Rearrangement of lithiated S-alkyl O,O-dialkyl thiophosphates: Scope and stereochemistry of the thiophosphate-mercaptophosphonate rearrangement

Article abstract of DOI:10.1039/c1ob05246b

S-Alkyl O,O-dialkyl thiophosphates are prepared by alkylation of the triethylammonium salt of O,O-diisopropyl thiophosphoric acid. S-Benzyl thiophosphate was metallated at temperatures of ≥-45 °C by trityllithium and LiTMP (lithium 2,2,6,6-tetramethylpiperidide) and S-alkyl thiophosphates only by LiTMP to give dipole-stabilised carbanions which rearrange to α-mercaptophosphonates in yields of up to 45%. Metallation occurs with a high primary kinetic isotope effect (k_H/k_D up to ≈50). When the lithium (R)-N-isopropyl-1-phenylethylamide was used to induce the isomerisation of S-pentyl thiophosphate an α-mercaptophosphonate with an ee of 22% was isolated. (R)-S-[1-D₁]hexyl O,O-diisopropyl thiophosphate was rearranged to a dextrorotary α-mercapto-[1-D ₁]hexylphosphonate, whose (R)-configuration was determined by chemical correlation. The thiophosphate-mercaptophosphonate rearrangement proceeds with retention of configuration. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05246b

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PAPER
Rearrangement of lithiated S-alkyl O,O-dialkyl thiophosphates: Scope and
stereochemistry of the thiophosphate–mercaptophosphonate rearrangement†
Violeta Philippitsch and Friedrich Hammerschmidt*
Received 23rd February 2011, Accepted 12th April 2011
DOI: 10.1039/c1ob05246b
S-Alkyl O,O-dialkyl thiophosphates are prepared by alkylation of the triethylammonium salt of
O,O-diisopropyl thiophosphoric acid. S-Benzyl thiophosphate was metallated at temperatures of
≥-45 ◦C by trityllithium and LiTMP (lithium 2,2,6,6-tetramethylpiperidide) and S-alkyl
thiophosphates only by LiTMP to give dipole-stabilised carbanions which rearrange to
a-mercaptophosphonates in yields of up to 45%. Metallation occurs with a high primary kinetic
isotope effect (kH/kD up to ª50). When the lithium (R)-N-isopropyl-1-phenylethylamide was used to
induce the isomerisation of S-pentyl thiophosphate an a-mercaptophosphonate with an ee of 22% was
isolated. (R)-S-[1-D1]hexyl O,O-diisopropyl thiophosphate was rearranged to a dextrorotary
a-mercapto-[1-D1]hexylphosphonate, whose (R)-configuration was determined by chemical correlation.
The thiophosphate–mercaptophosphonate rearrangement proceeds with retention of configuration.
(Scheme 1). The intermediate a-hetero-atom substituted lithium
complexed carbanions 2a,b are configurationally stable and re-
arrange with retention of configuration to phosphonates 3a,b
giving 4a,b on workup. The intermediates 2a,b represent a
unique class of dipole-stabilised and very likely short-lived car-
banions. The reverse processes are also known. To be more
precise, the 1,2-migration of the dialkoxyphosphinyl group
from the hetero-atom to the carbon atom should be termed
phosphate–a-hydroxyphosphonate rearrangement for X = O and
phosphoramidate–a-aminophosphonate rearrangement for X =
NR. It was tempting to extend this rearrangement to S-alkyl
thiophosphates 1c. Surprisingly, only rare examples related to this
rearrangement have been reported in the literature. Kawashima
et al. reported that S-methyl phosphinothioates 5 furnished
methylthiomethylphosphinoxides 6, along with other products,
on metallation with lithium dialkylamides and alkylation with
methyl iodide.10 Masson et al. found that the phosphorylated
mercaptophosphonate 7, which can be deprotonated easily by
nBuLi, gives mercaptodiphosphonate 8 (Scheme 2).11 The third
example of Scheme 2 refers to the a-mercaptophosphonate–
thiophosphate rearrangement.12
Introduction
Some zinc-containing metallo-enzymes are strongly inhibited by
derivatives of mercaptocarboxylic acids, whereby the sulfur atom
is an extra ligand for the metal cofactor. Renin,1 angiotensin-
converting enzyme2 (ACE), neutral endopeptidase2 and matrix
metalloproteinases3 are typical representatives of this enzyme
class. We reasoned that a-mercaptophosphonic acids as struc-
tural analogues of a-mercaptocarboxylic acids could produce
even stronger inhibitors. a-Mercaptophosphonic acid derivatives
can be transformed into a-phosphonosulfonic acids acting as
squalene synthase inhibitors.4 Generally applicable methods for
the preparation of racemic and especially chiral, nonracemic a-
mercaptophosphonates and derivatives thereof are missing despite
various approaches to them.5 Recently, we have shown that chiral,
nonracemic a-hydroxyphosphonates can be manipulated to afford
a-mercaptophosphonates of the same ee as the starting material.6
Results and discussion
In the course of our ongoing program7 directed at the use
of the phosphate–phosphonate and phosphonate–phosphate re-
arrangements, we decided to test it also for the synthesis
of a-mercaptophosphonates. Briefly, this 1,2-migration of the
phosphinyl group follows metallation of phosphates 1a and
phosphoramidates8 1b with strong bases at low temperatures
Institute of Organic Chemistry, University of Vienna, Wa¨hringerstrasse
38, A-1090, Wien, Austria. E-mail: friedrich.hammerschmidt@univie.ac.at;
Fax: +43 (1) 4277-9521; Tel: +43 (1) 4277-52105
† Electronic supplementary information (ESI) available: Full characteri-
sation data for 18d and H, 13C and 31P NMR spectra of 18f. See DOI:
10.1039/c1ob05246b
1
Scheme 1 1,2-Migration of dialkoxyphosphinyl groups.
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Scheme 4 Rearrangement of S-alkyl thiophosphates.
Scheme 2 Examples for the thiophosphate–a-mercaptophosphonate
rearrangement and the reverse process.
amine and nBuLi in dry diethyl ether or THF at 0 ◦C was stirred
at -78 ◦C for 25 h and at -50 ◦C for 2 h, quenched with AcOH and
worked up, the a-mercaptophosphonate ( )-18b was obtained in
31% and 36% yield, respectively. Some starting material (25%)
was recovered as well. The experiment was repeated similarly,
except that the reaction was performed at -45 ◦C for 7 h. The
starting thiophosphate was virtually consumed (TLC) and the a-
mercaptophosphonate was obtained in 45% yield. As the yields
in THF were higher than in diethyl ether, THF was also used
as solvent for the rearrangement of thiophosphates 15a,c–e. The
yield for a-mercaptophosphonate ( )-18f was merely 3%. The very
low yield was attributed to an E2-elimination of isobutene from
a tbutyl group, which is more favorable than the elimination of
propene from an isopropyl group, as an alternative to metallation.
Although the yields were low and need improvement, these
experiments demonstrate the feasibility of this rearrangement
for the preparation of a-mercaptophosphonates. Normally, the
crude products contained a few percentages (1H NMR) of
dialkyl phosphite which was probably formed by a base-catalysed
decomposition of a-mercaptophosphonates. This retro-Abramov
reaction yielded an unstable thioaldehyde.15 One exploratory ex-
periment was performed with the lithium amide derived from (R)-
N-isopropyl-1-phenylethylamine16 and thiophosphate 15b under
standard conditions (THF, -45 ◦C, 4 h). The corresponding chiral,
nonracemic a-mercaptophosphonate (+)-18b {[a]2D0 +3.82 (c 2.2
in acetone)} was obtained in 35% yield. Its enantiomeric excess
of 22% was determined by 31P NMR spectroscopy using (R)-
(+)-t-butylphenylmonothiophosphinic acid (2 equiv.) as chiral
solvating agent in C6D6.17 Two signals were observed at 26.08
and 26.01 ppm, the former being the more intense. Although
the absolute configuration of the major enantiomer cannot be
given, the method can be extended to the preparation of chiral,
nonracemic a-mercaptophosphonates.
To study the metallation of thiophophates, we first prepared
the S-alkyl thiophosphates 15 by a modified literature proce-
dure (Scheme 3).13 Reaction of phosphites 13 with sulfur and
triethylamine at 50 ◦C for 2 h or at reflux for 30 min furnished
triethylammonium salts 14, which were alkylated by primary alkyl
halides or p-tosylates to give S-alkyl phosphates 15 as distillable
oils. The isopropyl group was the preferred protecting group as it
is quite stable under basic conditions and shields the phosphorus
atom against nucleophilic attack. When S-pentyl thiophosphate
15b was treated in analogy to the rearrangement of phosphates
with 2 equiv. of sBuLi/TMEDA in dry diethyl ether or THF
at -78 ◦C for 2 h, the starting material was consumed, but
surprisingly no a-mercaptophosphonate could be detected by 1H
NMR spectroscopy in the crude product after workup (Scheme 4).
To determine the configurational stability of the dialkyloxy-
phosphinylthio-substituted carbanion 16d and the stereochem-
istry of the rearrangement, deuterated (R)-S-benzyl thiophosphate
(R)-[1-D1]15d was prepared (Scheme 5).
Benzyl alcohol (S)-[1-D1]19 was prepared by horse-liver alcohol
dehydrogenase catalysed reduction18 of [formyl-D1]benzaldehyde19
obtained by Swern oxidation of dideuterated benzyl alcohol. The
homochiral alcohol was transformed into the alcoholate and p-
tosylated. The crude product was treated with the thiophosphate
14a. Rearrangement of (R)-[1-D1]15d under the standard condi-
tions (LiTMP, -45 ◦C, THF, 6 h, quenching with AcOH) furnished
a-mercaptophosphonate 18d, which was both nondeuterated (by
Scheme 3 Preparation of S-alkyl thiophosphates.
Probably, sBu- did not metallate the S-alkyl thiophosphate, but
attacked it at the phosphorus atom to substitute C5H11S-. Simi-
larly, thiophosphate 15f with an even more shielded phosphorus
atom than 15b did not give the desired a-mercaptophosphonate.
Therefore, a sterically hindered, non nucleophilic base was
mandatory and we decided to test LiTMP (lithium 2,2,6,6-
tetramethylpiperidide, pKa 37.3).14 When one equiv. was used
to induce the rearrangement of a thiophosphate, virtually no
a-mercaptophosphonate was formed. However, when a mixture
of thiophosphate 15b and 2 equiv. of LiTMP prepared from the
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Scheme 6 Preparation and rearrangement of S-pentyl thiophosphate
( )-[1-D1]15b.
are also high (up to 100 at -78 ◦C). With this information
in hand, we could address the configurational stability of
the intermediate a-thioalkyl carbanions of the thiophosphate–
mercaptophosphonate rearrangement using a chirally deuterated
substrate.
Scheme 5 Preparation and rearrangement of deuterated S-benzyl thio-
phosphate (R)-[1-D1]15d.
Rearrangement of (R)-S-[1-D1]hexyl thiophosphate and
determination of the configuration of (+)-a-mercaptohexyl-
phosphonate formed
1H NMR spectroscopy, 400 MHz) and racemic proven by 31P
NMR spectroscopy with the chiral solvating agent given above.
The signal of the two diastereomeric complexes at 22.06 and
22.11 ppm were of equal intensity. We propose the following
mechanism for that result. Metallation of (R)-[1-D1]15d with
preferential removal of the proton over the deuteron induced a re-
arrangement producing mainly mercaptide [1-D]17d of unknown
configuration, which is dedeuterated by LiTMP. The dianion
20 is configurationally labile and is protonated by AcOH when
quenched. It is likely that metallation of [1-D]17d is as easy as
that of (R)-[1-D1]15d. Nevertheless, we tested also trityllithium20
with a pKa of 32.921 as base (Et2O, 2 equiv. of base, -78 ◦C, 16 h,
or THF, -45 ◦C, 2 h; AcOH for quenching), which is weaker
than LiTMP. Only nondeuterated, a-mercaptophosphonates ( )-
18d (20%, 25%) were isolated along with some starting material
(14%) when diethyl ether was used as solvent. The complementary
experiment using nondeuterated thiophosphate 15d, but AcOD
for quenching, furnished deuterated (D > 95% by 1H NMR)
a-mercaptophosphonate ( )-[1-D]18d in 25% yield. Surprising
results were obtained when only 1.1 equiv. of trityllithium were
used as base for the rearrangement of ( )-[1-D1]15d in diethyl
ether at -78 ◦C and -45 ◦C for 16 h and 8 h, respectively. The
yields of the a-mercaptophosphonates ( )-[1-D]18d were 19%
(77% D) and 10% (34% D) and of the starting materials 30%
and 24%, respectively. The rearrangement of ( )-[1-D1]15d with
2 equiv. of trityllithium in diethyl ether at -45 ◦C for 1 h gave
only nondeuterated ( )-18d (24%) along with a small amount of
starting material (3%).
Homochiral (S)-[1-D1]hexanol (D ≥ 99%, ee ≥ 98%),9 accessed
again by horse-liver alcohol dehydrogenase catalysed reduction18
of [1-D1]hexanal, was converted via tosylate to the levorotary
(R)-[1-D1]hexyl thiophosphate (R)-[1-D1]15c (Scheme 7). The
rearrangement was performed at -45 and 0 ◦C yielding dextro-
rotary a-mercapto-[1-D]hexylphosphonates in yields of 44 and
31%, respectively. The deuterium content decreased from 93%
for the experiment performed at -45 ◦C to 88% for the one at
0 ◦C, corresponding to significant primary kinetic isotope effects
kH/kD of 13.3 and 7.3, respectively. The enantiomeric excesses
could be determined by using the above given CSA and NMR
(1H and 31P, C6D6) spectroscopy and were inversely proportional
to the deuterium contents. Assuming that the intermediate a-
thiohexyllithiums are configurationally stable for their short life-
time and the rearrangement is stereospecific, the labelled and
unlabelled species will give a-mercaptophosphonates of opposite
configuration. Consequently, the product from the experiment
performed at -45 ◦C will be a mixture with an enantiomeric
ratio of 93 : 7, giving an ee of 86%, in perfect agreement with
experiment (86%). The enantiomeric ratio for the experiment
performed at 0 ◦C was 88 : 12, corresponding to a calculated ee
of 76%, still in agreement within experimental error with the
one found (79%). Therefore, the supposedly (very) short-lived
To see whether the second metallation is limited to the ben-
zylic position, deuterated pentyl thiophosphate ( )-[1-D1]15b was
prepared as well and isomerised (Scheme 6).
When trityllithium was used as base (2 equiv./Et2O/-78 ◦C/
19 h, AcOH for quenching), the starting material was consumed,
but no a-mercaptophosphonate was formed. With LiTMP (2
◦
equiv./THF/-45 C/6 h/AcOH) as base for the rearrangement
the desired, deuterated a-mercaptophosphonate was isolated
(44%). The extent of deuteration (98%) is significant and indicates
a high primary kinetic isotope effect (kH/kD ª 50). The isotope
effects for the metallation of phosphates9 and phosphoramidates8
Scheme
thiophosphate.
7
Preparation and rearrangement of (R)-S-[1-D1]hexyl
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a-thioalkyllithiums are microscopically configurationally stable
up to 0 ◦C from generation by deprotonation to the rearrangement.
If the intermediate a-thiohexyllithiums were configurationally
labile, the enantiomeric ratio could reach a value of 50 : 50 at worst
for completely labile species. To unravel the stereochemistry of
this stereospecific 1,2-migration of the phosphinyl group, whether
it follows a retentive or an invertive course, the configuration of
the dextrorotary a-mercaptohexylphosphonate (1-D]18c has to be
determined.
temperature was increased every 10 min by 10 ◦C and a spectrum
was recorded. At -40 ◦C the reaction rate was very slow, but
increased from -30 ◦C on to +10 ◦C rapidly. The resonances of the
thiophosphate and lithiated a-mercaptophosphonate were 36.79
and 27.84 ppm, respectively. After 10 min at +10 ◦C the signal
for the starting material had disappeared and only the signal of
the rearranged product was visible. It was a clean transformation,
although the yield of isolated a-mercaptophosphonate ( )-18e was
35% on a preparative scale.
The starting materials for the chemical correlation were the
known chiral, nonracemic a-hydroxyphosphonates (R)-(-)- and
(S)-(+)-25 (Scheme 8). They were obtained by acetylating22 ( )-
2523 and performing a lipase AP 6 catalysed kinetic resolution24
(conversion 45%) of the ester in a biphasic phosphate buffer
system. The isolated a-hydroxyphosphonate (S)-(+)-25 had an
ee of 88% and the recovered ester furnished upon transesterifi-
cation (R)-(-)-25 of 53% ee. The further transformations of the
latter into the desired mercaptophosphonate (R)-(+)-18c were
straight forward in analogy to a literature procedure.6 First,
the alcohol was esterified with p-nitrobenzenesulfonyl chloride
to furnish p-nitrobenzenesulfonate (nosylate) (R)-(-)-26 in 94%,
which was converted to the thiocyanate (R)-(+)-27 with inversion
of configuration (as sulfur has a higher atomic weight than
phosphorus, the descriptor does not change) in 84% yield.
Reduction delivered a-mercaptophosphonate (R)-(+)-18c in 83%
yield with an ee of 53% (CSA, NMR), the same as that of
the starting a-hydroxyphosphonate. Similarly, the enantiomeric
a-hydroxyphosphonate (S)-(+)-25 of 88% ee was converted to
the a-mercaptophosphonate (S)-(-)-18c with an ee of again
88%. These two complementary reaction sequences show that
the dextrorotary [1-D]18c formed from (R)-[1-D1]15c (Scheme 7)
must also have (R)-configuration. Therefore, the thiophosphate–
mercaptophosphonate rearrangement follows a retentive course.
Conclusions
In summary, we have achieved the metallation of easily accessible
S-alkyl O,O-dialkyl thiophosphates and their rearrangement to
a-mercaptophosphonates. Furthermore, we have unraveled some
mechanistic details of this transformation and found that the iso-
merisation proceeds with retention of configuration. Although the
intermediate secondary a-(dialkoxyphosphinylthio)alkyllithiums
are very likely short-lived, they are microscopically configu-
rationally stable. This finding enlarges the small number of
configurationally stable (microscopically or macroscopically) a-
thioalkyllithiums.25
Experimental
General experimental
1H, 13C (J modulated) and 31P NMR spectra were recorded in
CDCl3 (unless otherwise given) at 300 K on a Bruker AM 400
WB (400.13, 100.61 and 161.98 MHz) and a Bruker DPX 250
(250.1 and 62.9 MHz). Chemical shifts were referenced to residual
CHCl3 (dH 7.24) and CDCl3 (dC 77.00) and external H3PO4 (85%).
Chemical shifts are given in d in ppm and J values in Hz. IR
spectra were run on a Perkin–Elmer 1600 FT-IR spectrometer;
samples were measured as films (normally obtained by applying
part of the NMR sample and evaporation of CDCl3) on a silicon
disc.26 Optical rotations were measured at 20 ◦C on a Perkin–
Elmer 351 polarimeter in a 1 dm cell. TLC was carried out on
Merck plates, silica gel 60 F254 (0.25 mm thick) on glass. Flash
(column) chromatography was performed with Merck silica gel 60
(230–400 mesh). Spots were visualised by UV and/or dipping
the plate into a solution of (NH4)6Mo7O24·4H2O (23.0 g) and
of Ce(SO4)2·4H2O (1.0 g) in 10% aqueous H2SO4 (500 mL),
followed by heating with a heat gun. CH3CN and pyridine were
dried by refluxing over P2O5 and powdered CaH2, respectively,
˚
then distillation and storage over molecular sieves (4 A). CH2Cl2
was dried by passing through aluminum oxide 90 active, neutral
(0.063–0.200 mm, activity I) and stored over molecular sieves
˚
˚
(3 A). Hexane was dried by storage over molecular sieves (4 A).
Et2O was refluxed over LiAlH4, THF over potassium and distilled
prior to use. Melting points were determined on a Reichert
Thermovar instrument and were uncorrected.
Preparation13 of S-alkyl O,O-diisopropyl thiophosphates (general
procedure A). A mixture of (iPrO)2P(O)H (1.66 g, 10 mol), sulfur
(0.32 g, 10 mmol) and Et3N (1.21 g, 1.67 mL, 12 mmol) in iPrOH
(25 mL) was stirred for 2 h at 50 ◦C or 30 min at reflux. The mixture
was cooled, the halogenoalkane (12 mmol) or alkyl p-tosylate
(12 mmol) was added and stirring and heating at 50 ◦C were
continued for 3 h (refluxing for 1 h for tosylates and 6 h for 15e).
Scheme 8 Conversion of enantiomeric a-hydroxyhexylphosphonates 25
to the corresponding mercaptophosphonates 18c.
Finally, the rearrangement of 15e with LiTMP in THF w◦as stud-
ied qualitatively by 31P NMR spectroscopy starting at -60 C. The
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The cold solution was concentrated in vacuo. Water (10 mL) was
added to the residue and the mixture was extracted with CH2Cl2
(2 ¥ 10 mL). The combined organic phases were washed with H2O
(2 ¥ 10 mL), dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by flash chromatography, followed by bulb
to bulb distillation if appropriate.
Preparation of ( )-O,O-diisopropyl S-[1-D1]pentyl thiophosphate
{( )-[1-D1]15b}
( )-[1-D1]Pentanol {( )-[1-D1]22}. A solution of pentanal
(1.62 g, 18.8 mmol) in dry Et2O (15 mL) was added dropwise
to a stirred suspension of LiAlD4 (0.395 g, 9.4 mmol, 98% atom%
D) in dry Et2O (25 mL). The mixture was refluxed for 30 min,
cooled and cautiously quenched with water. Hydrochloric acid (4
M) was added until precipitate had dissolved. The organic layer
was separated and the aqueous phase was extracted with Et2O
(2 ¥ 15 mL). The combined organic layers were washed with H2O
and a saturated aqueous solution of NaHCO3, dried (MgSO4)
and cautiously concentrated in vacuo. Bulb to bulb distillation
Thiophosphate–mercaptophosphonate rearrangement using
lithium 2,2,6,6-tetramethylpiperidide (LiTMP) as base (general
procedure B). A solution of nBuLi (1.9 mL, 3 mmol, 1.6 M
in hexane) was added dropwise to a stirred solution of 2,2,6,6-
tetramethylpiperidine (0.42 g, 0.5 mL, 3 mmol) in dry THF (4 mL)
at 0 ◦C under argon. After 30 min, the solution was cooled to
-45 ◦C and the S-alkyl thiophosphate (1.5 mmol) dissolved in dry
THF (2 mL) was added. Stirring was continued for some h (see
individual compounds) at that temperature kept constant within
2.5 ◦C. The reaction was quenched with a solution of AcOH
(0.5 mL) in dry THF (1 mL). The cooling bath was removed and
the reaction mixture was concentrated when it had warmed up to
room temperature. The residue was taken up in CH2Cl2 (25 mL)
and washed with HCl (10 mL, 2 N) and a saturated aqueous
solution of NaHCO3, dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash chromatography.
◦
(80–90 C/80 mm) of the residue furnished deuterated pentanol
( )-[1-D1]22 (1.59 g, 95%) as a colourless liquid; dH (400.1 MHz,
CDCl3) 0.87 (t, J 6.8, 3H), 1.29 (m, 4H), 1.52 (br.q, J 6.7, 2H),
1.76 (br.s, 1H); dC (100.6 MHz, CDCl3) 14.0, 22.4, 27.9, 32.3, 62.5
(t, J 21.8).
( )-O,O-Diisopropyl S-[1-D1]pentyl thiophosphate {( )-[1-
D1]15b}. To a solution of ( )-[1-D1]pentanol (0.89 g, 10 mmol) in
dry THF (20 mL), stirred at -78 ◦C under argon, nBuLi (7.5 mL,
12 mmol, 1.6 M solution in hexane) was added, followed by a
solution of p-tosyl chloride (2.28 g, 12 mmol) in dry THF (8 mL)
after 5 min. The reaction mixture was allowed to warm up in the
cooling bath to -10 ◦C within 5 h. Water and CH2Cl2 were added.
The organic phase was separated and aqueous one was extracted
with CH2Cl2. The combined organic layers were washed twice with
H2O, dried (Na2SO4) and concentrated in vacuo. The crude tosylate
was dissolved in iPrOH (10 mL) and used for the alkylation of
the triethylammonium salt of O,O-diisopropyl thiophosphoric
acid prepared from 10 mmol of (iPrO)2P(O)H according to
general procedure A. Flash chromatography (hexane-EtOAc 4 : 1)
of the crude thiophosphate and bulb to bulb distillation (90–
95 ◦C/0.7 mm) furnished thiophosphate ( )-[1-D1]15b (1.98 g,
70%) as a colourless liquid; the spectroscopic data were identical
to those of 15b except for dH (400.1 MHz) 1.68 (quint, J 6.6, 2H),
2.81 (dtt, J 1.6, 6.6, 12.1, 1H, SCHD) and dC (100.6 MHz) 30.3
(d, J 6.1), 30.7 (dt, J 3.8, 22.2, SCHD).
Thiophosphate–mercaptophosphonate rearrangement using
triphenylmethyllithium as base (general procedure C). A solution
of nBuLi (1.95 mL, 3.1 mmol, 1.6 M) was added dropwise to a
stirred solution of Ph3CH (0.73 g, 3 mmol) in dry THF (4 mL)
at ambient temperature under argon. After 30 min, the solution
◦
was cooled to -45 C and the S-alkyl thiophosphate (1.5 mmol)
dissolved in dry THF (2 mL) was added. The further procedure is
as given in general procedure B.
O,O-Diisopropyl S-methyl thiophosphate (15a). It was pre-
pared according to general procedure A using MeI (2 h at 25 ◦C,
1 h at 50 ◦C). Flash chromatography (hexane-EtOAc 3 : 1, Rf 0.48)
of the crude product and bulb to bulb distillation (83–90 ◦C/6 mm)
furnished thiophosphate 15a (1.52 g, 72%) as a colourless liquid;
dH (250.1 MHz) 1.37 (d, J 6.2, 6H), 1.39 (d, J 6.2, 6H), 2.29 (d,
J 14.9, 3H), 4.77 (dsept, J 6.2, 9.1, 2H); dC (62.9 MHz) 12.6 (d,
J 4.6), 23.5 (d, J 5.5, 2C), 23.8 (d, J 4.1, 2C), 72.5 (d, J 6.0, 2C);
dP (162 MHz) 27.1; IR (Si): nmax 2980, 2935, 1387, 1376, 1254,
982 cm-1; C7H17O3PS (212.25): calcd. C 39.61, H 8.07; found: C
39.53, H 8.13.
S-Hexyl O,O-diisopropyl thiophosphate (15c). Hexanol
(1.02 g, 10 mmol) was transformed according to the procedure
used for the preparation of ( )-[1-D1]15b into thiophosphate
15c. Flash chromatography (hexane-EtOAc 4 : 1, Rf 0.33) of the
crude product and bulb to bulb distillation (95 ◦C/0.3 mm)
furnished thiophosphate 15c (2.07 g, 73%) as a colourless liquid;
dH (400.1 MHz) 0.86 (t, J 7.0, 3H), 1.31 (m, 6H), 1.32 (d, J 6.3,
6H), 1.34 (d, J 6.3, 6H), 1.66 (quint, J ª 7.3, 2H), 2.80 (dt, J 7.3,
13.4, 2H), 4.71 (dsept, J 6.3, 9.1, 2H); dC (100.6 MHz) 14.0, 22.5,
23.6 (d, J 6.1, 2C), 23.9 (d, J 4.0, 2C), 28.3, 30.7 (d, J 6.1), 31.1
(d, J 4.6), 31.2, 72.4 (d, J 6.9, 2C); dP (162 MHz) 27.0; IR (Si):
nmax 2979, 2931, 2859, 1386, 1375, 1256, 978 cm-1; C12H27O3PS
(282.38): calcd. C 51.04, H 9.64; found: C 51.07, H 9.40.
O,O-Diisopropyl S-pentyl thiophosphate (15b). It was pre-
pared from (iPrO)2P(O)H (20 mmol) and 1-bromopentane (3.62 g,
24 mmol) according to general procedure A. Flash chromatogra-
phy (hexane-EtOAc 3 : 1, Rf 0.42) of the crude product and bulb
to bulb distillation (80 ◦C/0.2 mm) furnished thiophosphate 15b
(4.10 g, 77%) as a colourless liquid; dH (400.1 MHz) 0.90 (t, J
7.0, 3H), 1.35 (d, J 6.5, 6H), 1.36 (m, 4H), 1.37 (d, J 6.5, 6H),
1.70 (quint, J 7.5, 2H), 2.83 (dt, J 7.5, 13.6, 2H), 4.74 (dsept, J
6.5, 9.0, 2H); dC (100.6 MHz) 13.8, 22.1, 23.6 (d, J 5.4, 2C), 23.9
(d, J 3.8, 2C), 30.4 (d, J 6.1), 30.7, 31.0 (d, J 3.8), 72.4 (d, J 6.1,
2C); dP (162 MHz) 27.1; IR (Si): nmax 2979, 2933, 2874, 1468, 1386,
1375, 1256, 978 cm-1; C11H25O3PS (268.32): calcd. C 49.23, H 9.39;
found: C 49.20, H 9.46.
(R)-(-)-[1-D1]-S-Hexyl O,O-diisopropyl thiophosphate {(R)-[1-
D1]15c}. (S)-(+)-[1-D1]Hexanol {0.106 g, 1.03 mmol; [a]2D0 +0.34
(c 20.05, acetone), D ≥ 99% , ee ≥ 98} was converted to (R)-[1-
D1]15c {0.20 g, 69%; [a]D20 -0.22 (c 10.72, CH2Cl2)} according
to the procedure used for the preparation of the unlabelled
thiophosphate 15c, except that the tosylate was reacted with the
salt of the O,O-diisopropyl thiophosphoric acid for 2.5 h at 80 ◦C
5224 | Org. Biomol. Chem., 2011, 9, 5220–5227
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and that the thiophosphate was not bulb to bulb distilled. The
spectroscopic data were identical to those of 15c except for dH
(400.1 MHz) 1.65 (q, J 7.3, 2H), 2.79 (m, 1H) and dC (100.6 MHz)
30.5 (d, J 6.1), 30.8 (dt, J 3.8, 22.2, SCHD).
C12H27O3PS (282.38): calcd. C 51.04, H 9.64; found: C 51.04, H
9.40.
Diisopropyl mercaptomethylphosphonate (18a). Thiophos-
phate 15a (0.32 g, 1.5 mmol) was rearranged according to general
procedure B (reaction time: 6 h). Flash chromatography (hexane-
EtOAc 2 : 1, Rf 0.23 for 1 : 1) of the crude product furnished
mercaptophosphonate 18a (0.10 g, 30%) as a colourless liquid
and starting material (0.08 g, 25%); dH (250.1 MHz) 1.36 (d, J 6.2,
6H), 1.37 (d, J 6.2, 6H), 1.83 (dt, J 8.2, 9.4, 1H), 2.65 (dd, J 8.2,
13.3, 2H), 4.77 (dsept, J 6.2, 7.5, 2H); dC (100.6 MHz) 18.6 (d, J
152.2), 23.9 (d, J 5.4, 2C), 24.0 (d, J 3.2, 2C), 71.4 (d, J 6.9, 2C);
dP (162 MHz) 21.5; IR (Si): nmax 2979, 1386, 1252, 1107, 986 cm-1;
C7H17O3PS (212.25): calcd. C 39.61, H 8.07; found: C 39.49, H
8.11.
S-Benzyl O,O-diisopropyl thiophosphate (15d). It was pre-
pared according to general procedure A using benzyl bromide
(2.05 g, 12 mmol) as alkylating agent. Flash chromatography
(hexane-EtOAc 4 : 1, Rf 0.48 for 3 : 1) of the crude product and bulb
to bulb distillation (100 ◦C/0.15 mm) furnished thiophosphate 15d
(2.41 g, 84%) as a colourless liquid; dH (250.1 MHz) 1.31 (d, J 6.2,
6H), 1.35 (d, J 6.2, 6H), 4.08 (d, J 13.0, 2H), 4.71 (dsept, J 6.2,
8.9, 2H), 7.34 (m, 5H); dC (62.9 MHz) 23.5 (d, J 6.0, 2C), 23.8
(d, J 4.1, 2C), 35.2 (d, J 3.7), 72.6 (d, J 6.4, 2C), 127.5, 128.6
(2C), 128.9 (2C), 137.5 (J 6.0); dP NMR (162 MHz) 25.3; IR (Si):
nmax 2980, 2935, 1455, 1386, 1375, 1257, 979 cm-1; C13H21O3PS
(288.35):calcd. C 54.15, H 7.34; found: C 54.17, H 7.45.
( )-Diisopropyl 1-mercaptopentylphosphonate {( )-18b}, (+)-
18b and ( )-[1-D1]18b}. Thiophosphate 15b (0.40 g, 1.5 mmol)
was rearranged according to general procedure B (reaction time:
7 h). Flash chromatography (hexane-EtOAc 4 : 1, Rf 0.19) of
the crude product furnished thiol ( )-18b (0.18 g, 45%) as a
colourless liquid and starting material (0.10 g, 25%). Similarly,
thiophosphate ( )-[1-D1]15b was rearranged (6 h) to ( )-[1-D1]18b
(0.18 g, 44%). The rearrangement of thiophosphate 15b according
to general procedure B (reaction time: 6 h) replacing TMPH
by (R)-PhCH(CH3)NHiPr [a]D20 +61.8 (neat) furnished (+)-18b
{(0.14 g, 35%, [a]2D0 +3.82 (c 2.2, CH2Cl2), ee 22%} and starting
material (0.16 g, 39%). dH (400.1 MHz) 0.85 (t, J 7.0, 3H), 1.27
(d, J 6.5, 9H), 1.28 (d, J 6.5, 3H), 1.28 (m, 3H), 1.45 (m, 1H), 1.58
(m, 1H), 1.79 (t, J 8.5, 1H), 1.95 (m, 1H), 2.67 (dddd, J 3.5, 8.5,
10.0, 15.1, 1H), 4.70 (m, 2H); dC (100.6 MHz) 13.8, 22.1, 23.87 (d,
J 5.4), 23.89 (d, J 5.4), 24.1 (d, J 6.9), 24.3 (d, J 6.9), 29.3 (d, J
12.2), 31.7 (d, J 1.5), 34.8 (d, J 150.7), 71.2 (d, J 7.6), 71.4 (d, J
6.9); dP (162 MHz) 25.9; IR (Si): nmax 2978, 2934, 2873, 1467, 1385,
1375, 1247, 1107, 1010, 986 cm-1; C11H25O3PS (268.35): calcd. C
49.23, H 9.39; found: C 49.48, H 9.36.
(R)-(-)- and ( )-S-[1-D1]benzyl O,O-diisopropyl thiophos-
phate {(R)-(-)- and ( )-[1-D1]15d}. (S)-(+)-[1-D1]Benzyl alcohol
[0.763 g, 7 mmol, [a]2D0 +1.59 (neat)] was transformed by the
procedure used for the preparation of ( )-[1-D1]15b into the thio-
phosphate. Flash chromatography of the crude product and bulb
to bulb distillation (100–107 ◦C/0.2 mm) furnished thiophosphate
(R)-[1-D1]15d (1.178 g, 58%) as a colourless liquid; [a]2D0 -0.61 (c
20
365
23.45, acetone), [a] -2.53 (c 23.45, acetone); the spectroscopic
data were identical to those of 15d except for dH (400.1 MHz) 4.06
(dt, J 1.4, 12.9, 1H) and dC (100.6 MHz) 34.8 (dt, J 3.8, 22.2) and
137.4 (d, J 6.1). ( )-[1-D1]15d was prepared similarly from racemic
[1-D1]benzyl alcohol in 63% yield.
O,O-Diisopropyl S-2-methylpropyl thiophosphate (15e). It was
prepared according to general procedure A using isobutyl bromide
(1.64 g, 12 mmol) as alkylating agent (refluxing for 6 h). Flash
chromatography (hexane-EtOAc 4 : 1, Rf 0.63 for 3 : 1) of the
crude product and bulb to bulb distillation (68 ◦C/0.2 mm)
furnished thiophosphate 15e (2.17 g, 85%) as a colourless liquid;
dH (250.1 MHz, CDCl3) 1.03 (d, J 6.6, 6H), 1.37 (d, J 6.2, 6H),
1.39 (d, J 6.2, 6H), 1.94 (non, J 6.6, 1H), 2.76 (dd, J 6.6, 12.6, 2H),
4.76 (dsept, J 6.2, 9.1, 2H); dC (62.9 MHz, CDCl3) 21.7 (2C), 23.6
(d, J 5.5, 2C), 23.9 (d, J 4.1, 2C), 29.5 (d, J 6.4), 39.5 (d, J 3.7),
72.4 (d, J 6.4, 2C); dP NMR (162 MHz, CDCl3) 27.2; IR (Si): nmax
2979, 2933, 1386, 1375, 979 cm-1; C10H23O3PS (254.33): calcd. C
47.23, H 9.12; found: C 47.35, H 8.91.
( )-Diisopropyl 1-mercaptohexylphosphonate [( )-18c]. Thio-
phosphate 15c (0.42 g, 1.5 mmol) was rearranged according to
general procedure B (reaction time: 2 h). Flash chromatography
(hexane-EtOAc 5 : 1, Rf 0.12 for 4 : 1) of the crude product fur-
nished ( )-18c (0.16 g, 38%) as a colourless liquid; dH (400.1 MHz)
0.83 (t, J 6.8, 3H), 1.27 (d, J 6.1, 9H), 1.28 (d, J 6.1, 3H), 1.29
(m, 3H), 1.46 (m, 2H), 1.60 (m, 2H), 1.80 (t, J 8.6, 1H), 1.94
(m, 1H), 2.67 (dddd, J 3.5, 8.3, 10.2, 18.7, 1H), 4.70 (m, 2H); dC
(100.6 MHz) 14.0, 22.4, 23.8 (d, J 2.3), 23.9 (d, J 2.3), 24.1 (d,
J 3.1), 24.2 (d, J 3.1), 26.8 (d, J 12.2) 31.1, 32.0 (d, J 1.5) 34.8
(d, J 150.7), 71.2 (d, J 7.7), 71.4 (d, J 6.9); dP (162 MHz) 25.9;
IR (Si): nmax 2978, 2958, 2932, 1385, 1375, 1241, 1010, 988 cm-1;
C12H27O3PS (282.38): calcd. C 51.04, H 9.64; found: C 51.25, H
9.46.
O,O-Di-t-butyl S-2-methylpropyl thiophosphate (15f). A mix-
ture of (tBuO)2P(O)H (1.94 g, 10 mmol), sulfur (0.32 g, 10 mmol)
and Et3N (1.11 g, 1.53 mL, 11 mmol) in t-BuOH (25 mL) was
stirred for 19 h at 80 ◦C. The mixture was cooled, isobutyl bromide
(1.64 g, 12 mmol) was added and stirring and refluxing were
continued for 7 h. The cold solution was concentrated in vacuo.
Water (10 mL) was added to the residue and the mixture was
extracted with CH2Cl2 (3 ¥ 10 mL). The combined organic phases
were washed with H2O (10 mL), dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by flash chromatography
(hexane-EtOAc 5 : 1, Rf 0.57 for 3 : 1) to furnish thiophosphate 15f
(1.25 g, 44%) as a colourless liquid. dH (250.1 MHz) 1.02 (d, J 6.7,
6H), 1.55 (s, 9H), 1.56 (s, 9H), 1.95 (sept, J 6.7, 1H), 2.74 (dd,
J 6.7 13.5, 2H); dC (100.6 MHz) 21.7 (2C), 29.2 (d, J 6.1), 30.2
(d, J 4.6, 6C), 39.9 (d, J 4.6), 84.1 (d, J 9.2, 2C); dP (162 MHz)
19.2; IR (Si): nmax 2979, 2931, 1370, 1263, 1170, 1038, 976 cm-1;
(+)-Diisopropyl 1-mercapto-[1-D1]hexylphosphonate {(+)-[1-
D1]18c}. Deuterated S-hexyl thiophosphate (R)-[1-D1]15c
(0.81 mmol, 0.23 g) was isomerised by general procedure B
(LiTMP, -45 ◦C/6 h). Flash chromatography (hexane-EtOAc 5 : 1,
Rf 0.41 for 3 : 1) gave recovered thiophosphate (0.008 g, 4%) and
(+)-[1-D1]18c (0.10 g, 44%) as a colourless oil; [a]2D0 +21.32 (c
1.60, CH2Cl2), ee 86% (determined by using 2 equiv. of (S)-(+)-t-
1
butylphenylmonothiophosphinic acid as CSA, C6D6, H and 31P
NMR); D 93%, kH/kD 13.3.
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Similarly, an experiment performed at 0 ◦C for 2 h yielded (+)-
[1-D1]18c (0.042 g, 31%); [a]2D0 +16.04 (c 2.08, CH2Cl2); ee 79%; D
88%; kH/kD 7.3.
The spectroscopic data of (+)-[1-D1]18c were identical to those
of ( )-18c except for dH (400.1 MHz) 1.82 (d, J 8.8, 1H) and 2.57
(missing signal) and dC (100.6 MHz) 31.9 (d, J 2.3) and 34.3 (dt,
J 22.2, 150.7, CDP).
and a-hydroxyphosphonate (S)-(+)-25 {0.62 g (21%), [a]2D0 +12.50
(c 1.48, acetone), ee 88% by 31P NMR24 of (R)-Mosher ester}.
The a-acetoxyphosphonate (1.58 g, 5.44 mmol) was transesterified
(mixture of 54.4 mL of MeOH, 2.72 mL of H2O and 10.88 mL of
Et3N, ambient). Concentration of the reaction mixture after 48 h
in vacuo and flash chromatography (hexane-EtOAc 1 : 1, Rf 0.40
for 1 : 2) gave (R)-(-)-25 {1.28 g, 88%, [a]2D0 -6.89 (c 1.93, acetone),
ee 53% by 31P NMR of (R)-Mosher ester}.
( )-Diisopropyl 1-mercapto-1-phenylmethylphosphonate [( )-
18d]. Thiophosphate 15d (0.43 g, 1.5 mmol) was rearranged
according to general procedure B (reaction time: 7.5 h). Flash
chromatography (hexane-EtOAc 4 : 1, Rf 0.26 for 3 : 1) of the crude
product furnished ( )-18d6 (0.15 g, 35%) as a colourless liquid and
starting material (0.075 g, 17%).
15d (0.43 g, 1.5 mmol) was also rearranged according to general
procedure C (reaction time: 16 h/-78 ◦C). Flash chromatography
(hexane-EtOAc 5 : 1) of the crude product furnished ( )-18d
(0.14 g, 32%) and starting material (0.020 g, 5%). The analytical
data of ( )-18d (see ESI†) agreed with those of the literature.6
(R)-(-)- and (S)-(+)-O,O-diisopropyl 1-(p-nitrobenzene-sulfony-
loxy)hexylphosphonate [(R)-(-)- and (S)-(+)-26]. Freshly distilled
Et3N (0.75 mL) and 0.06 g DMAP dissolved in dry CH2Cl2 (1 mL)
were added to a solution of a-hydroxyphosphonate (R)-(-)-25
(0.53 g, 2 mmol) in dry CH2Cl2 (7 mL) under argon.6 Then
p-nitrobenzenesulfonyl chloride (0.53 g, 2.4 mmol, 1.2 equiv.,
dissolved in 2 mL of dry CH2Cl2) was added at 0 ◦C. After stirring
for 22 h at room temperature, H2O (5 mL) and concentrated HCl
(0.8 mL) were added. The organic phase was separated and the
aqueous one extracted with CH2Cl2 (3 ¥ 10 mL). The combined
organic layers were washed with a saturated aqueous solution of
NaHCO3, dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash chromatography (hexane-EtOAc 3 : 1, Rf 0.50
for 2 : 1) to give nosylate (R)-(-)-26 (0.85 g, 94%) as a colourless
oil; [a]2D0 -4.29 (c 1.17, acetone).
( )-Diisopropyl 1-mercapto-2-methylpropylphosphonate [( )-
18e]. Thiophosphate 15e (0.38 g, 1.5 mmol) was rearranged
according to general procedure B (reaction time: 7 h). Flash
chromatography (hexane-EtOAc 6 : 1, Rf 0.15 for 4 : 1) of the crude
product furnished ( )-18e (0.16 g, 42%) as a colourless liquid and
starting material (0.05 g, 13%); dH (400.1 MHz) 0.94 (d, J 6.5, 3H),
0.98 (dd, J 1.5, 6.5, 3H), 1.27 (d, J 6.3, 9H), 1.28 (d, J 6.0, 3H),
1.63 (t, J 10.6, 1H), 2.32 (ddsept, J 3.0, 6.5, 8.3, 1H), 2.66 (ddd, J
3.0, 10.6, 19.5, 1H), 4.70 (m, 2H); dC (100.6 MHz) 17.4 (d, J 2.3),
21.5 (d, J 15.3), 23.8 (d, J 5.4), 23.9 (d, J 5.4), 24.1 (d, J 3.1), 24.3
(d, J 3.1), 28.6, 42.0 (d, J 147.6), 71.0 (d, J 7.6), 71.5 (d, J 7.6);
dP (162 MHz) 25.2; IR (Si): nmax 2978, 2933, 1386, 1374, 1247,
988 cm-1; C10H23O3PS (254.33): calcd. C 47.23, H 9.12; found: C
47.34, H 8.44.
Similarly, (S)-(+)-25 (0.53 g, 2 mmol) was converted to (S)-(+)-
26 (0.81 g, 90%); [a]D20 +10.76 (c 1.05, acetone).
dH (400.1 MHz) 0.80 (t, J 6.8, 3H), 1.18 (d, J 6.6, 3H), 1.20
(d, J 6.6, 3H), 1.21 (m, 4H), 1.24 (d, J 6.6, 6H), 1.39 (m, 2H),
1.80 (m, 2H), 4.57 (dsept, J 6.6, 7.1, 1 H), 4.64 (dsept, J 6.6, 7.1,
1H), 4.82 (dt, J 4.6, 9.0, 1H), 8.21 (AA¢BB¢-system, J 8.9, 4H); dC
(100.6 MHz) 13.9, 22.3, 23.7 (d, J 5.4), 23.9 (d, J 5.4), 24.00 (d, J
4.6), 24.04 (d, J 3.8), 25.1 (d, J 9.9), 30.4, 31.1, 72.1 (d, J 7.7), 72.2
(d, J 6.9), 78.6 (d, J 170.6), 124.1 (2C), 129.3 (2C), 142.9, 150.7; dP
(162 MHz) 16.3; IR (Si): nmax 2981, 2958, 2934, 1535, 1376, 1351,
1313, 1187, 993 cm-1; C18H30NO8PS (451.47): calcd. C 47.89, H
6.70, N 3.10; found: C 47.68, H 6.50, N 3.07.
( )-Di-t-butyl 1-mercapto-2-methylpropylphosphonate [( )-18f].
Thiophosphate 15f (0.42 g, 1.5 mmol) was rearranged according
to general procedure B (reaction time: 8 h). Flash chromatography
(hexane-EtOAc 6 : 1, Rf 0.13 for 4 : 1) of the crude product
furnished ( )-18f (0.010 g, 3%) as a colourless oil; dH (250.1 MHz)
1.03 (d, J 6.6, 3H), 1.08 (dd, J 1.5, 6.6, 3H), 1.54 (s, 9H), 1.55
(s, 9H), 1.69 (dd, J 9.4, 11.9, 1H), 2.41 (m, 1H), 2.67 (ddd, J 3.4,
9.4, 18.0, 1H); dC (100.6 MHz) 17.6 (d, J 3.1), 22.2 (d, J 14.5),
29.0, 29.7 (2C), 30.4 (d, J 3.8, 3C), 30.5 (d, J 3.8, 3C), 44.3 (d, J
149.9); dP (162 MHz) 18.4; IR (Si): nmax 2962, 2928, 1369, 1261,
1038, 1009, 983 cm-1.
(R)-(+)- and (S)-(-)-diisopropyl 1-thiocyanatohexylphosphonate
[(R)-(+)- and (S)-(-)-27]. A mixture of p-nitrobenzenesulfonate
(R)-(-)-26 (0.73 g, 1.62 mmol), KSCN (0.63 g, 6.48 mmol, 4
equiv.), 18-crown-6 (0.17 g) and dry CH3CN (15 mL) was refluxed
for 23 h under argon.6 After cooling and addition of water (10 mL),
the mixture was extracted with Et2O (3 ¥ 10 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. The
residue was flash chromatographed (hexane/EtOAc 2 : 1, Rf 0.65
for 1 : 1) to yield thiocyanate (R)-(+)-27 (0.42 g (84%) as an oil;
[a]2D0 +5.80 (c 2.47, acetone).
(R)-(-)- and (S)-(+)-diisopropyl 1-hydroxyhexylphosphonate
{(R)-(-)- and (S)-(+)-25}. Racemic phosphonate ( )-2523 (3.2 g,
12 mmol) was acetylated22 and purified by flash chromatography
(CH2Cl2-EtOAc 2 : 1, Rf 0.67) and bulb to bulb distillation (90–
Similarly, (S)-(+)-26 (0.73 g, 1.62 mmol) was converted to
◦
130 C/0.8 mbar) to give the acetate24 (3.58 g, 97%). The
thiocyanate (S)-(-)-27 (0.42 g, 84%); [a]2D0 -10.55 (c 2.82, acetone).
spectroscopic data were identical to those of the literature.24
Racemic a-acetoxyphosphonate (3.42 g, 11.1 mmol) were kineti-
cally resolved at room temperature (50 mL of 50 mM phosphate
buffer, 17 mL of hexane, 6 ml of t-BuOMe, 0.6 g of AP 6, pH
kept constant with an autotitrator using 0.5 M NaOH, conver-
sion: 45%). Flash chromatography (hexane-EtOAc 1 : 1, Rf 0.61
and 0.40 for a-acetoxyphosphonate and a-hydroxyphosphonate,
respectively, for 1 : 2) of the crude mixture gave recovered a-
acetoxyphosphonate {1.82 g (53%), [a]2D0 -16.01 (c 3.04, acetone)}
dH (400.1 MHz) 0.85 (t, J 6.8, 3H), 1.25 (m, 4H), 1.31 (d, J 6.3,
12H), 1.44 (m, 1H), 1.63 (m, 1H), 1,76 (m, 1H), 2.09 (m, 1H), 2.94
(ddd, J 4.2, 10.3, 15.4, 1H), 4.72 (m, 2H); dC (100.6 MHz) 13.9,
22.3, 23.8 (d, J 4.6), 23.9 (d, J 4.6), 24.0 (d, J 3.8), 24.0 (d, J 3.8),
26.6 (d, J 10.7), 29.5, 30.9, 43.4 (d, J 150.7), 72.4 (d, J 6.9), 72.5
(d, J 7.7), 110.3 (d, J 4.6); dP (162 MHz) 20.1; IR (Si): nmax 2980,
2959, 2933, 2873, 2155, 1467, 1387, 1376, 1256, 1105, 990 cm-1;
C13H26NO3PS (307.39): calcd. C 50.80, H 8.53, N 4.56; found: C
50.74, H 8.43, N 4.50.
5226 | Org. Biomol. Chem., 2011, 9, 5220–5227
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(R)-(+)- and (S)-(-)-diisopropyl 1-mercaptohexylphosphonate
[(R)-(+)- and (S)-(-)-18c]. A solution of thiocyanate (R)-(+)-27
(0.098 g, 0.32 mmol) and TMSCl (0.17 g, 1.59 mmol. 0.20 mL, 5
equiv.) in dry THF (4 mL) was added dropwise to a stirred solution
of LiBH4 (0.020 g, 1.59 mmol, 5 equiv.) in dry THF (4 mL) under
argon at room temperature.6 After◦stirring for 3 h, the mixture was
poured into HCl (10 mL, 2 M, 0 C) and extracted with EtOAc
(3 ¥ 10 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. The crude product was purified by
flash chromatography (hexane-EtOAc 3 : 1, Rf 0.75 for 1 : 1) to
yield a-mercaptophosphonate (R)-(+)-18c (0.075 g, 83%) as an
oil; [a]2D0 +16.23 (c 1.06, CH2Cl2), ee 54% (2 equiv. of CSA, C6D6,
1H and 31P NMR).
S. C. Taylor, S.-J. Lan, C. P. Ciosek Jr., T. W. Harrity, K. G. Jolibois,
L. K. Kunselman and D. A. Slusarchyk, J. Am. Chem. Soc., 1996, 118,
11668–11669.
5 For a review, see: M. Gulea and S. Masson, In Topics in Current
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to those of the racemate.
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Acknowledgements
This work was supported by grant no. P13017-CHE from Fonds
zur Fo¨rderung der Wissenschaftlichen Forschung. We are grateful
to S. Felsinger for recording part of the NMR spectra and Amano
Enzyme Limited (UK) for lipase AP 6.
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