 4-6 h
R2
3
7c R = cC H CH , 53% (2 steps)
6
11
2
3b-d
OBn
3
7d R = CH , 64% (2 steps)
3
R1
R2
O
NaH, THF
0 oC to room temp., 2-3 h
O
P
EtO
In summary, we have demonstrated ,-epoxy
vinyl phosphonates undergo stereospecific
palladium-catalyzed addition of primary alcohols
to give vinyl phosphonates. Reduction and
cyclization of the vinyl phosphonates yields
phostones as single diastereoisomers. An
investigation of stereoselective mono and
dihydroxylation reactions of vinyl phosphonates
is ongoing.
1
2
OBn
14b R = H, R = nC H 73% (2 steps)
5
11
1
2
1
4c R = H, R = CH OBn 61% (2 steps)
2
1
2
1
4d R = CH OBn, R = H 75% (2 steps)
2
To expand the scope of the method, the
reaction of the benzyloxymethyl substituted
trans-epoxy vinyl phosphonate 9c with other
alcohol nucleophiles was examined (Scheme 7).
In general, primary alcohols reacted smoothly to
give syn monoprotected diols 15a-d. However,
the yield with pentadecanol was low due to the
lack of solubility of this alcohol in the reaction
solvent (THF). Attempted reaction of secondary
alcohols, such as iPrOH and cyclohexanol, lead
to complex mixtures and often the phenol
Experimental Section
All reactions were carried out in oven dried
glassware under an atmosphere of argon unless
otherwise noted. THF was distilled from
Na/benzophenone, MeOH from Mg/Mg(OMe)
CH Cl from CaH , t-Butanol from Na/t-BuONa)
and CH CN was stored over activated 3Å
,
2
released from the B(OPh) was a more competent
2
2
2
3
nucleophile leading to the formation of 15e.
3
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molecular sieves prior to use. H, 13C and 31
1
P
10% aqueous NH Cl. After 10 minutes, the
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR spectra were recorded in CDCl at 300, 75
aqueous solution was extracted three times with
EtOAc. The combined organic layer was washed
3
1
and 121 MHz, respectively. H NMR spectra are
1
3
referenced to CDCl (7.27 ppm), C NMR
with aqueous NaHCO and brine, and then dried
3
3
spectra are referenced to the center line of CDCl
(77.23 ppm) and P NMR spectra are referenced
over anhydrous Na SO . The solution was
3
2
4
3
1
concentrated under reduced pressure and pure
epoxy vinylphosphonate 8 was isolated by
to external H PO . Coupling constants, J, are
3
4
reported
in
Hz.
Analytical
thin-layer
column chromatography (SiO , 30-60% EtOAc
2
chromatography (TLC) analyses were performed
on silica gel plates 60PF . Visualization was
in hexane).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
54
(±) Diethyl (E)-2((2S3S)-3-phenyloxiran-2-
accomplished with UV light, KMnO solution or
18
4
yl)vinylphosphonate
(8a).
Epoxy
iodine.
cinnamaldehyde (6a) (1.8 g, 12.5 mmol) was
General procedure for the synthesis of epoxy
aldehydes (6a-d). To the ice bath cooled
solution of epoxy alcohol in dry CH Cl (4
reacted as above to give (8a) as thick yellow oil
1
(3.17 g, 90%). H NMR (CDCl ) δ 7.32-7.18 (m,
3
5H), 6.67 (ddd, JHP = 21.5, JHH = 17.1, 6.2 Hz,
1H), 6.08 (ddd, JHP = 18.6, JHH = 17.1, 0.6 Hz,
1H), 4.04 (m, 4H), 3.73 (d, JHH = 1.6 Hz, 1H),
2
2
mL/mmol) was added Et N. Then a solution of
3
pyridine sulfur trioxide in dry DMSO (1.5
mL/mmol) was added slowly via an addition
funnel over a period of one hour. The reaction
mixture was stirred at ice bath temperature for an
additional three hours. The reaction was
quenched by the addition of 10% aqueous citric
acid and resulting aqueous solution was extracted
three times using CH Cl . The combined organic
3.39 (m, 1H), 1.27 (dt, J = 7.0, JHP = 1.5 Hz,
HH
13
1
6H); C{ H} NMR (CDCl ) δ 147.5 (d, J = 6.1
3
CP
Hz), 135.9, 128.6, 128.5, 125.4, 120.1 (d, JCP
=
187.5 Hz), 61.9 (d, JCP = 5.2 Hz), 61.3, 61.0 (d,
3
1
1
JCP = 1.5 Hz), 16.3 (d, JCP = 6.3 Hz); P{ H}
NMR (CDCl ) δ 16.8; HRMS (FAB, MH+) calcd
3
for C H O P: 283.1099, Found 283.1117.
2
2
14 20
4
layer was washed with saturated NaHCO and
3
(±) Diethyl (E)-2-((2S,3S)-3-pentyloxiran-2-
yl)vinylphosphonate (8b). Epoxy octanal (6b)
brine, and dried over Na SO . The solution was
2
4
concentrated under reduced pressure and the pure
epoxy aldehyde was isolated by column
(2.29 g, 16 mmol) was reacted as above to give
(8b) as a pale yellow oil (3.39 g, 77%). IR (neat)
chromatography (SiO , 10-20% EtOAc in
-1 1
2
2928, 2858, 1631 cm ; H NMR (CDCl ) δ 6.54
3
1
hexane). The H NMR spectrum for each epoxide
(
(
ddd, JHP = 21.5, JHH = 17.1, 6.4 Hz, 1H), 5.9
ddd, JHP = 19.0, JHH 17.1, 0.7 Hz, 1H), 4.08 (m,
was consistent with the literature values (see
supporting information).
4
H), 3.19 (m, 1H), 2.85 (m 1H), 1.60 (m, 2H),
(
±) 3-phenyloxirane-2-carbaldehyde (6a)17
(±) 3-pentyloxirane-2-carbaldehyde (6b)15b
1.43 (m, 2H), 1.32 (m, 10H), 0.89 (t, J 7.1 Hz,
HH
1
3
1
3H); C{ H} NMR (CDCl ) δ 148.8 (d, J = 6.0
3
CP
Hz), 119.2 (d, JCP = 188.2 Hz), 61.5 (d, JCP
21.7 Hz), 56.8 (d, JCP = 27.7 Hz), 31.5 (d, JCP
=
=
(
±) 3-((benzyloxy)methyl)oxirane-2-
1
5d
carbaldehyde (6c)
2
5.5 Hz), 25.3, 22.4, 16.2 (d, J = 6.0 Hz), 13.6;
CP
(±) 3-((benzyloxy)methyl)oxirane-2-
31
1
P{ H} NMR (CDCl ) δ 16.9; HRMS (FAB,
3
1
5c
carbaldehyde (6d)
+
MH ) calcd For C H O P: 277.1568, Found
1
3
26
4
General procedure for the synthesis of vinyl
epoxy phosphonates (8a-d). Sodium hydride
2
77.1582.
(±)
Diethyl
(E)-2-(2S,3S)-3-
(
1.5 eq) was suspended in dry THF (1
mL/mmol). The suspension was cooled in an ice
bath and then tetraethyl
(benzyloxymethyl)oxiran-2-
yl)vinylphosphonate (8c). trans-Benzyloxy
epoxy butanal (6c) (2.40 g, 12.45 mmol) was
reacted as above to give (8c) as a yellow oil (3.27
methylenebis(phosphonate) (7) (1.5 eq) was
added slowly over 5 minutes. The resulting
mixture was stirred for one hour, then the epoxy
aldehyde 6 (1 eq) dissolved in dry THF (3
mL/mmol) was added dropwise. The reaction
mixture was stirred for two hours at ice bath
temperature, then the reaction was quenched with
-1
g, 81 %). IR (neat) 2981, 2862, 1632, 1240 cm ;
1
H NMR (CDCl ) δ 7.33-7.11 (m, 5H), 6.44
3
(
(
ddd, JHP = 21.5, JHH 17.1, 6.5 Hz, 1H), 5.95
ddd, JHP = 18.6, JHH 17.1, 0.6 Hz, 1H), 4.48 (q,
JHH =11.9 Hz, 2H), 3.99 (m, 4H), 3.57 (m, 2H),
4
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The Journal of Organic Chemistry
3
.32 (m, 1H), 3.04 (m, 1H), 1.23 (m, 6H);
Diethyl
yl)phosphonate
vinylphosphonate (8a) (0.1 g, 0.354 mmol) was
reacted as above to give (10a) (0.093 g, 93 %).
H NMR (CDCl ) δ 7.93-7.90 (m, 2H), 7.59-7.41
(m, 3H), 6.97 (m, 2H), 4.12 (m, 4H), 2.85 (dd,
(E)-(4-oxo-4-phenylbut-2-en-1-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
19
C{ H} NMR (CDCl ) δ 147.8 (d, J = 6.2 Hz),
(10a).
Epoxy
3
CP
1
37.5, 128.4, 127.8, 127.7, 120.4 (d, JCP = 188.2
Hz), 73.4, 69.0, 61.9 (d, JCP = 6.0 Hz), 59.5 (d,
JCP = 1.5 Hz), 54.3 (d, J = 29.2 Hz), 16.4 (d,
JCP = 6.7 Hz); P{ H} NMR (CDCl ) δ 16.6;
HRMS (FAB, MH ) calcd For C H O P:
1
CP
3
3
1
1
3
+
JHP = 23.5, J = 7.0 Hz, 2H), 1.32 (t, J HH = 7.1
1
6
24
5
HH
13
1
3
27.1361, Found 327.1376.
±) Diethyl
(benzyloxymethyl)oxiran-2-
Hz, 6H); C{ H} NMR (CDCl ) δ 190.1 (d, J
3 CP
=
1
6
2.9 Hz), 137.8 (d, J = 11.4 Hz), 137.5, 133.2,
CP
30.2 (d, J = 13.3 Hz), 128.8 (s), 62.6 (d, J =
(
(E)-2-(2S,3R)-3-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CP CP
.7 Hz), 31.3 (d, J = 138.1 Hz), 16.7 (d, JCP
=
yl)vinylphosphonate (8d). cis-Benzyloxy epoxy
butanal (6d) (2.5 g, 13.01 mmol) was reacted as
above to give (8d) as a pale yellow oil (3.68 g,
CP
3
1
1
6.0 Hz). P{ H} NMR (CDCl ) δ 24.5; HRMS
3
+
(
ESI, MH ) calcd For C H O P: 283.1099,
Found 283.1093
14 20
4
-1
1
8
7%). IR (neat) 2980, 2903, 1629, 1243 cm ; H
NMR (CDCl ) δ 7.40-7.30 (m, 5H), 6.62 (ddd,
JHP = 21.6, JHH = 17.1, 6.0 Hz, 1H), 6.05 (ddd,
JHP = 18.7, JHH = 17.1, 1.0 Hz, 1H), 4.57 (q, JHH
Diethyl (E)-(5-(benzyloxy)-4-oxopent-2-en-1-
yl)phosphonate (10c). Formed from epoxy vinyl
phosphonate (8c) (0.1 g, 0.306 mmol) as above
3
=
11.8 Hz, 2H), 4.06 (m, 4H), 3.60 (m, 3H), 3.45
reaction, but in the absence of B(OPh) (0.041
3
13
1
(m, 1H), 1.32 (m, 6H); C{ H} NMR (CDCl ) δ
mg, 41 %). IR (neat) 2980, 2904, 1692, 1625,
3
-
1
1
1
1
45.1 (d, JCP = 6.6 Hz), 137.6, 128.5, 128.0,
1243 cm
H NMR (CDCl ) δ 7.38-7.27 (m,
;
3
27.8, 122.3 (d, J = 188.6 Hz), 73.4, 67.5, 62.0
5H), 6.87 ( m, 1H), 6.43 (m, 1H), 4.60 (s, 2H),
4.22 (s, 2H), 4.10 (m, 4H), 2.75 (ddd, JHP = 23.2,
CP
(d, JCP = 5.5 Hz), 57.5, 55.1 (d, J = 28.2 Hz),
CP
3
1
1
16.4 (d, JCP = 6.4 Hz); P{ H} NMR (CDCl ) δ
16.3; HRMS (FAB, MH ) calcd For C H O P,
3
J
= 7.8, 1.3 Hz, 2H), 1.30 (t, J = 7.1 Hz, 6H);
C{ H} NMR (CDCl ) δ 196.2, 137.2, 137.0 (d,
3
HH
13
HH
+
1
1
6
24
5
3
27.1361, Found 327.1367.
JCP = 11.1 Hz), 130.0 (d, JCP = 13.4 Hz), 128.6,
28.1 (d, JCP = 5.6 Hz), 128.1, 74.2, 73.5, 62.5
d, JCP = 6.6 Hz), 31.2 (d, J = 138.1 Hz), 16.5
1
(
(
General procedure for the synthesis of
vinylphosphonates (9 or 15). To a solution of
triphenyl borate (1.5 eq) in dry THF (1
mL/mmol) was added benzyl alcohol (6 eq). The
resulting solution was stirred for two hours. In a
separate flask, Pd dba (0.04 eq) and dppe (0.1
eq) were added to a solution of the epoxy vinyl
phosphonates 8 (1 eq) in THF (3 mL/mmol).
After one hour of stirring, the palladium solution
was added to the alcohol solution and the
resulting mixture was stirred for one hour at ice
bath temperature. The reaction mixture was then
allowed to warm to room temperature and
stirring was continued until the reaction was
CP
3
1
1
d, J = 5.9 Hz). P{ H} NMR (CDCl ) δ 24.1;
CP
3
+
HRMS (FAB, MNa ) calcd For C H O PNa:
349.1180, Found 349.1182.
16 23
5
(±) Diethyl (3S,4S,E)-3-(benzyloxy)-4-
2
3
hydroxynon-1-enylphosphonate (9b). Epoxy
vinyl phosphonate (8b) (0.5 g, 1.81 mmol) was
as above reacted to give (9b) as a yellow oil
(0.425 g, 61%). IR (neat) 3412, 2946, 2862, 1201
-1
1
cm ; H NMR (300 MHz, CDCl ) δ 7.29-7.17
3
(m, 5H), 6.61 (ddd, JHP = 22.3, JHH = 17.3, 5.7
Hz, 1H), 5.9 (ddd, JHP = 20.6, JHH 17.2, 1.0 Hz,
1H), 4.40 (q, JHH = 11.4 Hz, 2H), 3.98 (m, 4H),
3.74 (m, 1H), 3.47 (t JHH = 5.6 Hz, 1H), 2.90 (br,
1H), 1.36 (m, 2H), 1.21 (m 12H), 0.77 (t, J
6.7 Hz, 3H). C{ H} NMR (75 MHz, CDCl ) δ
149.1 (d, JCP = 5.0 Hz), 137.4, 128.4, 127.9,
127.8, 120.1 (d, JCP = 186.6 Hz), 82.8 (d, JCP =
21.1 Hz), 72.9, 71.6, 61.8 (d, J = 5.6 Hz), 32.4,
3
1
complete (as observed by P NMR and TLC, 2-3
h). The reaction was quenched by addition of
10% aqueous NH Cl and extracted with three
times with EtOAc. The combined organic layer
was washed with aqueous saturated NaHCO and
=
HH
1
3
1
4
3
3
brine, and then dried over anhydrous Na SO .
2
4
CP
The solution was concentrated under reduced
pressure and pure products (9, 10 or 15) were
isolated by column chromatography (SiO 60-
31.7, 25.1, 22.5, 16.3 (d, J = 6.3 Hz), 14.0;
CP
3
1
1
P{ H} NMR (CDCl ) δ 17.4 HRMS (FAB,
3
+
MH ) calcd For C H O P: 385.2143, Found
2
,
20 34
5
80% EtOAc in hexanes).
385.2162.
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The Journal of Organic Chemistry
Page 6 of 11
(
±) Diethyl (3S,4S,E)-3,5-bis(benzyloxy)-4-
187.0 Hz), 80.1 (d, JCP = 21.4 Hz), 73.7, 72.3,
70.7, 70.2, 62.0 (d, JCP = 4.5 Hz), 32.0, 29.9,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hydroxypent-1-enylphosphonate (9c). Epoxy
vinyl phosphonate (8c) (0.5 g, 1.53 mmol) was
reacted to give (9c) as a yellow oil (0.459 g,
69%). IR (neat) 3412 (br), 2981, 1201 cm ; H
NMR (CDCl ) δ 7.24-7.21 (m, 10H), 6.66 (ddd,
29.8, 29.7, 29.7, 29.6, 29.5, 26.2, 22.8, 16.5 (d,
3
1
1
JCP = 6.1 Hz), 14.3; P{ H} NMR (CDCl ) δ
3
-1
1
+
17.6; HRMS (FAB, MH ) calcd For C H O P:
3
1
56
6
555.3814, Found 555.3790.
(±) Diethyl (3S,4S,E)-5-(benzyloxy)-4-
hydroxy-3-(4-methoxybenzyloxy)pent-1-
enyl)phosphonate (15b). Epoxy
3
JHP = 22.1, JHH = 17.3, 5.7 Hz, 1H), 5.94 (ddd,
JHP = 20.4, JHH 17.3, 1.3 Hz, 1H), 4.45 (q, JHH
=
1
4
4
1.4 Hz, 2H), 4.44 (s, 2H), 4.10 (m, 1H), 3.9(m,
H), 3.75 (m, 1H), 3.46 (m, 2H), 2.49 (d J
.7 Hz, 1H), 1.25 (t, JHH = 7.1 Hz, 6H); C{ H}
NMR (CDCl ) δ 148.7 (d, J = 5.1 Hz), 137.8,
37.4, 128.5, 128.5, 128.0, 127.8, 119.9 (d, J =
87.0 Hz), 79.5 (d, JCP = 21.5 Hz), 73.5,72.2,
2.0, 61.9 (d, J = 5.5 Hz), 16.4 (d, JCP = 6.2
Hz); P{ H} NMR (CDCl ) δ 17.3; HRMS
vinyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
HH
1
phosphonate (8c) (0.423 g, 1.30 mmol) was
reacted as above to give (15b) as a yellow oil
(0.512 g, 85%). IR (neat) 3381 (br), 2980, 2904,
1
3
3
CP
1
1
7
-1 1
CP
2864, 1610, 1241 cm ; H NMR (CDCl ) δ 7.39-
3
7.29 (m, 5H), 7.25-7.20 (m, 2H), 6.90-6.85 (m,
2H), 6.73 (ddd, JHP = 22.1, JHH = 17.2, 5.7 Hz,
1H), 6.0 (ddd, JHP = 20.5, JHH = 17.3, 1.3 Hz,
1H), 4.51 ( s, 2H), 4.45 (q, JHH = 11.1 Hz, 2H),
CP
3
1
1
3
+
(
FAB, MH ) calcd For C H O P 435.1936,
Found 435.1938.
23 32
6
4
.08 (m, 5H), 3.79 (m, 4H), 3.52 (m, 2H), 1.32 (t,
13
1
(±) Diethyl (3R,4S,E)-3,5-bis(benzyloxy)-4-
JHH = 7.1 Hz, 6H); C{ H} NMR (CDCl ) δ
3
hydroxypent-1-enylphosphonate (9d). Epoxy
vinyl phosphonate (8d) (0.5 g 1.53 mmol) was
reacted as above to give (9d) as a yellow oil
(0.493 g, 74%). IR (neat) 3364 (br), 3028, 2980,
159.5, 148.9 (d, JCP = 5.3 Hz), 137.9, 129.8,
129.5, 128.5, 127.92 112.0 (d, JCP = 186.9 Hz),
114.0, 79.1 (d, JCP = 21.5 Hz).73.6, 72.3, 71.8,
70.3, 62.0 (d, J = 4.1 Hz), 55.4, 16.5 (d, JCP
=
CP
-1 1
31
1
2864, 1630, 1225 cm H NMR (CDCl ) δ 7.38-
6.2 Hz); P{ H} NMR (CDCl ) δ 17.4. HRMS
3
3
+
7
5
1
.29 (m, 10H), 6.79 (ddd, JHP = 22.1, JHH = 17.2,
.6 Hz, 1H), 6.00 (ddd, JHP = 20.6, JHH = 17.2,
.3 Hz, 1H), 4.52 ( s, 2H), 4.52 (q, JHH = 11.5
Hz, 2H), 4.08 (m, 5H), 3.89 (m, 1H), 3.59 (m,
H), 2.43 (d, J = 5.3 Hz, 1H), 1.33 (t, JHH = 7.1
Hz, 6H); C{ H} NMR (CDCl ) δ 149.3, 137.9,
137.6, 128.6, 128.6, 128.0, 128.0, 127.9, 120.0
d, J = 186.4 Hz), 79.8 (d, J = 21.6 Hz), 73.5,
2.3 (d, JCP = 1.2 Hz), 70.5, 62.0 (d, J = 5.6
(FAB, MH ) calcd For C H O P: 465.2042,
24
34
7
Found 465.2052.
(±) Diethyl
(cyclohexylmethoxy)-4-hydroxypent-1-
enyl)phosphonate (15c). Epoxy
(3S,4S,E)-5-(benzyloxy)-3-
2
HH
1
vinyl
1
3
3
phosphonate (8c) (0.5 g, 1.53 mmol) was reacted
as above to give (15c) as a yellow oil (0.376 g,
(
7
-
CP
CP
56%). IR (neat) 3356 (br), 2920, 2850, 1232 cm
1
1
CP
; H NMR (CDCl ) δ 7.36-7.24 (m, 5H), 6.65
3
3
1
1
Hz, 16.5 (d, JCP = 6.4 Hz); P{ H} NMR
CDCl ) δ 17.5. HRMS (FAB, MH ) calcd For
C H O P: 435.1936, Found 435.1925.
23 32
(ddd, JHP = 22.2, JHH = 17.1, 5.4 Hz, 1H), 5.92
(ddd, JHP = 20.7, JHH = 17.2, 1.3 Hz, 1H), 4.51
(m, 2H), 4.02 (m, 5H), 3.75 (m, 1H), 3.50 (m,
2H), 3.19 (m, 2H), 1.68 (m, 5H), 1.54 (m, 1H),
+
(
3
6
(
±)
hydroxy-3-(pentadecyloxy)pent-1-
enylphosphonate (15a). Epoxy
Diethyl
(3S,4S,E)-5-(benzyloxy)-4-
13
1
1.23 (m, 10H), 0.89 (m, 2H); C{ H} NMR
vinyl
(CDCl ) δ 149.3 (d, J = 5.1 Hz), 137.9, 128.5,
3
C-P
phosphonate (8c) (0.5 g, 1.53 mmol) was reacted
as above to give (15a) as a yellow oil (0.346 g,
127.9, 127.8, 119.3 (d, JCP = 186.9 Hz), 80.1 (d,
JCP = 21.3 Hz), 76.2, 73.6, 72.2, 70.2, 30.0 (d, J
CP
-
41%). IR (neat) 3431 (br), 2920, 2851, 1224 cm
= 1.7 Hz), 38.2, 30.1, 30.0, 26.5, 25.8, 16.4 (d,
1
1
31
1
;
H NMR (CDCl ) δ 7.39-7.30 (m, 5H), 6.67
JCP = 5.7 Hz); P{ H} NMR (CDCl ) δ 17.7
3
3
+
(
(
(
ddd, JHP = 22.5, JHH = 17.2, 5.4 Hz, 1H), 5.95
ddd, JHP = 20.7, JHH = 17.3, 1.2 Hz, 1H), 4.56
m, 2H), 4.06 (m, 5H), 3.75 (m, 1H), 3.54 (m,
H), 3.33 (m, 1H), 2.60 (d, JHH = 4.5 Hz, 1H),
1.56 (m, 2H), 1.30 (m, 30H), 0.88 (t, J = 6.9
HRMS (FAB, MH ) calcd For C H O P:
23
38
6
441.2406, Found 441.2387.
(±) Diethyl (3S,4S,E)-(5-(benzyloxy)-4-
3
hydroxy-3-methoxypent-1-enyl)phosphonate
(15d). Epoxy vinyl phosphonate (8c) (0.5 g, 1.53
mmol) was reacted to give (15d) as a yellow oil
(0.364 g, 66%). IR (neat) 3363 (br), 2980, 2912,
HH
1
3
1
Hz, 3H); C{ H} NMR (CDCl ) δ 149.3 (d, J
3
CP
=
5.2 Hz), 1387.9, 128.6, 127.9, 119.5 (d, JCP
=
6
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-1
1
1
225 cm ; H NMR (CDCl ) δ 7.35-7.27 (m,
(m, 4H), 4.08 (m, 4H), 3.86 (s, 1H), 3.59 (m,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
1
1
H), 6.63 (ddd, JHP = 22.3, JHH = 17.3, 5.7 Hz,
H), 5.94 (ddd, JHP = 20.5, JHH = 17.3, 1.3 Hz,
H), 4.51 (q, JHH = 12.1 Hz, 2H), 4.08 (m, 4H),
3H), 2.89 (s, 1H), 1.89 (m, 4H), 1.32 (t, J = 7.1
HH
1
3
1
Hz, 6H); C{ H} NMR (CDCl ) δ 138.0, 137.9,
3
128.4, 128.0, 127.8, 127.7, 78.6 (d, JCP = 16.3
3.88 (m, 1H), 3.74 (m, 1H), 3.51 (m, 2H), 3.33
(s, 3H), 2.87 (s, br, 1H), 1.28 (t, J = 7.1 Hz,
6
Hz), 137.9, 128.6, 128.0, 120.1 (d, JCP = 186.9
Hz), 82.1 (d, JCP = 21.5 Hz), 73.7, 72.3, 70.3,
Hz), 73.4, 72.6, 71.2, 71.1, 61.5 (d, J = 6.4 Hz),
CP
23.3 (d, JCP = 4.5 Hz), 21.5 (d, J = 142.0 Hz),
HH
CP
13
1
31
1
H); C{ H} NMR (CDCl ) δ 148.5 (d, J = 5.2
16.5 (d, JCP = 6.0 Hz); P{ H} NMR (CDCl ) δ
3
CP
3
+
32.3; HRMS (FAB, MNa ) calcd For
+
C H O PNa : 459.1912, Found 459.1906.
23
33
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
2.1 (d, J = 4.8 Hz), 58.1, 16.5 (d, JCP = 6.3
CP
1
(±) Diethyl (3R,4S)-(3,5-bis(benzyloxy)-4-
hydroxypentylphosphonate (13d). Vinyl
3
1
Hz); P{ H} NMR (CDCl ) δ 17.4; HRMS
(FAB, MNa ) calcd For C H O PNa :
3
+
+
1
7
27
6
phosphonate (9d) (0.1 g 0.230 mmol) was
reduced to give (13d) in quantitative yield. IR
3
81.1442, Found 381.1436.
General procedure for hydrogenation of the
vinyl phosphonate. The vinyl phosphonate (9 or
5) was dissolved in MeOH (3 mL/mmol)
containing pyridine (0.05-0.5 eq.) and then moist
% Pd/C (10% by weight of vinyl phosphonate)
-1
1
(neat) 3246 (br), 2980, 2905, 1201 cm ; H
NMR (CDCl ) δ 7.36-7.29 (m, 10H), 4.53 (m,
3
1
4H), 4.10 (m, 4H), 3.84 (m, 1H), 3.59 (m, 3H),
2.58 (d, JHH = 4.6 Hz, 1H), 1.85 (m, 4H), 1.31 (t,
1
3
1
5
JHH = 7.1 Hz, 6H); C{ H} NMR (CDCl ) δ
3
was added. The flask was flushed with argon,
followed by H (balloon pressure). H pressure
was maintained while the reaction mixture was
rapidly stirred. The reaction progress was
followed by
complete reduction (4-6h), the reaction mixture
138.2, 138.0, 128.5, 128.5, 128.0, 127.9, 127.9,
78.6 (d, JCP = 15.7 Hz), 73.5, 72.2, 71.2, 71.0,
61.7 (d, JCP = 6.4 Hz), 22.6 (d, JCP = 4.4 Hz),
2
2
20.6 (d, J = 142.0 Hz), 16.6 (d, JCP = 6.0 Hz);
CP
3
1
31
1
P NMR spectroscopy. After
P{ H} NMR (CDCl ) δ 33.0; HRMS (FAB,
MH ) calcd For C H O P: 437.2093, Found
3
+
2
3
34
6
®
was filtered through Celite , rinsed with MeOH,
437.2075.
±) Diethyl (3S,4S)-5-(benzyloxy)-4-hydroxy-
-(pentadecyloxy)pentylphosphonate (16a).
and evaporated under reduced pressure to give
the saturated phosphonate (13 or 16), typically in
quantitative yields.
(
3
Vinyl phosphonate (15a) (0.329 g, 0.593 mmol)
was reduced to give (16a) in quantitative yield.
(±)
Diethyl
(3S,4S)-3-(benzyloxy)-4-
(13b). Vinyl
-1
1
hydroxynonylphosphonate
IR (neat) 3370 (br), 2920, 2850, 1228 cm ; H
phosphonate (9b) (0.339 g, 0.88 mmol) was
reduced to give (13b) in quantitative yield. IR
NMR (CDCl ) δ 7.36-7.31 (m, 5H), 4.55 (s, 2H),
3
4.09 (m, 4H), 3.76 (s, 1H), 3.52 (m, 3H), 3.42
(m, 2H), 2.50 (s, br, 1H), 1.84 (m, 4H), 1.52 (m,
(
(
neat) 3388 (br), 2928, 2858, 1223 cm-1 1H NMR
CDCl ) δ 7.36-7.26 (m, 5H), 4.56 (q, JHH = 11.3
2H), 1.29 (m, 30H), 0.88 (t, J = 6.9 Hz, 3H);
3
HH
1
3
1
Hz, 2H), 4.06 (m, 4H), 3.53 (m, 1H), 3.35 (m,
1H), 1.95 (m, 1H), 1.77 (m, 3H), 1.44 (m, 3H),
C{ H} NMR (CDCl ) δ 138.0, 128.6, 127.9,
3
127.9, 78.9 (d, JCP = 16.7 Hz), 73.6, 71.4, 71.2,
71.1, 61.7 (d, JCP = 6.4 Hz), 32.1, 30.2, 29.8,
29.8, 29.6, 29.5, 26.3, 23.4 (d, JCP = 4.5 Hz ,
22.8, 21.5 (d, J = 142.3 Hz), 16.6 (d, J = 6.0
1
.27 (m, 11H), 0.87 (t, J = 6.9 Hz, 3H);
HH
13
1
C{ H} NMR (CDCl ) δ 138.1, 128.5, 127. 9,
3
1
2
2
27.8, δ 81.5 (d, JCP = 15.6 Hz), 72.4 (d, JCP
=
CP
C-
3
1
1
5.2 Hz), 61.5 (d, J = 6.4 Hz), 33.1, 31.9, 25.5,
Hz), 14.3; P{ H} NMR (CDCl ) δ 32.4; HRMS
(FAB, MH ) calcd For C H O P: 557.3971,
CP
3
+
2.9 (d, J = 4.5 Hz), 22.6, 21.10 (d, J = 141.3
CP
CP
1
31 58
6
3
1
Hz), 16.4 (d, JCP = 5.9 Hz), 14.1; P{ H} NMR
Found 557.3991.
+
(CDCl ) δ 32.4. HRMS (FAB, MH ) calcd For
3
(±) Diethyl (3S,4S)-5-(benzyloxy)-4-hydroxy-
3-(4-methoxybenzyloxy)pentylphosphonate
(16b). Vinyl phosphonate (15b) (0.380 g 1.17
mmol) was reduced to give (16b) in quantitative
yield. IR (neat) 3346 (br), 2978, 2905, 1609,
C H O P: 387.2300, Found 387.2315
2
0
36
5
(±) Diethyl (3S,4S)-3,5-bis(benzyloxy)-4-
hydroxypentylphosphonate (13c). Vinyl
phosphonate (9c) (0.450 g, 1.17 mmol) was
reduced to give (13c) in quantitative yield. IR
-1
1
1241 cm ; H NMR (CDCl ) δ 7.30-7.24 (m,
3
-1
1
(neat) 34373 (br), 2979, 2903, 1228 cm ; H
5H), 7.20-7.17 (m, 2H), 6.84-6.80 (m, 2H), 4.46
(m, 4H), 4.02 (m, 5H), 3.76 (m, 4H), 3.49 (m,
NMR (300 MHz, CDCl ) δ 7.35 (m, 10H), 4.57
3
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3
H), 2.74 (s, 1H), 1.83 (m, 4H), 1.26 (m, 6H);
extracted with EtOAc (three times). The combine
organic layer was washed with saturated
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
C{ H} NMR (CDCl ) δ 159.3, 137.9, 130.2,
3
1
7
29.7, 128.5, 128.4, 127.9, 127.8, 127.8, 113.8,
8.2 (d, JCP = 16.5 Hz), 73.5, 72.3, 71.3, 71.1,
NaHCO , brine and dried over anhydrous
3
Na SO . The solution was concentrated under
2 4
61.6, 61.5, 55.2, 23.3 (d, JCP = 4.6 Hz), 21.5 (d,
JCP = 142.0 Hz), 16.5 (d, JCP = 6.0 Hz); P{ H}
NMR (CDCl ) δ 32.3; HRMS (FAB, MNa )
calcd For C H O PNa : 489.2018 Found
reduced pressure and the pure phostone (14 or
17) was isolated by column chromatography
3
1
1
+
(SiO 60-80% EtOAc in hexanes).
3
2
+
2
4
35
7
(±) (5S)-(benzyloxy)-2-ethoxy-6-pentyl-1,2-
oxaphosphinane 2-oxide (14b). Phosphonate
(13b) (0.319 g, 0.83 mmol) was reacted as above
to give phostone (14b) (0.204 g, 73%) which was
4
89.1999.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(±)
Diethyl
(3S,4S)-5-(benzyloxy)-3-
(cyclohexylmethoxy)-4-
hydroxypentylphosphonate
phosphonate (15c) (0.325 g 0.737 mmol) was
reduced to give (16c) in quantitative yield. IR
o
(16c).
Vinyl
recrystallized from hexane. m.p. 82.6 C; IR
-1
1
(neat) 2924, 2855, 1243 cm ; H NMR (CDCl )
3
δ 7.34-7.26 (m, 5H), 4.53 (q, JHH = 12.0 Hz, 2H),
4.11 (m, 3H), 3.39 (m, 1H), 2.39 (m, 1H), 1.89
(m, 5H), 1.49 (m, 2H), 1.33 (t, JHH = 7.0, 3H),
-1
1
(neat) 3378 (br), 2919, 2850, 1227 cm ; H
NMR (CDCl ) δ 7.38-7.29 (m, 5H), 4.55 (s, 2H),
4.07 (m, 4H), 3.75 (m, 1H), 3.51 (m, 2H), 3.30
3
1
3
1
1.24 ( m, 4H), 0.86 (t, JHH = 6.7 Hz, 3H); C{ H}
(m, 3H), 1.79 (m, 11H), 1.26 (m, 9H), 0.90 (m,
NMR (CDCl ) δ 137.9, 128.5, 127.9, 127.8, δ
3
13
1
2
1
7
2
H); C{ H} NMR (CDCl ) δ 137.8, 128.3,
27.7, 127.7, 78.7 (d, JCP = 16.5 Hz), 73.3, 71.4,
1.1, 61.5 (d, JCP = 6.4 Hz), 38.3, 30.0 (d, JCP
83.2 (d, JCP = 7.9 Hz), 72.0 (d, JCP = 5.3 Hz),
70.8, 60.6 (d, JCP = 6.5 Hz), 32.3 (d, JCP = 7.4
3
=
Hz), 31.6, 25.1, 24.8 (d, J = 7.8 Hz), 22.7, 17.4
CP
.1 Hz), 26.4, 25.7, 23.2 (d, JCP = 4.5 Hz), 22.2,
( d, J = 128.3 Hz), 16.6 (d, J = 5.6 Hz), 14.2;
CP
CP
3
1
1
21.3 (d, J = 148.4 Hz), 16.4 (d, JCP = 5.9 Hz);
P{ H} NMR (CDCl ) δ 23.3; HRMS (FAB,
CP
3
3
1
1
+
+
P{ H} NMR (CDCl ) δ 33.0; HRMS (FAB,
MNa ) calcd For C H O PNa : 363.1701,
18 29 4
3
+
+
MNa ) calcd For C H O PNa : 465.2381,
Found 465.2390.
Found 363.1704.
2
3
39
6
(±)
(5S)-5-(benzyloxy)-6-
(±) Diethyl (3S,4S)-5-(benzyloxy)-4-hydroxy-
((benzyloxy)methyl)-2-ethoxy-1,2-
3-methoxypentylphosphonate (16d). Vinyl
phosphonate (15d) (0.3 g 0.837 mmol) was
reduced to give (16d) in quantitative yield. IR
oxaphosphinane 2-oxide (14c). Phosphonate
(13c) (0.430 g, 0.985 mmol) was reacted as
above to give phostone (14c) as pale-yellow
product (0.243 g, 61%). IR (neat) 2976, 2924,
-1
1
(neat) 3385 (br), 2977, 2864, 1226 cm ; H
-1 1
NMR (300 MHz, CDCl ) δ 7.37-1.25 (m, 5H),
4
2866, 1242 cm ; H NMR (CDCl ) δ 7.36-7.26
3
3
.53 (s, 2H), 4.06 (m, 4H), 3.76 (m, 1H), 3.51
(m, 10H), 4.50 (m, 4H), 4.37 (m, 1H), 4.13 (m,
2H), 3.79 (m 1H), 3.68 (m, 2H), 2.38 (m, 1H),
(m, 2H), 3.38 (s, 3H), 3.39 (m, 1H), 1.83 (m,
1
3
1
4H), 1.29 (t, JHH = 7.0 Hz, 6H); C{ H} NMR
(CDCl ) δ 138.0, 128.6, 127.9, 80.6 (d, J
1
5
2.09 (m, 1H),1.89 (m, 2H), 1.35 (t, J = 7.0 Hz,
HH
1
3
1
=
3H); C{ H} NMR (CDCl ) δ 137.8, 137.7,
3
CP
3
6.4 Hz), 73.6, 71.3, 71.2, 61.7 (d, J = 6.5 Hz),
128.3, 127.7, 127.6, 127.5, 81.0 (d, J = 7.3 Hz),
CP
CP
8.6, 22.9 (d, JCP = 4.6 Hz), 21.3 (d, J = 142.4
73.1, 70.3, 69.9 (d, JCP = 5.6 Hz), 69.3 (d, JCP
=
CP
1
3
1
Hz), 16.6 (d, JCP = 6.0 Hz); δ P{ H} NMR
9.5 Hz), 60.8 (d, J = 6.5 Hz), 24.6 (d, J = 8.0
CP
CP
+
(CDCl ) δ 32.3; HRMS (FAB, MNa ) calcd For
Hz), 17.2 (d, J = 120.6 Hz), 16.3 (d, JCP = 2.8
CP
3
+
31
1
C H O PNa : 383.1599, Found 383.1595.
Hz); P{ H} NMR (CDCl ) δ 23.2; HRMS
17 29
6
3
+
(FAB, MH ) calcd For C H O P: 391.1674,
General procedure for cyclization. To a
stirred suspension of sodium hydride (1.1 eq) in
dry THF (2 mL/mmol), was added a solution of
saturated phosphonate (13 or 16) in THF
dropwise at ice bath temperature. The reaction
mixture was allowed to warm to room
temperature and stirring was continued until the
reaction was complete (2-3 h). The reaction was
21 28
5
Found 391.1680
(±)
(5R)-5-(benzyloxy)-6-
((benzyloxy)methyl)-2-ethoxy-1,2-
oxaphosphinane 2-oxide (14d). Phosphonate
(13d) (0.492 g, 1.13 mmol) was reacted as above
to give phostone (14d) as yellow oil (0.333 g,
-1
1
75%). IR (neat) 2925, 2866, 1240 cm ; H NMR
quenched by the addition of 10% NH Cl and then
(CDCl ) δ 7.27-7.14 (m, 10H), 4.48 (m, 4H),
4
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4
.10 (m, 3H), 3.66 (m, 3H), 2.25 (m, 1H), 1.82
(16c) (0.219 g, 0.494 mmol) was reacted as
above to give phostone (17c) as pale-yellow oil
(0.105 g, 53%). IR (neat) 2919, 2849, 1721, 1245
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
(m, 3H), 1.26 (t, JHH = 7.1 Hz, 3H); C{ H}
NMR (CDCl ) δ 138.1, 137.6, 128.5 , 128.3,
3
-1 1
1
27.9, 127.8, 127.6, 127.64, 81.5 (d, JCP = 7.5
cm ; H NMR (CDCl ) δ 7.42-7.31 (m, 5H), 4.55
3
Hz), 73.6, 72.7 (d, JCP = 5.0 Hz), 72.1, 69.5 (d,
J = 7.0 Hz), 61.2 (d, J = 6.5 Hz), 26.0 (d, J
(q, JHH = 11.7 Hz, 2H), 4.37 (m, 1H), 4.17 (m,
2H), 3.85 (m, 1H), 3.68 (m, 1 H), 3.52 (d, JHH
=
CP
CP
CP
CP
=
=
7.7 Hz), 20.3 ( d, J = 128.8 Hz), 16.4 ( d, J
5.7 Hz); P{ H} NMR (CDCl ) δ 23.6; HRMS
1.5 Hz, 1H), 3.22 (m, 2H), 2.42 (m, 1H), 2.07 (m,
CP
31
1
1H), 1.86 (m, 7H), 1.55 (m 1H), 1.37 (t, J = 7.0
3
HH
+
13
1
(FAB, MNa ) calcd For C H O PNa: 413.1493,
Hz, 3H), 1.22 (m, 3H), 0.96 ( 2H); C{ H} NMR
2
1
27
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Found 413.1515.
(CDCl ) δ 138.0, 128.6, 127.9, 81.3 (d, J = 7.2
3
CP
Hz), 75.2, 73.8, 70.7 (d, JCP = 5.6 Hz), 69.5 (d,
JCP = 9.6 Hz), 60.9 (d, JCP = 6.5 Hz), 38.3, 30.2
(±) (5S)-6-((benzyloxy)methyl)-2-ethoxy-5-
pentadecyloxy)-1,2-oxaphosphinane 2-oxide
17a). Phosphonate (16a) (0.25 g, 0.45mmol)
(
(
(d, JCP = 1.2 Hz), 26.7, 26.0, 24.5 (d, JCP = 8.0
Hz), 17.3 (d, J = 128.5 Hz), 16.6 (d, JCP = 5.8
was reacted as above to give phostone (17a) as
pale-yellow oil (0.154 g, 67%). IR (neat) 2919,
2
(m, 5H), 4.55 (q, JHH = 11.7 Hz, 2H), 4.33 (m,
1
3
CP
1
3
1
Hz), 16.4; P{ H} NMR (CDCl ) δ 23.5; HRMS
3
+
-1
1
(FAB, MNa ) calcd For C H O PNa: 419.1963
850, 1248 cm ; H NMR (CDCl ) δ 7.39-7.28
21 33
5
3
Found 419.1974
H), 4.13 (m, 2H), 3.81 (m, 2H), 3.64 (m, 1H)
.53 (m, 2H), 3.25 (m, 1H), 2.37 (m, 1H), 2.05
(±) 6-((benzyloxy)methyl)-2-ethoxy-5-
methoxy-1,2-oxaphosphinane 2-oxide (17d).
Phosphonate (16d) (0.216 g, 0.603 mmol) was
reacted as above to give phostone (17d) as pale-
yellow oil (0.121 g, 64%). IR (neat) 2927, 2867,
(m, 1H), 1.78 (m, 2H), 1.52 (m, 2H), 1.29 (m,
1
3
1
2
7H), 0.88 (t, JHH = 6.9 Hz, 3H); C{ H} NMR
(CDCl ) δ 138.0, 128.5, 127.9, 127.8, 81.2 (d, JCP
3
-1 1
= 7.3 Hz), 77.6, 77.2, 76.8, 73.7, 70.7, 70.6, 69.4
(d, JCP = 6.8 Hz), 60.9 (d, JCP = 6.4 Hz), 32.0,
2
1244 cm ; H NMR (300 MHz, CDCl ) δ 7.35-
3
7.24 (m, 5H), 4.55 (q, JHH = 11.8 Hz, 2H), 4.31
(m, 1H), 4.10 (m, 2H), 3.69 (m, 2H), 3.41 (m,
1H), 3.20 (s, 3H), 2.39 (m, 1H), 1.96 (m, 1H),
9.9, 29.8, 29.8, 29.7, 29.6, 29.5, 26.4, 24.7 (d,
JCP = 7.9 Hz), 22.8, ), 17.2 (d, JCP = 128.4 Hz),
3
1
1
13
1
1
6.4 (d, JCP = 5.7 Hz), 14.2; P{ H} NMR
1.76 (m, 2H), 1.31 (t, JHH = 7.0 Hz, 3H); C{ H}
+
(CDCl ) δ 23.4; HRMS (FAB, MH ) calcd For
NMR (CDCl ) δ 138.0, 128.5, 127.7, 127.8, 81.0
3
3
C H O P: 511.3552, Found 511.3527.
(d, JCP = 7.3 Hz), 77.7, 77.2, 76.8, 73.6, 72.2 (d,
29 52
5
J = 5.6 Hz), 69.4 (d, J = 9.4 Hz), 60.9 (d, J
(
±)
(benzyloxy)methyl)-2-ethoxy-1,2-
oxaphosphinane 2-oxide (17b). Phosphonate
16b) (0.191 g, 0.40 mmol) was reacted as above
to give phostone (17b) as pale-yellow oil (0.109
(5S)-5-(benzyloxy)-6-
CP
CP
CP
= 6.5 Hz), 56.8, 23.8 (d, JCP = 8.0 Hz), 17.1 (d,
(
31
1
JCP = 128.2 Hz), 16.5 (d, J
CP
= 5.7 Hz); P{ H}
+
NMR (CDCl ) δ 23.1; HRMS (FAB, MNa )
calcd For C H O PNa : 337.1180 Found
(
3
+
15 23
5
-1
337.1182.
g, 65%). IR (neat) 2928, 2865, 1609, 1297 cm ;
1
H NMR (CDCl ) δ 7.38-1.27 (m, 5H), 7.21 (d,
3
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
JHH = 8.5 Hz, 2H), 6.85 (d JHH = 8.5 Hz, 2H),
4
1
1
.50 (m, 5H), 4.13 (m, 2H), 3.79 (s, 3H), 3.75 (m
H), 3.64 (m, 2H), 2.23 (m, 2H), 1.80 (m, 2H),
.34 (t, JHH = 7.0 Hz, 3H); C{ H} NMR
1
3
1
1H, 13C and 31P NMR spectra for all compounds, X-ray
crystallographic data (PDF)
(CDCl ) δ 159.3, 137.9, 129.8, 129.4, 128.48,
3
127.8, 127.8, 113.8, δ 81.2 (d, JCP = 7.3 Hz),
3.6, 70.5, 69.5, 69.4 (d, JCP = 2.1 Hz), 60.9 (d,
JCP = 6.5 Hz), 55.3, 17.3 (d, J = 128.25 Hz),
7
AUTHOR INFORMATION
CP
Corresponding Author
3
1
1
1
6.5 (d, JCP = 6.0 Hz); P{ H} NMR (CDCl ) δ
3
* E-mail: cspill@umsl.edu.
+
2
3.2; HRMS (FAB, MNa ) calcd For
+
Author Contributions
C H O PNa : 443.1599, Found 443.1577.
22 29
6
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
(
±)
cyclohexylmethoxy)-2-ethoxy-1,2-
oxaphosphinane 2-oxide (17c). Phosphonate
6-((benzyloxy)methyl)-5-
(
Notes
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Page 10 of 11
The authors declare no competing financial interest.
Synthesis of Phostone-Phostone Dimers. J. Org. Chem. 2013,
78, 6858-6867.
5) (a) Stoianova, D. S.; Hanson, P. R. A Ring-Closing
Metathesis Strategy to Phosphonosugars. Org. Lett. 2001, 3,
3285-3288. (b) Zhang, H.; Tsukuhara, R.; Tigyi, G.;
Prestwich, G. D. Synthesis of Cyclic Phosphonate Analogues
of (Lyso)phosphatidic Axid Using Ring-Closing Metathesis
Reaction. J. Org. Chem. 2006, 71, 6061-6066.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
ACKNOWLEDGMENT
The project described was supported by a grant
from the National Science Foundation (CHE-
1
465196). We are also grateful to the National
Science Foundation for grants to purchase the
NMR spectrometers (CHE-9974801 and
0959360), the x-ray diffractometer (CHE-
(6) (a) Kiiru, K.M.; Spilling C.D. Comparison of Substrates
for the Formation of Phosphono-Subituted pi-allyls Abstract,
th
4
8 Midwest Regional of the American Chemical Society,
2013 NRWM-168. (b) Kiiru, K.M.; Spilling C.D. Comparison
of Substrates for the Formation of Phosphono-Subituted pi-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
9
420497) and the mass spectrometer (CHE-
708640) used in this project. We thank Mahesh
th
allyls Abstract, 47 Midwest Regional of the American
Chemical Society, 2012 NRWM-407.
(7) (a) Roy, S.; Spilling, C. D. Synthesis of the C (18)- C (34)
Paudel, Mercy Kiiru and Andrew Kamadulski for
some preliminary studies.
Fragment of Amphidinolide C and the C (18)– C (29)
Fragment of Amphidinolide F. Org. Lett. 2010, 12, 5326-
5
329. (b) Dutta, S.; Malla, R. K.; Bandyopadhyay, S.;
REFERENCES
Dupureur, C. M.; Spilling, C. D. Synthesis and Kinetic
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Spilling, C. D. Stereoselective Synthesis of Cyclic Ethers via
the Palladium-Catalyzed Intramolecular Addition of Alcohols
to Phosphono Allylic Carbonates. Org. Lett. 2009, 11, 3124-
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