The α-hydroxyphosphonate-phosphate rearrangement of a noncyclic substrate-some new observations

Article abstract of DOI:10.1039/c8ob00419f

Racemic ethyl hydrogen (1-hydroxy-2-methylsulfanyl-1-phenylethyl)phosphonate was resolved with (R)-1-phenylethylamine. The (R)-configuration of the (-)-enantiomer was determined by chemical correlation. Esterification of the (-)-enantiomer with a substituted diazomethane derived from 3-hydroxy-1,3,5(10)-estratrien-17-one delivered two epimeric phosphonates separated by HPLC. Methylation with methyl fluorosulfate at the sulfur atom and treatment with a strong base induced an α-hydroxyphosphonate-phosphate rearrangement with formation of dimethyl sulphide and two enantiomerically pure enol phosphates. Their oily nature interfered with a single crystal X-ray structure analysis to determine the stereochemistry at the phosphorus atom.

Full text of DOI:10.1039/c8ob00419f

Organic &
Biomolecular Chemistry
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The α-hydroxyphosphonate-phosphate
rearrangement of a noncyclic substrate –
some new observations†
Cite this: DOI: 10.1039/c8ob00419f
a
b
a
Susanne Prechelmacher, Kurt Mereiter
and Friedrich Hammerschmidt
*
Racemic ethyl hydrogen (1-hydroxy-2-methylsulfanyl-1-phenylethyl)phosphonate was resolved with
R)-1-phenylethylamine. The (R)-configuration of the (−)-enantiomer was determined by chemical corre-
lation. Esterification of the (−)-enantiomer with a substituted diazomethane derived from 3-hydroxy-1,3,5
10)-estratrien-17-one delivered two epimeric phosphonates separated by HPLC. Methylation with methyl
(
(
Received 16th February 2018,
Accepted 24th April 2018
fluorosulfate at the sulfur atom and treatment with a strong base induced an α-hydroxyphosphonate-
phosphate rearrangement with formation of dimethyl sulphide and two enantiomerically pure enol phos-
phates. Their oily nature interfered with a single crystal X-ray structure analysis to determine the stereo-
chemistry at the phosphorus atom.
DOI: 10.1039/c8ob00419f
rsc.li/obc
3
–5
phosphate)α)hydroxyphosphonate rearrangement. This
and
Introduction
6
,7
8
the versions for X = S and N have extensively been studied
When phosphoric acid derivatives (± ±)1 are treated with strong by Hammerschmidt’s group. The reverse process with many
9
–17
bases in stoichiometric amounts such as alkyl lithiums or examples
for X = O, the α)hydroxyphosphonate)phosphate
lithium amides at low temperatures, they are deprotonated to rearrangement, also termed [1,2])phospha)Brook rearrange)
1
7
give short)lived organolithiums (± ±)2 containing dipole)stabil) ment, has been found by Pudovik and Konovalova before the
1
ised carbanions (Scheme 1±. These undergo rearrangements phosphate–phosphonate rearrangement. This isomerisation is
via (± ±)3 to lithiated α)substituted phosphonates (± ±)4 and on normally catalysed by a variety of catalytic bases such as e.g.
work up to α)hydroxy), α)sulfanyl) and α)aminophosphonates NaOH, NaOEt and DBU. While the transformation of (± ±)1 into
2
3
(
± ±)5. This isomerisation discovered for X = O by Sturtz and (± ±)5 for X = O is feasible even for R = alkyl and R = H, the
2
2
3
Corbel is called phosphate–phosphonate or more specifically reverse process not. At least one of the substituents, R or R ,
should stabilise the developing negative charge on the carbon
atom in (± ±)3 upon cleavage of the C–P bond. An aromatic sub)
stituent suffices to stabilise the intermediate carbanion. The
driving force for the phosphate–phosphonate rearrangements
is the stronger Li–O than Li–C bond. The reverse process (O–H +
P–C → C–H + P–O± is dominated by the much higher P–O
than P–C bond energy. These isomerisations are related to the
1
8
Brook and retro)Brook rearrangements in silicon chemistry.
3
,5
The phosphate–phosphonate rearrangement for X = O,
7
8
11,15,16
S and N and the reverse process for X = O
follow a reten)
tive course at the respective carbon atoms. The stereochemistry
at the phosphorus atom upon the a)hydroxyphosphonate)
phosphate rearrangement follows a retentive course too,
Scheme 1 Phosphate–phosphonate rearrangements and reverse
processes.
proven only for α)hydroxyphosphonates with the phosphorus
a
11,16
Institute of Organic Chemistry, University of Vienna, Währingerstrasse 38,
atom as part of a six)membered ring.
It was found that dia)
A-1090 Vienna, Austria. E-mail: friedrich.hammerschmidt@univie.ac.at
stereomeric α)hydroxyphosphonates (R,SP±) and (R,R ±)7
P
b
Institute of Chemical Technologies and Analytics, Vienna University of Technology,
obtained by esterification of enantiomer (R±)6 and fractional
Getreidemarkt 9/164, A-1060 Vienna, Austria. E-mail: kurt.mereiter@tuwien.ac.at
1
0
crystallisation rearrange stereospecifically (Scheme 2±. Here
the phosphorus atom was not part of a ring system and the
developing negative charge on the α)carbon atom upon
†
Electronic supplementary information (ESI± available: Copies of NMR spectra.
Crystallographic data. CCDC 1818362. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c8ob00419f
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Scheme 4 Determination of absolute configuration of (−±-10.
Scheme 2 α-Hydroxyphosphonate-phosphate rearrangement of dia-
stereomeric α-hydroxyphosphonates 7 to enantiomerically pure enol
phosphates 8.
can be methylated and give the good leaving group dimethyl
sulfide. (R±)(+±)1)Phenylethylamine [(R±)11] was found to be a
better resolving agent for phosphonic acid (± ±)10 than brucine.
1
The crystals obtained from Et
2
O/CH
2
Cl
2
contained Et
2
O (by H
cleavage of the P–C bond eliminated a β)chloride, resulting in
enantiomerically pure enol phosphates (+±) and (−±)8. As they
were oils, their absolute configuration could not be deter)
mined by X)ray structure analysis and the stereochemistry at
the phosphorus atom had to remain unanswered.
1
NMR, salt/Et O, 2.6 : 1.0± and had a de of already 86% (by H
2
NMR, the two methylsulfanyl groups of the two diastereomers
resonate as two singlets at δ 1.77 and 1.79±. Two crystallisa)
tions from CHCl3 delivered crystals of hemihydrate (R±)11 ×
(
2
−±)10 × 0.5H O of de > 98% in 56% yield. When this salt was
dissolved in aqueous ammonia (25%± and extracted with
CH Cl , the (R±)1)phenylethylamine was recovered. The free
2
2
Results and discussion
acid (−±)10 was isolated from the aqueous phase by passage
through Dowex 50 W, H and removal of water under reduced
pressure.
To determine the absolute configuration of (−±)10, it was
transformed into the known α)hydroxyphosphonate (S±)(−±)12
+
The highly enantioselective synthesis of acyclic phosphate trie)
1
9,20
19
sters is difficult and challenging.
While Hall and Inch
built their syntheses on 5) and 6)membered cyclic phosphorus
compounds derived from (−±)ephedrine and D)glucose,
(
Scheme 4±. This was achieved by desulfurisation of the
2
0
Nakayama and Thompson applied (S±)proline derivatives. We
reasoned that the α)hydroxyphosphonate)phosphate rearrange)
ment of acyclic substrates with a stereogenic P)atom of known
configuration would give chiral, nonracemic phosphate triester
and alkenyl dialkyl ester. In order to assign the configuration
to the P)chiral product, the stereochemistry of the rearrange)
ment at the phosphorus atom has to be known. Here we start
another approach to unravel it.
22
respective potassium salt with aged RANEY)nickel, followed
by passage through Dowex 50 W, H to get the free acid.
Esterification with diazoethane furnished phosphonic acid
+
23
diethyl ester (−±)12 (in 22% overall yield±, which has (S±)con)
figuration based on the comparison of the specific optical
3
rotation with the literature value. When freshly prepared
3
RANEY)nickel was used, the CH S and OH groups were both
reductively removed. This experiment proved that phosphonic
At first, an enantiomerically pure alkyl hydrogen
α)hydroxyphosphonate was prepared and resolved (Scheme 3±.
3
acid (−±)10 has (R±)configuration. The change of the descrip)
tor is caused by the change in the priority for the substituents
according to the CIP rules [for (S±)(−±)12: P > Ph > CH ; for
3
3
Ethyl bis(trimethylsilyl± phosphite was added to ketone
2
1
9
to give a protected α)hydroxyphosphonate as intermediate,
that was hydrolysed to phosphonic acid monoethyl ester
± ±)10 upon aqueous workup and isolated in 59% yield. The
(
R±)(−±)10: P > CH SCH > Ph.
2
3
The next step was the esterification of phosphonic acid
(
(
R±)(−±)10 with a diazoalkane under mild conditions, which
phenyl ketone was selected, because the phenyl substituent
with its anion)stabilising effect will ascertain that the
α)hydroxyphosphonate)phosphate rearrangement at the end of
the sequence will be feasible. The methylsulfanyl substituent
should give (1± separable diastereomeric α)hydroxyphosphonates
and (2± at least one crystalline phosphate upon
α)hydoxyphosphonate)phosphate rearrangement. Previously, a
variety of bromoaryldiazomethanes were tested, but they deli)
vered inseparable mixtures of α)hydroxyphosphonates and oily
2
4
phosphates unfortunately. We reasoned that a steroid such
as the fairly easily available 1,3,5(10±)estratrien)3)yldiazo)
methane (19± could fulfil the outlined requirements
(
Scheme 5±. The centres of chirality of the steroid are too far
away from the phosphorus atom to have an influence on the
rearrangement. 1,3,5(10±)Estratrien)3)ol (13± prepared by a lit)
2
5
erature procedure from 3)hydroxy)1,3,5(10±)estratrien)17)one
was esterified with triflic anhydride in the presence of 2,4,6)
2
6
collidine and DMAP at −30 °C to give triflate 14 in 85% yield.
2
7
2
Alkoxycarbonylation catalysed by Pd(OAc± )1,3)bis(diphenyl)
Scheme 3 Preparation and resolution of ethyl hydrogen phosphonate
(
± ±-10.
phosphino±propane of the phenolic triflate with CO/MeOH/
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Scheme 5 Preparation of substituted diazomethane 19.
Fig. 1 The molecular structure of 23 in solid state showing displace-
ment ellipsoids at 20% probability.
Et N at 70 °C delivered benzoate 15 in 80% yield, which was
3
quantitatively reduced to benzyl alcohol 16 with LiAlH . Swern
4
oxidation of 16 to the aldehyde 17 was less effective (54%
Separation by preparative HPLC delivered the less polar 20 of
yield± than PCC oxidation (91%± in the presence of 3 Å mole)
cular sieves, which facilitated a smooth reaction and workup.
8
8% de and the more polar 23 of 96% de. Crystallisation of
epimer 20 from hexanes or cyclohexane furnished crystals of
98% de, which contained solvent (20/hexanes, 3.13 : 1; 20/
2
8
Heating a mixture of aldehyde 17 with tosyl hydrazine in
>
2
9
1
MeOH at 40 °C, furnished in 95% yield tosyl hydrazone 17,
the starting material for the preparation of the substituted dia)
zomethane. Refluxing a mixture of the hydrazone and sodium
bis(trimethylsiyl±amide in dry THF for 90 min gave the substi)
cyclohexane, 2 : 1, by H NMR±. The more polar epimer 23 was
crystallised from hexanes/i)PrOH to give crystals of also de
>98%, which were suitable for an X)ray crystal structure. It
allowed to assign (R,R ±)configuration (Fig. 1± to the phospho)
nic acid part of 23 and consequently (R,S ±)configuration to
P
that of 20 (the PvO bond is considered a single bond when
the sequence rule is used!±. Both epimers were methylated at
the sulfur atom with methyl fluorosulfate at −35 °C. The
respective sulfonium salts 21 and 24 were deprotonated at the
P
2
9,30
tuted diazomethane 19.
Crude 19 was not purified, but immediately used for the
esterification of phosphonic acid (R±)(−±)10 in CH Cl at room
2
2
temperature (Scheme 6±. Flash chromatography of the crude
1
product provided a 1 : 1 mixture of epimers 20 and 23 (by H
3
1
NMR; epimers displayed the same polarity± in 90% yield.
hydroxyl groups with phosphazene base P )t)Bu, a stronger
1
base than DBU, to induce α)hydroxyphosphonate)phosphate
rearrangements as detailed for 24 in Scheme 7.
The alkoxide 26 has two options. Firstly (pathway A±, it can
3
2
disintegrate (retro)Abramov reaction ± into phosphite anion
9 and sulfonium salt 28, which in turn react with each other
2
to sulfonium ylide 30 and H)phosphonate 31. The carbonyl
group of the ylide is not electrophilic enough to allow addition
Scheme 6 Esterification
α-hydroxyphosphonates 20 and 23 for the rearrangement to phosphates
2 and 25.
of
(R±-10
to
give
epimeric
2
Scheme 7 Reaction pathways for alkoxide 26.
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phate rearrangements. We found that the rearrangement is
stereospecific. However, the stereochemistry could not be
determined as the obtained phosphate was not crystalline to
perform a single crystal X)ray structure analysis. The sequence
allows to prepare enantiomerically pure enol phosphates.
Experimental
General
1
1
13
31
Fig. 2 EstCH
(
2
O segments of H NMR spectra of enol phosphates 22
H, C (J)modulated± and P NMR spectra were recorded
left± and 25 (middle± and of 1 : 1 mixture of 22 and 25 (right±.
1
13
3
in CDCl on Bruker Avance AV 400 ( H: 400.13 MHz, C:
3
1
1
1
00.61 MHz, P: 161.97 MHz± and AV III 600 ( H: 600.25 MHz,
C: 150.93 MHz, P: 242.94 MHz± spectrometers at 25 °C.
1
3
31
of the phosphite anion, which would lead to epimeric
α)hydroxyphosphonates. Additionally, sulfur ylide 30 is not
basic enough to deprotonate 31 to give 29. The H)phosphonate
1 was detected in the crude reaction mixture by H NMR spec)
troscopy [P(O±H: δH = 6.84, d, JHP = 698.0 Hz]. Secondly
pathway B±, alkoxide 26 can undergo the rearrangement to
enol phosphate 25 via cyclic species 27, which might be either
an intermediate or a transition state. We assume that 27 has
a trigonal bipyramidal structure formed by an apical attack of
the alkoxide anion on the electrophilc phosphorus atom from
Chemical shifts (δ± are reported in parts per million (ppm±
relative to CHCl /CDCl (δ 7.24, δ 77.00± and external H PO
4
3
3
H
C
3
(
85%; δ
P
0.00± and coupling constants (J± in Hz. Data for
1
3
1
H NMR spectra are reported as follows: chemical shift, multi)
plicity (s = singlet, d = doublet, t = triplet, q = quartet, sept =
septet, m = multiplet±, coupling constants, and integration.
IR spectra were run as films between NaCl plates or on a
silicon disc using a PerkinElmer 1600 FT)IR spectrometer.
Optical rotations were measured on a PerkinElmer 351 polari)
meter in a 1 dm cell. Analytical HPLC was performed on a
Jasco System (PU)980 pump, UV 975 and RI 930± using a
Nucleosil 50)4 column (Macherey)Nagel±, Ø 0.4 cm × 25 cm.
(
3
3
3
4
the less hindered side opposite to the EstCH O substituent.
2
The P–C bond will be equatorially orientated. The negative
charge building up on the α)carbon atom in 25 upon cleavage
of the P–C bond eliminates dimethyl sulphide. The two enol
phosphates 22 and 25 were obtained in yields of 46% and
8%, respectively. Their specific optical rotations were [α]2
Preparative HPLC was performed on
a
Rainin System
(
Dynamix Model SD)1 pump, Model UV)1 UV detector,
2
54 nm± using a Nucleosil 50)7 column, Ø 6.3 cm × 28.8 cm.
0
D
4
4
+
Melting points were measured on a Leica Galen III Thermovar
instrument and are uncorrected. Flash (column± chromato)
graphy was performed with silica gel 60 (230–400 mesh± and
monitored by TLC conducted on glass)backed 0.25 mm thick
silica gel 60 F254. Spots were visualised by UV and/or dipping
the plate into a solution of (NH
Ce(SO × 4H O (1.0 g± in 10% aqueous H
lowed by heating with a heat gun.
6.8 and + 41.9, respectively. These compounds contain beside
the stereogenic phosphorus atom some stereogenic carbon
ones in the steroidal substituent. Therefore the specific optical
rotations cannot have the same absolute values with opposite
signs. NMR spectroscopically, they are virtually identical ( H,
C, P± except for the resonances of EstCH
1
4
±
6
Mo
7
O
24 × 4H O (23.0 g± and
2
1
3
31
2
OP group (AB
4
±
2
2
2
SO (500 mL±, fol)
4
1
parts of ABP systems± in the H NMR spectrum (Fig. 2±.
Inspection of the three segments of the relevant H NMR
1
spectra reveal that the two enol phosphates 21 and 25 are
enantiomerically pure. Unfortunately, none of the two oils
could be induced to crystallise and the absolute configuration
of the stereogenic phosphorus atom could not be determined
by single X)ray structure analysis. The stereochemical course of
the α)hydroxyphosphonate)phosphate rearrangement of a non)
cyclic α)hydroxyphosphonates remains to be determined.
However, it must be a stereospecific reaction yielding enantio)
merically pure enol phosphates.
(
± ±)-Ethl thdrogen (1)thdroxh)2)meEthlsulfanhl)1)ptenhl±)
ptosptonaEe [(± ±)10ꢀ
A solution of ethyl bis(trimethylsilyl± phosphite (36.13 g,
3
2
1
1
42 mmol± and methylsulfanylmethyl phenyl ketone (9±
23.61 g, 142 mmol± in dry toluene (100 mL± was heated for
8 h at 70 °C under exclusion of moisture, cooled and then
diluted with water (200 mL±. After stirring vigorously for
0 min the mixture was neutralised with NaOH (2 M,
phenolphthalein±. The organic phase was separated and dis)
carded. The aqueous one was continuously extracted with Et
(
1
3
2
O
for 2 h and the extract was discarded. The aqueous layer was
acidified with diluted H SO (10 mL conc. H SO and 30 mL
Conclusions
2
4
2
4
In summary, we prepared
a
racemic ethyl hydrogen
H
2
O± and again continuously extracted with Et
2
O for 1 h. This
α)hydroxyphosphonate, resolved it with (R±)1)phenylethylamine extract was concentrated under reduced pressure and dried to
and esterified it with a diazomethane derived from 3)hydroxy) yield crystalline phosphonic acid (± ±)10 (28.0 g±. Continuous
1
,3,5(10±)estratrien)17)one. Each epimer obtained by HPLC extraction for another 2 h gave another 1 g phosphonic acid.
separation was methylated at the methylsulfanyl substitutent The combined products were crystallised from Et O (with
and treated with base to induce α)hydroxyphosphonate)phos) cooling at −20 °C± to yield phosphonic acid (± ±)10 (23.0 g,
2
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5
9%± as colourless crystals. The analytical sample was recrys) (20 mL± and ammonia solution (2 mL, 25%± were mixed. The
tallised from EtOAc/Et O; mp 95–98 °C.
organic phase was separated and the aqueous one was
extracted with CH Cl (2 × 15 mL±. The organic phases contain)
2
IR (nujol±: ν 3409, 3100–2000, 1332, 1162, 1035 cm−
1
;
2
2
1
3
H NMR (400.13 MHz, CDCl ±: δ 1.16 (t, J = 7.1 Hz, 3H±, 1.80 (s, ing the amine were discarded and the aqueous phase was con)
3
2
2
H±, 3.33 (AB part of ABP system, JAB = 14.1 Hz, J = 8.2, 6.6 Hz, centrated under reduced pressure. The residue was dissolved
H±, 3.86–4.00 (m, 2H±, 7.25–7.29 (m, 1H±, 7.34 (t, J = 7.7 Hz, in water and applied to a Dowex 50W × 8, H column and
H±, 7.40 (br. s, 2H±, 7.54–7.60 (m, 2H±; when excess (R±)(+±)1) eluted with water until neutral. The eluate was concentrated
+
phenylethylamine was added to the NMR sample, two diaster) under reduced pressure and dried (0.5 mbar/RT± to give phos)
eomeric salts formed with the methylsulfanyl groups resonat) phonic acid (−±)10 (0.710 g, 94%± as colourless gum, which
ing at 1.77 and 1.79 ppm. The singlet at lower field corres) crystallised; mp 61–63 °C (i)Pr
2
O/few drops of CH
2 2
Cl ±;
1
3
18
ponds to the CH S of the salt of the dextrorotary acid.
C
[α] –16.9 (c. 1.45, dry EtOH±. Anal. calcd for C H O PS:
3
D
11 17 4
3
NMR (150.93 MHz, CDCl ±: δ 16.2 (d, J = 5.9 Hz±, 17.1, 43.1 (d, C, 47.82; H, 6.20; O, 23.16; S, 11.60. Found: C, 47.83; H, 6.20;
J = 6.8 Hz±, 63.8 (d, J = 8.6 Hz±, 74.2 (d, J = 165.4 Hz±, 126.4 (d, O, 23.40; S, 11.71.
J = 4.2 Hz±, 127.8 (d, J = 2.8 Hz±, 128.1 (d, J = 2.5 Hz±, 138.6;
3
1
DesulfurisaEion of poEassium salE of (−±)eEthl thdrogen
1)thdroxh)2)meEthlsulfanhl)1)ptenhleEthl±ptosptonaEe (−±)10
3 17 4
P NMR (242.99 MHz, CDCl ±: δ 23.4. Anal. calcd for C11H O PS:
(
C, 47.82; H, 6.20; P, 11.21. Found: C, 47.95; H, 6.00; P, 11.58.
2
2
RANEY)nickel prepared by a literature procedure was washed
with water (10 × 250 mL portions± and stored in water for 72 h
at room temperature prior to use (it has to be handled quickly
when moist as it is pyrophoric!±.
OpEical resoluEion of (± ±)eEthl thdrogen (1)thdroxh)
2
1
)meEthlsulfanhl)1)ptenhleEthl±ptosptonaEe wiEt (R±)
)ptenhleEthlamine [(R±)11ꢀ
2
3
Racemic phosphonic acid (± ±)10 (16.56 g, 60 mmol± was dis)
solved in CH Cl (30 mL± and (R±)(+±)1)phenylethylamine (7.27 g, and Et O (30 mL± cooled at −35 °C (bath temperature±
0 mmol, 7.68 mL± was dropwise added with cooling. After the N)nitroso)N)ethylurea (4.0 g± was added in portions within
addition of Et O (300 mL± and seeding crystals obtained by slow 5 min. The mixture was stirred until the urea had dissolved
Diazoethane: To a solution of KOH (15 g± in water (45 mL±
2
2
2
3
5
6
2
evaporation of solvent from a CHCl
solution was left for 24 h at 4 °C. The formed crystals were col) directly for esterification.
lected, washed with Et O/CH Cl (10/1± and dried at 0.5 mm/
The free phosphonic acid obtained by general procedure A
0 °C for 30 min to give 9.1 g of salt, de 86% (by H NMR, salt/ from (R±)1)phenylethylammonium salt hemihydrate (R±)11 ×
Et O, 2.6 : 1.0±. The crystals were dissolved in hot CHCl
(−±)10 × 0.5H O (0.80 g, 1.97 mmol± was dissolved in a mixture
136.5 mL±. The flask with the solution was placed into a Dewar of ethanol (12 mL± and water (8 mL± and neutralised with KOH
3
solution of this salt, the (20 min±. The yellow ethereal solution of diazoethane was used
2
2
2
1
2
2
3
2
(
with warm water (50–55 °C±. The Dewar topped with a Styropor (10%, phenolphthalein±. After the addition of moist RANEY)
plate was allowed to slowly cool in the fridge until the water had nickel (5.3 g± the mixture was stirred for 15 h at room tempera)
4
°C. The colourless crystals not containing Et O were collected, ture and filtered. The RANEY® nickel was washed with a
2
washed with cold CHCl
were recrystallised from CHCl
phonic acid salt (R±)11 × (−±)10 × 0.5H O (6.8 g, 56%± as colour) through Dowex 50 W × 8, (H ± and eluted with water until
3
and dried; 8.03 g, de 98%. The crystals mixture of EtOH/water (the spent RANEY®)nickel was inacti)
3
as before and furnished phos) vated by storage under CH Cl ±. The filtrate was passed
2
+
2
2
2
0
less crystals; mp 120–123 °C; [α] –7.0 (c. 1.53, CH
2 2
Cl ±.
neutral. The eluate was concentrated under reduced pressure,
D
IR (nujol±: ν = 3410, 3100–2000, 1620, 1550, 1300, 1190, dissolved in EtOH and esterified with diazoethane. The solu)
170, 1160, 1050 cm− ; H NMR (600.25 MHz, CDCl ±: δ = 0.99 tion was concentrated under reduced pressure. The oily
1
1
1
3
(
t, J = 6.9 Hz, 3H±, 1.42 (d, J = 6.6 Hz, 3H±, 1.76 (s, 3H±, 2.11 residue was flash chromatographed (CH Cl /EtOAc, 5 : 1,
2 2
(br. s±, 3.26 (AB part of ABP system, JAB = 13.7 Hz, J = 3.1, Rf 0.17 and 0.07±. The less polar product (0.060 g± although evi)
6
.1 Hz, 2H±, 3.50–3.70 (m, 2H±, 3.98 (q, J = 6.9 Hz, 1H±, dently homogeneous by TLC was an inseparable mixture of
7
.17–7.37 (m, 4H±, 7.57 (d, J = 7.4 Hz, 1H±, 8.32 (br. s±; diethyl 1)hydroxy)2)methylsulfanyl)1)phenylethylphosphonate
1
3
1
C NMR (150.93 MHz, CDCl
3
±: δ 16.7 (d, J = 6.4 Hz±, 17.1, 20.9, and diethyl 1)phenylethylphosphonate (ratio by H NMR:
4
4.5, 50.7, 62.0 (d, J = 6.6 Hz±, 76.2 (d, J = 149.4 Hz±, 126.5 19 : 81±. The more polar product was flash chromatographed a
(
1
d, J = 3.1 Hz, 3C±, 126.9 (2C±, 127.6 (d, J = 1.6 Hz, 2C±, 128.4, second time (CH Cl /EtOAc, 2 : 1, R 0.17± to give diethyl
2 2 f
3
1
3
28.8 (2C±, 139.4, 142.1; P NMR (242.99 MHz, CDCl ±: δ 17.4. 1)hydroxy)1)phenylethylphosphonate (−±)12 (0.11 g, 22%± as a
2
0
Anal. calcd for C H NO PS: C, 57.42; H, 7.10; N, 3.52; calcd colourless oil; [α] –36.4 (c. 3.4, CHCl ±, after distillation
for C19H28NO PS × 0.5H O: C, 56.14; H, 7.19; N, 3.44. Found: (115–120 °C/0.005 mm± [α] –35.67 (c. 1.8, CHCl ± {lit. [α] –
1
9
28
4
3
D
2
0
3
20
4 2
3
D
D
C, 56.12; H, 6.80; N, 3.39.
37.2 (c. 2.12, CHCl ± for known 1)hydroxy)1)phenylethyl)
3
phosphonate (S±)(−±)12}.
Conversion of (R±)1)ptenhleEthlammonium salE of eEthl thdrogen
(1)thdroxh)2)meEthlsulfanhl)1)ptenhleEthl±)ptosptonaEe Eo
1,3,5(10±)-sEraErien)3)hl ErifluoromeEtanesulfonaEe (14±
free ptosptonic acid (−±)10 (general procedure A±
25
1
,3,5(10±)Estratrien)3)ol (13± (11.7 g, 45.6 mmol, crystalline
The (R±)1)phenylethylammonium salt hemihydrate (R±)11 × product, freed from EtOH by dissolution in toluene and
−±)10 × 0.5H O (1.105 g, 2.72 mmol±, CH Cl (20 mL±, water concentration under reduced pressure± was dissolved in
(
2
2
2
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dry CH
2
Cl
2
(150 mL± under argon atmosphere. 2,4,6) added, followed by H
2
SO
4
(120 mL, 2 M±. The organic phase
Trimethylpyridine (9.53 g, 78.7 mmol, 10.4 mL, 1.73 equiv.± was separated and the aqueous one extracted with Et O
2
and 4)dimethylaminopyridine (1.30 g, 10.6 mmol, 0.23 equiv.± (2 × 120 mL±. The combined organic layers were washed with
were added, followed by cooling at −30 °C and dropwise brine (120 mL±, dried (MgSO
4
± and concentrated under
addition of triflic anhydride (19.4 g, 69 mmol, 11.33 mL, reduced pressure. The residue was purified by flash chromato)
2
6
1
2
.5 equiv.±. The mixture was stirred for 10 min at −30 °C and graphy (CH
2 2 f
Cl , R 0.32± to give 1,3,5(10±)estratrien)3)ylmetha)
h at room temperature. The mixture was washed with 2 M HCl, nol (16± (7.51 g, 97%± as colourless crystals; mp 99–101 °C
water and a saturated aqueous solution of NaHCO (each with (methanol±; [α] + 84.7 (c. 1.99, acetone±.
2
0
3
D
1
00 mL±. The organic phase was dried (MgSO
4
±, concentrated
IR (Si±: ν 3286, 2932, 2868, 1452, 1428, 1377, 1155, 1046,
under reduced pressure. The residue was flash chromato) 1014, 1002 cm− ; H NMR (400.13 MHz, CDCl
1
1
±: δ 0.73 (s, 3H±,
graphed (hexanes, R 0.27± to give triflate 14 (15.1 g, 85%± as 1.09–1.54 (m, 8H±, 1.55 (br s, 1H±, 1.60–1.81 (m, 3H±, 1.84–1.91
colourless crystals; mp 51–52 °C (hexanes±; [α] + 58.7 (c. 1.06, (m, 2H±, 2.20–2.34 (m, 2H±, 2.80–2.95 (m, 2H±, 4.61 (s, 2H±,
3
f
2
D
0
acetone±.
IR (Si±: ν 2935, 2870, 1490, 1424, 1249, 1211, 1172,
7.08 (s, 1H±, 7.12 (d, J = 8.0 Hz, 1H±, 7.29 (d, J = 8.0 Hz, 1H±;
1
3
C NMR (100.61 MHz, CDCl ±: δ 17.5, 20.5, 25.2, 26.6, 28.0,
3
143 cm−
1
; H NMR (400.13 MHz, CDCl ±: δ 0.73 (s, 3H±, 29.6, 38.8, 39.0, 40.5, 41.0, 44.4, 53.6, 65.3, 124.3, 125.6, 127.7,
1
1
1
2
2
3
.09–1.80 (m, 11H±, 1.85–1.97 (m, 2H±, 2.18–2.30 (m, 2H±, 137.1, 138.0, 140.4. Anal. calcd for C19
.83–2.93 (m, 2H±, 6.94 (d, J = 2.6 Hz, 1H±, 6.99 (dd, J = 8.6, Found: C, 83.83; H; 9.80.
H
26O: C, 84.39; H, 9.70.
1
3
.6 Hz, 1H±, 7.32 (d, J = 8.6 Hz, 1H±; C NMR (100.61 MHz,
±: δ 17.4, 20.5, 25.2, 26.5, 27.6, 29.7, 38.5, 38.7, 40.4,
1,3,5(10±)-sEraEriene)3)carbaldethde (17±
CDCl
3
4
1
1.0, 44.2, 53.6, 118.0, 118.8 (q, JCF = 321.0 Hz, CF ±, 121.1, Pyridinium chlorochromate (10.91 g, 50.6 mmol± was portion
3
27.2, 139.6, 141.3, 147.4. Anal. calcd for C19
H
23
F
3
O
3
S: wise added to a stirred mixture of 1,3,5(10±)estratrien)3)
C, 58.75; H, 5.97. Found: C, 58.65; H, 6.03.
ylmethanol (16± (6.84 g, 25.3 mmol± und molecular sieves
2
8
(
25 g, 3 ű in dry CH Cl (125 mL± under cooling with cold
2 2
MeEthl 1,3,5(10±)esEraEriene)3)carboxhlaEe (15±
water. The mixture was stirred for 1.5 h at room temperature.
O (380 mL±, the mixture was filtered
10±)Estratrien)3)yl trifluoromethanesulfonate (14± (14.4 g, through silica 60 (50 g±. The reaction flask was washed with
7.1 mmol± were dissolved in a stirred mixture of dry methanol Et O (3 × 80 mL±. The filtrate was concentrated under reduced
74 mL± and dry DMSO (110 mL±. Triethylamine (8.2 g, pressure. The residue was purified by flash chromatography
This reaction was performed in a well vented hood (CO!±. 1,3,5 After addition of Et
(
3
(
2
2
8
0
2
1 mmol, 11.3 mL, 2.2 equiv.±, Pd(OAc± (0.499 g, 2.22 mmol, (hexanes/CH Cl , 2 : 1, R 0.17± to give aldehyde 17 (6.18 g,
2 2 2 f
.06 equiv.± and 1,3)bis(diphenylphosphino±propane (0.914 g, 91%± as colourless crystals; mp 95–97 °C (hexanes/CH
2
Cl ±;
2
2
7
20
.22 mmol, 0.06 equiv.± were added. The apparatus was [α] + 88.4 (c. 2.04, acetone±.
D
flushed with CO for 15 min and then the mixture was heated
IR (Si±: ν 2946, 1691, 1606, 1568, 1453, 1378, 1281, 1226,
at 70 °C (oil bath temperature± under the CO atmosphere for 1153 cm−
1
;
1
3
H NMR (400.13 MHz, CDCl ±: δ 0.73 (s, 3H±,
4
h. After cooling to room temperature water (380 mL± 1.10–1.82 (m, 11H±, 1.85–2.00 (m, 2H±, 2.24–2.37 (m, 2H±,
was added and the mixture was extracted with CH Cl
2.88–2.98 (m, 2H±, 7.45 (d, J = 8.0 Hz, 1H±, 7.57 (d, J = 1.2 Hz,
2
2
1
3
(
3 × 120 mL±. The combined organic layers were washed with 1H±, 7.63 (dd, J = 8.0, 1.2 Hz, 1H±, 9.92 (s, 1H±; C NMR
HCl (2 M±, water and a saturated aqueous solution of NaHCO (100.61 MHz, CDCl ±: δ 17.5, 20.5, 25.2, 26.4, 27.7, 29.4, 38.5,
dried (Na SO ± and concentrated under reduced pressure. The 38.7, 40.4, 40.9, 45.0, 53.7, 126.1, 127.0, 130.3, 134.0, 137.8,
3
,
3
2
4
2 2
residue was flash chromatographed (hexanes/CH Cl , 2 : 1, 148.3, 192.4. Anal. calcd for C19H24O: C, 85.03; H, 9.01. Found:
R
f
0.24± to give methyl ester 15 (8.83 g, 80%± as colourless crys) C, 85.12; H, 9.07.
2
0
tals; mp 92–94 °C (hexanes±; [α]D + 78.6 (c. 1.58, acetone±.
IR (Si±: ν 2948, 2868, 1723, 1435, 1291, 1263, 1193 cm−
1
;
1,3,5(10±)-sEraEriene)3)carbaldethde Eoshlthdrazone (18±
1
3
H NMR (400.13 MHz, CDCl ±: δ 0.73 (s, 3H±, 1.08–1.82 (m, A solution of 1,3,5(10±)estratriene)3)carbaldehyde (17± (6.10 g,
1
3
7
1H±, 1.84–1.91 (m, 2H±, 2.23–2.36 (m, 2H±, 2.85–2.95 (m, 2H±, 22.7 mmol± and tosyl hydrazide (4.95 g, 26.6 mmol, 1.17
.87 (s, 3H±, 7.34 (d, J = 8.2 Hz, 1H±, 7.73 (d, J = 1.6 Hz, 1H±, equiv.± in dry methanol (75 mL± was stirred for 1 h at room
1
3
29
3
.77 (dd, J = 8.2, 1.6 Hz, 1H±; C NMR (100.61 MHz, CDCl ±: temperature and 1 h at 40 °C. The solution was concentrated
δ 17.5, 20.5, 25.2, 26.4, 27.8, 29.5, 38.6, 38.7, 40.4, 41.0, 44.8, under reduced pressure. The residue was purified by flash
1.9, 53.7, 125.4, 126.6, 127.2, 130.1, 137.0, 146.3, 167.4. Anal. chromatography (CH Cl , R 0.29± to yield hydrazone 18
calcd for C20 : C, 80.50; H, 8.78. Found: C, 80.28; H, 8.79. (9.40 g, 95%± as crystals; mp 189–192 °C (toluene/EtOH±;
5
2
2
f
26 2
H O
2
0
[
α] + 46.9 (c. 1.92, CHCl3±.
D
1
,3,5(10±)-sEraErien)3)hlmeEtanol (16±
A solution of methyl 1,3,5(10±)estratriene)3)carboxylate (15± 1052 cm−1
IR (Si±: ν 3196, 2925, 2867, 1451, 1364, 1321, 1167,
1
;
H NMR (400.13 MHz, CDCl
3
±: δ 0.71 (s, 3H±,
(8.57 g, 28.7 mmol± in dry Et O (40 mL± was dropwise added to 1.07–1.80 (m, 11H±, 1.82–1.95 (m, 2H±, 2.18–2.31 (m, 2H±, 2.38
2
a stirred suspension of LiAlH
in dry Et O (50 mL± at 0 °C. The mixture was refluxed for 2 h (br s, 1H±, 7.82–7.87 (m, 2H±; C NMR (100.61 MHz, CDCl
and cooled at 0 °C. Then water (12 mL, 0 °C± was dropwise δ 17.5, 20.5, 21.5, 25.2, 26.4, 27.8, 29.5, 38.69, 38.74, 40.4, 41.0,
4
(0.82 g, 21.5 mmol, 1.5 equiv.± (s, 3H±, 2.79–2.87 (m, 2H±, 7.24–7.34 (m, 5H±, 7.68 (s, 1H±, 7.74
1
3
2
3
±:
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4
1
4.7, 53.6, 124.7, 125.7, 127.8, 127.9 (2C±, 129.7 (2C±, 130.3, 11.6 Hz, J = 7.8, 6.9 Hz, 2H±, 7.02 (br. s, 1H±, 7.09 (dd, J = 8.0,
13
35.3, 137.3, 143.8, 144.1, 148.5. Anal. cald for C H N O S: 1.5 Hz, 1H±, 7.25–7.37 (m, 4H±, 7.60–7.65 (m, 2H±; C NMR
2
6
32 2 2
C, 71.52; H, 7.39; N, 6.42. Found: C, 71.43; H, 7.29; N, 6.35.
(100.65 MHz, CDCl
3
±: δ 16.2 (d, J = 5.8 Hz±, 17.1, 17.5, 20.6,
2
4
7
2
5.2, 26.6, 26.9 (cyclohexane±, 28.0, 29.6, 38.8, 38.9, 40.5, 41.0,
(
(
(
p p
1R,S ±) and (1R,R ±)(1′,3′,5′(10′±)esEraErien)3′)hlmeEthl± eEthl
1)thdroxh)2)meEthlsulfanhl)1)ptenhleEthl±ptosptonaEe
20 and 23±
3.8 (d, JPC = 6.5 Hz±, 44.5, 53.7, 63.9 (d, J = 6.5 Hz±, 68.6 (d, J =
.5 Hz±, 75.0 (d, J = 161.7 Hz±, 125.3, 125.6, 126.4 (d, J = 4.2 Hz,
C±, 127.8 (d, J = 2.8 Hz±, 128.2 (d, J = 2.7 Hz, 2C±, 128.7, 133.3
3
1
Preparation of 1,3,5(10±)estratrien)3)yl)diazomethane (19± (d, J = 6.7 Hz±, 137.1, 138.9, 141.2. P NMR (162.03 MHz,
from 1,3,5(10±)estratrien)3)carbaldehyde tosyl hydrazone (18±: CDCl ±: δ 21.37. Anal. calcd for C30 PS×0.5C 12:C, 69.44;
A mixture of tosyl hydrazone 18 (1.51 g, 3.46 mmol± and H, 8.30. Found: C, 69.06; H, 8.12.
NaHMDS (0.80 g, 4.15 mmol, 95%, 1.2 equiv.± in dry THF 23: More polar epimer; mp 108–112 °C (hexanes/i)PrOH±;
45 mL± was refluxed for 90 min After cooling at room tem) [α] + 31.7 (c. 0.99, CHCl ±. IR (Si±: ν 3280, 2922, 2866, 1449,
D
3
perature the solvent was removed under reduced pressure. 1377, 1222, 1102, 1047, 1037, 999, 985 cm
3
H
41
O
4
6
H
3
0
20
(
−
1
1
.
H NMR
Water (60 mL± was added and the mixture was extracted with (400.13 MHz, CDCl ±: δ 0.72 (s, 3H±, 1.07–1.81 (m, 11H±, 1.25
3
CH
2
Cl
2
(3 × 40 mL±. The combined organic layers were washed (t, J = 7.0 Hz, 3H±, 1.83 (s, 3H±, 1.85–1.96 (m, 2H±, 2.16–2.33
SO ± and concentrated under reduced (m, 2H±, 2.73–2.90 (m, 2H±, 3.40 (AB part of ABP system, JAB =
with water, dried (Na
2
4
pressure. The residue was twice dissolved in toluene und con) 14.1 Hz, J = 7.8, 7.5 Hz, 2H±, 3.61 (d, J = 17.4 Hz, 1H±, 4.05–4.18
centrated each time under reduced pressure. The dark red (m, 2H±, 4.71 (AB part of ABP system, JAB = 11.5 Hz, J = 7.5,
residue was dried for 10 min (0.5 mbar/RT± and then immedi) 6.5 Hz, 2H±, 6.88 (s, 1H±, 6.96 (d, J = 7.9 Hz, 1H±, 7.22 (d, J =
13
ately used for the next step.
7.9 Hz, 1H±, 7.26–7.39 (m, 3H±, 7.60–7.67 (m, 2H±; C NMR
±: δ 16.3 (d, J = 5.8 Hz±, 17.1, 17.5, 20.5,
2
. Esterification of phosphonic acid: A solution of (R±)(−±) (100.61 MHz, CDCl
3
ethyl hydrogen (1)hydroxy)2)methylsulfanyl)1)phenylethyl±) 25.2, 26.5, 27.9, 29.6, 38.77, 38.83, 40.4, 41.0, 43.7 (d, J =
phosphonate [(R±)(−±)10] (0.577 g, 2.1 mmol, prepared from 6.6 Hz±, 44.4, 53.6, 63.5 (d, J = 7.6 Hz±, 68.9 (d, J = 7.3 Hz±, 75.0
the (R±)1)phenylethylammonium salt by general procedure A± (d, J = 161.3 Hz±, 125.1, 125.5, 126.4 (d, J = 4.1 Hz, 2C±, 127.8
in dry CH
of the above prepared crude steroidal diazomethane in dry 6.5 Hz±, 136.9, 138.9, 141.0; P NMR (161.98 MHz, CDCl3±:
CH Cl (25 mL± within 15 min at room temperature. While the δ 22.13. Anal. calcd for C30 PS: C, 68.16; H, 7.82. Found:
2 2
Cl (20 mL± was dropwise added to a stirred solution (d, J = 2.8 Hz±, 128.1 (d, J = 2.3 Hz, 2C±, 128.5, 133.2 (d, JPC =
3
1
2
2
41 4
H O
reaction mixture was stirred for 40 min at room temperature, C, 68.36; H, 7.77.
the colour changed from deep red to orange. Excess diazo)
[
1′,3′,5′(10′±)-sEraErien)3′)hlmeEthlꢀ eEthl 1)ptenhleEtenhl
methane was destroyed by dropwise addition of AcOH (colour
changed to yellow±. The solvent was removed under reduced
ptosptaEe [22, prepared from 20ꢀ
pressure. The residue was purified by flash chromatography A solution of methyl fluorosulfate (0.32 g, 2.8 mmol, 0.22 mL,
CH Cl /EtOAc, 10 : 1, R 0.28± to give a mixture of epimers 20 2.0 equiv.± in dry CH Cl (1.2 mL± was dropwise added
(
2
2
f
2
2
1
and 23 (0.99 g, 90%; ratio 1 : 1, by H NMR± as a colourless oil. to a stirred solution of α)hydroxyphosphonate 20 (0.741 g,
The epimers were separated by HPLC (analytical HPLC: 1.4 mmol± in dry CH Cl (10 mL± at −35 °C. The mixture was
2
2
Nucleosil 50–4 column, 0.46 × 25 cm, 5% i)PrOH in hexanes, stirred for 35 min at −35 °C and 2 h at room temperature.
mL × min− , t
1
1
R
= 10.7 and 11.4 min; preparative HPLC: Then, the solvent was removed under reduced pressure. The
Nucleosil 50–7 column, 6.3 × 28.8 cm, 2.5% i)PrOH in residue was dried for 45 min and dissolved in dry DMSO
3
1
1
hexanes±. The less polar epimer 20 had a de of 88% and the (10 mL±. Phosphazene base P )t)Bu (0.656 g, 2.8 mmol,
more polar 23 of 96%. Crystallisation increased the de of the 0.71 mL, 2.0 equiv.± was added. After stirring for 30 min at
former to >98% [from hexanes, crystals contained solvent; 20/ room temperature, water (75 mL± was added and the mixture
1
hexanes, 3.13 : 1, by H NMR] and of the latter to also >98% was twice extracted with Et
2
O (75 mL and 50 mL±. To improve
(hexanes/i)PrOH±. Crystals of 23 were unsolvated and used for phase separation, the aqueous layer was saturated with
the determination of the X)ray structure.
NaCl. The combined organic layers were washed with water
± and concentrated under reduced
3
2–54 °C; [α]D + 18.24 (c. 1.03, CHCl ±. Crystallisation from pressure. The residue was purified by flash chromatography
2
0: Less polar epimer; for crystals from hexanes: mp (3 × 50 mL±, dried (MgSO
4
2
0
5
cyclohexane furnished crystals containing cyclohexane (hexanes/EtOAc, 3 : 1; R 0.31± to give phosphate 22 (0.308 g,
f
1
20
(
20/cyclohexane, 2 : 1, by H NMR±, mp 49–52 °C.
46%± as a colourless oil; [α]D + 46.8 (c. 2.01, ethanol±.
IR (Si±: ν 3280, 2932, 2867, 1449, 1376, 1220, 1100, 1014,
IR (Si±: ν 2933, 2868, 1635, 1449, 1377, 1270, 1158, 1103,
85, 972 cm− . NMR spectra are given for cyclohexane)contain) 1014 cm
1
−1
. H NMR (400.13 MHz, CDCl ±: δ 0.72 (s, 3H±,
3
1
9
1
ing crystals. H NMR (400.27 MHz, CDCl
3
±: δ 0.72 (s, 3H±, 1.06 1.09–1.82 (m, 11H±, 1.32 (td, J = 7.4, 0.8 Hz, 3H±, 1.80–1.96 (m,
(
td, J = 7.0, 0.4 Hz, 3H±, 1.09–1.80 (m, 11H±, 1.41 (s, 6H, cyclo) 2H±, 2.22–2.32 (m, 2H±, 2.76–2.91 (m, 2H±, 4.17 (quin, J =
hexane±, 1.81 (s, 3H±, 1.83–1.95 (m, 2H±, 2.18–2.33 (m, 2H±, 7.4 Hz, 2H±, 5.07 (AB part of ABP system, JAB = 11.5 Hz, J = 8.0,
.77–2.91 (m, 2H±, 3.39 (AB part of ABP system, JAB = 14.0 Hz, 7.9 Hz, 2H±, 5.21 (≈ t, J = 2.6 Hz, 1H±, 5.26 (≈ t, J = 2.5 Hz, 1H±,
J = 7.8, 7.4 Hz, 2H±, 3.47 (d, J = 17.6 Hz, 1H±, 3.67–3.79 7.05 (br. s, 1H±, 7.11 (br. d, J = 8.1 Hz, 1H±, 7.26 (d, J = 8.1 Hz,
2
13
(m, 1H±, 3.82–3.93 (m, 1H±, 5.03 (AB part of ABP system, JAB
=
1H±, 7.29–7.36 (m, 3H±, 7.50–7.56 (m, 2H±;
C NMR
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(
100.61 MHz, CDCl
6.5, 27.9, 29.5, 38.79, 38.83, 40.5, 41.0, 44.4, 53.6, 64.6 (d, J =
.1 Hz±, 69.8 (d, J = 5.7 Hz±, 97.3 (d, J = 3.6 Hz±, 125.21 (2C±,
25.23, 125.6, 128.3 (2C±, 128.6, 129.0, 132.6 (d, J = 6.9 Hz±,
34.3 (d, J = 6.9 H±, 137.1, 141.3, 152.3 (d, J = 7.9 Hz±. Anal.
3
±: δ 16.1 (d, J = 6.9 Hz±, 17.5, 20.5, 25.2,
8 (a± F. Hammerschmidt and M. Hanbauer, J. Org. Chem.,
2000, 65, 6121; (b± E. Kuliszewska, M. Hanbauer and
F. Hammerschmidt, Chem. – Eur. J., 2008, 14, 8603.
9 (a± W. F. Barthel, B. H. Alexander, P. A. Giang and
S. A. Hall, J. Am. Chem. Soc., 1955, 77, 2424; (b± W. Lorenz,
A. Henglein and G. Schrader, J. Am. Chem. Soc., 1955, 77,
2
6
1
1
cald for C29
37 4
H O P: C, 72.48; H, 7.76. Found: C, 72.05; H, 7.71.
2554; (c± M. S. Kharasch and I. S. Bengelsdorf, J. Org.
[
1′,3′,5′(10′±)-sEraErien)3′)hlmeEthlꢀ eEthl 1)ptenhleEtenhl
Chem., 1955, 20, 1356; (d± I. S. Bengelsdorf, J. Org. Chem.,
1956, 21, 475; (e± G. W. Fischer and P. Scheider, J. Prakt.
Chem., 1977, 319, 399.
0 (a± M.)J. Brienne and M. J. Jacques, C. R. Acad. Sci., Ser. C,
1975, 280, 291; (b± M. J. Brienne, J. Jacques, M. C. Brianso
and E. Surcouf, Nouv. J. Chim., 1978, 2, 19.
ptosptaEe [25, prepared from 23ꢀ
The α)hydroxyphosphonate 23 (0.741 g, 1.4 mmol± was con)
verted to 25 (0.322 g, 48%± as colourless oil by the procedure
as used for the preparation of 22; [α] + 41.9 (c. 1.92, ethanol±.
1
2
0
D
1
3
31
The IR spectrum and the C and P NMR spectra are iden)
1
11 K. Pallitsch, A. Roller and F. Hammerschmidt, Chem. – Eur.
J., 2015, 21, 10200.
tical to those of 22. The H NMR spectrum is identical to that
of 22 except for the resonances of the POCH
2
group (see
1
1
1
2 F. Hammerschmidt and E. Zbiral, Monatsh. Chem., 1980,
11, 1015.
3 A. E. Wroblewski and W. Karolczak, Pol. J. Chem., 1999, 73,
191.
4 A selection: (a± L. A. R. Hall, C. W. Stephens and
J. J. Drydale, J. Am. Chem. Soc., 1957, 79, 1768;
Fig. 2±: δ 5.07 (AB part of ABP system, JAB = 11.6 Hz, JAP = JBP
=
1
7
.9 Hz, 2H±. Anal. calcd for C H O P: C, 72.48; H, 7.76.
29 37 4
Found: C, 72.20; H, 7.66.
1
Conflicts of interest
(
(
b± H. Timmler and J. Kurz, Chem. Ber., 1971, 104, 3740;
c± F. Hammerschmidt, E. Schneyder and E. Zbiral, Chem.
There are no conflicts to declare.
Ber., 1980, 113, 3891; (d± M. Kuroboshi, T. Ishihara and
T. Ando, J. Fluorine Chem., 1988, 39, 293; (e± C. Meier,
Angew. Chem., Int. Ed. Engl., 1993, 32, 1704; (f± C. Meier,
L. W. Halbel, J. Balzarini and E. De Clercq, Liebigs Ann.
Chem., 1995, 2195; (g± R. Gancarz, I. Gancarz and
A. Deron, Phosphorus, Sulfur Silicon, 2000, 161, 61;
(h± K. Pachamuthu and R. R. Schmidt, Chem. Commun.,
2004, 1078; (i± C. C. Bausch and J. S. Johnson, Adv. Synth.
Catal., 2005, 347, 1207; ( j± A. S. Demir, Ö. Reis,
A. Òª. İğdir, İ. Esiringü and S. Eymur, J. Org. Chem., 2005,
70, 10584; (k± L. E. Kaim, L. Gaultier, L. Grimaud and
A. D. Santos, Synlett, 2005, 2335; (l± A. S. Demir, B. Reis,
Ö. Reis, S. Eymür, M. Göllü, S. Tural and G. Saglam, J. Org.
Chem., 2007, 72, 7439; (m± R. Ruel, J.)P. Bouvier and
R. N. Young, J. Org. Chem., 1995, 60, 5209; (n± D. Coffinier,
L. E. Kaim and L. Grimaud, Synlett, 2008, 1133;
(o± M. Hayashi and S. Nakamura, Angew. Chem., Int. Ed.,
2011, 50, 2249; (p± M. T. Corbett, D. Uraguchi, T. Ooi and
J. S. Johnson, Angew. Chem., Int. Ed., 2012, 51, 4685;
(q± A. Kondoh and M. Terada, Org. Lett., 2013, 15, 4568;
(r± A. Kondoh, T. Aoki and M. Terada, Org. Lett., 2014, 16,
3528; (s± A. Kondoh and M. Terada, Org. Chem. Front.,
2015, 2, 801; (t± A. Kondoh, T. Aoki and M. Terada, Chem.
– Eur. J., 2015, 21, 12577; (u± M. A. Horwitz, N. Tanaka,
T. Yokosaka, D. Uraguchi, J. S. Johnson and T. Ooi,
J. Chem. Sci., 2015, 6, 6086; (v± A. Kondo, A. Takai and
M. Terada, Synlett, 2016, 1848; (w± H. Yoneyama,
K. Uemura, Y. Usami and S. Hurusawa, Tetrahedron, 2017,
73, 6109; (x± for the rearrangement of a β)oxophosphonate
to a phosphate see: M. Anitha, G. Gangadhararao and
K. C. Kumara Swamy, Org. Biomol. Chem., 2016, 14,
3591.
Acknowledgements
The authors thank S. Felsinger for recording NMR spectra,
S. Schneider for the preparative HPLC separation, J. Theiner
for combustion analyses, H. Völlenkle for assistance with X)ray
diffraction, and Schering AG for a gift of 3)hydroxy)1,3,5(10±)
estratrien)17)one. S. Prechelmacher thanks the Austrian
Academy of Sciences for a DOC scholarship. This work was
supported by the Austrian Science Fund (FWF, grant no.
P19869)N19±.
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