The chemistry of lithiated phosphine oxides: The stereoselective syntheses of alkene-4,5-diols

Article abstract of DOI:10.1039/b008500f

The synthesis of single enantiomers of (E)-1,5-diarylpentene-4,5-diols by elimination reaction was discussed. The stereochemistry was controlled by an asymmetric dihydroxylation, and a stereoselective reduction of a β-keto phosphine oxide. Results showed

Full text of DOI:10.1039/b008500f

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The chemistry of lithiated phosphine oxides: the stereoselective
synthesis of alkene-4,5-diols
Thomas Boesen, Neil Feeder, Martin D. Eastgate, David J. Fox, Jonathan A. Medlock,
Charles R. Tyzack and Stuart Warren*
1
University Chemistry Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge, UK) 20th October 2000, Accepted 27th October 2000
First published as an Advance Article on the web 14th December 2000
Single enantiomers of (E)-1,5-diarylpentene-4,5-diols have been synthesised by Horner–Wittig elimination.
The stereochemistry is controlled by an asymmetric dihydroxylation, and a stereoselective reduction of a β-keto
phosphine oxide.
Phosphine oxides are useful intermediates in the synthesis
of phosphines and other organic molecules.1 Much of this
chemistry relies on the reactions of α-lithiated phosphine oxides
1, for instance their addition to carbonyl compounds in the
Horner–Wittig synthesis of alkenes 2 (Scheme 1),2 or their
(Scheme 2).6 The tetrahedral intermediate formed in the initial
addition to the ester functionality can be trapped by the tri-
methylsilyl chloride within the reaction.7 Ketones formed by
the acyl-transfer process can be reduced diastereoselectively
to syn-β-hydroxy phosphine oxides 4, which in turn give (E)-
alkenes stereospecifically by base mediated elimination. A
phosphine oxide containing both γ- and δ-acyloxy groups could
transfer either of the two acyl-groups, and we report the select-
ivity of this process. We made the bis-ester 6 required for the
acyl-transfer process from a vicinal diol 5, and this was made in
enantiomerically pure form by asymmetric dihydroxylation of
an alkene. The acyl-transfer product was reduced and converted
into an (E)-alkene, as with other β-keto phosphine oxides
(Scheme 3). Such an alkene 7 is an enantiomerically pure 1,2-
Scheme 1
oxidative dimerisation in the synthesis of homochiral bis-
phosphine 1,2-bis[(o-methoxyphenyl)phenyl phosphino]ethane
(DIPAMP).3 Pioneering work by Snaith and others has pro-
vided both evidence for the structures of lithiated phosphine
oxides4 and a greater mechanistic understanding of stereo-
selectivity in Horner–Wittig additions with aldehydes.5
Phosphine oxides with γ- or δ-acyloxy groups, once lithiated
3, react intramolecularly to give the products of acyl transfer
Scheme 3
dihydroxypent-4-ene, the product of the imaginary regio- and
stereoselective dihydroxylation of a 1,4-diene.
Synthesis
(E)-β-Substituted styrenes tend to be dihydroxylated with
high enantioselectivity using the commercial AD-mix reagents.8
It was envisaged that such a substrate containing an appropri-
ately positioned phosphinoyl group could be synthesised by
a Heck coupling onto (but-3-enyl)diphenylphosphine oxide 8
(Scheme 4). This reaction however, using either iodobenzene or
4-iodoanisole, gave inseparable mixtures of products, despite
Scheme 2
Scheme 4
118
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b008500f

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Table 1 Bis-esters from the benzoylation of diols 13 and 14, and cyclic
many attempts at varying the reagents and reaction conditions.
This area is a matter of continuing interest within this group.
An alternative synthesis of these alkenes was possible by
alkylation of lithiated (diphenyl)methylphosphine oxide 11
(Scheme 5). In the case of product 10 the electrophile was
ketals formed by lithiation and in situ trapping with trimethylsilyl
chloride
Yield
Compound (%)
Yield
Compound (%)
Ar1
Ar2
Ph
Ph
Ph
15
98
95
57
73
19
20
21
22
81
89
51
30
4-MeOC6H4 16
17
4-MeOC6H4 4-MeOC6H4 18
4-MeOC6H4 Ph
Table 2 In situ reduction of phosphoryl ketones to give mono-
benzoates (yields of isolated major diastereoisomers) and triols
(combined yields of both diastereoisomers)
Mono-
Ketone benzoate (%)
Yield
Yield
Triol (%)
Ar1
Ar2
Ph
Ph
Ph
23
26
27
28
28
34
—
29
30
31
60
—
50
4-MeOC6H4 24
4-MeOC6H4 Ph
25
Generally, if lithiated (diphenyl)methylphosphine oxide 11 is
added very slowly to an excess of the electrophile then the
formation of this by-product can be reduced. It is interesting
to note that the formation of diene 12 is accompanied by
the appearance of a dark green colour in the reaction mixture.
The cause of this unusual colouration was established by the
independent treatment of alkene 9 with lithium diisopropyl-
amide to give a dark green solution of the lithiated phosphine
oxide, which could be reprotonated to give starting material.
The enantioselectivity of the asymmetric dihydroxylation was
established by chiral HPLC in comparison with authentic
racemic samples of diols 13 and 14 synthesised using the
non-asymmetric variant of the dihydroxylation procedure.9
The stereoselectivities are very high (>95% ee) for these 4-
phosphinoylalkenes using the standard AD-mix. This is not the
case for similar 3-phosphinoylalkenes, where the enantioselec-
tivities are lower, possibly due to unfavourable interactions
between the phosphine oxide group and the osmium or the
ligand in the transition structure.10
Scheme 5 Reagents and conditions: i, Me3SiCl, NaI, THF, Ϫ78 ЊC; ii,
11, THF, Ϫ78 ЊC, 39% (9), 44% (10, 2 steps).
made in situ from 4-methoxycinnamyl alcohol. Asymmetric
dihydroxylation was then achieved with excellent enantioselec-
tivity to give diols 13 and 14, followed by acylation producing
four bis-esters 15 to 18. Lithiation of these compounds with
lithium diisopropylamide in the presence of trimethylsilyl
chloride (Ϫ78 ЊC to room temperature) gave cyclic ketals 19 to
22 with high stereoselectivity (Scheme 6 and Table 1). In the
Acyl transfer from oxygen to carbon has been observed for
both γ- and δ-acyloxy phosphine oxides.6 Before this study it
was unknown whether there would be any selectivity in the
reaction of a lithiated phosphine oxide containing both ester
groups. Here however substrates 15 to 18 did react only by
addition to the proximal ester group, as seen by in situ trapping
to form the 5-membered-ring ketals 19 to 22. This can be
explained by assuming that the (4,5)-bicyclic transition
structure 34 would form significantly faster than the (4,6) altern-
ative 35 (Scheme 9). The structure of the 5-membered-ring
ketals has been established for a similar compound by X-ray
crystallography, by which it was also shown that the trimethyl-
silyloxy and phosphinoyl groups adopt a syn-relationship in the
product.7 This stereochemistry is possibly a result of the chel-
ation of the lithium to both the phosphine oxide and carbonyl
groups in the transition structure 34, similar to that proposed
by Snaith et al. for similar reactions with aldehydes.5 The
C(5)-stereochemistry in the ring may be due to the preferred
pseudo-equatorial orientation of the side chain in the transition
structure.
The best yields of ketals 19 to 22 were obtained when the
reactions were allowed to warm slowly from Ϫ78 ЊC to ambient
temperature, and by quenching the reaction with silica gel
instead of an aqueous work-up. This is especially true for the
4-methoxybenzoate esters 16 and 18 which, once lithiated at
Ϫ78 ЊC, do not react to any measurable extent at this tem-
perature. Lithiated versions of benzoate esters 15 and 17 do
however react at Ϫ78 ЊC and the non-silylated acyl-transfer
products 23 and 25 can be obtained by quenching the reactions
Scheme 6 Reagents and conditions: i, AD-α-mix, MeSO2NH2, t-BuOH,
H2O, 98% (13), 58% (14); ii, Ar2COCl, Et3N, DMAP, CH2Cl2; iii, LDA,
Me3SiCl, THF, Ϫ78 ЊC to rt, SiO2.
case of bis-esters 15 and 17 simple acyl-transfer of the proximal
benzoate group could be achieved at Ϫ78 ЊC without the use of
trimethylsilyl chloride. The similar ketone 24 was synthesised
by treatment of ketal 20 with tetra-n-butylammonium fluoride
(TBAF). These ketones were reduced to give mono-benzoates
26 to 28 or triols 29 to 31 (Scheme 7 and Table 2), which were
treated with sodium hydride to produce alkenediols 32 to 34 as
single geometric isomers (Scheme 8).
Discussion
The synthesis of dihydroxylation substrate 9 by alkylation
can also produce dialkylation product 12 as a by-product.
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126
119

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Scheme 7 Reagents and conditions: LDA, THF, Ϫ78 ЊC; ii, TBAF, THF; iii, NaBH4, EtOH.
Scheme 9
reductions. The reduction of ketone 23 produced a mixture of
Scheme 8 Reagents and conditions: i, NaH (2 eq.), DMF, 20 to 60 ЊC,
71% (32), 35% (33); ii, NaH (3 eq.), DMF, 20 to 60 ЊC, 60% (32), 60%
(34).
two diastereoisomers of a triols 29a and 29b, and their mono-
benzoates 26a and 26b. It seems that the diastereomeric ratio
of mono-benzoates and triols is similar, indicating that the
benzoate cleavage either does not affect the ketone reduction
selectivity, or occurs subsequently. The major diastereoisomer
of the mono-benzoate could be isolated by chromatography,
but the two diastereoisomers of the triol were isolated as a 3.4
to 1 mixture.
The absolute stereochemistry of the major diastereoisomer
of mono-benzoate 26 was not determined, but it was eliminated
by treatment with sodium hydride to give the (E)-alkene 32
(Scheme 8), showing that structure has a C(1)–C(2) syn-
stereochemistry and is either compound 26a or 26b (Scheme 7).
at low temperature with ammonium chloride. The difference in
behaviour between the benzoate and 4-methoxybenzoate esters
is possibly due to the deactivation of the ester by the electron-
donating methoxy substituent.
The β-keto phosphine oxides, produced either by low tem-
perature acyl transfer or by treatment of a silyl ketal with TBAF,
were reduced with sodium borohydride to give mixtures of diols
26 to 28 and triols 29 to 31, the result of reductive cleavage
of the second benzoate group. Benzoate cleavage seems to be
time- and temperature-dependent, but is slower than the ketone
120
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126

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activated 4 Å molecular sieves. n-Butyllithium was titrated
against diphenylacetic acid before use. All reactions were
carried out with oven-dried glassware and all reactions in
non-aqueous solutions were carried out under an atmosphere
of argon.
Flash column chromatography was carried out using Merck
Kieselgel 60 (230–400 mesh). Thin layer chromatography was
carried out on commercially available pre-coated plates (Merck
Kieselgel 60F254). Proton, carbon and phosphorus NMR
spectra were recorded on Bruker DPX250, AM400, DRX400
or DRX500 Fourier Transform spectrometers using an internal
deuterium lock. Chemical shifts are quoted in parts per million
down field of tetramethylsilane and values of coupling con-
stants (J) are given in Hz. Carbon NMR spectra were recorded
with broad band proton decoupling and Attached Proton Test
or DEPT. Where indicated the symbols ϩ and Ϫ after the carbon
NMR chemical shift indicate odd and even numbers of
attached protons respectively. Signals marked with * in proton
NMR disappear when a D2O shake is performed.
Melting points were measured on a Stuart Scientific melting
point apparatus (SMP 1) and are uncorrected. Infrared spectra
were recorded on a Perkin-Elmer 1600 (FT-IR) spectro-
photometer. Mass spectra were recorded on a Kratos (MS890)
single beam spectrometer or a micromass platform with an
HP1050 LC system. Microanalyses were carried out by the staff
of the University Chemical Laboratory using Carlo Erba 1106
or Perkin-Elmer 240 automatic analysers.
Fig. 1
It should be noted that these conditions also lead to the removal
of the remaining benzoate group. Similarly, the mixture of
triols 29a and 29b also gave the same alkenediol 32 as a single
geometric isomer, indicating that they both also have C(1)–C(2)
syn-stereochemistry. While the high 1,2-syn-selectivity for the
reduction of β-keto phosphine oxides is well known, the 1,3-
selectivity for this reduction is not well understood.11 Reduction
of ketone 25 produced triols 31a and 31b as a mixture (mono-
benzoate 28 was not detected), and reduction of ketone 24
produced a major diastereoisomer of mono-benzoate 27
without any triol 30. Treatment with sodium hydride gave the
corresponding (E)-alkenediols 33 and 34. The structure of
alkene 34 was confirmed by X-ray crystallography (Fig. 1).
The alkenediols 32–34 are the products of a formal regio-
and enantioselective dihydroxylation of 1,5-diarylpenta-1,4-
dienes. While selective dihydroxylations of dienes are known,
they are usually performed on substrates containing two or
more alkene groups with distinctly different steric or electronic
properties. For instance, Sharpless and co-workers have studied
the asymmetric dihydroxylation of a range of conjugated sys-
tems,12 and Evans et al. have reported a selective dihydroxyl-
ation of a non-conjugated diene as part of a synthesis of
Zaragozic acid C.13 The selective asymmetric dihydroxylation
of (E)-hexa-1,4-diene has been reported by Sharpless and co-
workers. In this case the more substituted double bond reacted
with a 13:1 selectivity.12 Diols such as 32–34 have not been
obtained by simple selective dihydroxylation of symmetrical
or near-symmetrical dienes, and the methodology presented
here represents a simple and extremely adaptable method of
synthesising such compounds.
Optical rotations were recorded on a Perkin-Elmer 241 polar-
imeter (using the sodium D line; 589 nm). Specific rotations are
given in units of 10Ϫ1 deg dm2 gϪ1
.
[(E)-4-Phenylbut-3-enyl]diphenylphosphine oxide 9 and (E,E)-
1,7-diphenyl-4-diphenylphosphinoyl-hepta-1,6-diene 12
By the method of Nelson and co-workers,10 n-butyllithium
(19.5 cm3 of a 2 M solution in hexane; 23.31 mmol) was added
dropwise to a stirred solution of methyldiphenylphosphine
oxide (5.00 g, 23.31 mmol) in dry THF (100 cm3) under argon at
0 ЊC and the deep red solution was cooled to Ϫ78 ЊC. After
1 hour, the lithiated phosphine oxide solution was added by
cannula over a period of 15 minutes to a stirred solution of
cinnamyl bromide (5.2 g, 3.95 cm3, 26.5 mmol) in dry THF (60
cm3) under argon at Ϫ78 ЊC and stirred for 3 h. The resulting
dark green solution was allowed to warm to 10 ЊC overnight
(colour changed to red). Saturated ammonium chloride solu-
tion (50 cm3) was added and the mixture was filtered. The
aqueous layer was extracted with dichloromethane (4 × 100
cm3). The combined organic extracts were washed with brine
(50 cm3), dried (MgSO4) and evaporated under reduced pres-
sure to give a crude product as an orange oil. Purification by
flash chromatography on silica with EtOAc as eluent gave the
alkene product10 9 (3.68 g, 39%) and diene 12 (834 mg, 8%) as
white amorphous solids. The diene product: mp 134–136 ЊC
Conclusion
The synthesis of enantiomerically pure (E)-1,5-diaryl-1,2-
dihydroxypent-4-enes can be performed using a combination
of the stereochemically reliable asymmetric dihydroxylation
reaction and phosphine oxide mediated olefin synthesis. Along
with these reactions it has been shown that the addition of a
lithiated phosphine oxide to a γ-acyloxy substituent occurs
selectively in the presence of a similar δ-substituent, and that
these acyl-transfer products can be reduced with both 1,2- and
1,3-stereoselectivity, en route to diastereo- and enantiomerically
pure alkenediols.
(from EtOAc); Rf (EtOAc) 0.44; νmax(CDCl3)/cmϪ1 1817 (C᎐C),
᎐
1597 (Ph), 1437 (P-Ph) and 1177 (P=O); δH(400 MHz; CDCl3)
8.22–7.81 (4 H, m, o-Ph2PO), 7.53–7.45 (6 H, m, o-Ph2PO,
m-Ph2PO), 7.37–7.15 (10 H, m, Ph), 6.29 (2 H, d, J 15.5,
PhCH), 6.10 (1 H, dt, J 15.5, 6.5, CHCH2), 3.12–2.47 (5 H, m,
CH2 and CH); δC(100 MHz; CDCl3) 137.2Ϫ (i-Ph), 132.6Ϫ (d,
J 94, i-Ph2PO), 132.2ϩ (PhCH), 131.6ϩ (p-Ph2PO), 131.0ϩ (d,
J 8.6, o-Ph2PO), 128.7ϩ (d, J 11.3, m-Ph2PO), 128.4ϩ, 126.1ϩ
(o-Ph, m-Ph), 127.7ϩ (d, J 10.3, PhCHCH), 126.1ϩ, (p-Ph),
38.4ϩ (d, J 69, PCH), 31.3Ϫ (PCHCH2); m/z (EIϩ) 448 (65%,
Experimental
General
Mϩ), 331 (95, Ph P᎐OCH CH CHCHPh) and 201 (100,
᎐
2
2
2
All solvents were distilled before use. THF was freshly distilled
from lithium aluminium hydride whilst CH2Cl2 was freshly
distilled from calcium hydride. Triphenylmethane was used as
an indicator for THF. Methanol was freshly distilled from
sodium methoxide. Diisopropylamine, DMF, and DMSO were
dried by stirring over and distilling from calcium hydride
(at reduced pressure when necessary) and were stored over
Ph2PO) (Found: Mϩ, 448.19665. C31H29OP requires M,
448.19560).
[(E)-4-(4-Methoxyphenyl)but-3-enyl]diphenylphosphine oxide 10
(E)-3-(4-Methoxyphenyl)prop-2-enol14 (0.200 g, 1.22 mmol)
and sodium iodide (0.183 g, 1.22 mmol) were dissolved in dry
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126
121

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THF (10 cm3) under argon and shaded from light by tin foil.
The clear solution was degassed and subsequently trimethylsilyl
chloride (0.33 g, 3.04 mmol) was added slowly at room temper-
ature over a period of 2 min. The resulting solution was stirred
for a further 1 h. In a separate flask n-butyllithium (1.7 cm3 of a
1.44 M solution in hexane, 2.44 mmol) was added at 0 ЊC to a
stirred solution of methyldiphenylphosphine oxide (0.53 g, 2.44
mmol) in dry THF (10 cm3), stirred for 1 h, subsequently cooled
to Ϫ78 ЊC and stirred for a further 15 min. The resulting orange
solution was added by cannula over a period of 10 min at
Ϫ78 ЊC to a stirred solution of the iodide. The resulting yellow
solution was stirred at Ϫ78 ЊC in the dark for 9 h. Saturated
ammonium chloride (5 cm3), water (10 cm3) and ethyl acetate
(30 cm3) were added and the mixture was allowed to warm to
room temperature. The organic layer was separated from the
aqueous layer, washed with 10% sodium thiosulfate solution
(2 × 25 cm3), brine (10 cm3), dried (MgSO4) and evaporated
under reduced pressure to give a crude product as a yellow oil.
Purification by column chromatography on silica with EtOAc
as eluent gave the phosphine oxide (0.195 g, 44%) as a white
solid; Rf (EtOAc) 0.32; a sample was recrystallized (EtOAc–
hexane) as long needles, mp 94–96 ЊC (EtOAc–hexane);
νmax(CH2Cl2)/cmϪ1 1607 (Ar) and 1175 (P᎐O); δ (400 MHz;
pyridine in dry dichloromethane at room temperature. The
reaction was stirred for 18 h, quenched with water, extracted
with dichloromethane, dried and evaporated under reduced
pressure to give the crude product.
(1S,2S)-1,2-Bis(benzoyloxy)-4-diphenylphosphinoyl-1-phenyl-
butane 15
Using the general procedure, triethylamine (4.3 g, 42.5 mmol),
benzoyl chloride (5.3 g, 37.7 mmol), diol 1310 (3.00 g, 8.16
mmol) and 4-(dimethylamino)pyridine (1.70 g, 14.2 mmol) in
dry dichloromethane (70 cm3) gave a crude product. Purific-
ation by flash chromatography on silica with 2:1 EtOAc–
hexane as eluent gave the diester (4.20 g, 98%) as white needles,
mp 159–161 ЊC; Rf (EtOAc–hexane, 2:1) 0.14; [α]D23 Ϫ2.0 (c 1.61,
CHCl3); νmax(CDCl3)/cmϪ1 1720 (C᎐O), 1438 (P–Ph) and 1178
᎐
(P᎐O); δ (400 MHz; CDCl ) 8.02–7.85 (4 H, m, PhCO ), 7.70–
᎐
H
3
2
7.22 (21 H, m, Ph2PO, Ph and PhCO2), 6.10 (1 H, d, J 7.5,
PhCH), 5.70 (1 H, q, J 6.5, CH2CH), 2.40–2.20 (2 H, m, PCH2)
and 2.00–1.90 (2 H, m, PCH2CH2); δC(100.6 MHz; DMSO-d6)
165.0Ϫ (C᎐O), 164.5Ϫ (C᎐O), 137–126 (m, Ph PO and Ph),
᎐
᎐
2
75.7ϩ (PhCH), 75.0ϩ (d, J 15.0, CH2CH), 24.1Ϫ (d, J 72.5,
PCH2) and 22.5Ϫ (PCH2CH2); m/z (ESϩ) 597 (35%, MNaϩ),
576 (100, Mϩ), 453 (22, M Ϫ PhCO2H), 316 (54, M Ϫ
᎐
H
CDCl3) 7.78–7.72 (4 H, m, o-Ph2P), 7.52–7.43 (6 H, m, p-Ph2P),
7.17 (2 H, d, J 8.5, o-MeOC6H4), 6.80 (2 H, d, J 8.5, m-
Ph P᎐OMe, ϪCO ), 261 (30, Ph P᎐OMeCO ) and 217 (49,
᎐
᎐
᎐
2
2
2
2
Ph P᎐OMe) (Found: MNaϩ, 597.1809. C H ONaP requires
2
36 31
MeOC H ), 6.31 (1 H, d, J 16.0, ArCH᎐CH), 6.02 (1 H, dt,
᎐
6
4
M, 597.1807).
J 16.0, 6.5, CHCH2), 3.76 (3 H, s, CH3O), 2.55–2.47 (2 H, m,
PCH2), 2.45–2.38 (2 H, m, CHCH2); δC(100 MHz; CDCl3)
159.3 (CH3OC), 133.4 (d, J 98, i-Ph2PO), 132.1 (d, J 2,
p-Ph2PO), 131.2 (d, J 9, o-Ph2PO), 130.5 (ArCH), 130.4
(i-MeOC6H4), 129.1 (d, J 12, m-Ph2PO), 127.5 (m-MeOC6H4),
127.3 (d, J 15, CHCH2), 55.7 (OCH3), 30.2 (d, J 71, PCH2) and
25.4 (d, J 3, CHCH2); δP(162 MHz; CDCl3) 34.4; m/z (EIϩ) 362
(100%, Mϩ) and 201 (55, Ph2PO) (Found: Mϩ, 362.1413.
C23H23O2P requires M, 362.1435).
(1S,2S)-Bis(4-methoxybenzoyloxy)-4-diphenylphosphinoyl-1-
phenylbutane 16
Using the general procedure, triethylamine (0.80 cm3, 5.73
mmol), 4-methoxybenzoyl chloride (847 mg, 4.97 mmol),
diol 1310 (700 mg, 1.91 mmol) and 4-(dimethylamino)pyridine
(397 mg, 3.25 mmol) gave a crude product. Purification by flash
chromatography on silica with 1:9 MeOH–EtOAc as eluent
gave the diester (1.21 g, >95%) as a white solid, mp 150–152 ЊC
(EtOAc); Rf (MeOH–EtOAc 1:9) 0.34; [α]D23 ϩ3.99 (c 0.60,
(1S,2S)-4-Diphenylphosphinoyl-1–(4-methoxyphenyl)butane-1,2-
diol 14
CHCl3); νmax(CHCl3)/cmϪ1 1712 (C᎐O), 1606 (Ar), 1511 (Ar),
᎐
By the method of Nelson and co-workers,10 AD-mix-α (6.18 g),
methanesulfonamide (0.420 g, 4.41 mmol) and [(E)-4-(4-
methoxyphenyl)but-3-enyl]diphenylphosphine oxide 10 (1.60 g,
4.41 mmol) in 1:1 tert-butyl alcohol–water (88 cm3) (shaded
from the light) were stirred for 5 days to give a crude product as
a white amorphous solid. Purification by flash chromatography
on silica with 1:19 MeOH–EtOAc and then 1:9 MeOH–EtOAc
as eluent gave the diol (1.02 g, 58%) as white needles, mp 130–
132 ЊC (from EtOAc); Rf (MeOH–EtOAc 1:19) 0.32; HPLC:
Chiralpak AD, 13.4 min (isopropyl alcohol–isohexane 30:70,
1 cm3 minϪ1) >99% ee; [α]D19 Ϫ12.9 (c 0.17, CH2Cl2); νmax(CH2-
Cl2)/cmϪ1 3269 (OH), 3069 (OH), 1608 (Ar), 1514 (Ar), 1437
H
3
1437 (P–Ph) and 1169 (P᎐O); δ (400 MHz; CDCl ) 7.91 (2 H,
᎐
d, J 9, o-MeOC6H4), 7.88 (2 H, d, J 9.0, MeOC6H4), 7.65–
7.57 (4 H, m, Ph2PO), 7.51–7.32 (7 H, m, Ph2PO and Ph), 7.30–
7.26 (4 H, m, Ph), 6.819 (2 H, d, J 9, m-MeOC6H4), 6.86 (2 H, d,
J 9 m-MeOC6H4), 6.05 (1 H, d, J 7.5, PhCHOH), 5.69–5.64
(1 H, m, CH2CHO), 3.82 (3 H, s, OCH3), 3.80 (3 H, s, OCH3),
2.38–2.27 (2 H, m, PCH2), 2.00–1.92 (2 H, m, PCH2CH2);
δ (100 MHz; CDCl ) 167.8 (C᎐O), 167.3 (C᎐O), 165.7 (MeOC),
᎐
᎐
C
3
165.6 (MeOC), 138.6 (i-Ph), 134.5 (d, J 99, i-Ph2PO), 134.0–
130.0 (m, Ar), 129.5ϩ (o-MeOC6H4), 124.2 (CCO2), 124.0
(CCO2), 114.1ϩ (m-MeOC6H4), 114.0ϩ (m-MeOC6H4), 78.5ϩ
(PhCHOH), 78.0ϩ (d, J 15, CH2CHO), 57.5ϩ (2 × OCH3),
27.8Ϫ (d, J 72, PCH2) and 25.7Ϫ (br s, PCH2CH2); m/z (EIϩ)
(P–Ph) and 1174 (P᎐O); δ (400 MHz; CDCl ) 7.68–7.61 (4 H,
᎐
H
3
482 (40%, M Ϫ MeOC H OH), 393 (55, M Ϫ Ph P᎐OCH -
᎐
m, o-Ph2PO), 7.51–7.38 (6 H, m, m-Ph2PO, p-Ph2PO), 7.17 (2
H, d, J 8.5, o-MeOC6H4), 6.69 (2 H, d, J 8.5, m-MeOC6H4),
4.89 (1 H, d, J 4.0, OH), 4.31 (1 H, dd, J 7.0, 2.5, ArCHOH),
3.83 (1 H, d, J 2.5, OH), 3.75 (3 H, s, OCH3), 3.73–3.67 (1 H, m,
CH(OH)CH2), 2.45–2.25 (2 H, m, PCH2), 1.73–1.55 (2 H, m,
PCH2CH2); δC(100 MHz; CDCl3) 159.3 (MeOC), 133.5 (i-Me-
OC6H4), 132.5 (d, J 98, i-Ph2PO), 132.3ϩ (p-Ph2PO), 132.0ϩ (d,
J 9, o-Ph2PO), 129.2ϩ (d, J 12, m-Ph2PO), 128.6ϩ (o-MeOC6H4),
114.2ϩ (m-MeOC6H4), 77.5ϩ (ArCHOH), 76.2ϩ (d, J 10, CH2-
CHOH), 55.7ϩ (OCH3), 27.1Ϫ (CH2CH) and 26.2Ϫ (d, J 72,
PCH2); δP(162 MHz; CDCl3) 36.8; m/z (EIϩ) 378 (28%, M Ϫ
6
4
2
2
CH ), 347 (55, Ph P᎐OCH CHCHCHOHPh), 201 (30, Ph PO)
᎐
3
2
2
2
and 135 (100, MeOC6H4CO) (Found: M Ϫ MeOC6H4OH,
482.16424. C30H27O4P requires M, 482.16470).
(1S,2S)-Bis(benzoyloxy)-4-diphenylphosphinoyl-1-(4-methoxy-
phenyl)butane 17
Using the general procedure, triethylamine (0.35 cm3, 2.57
mmol), benzoyl chloride (0.27 cm3, 2.33 mmol), the diol 14
(370 mg, 0.93 mmol), and 4-(dimethylamino)pyridine (171 mg,
1.40 mmol) in dry dichloromethane (10 cm3) were stirred for 8 h
to give a crude product. Purification by flash chromatography
on silica with 2:1 EtOAc–hexane as eluent gave the diester
(323 mg, 57%) as a white solid, mp 160–161 ЊC (from EtOAc);
Rf (EtOAc) 0.33; [α]D23 ϩ3.1 (c 0.71, CH2Cl2); νmax(CH2Cl2)/cmϪ1
H O), 259 (100, Ph P᎐OCH CH CHOH) and 201 (55, Ph PO)
᎐
2
2
2
2
2
(Found: M Ϫ H2O, 378.1384. C23H23O3P requires M, 378.1385).
General procedure for the preparation of benzoic and methoxy-
benzoic acid esters
1721 (C᎐O); δ (400 MHz; CDCl ) 7.96 (2 H, d, J 7.0,
᎐
H
3
Triethylamine and the chosen acid chloride were added drop-
wise to a stirred solution of the diol and 4-(dimethylamino)-
o-PhCO2), 7.90 (2 H, d, J 7.0, o-PhCO2), 7.65–7.57 (4 H, m,
Ph2PO), 7.53–7.29 (14 H, m, Ph2PO and Ar), 6.82 (2 H, d, J 9.0,
122
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126

View Article Online
MeOC6H4), 6.06 (1 H, d, J 8.0, ArCHOH), 5.73–5.68 (1 H, m,
CH2CHO), 3.76 (3 H, s, OCH3), 2.41–2.25 (2 H, m, CH2P),
(1ЈS,2R,3R,5S)-3-Diphenylphosphinoyl-2-(4-methoxyphenyl)-5-
[phenyl(4-methoxybenzoyloxy)methyl]-2-trimethylsilyloxy-
2.03–1.90 (2 H, m, CHCH ); δ (100 MHz; CDCl ) 168.5 (C᎐O),
tetrahydrofuran 20
᎐
2
C
3
167.9 (C᎐O), 162.4 (CH OC), 133–128 (m, Ar), 114.7ϩ
᎐
Using the general procedure, n-butyllithium (0.80 cm3 of a 2.5
M solution in hexane, 2 mmol) diisopropylamine (202 mg,
2 mmol), diester 16 (639 mg, 1.01 mmol), chlorotrimethylsilane
(438 mg, 4.03 mmol) were stirred for 48 h to give the silica
adsorbed residue. Purification by flash chromatography on
silica with ethyl acetate as eluent gave the tetrahydrofuran (638
mg, 89%) as an amorphous solid, mp 88–90 ЊC (from EtOAc);
Rf (EtOAc) 0.55; [α]D19 Ϫ5.8 (c 0.53, CHCl3); νmax(CH2Cl2)/cmϪ1
3
(m-MeOC6H4), 76.9ϩ (ArCHOH), 75.6ϩ (d, J 15, CHOH),
55.7ϩ (CH3O), 26.6Ϫ (d, J 72, PCH2), 25.7Ϫ (PCH2CH2); δP(162
MHz; CDCl3) 32.2; m/z (ESϩ) 627 (100%, MNaϩ), 576 (20,
M Ϫ CH2CH3) and 483 (45, M Ϫ PhCO2) (Found: MNaϩ,
627.1949. C37H33O6NaP requires M, 627.1912).
(1S,2S)-1,2-Bis(4-methoxybenzoyloxy)-4-diphenylphosphinoyl-1-
(4-methoxyphenyl)butane 18
1710 (C᎐O), 1606 (Ar), 1511 (Ar), 1438 (P–Ph) and 1168 (P᎐O);
᎐
᎐
Using the general procedure, triethylamine (0.21 cm3, 1.48
mmol), 4-methoxybenzoyl chloride (225 mg, 4.97 mmol), diol
14 (195 mg, 0.49 mmol) and 4-(dimethylamino)pyridine (128
mg, 1.06 mmol) gave a crude product. Purification by flash
chromatography on silica with EtOAc as eluent gave the diester
(239 mg, 73%) as a white solid, mp 171–172 ЊC (EtOAc); Rf
(EtOAc) 0.26; [α]D23 ϩ14.2 (c 0.52, CHCl3); νmax(CH2Cl2)/cmϪ1
δH(250 MHz; CDCl3) 8.11 (2 H, d, J 9.0, MeOC6H4), 7.67–7.28
(15 H, m, Ph2PO, Ph), 7.18 (2 H, d, J 9.0, MeOC6H4), 6.94 (2 H,
d, J 9.0, MeOC6H4), 6.72 (2 H, d, J 9.0, MeOC6H4), 6.18 (1 H,
d, J 4.0, PhCHO), 5.04 (1 H, dt, J 10.0 and 5.5, CH2CHO), 3.87
(3 H, s, OCH3), 3.80 (3 H, s, OCH3), 3.25 (1 H, dt, J 10.0 and 4.5,
PCH), 2.49–2.18 (2 H, m, CHCH2) and Ϫ0.19 (SiMe3); δC(100
MHz; CDCl ) 165.4Ϫ (C᎐O), 163.5Ϫ (MeOC), 159.0Ϫ (MeOC),
᎐
3
137.0Ϫ, 136.0Ϫ (i-Ar), 133.8Ϫ (d, J 97, i-PhP), 133.2Ϫ (d, J 102,
i-PhP), 130–126 (Ar), 122.5Ϫ (i-Ar), 113.7ϩ (m-MeOC6H4),
112.9ϩ (m-MeOC6H4), 108.3Ϫ (SiOCO), 80.4ϩ (CH2CHO),
76.8ϩ (PhCHOC6H4OMe), 55.5ϩ (CH3O), 55.2ϩ (CH3O), 52.0ϩ
(d, J 73, CHP), 30.4Ϫ (CH2) and 0.8ϩ (SiMe3); m/z (EIϩ) 706
(6%, M), 555 (43, M Ϫ MeOC6H4CO2), 465 (60, M Ϫ MeOC6-
1714 (C᎐O), 1599 (Ar), 1436 (P–Ph) and 1169 (P᎐O); δ (250
᎐
᎐
H
MHz; CDCl3) 7.93 (2 H, d, J 9.0, MeOC6H4CO2), 7.87 (2 H, d,
J 9.0, MeOC6H4CO2), 7.69–7.55 (4 H, m, Ph2PO), 7.53–7.32
(6 H, m, Ph2PO), 7.33 (2 H, d, J 9.0, MeOC6H4), 6.87 (2 H, d,
J 9.0, MeOC6H4), 6.82 (2 H, d, J 9.0, MeOC6H4), 6.81 (2 H, d,
J 9.0, MeOC6H4), 6.01 (1 H, d, J 8.0, CH2CHCH), 5.72–5.61
(1 H, m, CH2CH), 3.84 (3 H, s, OCH3), 3.81 (3 H, s, OCH3),
3.78 (3 H, s, OCH3), 2.39–2.24 (2 H, m, PCH2), 2.02–1.87
H CO H, ϪMe SiOH), 201 (40, Ph P᎐O) and 135 (100, MeOC -
᎐
4
2
3
2
6
H4CO) (Found: Mϩ, 706.25078. C41H43O7PSi requires M,
706.25157).
(2 H, m, PCH CH ); δ (100 MHz; CDCl ) 165.8 (C᎐O), 165.2
᎐
2
2
C
3
(C᎐O), 163.6, 163.4, 159.4 (CH OC), 139–113 (m, Ar), 76.2
᎐
3
(ArCHOH), 74.9 (d, J 15, CH2CHO), 57.5, 57.5, 55.3
(3 × OCH3), 25.6 (d, J 72, PCH2) and 23.2 (d, J 2, PCH2CH2);
m/z (EIϩ) 512 (10%, M Ϫ MeOC6H4CO2H), 201 (30, Ph2PO)
and 135 (100, MeOC6H4CO) (Found: Mϩ, 512.17471.
C31H29O5P requires M, 512.17526).
(1ЈS,2R,3R,5S)-3-Diphenylphosphinoyl-5-[4-methoxyphenyl-
(benzoyloxy)methyl]-2-phenyl-2-trimethylsilyloxytetrahydro-
furan 21
Using the general procedure, n-butyllithium (0.42 cm3 of a 1.44
M solution in hexane, 0.6 mmol) diisopropylamine (65 mg,
0.6 mmol), diester 17 (245 mg, 0.41 mmol) and chlorotrimethyl-
silane (176 mg, 1.62 mmol) gave the silica adsorbed residue.
Purification by flash chromatography on silica with ethyl acet-
ate as eluent gave the tetrahydrofuran (140 mg, 51%) as a white
solid, mp 73–74 ЊC (from EtOAc); Rf (EtOAc) 0.55; [α]D19 ϩ10.6
General procedure for the preparation of ketals
By the method of Hutton and co-workers,7 a solution of LDA
was prepared by the dropwise addition of n-butyllithium (1.5 M
solution in hexane, 2.55 mmol) to a stirred solution of diiso-
propylamine (3.48 mmol) in dry THF (10 cm3) at 0 ЊC. The
prepared LDA was added dropwise to a solution of the diester
(1.74 mmol) and chlorotrimethylsilane (6.97 mmol) in dry THF
(25 cm3) at Ϫ78 ЊC. The reaction mixture was stirred for 4 h and
warmed to room temperature. The reaction was quenched
by the addition of silica (4 g) and evaporated under reduced
pressure to give a silica absorbed residue.
(c 0.53, CHCl3); νmax(CH2Cl2)/cmϪ1 1714 (C᎐O), 1605 (Ar),
᎐
1437 (P–Ph) and 1169 (P᎐O); δ (250 MHz; CDCl ) 8.13 (2 H, d,
᎐
H
3
J 7.5, o-PhCO2), 7.69–7.16 (20 H, m, Ph2PO, Ph, and
MeOC6H4), 6.86 (2 H, d, J 8.5, m-MeOC6H4), 6.16 (1 H, d,
J 5.0, MeOC6H4CHO), 5.15–5.05 (1 H, m, CHO), 3.78 (3 H, s,
OCH3), 3.28 (1 H, dt, J 10.0 and 4.0, PCH), 2.49–2.10 (2 H, m,
CHCH2) and Ϫ0.16 (9 H, SiMe3); δC(100 MHz; CDCl3) 165.8
(C᎐O), 159.7 (CH OC), 145.5 (i-Ar), 135.5–125.7 (m, Ar), 113.9
᎐
3
(m-MeOC6H4), 108.5 (d, J 4, OCO), 80.7 (CH2CHO), 77.2
(ArCHOBz), 55.3 (CH3O), 52.1 (d, J 73, PCH), 30.6 (CH2) and
0.9 (SiMe3); m/z (EIϩ) 661 (15%, M Ϫ Me), 554 (20, M Ϫ
MeOC6H4, ϪMe), 435 (100, M Ϫ MeOC6H4CO2CHPh) and
201 (55, Ph2PO) (Found: M Ϫ Meϩ, 661.21857. C39H38O6PSi
requires M, 661.21753).
(1ЈS,2R,3R,5S)-3-Diphenylphosphinoyl-5-[phenyl(benzoyloxy)-
methyl]-2-phenyl-2-trimethylsilyloxytetrahydrofuran 19
Using the general procedure, n-butyllithium (1.7 cm3 of a 1.5 M
solution in hexane, 2.55 mmol), diisopropylamine (352 mg, 3.48
mmol), diester 15 (1.00 g, 1.74 mmol) and chlorotrimethylsilane
(757 mg, 6.97 mmol) gave the silica adsorbed residue. Purific-
ation by flash chromatography on silica with 2:1 EtOAc–
hexane as eluent gave the tetrahydrofuran (920 mg, 81%) as
colourless needles, mp 77–79 ЊC; Rf (EtOAc–hexane 2:1) 0.68;
[α]D23 ϩ9.8 (c 1.04, CHCl3); νmax(CDCl ) 1720 (C᎐O), 1438 (PhP)
(1ЈS,2R,3R,5S)-3-Diphenylphosphinoyl-5-[4-methoxyphenyl(4-
methoxybenzoyloxy)methyl]-2-(4-methoxyphenyl)-2-trimethyl-
silyloxytetrahydrofuran 22
᎐
3
and 1177 (P᎐O); δ (400 MHz; CDCl ) 8.20–7.10 (25 H, m,
Using the general procedure, n-butyllithium (0.4 cm3 of a 2.5 M
solution in hexane, 1 mmol) diisopropylamine (101 mg,
1 mmol), diester 18 (150 mg, 0.23 mmol) and chlorotrimethyl-
silane (101 mg, 0.90 mmol) were stirred at 0 ЊC for 24 h to give
the silica adsorbed residue. Purification by flash chrom-
atography on silica with ethyl acetate as eluent gave the tetra-
hydrofuran (50 mg, 30%) as an amorphous solid; Rf (EtOAc)
᎐
H
3
Ph), 6.20 (1 H, d, J 5.5, PhCHCH), 5.10 (1 H, dt, J 10.0 and
5.5, PhCHCH), 3.25 (1 H, dt, J 10.5 and 3.5, Ph2POCH), 2.43
(1 H, dddd, J 19.0, 13.0, 5.5 and 4.5, CHACHB), 2.26 (1 H,
ddt, J 29.0, 19.5 and 10.5, CHACHB) and Ϫ0.20 (9 H, Me3Si);
δ (100.6 MHz; CDCl ) 165.0 (C᎐O), 132–124 (m, Ph), 79.9ϩ
᎐
C
3
(PhCHOBz), 76.0ϩ (CH2CHO), 59.6 (COSi), 51.3ϩ (d, J 80.0,
PCH) 29.7Ϫ (CH2) and 0.0ϩ (SiMe3); m/z (EIϩ) 435 (18%,
M Ϫ PhCO2CHPh), 345 (100, M Ϫ PhCO2CHPh, ϪMe3SiO)
and 201 (38, Ph2PO) (Found MNaϩ, 669.2181. C39H39O5SiPNa
requires M, 669.2202).
0.48; νmax(CDCl3)/cmϪ1 1725 (C᎐O), 1605 (Ar), 1441 (P–Ph)
᎐
and 1176 (P᎐O); δ (400 MHz; CDCl ) 8.07 (2 H, d, J 9.0,
᎐
H
3
o-MeOC6H4CO2), 7.64–7.59 (4 H, m, Ph2PO), 7.46 (2 H, d,
J 9.0, o-MeOC6H4), 7.44–7.27 (6 H, m, Ph2PO), 7.16 (2 H, d,
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126
123

View Article Online
J 9.0, o-MeOC6H4), 6.90 (2 H, d, J 9.0, m-MeOC6H4), 6.84
(2 H, d, J 9.0, m-MeOC6H4), 6.70 (2 H, d, J 9.0, m-MeOC6H4),
6.11 (1 H, d, J 5.5, MeOC6H4CHO), 5.02 (1 H, dt, J 10.0 and
5.5, CH2CHO), 3.84 (3 H, s, OCH3), 3.78 (3 H, s, OCH3), 3.76
(3 H, s, OCH3), 3.24 (1 H, dt, J 10.0 and 4.5, PCH), 2.49–2.35
(2 H, m, CHCH2) and Ϫ0.17 (SiMe3); δC(100 MHz; CDCl3)
νmax(CDCl3)/cmϪ1 3586 (OH), 3316 (br, OH) and 1438 (P–Ph);
m/z 495 (100%, MNaϩ) and 473 (3, Mϩ) (Found MNaϩ
495.1699. M, requires 495.1803).
Compound 29. Major diastereoisomer: δH(400 MHz; CDCl3)
7.64–7.56 (4 H, m, Ph2PO), 7.50–7.05 (14 H, m, Ph2PO and
2 × Ph), 7.01–6.96 (2 H, m, Ph), 5.04 (1 H, td, J 5.7 and 15.6,
PCHCHOH), 4.56 (1 H, d, J 6.0, OH), 4.13 (1 H, dd, J 3.4 and
6.5, PhCHOHCHOH), 4.02 (1 H, d, J 3.9, OH), 3.43–3.35 (1 H,
m, CH2CHOH), 3.17 (1 H, d, J 3.2, OH), 3.15–3.07 (1 H,
m, PCH), 1.80–1.60 (2 H, m, CH2); δC(100 MHz; CDCl3) 140.5Ϫ
(Ar), 132–126 (m, Ar), 77.3ϩ, 74.9ϩ, 73.9ϩ (3 × CHOH), 42.4ϩ
(d, J 67.1, CHP) and 30.1Ϫ (CH2).
165.5 (C᎐O), 163.5 (CH OC), 160.9 (CH OC), 159.0 (CH OC),
᎐
3
3
3
137.8 (i-Ar), 134.7 (d, J 97, i-PhP), 134.0 (d, J 102, i-PhP),
131.8–127.0 (m, Ar), 122.6 (i-Ar), 113.8, 113.6, 113.0 (m-Ar),
108.5 (OCOSi), 80.5 (CH2CHO), 77.2 (MeOC6H4CHO), 55.4
(CH3O), 55.2 (CH3O), 55.2 (CH3O), 52.1 (d, J 73, PCH), 30.6
(CH2) and 0.7 (SiMe3); m/z (ESϩ) 759 (100%, MNaϩ) and 735
(5, Mϩ) (Found: MNaϩ, 759.25330. C38H37O7NaP requires M,
759.25190).
Compound 29. Minor diastereoisomer: δH(400 MHz; CDCl3)
7.78–7.72 (2 H, m, Ph2PO), 7.54–7.05 (16 H, m, Ph2PO and
2 × Ph), 6.95–6.90 (2 H, m, Ph), 4.77 (1 H, ddd, J 4.4, 7.8 and
12.3, PCHCHOH), 4.52 (1 H, d, J 4.5, OH), 4.06 (1 H, dd, J 4.7
and 7.1, PhCHOHCHOH), 3.77 (1 H, d, J 4.4, OH), 3.28–3.20
(1 H, m, CH2CHOH), 3.15–3.07 (1 H, m, PCH), 2.84 (1 H, d,
J 3.6, OH), 1.80–1.60 (2 H, m, CH2); δC(100 MHz; CDCl3)
141.8Ϫ (Ar), 132–126 (m, Ar), 78.0ϩ, 74.6ϩ, 73.7ϩ (3 × CHOH),
42.4ϩ (d, J 67.1, CHP) and 30.1Ϫ (CH2).
General procedure for the preparation of triols and mono-
benzoates by acyl transfer
A solution of LDA was prepared by the dropwise addition of
n-butyllithium (1.25 M solution in hexane, 0.44 mmol) to a
stirred solution of diisopropylamine (0.44 mmol) in dry THF
(10 cm3) at 0 ЊC. The prepared LDA was added dropwise to a
solution of the diester (0.83 mmol) in dry THF (10 cm3) at
Ϫ78 ЊC and stirred for 5 h. The reaction mixture was quenched
with saturated ammonium chloride and subsequently warmed
to room temperature. Ethyl acetate (50 cm3) was added and the
mixture filtered. The aqueous layer was separated from the
organic layer and extracted with ethyl acetate (2 × 50 cm3). The
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure to give a crude product which was
dissolved in refluxing ethanol (12 cm3) and sodium borohydride
(1 to 5 eq.) added. The mixture was heated under reflux for 4 h
and then cooled to room temperature. Saturated ammonium
chloride (6 cm3) was added and the ethanol removed under
reduced pressure. The aqueous residue was acidified by the
addition of dilute HCl, diluted with brine (10 cm3) and
extracted with dichloromethane (3 × 40 cm3). The organic
layers were pooled, dried (MgSO4) and evaporated under
reduced pressure to give the crude product.
Compound 26(a or b). Major diastereoisomer: (130 mg, 28%)
has the following data: Rf (EtOAc–hexane) 0.11; [α]D23 Ϫ24.8
(c 0.139, CH2Cl2); νmax(CDCl3)/cmϪ1 3589 (OH), 3316 (br, OH),
1437 (P–Ph) and 1177 (P᎐O); δ (400 MHz; CDCl ) 7.92 (2 H, d,
᎐
H
3
J 7.1 Ar), 7.74–7.62 (4 H, m, Ph2PO), 7.55 (1 H, br t, J 6.2, Ar),
7.47–7.28 (8 H, m, Ph2PO and Ar), 7.26–7.20 (5 H, m, Ar),
7.15–7.11 (3 H, m, Ar), 7.07–7.03 (2 H, m, Ar), 5.51 (1 H, d,
J 4.9, PhCHOCOPh), 5.13 (1 H, dd, 2.4 and 4.5, OH), 4.87 (1
H, ddd, J 4.3, 7.2 and 15.0, PhCHOH), 3.35–3.25 (2 H, m, PCH
and CHOH), 2.63 (1 H, dd, J 4.8 and 8.6, OH), 1.65 (1 H, br q,
J 11.0, CHAHB) and 1.42–1.34 (1 H, m, CHAHB); δC(100 MHz,
CDCl3) 165.5Ϫ (C᎐O), 142.1Ϫ (Ar), 136.8Ϫ (Ar), 134–126 (m,
᎐
Ar), 79.2ϩ (PhCHOCOPh), 74.5ϩ (CHOH), 71.2ϩ (d, J 10.3,
PhCHOH), 40.4ϩ (d, J 67.3, PCH) and 29.9Ϫ (CH2); m/z (ESϩ)
599.2 (48%, MNaϩ), 576.4 (M) and 558.4 (M Ϫ H2O); m/z
(EIϩ) 201 (100%, Ph2PO) (Found MNaϩ 599.1989. M, requires
599.1963).
(1R,2R,4S,5S)- or (1S,2S,4S,5S)-5-Benzoyloxy-2-diphenyl-
phosphinoyl-1,5-diphenylpentane-1,4-diol 26(a or b) and
(1R,2R,4S,5S)- and (1S,2S,4S,5S)-2-diphenylphosphinoyl-
1,5-diphenylpentane-1,4,5-triol 29(a and b)
(1R,2R,4S,5S)- or (1S,2S,4S,5S)-5-(4-Methoxybenzoyloxy)-2-
diphenylphosphinoyl-1-(4-methoxyphenyl)-5-phenylpentane-1,4-
diol 27(a or b)
A solution of LDA was prepared by the dropwise addition of
n-butyllithium (0.6 cm3 of a 2 M solution in hexane, 1.2 mmol)
to a stirred solution of diisopropylamine (0.168 cm3, 1.2 mmol)
in dry THF (10 cm3) at 0 ЊC. The prepared LDA was added
dropwise to a solution of the diester 15 (0.460 g, 1 mmol) in dry
THF (10 cm3) at Ϫ78 ЊC and stirred for 5 h. The reaction
mixture was quenched with saturated ammonium chloride (10
cm3) and subsequently warmed to room temperature. Ethyl
acetate (50 cm3) was added and the mixture filtered. The aque-
ous layer was separated from the organic layer and extracted
with ethyl acetate (2 × 50 cm3). The combined organic extracts
were dried (MgSO4) and evaporated under reduced pressure to
give an off-white solid which was dissolved in ethanol (14 cm3)
and sodium borohydride (25 mg, 5 mmol, 5 eq.) added. The
mixture was heated under reflux for 4 h and then cooled to
room temperature. Saturated ammonium chloride (10 cm3) was
added and the ethanol was removed under reduced pressure.
The aqueous residue was acidified by the addition of dilute
HCl, diluted with brine (10 cm3) and extracted with dichloro-
methane (3 × 40 cm3). The combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure to give
an amorphous white solid. Purification by flash chrom-
atography on silica with 1:1 EtOAc–hexane as eluent gave the
triols 29 and mono-benzoate 26 as a colourless oil. The triol (232
mg, 60%) was an inseparable 3.4:1 mixture of diastereoisomers
which has the following data: Rf (EtOAc–hexane 1:1) 0.03;
A solution of tetra-n-butylammonium fluoride in tetrahydro-
furan (1 M, 0.29 cm3, 0.29 mmol, 1.0 eq.) was added at room
temperature to a solution of tetrahydrofuran 20 (204 mg, 0.29
mmol, 1.0 eq.) in tetrahydrofuran (8 cm3). The resulting yellow
solution was stirred for 30 min and became brown. The solvent
was evaporated under reduced pressure and the residue (brown
oil) was filtered through a pad of silica gel (1 cm) eluting with
ethyl acetate (250 cm3) and evaporated to give an off-white
foam. This was dissolved in absolute ethanol (15 cm3), sodium
borohydride was added in intervals of approximately 3 h (110
mg, 2.9 mmol) and the resulting solution was stirred overnight.
Saturated ammonium chloride (5 cm3) was added and the
ethanol was removed under reduced pressure. The aqueous
residue was diluted with brine (5 cm3), acidified with dilute
hydrochloric acid and extracted with dichloromethane (3 × 75
cm3). The combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure. Purification by flash
chromatography on silica with 1:19 MeOH–CH2Cl2 as eluent
gave the diol (59 mg, 34%) as a single diastereoisomer as a thick
oil; Rf (MeOH–CH2Cl2 1:19) 0.28; [α]D19 Ϫ23.7 (c 0.9, CHCl3);
νmax(CDCl3)/cmϪ1 3690 (OH), 3603 (br OH), 1712 (C᎐O), 1438
᎐
(P–Ph) and 1168 (P᎐O); δ (400 MHz; CDCl ) 7.87 (2 H, d,
᎐
H
3
J 9.0, o-MeOC6H4), 7.73–7.04 (17 H, m, Ph2PO, Ph and
o-MeOC6H4), 6.87 (2 H, d, J 9.0, m-MeOC6H4), 6.67 (2 H, d,
J 9.0, m-MeOC6H4), 5.48 (1 H, d, J 5.0, PhCH), 4.99 (d, 1H,
124
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126

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J 4.0, OH), 4.82 (1 H, ddd, J 12.0, 8.0 and 4.0, MeOC6H4CHO),
3.87 (3 H, s, OCH3), 3.74 (3 H, s, OCH3), 3.26–3.23 (2 H, m,
PCH and CHOH), 2.65 (1 H, br s, OH) and 1.70–1.24 (2 H, m,
suspension was heated to 50 ЊC over 10 min during which a
white precipitate was formed. The reaction mixture was stirred
for a further 30 min until the diphenylphosphine oxide was con-
sumed according to TLC and subsequently cooled to room
temperature. Water (7 cm3) was added and the white precipitate
dissolved. The mixture was diluted with brine (7 cm3) and
extracted with EtOAc (3 × 30 cm3). The combined organic
extracts were washed with dilute HCl (0.1 M, 3 × 10 cm3), brine
(5 cm3), dried (MgSO4) and evaporated under reduced pressure
to give the crude product.
CHCH ); δ (100 MHz; CDCl ) 165.5 (C᎐O), 163.5 (CH OC),
᎐
2
C
3
3
159.2 (CH3OC), 137.1 (i-Ar), 134.1 (i-Ar), 132.0–126.4 (m, Ar),
122.1 (i-Ar), 113.6, 113.4 (m-MeOC6H4), 78.8, 74.1, (CHO),
71.4 (d, J 9, CH2CHO), 55.5 (OCH3), 55.2 (OCH3), 40.7
(d, J 68, CHP) and 29.9 (CH2); m/z (ESϩ) 659 (20%, MNaϩ),
637 (40, MHϩ), 467 (100, M Ϫ MeOC6H4CO2, ϪH2O) and
265 (60, MeOC6H4CHOHCHCHCHCHPh) (Found: MNaϩ,
659.21440. C38H37O7NaP requires M, 659.21746).
(E,1S,2S)-1,2-Dihydroxy-1,5–diphenylpent-4-ene 32
(1R,2R,4S,5S)- and (1S,2S,4S,5S)-2-Diphenylphosphinoyl-5-
(4-methoxyphenyl)-1-phenylpentane-1,4,5-triol 31(a and b)
Using the general procedure, sodium hydride (27 mg, 0.68
mmol), triol 29 (109 mg, 0.23 mmol) in dry DMF (7 cm3) gave a
crude product. Purification by flash chromatography on silica
with 1:1 EtOAc–hexane as eluent gave the alkene (35 mg, 60%)
as a colourless oil; Rf (EtOAc–hexane 1:1) 0.33; [α]D23 Ϫ12.6
(c 0.3, CHCl3); νmax(CDCl3)/cmϪ1 3682 (OH), 3618 (OH) and
A solution of LDA was prepared by the dropwise addition
of n-butyllithium (0.79 cm3 of a 1.25 M solution in hexane,
1.0 mmol) to a stirred solution of diisopropylamine (0.1 g,
1.0 mmol) in dry THF (10 cm3) at 0 ЊC. The prepared LDA was
added dropwise to a solution of the diester 17 (500 mg, 0.83
mmol) in dry THF (10 cm3) at Ϫ78 ЊC and stirred for 5 h. The
reaction mixture was quenched with saturated ammonium
chloride (10 cm3) and subsequently warmed to room temper-
ature. Ethyl acetate (50 cm3) was added and the mixture filtered.
The aqueous layer was separated from the organic layer and
extracted with ethyl acetate (2 × 50 cm3). The combined organic
extracts were dried (MgSO4) and evaporated under reduced
pressure to give an off-white solid (405 mg) which was dissolved
in ethanol (12 cm3) and sodium borohydride (25 mg, 0.67
mmol, 1 eq.) was added. The mixture heated at reflux for 4 h
and then cooled to room temperature. Saturated ammonium
chloride (6 cm3) was added and the ethanol was removed under
reduced pressure. The aqueous residue was acidified by the add-
ition of dilute HCl, diluted with brine (10 cm3) and extracted
with dichloromethane (3 × 40 cm3). The organic layers were
pooled, dried (MgSO4) and evaporated under reduced pressure
to give an amorphous solid. Purification by flash chrom-
atography on silica with 1:9 MeOH–EtOAc as eluent gave the
triol (209 mg, 50%) as a white amorphous solid, an inseparable
3:2 mixture of diastereoisomers which has the following
data; Rf (EtOAc) 0.30; νmax(CDCl3)/cmϪ1 3684 (OH), 3592
1521 (C᎐C); δ (400 MHz; CDCl ) 7.38–7.22 (10 H, m, 2 × Ph),
᎐
H
3
6.41 (1 H, d, J 15.9, PhCHCH), 6.20 (1 H, ddd, J 6.9, 8.2 and
15.9, PhCHCH), 4.54 (1 H, d, J 6.8, PhCHOH), 3.84 (1 H, ddd,
J 4.3, 7.0 and 7.5, CH2CHOH), 2.35–2.25 (2 H, m, CH2) (no
OH peaks observed); δC(100 MHz; CDCl3) 140.8Ϫ (i-Ph),
137.2Ϫ (i-Ph), 133.2ϩ, 130.2ϩ, 128.6ϩ, 128.5ϩ, 128.4ϩ, 128.2ϩ,
127.3ϩ, 126.9ϩ, 126.1ϩ, 125.7ϩ (2 × Ph and C᎐C), 75.4ϩ
᎐
(2 × CHOH), 36.5Ϫ (CH2); m/z (ESϩ) 277 (100%, Mϩ) (Found
MNaϩ, 277.11990. C17H18O2Na requires M, 277.1204).
Alternative synthesis of (E,1S,2S)-1,2-dihydroxy-1,5-
diphenylpent-4-ene 32
Sodium hydride (15 mg, 0.4 mmol), diol 26 (70 mg, 0.12 mmol)
in dry DMF (3 cm3) gave by the same general procedure as for
compound 32 above a crude product. Purification by flash
chromatography on silica with 1:1 EtOAc–hexane as eluent
gave the alkene (50 mg, 71%) as a colourless oil (Data identical
to that above).
(E,1S,2S)-1,2-Dihydroxy-1-phenyl-5-(4-methoxyphenyl)pent-4-
ene 33
(OH), 3339 (br OH), 1438 (P–Ph) and 1174 (P᎐O); m/z (ESI)
᎐
By the general procedure for compound 26: sodium hydride
(5.9 mg, 0.15 mmol) and diol 27 (47 mg, 0.07 mmol) gave the
crude product. Purification by flash chromatography on silica
with 1:1 EtOAc–hexane as eluent gave the alkene (7 mg, 35%)
as a yellow oil; Rf (EtOAc–hexane 1:1) 0.43; [α]D23 Ϫ3.6 (c 0.2,
CHCl3); δH(500 MHz; CDCl3) 7.38–7.34 (4 H, m, Ar and Ph),
7.33–7.27 (1 H, m, Ph), 7.26–7.24 (2H, m, Ph), 6.82 (2 H, d,
J 8.5, m-MeOC6H4), 6.37 (1 H, d, J 16.0, MeOC6H4CHCH),
6.04 (1 H, ddd, J 16.0, 8.0, and 7.0, MeOC6H4CHCH), 4.54
(1 H, d, J 6.5, PhCHOH), 3.84–3.80 (1 H, m, CH2CHOH), 3.79
(3H, s, OCH3), 2.69 (1 H, br s, OH), 2.38 (1 H, br s, OH) and
2.36–2.15 (2 H, m, CH2); δC(100 MHz; CDCl3) 159.0Ϫ
(CH3OC), 140.8Ϫ (i-Ar), 132.7ϩ (ArCH), 129.9Ϫ (i-Ar), 128.5ϩ,
127.2ϩ, 126.9ϩ (o-Ar, m-Ar), 128.1ϩ, 123.2ϩ (p-Ph, ArCHCH),
113.9ϩ (m-MeOC6H4), 77.5ϩ (PhCHOH), 75.4ϩ (CH2CHOH),
55.2ϩ (CH3O) and 36.5Ϫ (CH2); m/z (EIϩ) 284 (20%, Mϩ), 147
(100, MeOC6H4CHCHCH2), 134 (50, MeOC6H4CHCH) and
121 (70, MeOC6H4CH) (Found: Mϩ, 284.14006. C18H20O3
requires M, 284.14125).
503 (100%, MHϩ), 467 (75, M Ϫ 2 × OH) and 265 (79,
M Ϫ 2 × OH, ϪPh2PO) (Found: (M Ϫ MeOC6H4CHOH)ϩ,
365.1292. C22H22O3P requires M, 365.1307).
Major diastereoisomer: δH(500 MHz; DMSO-d6) 7.76–7.68
(3 H, m, Ph2PO), 7.64–7.60 (1 H, m, Ph2PO), 7.54–7.35 (6 H, m,
Ph2PO), 7.27–7.08 (5 H, m, Ph), 6.85 (2 H, d, J 8.5, MeOC6H4),
6.72 (2 H, d, J 8.5, MeOC6H4), 5.50 (1 H, d J 4.5, OH), 4.86
(1 H, d, J 4.5, MeOC6H4CH), 4.83–4.75 (1 H, m, PhCH), 4.71
(1 H, d, J 4.5, OH), 3.85–3.83 (1 H, m, CH(OH)CH2), 3.70 (3
H, s, OCH3), 3.33–3.19 (2 H, m, PCH and OH) and 1.42–1.17
(2 H, m, CH2); δC(100 MHz; DMSO-d6) 159.3 (MeOC), 143.2–
126.9 (m, Ar), 113.2 (m-MeOC6H4), 76.7 (CHO), 73.2 (d, J 9,
CHO), 72.8 (CHO), 41.2 (d, J 69, CHPO) and 29.0 (CH2).
Minor diastereoisomer: δH(500 MHz; DMSO-d6) 7.76–7.68
(3 H, m, Ph2PO), 7.64–7.60 (1 H, m, Ph2PO), 7.54–7.35 (6 H, m,
Ph2PO), 7.27–7.08 (5 H, m, Ph), 6.85 (2 H, d, J 8.5, MeOC6H4),
6.70 (2 H, d, J 8.5, MeOC6H4), 5.68 (1 H, d, J 4.5, OH), 4.88
(1 H, d, J 4.5, MeOC6H4CH), 4.83–4.75 (1 H, m, PhCH), 4.80
(1 H, d, J 4.5, OH), 4.02–4.00 (1 H, m, CH(OH)CH2), 3.70
(3 H, s, OCH3), 3.33–3.19 (2 H, m, PCH and OH), 1.42–1.17
(2 H, m, CH2); δC(100 MHz; DMSO-d6) 159.2 (MeOC), 143.2–
126.9 (m, Ar), 113.2 (m-MeOC6H4), 75.6 (CHO), 72.5 (d, J 9,
CHO), 73.2 (CHO), 41.2 (d, J 69, CHPO), 29.0 (CH2).
(E,1S,2S)-1,2-Dihydroxy-1-(4-methoxyphenyl)-5-phenylpent-4-
ene 34
Using the general procedure, sodium hydride (30 mg, 0.75
mmol), triol 31 (132 mg, 0.26 mmol) in dry DMF (7 cm3) gave a
crude product. Purification by flash chromatography on silica
with 1:1 EtOAc–hexane as eluent gave the alkene (45 mg, 60%)
which was recrystallised from diethyl ether–petroleum ether
(40–60 ЊC) (1:1) to give needles, mp 66–67 ЊC (diethyl ether);
General procedure for the preparation of diol containing alkenes
Sodium hydride (0.75 mmol) was added under argon to a solu-
tion of the triol (0.26 mmol) in dry DMF (7 cm3). The resulting
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126
125

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Rf (EtOAc–hexane 1:1) 0.29; [α]D23 Ϫ20.7 (c 0.61, CHCl3);
British Biotech for a CASE award (M. D. E.), the Danish
νmax(CDCl3)/cmϪ1 3686 (OH), 3603 (br, OH) and 1612 (C᎐C);
Natural Science Research Council and the Danish Technical
Research Council (T. B.), Pfizer and the Newton Trust (C. R. T.)
for financial support. Most particularly we acknowledge
the influence of the late Ron Snaith on our work. He taught us
to see organo-lithium compounds as they really are as well as
contributing the skills essential for the isolation and character-
isation of these vital intermediates. Such confidence as we have
in interpreting the reactions in this paper come from our long
association with Ron. We all miss him very much.
᎐
δH(400 MHz; CDCl3) 7.35–7.28 (6 H, m, Ar-H), 7.22 (1 H, t,
J 7.0, Ar-H), 6.91 (2 H, d, J 8.5, Ar-H), 6.41 (1 H, d, J 16.0,
PhCHCH), 6.20 (1 H, ddd, J 16.0, 8.0 and 7.0, PhCHCH),
4.49 (1 H, br d, J 7.0, CH(OH)Ar), 3.85–3.79 (4 H, m,
CH2CHOH and OMe), 2.76 (1 H, d, J 2.5, OH), 2.59 (1 H, d,
J 2.8, OH), 2.33 (1 H, dddd, J 14.5, 7.0, 4.0 and 1.2, CHAHB)
and 2.25 (1 H, dtd, J 14.5, 8.0 and 1.2, CHAHB); δC(100 MHz;
CDCl3) 157.5Ϫ (MeOC), 135.2Ϫ (i-Ar), 131.0ϩ (PhCH), 130.8Ϫ
(i-Ar), 126.4ϩ, 126.1ϩ, 124.0ϩ (o-Ar, m-Ar), 125.2ϩ, 123.7ϩ
(p-Ph, PhCHCH), 111.9ϩ (m-MeOC6H4), 74.9ϩ (MeOC6H4-
CHOH), 73.4ϩ (CH2CHOH), 53.2ϩ (CH3O) and 34.5Ϫ (CH2);
m/z (EIϩ) 284 (23%, Mϩ), 137 (100, MeOPhCHOH), 121 (37,
MeOC6H4CH) (Found: Mϩ, 284.14010. C18H20O3 requires M,
284.14125).
References
1 J. Clayden and S. Warren, Angew. Chem., Int. Ed. Engl., 1996, 35,
241.
2 A. D. Buss and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1985,
2307.
Single crystals of 34 were recrystallised from EtOAc–
hexanes, mounted in inert oil and transferred to the cold gas
stream of the diffractometer.
3 B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachmann and
D. J. Weinkauff, J. Am. Chem. Soc., 1977, 99, 5946.
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Crystal structure determination of alkenediol 34
Crystal data.† C18H20O3, M = 284.34, monoclinic, a =
11.3620(10), b = 4.8730(5), c = 13.9800(8) Å, β = 100.937(6)Њ,
U = 759.97(11) Å3, T = 180(2) K, space group P21, Z = 2, µ(Mo-
Kα) = 0.083 mmϪ1, 4628 reflections measured, 2306 unique
(Rint = 0.0441) which were used in all calculations. The final
wR(F2) was 0.1003 (all data). The absolute stereochemical
configuration was not determined.
9 J. Eames, H. J. Mitchell, A. Nelson, P. O’Brien, S. Warren and
P. Wyatt, Tetrahedron Lett., 1995, 36, 1719.
10 A. Nelson and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1997, 2645.
11 A. Nelson and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1999,
1963.
Acknowledgements
12 D. Xu, G. A. Crispino and K. B. Sharpless, J. Am. Chem. Soc., 1992,
114, 7570.
We thank the EPSRC for a studentship (J. A. M.), BBSRC and
13 D. A. Evans, J. C. Barrow, J. L. Leighton, A. J. Robichaud and
M. Sefkow, J. Am. Chem. Soc., 1994, 116, 12111.
14 T. A. Engler, K. O. LaTessa, R. Iyengar, W. Y. Chai and K. Agrios,
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† CCDC reference number 152854. See http://www.rsc.org/suppdata/
p1/b0/b008500f/ for crystallographic data in CIF or other electronic
format.
126
J. Chem. Soc., Perkin Trans. 1, 2001, 118–126