Stereoselective synthesis of allylic amines by rearrangement of allylic trifluoroacetimidates: Stereoselective synthesis of polyoxamic acid and derivatives of other α-amino acids

Article abstract of DOI:10.1039/a905772b

On heating in xylene under reflux, allylic trifluoroacetimidates undergo [3,3] sigmatropic rearrangement to regioisomeric allylic trifluoroacetamides. Examples include the rearrangements of the trifluoroacetimidates 16 and 73 to the trifluoroacetamides 17 and 74, which were incorporated into stereoselective syntheses of polyoxamic acid 1, and the rearrangement of the trifluoroacetimidate 26. The rearrangement was the key step in asymmetric syntheses of the (S)- and (R)-valine derivatives 37 and 48. Other examples include rearrangements of the trifluoroacetimidates 52, 54 and 56 prepared from geraniol, cinnamyl alcohol and sorbyl alcohol, respectively, and the more complex trifluoroacetimidates 62 and 69. The stereoselectivity of these rearrangements, which are somewhat faster than rearrangements of analogous allylic trichloroacetimidates, is consistent with the participation of chair-like, six-membered, transition structures. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905772b

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Stereoselective synthesis of allylic amines by rearrangement of
allylic trifluoroacetimidates: stereoselective synthesis of polyoxamic
acid and derivatives of other ꢀ-amino acids
Ian Savage,a Eric J. Thomas*b and Peter D. Wilsonb
a The Dyson Perrins Laboratory, South Parks Road, Oxford, UK OX1 3QY
b The Department of Chemistry, The University of Manchester, Manchester, UK M13 9PL
Received (in Cambridge, UK) 19th July 1999, Accepted 10th September 1999
On heating in xylene under reflux, allylic trifluoroacetimidates undergo [3,3] sigmatropic rearrangement to
regioisomeric allylic trifluoroacetamides. Examples include the rearrangements of the trifluoroacetimidates 16 and
73 to the trifluoroacetamides 17 and 74, which were incorporated into stereoselective syntheses of polyoxamic acid 1,
and the rearrangement of the trifluoroacetimidate 26. The rearrangement was the key step in asymmetric syntheses
of the (S)- and (R)-valine derivatives 37 and 48. Other examples include rearrangements of the trifluoroacetimidates
52, 54 and 56 prepared from geraniol, cinnamyl alcohol and sorbyl alcohol, respectively, and the more complex
trifluoroacetimidates 62 and 69. The stereoselectivity of these rearrangements, which are somewhat faster than
rearrangements of analogous allylic trichloroacetimidates, is consistent with the participation of chair-like, six-
membered, transition structures.
The [3,3] sigmatropic rearrangement of allylic trichloroacetim-
idates introduced and developed by Overman, is widely used for
the stereoselective synthesis of amines.1 Polyoxamic acid 1 a
through to polyoxamic acid 1 and its 2-epimer. Since the
Overman rearrangement is known to proceed with effective 1,3-
transfer of chirality,1 it was decided to investigate the rearrange-
ment of trichloroacetimidates derived from the chiral alcohols
6 as a stereoselective route via amines 7 to polyoxamic acid 1.
During the course of this work, the [3,3] sigmatropic rearrange-
ments of trifluoroacetimidates were investigated. We here report
full details of these investigations including stereoselective
syntheses of polyoxamic acid and derivatives of other α-amino
acids using trifluoroacetimidates.5,6
Results and discussion
Stereoselective synthesis of polyoxamic acid
The trichloroacetimidate 14 was prepared as outlined in
Scheme 1. The ylide 10 was prepared from the thioester 9 and
an excess of methylenetriphenylphosphorane, and on heating
with the -threose derivative 117 in benzene under reflux gave a
good yield of the enone 12. Reduction of this enone using
-Selectride at Ϫ78 ЊC was highly stereoselective and gave the
alcohol 13, the all-syn configuration initially being assigned to
the alcohol on the basis of Felkin–Anh control of the reduc-
tion,8 and was later confirmed by the conversion of the alcohol
component of the polyoxins, a group of nucleoside antibiotics
exemplified by polyoxin B 2,2 has been the subject of many
synthetic studies3 including an early non-stereoselective syn-
thesis based on the Overman rearrangement of the trichloro-
acetimidate 3.4 This rearrangement gave a mixture of the
trichloroacetamides 4 and 5 which were separated and taken
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303
This journal is © The Royal Society of Chemistry 1999
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Scheme 1 Reagents and conditions: i, KOH, MeOH then dicyclohexylcarbodiimide, 2-mercaptopyridine (70%); ii, Ph3PMeBr, butyllithium (75%);
iii, benzene, reflux, 5 h (85%); iv, -Selectride, tetrahydrofuran, Ϫ78 ЊC, 40 min (90%); v, butyllithium, trichloroacetonitrile (85%); vi, xylene, heat,
48 h (40%).
Scheme 2 Reagents and conditions: i, xylene, heat, 20 h (80%); ii, NaBH4, ethanol (75%); iii, (Boc)2O, Et3N (>95%); iv, ozone, methanol, dimethyl
sulfide; v, RuCl3, NaIO4, MeCN (69%); vi, trifluoroacetic acid, methanol (72%); vii, Ac2O, methanol (60%).
13 into polyoxamic acid 1. It was important to quench this
reduction by the addition of glacial acetic acid at a low tem-
perature. If the reaction mixture was allowed to warm to room
temperature before acidification, a mixture of the alcohol 13
and its regioisomer in which the tert-butyldiphenylsilyl group
had migrated from the 4-OH to the 3-OH was obtained. Con-
version of the alcohol 13 into the trichloroacetimidate 14 was
carried out by deprotonation of the alcohol using butyllithium
and addition of the solution of the alkoxide to a solution of
trichloroacetonitrile (85%).9
The rearrangement of the trichloroacetimidate 14 into the
trichloroacetamide 15 was carried out by heating under reflux
in xylene and was highly stereoselective, the syn-configuration
of the product being assigned on the basis of participation of a
chair-like transition structure in the [3,3] sigmatropic rearrange-
ment.1 However, the reaction required heating for a long period
of time for completion (ca. 48 h) and only a modest yield (40%)
of the trichloroacetamide was isolated because of competing
decomposition under the prolonged reaction conditions. The
slowness of the reaction was attributed to the presence of
several oxygen-containing, electron-withdrawing groups in the
allyl component of the trichloroacetimidate.10 It was decided to
investigate the rearrangement of the corresponding trifluoro-
acetimidate since it was felt that the presence of three, very
electron-withdrawing, fluorine substituents in the acetimidate
component would allow the sigmatropic rearrangement to
proceed under milder conditions.1
The trifluoroacetimidate 16 was prepared by adding a solu-
tion of the lithium alkoxide of the alcohol 13 to a solution of
trifluoroacetonitrile in tetrahydrofuran at Ϫ78 ЊC,11 see Scheme
2. The rearrangement of the trifluoroacetimidate into the tri-
fluoroacetamide 17 in xylene under reflux was found to be
highly stereoselective and was complete after 20 h. A good yield
(85%) of the trifluoroacetamide 17 was obtained with no other
stereoisomer being isolated or detected (≤4%). To complete a
stereoselective synthesis of polyoxamic acid, the trifluoro-
acetamide 17 was converted into the amine 18 by reduction
using sodium borohydride in ethanol12 and the amine con-
verted into the carbamate 19 under standard conditions.
Ozonolysis of the carbamate gave the aldehyde 20 which was
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Scheme 3 Reagents and conditions: i, 10, benzene, heat (65%); ii, -Selectride, tetrahydrofuran, Ϫ78 ЊC, then add acetic acid (82%); iii, butyllithium,
trifluoroacetonitrile, Ϫ78 ЊC (70%); iv, xylene, heat, 20 h (76%).
immediately converted into the acid 21 using ruthenium tri-
chloride and sodium periodate.13 Deprotection using trifluoro-
acetic acid then gave polyoxamic acid 1 the structure of which
was confirmed by conversion into the lactone 22 on treatment
with acetic anhydride, and direct comparison of the lactone
with an authentic sample.4
To check that the stereoselectivity of the trifluoroacetimidate
rearrangement was not being influenced significantly by the
presence of remote chiral centres in the substrate, rearrange-
ment of the isomeric trifluoroacetimidate 26 was examined, see
Scheme 3. This was prepared from the threose derivative 23 and
was found to rearrange stereoselectively to the trifluoro-
acetamide 27 (76%) on heating in xylene under reflux; no other
isomeric rearrangement product was isolated or detected
(≤4%).
It would appear that the [3,3] sigmatropic rearrangement of
allylic trifluoroacetimidates to allylic trifluoroacetamides is an
efficient process. It was decided to investigate this reaction
further to evaluate its use for stereoselective synthesis.
Further evaluation of the allylic trifluoroacetimidate to
trifluoroacetamide rearrangement
The trifluoroacetimidate rearrangement was applied to com-
plete asymmetric syntheses of derivatives of (S)- and (R)-
valine, see Schemes 4 and 5. In this work it was decided to use
chelation control to direct the reduction of the intermediate
enone to avoid the problems associated with migration of the
O-silyl protecting group encountered during the synthesis of
polyoxamic acid.
Isobutyl (R)-lactate 28 was protected as its benzyloxymethyl
ether 29 which was converted into the ketophosphonate 30 by
treatment with lithiated dimethyl methylphosphonate. Conden-
sation of this ketophosphonate with 2-methylpropanal gave the
enone 31 (77%) which was reduced to the anti-alcohol 32 using
zinc borohydride,14 ca. 99:1 anti:syn stereoselectivity,† the anti-
configuration being assigned to the major product on the basis
of chelation control of the reduction.8 The alcohol 32 was
converted into the trifluoroacetimidate 33 by treatment with
butyllithium and trifluoroacetonitrile at Ϫ78 ЊC, the optimum
conditions requiring only a catalytic amount of base. The [3,3]
rearrangement of the trifluoroacetimidate proceeded cleanly in
xylene heated under reflux to give the trifluoroacetamide 34
Scheme 4 Reagents and conditions: i, benzyl chloromethyl ether, N,N-
diisopropylethylamine (83%); ii, (MeO)2P(O)CH2Li, tetrahydrofuran
(92%); iii, lithium chloride, DBU, 2-methylpropanal (77%); iv,
Zn(BH4)2, ether, Ϫ35 ЊC (97%); v, butyllithium (0.2 eq.), trifluoroac-
etonitrile, Ϫ78 ЊC (90%); vi, xylene, reflux, 4 h (89%); vii, Ba(OH)2,
methanol; viii, Boc2O, Et3N, ether (79% from 34); ix, ozone, methanol,
Ϫ78 ЊC, then dimethyl sulfide followed by bromine in methanol (65%);
x, trifluoroacetic acid, methanol; xi, (S)-methoxytrifluoromethyl-
phenylacetyl chloride, pyridine (73% from 37).
with immediate oxidation of the intermediate aldehyde using
bromine in methanol15 to give the (S)-valine derivative 37. This
procedure was found to minimize racemisation during the
ozonolysis and oxidation steps but gave a mixture of the methyl
ester 37 and methyl (R)-2-benzyloxymethoxypropanoate 40.
The isolation of ester 40 corresponds, at least formally, to a
recovery of the chiral auxiliary used in this synthesis since the
isobutyl ester 29 was the original source of chirality. However,
the two methyl esters 37 and 40 were difficult to separate and
the (S)-valine derivative 37 was only obtained pure using
1
(89%) which appeared to be a single diastereoisomer by H
NMR. The trifluoroacetamide was converted into the tert-
butoxycarbonyl derivative 36 which was cleaved by ozonolysis
† In all cases, the product mixture from reduction of the enones using
zinc borohydride was compared by HPLC with a mixture of syn and
anti-diastereoisomeric alcohols prepared by non-stereoselective reduc-
tion using sodium borohydride. The chelation controlled reduction was
invariably ≥98:2 stereoselective.
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Scheme 5 Reagents and conditions: i, lithium chloride, DBU, 2-methyl-
propanal (75%); ii, Zn(BH4)2, ether, Ϫ35 ЊC (95%); iii, butyllithium (0.2
eq.), trifluoroacetonitrile, Ϫ78 ЊC (92%); iv, xylene, reflux, 4 h (91%); v,
Ba(OH)2, methanol; vi, benzyl chloroformate, KHCO3 (86% from 45);
vii, ozone, methanol, Ϫ78 ЊC, then dimethyl sulfide followed by brom-
ine in methanol (84%); viii, NaBH4, lithium chloride (95%); ix, (R)-
methoxytrifluoromethylphenylacetyl chloride, pyridine (>95%).
HPLC. Its optical purity was estimated to correspond to an ee
of ca. 80% using the 19F NMR spectrum of its (S)-Mosher’s
derivative 39.
Scheme 6 Reagents and conditions: i, Ph3PCHؒCHO (87%); ii, ethane-
When this sequence was repeated in the enantiomeric series
starting with the (S)-phosphonate 41, prepared from ethyl (S)-
lactate, the rearrangement product 45 was converted into its
benzyloxycarbonyl derivative 47 before the oxidative cleavage
steps. This gave the methyl ester of Cbz-protected (R)-valine 48
which was more easily separated from the recovered auxiliary
49. Reduction of the ester 48 using sodium borohydride–
lithium chloride gave the alcohol 50 which was estimated to
have an ee of 85% from the 19F NMR spectrum of its (R)-
Mosher’s derivative 51.
1,2-diol, toluene-p-sulfonic acid (cat.), benzene (76%); iii, NBu4F,
tetrahydrofuran (94%); iv, butyllithium, trifluoroacetonitrile (79%); v,
xylene, heat (93%).
Except for the formation of 57, in all cases investigated, the
rearrangement of allylic trifluoroacetimidates was efficient and
appeared to be highly stereoselective, but in some cases diffi-
culties were experienced in preparing the allylic trifluoroacet-
imidates efficiently from the alcohol and trifluoroacetonitrile.
In particular, the hydroxyalkenylcyclopropane 65, prepared by
To evaluate further the scope of the trifluoroacetimidate
rearrangement, the trifluoroacetimidates 52, 54 and 56 were
prepared from geraniol, cinnamyl alcohol and sorbyl alcohol,
respectively. The sigmatropic rearrangements were carried out
in xylene heated under reflux and gave the corresponding tri-
fluoroacetamides 53, 55 and 57 in reasonable yields (ca. 80%,
not optimised) except for the hexadienyl trifluoroacetamide 57
which was only obtained in a yield of 35%. The reasons for this
low yield were not investigated. As a preliminary study for a
proposed synthesis of an unsaturated amino-acid, (S)-2-tert-
butyldimethylsilylpropanal 5816 was converted into the unsatur-
ated acetal 60 via the enal 59 (Scheme 6). Desilylation of the
enal gave the alcohol 61 which was converted into the trifluoro-
acetimidate 62. Rearrangement of this under the standard
conditions gave the trifluoroacetamide 63 in excellent yield.
chelation controlled reduction of the enone 64, gave a complex
mixture of products perhaps formed by participation of an
allylic carbocation. Similarly only a modest yield of the
trifluoroacetimidate 69 was obtained from the alcohol 68
(Scheme 7) although the rearrangement of 69 into the trifluoro-
acetamide 70 was both efficient and stereoselective (1H NMR).
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In this case it may be that the Boc-protected amine is interfering
with the conversion of the alcohol into its trifluoroacetimidate.
Finally, an improved synthesis of polyoxamic acid was
developed as outlined in Scheme 8. Condensation of the phos-
phonate 30 with the aldehyde 11 gave the enone 71. Chelation
controlled reduction gave the alcohol 72 which was converted
into the trifluoroacetimidate 73. Rearrangement of the tri-
fluoroacetimidate in xylene heated under reflux gave the
trifluoroacetamide 74 with excellent stereoselectivity (≥96:4, 1H
NMR). Oxidative cleavage of the carbamate 76, available
in two steps from the trifluoroacetamide, by ozonolysis fol-
lowed by treatment of the ozonide with bromine in methanol,
gave the methyl ester 77 together with BOM-protected methyl
lactate 40. Saponification of this mixture gave the acid 21 which
was taken through to polyoxamic acid 1 and the lactone 22 as
before.
Fig.
1
Chair-like transition state for the trifluoroacetimidate
rearrangement.
rearrangement would appear to be faster than rearrange-
ment of the corresponding trichloroacetimidates, e.g. for the
rearrangement of the trifluoroacetimidate 16 in xylene under
reflux, t1/2 is about 10 h, whereas for the trichloroacetimidate
14, it is about 20 h. This increase in reactivity can lead to
improved yields in some cases. The use of this reaction in
synthesis may be limited by the precautions necessary when
handling trifluoroacetonitrile, which is a highly toxic gas, and
the difficulties encountered in some cases in preparing the
trifluoroacetimidates. Nevertheless, this rearrangement has
been used to complete asymmetric syntheses of α-amino-
acids including polyoxamic acid 1. The accompanying paper
reports a total synthesis of thymine polyoxin C using this
chemistry.17
Conclusions
The [3,3] sigmatropic rearrangement of allylic trifluoro-
acetimidates would appear to be an efficient process with
effective 1,3-transfer of chirality consistent with the partici-
pation of a chair-like transition structure, cf. Fig. 1. This
Experimental
1H NMR spectra were recorded on Varian Unity 500, Bruker
AC 300, Varian XL 300 and Varian Gemini 200 spectrometers
in chloroform-d1 unless otherwise stated. 13C NMR spectra
were recorded on a Bruker AC 300 spectrometer operating at 75
MHz. IR spectra were recorded on a Perkin-Elmer 1710FT
spectrometer as liquid films unless otherwise stated. Mass
spectra were recorded on a Kratos MS25 mass spectrometer
using electron impact (El), chemical ionisation (CI) and fast
atom bombardment (FAB) ionisation. Melting points were
determined on a Kofler Block apparatus and are uncorrected.
Optical rotations were recorded on an Optical Activity AA100
polarimeter. Chromatography refers to flash column chrom-
atography using Merck silica gel 60H (40–63 µm, 230–300
mesh) or May and Baker Sorbsil C60 (40–60 µm) silica gel as
the stationary phase. Light petroleum refers to the fraction
boiling between 40 and 60 ЊC and was distilled before use. All
reagents and solvents were purified and dried by standard
procedures.
Trifluoroacetonitrile was used as a gas or in solution in
Scheme 7
Scheme 8 Reagents and conditions: i, zinc borohydride, ether, Ϫ35 ЊC (99%); ii, butyllithium, trifluoroacetonitrile, Ϫ78 ЊC (86%); iii, xylene, heat
under reflux, 9.5 h (91%); iv, barium hydroxide, methanol; v, (Boc)2O, Et3N (84% from 74); vi, ozone, methanol, Ϫ78 ЊC then bromine, methanol,
NaHCO3 (91%); vii, LiOH, aqueous tetrahydrofuran (96%).
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tetrahydrofuran and was either purchased‡ or prepared as
follows.18 An intimate mixture of powdered trifluoroacetamide
(10 g, 88 mmol) and phosphorus pentoxide (24 g, 148 mmol)
was prepared in a 500 cm3 round bottomed flask fitted with a
nitrogen inlet and water cooled condenser. From the top of the
condenser a PTFE tube led first to a trap cooled in an ice–salt
mixture, then to a trap cooled to ~Ϫ100 ЊC (ether–liq. N2) and
finally, via a tube packed with calcium chloride, to a bath con-
taining aqueous sodium hydroxide. The reaction mixture was
heated gradually to 150 ЊC and held at this temperature for 3 h
under a gentle stream of dry nitrogen. The trifluoroacetonitrile
distilled out and was collected as a colourless liquid (~6 cm3) in
the low temperature trap. Previously cooled tetrahydrofuran
(20 cm3) was then added to the condensed trifluoroacetonitrile
to provide a stock solution.
s, CH3), 3.8 (3 H, m, 4-H and 1Ј-H2), 4.3 (1 H, q, J 6, 4Љ-H), 4.55
(1 H, dd, J 6, 2, 5-H), 6.95 (2 H, m, 1Љ-H and 2Љ-H) and 7.35–7.8
(10 H, m, ArH); m/z (EI) 526 (Mϩ Ϫ 57, 20%), 507 (50) and 135
(100).
Following this procedure, the aldehyde 237 (0.26 g, 0.94
mmol) gave the (4R,5R)-isomer of the title compound 24 (0.36 g,
65%), [α]D23 Ϫ32 (c 1.1, CHCl3) (Found: C, 68.1; H, 8.35.
C33H50O5Si2 requires C, 68.0; H, 8.65%); νmax/cmϪ1 (CHCl3)
1700, 1630, 1470, 1430, 1380 and 1250; δH 0.1 (6 H, s, 2 ×
SiCH3), 0.9 and 1.1 [each 9 H, s, SiC(CH3)3], 1.3 (3 H, d, J 7,
5Љ-H3), 1.4 and 1.45 (each 3 H, s, CH3), 3.85 (3 H, m, 4-H and
1Ј-H2), 4.3 (1 H, q, J 7, 4Љ-H), 4.55 (1 H, m, 5-H), 6.95 (1 H, dd,
J 16, 4, 1Љ-H), 7.0 (1 H, dd, J 16,1, 2Љ-H) and 7.35–7.8 (10 H, m,
ArH).
(4S,5S)- and (4R,5R)-4-(tert-Butyldimethylsilyloxymethyl)-5-
[(3S,4S,1E)-4-tert-butyldiphenylsilyloxy-3-hydroxypentenyl]-
2,2-dimethyl-1,3-dioxolane 13 and 25
(S)-3-(tert-Butyldiphenylsilyloxy)-2-oxobutylenetriphenyl-
phosphorane 10
A solution of the ethyl ester 819 (0.39 g, 1.09 mmol) and
potassium hydroxide (0.31 g, 4.4 mmol) was stirred at ambient
temperature in methanol (5 cm3) for 10 h. After acidification
with aqueous hydrogen chloride (1 M; 10 cm3), the mixture was
extracted with ether and the organic extract dried (MgSO4) and
concentrated under reduced pressure. The residue was dissolved
in ethyl acetate (5 cm3), 2-mercaptopyridine (0.11 g, 1 mmol)
and dicyclohexylcarbodiimide (0.24 g, 1.17 mmol) were added
and the mixture stirred at ambient temperature for 9 h. The
mixture was filtered, and the filtrate washed with brine, dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography of the residue using light petroleum–ethyl acetate
(9:1) as eluent afforded S-(2-pyridyl) (S)-2-(tert-butyldiphenyl-
silyloxy)thiopropanoate 9 (0.31 g, 70%) as a yellow oil: [α]D23
Ϫ70.7 (c 1, CHCl3); νmax/cmϪ1 (CHCl3) 1705, 1585, 1450, 1430,
1420, 1155, 1115 and 1105; δH 1.25 [12 H, m, CH3 and
C(CH3)3], 4.5 (1 H, q, J 6.5, 2-H), 7.2–7.9 (13 H, m, ArH) and
8.7 (1 H, m, ArH); m/z (CI) 422 (Mϩ ϩ 1, 60%) and 112 (100).
Butyllithium (1.6 M in hexane; 0.21 cm3, 0.34 mmol) was
added to a suspension of methyltriphenylphosphonium brom-
ide (0.125 g, 0.35 mmol) in tetrahydrofuran (2 cm3) at ambient
temperature. After 5 min, a solution of the thioester 9 (67 mg,
0.16 mmol) in tetrahydrofuran (2 cm3) was added and the
resulting suspension was stirred for 30 min then filtered through
Celite. Ether and aqueous potassium carbonate were added and
the organic layer was dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate–light petroleum as eluent (3:1) gave the title compound
10 (70 mg, 75%) as a yellow foam (Found: C, 77.95; H, 7.05; P,
5.0. C38H39O2PSi requires C, 77.8; H, 6.7; P, 5.3%); [α]D23 Ϫ18.6
(c 0.7, CHCl3); νmax/cmϪ1 (CHCl3) 3060, 1620, 1590, 1520, 1440,
1140 and 1110; δH 1.15 [9 H, s, C(CH3)3], 1.35 (3 H, d, J 5,
4-H3), 4.2 (1 H, q, J 5, 3-H), 4.5 (1 H, d, J 25, 1-H), 7.2–7.8 (25
H, m, ArH); m/z (CI) 586 (Mϩ, 30%), 508 (20) and 303 (100).
Lithium tri-sec-butylborohydride in tetrahydrofuran (1 M; 2.05
cm3, 2.05 mmol) was added to a solution of the enone 12 (1 g,
1.71 mmol) in tetrahydrofuran (5 cm3) at Ϫ78 ЊC and the reac-
tion mixture stirred at this temperature for 40 min. Glacial
acetic acid (0.3 cm3) was added and the mixture allowed to
warm to ambient temperature. Water was added and the mix-
ture extracted into ether. The organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography using light petroleum–ether (4:1) as eluent gave the
(4S,5S)-isomer of the title compound 13 (0.9 g, 90%) (Found: C,
68.00; H, 9.15. C33H52O5Si2 requires C, 67.75; H, 8.95%. Found
M Ϫ OH, 567.3320. C33H51O4Si2 requires M, 567.3326); [α]D23
Ϫ19.4 (c 1.1, CHCl3); νmax/cmϪ1 (CHCl3) 3560, 1470, 1460,
1430, 1380, 1255 and 1110; δH (C6D6) 0.1 (6 H, s, 2 × SiCH3),
0.9 [9 H, s, SiC(CH3)3], 1.0 (3 H, d, J 6, 5Љ-H3), 1.1 [9 H, s,
SiC(CH3)3], 1.4 and 1.46 (each 3 H, s, CH3), 2.1 (1 H, d, J 5,
OH), 3.6 (1 H, dd, J 11, 5, 1Ј-H), 3.7 (1 H, dd, J 11, 4, 1Ј-HЈ),
3.8 (2 H, m, 4-H and 4Љ-H), 4.0 (1 H, m, 3Љ-H), 4.5 (1 H, dd, J 7,
8, 5-H), 5.9 (1 H dd, J 16, 3, 2Љ-H), 6.0 (1 H, dd, J 16, 6, 1Љ-H)
and 7.2–7.8 (10 H, m, ArH); m/z (CI) 527 (Mϩ Ϫ 57, 50%) and
311 (100).
Following this procedure, the enone 24 (30 mg, 0.05 mmol) in
tetrahydrofuran (1 cm3) gave the (4R,5R)-isomer of the title
compound 25 (25 mg, 82%); [α]D23 Ϫ5.1 (c 1, CHCl3), νmax/cmϪ1
(CHCl3) 3560, 1470, 1430, 1380 and 1255; δH 0.1 (6 H, s,
2 × SiCH3) 0.9 [9 H, s, SiC(CH3)3], 1.0 (3 H, d, J 6, 5Љ-H3), 1.1
[9 H, s, SiC(CH3)3], 1.4 (6 H, s, 2 × CH3), 2.5 (1 H, d, J 4, OH),
3.9 (4 H, m), 4.0 (1 H, m, 3Љ-H), 4.3 (1 H, m, 5-H), 5.9 (2 H, m,
1Љ-H and 2Љ-H) and 7.2–7.8 (10 H, m, ArH).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4S,1E)-4-
tert-butyldiphenylsilyloxy-3-(2,2,2-trichloroacetimidoyloxy)-
pentenyl]-2,2-dimethyl-1,3-dioxolane 14
Butyllithium (1.6 M in hexane; 1.5 cm3, 2.4 mmol) was added to
a solution of the alcohol 13 (1.4 g, 2.4 mmol) in tetrahydro-
furan (20 cm3) at Ϫ78 ЊC and the solution stirred at this tem-
perature for 1 h before being transferred to a solution of
trichloroacetonitrile (0.42 g, 2.88 mmol) in tetrahydrofuran (10
cm3) at Ϫ78 ЊC. The mixture was allowed to warm to ambient
temperature. and was stirred for 2 h. Saturated aqueous ammo-
nium chloride (0.5 g, 8.8 mmol) was added and the mixture
extracted into ether. The organic extracts were dried (MgSO4)
and concentrated under reduced pressure. Chromatography
using light petroleum–ether (19:1) gave the title compound 14
(1.48 g, 85%) as a yellow oil (Found: C, 57.65; H, 7.45; N, 1.75.
C35H52C13NO5Si2 requires C, 57.65; H, 7.2; N, 1.9%); [α]D23 Ϫ13
(c 1, CHCl3); νmax/cmϪ1 (CHCl3) 3340, 1665, 1470, 1430, 1380,
1255, 1112 and 840; δH 0.1 (6 H, s, 2 × SiCH3), 0.9 [9 H, s,
SiC(CH3)3], 1.0 (3 H, d, J 6, 5Љ-H3), 1.1 [9 H, s, SiC(CH3)3], 1.5
(6 H, s, 2 × CH3), 3.7 (3 H, m, 4-H and 1Ј-H2), 4.1 (1 H, quintet,
J 6, 4Љ-H), 4.4 (1 H, br t, J 5, 5-H), 5.5 (1 H, t, J 6, 3Љ-H), 5.85
(4S,5S) and (4R,5R)-4-(tert-Butyldimethylsilyloxymethyl)-5-
[(4S,1E)-4-tert-butyldiphenylsilyloxy-3-oxopentenyl]-2,2-
dimethyl-1,3-dioxolanes 12 and 24
A solution of the phosphorane 10 (5.6 g, 9.45 mmol) and alde-
hyde 117 (2.6 g, 9.45 mmol) in benzene (120 cm3) was heated
under reflux for 5 h then concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ether
(19:1) as eluent gave the (4S,5S)-isomer of the title compound
12 (4.65 g, 85%) (Found: C, 67.75; H, 8.95. C33H50O5Si2 requires
C, 68.0; H, 8.65%); [α]D23 Ϫ38 (c 1, CHCl3); νmax/cmϪ1 (CHCl3)
1700, 1630, 1470, 1460, 1430, 1380, 1370, 1250 and 1112;
δH 0.09 and 0.1 (each 3 H, s, SiCH3), 0.9 and 1.1 [each 9 H, s,
SiC(CH3)3], 1.22 (3 H, d, J 6, 5Љ-CH3), 1.41 and 1.46 (each 3 H,
‡ Supplied by Fluorochem Ltd., Wesley Street, Old Glossop, Derby-
shire, UK SK13 9RY.
3296
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303

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(1 H, dd, J 16, 6, 2Љ-H), 5.9 (1 H, dd, J 16, 5, 1Љ-H), 7.3–7.8 (10
H, m, ArH) and 8.2 (1 H, s, NH); m/z (EI) 670 (Mϩ Ϫ 57, 25%),
612, 614 (50) and 311 (100).
sure, chromatography of the residue using light petroleum–
ether (15:1) gave the title compound 17 (74 mg, 82%), [α]D23 Ϫ50.6
(c 1.1, CHCl3) (Found: C, 61.5; H, 8.05. C35H52F3NO5Si2
requires C, 61.8; H, 7.7%; Found: Mϩ Ϫ C4H9, 622.6225. C31H43-
F3NO5Si2 requires M, 622.2632); νmax/cmϪ1 (CHCl3) 3420, 1730,
1530, 1480, 1470, 1430, 1370, 1170, 1110, 1080 and 840; δH 0.1
(6 H, s, 2 × SiCH3), 0.9 and 1.1 [each 9 H, s, SiC(CH3)3], 1.2
(3 H, d, J 6, 5Љ-H3), 1.4 (6 H, s, 2 × CH3), 3.7 (2 H, m, 1Ј-H2),
3.85 (1 H, m, 4-H), 4.0 (1 H, dd, J 8, 2, 5-H), 4.3 (1 H, quintet,
J 6, 4Љ-H), 4.67 (1 H, t, J 7.5, 1Љ-H), 5.5 (1 H, dd, J 16, 7, 2Љ-H),
5.75 (1H, dd, J 16, 6, 3Љ-H), 6.85 (1 H, d, J 9, NH) and 7.3–7.8
(10 H, m, ArH); m/z (EI) 664 (Mϩ Ϫ 15, 60%) and 662 (60).
The following trifluoroacetamide was prepared using this
procedure.
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(1R,4S,2E)-
tert-butyldiphenylsilyloxy-1-(2,2,2-trichloroacetylamino)pent-2-
enyl]-2,2-dimethyl-1,3-dioxolane 15
A solution of the trichloroacetimidate 14 (70 mg, 0.096 mmol)
in xylene was thoroughly degassed using a stream of argon then
heated under reflux for 48 h. After concentration under reduced
pressure, chromatography of the residue using light petroleum–
ether (19:1) gave the title compound 15 (28 mg, 40%), [α]D23 Ϫ40.6
(c 1, CHCl3) (Found: Mϩ Ϫ C4H9, 670.1723. C31H43Cl3NO5Si2
requires M, 670.1745); νmax/cmϪ1 (CHCl3) 3420, 1720, 1500,
1480, 1430, 1380, 1370, 1255, 1120 and 1085; δH 0.1 (6 H, s,
2 × SiCH3), 0.9 and 1.1 [each 9 H, s, SiC(CH3)3], 1.2 (3 H, d, J 6,
5Љ-H3), 1.39 and 1.41 (each 3 H, s, CH3), 3.7–3.9 (3 H, m, 4-H
and 1Ј-H2), 4.05 (1 H, d, J 7.5, 5-H), 4.3 (1 H, quintet, J 6,
4Љ-H), 4.55 (1 H, dd, J 7.5, 7, 1Љ-H), 5.6 (1H, dd, J 16, 7.5, 2Љ-H),
5.9 (1 H, dd, J 16, 6, 3Љ-H), 7.1 (1 H, d, J 8, NH) and 7.3–7.8 (10
H, m, ArH); m/z (EI) 670 (Mϩ Ϫ 57, 10%).
(4R,5R)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(1R,4S,2E)-
4-tert-butyldiphenylsilyloxy-1-(2,2,2-trifluoroacetylamino)pent-
2-enyl]-2,2-dimethyl-1,3-dioxolane 27. (38 mg, 76% from the
trifluoroacetimidate 26, 50 mg, 0.074 mmol), [α]D23 Ϫ36 (c 0.8,
CHCl3) (Found: C, 61.75; H, 7.4. C35H52F3NO5Si2 requires C,
61.8; H, 7.7%); νmax/cmϪ1 (CHCl3) 3420, 1730, 1530, 1480, 1430
and 1370; δH 0.1 (6 H, s, 2 × SiCH3), 0.9 and 1.1 [each 9 H, s,
SiC(CH3)3], 1.15 (3 H, d, J 6, 5Љ-H3), 1.32 and 1.38 (each 3 H, s,
CH3), 3.8 (3 H, m, 4-H and 1Ј-H2), 4.0 (1 H, dd, J 7, 4, 5-H), 4.4
(1 H, quintet, J 6, 4Љ-H), 4.65 (1 H, dt, J 4, 8, 1Љ-H), 5.7 (1 H,
dd, J 15, 8, 2Љ-H), 5.9 (1 H, dd, J 15, 6, 3Љ-H), 6.7 (1 H, d, J 8,
NH) and 7.3–7.8 (10 H, m, ArH).
Preparation of trifluoroacetimidates using gaseous trifluoro-
acetonitrile
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4S,1E)-
4-tert-butyldiphenylsilyloxy-3-(2,2,2-trifluoroacetimidoyloxy)-
pentenyl]-2,2-dimethyl-1,3-dioxolane 16. Butyllithium (1.6 M in
hexane; 0.29 cm3, 0.46 mmol) was added to a solution of the
alcohol 13 (0.25 g, 0.43 mmol) in tetrahydrofuran (6 cm3) at
Ϫ78 ЊC and the solution stirred for 1 h. A stream of trifluoro-
acetonitrile was bubbled through the solution for 5 min then the
solution was allowed to warm to ambient temperature over a
period of 1 h. Ammonium chloride (0.2 g, 3.6 mmol) was added
and the mixture concentrated under reduced pressure. Chrom-
atography of the residue using light petroleum–ether (9:1) gave
the title compound 16 (0.24 g, 81%), [α]D23 Ϫ5.7 (c 0.5, CHCl3)
(Found: C, 61.7; H, 7.4. C35H52F3NO5Si2 requires C, 61.8; H,
7.7%; Found: Mϩ Ϫ C4H9, 622.2630. C31H43F3NO5Si2 requires
M, 622.2632); νmax/cmϪ1 (CHCl3) 3360, 1680, 1470, 1430,
1380, 1200, 1170, 1112 and 840; δH 0.1 (6 H, s, 2 × SiCH3),
0.9 [9 H, s, SiC(CH3)3], 1.0 (3 H, d, J 7, 5Љ-H3), 1.1 [9 H, s,
SiC(CH3)3], 1.45 (6 H, s, 2 × CH3), 3.74 (3 H, 1Ј-H2 and
4-H), 4.2 (1 H, quintet, J 6, 4Љ-H), 4.44 (1 H, m, 5-H), 5.5 (1 h, t,
J 6, 3Љ-H), 5.85 (1 H, dd, J 5, 6, 2Љ-H), 5.9 (1 H, dd, J 16, 5,
1Љ-H), 7.3–7.8 (10 H, m, ArH) and 8.2 (1 H, s, NH); m/z (EI)
622 (Mϩ Ϫ 57, 4%).
(4S,5S)-5-[(1R,4S,2E)-1-Amino-4-tert-butyldiphenylsilyloxy-
pent-2-enyl]-4-(tert-butyldimethylsilyloxymethyl)-2,2-dimethyl-
1,3-dioxolane 18
Sodium borohydride (32 mg, 0.8 mmol) was added to a solution
of the trifluoroacetamide 17 (70 mg, 0.1 mmol) in ethanol (0.75
cm3) at 0 ЊC. The reaction mixture was allowed to warm to
23 ЊC and was stirred for 5 h. Saturated aqueous ammonium
chloride (2 cm3) was added and the mixture extracted into
ether. The organic extracts were dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
using light petroleum–ethyl acetate (3:1) as eluent gave the title
compound 18 (44 mg, 75%), [α]D23 Ϫ29.9 (c 1.1, CHCl3) (Found:
C, 68.05; H, 9.45. C33H53NO4Si2 requires C, 67.85; H, 9.15%;
Found: Mϩ Ϫ C4H9, 526.2808. C29H44NO4Si2 requires M,
526.2809); νmax/cmϪ1 (CHCl3) 3300br, 1590, 1470, 1460, 1430,
1380, 1370, 1250, 1140, 1110, 1080, 970 and 840; δH 0.1 (6 H, s,
2 × SiCH3), 0.9 and 1.1 [each 9 H, s, C(CH3)3], 1.2 (3 H, d, J 6,
5Љ-H3), 1.39 and 1.42 (each 3 H, s, CH3), 1.5 (2 H, br s, NH2),
3.3 (1 H, t, J 7, 1Љ-H), 3.7 (2 H, m, 1Ј-H2), 3.75 (1 H, dd, J 7, 6,
5-H), 3.9 (1 H, m, 4-H), 4.3 (1 H, quintet, J 6, 4Љ-H), 5.3
(1 H, dd, J 16, 8, 2Љ-H), 5.7 (1 H, dd, J 16, 6, 3Љ-H) and 7.3–7.8
(10 H, m, ArH); m/z (EI) 584 (Mϩ ϩ 1, 13%), 526 (60) and 199
(100).
The following trifluoroacetimidate was prepared using this
procedure.
(4R,5R)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4S,1E)-
4-tert-butyldiphenylsilyloxy-3-(2,2,2-trifluoroacetimidoyloxy)-
pentenyl]-2,2-dimethyl-1,3-dioxolane 26. (47 mg, 70% from the
alcohol 25 (60 mg, 0.1 mmol), [α]D23 Ϫ15.2 (c 1.2, CHCl3) (Found:
C, 61.65; H, 7.4. C33H52F3NO5Si2 requires C, 61.8; H, 7.7%);
νmax/cmϪ1 (CHCl3) 3360, 1680, 1470, 1430 and 1380; δH 0.1 (6 H,
s, 2 × SiCH3), 0.9 [9 H, s, SiC(CH3)3], 1.0 (3 H, d, J 6, 5Љ-H3),
1.1 [9 H, s, SiC(CH3)3], 1.4 (6 H, s, 2 × CH3), 3.8 (3 H, m, 4-H
and 1Ј-H2), 4.1 (1 H, quintet, J 6, 4Љ-H), 4.4 (1 H, dd, J 7.5, 5,
5-H), 5.5 (1 H, t, J 6, 3Љ-H), 5.85 (1 H, dd, J 16, 5, 1Љ-H), 5.95
(1 H, dd, J 16, 6, 2Љ-H), 7.3–7.8 (10 H, m, ArH) and 8.2 (1 H, s,
NH).
(4S,5S)-5-[(1R,4S,2E)-1-tert-Butoxycarbonylamino-4-tert-
butyldiphenylsilyloxypent-2-enyl]-4-(tert-butyldimethylsilyloxy-
methyl)-2,2-dimethyl-1,3-dioxolane 19
Di-tert-butyl dicarbonate (65 mg, 0.29 mmol) was added to a
solution of the amine 18 (0.16 g, 0.27 mmol) and triethylamine
(0.04 cm3, 0.29 mmol) in ether (3.5 cm3) at 23 ЊC and the solu-
tion stirred for 20 h. After concentration under reduced
pressure, chromatography of the residue using light petroleum–
ether (13:1) gave the title compound 19 (0.18 g, 100%) as a
colourless oil, [α]D23 Ϫ31 (c 1.1, CHCl3); νmax/cmϪ1 (CHCl3) 3450,
1710, 1500, 1470, 1430 and 1370; δH 0.1 (6 H, s, 2 × SiCH3), 0.9
and 1.1 [each 9 H, s, SiC(CH3)3], 1.15 (3 H, d, J 5, 5Љ-H3), 1.4
(6 H, s, 2 × CH3), 1.45 [9 H, s, OC(CH3)3], 3.6–4.0 (4 H, m,
SiOCH2CHCH), 4.3 (2 H, m, 1Љ-H and 4Љ-H), 5.1 (1 H, d, J 8,
NH), 5.5 (1 H, dd, J 15, 5, 2Љ-H), 5.7 (1 H, dd, J 15, 5, 3Љ-H) and
7.3–7.8 (10 H, m, ArH).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(1R,4S,2E)-4-
tert-butyldiphenylsilyloxy-1-(2,2,2-trifluoroacetylamino)pent-2-
enyl]-2,2-dimethyl-1,3-dioxolane 17
A solution of the trifluoroacetimidate 16 (90 mg, 0.13 mmol) in
xylene (2 cm3) was thoroughly degassed with argon and heated
under reflux for 20 h. After concentration under reduced pres-
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303
3297

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(4S,5S)-5-[(1S)-(tert-Butoxycarbonylamino)(carboxy)methyl]-
4-(tert-butyldimethylsilyloxymethyl)-1,3-dioxolane 21
Chromatography of the residue using ether–light petroleum
(1:15) as eluent gave the title compound 29 (4.93 g, 41%) as
a colourless oil, [α]D23 ϩ67.7 (c 3 in CHCl3) (Found: Mϩ,
267.1603. C15H22O4 requires M, 267.1518); νmax/cmϪ1 1750,
1176, 1123 and 1051; δH 0.93 (3 H, d, J 6.5, 3-H3), 1.45 (6 H, d,
J 7, 2 × CH3), 1.94 (1 H, septet, J 6.5, CH), 3.91 (2 H, m,
OCH2), 4.33 (1 H, q, J 6.5, 2-H), 4.65 (2 H, s, PhCH2), 4.85
(2 H, s, OCH2O) and 7.33 (5 H, m, ArH); m/z (EI) 267 (Mϩ ϩ 1,
100%) and 237 (46).
A solution of the alkene 19 (40 mg, 0.059 mmol) in methanol (2
cm3) was cooled to Ϫ78 ЊC whilst oxygen was bubbled through.
After 10 min, ozone was passed through the solution until
starting material had been consumed (TLC using 3:1 light
petroleum–ether). The reaction mixture was purged with oxy-
gen for a further 10 min, then dimethyl sulfide (0.05 cm3, 0.7
mmol) was added and the reaction mixture allowed to warm to
ambient temperature over 1 h. After concentration under
reduced pressure, chromatography of the residue using light
petroleum–ether (3:1) as eluent gave the aldehyde 20 (21 mg).
This was dissolved in a mixture of carbon tetrachloride (0.2
cm3), acetonitrile (0.2 cm3) and water (0.3 cm3) and sodium
periodate (40 mg, 0.18 mmol) was added. The mixture was
stirred at ambient temperature for 15 min then ruthenium tri-
chloride (1 mg) was added. The mixture was stirred for 1 h at
ambient temperature then partitioned between ether and water.
The organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
ether–light petroleum–acetic acid (24:75:1) as eluent gave the
title compound 21 (16.5 mg, 69%) as a white powder, mp 131–
133 ЊC, [α]D26 Ϫ4.2 (c 1.32, CHCl3) (Found: C, 54.6; H, 9.1; N, 3.3.
C19H37NO7Si requires C, 54.4; H, 8.9; N, 3.3%; Found:
Dimethyl [(3R)-3-benzyloxymethoxy-2-oxobutyl]phosphonate 30
Butyllithium (1.6 M in hexane, 21 cm3, 33.6 mmol) was added
to a solution of dimethyl methylphosphonate (4.1 g, 33 mmol)
in tetrahydrofuran (20 cm3) at Ϫ78 ЊC. After 1 h, a solution of
the ester 29 (4 g, 15 mmol) in tetrahydrofuran (10 cm3) was
added and the mixture stirred for a further 2 h. Water (30
cm3) was added and the mixture allowed to warm to ambient
temperature. Ether (200 cm3) was added and the aqueous
layer acidified with aqueous hydrogen chloride (2 M) to ~pH 2.
The aqueous layer was extracted with ether (2 × 100 cm3), and
the extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate–methanol (6:2:1) as eluent gave the
title compound 30 (4.35 g, 92%) as a colourless oil, [α]D ϩ27.7 (c
7.8 in CHCl3) (Found: Mϩ ϩ NH4, 334.1426. C14H25NO6P
requires M, 334.1420); νmax/cmϪ1 1722, 1455, 1259, 1182, 1037
and 812; δH 1.37 (3 H, d, J 7, 4-H3), 3.27 (2 H, m, 1-H2), 3.77
(6 H, d, J 11, 2 × CH3O), 4.3 (1 H, q, J 7, 3-H), 4.61 and 4.67
(each 1 H, d, J 12, PhCHH), 4.82 and 4.87 (each 1 H, d, J 7,
OCHHO) and 7.33 (5 H, m, ArH); m/z (CI) 334 (Mϩ ϩ 18,
69%), 317 (92) and 287 (100).
Mϩ ϩ H, 420.2408. C19H38NO7Si requires M, 420.2418); νmax
/
cmϪ1 (CHCl3) 3600–2200, 1713, 1502, 1370, 1253, 1165, 1090
and 840; δH (C6D6) 0.1 (6 H, s, 2 × SiCH3), 0.9 [9 H, s,
SiC(CH3)3], 1.33 and 1.39 (each 3 H, s, CH3), 1.45 [9 H, s,
C(CH3)3], 3.7 and 3.8 (each 1 H, dd, J 10, 3, 1Ј-H), 4.1 (1 H, m,
5-H), 4.71 (1 H, d, J 8, 4-H), 4.9 (1 H, d, J 10, 1Љ-H) and 5.6 (1
H, d, J 10, NH); m/z (CI) 437 (Mϩ ϩ 18, 2%), 420 (Mϩ ϩ 1, 47)
and 320 (100).
Following this procedure, the (S)-enantiomer of the title
compound 41 (2.38 g, 90%) was prepared as a colourless
oil from ethyl (S)-2-benzyloxymethoxypropanoate20 (2 g, 8.4
mmol), [α]2D6 Ϫ26.2 (c 0.9 in CHCl3) (Found: Mϩ ϩ 1,
317.1165. C14H22O6P requires M, 317.1154).
Polyoxamic acid 1
A mixture of trifluoroacetic acid (0.27 cm3, 3.54 mmol) and
methanol (0.03 cm3) cooled to 0 ЊC was added to the dioxolane
21 (28 mg, 0.067 mmol) and the solution stirred at ambient
temperature for 30 min. After concentration under reduced pre-
sure, the residue was dissolved in aqueous ammonium hydrox-
ide (0.6 M; 2 cm3) and chromatographed through a column of
Dowex 50W X8 (Hϩ) to give polyoxamic acid 1 (8 mg, 72%): mp
149–162 ЊC decomp. (lit.,4 171–173 ЊC decomp.), [α]D23 6.38 (c 0.4,
H2O) (lit.,4 2.8 (c 1, H2O)); δH (D2O) 3.5–3.6 (2 H, m, 5-H2), 3.75
(1 H, m, 2-H), 3.78 (1 H, m, 4-H) and 4.09 (1 H, t, J 2.5, 3-H);
m/z (FAB) 166 (Mϩ ϩ 1, 100%).
Synthesis of enones using phosphonates 30 and 41
(2R,4E)- and (2S,4E)-2-(Benzyloxymethoxy)-6-methylhept-4-
en-3-one 31 and 42. A solution of the phosphonate 30 (3.89 g,
12.3 mmol) in acetonitrile (10 cm3) was added to a suspension
of lithium chloride (0.53 g, 12.4 mmol) in acetonitrile (40 cm3).
1,8-Diazabicyclo[5.7.0]undec-7-ene (1.6 cm3, 10.7 mmol) was
added after 15 min and, after a further 30 min, 2-methyl-
propanal (0.95 cm3, 10.5 mmol) was added. The resulting
solution was stirred for 20 h, then saturated aqueous ammo-
nium chloride was added and the mixture was extracted with
dichloromethane (3 × 150 cm3). The organic extracts were
washed with water (30 cm3), brine (30 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography using
light petroleum–ether (10:1) as eluent gave the (2R,4E)-
enantiomer of the title compound 31 (2.11 g, 77%) as a colour-
less oil (Found: Mϩ ϩ NH4, 280.1907. C16H26NO3 requires M,
280.1913), [α]D ϩ54.9 (c 3.7 in CHCl3); νmax/cmϪ1 1697, 1627,
1455, 1108, 1041, 989, 738 and 699; δH 1.06 (6 H, d, J 6.5,
2 × CH3), 1.37 (3 H, d, J 7, 1-H3), 2.47 (1 H, m, 6-H), 4.38 (1 H,
q, J 7, 2-H), 4.63 (2 H, s, PhCH2), 4.78 and 4.81 (each 1 H, d,
J 8, OHCHO), 6.36 (1 H, dd, J 16, 1.5, 4-H), 6.99 (1 H, dd, J 16,
6.5, 5-H) and 7.31 (5 H, m, ArH); m/z (CI) 280 (Mϩ ϩ 18, 10%),
263 (15), 233 (40) and 199 (100%).
Acetic anhydride (0.1 cm3, 1 mmol) was added to a solution
of synthetic polyoxamic acid 1 (10 mg, 0.06 mmol) in methanol
(0.75 cm3) at ambient temperature and the mixture stirred for
20 h. Water (0.2 cm3) was added and the mixture concentrated
under reduced pressure. Chromatography of the residue using
ethyl acetate–methanol (19:1) gave the lactone 22 (6.7 mg,
60%) as a white solid, mp 150 ЊC decomp. (lit.4, mp 150–
152 ЊC); δH (acetone-d6) 1.9 (3 H, s, COCH3), 3.9 and 4.0 (each
1 H, m, 5-H), 4.1 (1 H, t, J 6, OH), 4.55 (2 H, m, 2-H and 4-H),
4.7 (1H, dt, J 7.5, 5, 3-H), 5.1 (1 H, d, J 5, OH) and 7.8 (1 H, br
s, NH); m/z (CI) 207 (Mϩ ϩ 18, 34%), 190 (Mϩ ϩ 1, 84) and
172 (100).
2-Methylpropyl (R)-2-(benzyloxymethoxy)propanoate 29
Benzyl chloromethyl ether (7.5 cm3, 54 mmol) was added to a
solution of 2-methylpropyl (R)-lactate 28 (6.56 g, 45 mmol) and
N,N-diisopropylethylamine (15.5 cm3, 89 mmol) in dichloro-
methane (50 cm3) and the mixture was stirred at ambient tem-
perature for 15 h. Dichloromethane (100 cm3) was added and
the mixture washed with saturated aqueous ammonium
chloride (3 × 50 cm3), back extracting the combined washings
with dichloromethane (2 × 50 cm3). The organic extracts were
dried (MgSO4) and concentrated under reduced pressure.
This procedure using the (S)-phosphonate 41 gave the
(2S,4E)-enantiomer of the title compound 42 (Found: Mϩ ϩ H,
263.1641. C16H23O3 requires M, 263.1647), [α]2D6 Ϫ55.8 (c 0.98
in CHCl3).
The following enones were synthesised using this procedure.
[(4S,1E)-4-Benzyloxymethoxy-3-oxopent-1-enyl]cyclo-
propane 64. (0.26 g, 79%) From cyclopropanecarbaldehyde
(0.12 g, 1.71 mmol) as a colourless oil after chromatography
3298
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303

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using light petroleum–ether (8:1) as eluent, [α]D22 Ϫ39.2 (c 1.22,
CHCl3) (Found: Mϩ ϩ H, 261.1481. C16H21O3 requires M,
261.1490); νmax/cmϪ1 1691, 1615, 1498, 1454, 1380, 1269, 1179,
1107, 1040 and 936; δH 0.68 and 0.98 (each 2 H, m, CH2), 1.36
(3 H, d, J 7, 5Ј-H3), 1.60 (1 H, m, 1-H), 4.33 (1 H, q, J 7, 4Ј-H),
4.64 (2 H, s, PhCH2), 4.77 and 4.85 (each 1 H, d, J 7, OCHHO),
6.51 (2 H, m, 1Ј-H and 2Ј-H) and 7.25–7.38 (5 H, m, ArH); δC
9.38, 15.33, 18.17, 69.97, 77.36, 93.83, 121.80, 127.61, 127.70,
128.29, 137.48, 154.53 and 198.81; m/z (CI) 278 (Mϩ ϩ 18,
22%), 261 (Mϩ ϩ 1, 69) and 153 (100).
[(3R,4S,1E)-4-Benzyloxymethoxy-3-hydroxypent-1-enyl]-
cyclopropane 65. (1.5 g, 97%) From the enone 64 (1.54 g, 5.91
mmol) as a colourless oil after chromatography using light
petroleum–ether (2:1) as eluent, [α]D18 ϩ11.5 (c 1, CHCl3)
(Found: Mϩ Ϫ OH, 245.1555. C16H21O2 requires M, 245.1541);
νmax/cmϪ1 3451, 3082, 1667, 1498, 1454, 1381, 1166, 1102, 1041
and 966; δH 0.39 and 0.72 (each 2 H, m, CH2), 1.17 (3 H, d, J 7,
5Ј-H3), 1.42 (1 H, m, 1-H), 2.55 (1 H, br s, OH), 3.82 (1 H, dq,
J 7, 3, 4Ј-H), 4.07 (1 H, m, 3Ј-H), 4.61 and 4.7 (each 1 H, d, J 12,
PhCHH), 4.82 and 4.86 (each 1 H, d, J 7, OCHHO), 5.25 (1 H,
ddd, J 15.5, 9, 4, 1Ј-H), 5.57 (1 H, dd, J 15.5, 7, 2Ј-H) and 7.35
(5 H, ArH); δC 6.89, 6.92, 13.72, 15.47, 69.77, 74.98, 77.63,
93.77, 125.27, 127.66, 127.72, 128.33, 137.42 and 137.71; m/z
(CI) 262 (Mϩ, 3%) and 245 (100); HPLC (column: Spheresorb 5
µm ODS PP/3634; eluent: 78:22 methanol–water) ratio of
epimers ≥95:5.
(2S)-[(4S,1E)-4-Benzyloxymethoxy-3-oxopent-1-enyl]-N-
(tert-butoxycarbonyl)pyrrolidine 67. (1.56 g, 76%) From the
formylpyrrolidine 6621 (1.05 g, 5.27 mmol) as a pale yellow gum
after chromatography using light petroleum–ether (4:3) as
eluent, [α]D20 ϩ110.8 (c 0.6, CHCl3) (Found: Mϩ ϩ H, 390.2270.
C22H32NO5 requires M, 390.2280); νmax/cmϪ1 1695, 1630, 1479,
1454, 1168, 1110 and 1040; δH 1.33 (3 H, d, J 7, 5-H3), 1.39 [9 H,
s, C(CH3)3], 1.65–1.85 (3 H, m, 3-H and 4-H2), 2.05 (1 H, m,
3-HЈ), 3.40 (2 H, m, 5-H2), 4.33 (1 H, q, J 7, 4Ј-H), 4.47 (1 H, m,
2-H), 4.58 (2 H, s, PhCH2), 4.72 and 4.81 (each 1 H, d, J 8,
OHCHO), 6.39 (1 H, d, J 16, 2Ј-H), 6.83 (1 H, dd, J 16, 6, 1Ј-H)
and 7.22–7.32 (5 H, m, ArH); m/z (CI) 390 (Mϩ ϩ 1, 3%), 290
(16), 198 (84) and 134 (100).
(2S)-2-[(3R,4S,1E)-4-Benzyloxymethoxy-3-hydroxypent-1-
enyl]-N-(tert-butoxycarbonyl)pyrrolidine 68. (0.19 g, 89%) From
the ketone 67 (0.21 g, 0.54 mmol) as a colourless gum after
chromatography using light petroleum–ether (4:5) as eluent,
[α]D25 Ϫ18.6 (c 0.7, CHCl3) (Found: Mϩ ϩ H, 392.2438. C22-
H34NO5 requires M, 392.2437); νmax/cmϪ1 3432, 1690, 1399,
1169, 1106 and 1041; δH 1.14 (3 H, d, J 6.5, 5Ј-H3), 1.44 [9 H, s,
C(CH3)3], 1.71 (1 H, m, 3-H), 1.83 (2 H, m, 4-H2), 2.01 (1 H, m,
3-HЈ), 2.25 (1 H, br s, OH), 3.37 (2 H, m, 5-H2), 3.83 (1 H, dq,
J 6.5, 3, 4Ј-H), 4.16 (1 H, m, 3Ј-H), 4.32 (1 H, m, 2-H), 4.61 and
4.67 (each 1 H, d, J 11, PhCHH), 4.82 and 4.85 (each 1 H, d,
J 7, OCHHO), 5.57 (2 H, m, 1Ј-H and 2Ј-H) and 7.35 (5 H, m,
ArH); m/z (CI) 409 (Mϩ ϩ 18, 5%), 392 (Mϩ ϩ 1, 8.2) and 318
(49).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(4R,1E)-4-
benzyloxymethoxy-3-oxopent-1-enyl]-2,2-dimethyl-1,3-dioxol-
ane 71. (2.1 g, 90%) From the aldehyde 11 (1.37 g, 5 mmol) as a
colourless oil after chromatography using light petroleum–ether
(7:1) as eluent, [α]D27 ϩ31.1 (c 0.88, CHCl3); νmax/cmϪ1 1702,
1634, 1380, 1255, 1168, 1098, 1040 and 838; δH 0.07 (6 H, s,
2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.37 (3 H, d, J 7, 5Љ-H3),
1.42 and 1.44 (each 3 H, s, CH3), 3.77 (3 H, m, 4-H and 1Ј-H2),
4.37 (1 H, q, J 7, 4Љ-H), 4.57 (1 H, m, 5-H), 4.64 (2 H, s,
PhCH2), 4.77 and 4.85 (each 1 H, d, J 7, OHCHO), 6.74
(1 H, dd, J 16, 1.5, 2Љ-H), 6.98 (1 H, dd, J 16, 5, 1Љ-H) and 7.30
(5 H, m, ArH); δC Ϫ5.25, Ϫ5.19, 17.93, 18.49, 26.06, 26.99,
27.12, 62.90, 70.21, 77.62, 78.12, 81.02, 94.11, 110.10, 124.723,
127.95, 128.61, 137.60, 144.37 and 199.66; m/z (FAB) 465
(Mϩ ϩ 1).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4R,1E)-
4-benzyloxymethoxy-3-hydroxypent-1-enyl]-2,2-dimethyl-1,3-
dioxolane 72. (1.9 g, 99%) From the enone 71 (1.92 g, 4.131
mmol), as
a colourless oil after chromatography using
light petroleum–ethyl acetate (5:1) as eluent, HPLC (column:
Spheresorb 5 silica NF0/262; eluent: 6:1 hexane–ethyl acetate)
3ЉS:3ЉR = 98:2, [α]D27 Ϫ19.7 (c 0.95, CHCl3); νmax/cmϪ1 3452,
1461, 1380, 1254, 1040 and 838; δH 0.05 (6 H, s, 2 × SiCH3),
0.90 [9 H, s, SiC(CH3)3], 1.17 (3 H, d, J 6.5, 5Љ-H3), 1.42 (6 H, s,
2 × CH3), 2.35 (1 H, br s, OH), 3.74 (3 H, m, 4-H and 1Ј-H2),
3.85 (1 H, dq, J 6.5, 3, 4Љ-H), 4.18 (1 H, m, 3Љ-H), 4.41 (1 H, m,
5-H), 4.61 and 4.69 (each 1 H, d, J 12, PhCHH), 4.82 and 4.85
(each 1 H, d, J 7, OCHHO), 5.83 (2 H, m, 1Љ-H and 2Љ-H) and
7.35 (5 H, m, ArH); δC Ϫ5.22, Ϫ5.12, 15.40, 18.55, 26.10, 27.14,
27.27, 62.60, 70.15, 74.33, 78.41, 81.73, 94.10, 109.28, 128.02,
128.08, 128.67, 130.13, 131.65 and 137.75; m/z (FAB) 489
(Mϩ ϩ 23).
Reduction of enones using zinc borohydride
(2R,3S,4E)- and (2S,3R,4E)-2-(Benzyloxymethoxy)-6-meth-
ylhept-4-en-3-ol 32 and 43. Zinc borohydride (0.15 M in ether;
75 cm3, 11 mmol) was added dropwise to a solution of the
ketone 31 (1.64 g, 6.25 mmol) in ether (50 cm3) at Ϫ35 ЊC.
After 2.5 h, water (25 cm3) was added and the mixture allowed
to warm to ambient temperature before the addition of acetic
acid (6 cm3, 105 mmol) in water (25 cm3). The mixture was
extracted with ether (3 × 75 cm3) and the organic extracts
were washed with saturated aqueous sodium bicarbonate
(2 × 50 cm3) and back extracted with ether (2 × 50 cm3). The
ethereal extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ether (3:1) as eluent gave the (2R,3S,4E)-isomer
of the title compound 32 (1.61 g, 97%), as a colourless oil,
[α]D Ϫ15.8 (c 2.09 in CHCl3) (Found: Mϩ ϩ NH4, 282.2049.
C16H28NO3 requires M, 282.2069); νmax/cmϪ1 3459, 1455, 1382,
1169, 1103, 1042, 975 and 737; δH 1.05 (6 H, d, J 6.5, 2 × CH3),
1.16 (3 H, d, J 6.5, 1-H3), 2.33 (1 H, m, 6-H), 3.83 (1 H, dq,
J 6.5, 3, 2-H), 4.09 (1 H, dd, J 7, 3, 3-H), 4.63 and 4.7 (each 1 H,
d, J 11.5, PhHH), 4.83 and 4.86 (each 1 H, d, J 7, OCHHO),
5.44 (1 H, ddd, J 15.5, 7, 1, 4-H), 5.7 (1 H, ddd, J 15.5, 6.5, 1,
5-H) and 7.33 (5 H, m, ArH); m/z (CI) 282 (Mϩ ϩ 18, 10%), 264
(Mϩ, 0.4%) and 217 (100%).
(4S,2E)-4-tert-Butyldimethylsilyloxypent-2-enal 59
(S)-2-tert-Butyldimethylsilyloxypropanal 58 (3.77 g, 20 mmol)
was added to a suspension of formylmethylene(triphenyl)-
phosphorane (6.7 g, 22 mmol) in benzene (200 cm3) and the
mixture stirred for 3 d before being filtered and concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ether (10:1) as eluent gave the title compound
59 (3.73 g, 87%), as a colourless oil, [α]D21 ϩ15.7 (c 1.25, CHCl3);
νmax/cmϪ1 1696, 1257, 1159, 1125, 1091, 1051, 977, 920, 837 and
778; δH (C6D6) 0.00 and 0.03 (each, 3 H, s, SiCH3), 0.97 [9 H, s,
SiC(CH3)3], 1.02 (3 H, d, J 6.5, 5-H3), 4.12 (1 H, m, 4-H), 6.16
(1 H, dd, J 16, 4, 3-H), 6.34 (1 H, ddd, J 15.5, 8, 1.5, 2-H) and
9.44 (1 H, d, J 8, 1-H): δC (C6D6) Ϫ4.92, Ϫ4.90, 18.21, 23.23,
25.84, 67.67, 130.21, 159.17 and 192.24; m/z (CI) 232 (Mϩ ϩ 18,
14%), 215 (Mϩ ϩ 1, 17) and 214 (Mϩ, 4).
Reduction of the (2S)-ketone 42 gave the (2S,3R,4E)-isomer
of the title compound 43 (Found: Mϩ ϩ NH4, 282.2084.
C16H28NO3 requires M, 282.2069), [α]2D6 ϩ14.3 (c 1.3 in
CHCl3).
2-[(3S,1E)-3-tert-Butyldimethylsilyloxybut-1-enyl]-1,3-
dioxolane 60
The following alcohols were prepared using this procedure.
A solution of the aldehyde 59 (1.49 g, 6.95 mmol), ethanediol
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303
3299

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(0.65 g, 10.5 mmol) and toluene-p-sulfonic acid (50 mg, 0.26
mmol) in benzene was heated under reflux for 1.5 h in a Dean–
Stark apparatus. The resulting solution was allowed to cool
and potassium carbonate (2.5 g) was added. The resulting sus-
pension was filtered and concentrated under reduced presure.
Chromatography of the residue using light petroleum–ether
(15:1) as eluent gave the title compound 60 (1.37 g, 76%), as a
pale yellow oil, [α]D21 ϩ6.6 (c 1.65, CHCl3) (Found: Mϩ ϩ H,
259.1726. C13H27O3Si requires M, 259.1729); νmax/cmϪ1 1696,
1473, 1394, 1255, 1149, 1087, 1053, 967, 836 and 778; δH (C6D6)
0.12 and 0.14 (each 3 H, s, SiCH3), 1.04 [9 H, s, SiC(CH3)3], 1.19
(3 H, d, J 6.5, 4Ј-H3), 3.47 and 3.63 (each 2 H, m, 2 × OCH2),
4.26 (1 H, m, 3Ј-H), 5.34 (1 H, d, J 4.5, 2-H) and 5.97 (2 H, m,
1Ј-H and 2Ј-H); δC (C6D6) Ϫ4.70, Ϫ4.48, 18.37, 24.28, 26.04,
64.83, 68.60, 103.82, 125.89 and 140.09; m/z (CI) 259 (Mϩ ϩ 1,
100%) and 127 (50).
3355, 1685, 1449, 1380, 1202, 1165, 1076 and 842; δH (C6D6)
1.50 and 1.55 (each 3 H, s, 2 × CH3), 1.7 (3 H, s, CH3), 1.95
(2 H, m, 5-H2), 2.05 (2 H, m, 4-H2), 4.74 (2 H, d, J 7, 1-H2), 5.15
(1 H, m, 6-H), 5.45 (1 H, m, 2-H) and 8.05 (1 H, br s, NH);
δC (C6D6) 16.26, 17.60, 25.69, 26.48, 39.65, 64.61, 116.22,
117.99, 124.13, 131.60, 143.08 and 157.61; δF (C6D6) Ϫ75.85;
m/z (CI) 267 (Mϩ ϩ 18, 11%), 250 (Mϩ ϩ 1, 2), 249 (Mϩ, 9) and
154 (99).
(E)-1-(2,2,2-Trifluoroacetimidoyloxy)-3-phenylprop-2-ene 54.
(0.27 g, 83%) From cinnamyl alcohol (0.19, 1.44 mmol), as a
colourless oil after chromatography on base washed silica using
gradient elution (40:1→20:1 light petroleum–ether) (Found:
Mϩ, 229.0721. C11H10F3NO requires M, 229.0714); νmax/cmϪ1
3349, 1686, 1356, 1202, 1166 and 1076; δH (C6D6) 4.68 (2 H, d,
J 7, 1-H2), 6.09 (1 H, dt, J 16, 6.5, 2-H), 6.42 (1 H, d, J 16, 3-H),
7.14 (5 H, m, ArH) and 8.10 (1 H, br s, NH); δC (C6D6) 68.27,
116.22, 122.15, 135.21, 136.42 and 157.42, remaining signals
obscured by C6D6; δF (C6D6) Ϫ75.81; m/z (EI) 229 (Mϩ, 30%),
200 (23), 160 (12) and 115 (100).
2-[(3S,1E)-3-Hydroxybut-1-enyl]-1,3-dioxolane 61
Tetrabutylammonium fluoride (1 M in tetrahydrofuran; 5 cm3,
5 mmol) was added to a solution of the silyl ether 60 (1.14 g,
4.41 mmol) in tetrahydrofuran at 0 ЊC and the mixture stirred
for 2 h at ambient temperature. Water (20 cm3) was added and
the resulting mixture extracted with dichloromethane (3 × 50
cm3). The organic extracts were dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
using light petroleum–ether (2:1) as eluent gave the title com-
pound 61 (0.6 g, 94%), as a colourless oil, [α]D20 ϩ11.3 (c 1.2,
CHCl3) (Found: Mϩ Ϫ H, 143.0709. C7H11O3 requires M,
143.0708); νmax/cmϪ1 3419, 1400, 1294, 1146, 1060 and 968;
δH (C6D6) 1.26 (3 H, d, J 6.5, 4Ј-H3), 2.00 (1 H, br s, OH), 3.59
and 3.76 (each 2 H, m, OCH2), 4.24 (1 H, m, 3Ј-H), 5.42 (1 H,
d, J 5, 2-H) and 6.30 (2 H, m, 1Ј-H and 2Ј-H); δC (C6D6)
23.75, 65.53, 68.00, 104.15, 126.72 and 140.95; m/z (EI) 144
(Mϩ, 0.3%), 143 (Mϩ Ϫ 1, 4), 127 (19) and 99 (100).
(2E,4E)-1-(2,2,2-Trifluoroacetimidoyloxy)hexa-2,4-diene 56.
(0.45 g, 77%) From sorbyl alcohol (0.3 g, 3.06 mmol), as a
colourless oil after chromatography on base washed silica using
gradient elution (40:1→20:1 light petroleum–ether) (Found:
Mϩ, 193.0720. C8H10F3NO requires M, 193.0714); νmax/cmϪ1
3300, 1686, 1201 and 1165; δH (C6D6) 1.55 (3 H, d, J 6.5, 6-H3),
4.62 (2 H, d, J 7, 1-H2), 5.52 (2 H, m), 5.89 (1 H, m), 6.12 (1 H,
m) and 8.10 (1 H, br s, NH); δC (C6D6) 17.91, 68.16, 116.21,
122.85, 130.85, 131.29, 135.90 and 157.44; δF (C6D6) Ϫ75.93;
m/z (EI) 193 (Mϩ, 5%) and 164 (2).
2-[(3S,1E)-3-(2,2,2-Trifluoroacetimidoyloxy)but-1-enyl]-1,3-
dioxolane 62. (0.2 g, 79%) From the alcohol 61 (0.15 g,
1.04 mmol), as a colourless oil after chromatography on base
washed silica using gradient elution (light petroleum–ether
20:1→10:1), [α]D20 Ϫ52.2 (c 1.18, PhH); νmax/cmϪ1 3304, 1684,
1400, 1204, 1161, 1082, 1038, 968 and 845; δH (C6D6) 1.12 (3 H,
d, J 6.5, 4Ј-H3), 3.48 (4 H, m, OCH2CH2O), 5.24 (1 H, m, 2-H),
5.52 (1 H, m, 3-H), 5.88 (2 H, m, 1Ј-H and 2Ј-H) and 8.05 (1 H,
br s, NH); δC (C6D6) 19.07, 64.80, 73.14, 103.02, 116.13, 129.37,
133.30 and 156.66; δF (C6D6) Ϫ76.22; m/z (CI) 239 (Mϩ, 4%),
127 (20) and 116 (22).
Synthesis of trifluoroacetimidates using a solution of
trifluoroacetonitrile in tetrahydrofuran
(2R,3S,4E)-
and
(2S,3R,4E)-2-(Benzyloxymethoxy)-6-
methyl-3-(2,2,2-trifluoroacetimidoyloxy)hept-4-ene 33 and 44.
Butyllithium (1.6 M in hexane; 0.05 cm3, 0.08 mmol) was added
to a solution of the alcohol 32 (0.1 g, 0.39 mmol) in tetrahydro-
furan (4 cm3) at 0 ЊC and the mixture stirred for 15 min then
cooled to Ϫ78 ЊC and stirred for a further 45 min. An excess of
the standard trifluoroacetonitrile solution (2 cm3) was added via
a cannula and the mixture stirred for 1 h before being allowed
to warm to ambient temperature. Ammonium chloride (50 mg)
and light petroleum (6 cm3) were added and the mixture was
filtered and concentrated under reduced pressure. Chrom-
atography on base washed silica using gradient elution (40:1→
20:1→10:1→3:1 light petroleum–ether) gave the (2R,3S,4E)-
isomer of the title compound 33 as a colourless oil (0.12 g, 91%),
[α]D26 ϩ57.3 (c 1.34 in CHCl3) (Found: Mϩ, 359.1697. C18H24-
F3NO3 requires M, 359.1708); νmax/cmϪ1 3353, 1685, 1498, 1382,
1201, 1167, 1081 and 1042; δH 1.01 (6 H, d, J 7, 2 × CH3), 1.21
(3 H, d, J 6.5, 1-H3), 2.35 (1 H, m, 6-H), 4.06 (1 H, dq, J 6.5, 3,
2-H), 4.63 (2 H, s, OCH2O), 4.84 (2 H, s, PhCH2), 5.66 (2 H, m,
3-H and 5-H), 5.81 (1 H, dd, J 14.5, 6.5, 4-H), 7.30 (5 H, m,
ArH) and 8.10 (1 H, br s, NH); δF 3.80 and 3.93 (3:97); m/z
(CI) 377 (Mϩ ϩ 18, 6%), 360 (Mϩ ϩ 1, 1) and 217 (100).
The alcohol 43 similarly gave the (2S,3R,4E)-isomer of the
title compound 44 (Found: Mϩ ϩ NH4, 377.2063. C18H28F3N2O3
requires M, 377.2052).
(2S)-2-[(3R,4S,1E)-4-Benzyloxymethoxy-3-(2,2,2-trifluoro-
acetimidoyloxy)pent-1-enyl]-N-(tert-butoxycarbonyl)pyrrolidine
69. (65 mg, 45%) From the alcohol 68 (0.12 g, 0.3 mmol)
as a colourless gum after chromatography on base washed
silica using gradient elution (20:1→10:1→ 3:1→1:1 light
petroleum–ether), [α]D25 Ϫ53 (c 2, PhH); νmax/cmϪ1 3281, 1691,
1396, 1199, 1165 and 1041; m/z (EI) 486 (Mϩ, 1%), 386 (15), 318
(60) and 91 (100).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4R,1E)-
4-benzyloxymethoxy-3-(2,2,2-trifluoroacetimidoyloxy)pent-1-
enyl]-2,2-dimethyl-1,3-dioxolane 73. (0.24 g, 86%) From alcohol
72 (0.23 g, 0.49 mmol), as a colourless oil after chromatography
on base washed silica using gradient elution (40:1→20:1 light
petroleum–ether), [α]D25 ϩ24.1 (c 1.00, PhH) (Found: Mϩ ϩ NH4,
579.3072. C27H46F3N2O6Si requires M, 579.3077); νmax/cmϪ1
3301, 3250, 1688, 1381, 1202, 1167, 1086, 1041 and 878;
δH (C6D6) 0.12 and 0.14 (each 3 H, s, SiCH3), 1.03 [9 H, s,
SiC(CH3)3], 1.13 (3 H, d, J 6.5, 5Љ-H3), 1.45 and 1.49 (each 3 H,
s, CH3), 3.73 (2 H, m, 1Ј-H2), 3.84 (1 H, m, 4-H), 4.02 (1 H, dq,
J 6.5, 4, 4Љ-H), 4.51 (1 H, m, 5-H), 4.61 (2 H, s, PhCH2), 4.68
and 4.77 (each 1 H, d, J 7.5 OHCHO), 5.67 (1 H, m, 3Љ-H), 6.06
(2 H, m, 1Љ-H and 2Љ-H), 7.13–7.42 (5 H, m, ArH) and 8.12
(1 H, br s, NH); δC (C6D6) Ϫ5.34, Ϫ5.29, 15.98, 18.47, 26.03,
27.09, 27.18, 63.07, 69.37, 73.36, 78.28, 79.76, 81.91, 93.27,
109.36, 116.21, 126.13, 128.52, 134.07, 138.55 and 156.94;
The following were prepared using this procedure.
(2E)-1-(2,2,2-Trifluoroacetimidoyloxy)-3,7-dimethylocta-2,6-
diene 52. (0.22 g, 88%) From geraniol (0.15 g, 0.98 mmol), as a
colourless oil after chromatography on base washed silica using
gradient elution (40:1→20:1 light petroleum–ether) (Found:
Mϩ, 249.1136. C12H18F3NO requires M, 249.1340); νmax/cmϪ1
3300
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303

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δF (C6D6) Ϫ76.04; m/z (CI) 580 (Mϩ ϩ 19, 10%), 579 (Mϩ ϩ 18,
2-[(1S,2E)-1-(2,2,2-Trifluoroacetylamino)but-2-enyl]-1,3-
8), 391 (50) and 361 (100).
dioxolane 63. (0.16 g, 93%) From the trifluoroacetimidate 62
(0.17 g, 0.71 mmol), as colourless crystals, after heating under
reflux in xylene (15 cm3) for 16 h and chromatography using
light petroleum–ether (4:1) as eluent, mp 53–54 ЊC, [α]D20 Ϫ16.6
(c 1.10, PhH) (Found: C, 45.4; H, 5.1; N, 6.0; F, 24.1.
C9H12F3NO3 requires C, 45.2; H, 5.1; N, 5.9; F, 23.8%; Found:
Mϩ ϩ NH4, 257.1115. C9H16N2F3O3 requires M, 257.1113);
νmax/cmϪ1 3280, 1706, 1561, 1211 and 1187; δH 1.75 (3 H, d, J 6.5
4Ј-H3), 3.97 (4 H, m, OCH2CH2O), 4.72 (1 H, t, J 7, 1Ј-H), 4.94
(1 H, d, J 2, 2-H), 5.42 (1 H, m, 2Ј-H), 5.80 (1 H, m, 3Ј-H) and
6.53 (1 H, d, J 5.5, NH); δC 17.88, 53.30, 65.45, 65.67, 103.29,
115.89, 124.16, 131.44 and 156.73; δF Ϫ77.478; m/z (CI) 257
(Mϩ ϩ 18, 46%), 240 (Mϩ ϩ 1, 9%) and 35 (100).
Rearrangement of trifluoroacetimidates
(2R,5S,3E)-2-(Benzyloxymethoxy)-6-methyl-5-(2,2,2-tri-
fluoroacetylamino)hept-3-ene 34. (60 mg, 89%) From the
trifluoroacetimidate 33 (67 mg, 0.19 mmol), as a white wax,
after heating under reflux in xylene (2 cm3) ~4 h and chrom-
atography using light petroleum–ether (6:1) as eluent, mp
49–51 ЊC, [α]D22 ϩ48.9 (c 1.12 CHCl3) (Found: C, 60.5; H, 6.8; N,
3.8; F, 15.5. C18H24F3NO3 requires C, 60.2; H, 6.8; N, 3.9; F,
15.9%; Found: Mϩ ϩ NH4, 377.2048. C18H28F3N2O3 requires
M, 377.2052); νmax/cmϪ1 3285, 3092, 3069, 3034, 1699, 1556,
1208, 1183, 1104 and 1038; δH 0.92 and 0.93 (each 3 H, d, J 6.5,
2 × CH3), 1.28 (3 H, d, J 6.5, 1-H3), 1.86 (1 H, m, 6-H), 4.30
(2 H, m, 2-H and 5-H), 4.55 and 4.67 (each 1 H, d, J 11.5,
PhCHH), 4.73 and 4.76 (each 1 H, d, J 6.5, OCHHO), 5.58
(2 H, m, 3-H and 4-H), 6.35 (1 H, br d, J 7, NH) and 7.30 (5 H,
m, ArH); δC 18.35, 18.80, 21.50, 32.25, 56.97, 69.68, 72.12,
92.14, 116.09, 127.91, 128.07, 128.35, 128.63, 135.04, 138.04
and 156.69; δF 2.90 and 3.07 (99:1); m/z (CI) 377 (Mϩ ϩ 18,
100%).
(2S)-2-[(1S,4S,2E)-4-Benzyloxymethoxy-1-(2,2,2-trifluoro-
acetylamino)pent-2-enyl]-N-(tert-butoxycarbonyl)pyrrolidine
70. (18 mg, 90%) From the trifluoroacetimidate 69 (20 mg,
0.042 mmol) in xylene (5 cm3), as a colourless gum, after heat-
ing under reflux in xylene for 7 h and chromatography using
light petroleum–ether (4:1) as eluent, [α]D22 Ϫ73.7 (c 0.63,
CHCl3) (Found: Mϩ ϩ H, 487.2419. C24H34F3N2O5 requires M,
487.2420); νmax/cmϪ1 3250, 1724, 1669, 1547, 1400 and 1164;
δH 1.27 (3 H, d, J 6.5, 5Ј-H3), 1.47 [9 H, s, C(CH3)3], 1.76–1.94
(4 H, m, 3-H2 and 4-H2), 3.35 (2 H, m, 5-H2), 3.98 (1 H, m,
2-H), 4.07 (1 H, m, 1Ј-H), 4.26 (1 H, m, 4Ј-H), 4.56 and 4.67
(each 1 H, d, J 12, OCHHO), 4.74 (2 H, s, PhCH2), 5.45 (1 H,
m, 2Ј-H), 5.73 (1 H, m, 3Ј-H), 7.35 (5 H, m, ArH) and 8.87 (1 H,
br d, J 6, NH); δC 21.29, 23.45, 28.15, 28.23, 47.09, 57.96,
59.03, 69.51, 72.17, 81.05, 92.09, 115.88, 127.49, 127.69, 127.91,
128.43, 136.64, 137.94, 157.178 and 157.81; δF Ϫ77.68, Ϫ77.86
(95:5); m/z (CI) 504 (Mϩ ϩ 18), 487 (Mϩ ϩ 1), 387 (50) and 293
(55).
(2S,5R,3E)-2-(Benzyloxymethoxy)-6-methyl-5-(2,2,2-tri-
fluoroacetylamino)hept-3-ene 45. (0.23, 91%) From the trifluoro-
acetimidate 44 (0.25 g, 0.7 mmol) in xylene (25 cm3), as a white
wax, after heaing under reflux in xylene for ~4 h and chrom-
atography using light petroleum–ether (6:1) as eluent, mp 49–
50 ЊC, [α]D23 Ϫ55.2 (c 0.86 CHCl3) (Found: C, 59.85; H, 7.0; N,
3.9. C18H24F3NO3 requires C, 60.2; H, 6.8; N, 3.9%; Found:
Mϩ ϩ NH4, 377.2055. C18H28F3N2O3 requires M, 377.2052).
3-(2,2,2-Trifluoroacetylamino)-3,7-dimethylocta-1,6-diene 53.
(0.16 g, 80%) From the trifluoroacetimidate 52 (0.19 g, 0.78
mmol), as a colourless oil, after heating under reflux in xylene
(15 cm3) for 8 h and chromatography using light petroleum–
ether (40:1) as eluent (Found: Mϩ, 249.1329. C12H18F3NO
requires M, 249.1340); νmax/cmϪ1 3326, 3089, 1712, 1547 and
1185; δH 1.53, 1.61 and 1.69 (each 3 H, s, CH3), 1.81 (2 H, m,
4-H2), 2.02 (2 H, m, 5-H2), 5.15 (3 H, m, 1-H2 and 6-H), 5.90
(1 H, dd, J 17, 10, 2-H) and 6.40 (1 H, br s, NH); δC 17.65,
22.56, 24.02, 25.59, 39.09, 58.81, 113.71, 115.65, 123.34, 133.33,
140.76 and 155.90; δF Ϫ77.75; m/z (EI) 249 (Mϩ, 2%), 234 (1.5),
166 (19) and 136 (44).
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-[(3S,4R,1E)-
4-benzyloxymethoxy-3-(2,2,2-trifluoroacetylamino)pent-2-enyl]-
2,2-dimethyl-1,3-dioxolane 74. (188 mg, 91%) From the tri-
fluoroacetimidate 73 (208 mg, 0.37 mmol), as a colourless oil,
after heating under reflux in xylene (20 cm3) for 9.5 h and
chromatography using light petroleum–ether (7:1) as eluent,
[α]D25 ϩ27 (c 0.8, CHCl3) (Found: Mϩ ϩ NH4, 579.3083.
C27H46F3N2O6Si requires M, 579.3077); νmax/cmϪ1 3319, 1730,
1526, 1255, 1212, 1169, 1093, 1039 and 838; δH 0.08 (6 H, s,
2 × SiCH3), 0.92 [9 H, s, SiC(CH3)3], 1.28 (3 H, d, J 6.5, 5Љ-H3),
1.38 and 1.42 (each 3 H, s, CH3), 3.69 (2 H, m, 1Ј-H2), 3.86 (1 H,
m, 4-H), 4.06 (1 H, dd, J 7, 2 5-H), 4.30 (1 H, m, 4Љ-H), 4.56 and
4.68 (each 1 H, d, J 11, PhHCH), 4.76 (3 H, m, OCH2O and 1Љ-
H), 5.69 (2 H, m, 3Љ-H and 4Љ-H), 6.69 (1 H, br d, J 8, NH) and
7.35 (5 H, m, ArH); δC Ϫ5.51, Ϫ5.42, 18.41, 21.23, 25.90, 26.90,
50.37, 63.24, 69.53, 71.62, 80.22, 92.12, 109.60, 115.89, 127.12,
127.72, 127.90, 128.45, 135.17, 137.92 and 156.64; δF Ϫ77.34;
m/z (CI) 579 (Mϩ ϩ 18, 60%) and 424 (100).
1-(2,2,2-Trifluoroacetylamino)-1-phenylprop-2-ene 55. (0.20 g,
81%) From the trifluoroacetimidate 54 (0.25 g, 1.09 mmol), as a
colourless crystalline solid, after heating under reflux in xylene
(15 cm3) for 5 h and chromatography using light petroleum–
ether (10:1) as eluent, mp 76–77 ЊC (needles from light petrol-
eum) (Found: C, 58.1; H, 4.7; F, 25.1; N, 6.0. C11H10F3NO
requires C, 57.6; H, 4.4; F, 24.9; N, 6.1%; Found: Mϩ, 229.0716.
C11H10F3NO requires M, 229.0714); νmax/cmϪ1 3308, 1701, 1549,
1205 and 1176; δH 5.34 (2 H, m, 3-H2), 5.64 (1 H, m, 1-H), 6.04
(1 H, m, 2-H), 6.5 (1 H, br s, NH) and 7.32 (5 H, m, ArH);
δC 55.76, 115.83, 117.33, 127.20, 128.52, 129.14, 135.26, 138.42
and 156.27; δF Ϫ77.33; m/z (EI) 229 (Mϩ, 59%) and 160 (55).
(2R,5S,3E)-2-(Benzyloxymethoxy)-6-methyl-5-(tert-butoxy-
carbonylamino)hept-3-ene 36
Barium hydroxide (0.19 g, 0.59 mmol) was added to a solution
of the trifluoroacetamide 34 (27 mg, 0.074 mmol) in methanol
(3 cm3) at 0 ЊC and the mixture stirred at ambient temperature
overnight. The mixture was then filtered through a pad of
Celite and silica, eluting with methanol, and the filtrate concen-
trated under reduced pressure to give the amine 35 (Found:
Mϩ ϩ H, 264.1963. C16H26NO2 requires M, 264.1963); δH 0.87
and 0.91 (each 3 H, d, J 8, 2 × CH3), 1.13 (2 H, br s, NH2), 1.28
(3 H, d, J 8, 1-H3), 1.62 (1 H, m, 6-H), 3.10 (1 H, m, 5-H), 4.27
(1 H, m, 2-H), 4.56 and 4.68 (each 1 H, d, J 12, PhCHH), 4.73
and 4.79 (each 1H, d, J 8, OCHHO), 5.47 and 5.61 (each 1 H,
dd, J 15, 7, 3-H and 4-H) and 7.32 (5 H, m, ArH): m/z (CI) 264
(Mϩ ϩ 1, 100%).
(E)-3-(2,2,2-Trifluoroacetylamino)hexa-1,4-diene 57. (0.14 g,
35%) From the trifluoroacetimidate 56 (0.38 g, 1.98 mmol), as a
colourless oil, after heating under reflux in xylene (25 cm3) for
9.5 h and chromatography using gradient elution (40:1→20:1
light petroleum–ether) (Found: Mϩ, 193.0712. C8H10F3NO
requires M, 193.0715); νmax/cmϪ1 3294, 1703, 1552 and 1185;
δH 1.73 (3 H, m, 6-H3), 4.99 (1 H, m, 3-H), 5.21 (1 H, m, 1-H),
5.26 (1 H, m, 1-HЈ), 5.45 (1 H, m, 4-H), 5.78 (2 H, m, 2-H and
5-H) and 6.45 (1 H, br s, NH); δC 17.72, 53.49, 115.85, 116.81,
127.48, 129.82, 135.34 and 156.19; δF Ϫ77.51; m/z (EI) 193 (Mϩ,
17%), 178 (15), 166 (9) and 152 (9).
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303
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The amine was dissolved in ether (1 cm3) and the resulting
solution cooled to 0 ЊC. Triethylamine (0.012 cm3, 0.086 mmol)
and a solution of di-tert-butyl dicarbonate (18 mg, 0.082 mmol)
in ether (2 cm3) were added and the solution stirred overnight
at ambient temperature. The mixture was concentrated under
reduced pressure and chromatography of the residue using light
petroleum–ether (5:1) as eluent gave the title compound 36
(21 mg, 79%), as a white wax (Found: C, 69.1; H, 9.2 and N,
3.9. C21H33NO4 requires C, 69.4; H, 9.2 and N, 3.9%; Found:
Mϩ ϩ H, 364.2413. C21H34NO4 requires M, 364.2487); δH 0.87
and 0.90 (each 3 H, d, J 7, 2 × CH3), 1.27 (3 H, d, J 6.5, 1-H3),
1.44 [9 H, s, C(CH3)3], 1.75 (1 H, m, 6-H), 3.99 (1 H, m, 5-H),
4.28 (1 H, m, 2-H), 4.48 (1 H, br d, J 7, NH), 4.55 and 4.68
(each 1 H, d, J 12, PhCHH), 4.72 and 4.77 (each 1 H, d, J 7,
OCHHO), 5.51 (2 H, m, 3-H and 4-H) and 7.35 (5 H, m, ArH);
m/z (CI) 381 (Mϩ ϩ 18, 46%), 364 (Mϩ ϩ 1, 4) and 91 (100).
CO2CH3), 4.62 (1 H, dd, J 9, 5, 2-H), 7.06 (1 H, br d, J 9, NH)
and 7.35–7.65 (5 H, m, ArH); δF Ϫ70.39, Ϫ70.70 (90:10); δH
(minor diastereoisomer) 0.95 and 1.0 (each 0.3 H, d, J 7, CH3).
(2S,5R,3E)-2-(Benzyloxymethoxy)-6-methyl-5-(benzyloxy-
carbonylamino)hept-3-ene 47
Barium hydroxide (0.83 g, 2.63 mmol) was added to a solution
of the trifluoroacetamide 45 (0.12 g, 0.33 mmol) in methanol
(10 cm3) at 0 ЊC and the mixture stirred overnight at ambient
temperature then filtered through a pad of Celite and silica
using methanol as eluent. The filtrate was concentrated under
reduced pressure and the residue dissolved in water (2 cm3) and
ethyl acetate (3 cm3). Benzyl chloroformate (68 mg, 0.4 mmol)
and potassium bicarbonate (0.165 g, 1.64 mmol) were added
and the mixture stirred overnight at ambient temperature. Ethyl
acetate (100 cm3) was added and the organic layer was washed
with saturated aqueous ammonium chloride (2 × 5 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography of the residue using light petroleum–ether (5:1) as
eluent gave the title compound 47 (0.11 g, 86%) as a pale yellow
gum, [α]D20 Ϫ81.7 (c 0.86, CHCl3) (Found: Mϩ ϩ NH4, 415.2608.
C24H35N2O4 requires M, 415.2597); νmax/cmϪ1 3328, 1705, 1455,
1238, 1100 and 1026; δH 0.88 and 0.92 (each 3 H, d, J 7,
2 × CH3), 1.27 (3 H, d, J 6.5, 1-H3), 1.78 (1 H, m, 6-H), 4.08
(1 H, m, 5-H), 4.27 (1 H, m, 2-H), 4.52–4.78 (5 H, m, OCH2O,
PhCH2 and NH), 5.12 (2 H, s, PhCH2OCO), 5.55 (2 H, m, 3-H
and 4-H) and 7.36 (10 H, m, ArH); m/z (CI) 415 (Mϩ ϩ 18,
32%), 307 (23), 264 (57) and 260 (100).
N-tert-Butoxycarbonyl-L-valine methyl ester 37
A solution of the alkene 36 (0.14 g, 0.38 mmol) in methanol
(8 cm3) was cooled to Ϫ78 ЊC whilst oxygen was bubbled through
the solution. After 10 min, ozone was bubbled into the solution
for 20 min and then the mixture was purged with oxygen for a
further 10 min. Dimethyl sulfide (0.3 cm3, 4 mmol) was added
and the reaction mixture was allowed to warm to ambient tem-
perature over 1 h then concentrated under reduced pressure.
The residue was dissolved in methanol (8 cm3) and water (0.15
cm3) and cooled to 0 ЊC. Sodium bicarbonate (0.64 g, 7.62
mmol) and bromine (0.3 g, 1.88 mmol) were added and the
resulting suspension stirred overnight at ambient temperature.
Sodium thiosulfate (0.3 g) and ether (100 cm3) were added and
the mixture washed with water (2 × 5 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ether (10:1) as eluent gave a
mixture of the methyl ester 37 and methyl (R)-2-benzyloxy-
methoxypropanoate 40 (0.11 g, 65%, ~1:1 mixture). Prepar-
ative HPLC (column: 5 µm ODS; eluent: 70:30 methanol–
water) afforded the title compound 37 as a colourless oil, [α]D18
Ϫ17.6 (c 3.23, MeOH) [lit.,22 Ϫ22.7 (c 2, MeOH)]; νmax/cmϪ1
3372, 1744, 1717, 1438, 1368 and 1160; δH 0.88 and 0.95 (each 3
H, d, J 7, CH3), 1.43 [9 H, s, C(CH3)3], 2.12 (1 H, m, 3-H), 3.73
(3 H, s, OCH3), 4.22 (1 H, m, 2-H) and 5.01 (1 H, br d, J 7,
NH); δC 17.63, 18.96, 28.32, 31.33, 51.99, 58.58, 79.78, 155.67
and 172.91. Methyl (R)-2-benzyloxymethoxypropanoate 40
was also isolated as a colourless oil, [α]D24 ϩ59.9 (c 0.6, CHCl3);
νmax/cmϪ1 1752, 1454, 1209, 1174, 1122, 1083, 1049 and 1026;
δH 1.43 (3 H, d, J 7, 3-H3), 3.70 (3 H, s, OCH3), 4.31 (1 H, q, J 7,
2-H), 4.61 and 4.67 (each 1 H, d, J 11, PhHCH), 4.83 (2 H, s,
OCH2O) and 7.35 (5 H, m, ArH); m/z (CI) 242 (Mϩ ϩ 18, 2%)
and 225 (Mϩ ϩ 1, 2).
N-Benzyloxycarbonyl-D-valine methyl ester 48
Following the general procedure for the ozonolysis–bromine
in methanol oxidation, the alkene 47 (92 mg, 0.23 mmol) gave
the title compound 48 (52 mg, 84%), as a colourless gum, after
chromatography using gradient elution (10:1→5:1 light
petroleum–ether), [α]D23 ϩ11.5 (c 0.9, MeOH) [lit. for the
enantiomer23 Ϫ18.9 (c 1, MeOH)] (Found: Mϩ, 265.1321.
C14H19NO4 requires M, 265.1314). Methyl (S)-2-benzyloxy-
methoxypropanoate 49 was also isolated as a colourless oil
(38 mg, 73%), [α]D20 Ϫ64.1 (c 1.67, CHCl3).
The ester 48 (42 mg, 0.16 mmol), sodium borohydride (60
mg, 1.6 mmol) and lithium chloride (67 mg, 1.6 mmol) in
ethanol (2.5 cm3) and tetrahydrofuran (1.5 cm3) were stirred for
2 h at ambient temeprature then acetic acid (0.25 cm3) and
water (3 cm3) were added. After extraction into ethyl acetate
and concentration under reduced pressure, chromatography of
the residue using light petroleum–ethyl acetate (2:1) as eluent
gave the alcohol 50 (36 mg, 95%), as a white wax, [α]D22 ϩ22.9
(c 0.45, CHCl3) [lit. for the enantiomer24 Ϫ16.9 (c 2, methanol)]
(Found: Mϩ ϩ H, 238.1438. C13H20NO3 requires M, 238.1443);
m/z (CI) 255 (Mϩ ϩ 18, 13%), 238 (Mϩ ϩ 1, 100); νmax/cmϪ1
3400, 1697, 1533 and 1245.
Following the general procedure, the alcohol 50 (20 mg,
0.085 mmol) afforded the (R)-Mosher’s derivative 51 (41 mg,
100%), as a colourless gum, after chromatography using light
petroleum–ether (3:1) as eluent; νmax/cmϪ1 3318, 1747, 1696,
1538 and 1453; δH 0.85 and 0.90 (each 3 H, d, J 7, CH3), 1.73
(1 H, m, 3-H), 3.47 (3 H, s, OCH3), 3.76 (1 H, m, 2-H), 4.35
(2 H, m, CH2O), 4.63 (1 H, d, J 9.5, NH), 5.05 (2 H, s, PhCH2)
and 7.28–7.49 (10 H, m, ArH), peaks due to a minor product
were also present, ratio, 92.3:7.7; m/z (EI) 453 (Mϩ, 3%), 189
(26) and 91 (100).
A solution of trifluoroacetic acid (0.9 cm3) in methanol
(0.1 cm3) was added at 0 ЊC to a 1:1 mixture of ester 37 and
methyl (R)-2-benzyloxymethoxypropanoate 40 (85 mg) and the
mixture stirred for 30 min at ambient temperature. Ethyl acetate
(7 cm3) was added and the mixture washed with saturated
aqueous sodium bicarbonate (3 × 5 cm3), then dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using dichloromethane–methanol (9:1) as eluent
gave the amine 38. This was dissolved in carbon tetrachloride
(10 drops) and pyridine (10 drops) and (S)-α-methoxy-α-
(trifluoromethyl)phenylacetyl chloride (94 mg, 0.37 mmol) was
added. The resulting suspension was stirred overnight at ambi-
ent temperature and then diluted with ether (50 cm3), washed
with saturated aqueous ammonium chloride (2 cm3), sodium
bicarbonate (2 cm3) and water (2 cm3) then dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ether (3:1) as eluent gave the
(S)-Mosher’s derivative 39 (48 mg, 73%), as a colourless oil;
δH (major diastereoisomer) 0.81 and 0.87 (each 3 H, d, J 7,
CH3), 2.21 (1 H, m, 3-H), 3.55 (3 H, s, OCH3), 3.77 (3 H, s,
(4S,5S)-4-[(1R,4R,2E)-1-(tert-Butoxycarbonylamino)-4-benzyl-
oxymethoxypent-2-enyl]-5-(tert-butyldimethylsilyloxymethyl)-
2,2-dimethyl-1,3-dioxolane 76
Barium hydroxide (0.75 g, 2.4 mmol) was added to a solution
of the trifluoroacetamide 74 (0.17 g, 0.30 mmol) in methanol
(10 cm3) at ambient temperature and the resulting suspension
3302
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303

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stirred for 19 h before being filtered through a pad of Celite and
silica and concentrated under reduced pressure. The residue
(145 mg) was dissolved in ether (2 cm3) cooled to 0 ЊC and
triethylamine (0.05 cm3, 0.36 mmol) and a solution of di-tert-
butyl dicarbonate (70 mg, 0.32 mmol) in ether (2 cm3) were
added. The mixture was stirred at ambient temperature for 14 h
then concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ether (7:1) as eluent afforded
the title compound 76 (142 mg, 84%) as a colourless oil, [α]D26
ϩ61.2 (c 0.74, CHCl3) (Found: Mϩ ϩ H, 566.3522. C30H52-
NO7Si requires M, 566.3513); νmax/cmϪ1 3354, 1720, 1368, 1253,
1169, 1085, 1038 and 838; δH 0.09 (6 H, s, 2 × SiCH3), 0.92 [9 H,
s, SiC(CH3)3], 1.28 (3 H, d, J 6.5, 5Љ-H3), 1.36 and 1.41 (each
3 H, s, CH3), 1.44 [9 H, s, C(CH3)3], 3.70 (1 H, m, 4-H), 3.81
(2 H, m, 1Ј-H2), 3.99 (1 H, m, 5-H), 4.29 (1 H, m, 4Љ-H), 4.41 (1
H, m, 1Љ-H), 4.54 and 4.68 (each 1 H, d, J 12, PhCHH), 4.72
and 4.78 (each 1 H, d, J 8, OCHHO), 5.26 (1 H, br d, J 7, NH),
5.65 (2 H, m, 2Љ-H and 3Љ-H) and 7.34 (5 H, m, ArH); δC Ϫ5.39,
18.44, 21.48, 25.99, 26.67, 27.01, 28.40, 50.96, 63.42, 69.43,
72.05, 79.49, 80.63, 91.88, 108.91, 127.64, 127.91, 128.41,
129.90, 132.93, 138.07 and 155.41; m/z (CI) 566 (Mϩ ϩ 1, 10%)
and 372 (100).
should also like to thank the EPSRC (SERC) and the Wellcome
Research Laboratories for support (to I. S.) under the CASE
scheme and the EPSRC for a studentship (to P. D. W.).
References
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(4S,5S)-4-[(S)-(tert-Butoxycarbonylamino)methoxycarbonyl-
methyl]-5-(tert-butyldimethylsilyloxymethyl)-2,2-dimethyl-1,3-
dioxolane 77
In accordance with the general procedure for ozonolysis–
bromine in methanol oxidation the alkene 76 (0.44 g, 0.78
mmol) afforded a mixture of the title compound 77 and methyl
(R)-2-benzyloxymethoxypropanoate 40 after chromatography
using gradient elution (10:1→5:1→3:1 light petroleum–ether)
as a colourless oil (0.47 g, ~90%): title compound 77; δH 0.10
(6 H, s, 2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.37 and 1.42 (each
3 H, s, CH3), 1.45 [9 H, s, C(CH3)3], 3.78 (3 H, s, CO2CH3), 3.82
(2 H, m, 1Ј-H2), 3.91 (1 H, m), 4.40 (1 H, m), 4.45 (1 H, m) and
5.35 (1 H, d, J 10, NH). Lithium hydroxide (50 mg, 1.19 mmol)
was added to a solution of the mixture of the methyl ester 77
and methyl (R)-2-benzyloxymethoxypropanoate 40 (0.19 g) in
tetrahydrofuran (3 cm3) and water (1 cm3) at 0 ЊC and the
resulting solution stirred for 3 h at ambient temperature.
Saturated aqueous ammonium chloride (30 cm3) was added and
the mixture extracted with ether (3 × 30 cm3). The organic
extracts were dried (MgSO4) and concentrated under reduced
pressure to give the acid 21 (0.12 g, 96%) as a white solid with
data identical to those obtained before. The aqueous layer was
then acidified to pH 2, and re-extracted with ether (3 × 30 cm3).
After drying (MgSO4), these extracts were concentrated under
reduced pressure to give the BOM-protected lactic acid (48 mg,
79%).
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Acknowledgements
We thank Dr G. H. Whitham of the Dyson Perrins Laboratory,
Oxford, for many helpful discussions during the course of this
work and Dr A. K. Ganguly of the Schering Plough Corpor-
ation for spectra and an authentic sample of the lactone 22. We
Paper 9/05772B
J. Chem. Soc., Perkin Trans. 1, 1999, 3291–3303
3303

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