Stereoselective synthesis of oxazolidinonyl-fused piperidines of interest as selective muscarinic (M1) receptor agonists: A novel M1 allosteric modulator

Article abstract of DOI:10.1039/c5ob02588e

Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7-arylmethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M₁ receptor agonists, are described. A key step in the synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one, was the addition of isopropenylmagnesium bromide to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal. This gave the 4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-isopropenyloxazolidinone with the 5-isopropenyl and 4-tert-butyldimethylsilyloxymethyl groups cis-disposed about the five-membered ring by chelation controlled addition and in situ cyclisation. This reaction was useful for a range of organometallic reagents. The hydroboration-oxidation of (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-(1-methoxyprop-2-en-2-yl)-1,3-oxazolidin-2-one gave (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-[(SR)-1-hydroxy-3-methoxyprop-2-yl]-1,3-oxazolidin-2-one stereoselectively. 4,7-Diaza-9-oxabicyclo[4.3.0]nonan-8-ones with substituents at C2 that could facilitate C2 deprotonation were unstable with respect to oxazolidinone ring-opening and this restricted both the synthetic approach and choice of 2-heteroaryl substituent. The bicyclic system with a 2-furyl substituent at C2 was therefore identified as an important target. The addition of 1-lithio-1-(2-furyl)ethene to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal gave (4SR,5RS)-4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-[1-(2-furyl)ethenyl]-1,3-oxazolidinone after chelation controlled addition and in situ cyclisation. Following oxazolidinone N-benzylation, hydroboration at 35 °C, since hydroboration at 0 °C was unexpectedly selective for the undesired isomer, followed by oxidation gave a mixture of side-chain epimeric alcohols that were separated after SEM-protection and selective desilylation. Conversion of the neopentylic alcohols into the corresponding primary amines by reductive amination, was followed by N-nosylation, removal of the SEM-groups and cyclisation using a Mitsunobu reaction. Denosylation then gave the 2-furyloxazolidinonyl-fused piperidines, the (1RS,2SR,6SR)-epimer showing an allosteric agonistic effect on M₁ receptors. Further studies resulted in the synthesis of other 2-substituted 4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones and an analogous tetrahydropyran.

Full text of DOI:10.1039/c5ob02588e

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Stereoselective synthesis of oxazolidinonyl-fused
piperidines of interest as selective muscarinic (M1)
receptor agonists: a novel M1 allosteric
modulator‡
Cite this: DOI: 10.1039/c5ob02588e
Kenneth J. Broadley,a Maxime G. P. Buffat,b Erica Burnell,b Robin H. Davies,†c
Xavier Moreau,b Stephen Sneeb and Eric J. Thomas*b
Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7-arylmethyl-4,7-diaza-
9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M1 receptor agonists, are described.
A key step in the synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxa-
bicyclo[4.3.0]nonan-8-one, was the addition of isopropenylmagnesium bromide to 2-benzyloxycarbonyl-
amino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal.
This
gave
the
4-tert-butyldimethyl-
silyloxymethyl-4-cyclobutyl-5-isopropenyloxazolidinone with the 5-isopropenyl and 4-tert-butyl-
dimethylsilyloxymethyl groups cis-disposed about the five-membered ring by chelation controlled addition
and in situ cyclisation. This reaction was useful for a range of organometallic reagents. The hydrobora-
tion–oxidation of (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-(1-methoxy-
prop-2-en-2-yl)-1,3-oxazolidin-2-one gave (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
cyclobutyl-5-[(SR)-1-hydroxy-3-methoxyprop-2-yl]-1,3-oxazolidin-2-one stereoselectively. 4,7-Diaza-9-
oxabicyclo[4.3.0]nonan-8-ones with substituents at C2 that could facilitate C2 deprotonation were
unstable with respect to oxazolidinone ring-opening and this restricted both the synthetic approach and
choice of 2-heteroaryl substituent. The bicyclic system with a 2-furyl substituent at C2 was therefore
identified as an important target. The addition of 1-lithio-1-(2-furyl)ethene to 2-benzyloxycarbonyl-
amino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal
gave
(4SR,5RS)-4-tert-butyldimethyl-
silyloxymethyl-4-cyclobutyl-5-[1-(2-furyl)ethenyl]-1,3-oxazolidinone after chelation controlled addition
and in situ cyclisation. Following oxazolidinone N-benzylation, hydroboration at 35 °C, since hydrobora-
tion at 0 °C was unexpectedly selective for the undesired isomer, followed by oxidation gave a mixture of
side-chain epimeric alcohols that were separated after SEM-protection and selective desilylation. Conver-
sion of the neopentylic alcohols into the corresponding primary amines by reductive amination, was fol-
lowed by N-nosylation, removal of the SEM-groups and cyclisation using a Mitsunobu reaction. Denosyla-
tion then gave the 2-furyloxazolidinonyl-fused piperidines, the (1RS,2SR,6SR)-epimer showing an allo-
steric agonistic effect on M1 receptors. Further studies resulted in the synthesis of other 2-substituted 4,7-
diaza-9-oxabicyclo[4.3.0]nonan-8-ones and an analogous tetrahydropyran.
Received 18th December 2015,
Accepted 8th January 2016
DOI: 10.1039/c5ob02588e
www.rsc.org/obc
Introduction
Muscarinic acetylcholine receptors are a group of widely dis-
tributed G-protein coupled receptors that are involved in many
metabolic processes.1 In particular, the M1 muscarinic acetyl-
aCardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University,
Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, UK
choline receptors have a critical role in cognitive processing.2
In patients with Alzheimer’s disease, decreased cholin-
ergic activity is associated with reduced acetylcholine mediated
neurotransmission in regions expressing M1 receptors,
although the receptors themselves appear to be unchanged.
Agonists of muscarinic M1 receptors are therefore targets as
chemotherapeutic agents for Alzheimer’s disease. Several
bThe School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK.
E-mail: e.j.thomas@manchester.ac.uk
cMuscagen Limited, 10, North Road, Cardiff, CF10 3DY, UK
†Deceased October 2012.
‡Electronic supplementary information (ESI) available. CCDC 1413286–1413288,
1424601 and 1424602. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5ob02588e
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butyl; Ar = Ph).9 Full details of this synthesis and the extension
of this approach to complete syntheses of several piperidines
4 and 5 are presented herein together with the results of
preliminary biological investigations.9
Results and discussion
Synthesis of 2-(alkoxymethyl)piperidines 4 from
oxazolidinones 7
The oxazolidinonyl-fused piperidine 8 with a methoxymethyl
group at C2 and a cyclobutyl substituent at C6 was selected as
the first target for synthesis, the size of the cyclobutyl substitu-
ent being optimal. The oxazolidinone 9 was identified as a
likely precursor of the piperidine 8 providing the configur-
ations of its three stereogenic centres could be controlled, with
the aldehyde 10 a possible intermediate for the synthesis of
oxazolidinone 9, see Fig. 3. The cyclobutyl group in the alde-
hyde 10 limited the options that were available for its syn-
thesis. It was decided to study the synthesis of this aldehyde
from the ketone 11 which in turn would be prepared from the
commercially available cyclobutane carboxylic acid (12).
The (tert-butyldimethylsilyloxy)methyl ketone 11 was pre-
pared from cyclobutane carboxylic acid (12) by reaction with
methyllithium, bromination, hydrolysis of the bromide and
silylation. A Wadsworth–Emmons–Horner reaction of ketone
11 then gave the unsaturated ester 16 that was reduced to give
the allylic alcohol 17, (Z) : (E) = 75 : 25, see Scheme 1. The (Z)-
geometry of the major product (Z)-17 was established by nOe
between H2 and 3-CH.
Fig. 1 Representative muscarinic M1 receptor agonists.
Fig. 2 Synthetic targets and possible routes.
[3,3]-Sigmatropic rearrangements were investigated for the
conversion of the alcohol 17 into the aldehyde 10.11–13 The
allylic alcohols 17 were first converted into the trifluoroaceti-
midates 18 that were heated under reflux in xylene to give the
tertiary trifluoroacetamide 19. The trifluoroacetamide was then
reduced using sodium borohydride to give the amine 20 that
was protected as its Cbz-derivative 21, see Scheme 2. This
intermediate was also prepared, more conveniently, by [3,3]-
sigmatropic rearrangement of the allylic cyanate derived from
the alcohols 17 by reaction with trichloroacetyl isocyanate with
in situ methanolysis of the adduct 22 to give the carbamate 23.
muscarinic M1 receptor agonists have been discovered, e.g.
1–3, see Fig. 1, including some that function via an allosteric
mechanism,3,4 and some agonists have been shown to alleviate
the symptoms of Alzheimer’s disease.5,6 Nevertheless, there
remains a need for more compounds that show selective
agonist activity against M1 receptors to avoid side-effects
arising from stimulation of other muscarinic receptor sub-
types.
Molecular modelling studies using the bacterial rhodopsin
as a substitute for the M1 receptor, led to the identification of
the oxazolidinonyl fused piperidines 4 and 5, characterised by
different substituents at C2, see Fig. 2, as possible M1 agonists
with improved selectivity.7 However to test this hypothesis it
was necessary to synthesise representative members of the
series so that they could be evaluated biologically. The first
approach to the 2-(alkoxymethyl)piperidines 4 that was investi-
gated involved the regio- and stereo-selective hydration of
1,2,5,6-tetrahydropyridines, e.g. 6, followed by oxazolidinone
formation. However, preliminary studies of the synthesis and
functionalisation of 1,2,5,6-tetrahydropyridines 6 en route to
the oxazolidinonylpiperidines 4 met with unexpected compli-
cations8 and was discontinued in favour of a second strategy in
which the piperidine ring was assembled on an oxazolidinone,
e.g. 7. This approach led to the successful synthesis of the first
member of the series, the piperidine 4 (R1 = Me; R2 = cyclo-
Fig. 3 Outline of the proposed synthesis of the oxazololidinonyl-fused
piperidine 8.
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Fig. 4 Suggested mechanism for formation of oxazolidinone 25.
Scheme 1 Synthesis of the alkenol 17. Reagents and conditions (i)
MeLi, Et2O, 0 °C to rt, 3 h (90%); (ii) Br2, MeOH, 0 °C to 15 °C, 1.5 h
(80%); (iii) KOCHO, MeOH, heat under reflux, 12 h (71%); (iv) TBSCl, imid.,
DMAP (cat.), TBAI (cat.), DCM, rt, 1 h (62%); (v) (EtO)2P(O)CH2CO2Et,
NaH, THF, rt, 45 min, add 11, rt, 2.5 h; (vi) DIBAL-H, hexanes, THF,
−78 °C, 3 h, rt, 30 min [89% from 11; (Z)-17 : (E)-17 = 75 : 25].
Fig. 5 The structure of epoxide 29 as established by X-ray diffraction.
group. This addition would give the adduct 27 that on stand-
ing was converted into the oxazolidinone 25 perhaps via the
isocyanate 28 formed by loss of bromomagnesium benzyloxide
from the adduct 27, see Fig. 4.
To convert the oxazolidinone 25 into the cyclisation pre-
cursor 9 it was necessary to oxidise the methyl group and to
hydrate the double bond stereoselectively. Epoxidation using
m-chloroperoxybenzoic acid gave a mixture of the epoxides 29
and 30, ratio 77 : 23. These epoxides could not easily be separ-
ated by chromatography, indeed this was not required for the
synthesis, but the major isomer could be crystallised out of the
mixture and was shown to be the epimer 29 by X-ray diffrac-
tion, see Fig. 5. The mixture of epoxides was reacted with
lithium 2,2,6,6-tetramethylpiperidide to effect ring-opening to
give the allylic alcohol 31.14 N-Benzylation then gave the
N-benzyloxazolidinone 32 with just minor amounts, ca. 5%, of
the benzyl ether 33, and the alcohol 32 was converted into its
methyl ether 34 using methyl iodide and sodium hydride, see
Scheme 3.
Scheme 2 Stereoselective synthesis of the racemic oxazolidinone 25.
Reagents and conditions (i) NaH, THF, rt, 1 h, add to CF3CN, THF, −115
to −78 °C, 1 h (88%); (ii) xylene, heat under reflux 18 h (91%); (iii) NaBH4,
EtOH, 0 °C to rt, 18 h (80%); (iv) CbzCl, Et3N, DCM, rt, 18 h (83%); (v) (a)
CCl3C(O)NCO, DCM, 0 °C, 1 h (b) MeOH, H2O, K2CO3, 0 °C to rt, 3 h
(70%); (vi) (a) Ph3P, CBr4, DCM, −10 °C, 1 h (b) BnONa, THF, rt, 1 h (83%).
(vii) O3, DCM, −78 °C, then Ph3P, rt (84%); (viii) CH3C(MgBr)vCH2, THF,
tol., −78 °C, 2 h, then rt, 48 h (66%).
The next step was to hydrate the double-bond of the methyl
ether 34. This was achieved by hydroboration using borane in
tetrahydrofuran at 0 °C followed by oxidation. A mixture of the
alcohols 35 and 36, ratio 85 : 15, was obtained. This mixture
could not be separated but the major product was confirmed
as the required isomer 35 later in the synthesis. It would
appear that the hydroboration of the double-bond had taken
place selectively on the desired face of the double-bond
perhaps via transition structure 42, see Fig. 6. The mixture of
alcohols 35 and 36 was desilylated to give a mixture of the
diols 9 and 37 (ratio still ca. 85 : 15) and this mixture was
cyclised by reaction of the corresponding bis-mesylates 38 with
benzylamine. This gave a mixture of the epimeric piperidines
39 and 40 from which the major epimer 39 was isolated by
chromatography and hydrogenolysis of the N-benzylpiperidine
39 gave the required NH-piperidine 8, see Scheme 3.
This was dehydrated to generate the cyanate that underwent a
spontaneous rearrangement to give the isomeric isocyanate 24
that in turn reacted with benzyl alcohol to give the Cbz-pro-
tected amine 21, see Scheme 2.13
The aldehyde 10 was prepared from the alkene 21 by ozono-
lysis and the reaction of aldehyde 10 with isopropenylmagne-
sium bromide. This gave the oxazolidinone 25 that has the
isopropenyl and tert-butyldimethylsilyloxymethyl groups cis-
disposed about the five-membered ring, see Scheme 2. The
configuration shown for the oxazolidinone 25 was established
by X-ray diffraction,9 and is consistent with the addition of the
Grignard reagent taking place on the less hindered face of the
N-deprotonated, chelated aldehyde 26 away from the cyclobutyl
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Scheme 3 Synthesis of the oxazolidinonylpiperidine 8. Reagents and conditions (i) mCPBA, DCM, rt, 18 h (75%, 29 : 30 = 77 : 23); (ii) 2,2,6,6-tetra-
methylpiperidine, THF, nBuLi, 0 °C to rt, 1 h, added to a mixture of 29 and 30, THF, 0 °C to rt, 3 h (67%); (iii) NaH, BnBr, THF, heat under reflux, 6 h
(32, 64%; 33, 5%); (iv) NaH, THF, MeI, rt, 18 h (90%); (v) BH3, THF, 0 °C, 18 h, then EtOH, NaOAc, 30% aq. H2O2, heat under reflux 1 h (95%, 35 : 36 =
85 : 15); (vi) TBAF, THF, 0 °C to rt , 30 min (67%, 9 : 37 = 85 : 15); (vii) MsCl , Et3N, DCM , 0 °C to rt, 1 h; (viii) BnNH2, 80 °C, 18 h (39, 36%; mixture of
39 and 40, 26%, 39 : 40 = 56 : 44); (ix) 10% Pd/C, HCO2H, MeOH, rt, 20 min (71%); (x) BBr3, DCM, THF, 0 °C, 4 h (61%).
Fig. 6 Hydroboration of alkene 34.
Fig. 7 The structure of the alcohol 41 as established by X-ray
crystallography.
Structures were assigned to the products in Scheme 3 using
spectroscopic data. The configurations of the piperidines 8, 39
1
M1 receptor with micromolar potency. The synthesis of other
members of the series was therefore investigated.
and 40 at C2 were difficult to assign by H NMR although the
vicinal coupling constant, J1,2
, was characteristic being
The allylic bromide 43 was prepared from the alcohol 32
and was converted into the 2-phenylethyl ether 44 by treatment
with the sodium alkoxide of 2-phenylethanol. Hydroboration/
oxidation in this case gave a 3 : 1 mixture of epimers, the
major epimer being identified as the required isomer 45 by
analogy with the earlier work, see Scheme 4. Moreover, follow-
ing desilylation, the structure of the crystalline diol 46 was
confirmed by X-ray crystallography, see Fig. 8. The diol 46 was
converted into the piperidine 48 via the bis-mesylate 47 as
before and transfer hydrogenolysis gave the oxazolidinonyl-
piperidine 49. The configurations of the piperidines 48 and 49 at
C2 were consistent with their J1,2 coupling constants of 2.5 Hz,
smaller, typically less than 5 Hz for the required epimers 8 and
39, and greater than 8 Hz for unwanted epimers, e.g. 40. The
structures of the piperidines and consequently of the hydro-
boration products 35 and 36 and intermediates 9, 37 and 38
were eventually confirmed by an X-ray crystal structure deter-
mination of the alcohol 41 prepared by demethylation of the
major N-benzyl(methoxymethyl)piperidine 39 using boron
tribromide,15 see Fig. 7.
The oxazolidinone-fused piperidine 8 was the first member
of the series that had been identified as potential muscarinic
M1 receptor agonists to be synthesised and preliminary bio-
logical studies showed that it was a 50% partial agonist of the
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Scheme 5 Synthesis of the 2-methylenepiperidine 53. Reagents and
conditions (i) NaH THF, rt, 30 min, PhCH2CH2Br, rt, 15 h (50, 38%; 51,
43%); (ii) TBAF, THF, rt (54%); (iii) MsCl, Et3N, DCM, 0 °C to rt, 1 h; (iv)
BnNH2, 95 °C, 18 h (53, 60%).
of the analogues 5 with hetaryl substituents at C2 was investi-
gated since it was thought that the hetaryl group would
improve selectivity for the M1 receptor.7
Scheme 4 Synthesis of the 2-(phenylethoxymethyl)piperidine 49.
Reagents and conditions (i) Ph3P, CBr4, MeCN, 0 °C, rt, 2 h (ca. 100%); (ii)
PhCH2CH2OH, NaH, rt, 30 min, add 43, rt, 3 h (99%); (iii) BH3.THF,
−20 °C to 0 °C, 18 h, add EtOH, NaOAc, 30% aq. H2O2, reflux, 2.5 h
(47%); (iv) TBAF, THF, 0 °C to rt, 30 min (70%); (v) MsCl, Et3N, 0 °C to rt,
1 h; (vi) BnNH2, 95 °C, 15 h (37% from 46); (vii) HCO2H, Pd/C, MeOH, rt
(61%).
Preliminary studies into the synthesis of 2-hetarylpiperidines 5
The 4-methyl-1,3-oxazole 54 was selected as the initial 2-hetaryl-
piperidine for synthesis,7 see Fig. 9.
At this point, the oxidation of the alcohol 41 was investi-
gated since the corresponding aldehyde and acid were per-
ceived as useful late-stage intermediates for the introduction
of various hetaryl groups at C2. However, oxidation of alcohol
41 using Swern conditions gave a good yield of the unsaturated
aldehyde 56 rather than the required aldehyde 55, see
Scheme 6. It would appear that the aldehyde 55 is unstable
under mildly basic conditions with respect to ring-opening of
the oxazolidinone with loss of carbon dioxide. Attempted oxi-
dation of alcohol 41 using the Dess–Martin periodinane gave a
complex mixture of products.
Fig. 8 The structure of the diol 46 as established by X-ray diffraction.
The introduction of the oxazole ring earlier in the synthesis
was therefore investigated. A Swern oxidation of the hydroxy-
methyloxazolidinone 32 gave the aldehyde 57 that was oxidised
further to give the carboxylic acid 58, see Scheme 7. Activation
of the acid using isobutyl chloroformate and reaction of the
ensuing mixed anhydride with 2-aminopropanol gave the
amide 59 as a mixture of epimers but only in a very modest
yield. Nevertheless, further oxidation gave the aldehyde 60 and
cyclisation under the Robinson–Gabriel conditions16 gave the
cf. the oxazolidinonylpiperidines 39 and 40, and with the X-ray
crystal structure of diol 46.
An alternative synthesis of the ether 44 was investigated
based on alkylation of the monosilylated diol 32. However,
during attempts to alkylate this alcohol using 2-phenylethyl
bromide and sodium hydride, none of the expected ether 44
was obtained. Instead intermolecular silyl migration competed
and a mixture of the bis-silyl ether 50 and the diol 51 was
obtained. Desilylation of the bis-silyl ether gave more of the
diol 51 that was cyclised to the piperidine 53 via its mesylate
52. The chemistry of the piperidine 53 was not taken further,
but the exocyclic double-bond would appear to provide a
handle for further modification if so desired, see Scheme 5.
Having established a synthesis of the oxazolidinone-fused
piperidines 4 with alkoxymethyl substituents at C2 as illus-
trated by the synthesis of piperidines 8 and 49, the synthesis
Fig. 9 The 2-(4-methyloxazol-2-yl)piperidine selected as the first
2-hetarylpiperidine for synthesis.
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Fig. 10 Planned approach to the oxazolidinonylpiperidine 64.
Scheme 6 Oxidation of the 2-hydroxymethylpiperidine 41. Reagents
and conditions (i) (COCl)2, DMSO, DCM, −78 °C, 20 min, add 41, DCM,
20 min, iPr2NEt, −78 °C to rt, 3 h (93%).
ing groups at C2 would be sensitive to basic conditions. It was
therefore decided to investigate the synthesis of the oxazolidi-
none-fused piperidine 64, see Fig. 10, with a furan at C2, since
the furan should be less effective than a 1,3-oxazole at acidify-
ing H2. Following the strategy used for the synthesis of the
2-methoxymethylpiperidine 8, it was thought that the 2-furyl-
piperidine 64 would be available by hydroboration of the
alkenyl-1,3-oxazolidinone 65 followed by cyclisation. The oxa-
zolidinone 65 in turn should be accessible from the aldehyde
10 by a chelation controlled addition of a vinylic Grignard
reagent with subsequent side-chain modification if necessary.
Synthesis of the 5-(furylethenyl)-1,3-oxazolidinone 65
Stille couplings17 were first investigated for the introduction of
the furan. N-Alkylation of the oxazolidinone 25 gave the N-ben-
zylated oxazolidinone 66. Ozonolysis gave the ketone 67 that
was converted into the enol triflate 68 by selective deprotona-
tion of the methyl group and trapping the enolate so formed
using phenyltriflimide.18 Using Pd(PPh3)4 in the presence of
lithium chloride and copper(1) iodide, the Stille coupling of
the enol triflate 68 with 2-tributylstannylfuran gave the
required alkene 65.19 Preliminary studies were also carried out
into the Pd(0) catalysed coupling of the enol triflate with other
metalated heterocycles. Thus treatment of an excess of 5-lithio-
2-phenyl-1,3-oxazole20 with zinc chloride gave the corres-
ponding organozincate that was coupled with the triflate 68 in
the presence of PdCl2(PPh3)2 as the catalyst to give the coupled
1,3-oxazole 69 albeit in only a modest yield, see Scheme 8.
Although the Stille coupling had given the required alkene
65 quite efficiently other syntheses of this key intermediate
from the aldehyde 10 were investigated. A longer synthesis, but
one that avoided the use of organostannanes, proceeeded via
the addition of ethenylmagnesium bromide to the aldehyde 10
to give the oxazolidinone 70 that was alkylated to give its
N-benzyl derivative 71. Ozonolysis than gave the aldehyde 72
that gave the alcohol 73 as a mixture of epimers on addition of
2-lithiofuran. Oxidation gave the ketone 74 and a Wittig reac-
tion gave the alkene 65, see Scheme 9.
Scheme 7 Approaches to the 2-oxazolylpiperidine 54. Reagents and
conditions (i) Dess–Martin periodinane, DCM, rt, 45 min; (ii) tBuOH,
H2O, 2-methylbut-2-ene, NaClO2, NaH2PO4, rt, 2 h (ca. 100%); (iii)
iBuOC(O)Cl, N-methylmorpholine, THF, rt, 1 h, add 2-aminopropanol, rt,
12 h (36%); (iv) Dess–Martin periodinane, DCM, rt, 45 min; (v) Ph3P, 2,6-
di-tert-butyl-4-methylpyridine, DCM, 1,2-dibromotetrachloroethane,
0 °C, 1 h, add MeCN, DBU, rt, 2.5 h (42%); (vi) BH3.THF, THF, 0 °C, 24 h,
add EtOH, NaOAc, 30% aq. H2O2, rt, 18 h (20%); (vii) TBAF, THF, rt, 1 h.
oxazole 61. Hydroboration of the oxazole gave a low yield of a
product provisionally identified as the alcohol 62 (exocyclic
configuration not confirmed) and desilylation gave the diol 63,
but attempts to cyclise this diol via its bis-mesylate to the
1
piperidine 54 using ammonia were unsuccessful. The H NMR
data of the crude products indicated that elimination had
taken place analogous to the formation of the aldehyde 56 but
no product was formally identified, see Scheme 7.
The instability to base of the aldehyde 55 and the difficul-
ties encountered on attempted isolation of the 1,3-oxazole 54,
suggested that oxazolidinonylpiperidines 5 with anion stabilis-
However the most efficient conversion of the aldehyde 10
into the alkene 65 involved just two steps. Tributyl-
stannylethenylfuran 76 was prepared from 2-acetylfuran 75 by
addition of tributyltin lithium with in situ dehydration using
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Conversion of the alkene 65 into oxazolidinonyl-fused
piperidines
Following the procedures developed during the synthesis of
the methoxymethylpiperidine 8, it was thought that conversion
of the alkene 65 into the target compound 64 would be
achieved by hydroboration, desilylation to the diol, and piper-
idine formation via the corresponding bis-mesylate. However,
although the hydroboration–oxidation gave the alcohols 78
and 79 as an inseparable mixture of epimers, ratio ca. 2 : 1 and
desilylation gave the diols 80 and 81, see Scheme 10, prelimi-
nary studies indicated that the preparation of the bis-mesylates
from the diols was capricious due to competing elimination.
Structures were assigned to the products 78–81 using spectro-
scopic data. At this point it was not known which alcohol, 78
or 79, was the major product from the hydroboration–oxi-
dation, although by analogy with the hydroborations of the
alkenes 34 and 44 it was thought that the required isomer 79
was probably the major isomer. Subsequently this was found
not to be the case, vide infra.
As the synthesis of the 2-furylpiperidine by displacement of
bis-mesylates was proving difficult, it was decided to introduce
the nitrogen of the piperidine ring before ring formation.
Desilylation of the alkene 65 gave the alcohol 82 but attempts
to convert this neopentylic alcohol directly into the nosylamide
86 by a Mitsunobu reaction were not succesful perhaps
because of steric hindrance. Therefore the alcohol was oxi-
dised to the aldehyde 83 that was converted into the amine 84
by reductive amination using propenylamine. A palladium(0)
catalysed de-allylation22 gave the primary amine 85 that was
converted into its nosyl derivative 86, see Scheme 11. However,
attempts to hydroborate nosylamide 86 were unsuccessful,
mixtures of products being isolated after oxidation. The struc-
tures were initially assigned to the products in Scheme 11 on
the basis of their spectroscopic data and earlier work. The
structure of the crystalline amine 84 was confirmed by X-ray
crystallography, see Fig. 11.
Scheme 8 Palladium(0) catalysed introduction of heteroarenes.
Reagents and conditions (i) NaH, THF, BnBr, reflux, 1 h (79%); (ii) O3,
DCM, −78 °C, PPh3, rt (93%); (iii) KHMDS, tol., −78 °C, 1 h, then add
PhNTf2, THF, −78 °C, 5 h (71%); (iv) Pd(Ph3P)4, LiCl, CuI, THF, 2-tributyl-
stannylfuran, reflux 3 h (65%); (v) 5-bromo-2-phenyl-1,3-oxazole, nBuLi,
THF, −18 °C, 45 min, ZnCl2, THF, rt, 30 min, add to 68 and PdCl2(PPh3)2
in THF, rt, 48 h (36%).
Although the hydroboration of the alkene 86 was not
successful, hydroxylation using osmium tetraoxide23 gave a
reasonable yield of a single diol 87, see Scheme 12. The con-
Scheme 9 Alternative syntheses of the alkene 65. Reagents and con-
ditions (i) CH2vCHMgBr, THF, −78 °C, 2 h, then rt, 16 h (91%); (ii) NaH,
BnBr, THF, 0 °C, refux, 6 h (71, 86%; 65, 78% from 10); (iii) O3, DCM,
−78 °C, Ph3P, rt, 3 h (90%); (iv) furan, nBuLi, hexanes, −78 °C, rt, 1.5 h,
cool to −78 °C, add 72, 5 h (60%); (v) TPAP, NMO, DCM, rt, 2 h (85%); (vi)
Ph3PMeBr, nBuLi, THF, rt, 1 h, add 74, rt, 15 min (72%); (vii) Bu3SnLi, THF,
rt, 1 h, MsCl, Et3N, rt, 16 h (59%); (viii) 76, nBuLi, THF, −78 °C, 10 min, add
10, −78 °C, 20 min, rt, 16 h.
mesyl chloride.21 Following transmetallation of the stannane
76 with n-butyllithium, addition of the resulting vinyllithium
to the aldehyde 10 gave the 1,3-oxazolidinone 77 that was
N-benzylated to give the alkene 65.13
Scheme 10 Hydroboration of the alkene 65. Reagents and conditions
(i) BH3.THF, 0 °C to rt, 3 h, then NaBO3·4H2O, rt, 16 h (60%; 2 : 1 mixture
of epimers); (ii) TBAF, THF, rt, 30 min (80, 62%; 81, 28%).
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via participation of the epoxide formed by dehydration of the
diol. In contrast, the mesylate 88, prepared from the diol 87,
on treatment with mild base, cyclised directly to give the piper-
idine 90.
The structure of the pyrrolidine 89 was established by 1H
NMR, the presence of an ABX system that simplified to an AB
system on shaking with D2O being assigned to the exocyclic
CH2OH fragment. No such ABX system was observed for the
piperidine 90. The structure of the piperidine 90 was consist-
ent with its spectroscopic data but its configuration at C2 was
not established.
Dehydroxylation of the piperidine 90 with triethylsilane in
the presence of boron trifluoride diethyletherate25 gave a
single product that was identified as the piperidine 91 on the
basis of its C1–C2 coupling constant of 6.0 Hz. The formation
of this epimer, that has the undesired configuration at C2, can
be explained by axial addition of hydride on to the less hin-
dered face of the boat-like oxonium ion 92 cis to the oxazolidi-
none ring, see Scheme 12.
Scheme 11 Introduction of the neopentylic amine. Reagents and con-
ditions (i) TBAF, THF, rt, 1 h (ca. 100%); (ii) Dess–Martin periodinane,
DCM, rt, 2 h; (iii) prop-2-enylamine, MgSO4, DCM, reflux, 16 h, then
NaCNBH3, THF, MeOH, HOAc, rt, 1 h (56% from 82); (iv) Pd(PPh3)4, DCM,
1,3-dimethylbarbituric acid, 35 °C, 2 h, (74%); (v) NosCl, Et3N, DCM, rt,
2 h (76%).
At this point, it was decided to use the reductive amination
sequence used to prepare the amide 86 on intermediates syn-
thesised from the hydroboration–oxidation products 78 and 79
to prepare precursors for cyclisation to piperidines, see
Scheme 13.
The hydroboration products 78 and 79 could not be separ-
ated but the mixture was reacted with SEM-chloride to convert
the free alcohols into the corresponding SEM-ethers 93 and
94. These were desilylated to give the the alcohols 95 and 101,
ratio 2 : 1, that could be separated. At this stage it was not
known which alcohol, 95 or 101, was the major product.
However, when the major product was taken through the syn-
thesis it led to the undesired piperidine 91 and so was identi-
fied as the epimer 95, see Scheme 13.
Fig. 11 The structure of the amine 84 as established by X-ray
crystallography.
Thus reductive amination of the aldehyde prepared by oxi-
dation of the major alcohol 95 gave the amine 96. Deallylation
and nosylation of the resulting amine 97 gave the amide 98
that was deprotected to give the alcohol 99. This cleanly
cyclised using the Mitsunobu protocol but gave the piperidine
91 that had already been prepared by dehydroxylation of the
hydroxypiperidine 90 and which had been identified as the C2
epimer of the required piperidine on the basis of its C1–C2
coupling constant of 6 Hz. Denosylation gave the deprotected
piperidine 100.
The formation of piperidine 91 from this sequence showed
that the alcohol 78 was the major product of hydroboration–
oxidation of the alkene 65. This was surprising since, by
analogy with earlier work, isomer 79 had been expected to be
the major product. It would appear that the hydroboration of
the alkene 65 occurred preferentially on the opposite face from
that observed for the alkoxymethyl alkenes 34 and 44, possibly
via transition structure 107, see Fig. 12, cf. transition structure
42 in Fig. 6. The required hydroboration product 79 was only
the minor product from hydroboration of the alkene at 0 °C.
However, when the hydroboration was repeated at higher
temperatures, the stereoselectivity dropped and at 35 °C the
ratio of the two products 78 and 79 was approximately 1 : 1.
Scheme 12 A synthesis of the piperidine 91. Reagents and conditions
(i) OsO4, NMO, THF, H2O, rt, 16 h (64%); (ii) Ph3P, DIAD, THF, rt, 16 h
(73%); (iii) MesCl, py., rt, 2 h; (iv) K2CO3, DMF, 45 °C, 1.5 h (42% from 87);
(v) Et3SiH, BF3·Et2O, DCM, 0 °C, 15 min, rt, 2 h (32%).
figuration of the tertiary alcohol was not established. Neverthe-
less, attempts to cyclise this to a piperidine that could be con-
verted to the target compound 64 were investigated. Using
modified Mitsunobu conditions,24 the diol 87 cyclised but
gave the pyrrolidine 89 not the required piperidine 90 perhaps
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Scheme 13 Synthesis of the piperidines 64 and 100. Reagents and conditions (i) BH3.THF, 0 °C, 3 h or warm to 35 °C, 3 h , NaOH, H2O2, rt, 30 min
(0 °C, 60%, 78 : 79 = 2 : 1; 35 °C, 65%, 78 : 79 ca. 1 : 1); (ii) 78 and 79, SEMCl, DMAP, TBAI, iPr2NEt, rt , 16 h (ca. 99%); (iii) 93 and 94, ratio ca. 1 : 1, TBAF,
THF, rt, 16 h (95, 43%; 101, 36%); (iv) (a) Dess–Martin periodinane, DCM , rt , 2 h (b) prop-2-enylamine, MgSO4, DCM , reflux , 16 h (c) NaCNBH3,
MeOH, HOAc, THF, rt , 1 h (96, 73%; 102, 70%); (v) Pd(PPh3)4, 1,3-dimethylbarbituric acid, DCM , 35 °C, 2 h; (vi) NosCl, Et3N , rt, 2 h (98, 60%; 104,
70%); (vii) MgBr2, nitromethane, ether, rt, 2 h (99, 77%; 105, 75%); (viii) Ph3P, DIAD, THF, rt, 2 h (91, 73%; 106, 80%); (ix) K2CO3, PhSH, acetonitrile, rt,
2 h (100, 75%; 64, 86%).
Fig. 12 The facial selectivity of hydroboration of alkene 65.
Fig. 13 The structure of the N-nosylpiperidine 106 as established by
X-ray crystallography.
Although not ideal, this mixture was taken through the syn-
thesis. Thus reaction with trimethylsilylethoxymethyl chloride
gave a mixture of the SEM-ethers 93 and 94 that were selec-
tively desilylated to give the alcohols 95 and 101, ratio ca. 1 : 1, over the N-nosylpiperidine 106 was crystalline and its structure
that were separated. The required epimer 101 was then taken was confirmed by X-ray crystallography, see Fig. 13.
through to the N-nosylpiperidine 106 by oxidation and reduc-
The stability of the 2-furyloxazolidinonylpiperidine 64 was
tive amination of the intermediate aldehyde to give the consistent with the hypothesis that the earlier problems in pre-
primary amine 103 after deallylation. Following N-nosylation paring oxazole 54 had been due to the increase in the acidity
and SEM-deprotection, cyclisation to the required N-nosyl- of H2. Therefore, it was decided to study oxazolidinonyl-fused
piperidine 106 was carried out using a Mitsunobu reaction. piperidines with arylmethyl and heteroarylmethyl substituents
Denosylation then gave the required oxazolidinonylpiperidine at C2 since these substituents should be less effective in acidi-
64. The structures of the piperidines 64 and 106 were consist- fying H2 and a wider range of heteroaryl groups should be
ent with their C1–C2 coupling constants of ca. 1.6 Hz. More- tolerated.
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Synthesis of oxazolidinonyl-fused piperidines with
2-(heteroarylmethyl)- and 2-(arylmethyl)-substituents
A synthesis of the oxazolidinonyl-fused piperidine with a
2-(2-phenyl-1,3-oxazol-5-yl)methyl substituent is outlined in
Scheme 14. 5-Bromo-2-phenyloxazole20 was reacted with
n-butyllithium to effect bromine–lithium exchange and the
organolithium species so formed was alkylated using the
bromide 43 in the presence of copper(I) cyanide/lithium chlor-
ide to give the oxazole 108. Hydroboration of this alkene
required stirring at room temperature overnight, but was still
usefully stereoselective, 9 : 1, in favour of the epimer 109 after
oxidation. Desilylation gave the diol 110 that was converted to
the bis-mesylate 111. Reaction with benzylamine gave the
piperidine 112 and transfer hydrogenolysis gave the required
2-(2-phenyloxazol-5-ylmethyl)piperidine 113, see Scheme 14.
The structures of the products in Scheme 14 were assigned
on the basis of their spectroscopic data. Of note is the stereo-
selectivity of the hydroboration of the alkene 108. The con-
figuration shown was assigned on the basis of the H1–H2
coupling constant observed for piperidines 112 and 113 that
were in the range 2.0–2.5 Hz diagnostic of the required con-
figuration at C2.
Scheme 15 Suzuki–Miyaura coupling of the bromide 43. Reagents and
conditions (i) 43, (Ph3P)PdCl2 (cat.), Na2CO3, THF, H2O, reflux, 3–12 h
(115, 73%; 117, 72%; 119, 73%).
phenylboronic acid 114, a good yield of the alkene 115 was
obtained using (Ph3P)2PdCl2 as the catalyst. However, the use
of furylboronic acid was more capricious in our hands,
perhaps because of the acid sensitivity of the furylboronic
acid, and better yields of the alkene 117 were obtained using
the MIDA-boronate 116 again with (Ph3P)2PdCl2 as the catalyst
and sodium carbonate as the base.27 The same conditions
gave a good yield of the alkene 119 using the phenyl-MIDA
boronate 118, see Scheme 15.
Although the coupling of 5-lithiated 2-phenyl-1,3-oxazole
with the bromide 43 had given a good yield of the alkene 108,
alternative coupling procedures were investigated based on the
Suzuki–Miyaura coupling of bromide 43 with commercially
available boronic acids and derivatives.26 With 3-methoxy-
Scheme 14 Synthesis of the 2-(2-phenyl-1,3-oxazolyl-5-ylmethyl)
piperidine 113. Reagents and conditions (i) 5-bromo-2-phenyloxazole,
nBuLi, THF, −18 °C, 45 min, cooled to −40 °C, CuCN, LiCl, THF, 1 h, add
43, THF, 18 h (80%); (ii) BH3.THF, 0 °C to rt, 24 h, EtOH, NaOAc, 30% aq.
H2O2, heat under reflux 1.5 h (50%; 9 : 1 mixture of epimers); (iii) TBAF,
THF, 0 °C to rt, 1 h (83%); (iv) MsCl, DCM, Et3N, 0 °C to rt, 1 h; (v) BnNH2,
90 °C, 18 h (81% from 110; a 9 : 1 mixture of epimers); (vi) 10% Pd/C,
HCO2H, MeOH, rt, 20 min (54%).
Scheme 16 Synthesis of the 2-benzyltetrahydropyran 122 and the
2-benzylpiperidine 125. Reagents and conditions (i) BH3.THF, 0 °C to rt,
16 h, EtOH, NaOAc, 30% aq. H2O2, heat under reflux 1.5 h (73%); (ii) Et3N,
MsCl, DCM, 0 °C to rt, 1 h; (iii) TBAF, THF, 0 °C to rt, 1 h (56% from 120);
(iv) TBAF, THF, 0 °C to rt, 1 h (72%); (v) Et3N, MsCl, DCM, 0 °C to rt, 1 h;
(vi) BnNH2, 90 °C, 18 h (64% from 123).
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Preliminary studies were undertaken into the hydroboration heteroaromatic ring from H2 and so discourage the elimi-
and cyclisation of the alkene 119. Hydroboration–oxidation nation process. This work was successful.
gave the alcohol 120 selectively. In this case two cyclisation
During these studies, compounds were prepared that
procedures were studied. Mesylation of the alcohol 120 fol- showed agonistic effects for the M1 muscarinic receptor.
lowed by desilylation of the mesylate 121 using TBAF was However, the syntheses involved were fairly challenging and
accompanied by in situ cyclisation and gave the tetrahydro- limited the number of compounds that could be prepared
pyran 122 as a single diastereoisomer, the configuration at C2 although it should be possible to improve and shorten the syn-
following from the H1–H2 coupling constant of 2.5 Hz and thesis of any compound considered to be worthy of further
from nOe studies. In contrast, desilylation of the mono- investigation. Moreover, simpler analogues with alternative
protected diol 120 gave the diol 123 that was mesylated and substituents, e.g. an isopropyl group rather than the cyclobutyl
reaction of the resulting bis-mesylate 124 with benzylamine group at C6, should be significantly more accessible, and so
gave the piperidine 125, the configuration at C2 again being the study of the effect of different alkyl groups at this site is of
confirmed by the H1–H2 coupling constant of 2.0 Hz, see interest. The allosteric activity of the piperidine 64 is clearly
Scheme 16.
worth further investigation. Finally, this work has contributed
to methodology for the synthesis of piperidines.28
Summary and conclusions
Experimental
General experimental details
This work has resulted in the synthesis of several oxazolidino-
nyl-fused piperidines of interest as possible agonists of
muscarinic M1 receptors and has opened up access to this 1H and 13C NMR spectra were recorded on Varian Unity Inova
class of piperidines. Indeed the 2-(methoxymethyl)piperidine 400 and Varian Unity Inova 300 spectrometers with residual
8 was a 50% partial agonist of the M1 receptor with micromolar non-deuterated solvent as the internal standard. Only dis-
potency as measured by the relaxation responses of rat duo- tinguishable peaks are reported for minor isomers in isomeric
denum compared with the full agonist McN-A-343. Significant mixtures. IR spectra were recorded on an ATI Mattson Genesis
preliminary studies also indicated that the 2-furylpiperidine 64 FTIR as thin films produced by evaporation of a dichloro-
was a positive allosteric modulator of the muscarinic M1 recep- methane solution on sodium chloride plates unless otherwise
tor as it potentiates the effects of an M1 receptor agonist stated. Mass spectra were recorded on Fison VG Trio 2000 and
without causing agonist or antagonistic activity on its own, see Kratos Concept spectrometers. Chemical ionisation (CI+) was
Experimental and ESI.‡
performed using ammonia. Chromatography refers to flash
Of interest in the synthetic work was the stereoselectivities column chromatography using Merck silica gel 60
H
observed for the addition of vinylic Grignard reagents to the (230–300 mesh). Tetrahydrofuran (THF) was dried and distilled
aldehyde 10. These were accompanied by in situ cyclisation to from sodium metal using benzophenone as an indicator
give oxazolidinones directly. Also of note was the stereo- under an atmosphere of nitrogen. Dichloromethane was dried
selectivity observed for the hydroboration–oxidation of the and distilled from calcium hydride under an atmosphere of
5-alkenyloxazolidinones. In most cases, at lower temperatures, nitrogen. Ether refers to diethyl ether, which was dried and
the selectivity was consistent with the transition structure 42 distilled from sodium metal using benzophenone as an indi-
shown in Fig. 6, but when a heteroaromatic ring was directly cator under an atmosphere of nitrogen. Light petroleum refers
attached to the double-bond the stereoselectivity was reversed, to the fraction of petroleum ether distilled between 40–60 °C.
consistent with transition structure 107, see Fig. 12. Molecular Benzene and hexane were dried over sodium metal. Butyl-
modelling studies were not carried out to probe the subtle lithium (1.6 M in hexanes) was titrated against a solution of
factors involved in the stereoselectivities of these reactions, propan-2-ol in xylene with 2,2′-bipyridine as an indicator.
transition structures 42 and 107 are just suggested as consist- Triethylamine and di-isopropylamine were dried over
ent with the observed stereoselectivities. However, in the latter potassium hydroxide pellets. Brine refers to saturated aqueous
case the stereoselectivity was reduced when higher tempera- sodium chloride.
tures were used and the synthesis of the 2-furylpiperidine 64
could be completed.
1-Cyclobutyl-2-hydroxyethanone (15). A solution of the
bromoketone 1410 (56.8 g, 320 mmol) and potassium formate
During the synthetic work, it was found that oxazolidinonyl- (67.5 g, 802 mmol, 2.5 eq.) in methanol (700 mL) was heated
piperidines with substituents at C2 that were able to facilitate under reflux for 12 h then concentrated under reduced
deprotonation were unstable with respect to oxazolidinone pressure. Ether was added and precipitated KBr was removed
ring-opening and loss of CO2. This limited the nature of the by filtration. Concentration under reduced pressure gave the
heterocyclic group that could be accommodated at this posi- title compound 15 (26 g, 71%), Rf = 0.23 (ethyl acetate : light
tion. In order to broaden the scope of heteroaromatic substitu- petroleum = 1 : 4) (Found: M+ + NH4, 132.1021. C6H14NO2
ents at C2, the synthesis of oxazolidinonylpiperidines with requires M, 132.1024); νmax/cm−1 3424, 2977, 2944, 2865, 1709,
2-heterarylmethyl and 2-arylmethyl substituents at C2 was 1460, 1351, 1246, 1075, 982 and 911; δH (300 MHz, CDCl3)
undertaken since the methylene group would separate the 1.85–2.37 (6 H, m, 3 × CH2), 3.29 (1 H, pent, J 8.2 Hz, 1′-H) and
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4.22 (2 H, s, 2-H2); δC (75 MHz, CDCl3) 18.3, 24.5, 41.4, 66.1 δH (300 MHz, CDCl3) 2.24 (1 H, br. s, OH), 3.31 (1 H, pent,
and 210.6; m/z (CI+) 132 (M+ + 18, 50%), 115 (M+ + 1, 10) and J 9.2 Hz, 3-CH) and 5.57 (1 H, t, J 6.2 Hz, 2-H); δC (75 MHz,
55 (100).
2-tert-Butyldimethylsilyloxy-1-cyclobutylethanone
CDCl3) 18.3, 19.2, 28.0, 35.9, 64.3, 122.8 and 143.2.
(Z)- and (E)-4-tert-Butyldimethylsilyloxy-3-cyclobutylbut-
(11). A
solution of the alcohol 15 (26 g, 228 mmol), TBSCl (37.6 g, 2-en-1-yl trifluoroacetimidates [(Z)- and (E)-18]. An intimate
250 mmol, 1.1 eq.), imidazole (31.2 g, 456 mmol, 2 eq.) DMAP mixture of powdered trifluoroacetamide (75 g, 663 mmol) and
(trace) and TBAI (trace) in DCM (500 mL) was stirred at rt for phosphorous pentoxide (150 g, 528 mmol, 0.80 eq.) was pre-
1 h. Water (200 mL) was added and the aqueous phase was pared in a 2 L round bottom flask fitted with a water cooled
extracted with ether (3 × 150 mL). The organic extracts were condenser, from the top of which led a PTFE tube to a trap
dried (Na2SO4) and concentrated under reduced pressure. cooled in a −78 °C bath. This trap was connected to a second
Chromatography (ethyl acetate : light petroleum = 1 : 30) of the trap cooled to −115 °C (ether/N2) which was attached to a cold
residue gave the title compound 11 (32.25 g, 62%), Rf = 0.64 finger. A calcium chloride tube protected the end of this trap
(ethyl acetate : light petroleum = 1 : 4) (Found: M+ + H, from moisture. This was connected to a scrubber bath contain-
229.1621. C12H25O2Si requires M, 229.1624); νmax/cm−1 2951, ing aqueous sodium hydroxide. The reaction mixture, under a
2859, 1712, 1471, 1434, 1390, 1360, 1344, 1258, 1171, 1108, gentle stream of dry nitrogen, was gradually warmed to 150 °C
1048, 1007, 939, 912, 841, 778 and 736; δH (300 MHz, CDCl3) and this temperature was maintained for 5 h. Trifluoroaceto-
0.07 (6 H, s, 2 × SiCH3), 0.91 [9 H, s, SiC(CH3)3], 1.71–2.36 nitrile was collected as a colourless liquid. Cooled THF
(6 H, m, 3 × CH2), 3.49 (1 H, pent, J 8.2 Hz, 1′-H) and 4.18 (2 H, (100 mL) at −78 °C, was then added to the condensed
s, 2-H2); δC (75 MHz, CDCl3) −5.6, 18.2, 18.3, 24.2, 25.7, 41.6, trifluoroacetonitrile.
67.8 and 211.4; m/z (CI+) 246 (M+ + 18, 27%) and 229 (M+ + 1,
Sodium hydride (1.5 g, 37.5 mmol, 1 eq., 60% in mineral
100%).
oil) was added to a mixture of the alcohols (Z)- and (E)-17
(Z)- and (E)-4-tert-Butyldimethylsilyloxy-3-cyclobutylbut- (9.2 g, 35.7 mmol) in THF (200 mL). The mixture was stirred at
2-en-1-ols [(Z)- and (E)-17]. Triethylphosphonoacetate rt for 1 h then cooled to −78 °C and added to the solution of
(13.65 mL, 68.7 mmol, 1.1 eq.) was added to a suspension of trifluoroacetonitrile in THF at −115 °C. The reaction mixture
sodium hydride (60% in mineral oil, 2.75 g, 68.7 mmol, 1.1 was warmed to −78 °C, stirred for 1 h, then warmed to rt and
eq.) in THF (250 mL) and the reaction mixture stirred at rt for nitrogen was bubbled through it for 45 min to purge the
45 min. The ketone 11 (14.27 g, 62.5 mmol) in THF (40 mL) excess of the trifluoroacetonitrile. Ammonium chloride (5 g)
was added and the reaction mixture stirred at rt for 2.5 h. Satu- was added and the mixture was diluted with light petroleum
rated aqueous ammonium chloride (100 mL) was added and (400 mL) then filtered through celite. Concentration of the fil-
the aqueous layer extracted with ether (3 × 150 mL). The trate under reduced pressure gave a mixture of the title com-
organic extracts were dried (MgSO4) and concentrated under pounds (Z)- and (E)-18 (11.1 g, 88%). Chromatography (ethyl
reduced pressure to give a mixture of the (Z)- and (E)-alkenes acetate : light petroleum = 1 : 20) gave a sample of the mixture
16 (18.66 g, 100%), Rf = 0.63 and 0.57 (ethyl acetate : light for characterisation, Rf = 0.27 (ethyl acetate : light petroleum =
petroleum = 1 : 4).
1 : 25) (Found: M+ + H, 352.1922. C16H29NO2F3Si requires
Di-isobutylaluminium hydride (1.0 M in hexanes, 162 mL, M, 352.1920); νmax/cm−1 3355, 2956, 2933, 2895, 2859, 1685,
162 mmol, 2.6 eq.) was added dropwise to the mixture of 1472, 1256, 1202, 1166, 1077, 837 and 776; δH (400 MHz,
esters 16 (18.66 g, 62.5 mmol) in THF (45 mL) at −78 °C. After CDCl3) major (Z)-isomer (Z)-18 0.07 (6 H, s, 2 × SiCH3), 0.90
3 h, the solution was allowed to warm to 0 °C and stirred for a [9 H, s, SiC(CH3)3], 1.70–2.15 (6 H, m, 3 × CH2), 3.12 (1 H,
further 30 min. Water (4.25 mL) was added at 0 °C followed by pent, J 8.5 Hz, 3-CH), 4.17 (2 H, s, 4-H2), 4.90 (2 H, d, J 6.7 Hz,
saturated aqueous potassium sodium tartrate (162 mL) and 1-H2), 5.43 (1 H, t, J 6.7 Hz, 2-H) and 8.14 (1 H, br. s, NH);
ether (162 mL). The reaction mixture was then allowed to minor (E)-isomer (E)-18 0.09 (6 H, s, 2 × SiCH3), 0.93 [9 H, s,
warm to rt and the aqueous layer was extracted with ether (3 × SiC(CH3)3], 3.36 (1 H, pent, J 9.0 Hz, 3-CH), 4.20 (2 H, s, 4-H2),
160 mL). The organic extracts were dried (MgSO4) and concen- 4.81 (2 H, d, J 7.2 Hz, 1-H2), 5.65 (1 H, tq, J 7.2, 1.7 Hz, 2-H)
trated under reduced pressure. Chromatography (ethyl acetate : and 8.12 (1 H, br. s, NH); δC (100 MHz, CDCl3) major (Z)-
light petroleum = 1 : 10) of the residue gave the (Z)- and (E)- isomer (Z)-18 −5.5, 17.9, 19.2, 25.9, 27.6, 39.5, 60.2, 64.3, 115.6
title compounds (Z)- and (E)-17 (14.4 g, 89%) as a colourless (q, J 279 Hz), 116.8, 148.4 and 157.6 (q, J 37 Hz); minor (E)-
oil, ratio (Z)-17 : (E)-17 = 75 : 25 (1H NMR) from which a sample isomer (E)-18 −5.4, 18.3(2), 25.9, 27.9, 36.0, 64.0, 64.1, 115.5
of the major (Z)-isomer (Z)-17 was isolated, Rf = 0.42 (ethyl (q, J 249 Hz), 116.3, 147.0 and 158.0 (q, J 38 Hz); δF (375 MHz,
acetate : light petroleum = 1 : 4); νmax/cm−1 3359, 2955, 2932, CDCl3) major (Z)-isomer (Z)-18 −70.91; minor (E)-isomer (E)-18
2885, 2859, 1471, 1389, 1361, 1254, 1088, 1007, 982, 839 and −70.97 m/z (CI+) 352 (M+ + 1, 2%) and 239 (100).
776; δH (300 MHz, CDCl3) 0.09 (6 H, s, 2 × SiCH3), 0.91 [9 H, s,
N-(1-tert-Butyldimethylsilyloxy-2-cyclobutylbut-3-en-2-yl) 2,2,2-
SiC(CH3)3], 1.65–2.13 (7 H, m, 3 × CH2, OH), 3.04 (1 H, pent, trifluoroacetamide (19). The mixture of trifluoroacetimidates
J 8.8 Hz, 3-CH), 4.14 (2 H, s, 4-H2), 4.20 (2 H, t, J 6.2 Hz, 1-H2) (Z)- and (E)-18 (11.1 g, 31.6 mmol) in xylene (900 mL) was
and 5.54 (1 H, t, J 7.0 Hz, 2-H); δC (75 MHz, CDCl3) −5.4, 17.8, heated under reflux for 18 h then cooled to rt. The xylene was
18.3, 25.9, 27.5, 39.9, 58.8, 60.3, 123.6 and 145.9; m/z (CI+) 274 removed by distillation under reduced pressure to give the title
(M+ + 18, 2%) and 239 (M+ + 1, 100); minor (E)-isomer (E)-17 compound 19 (10.1 g, 91%), Rf = 0.29 (ethyl acetate : hexane =
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1 : 25) (Found: M+ + H, 352.1913. C16H29NO2F3Si requires M, 64.3, 66.2, 114.6, 128.0, 128.1, 128.5, 136.7, 137.3 and 154.9;
352.1920); νmax/cm−1 3444, 3391, 3090, 2955, 2933, 2887, 2861, m/z (CI+) 391 (80%), 390 (M+ + 1, 75) and 282 (100).
1733, 1641, 1530, 1469, 1330, 1258, 1214, 1163, 1100, 1005,
Carbon tetrabromide (39.6 g, 119 mmol) in dichloro-
922, 839, 779 and 721; δH (400 MHz, CDCl3) 0.06 and 0.07 methane (93 mL) was added to the carbamates (Z)- and (E)-23
(each 3 H, s, SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.69–2.00 (6 H, (12.75 g, 42.6 mmol) and triphenylphosphine (27.94 g,
m, 3 × CH2), 3.05 (1 H, pent, J 9.0 Hz, 2′-CH), 3.68 and 3.76 106.5 mmol) in dichloromethane (536 mL) at −10 °C and the
(each 1 H, d, J 9.7 Hz, 1′-H), 5.11 (1 H, d, J 17.5 Hz, 4′-H), 5.30 reaction mixture was stirred at −10 °C for 1 h. After washing
(1 H, d, J 11.0 Hz, 4′-H′), 5.93 (1 H, dd, J 11.0, 17.5 Hz, 3′-H) with saturated aqueous NaHCO3 and brine, the solution was
and 6.52 (1 H, br. s, NH); δC (75 MHz, CDCl3) −5.8(2), 17.7, dried (MgSO4) and concentrated under reduced pressure. The
18.0, 23.3, 23.4, 25.6, 40.0, 62.5, 64.2, 115.6, 115.8 (q, J 290 residual oil was immediately dissolved in fresh tetrahydrofuran
Hz), 135.0 and 156.0 (q, J 36 Hz); δF (375 MHz, CDCl3) −74.8; (180 mL) and powdered 4 Å molecular sieves (22 g) were
m/z (CI+) 352 (M+ + 1, 100%). Attempted purification via flash added. Sodium benzyloxide [freshly prepared from benzyl
chromatography led to partial decomposition.
alcohol (8.8 mL, 85 mmol) and NaH (3.4 g, 85 mmol) in THF
1-tert-Butyldimethylsilyloxy-2-cyclobutylbut-3-en-2-ylamine (375 mL)] was added at 0 °C and the reaction mixture was
(20). Sodium borohydride (8 g, 214 mmol, 7.5 eq.) was added stirred at room temperature for 1 h. After diluting with ethyl
to the trifluoroacetamide 19 (10.1 g, 28.8 mmol) in ethanol acetate, the solution was washed with saturated aqueous
(85 mL) at 0 °C and the reaction mixture allowed to warm to rt NH4Cl and brine, then dried (MgSO4) and concentrated under
and stirred for 18 h. More sodium borohydride (5 g, reduced pressure. Chromatography of the residue (0–10%
134 mmol, 4.6 eq.) was added and the resulting slurry was ether/light petroleum) gave the title compound 21 (13.75 g,
stirred at rt for 6 h. Saturated aqueous sodium hydrogen car- 83%) as a colourless oil, Rf 0.65 (20% ether/light petroleum)
bonate (85 mL) was added and the mixture was extracted with (Found: M+ + Na, 412.2274. C22H35O3NNaSi requires M,
ether (3 × 100 mL). The organic extracts were dried (MgSO4) 412.2278) with spectroscopic data as obtained previously.2
and concentrated under reduced pressure. Chromatography
4-tert-Butyldimethylsilyloxy-3-cyclobutylbut-2-enyl carbamate
(ethyl acetate : light petroleum = 1 : 20 to 3 : 2) of the residue [(Z)- and (E)-23]. Trichloroacetyl isocyanate (190 μL, 1.6 mmol)
gave the title compound 20 (5.92 g, 80%), Rf = 0.12 (ethyl was added to the alcohols (Z)- and (E)-17 (200 mg, 0.8 mmol)
acetate : light petroleum = 1 : 2) (Found: M+ + H, 256.2096. in dichloromethane (5 mL) at 0 °C and the reaction mixture
C14H30NOSi requires M, 256.2097); νmax/cm−1 3378, 3083, was stirred at this temperature for 1 h. After concentration
2955, 2930, 2895, 2857, 1472, 1463, 1361, 1256, 1102, 1006, under reduced pressure, the residue was immediately taken up
918, 837 and 776; δH (400 MHz, CDCl3) 0.02 and 0.03 (each 3 in methanol (5 mL) and water (2.7 mL) and the solution was
H, s, SiCH3), 0.88 [9 H, s, SiC(CH3)3], 1.65–1.92 (6 H, m, 3 × cooled to 0 °C. Potassium carbonate (330 mg, 1.7 mmol) was
CH2), 2.52 (1 H, m, 2-CH), 3.32 and 3.38 (each 1 H, d, J 9.2 Hz, added and the reaction mixture was stirred at rt for 3 h. After
1-H), 5.13 (1 H, dd, J 10.7, 1.5 Hz, 4-H), 5.19 (1 H, dd, J 17.5, concentration under reduced pressure, chromatography of the
1.5 Hz, 4-H′) and 5.83 (1 H, dd, J 10.7, 17.5 Hz, 3-H); residue (20% ether/light petroleum) gave the title compounds
δC (100 MHz, CDCl3) −5.5, 17.6, 18.2, 22.6, 22.8, 25.8, 41.5, (Z)- and (E)-23 (170 mg, 70%) as a colourless oil, (Z) : (E) = 3 : 1;
58.2, 68.9, 113.6 and 141.5; m/z (CI+) 256 (M+ + 1, 100%).
Rf 0.20 (20% ethyl acetate/light petroleum) (Found: M+ + Na,
N-Benzyloxycarbonyl-1-tert-butyldimethylsilyloxy-2-cyclobutylbut- 322.1815. C15H29NO3NaSi requires M, 322.1809); νmax/cm−1
3-en-2-ylamine (21). Benzyl chloroformate (36 mL, 255 mmol, 3344, 2929, 2856, 1718, 1472, 1400, 1329, 1253, 1053, 836 and
11 eq.) and Et3N (10 mL, 69.5 mmol, 3 eq.) were added to the 776; δH (500 MHz, CDCl3) (Z)-isomer 0.07 (6 H, s, 2 × SiCH3),
amine 20 (5.92 g, 23.2 mmol) in DCM (36 mL) at rt and the 0.92 [9 H, s, SiC(CH3)3], 1.67–2.09 (6 H, m, 3 × CH2), 3.34 (1 H,
reaction mixture was stirred at rt for 18 h. Saturated aqueous m, 3-CH), 4.17 (2 H, s, 4-H2), 4.60 (2 H, d, J 7.0 Hz, 1-H2), 4.8
sodium hydrogen carbonate (70 mL) was added and the (2 H, br. s, NH2) and 5.53 (1 H, dt, J 7.0, 1.6 Hz, 2-H); (E)-
aqueous layer was extracted with ether (3 × 80 mL). The isomer 0.06 (6 H, s, 2 × SiCH3), 0.89 [9 H, s, SiC(CH3)3], 3.11
organic extracts were dried (MgSO4) and concentrated under (1 H, m, 3-CH), 4.15 (2 H, s, 4-H2), 4.67 (2 H, d, J 7.0 Hz, 1-H2),
reduced pressure. Chromatography (ethyl acetate : light pet- 5.33 (1 H, t, J 7.0 Hz, 2-H) δC (75 MHz, CDCl3) (Z)-isomer −5.4,
roleum = 1 : 30 to 1 : 20) of the residue gave the title compound 18.2, 19.2, 25.8, 27.6, 39.3, 59.8, 61.5, 118.0, 147.4 and 156.9;
21 (7.51 g, 83%), Rf = 0.65 (ethyl acetate : light petroleum = m/z (ES+) 322 (M+ + 23, 100%).
1 : 4) (Found: M+ + H, 390.2468. C22H36NO3Si requires M,
390.2464); νmax/cm−1 3445, 3359, 3087, 3067, 3033, 2952, 2933, cyclobutylpropanal (10). A mixture of ozone and oxygen was
2887, 2858, 1733, 1498, 1467, 1410, 1252, 1102, 1005, 917, 839, bubbled through solution of the alkene 21 (7.84 g,
2-Benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-
a
777 and 738; δH (300 MHz, CDCl3) 0.02 and 0.03 (each 3 H, s, 20.1 mmol) in DCM (220 mL) at −78 °C until the reaction
SiCH3), 0.88 [9 H, s, SiC(CH3)3], 1.61–1.94 (6 H, m, 3 × CH2), mixture turned blue. Triphenylphosphine (6.35 g, 24.1 mmol,
2.93 (1 H, pent, J 8.5 Hz, 2-CH), 3.69 and 3.80 (each 1 H, d, 1.2 eq.) was added and the reaction mixture was allowed to
J 9.5 Hz, 1-H), 4.91 (1 H, br. s, NH), 5.06 (2 H, s, PhCH2), 5.10 warm to rt. Following pre-absorbtion onto silica, chromato-
(1 H, d, J 17.5 Hz, 4-H), 5.24 (1 H, d, J 11.0 Hz, 4-H′), 5.90 (1 H, graphy (ethyl acetate : light petroleum = 1 : 100 to 1 : 10) gave
dd, J 11.0, 17.5 Hz, 3-H) and 7.29–7.38 (5 H, m, ArH); the title compound 10 (6.65 g, 84%), as a pale yellow oil, Rf =
δC (75 MHz, CDCl3) −5.6, 17.6, 18.2, 23.0, 23.1, 25.8, 40.3, 61.0, 0.42 (ethyl acetate : light petroleum = 1 : 9) (Found: M+ + H,
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392.2249. C21H34NO4Si requires M, 392.2257); νmax/cm−1 3409, and 2.93 (each 1 H, d, J 4.7 Hz, 3′-H), 3.61 and 3.73 (each 1 H,
3067, 3034, 2954, 2830, 2885, 2857, 1721, 1500, 1390, 1258, d, J 10.5 Hz, 4-HCH), 4.07 (1 H, s, 5-H) and 6.01 (1 H, br. s,
1108, 1064, 838 and 779; δH (300 MHz, CDCl3) 0.00 (6 H, s, 2 × NH); δC (75 MHz, CDCl3) −5.8, −5.7, 17.2, 18.2, 18.5, 22.4,
SiCH3), 0.84 [9 H, s, SiC(CH3)3], 1.73–2.07 (6 H, m, 3 × CH2), 24.0, 25.8, 39.5, 52.8, 54.4, 63.5, 65.6, 80.1 and 158.4; minor
2.97 (1 H, pent, J 9.7 Hz, 2-CH), 3.95 and 4.05 (each 1 H, d, epimer 30 2.59 and 2.88 (each 1 H, d, J 4.7 Hz, 3′-H), 3.64 and
J 10.0 Hz, 3-H), 5.09 (2 H, s, PhCH2), 5.45 (1 H, br. s, NH), 7.36 3.77 (each 1 H, d, J 10.2 Hz, 4-HCH), 4.01 (1 H, s, 5-H) and 6.09
(5 H, s, ArH) and 9.61 (1 H, s, CHO); δC (75 MHz, CDCl3) −5.8 (1 H, br. s, NH); δC (75 MHz, CDCl3) 17.1, 18.0, 22.2, 23.8, 40.1,
(2), 18.0, 18.3, 23.0, 23.7, 25.6, 37.2, 61.2, 66.7, 67.3, 128.1(2), 50.3, 54.6, 63.2, 65.2 and 81.9.
128.4, 136.1, 155.4 and 200.4; m/z (CI+) 392 (M+ + 1, 100%).
(4SR,5RS)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobutyl- 5-(1-hydroxyprop-2-en-2-yl)-1,3-oxazolidin-2-one (31). n-Butyl-
5-propen-2-yl-1,3-oxazolidin-2-one (25). Propen-2-ylmagne- lithium (1.6 M in THF, 60.4 mL, 96.6 mmol, 5 eq.) was added
(4SR,5RS)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobutyl-
sium bromide (0.5 M in toluene, 297 mL, 148.5 mmol, 3.75 to 2,2,6,6-tetramethylpiperidine (19.7 mL, 116 mmol, 6 eq.) in
eq.) was added over 1 h to the aldehyde 10 (15.5 g, 39.6 mmol) THF (85 mL) at 0 °C and the reaction mixture was allowed to
in THF (800 mL) at −78 °C, and the reaction mixture stirred at warm to rt and was stirred at this temperature for 1 h. The
−78 °C for 2 h then allowed to warm to rt overnight. The reac- reaction mixture was then added dropwise to the epoxides
tion mixture was stirred for another 36 h at rt before saturated 29 and 30 (6.6 g, 19.3 mmol) in THF (190 mL) at 0 °C and the
aqueous ammonium chloride (500 mL) was added. The reaction mixture was allowed to warm to rt and was stirred for
aqueous phase was extracted with ether (3 × 500 mL) and the 3 h. Saturated aqueous ammonium chloride (150 mL) was
organic extracts were dried (MgSO4) and concentrated under added and the aqueous phase was extracted with ether (3 ×
reduced pressure. Chromatography (ethyl acetate : light pet- 200 mL). The organic extracts were dried (MgSO4) and concen-
roleum = 1 : 10) of the residue gave the title compound 25 trated under reduced pressure. Chromatography (ethyl acetate :
(8.5 g, 66%) as a single diastereoisomer, Rf = 0.30 (ethyl light petroleum = 1 : 10 to 1 : 2) of the residue gave the title
acetate : light petroleum
= 1 : 4) as a white solid, m.p. compound 31 (4.43 g, 67%) as a white solid, Rf = 0.26 (ethyl
110–112 °C (Found: C, 62.76; H, 9.62; N, 4.20%. C17H31NO3Si acetate : light petroleum = 1 : 2), m.p. 157–158 °C (Found: C,
requires C, 62.73; H, 9.60; N, 4.30; Found: M+ + H, 326.2150, 59.94; H, 9.35; N, 4.05%; C17H31NO4Si requires C, 59.79; H,
C17H32NO3Si requires M, 326.2152); νmax/cm−1 3240, 3137, 9.15; N, 4.10%. Found: M+ + H, 342.2093. C17H32NO4Si
2952, 2935, 2892, 2859, 1756, 1465, 1384, 1344, 1254, 1106, requires M, 342.2101); νmax/cm−1 3258, 2952, 2933, 2891, 2859,
903, 840 and 777; δH (400 MHz, CDCl3) 0.02 (6 H, s, 2 × SiCH3), 1751, 1467, 1389, 1355, 1255, 1106, 1031, 840 and 778; δH
0.87 [9 H, s, SiC(CH3)3], 1.69–2.18 (6 H, m, 3 × CH2), 1.80 (3 H, (400 MHz, CDCl3) 0.05 (6 H, s, 2 × SiCH3), 0.88 [9 H, s, SiC
s, 3′-H3), 2.70 (1 H, pent, J 8.2 Hz, 4-CH), 3.43 (2 H, s, 4-CH2), (CH3)3], 1.74–2.19 (6 H, m, 3 × CH2), 2.38 (1 H, br. s, OH), 2.85
4.50 (1 H, s, 5-H), 5.04 and 5.13 (each 1 H, s, 1′-H) and 5.86 (1 H, pent J 8.5 Hz, 4-CH), 3.39 and 3.52 (each 1 H, d, J 10.2
(1 H, s, NH); δC (100 MHz, CDCl3) −5.9, −5.8, 17.4, 18.1, 19.9, Hz, 4-HCH), 4.19 (2 H, s, 1′-H2), 4.79 (1 H, s, 5-H), 5.33 and
22.4, 24.3, 25.7, 39.4, 63.9, 65.0, 82.2, 113.9, 138.0 and 158.9; 5.36 (each 1 H, s, 3′-H) and 6.28 (1 H, br. s, NH); δC (100 MHz,
m/z (CI+) 343 (M+ + 18, 75%) and 326 (M+ + 1, 100).
CDCl3) −5.8(2), 17.1, 18.2, 22.0, 23.7, 25.7, 37.9, 63.2, 64.6,
(4SR,5SR)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobutyl- 65.6, 80.1, 114.6, 142.9 and 159.0; m/z (CI+) 359 (M+ + 18, 80%)
5-(2-methyloxiran-2-yl)-1,3-oxazolidin-2-ones (29) and (30). and 342 (M+ + 1, 100%).
m-Chloroperoxybenzoic acid (12.4 g, 50.25 mmol, 2.1 eq.) was
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
added to the alkene 25 (7.79 g, 23.9 mmol) in DCM (95 mL) cyclobutyl-5-(1-hydroxyprop-2-en-2-yl)-1,3-oxazolidin-2-one
and the reaction mixture was stirred at rt for 18 h. Saturated (32). Sodium hydride (60% in mineral oil, 545 mg, 13.6 mmol,
aqueous sodium bicarbonate (75 mL) was added dropwise fol- 1.05 eq.) and benzyl bromide (3.21 mL, 25.94 mmol, 2 eq.)
lowed by saturated aqueous sodium sulfite (25 mL). Ether were added successively to the alcohol 31 (4.43 g, 13.0 mmol)
(100 mL) was added and the mixture stirred vigorously at rt for in THF (95 mL) and the reaction mixture was heated under
1 h. The aqueous phase was extracted with ether (3 × 100 mL) reflux for 6 h. Saturated aqueous ammonium chloride (50 mL)
and the organic extracts were dried (MgSO4) and concentrated was added and the aqueous phase was extracted with ether
under reduced pressure. Chromatography (ethyl acetate : light (3 × 75 mL). The organic extracts were dried (MgSO4) and con-
petroleum = 1 : 5 to 1 : 2) of the residue gave the title com- centrated under reduced pressure. Chromatography (ethyl
pounds 29 and 30 (6.15 g, 75%) as a colourless oil, a mixture acetate : light petroleum = 1 : 10 to 1 : 4) gave the benzyl ether
of epimers, 29 : 30 = 77 : 23, Rf = 0.51 (ethyl acetate : light pet- 33 (348 mg, 5%), Rf = 0.50 (ethyl acetate : light petroleum =
roleum = 1 : 2) (Found: M+ + H, 342.2103. C17H32NO4Si 1 : 4) (Found: M+ + H, 522.3040. C31H44NO4Si requires M,
requires M, 342.2101); νmax/cm−1 3222, 3137, 2931, 2895, 2857, 522.3040); νmax/cm−1 3086, 3063, 3031, 2951, 2932, 2890, 2858,
1754, 1468, 1395, 1346, 1297, 1258, 1102, 1064, 1001, 952, 856, 1751, 1496, 1465, 1402, 1356, 1255, 1099, 926, 841, 779 and
838 and 778; m/z (CI+) 359 (M+ + 18, 50%) and 342 (M+ + 1, 706; δH (300 MHz, CDCl3) −0.08 and −0.03 (each 3 H, s,
100). A sample of the major epimer 29 was isolated by crystalli- SiCH3), 0.85 [9 H, s, SiC(CH3)3], 1.52–2.01 (6 H, m, 3 × CH2),
sation, m.p. 148–150 °C; δH (300 MHz, CDCl3) major epimer 29 2.86 (1 H, pent, J 8.7 Hz, 4-CH), 3.47 and 3.55 (each 1 H, d,
0.07 (6 H, s, 2 × SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.46 (3 H, s, J 11.0 Hz, 4-HCH), 4.05 and 4.18 (each 1 H, d, J 12.7 Hz, 1′-H),
2′-CH3), 1.74–2.08 (6 H, m, 3 × CH2), 2.71 (1 H, m, 4-CH), 2.67 4.36 (1 H, d, J 16.0 Hz, PhHCHN), 4.47 and 4.57 (each 1 H, d,
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J 11.7 Hz, PhHCHO), 4.59 (1 H, d, J 16.0 Hz, PhHCHN), 5.05 tion mixture was heated under reflux for 1 h then cooled. The
(1 H, s, 5-H), 5.42 and 5.47 (each 1 H, s, 3′-H) and 7.22–7.40 aqueous phase was extracted with ether (3 × 35 mL) and the
(10 H, m, ArH); δC (75 MHz, CDCl3) −6.0, −5.8, 17.0, 18.1, 22.7, organic extracts were dried (MgSO4) and concentrated under
23.1, 25.7, 38.1, 45.8, 63.0, 68.3, 70.8, 72.4, 77.5, 117.2, 127.2, reduced pressure. Chromatography (ethyl acetate : light pet-
127.5, 127.7, 127.8, 128.3, 128.4, 137.8, 138.6, 140.6 and 158.9; roleum = 1 : 4) of the residue gave the title compounds 35 and
m/z (CI+) 522 (M+ + 1, 1%) and 91 (100). The second fraction 36 (648 mg, 95%), as a mixture of diastereoisomers, 35 : 36 =
was the title compound 32 (3.76 g, 64%), as a white solid, Rf = 85 : 15, Rf = 0.21 (ethyl acetate : light petroleum = 1 : 2) (Found:
0.31 (ethyl acetate : light petroleum = 1 : 2); m.p. 116–117 °C M+ + H, 464.2835. C25H42NO5Si requires M, 464.2833); νmax
(Found: C, 66.93; H, 8.69; N, 3.19%; C24H37NO4Si requires C, cm−1 3443, 2930, 2892, 2859, 1732, 1468, 1409, 1357, 1297,
66.78; H, 8.64; N, 3.24%. Found: M+
H, 432.2567. 1255, 1169, 1104, 1036, 840 and 777; δH (400 MHz, CDCl3)
/
+
C24H38NO4Si requires M, 432.2571); νmax/cm−1 3426, 3063, major epimer 35 0.04 and 0.05 (each 3 H, s, SiCH3), 0.88 [9 H,
3032, 2951, 2953, 2890, 2859, 1734, 1467, 1409, 1357, 1255, s, SiC(CH3)3], 1.50–2.05 (6 H, m, 3 × CH2), 2.22 (1 H, br. s,
1103, 1033, 919, 842 and 778; δH (400 MHz, CDCl3) −0.05 and OH), 2.37 (1 H, m, 2′-H), 2.57 (1 H, m, 4-CH), 3.36 (3 H, s,
−0.02 (each 3 H, s, SiCH3), 0.84 [9 H, s, SiC(CH3)3], 1.57–2.00 OCH3), 3.57 and 3.63 (each 1 H, dd, J 6.0, 9.5 Hz, 3′-H), 3.66
(6 H, m, 3 × CH2), 2.35 (1 H, br. m, OH), 2.81 (1 H, pent, J 9.0 (2 H, s, 4-CH2), 3.85–3.94 (2 H, m, 1′-H2), 4.17 (1 H, d, J 15.8
Hz, 4-CH), 3.46 and 3.49 (each 1 H, d, J 11.0 Hz, 4-HCH), 4.19 Hz, PhHCH), 4.48 (1 H, d, J 6.0 Hz, 5-H), 4.66 (1 H, d, J 15.8
(1 H, dd, J 13.7, 6.5 Hz, 1′-H), 4.28 (1 H, dd, J 13.7, 4.7 Hz, 1′- Hz, PhHCH) and 7.24–7.40 (5 H, m, ArH); minor epimer 36
H′), 4.38 and 4.57 (each 1 H, d, J 15.7 Hz, PhHCH), 5.07 (1 H, 0.03 and 0.05 (each 3 H, s, SiCH3), 0.87 [9 H, s, SiC(CH3)3],
s, 5-H), 5.28 and 5.41 (each 1 H, s, 3′-H) and 7.23–7.36 (5 H, m, 2.83 (1 H, br. t, J 5.5 Hz, OH), 3.36 (3 H, s, OCH3), 3.72 (1 H,
ArH); δC (100 MHz, CDCl3) −6.0, −5.8, 17.1, 18.2, 22.8, 23.1, dd, J 9.5, 3.5 Hz, 3′-H), 3.79 (1 H, dd, J 9.5, 5.5 Hz, 3′-H′), 4.55
25.8, 38.6, 45.8, 62.8, 63.9, 68.4, 78.0, 115.5, 127.4, 127.5, (1 H, d, J 7.8 Hz, 5-H) and 4.70 (1 H, d, J 15.7 Hz, PhHCH);
128.5, 138.5, 144.1 and 158.8; m/z (CI+) 449 (M+ + 18, 1%), 432 δC (100 MHz, CDCl3) major epimer 35 −5.9, −5.8, 17.2, 17.9,
(M+ + 1, 10) and 91 (100). Starting material 31 (0.8 g, 18%) was 23.1, 23.3, 25.7, 38.7, 40.8, 45.8, 59.1, 61.2, 62.3, 68.5, 73.3,
also recovered.
77.4, 127.3, 127.6, 128.5, 138.4 and 159.1; minor epimer 36
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- −5.8, 17.1, 17.9, 23.1, 23.4, 25.6, 38.7, 40.3, 45.8, 59.3, 60.8,
cyclobutyl-5-(1-methoxyprop-2-en-2-yl)-1,3-oxazolidin-2-one 64.4, 68.8, 73.6, 75.4, 127.2, 127.6, 128.4, 138.5 and 159.5; m/z
(34). Sodium hydride (132 mg, 3.29 mmol, 2 eq.) and MeI (CI+) 464 (M+ + 1, 1%) and 90 (100).
(1.05 mL, 16.4 mmol, 10 eq.) were added successively to the
(4SR,5RS)-3-Benzyl-4-hydroxymethyl-4-cyclobutyl-5-(1-hydroxy-
alcohol 32 (710 mg, 1.64 mmol) in THF (10 mL) and the reac- 3-methoxyprop-2-yl)-1,3-oxazolidin-2-ones (9) and (37). Tetra-
tion mixture was stirred at rt for 18 h before saturated aqueous n-butylammonium fluoride (1 M in THF, 1.67 mL, 1.67 mmol,
ammonium chloride (10 mL) was added. The aqueous phase 1.2 eq.) was added to the mixture of the silyl ethers 35 and 36
was extracted with ether (3 × 10 mL) and the organic extracts (648 mg, 1.39 mmol) at 0 °C and the mixture allowed to warm
were dried (MgSO4) and concentrated under reduced pressure. to rt. After stirring for 1 h, brine (7 mL) was added and the
Chromatography (ethyl acetate : light petroleum = 1 : 10) of the aqueous layer was extracted with ether (3 × 15 mL). The
residue gave the title compound 34 (660 mg, 90%), Rf = 0.54 organic extracts were dried (MgSO4) and concentrated under
(ethyl acetate : light petroleum = 1 : 2) (Found: M+, 445.2652. reducd pressure. Chromatography (ethyl acetate : light pet-
C25H39NO4Si requires M, 445.2648); νmax/cm−1 3063, 3031, roleum = 1 : 2 to neat ethyl acetate) of the residue gave the title
2951, 2932, 2892, 2859, 2822, 1752, 1467, 1403, 1356, 1255, compounds 9 and 37 (328 mg, 67%) as a mixture of diastereo-
1103, 930, 841 and 778; δH (400 MHz, CDCl3) −0.08 and −0.03 isomers, 9 : 37 = 85 : 15, Rf = 0.25 (EtOAc) (Found: M+ + H,
(each 3 H, s, SiCH3), 0.84 [9 H, s, SiC(CH3)3], 1.55–1.99 (6 H, 350.1970. C19H28NO5 requires M, 350.1968); νmax/cm−1 3418,
m, 3 × CH2), 2.87 (1 H, pent, J 9.0 Hz, 4-CH), 3.32 (3 H, s, 2938, 2894, 1722, 1432, 1415, 1357, 1253, 1093, 1070, 1036 and
OCH3), 3.46 and 3.51 (each 1 H, d, J 11.0 Hz, 4-HCH), 3.90 and 765; δH (400 MHz, CDCl3) major epimer 9 1.58–2.05 (6 H, m,
4.07 (each 1 H, d, J 13.0 Hz, 1′-H), 4.37 and 4.59 (each 1 H, d, 3 × CH2), 2.42 (1 H, m, 2′-H), 2.52–2.63 (2 H, m, 4-CH, OH),
J 15.7 Hz, PhHCH), 5.00 (1 H, s, 5-H), 5.37 and 5.40 (each 1 H, 3.36 (3 H, s, OCH3), 3.47–3.57 (3 H, m, 3′-H2, 4-HCH), 3.66
s, 3′-H) and 7.21–7.36 (5 H, m, ArH); δC (100 MHz, CDCl3) (1 H, d, J 13.0 Hz, 4-HCH), 3.82 (1 H, dd, J 4.0, 11.0 Hz, 1′-H),
−6.1, −5.9, 17.1, 18.1, 22.7, 23.1, 25.8, 38.1, 45.8, 58.1, 62.9, 3.96 (1 H, dd, J 5.5, 11.0 Hz, 1′-H′), 4.43 and 4.51 (each 1 H, d,
68.2, 73.0, 77.5, 116.8, 127.1, 127.4, 128.3, 138.6, 140.5 and J 15.7 Hz, PhHCH), 4.63 (1 H, d, J 4.5 Hz, 5-H) and 7.27–7.46
158.8; m/z (EI+) 445 (M+, 1%) and 91 (100).
(5 H, m, ArH); minor epimer 37 2.31 (1 H, br. s, OH), 3.73
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- (2 H, m, 1′-H2), 4.44 and 4.56 (each 1 H, d, J 15.7 Hz, PhHCH)
cyclobutyl-5-[(SR)- and -(RS)-1-hydroxy-3-methoxyprop-2-yl]- and 4.68 (1 H, d, J 6.2 Hz, 5-H); δC (100 MHz, CDCl3) major
1,3-oxazolidin-2-ones (35) and (36). Borane (1 M in THF, epimer 9 17.5, 22.8, 23.0, 39.0, 41.0, 45.3, 59.1, 60.7, 61.5, 68.6,
8.2 mL, 8.22 mmol, 5 eq.) was added dropwise to the alkene 34 73.5, 77.3, 127.8(2), 128.9, 138.3 and 159.0; minor epimer
(660 mg, 1.48 mmol) in THF (5 mL) at 0 °C and the reaction 3723.1, 39.1, 40.5, 59.2, 60.7, 64.2, 68.5, 72.5, 75.8, 138.4 and
mixture was stirred at this temperature for 18 h before ethanol 159.0; m/z (CI+) 350 (M+ + 1, 5%) and 91 (100).
(7.1 mL), saturated aqueous sodium acetate (23 mL) and
(1RS,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-
hydrogen peroxide (30% in H2O, 8 mL) were added. The reac- diaza-9-oxabicyclo[4.3.0]nonan-8-ones (39) and (40). Freshly
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distilled methane sulfonyl chloride (0.112 mL, 1.42 mmol, cm−1 3343, 3086, 3062, 3029, 2935, 2871, 2832, 2815, 1742,
3 eq.) and Et3N (0.20 mL, 1.42 mmol, 3 eq.) were added succes- 1672, 1496, 1454, 1432, 1409, 1345, 1199, 1167, 1146, 1112,
sively to a mixture of the diols 9 and 37 (166 mg, 0.475 mmol) 1090, 1071, 984, 759 and 707; δH (400 MHz, CDCl3) 1.54–2.00
in DCM (5 mL) at 0 °C. The reaction mixture was allowed to (7 H, m, 3 × CH2, 6-CH), 2.12 (1 H, m, 2-H), 2.37 (1 H, d, J 14.2
warm to rt and was stirred for 1 h before the addition of ether Hz, 5-H), 2.57 (1 H, t, J 12.0 Hz, 3-H), 2.61 (1 H, d, J 14.2 Hz,
(5 mL) and saturated aqueous ammonium chloride (10 mL). 5-H′), 2.91 (1 H, dd, J 6.5, 12.0 Hz, 3-H′), 3.31 (1 H, dd, J 6.0,
The aqueous phase was extracted with ether (3 × 10 mL) and 9.0 Hz, 2-CH), 3.36 (3 H, s, CH3), 3.52 (1 H, t, J 9.0 Hz, 2-CH′),
the organic extracts were dried (MgSO4) and concentrated 4.22 and 4.43 (each 1 H, d, J 15.7 Hz, PhHCH), 4.71 (1 H, d,
under reduced pressure to leave a mixture of the bis-mesylates J 2.7 Hz 1-H) and 7.24–7.39 (5 H, m, ArH); δC (100 MHz,
38 (228 mg) that was used without purification.
CDCl3) 17.5, 22.2, 22.8, 35.8, 38.5, 40.7, 44.6, 45.0, 59.0, 63.4,
The bis-mesylates 38 (228 mg) were dissolved in benzyl- 71.4, 73.6, 127.8, 127.8, 128.7, 138.1 and 158.7; m/z (CI+) 331
amine (15 mL) and the solution heated at 80 °C for 18 h. After (M+ + 1, 60%) and 91 (100).
cooling to rt, the benzylamine was removed by distillation
(1RS,2SR,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-hydroxymethyl-
under reduced pressure. Chromatography (ethyl acetate : light 4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (41). Boron tribromide
petroleum = 1 : 20 to 1 : 10) of the residue achieved partial sep- in THF (1 M in THF, 0.415 mL, 415 mmol, 0.8 eq.) was
aration of the piperidines 39 and 40 to give the title compound added dropwise to the methyl ether 39 (209 mg, 0.497 mmol)
39 (72 mg, 36%), Rf = 0.28 (ethyl acetate : light petroleum = in DCM (7 mL) at 0 °C and the reaction mixture was stirred at
1 : 2) (Found: M+, 420.2410. C26H32N2O3 requires M, 420.2413); 0 °C for 4 h. Saturated aqueous sodium bicarbonate (0.5 mL)
νmax/cm−1 3083, 3060, 3029, 2924, 2872, 2811, 1744, 1494, was added very slowly over 10 min, the reaction mixture was
1453, 1405, 1349, 1294, 1201, 1168, 1117, 1090, 1060, 1028, stirred at rt for 30 min and a second portion of a saturated
978, 818 and 746; δH (400 MHz, CDCl3) 1.40–1.78 (5 H, m, aqueous sodium bicarbonate (1 mL) was added. The aqueous
cyclobutyl H), 2.00 (1 H, m, cyclobutyl H), 2.10 (1 H, d, J 12.5 phase was extracted with ether (3 × 5 mL) and the organic
Hz, 5-H), 2.22 (1 H, m, 2-H), 2.36 (1 H, t, J 10.5 Hz, 3-H), 2.41 extracts were dried (MgSO4) and concentrated under reduced
(1 H, d, J 12.5 Hz, 5-H′), 2.49 (1 H, pent, J 8.7 Hz, 6-CH), 2.58 pressure. Chromatography (ethyl acetate : light petroleum =
(1 H, dd, J 7.25, 10.5 Hz, 3-H′), 3.32–3.37 (6 H, m, 2-CH, OCH3, 1 : 4 to 1 : 2) of the residue gave the title compound 41
PhCH2), 3.57 (1 H, t, J 8.5 Hz, 2-CH′), 3.91 and 4.28 (each 1 H, (124 mg, 61%), Rf = 0.15 (ethyl acetate : light petroleum = 1 : 1)
d, J 16.0 Hz, PhHCH), 4.51 (1 H, d, J 2.5 Hz, 1-H) and 7.21–7.34 (Found: M+ + H, 407.2339. C25H31N2O3 requires M, 407.2335);
(10 H, m, ArH); δC (100 MHz, CDCl3) 17.6, 22.9, 23.3, 36.7, νmax/cm−1 3422, 3030, 2942, 2872, 2815, 1727, 1495, 1413,
39.2, 44.7, 50.6, 53.0, 59.1, 61.9, 64.4, 72.0, 74.3, 127.2, 127.3, 1355, 1169, 1061, 1032, 977, 817 and 745; δH (400 MHz, CDCl3)
127.9, 128.3(2), 128.9, 138.0, 138.3 and 159.1; m/z (EI) 420 (M+, 1.41–1.81 (5 H, m, cyclobutyl H), 2.00 (1 H, m, cyclobutyl H),
1%) and 91 (100). The second fraction was a mixture of the 2.10 (1 H, d, J 12.2 Hz, 5-H), 2.18 (1 H, m, 2-H), 2.40 (1 H, d,
title compounds 39 and 40 (53 mg, 26%), 39 : 40 = 56 : 44, Rf = J 10.5 Hz, 3-H), 2.42 (1 H, d, J 12.2 Hz, 5-H′), 2.52 (1 H, pent,
0.28–0.22 (ethyl acetate : light petroleum = 1 : 2) (Found: M+, J 8.5 Hz, 6-CH), 2.59 (1 H, dd, J 7.2, 10.5 Hz, 3-H′), 3.32 and
420.2412. C26H32N2O3 requires M, 420.2413); νmax/cm−1 3083, 3.36 (each 1 H, d, J 13.0 Hz, PhHCH), 3.70 (1 H, dd, J 5.7, 10.7
3061, 3029, 2927, 2869, 2823, 1746, 1495, 1453, 1436, 1403, Hz, 2-CH), 3.83 (1 H, dd, J 7.7, 10.7 Hz, 2-CH′), 3.94 and 4.28
1355, 1334, 1193, 1170, 1106, 1053, 1027, 996, 923, 809 and (each 1 H, d, J 16.0 Hz, PhHCH), 4.57 (1 H, d, J 3.0 Hz, 1-H)
743; δH (400 MHz, CDCl3) minor epimer 40 2.75–2.85 (2 H, m, and 7.21–7.35 (10 H, m, ArH); δC (100 MHz, CDCl3) 17.6, 23.0,
3-H, 5-H), 3.24 (1 H, d, J 12.8 Hz, PhHCH), 3.47 (1 H, dd, J 3.0, 23.3, 38.4, 39.3, 44.7, 50.4, 53.4, 62.0, 62.3, 64.5, 74.7, 127.2,
9.5 Hz, 2-CH), 3.53 (1 H, dd, J 5.25, 9.5 Hz, 2-CH′), 4.02 (1 H, d, 127.4, 127.9, 128.3, 128.4, 128.9, 137.9, 138.2 and 159.0; m/z
J 15.5 Hz, PhHCH), 4.40 (1 H, d, J 8.7 Hz, 1-H) and 4.45 (1 H, (EI+) 406 (M+, 1%) and 91 (100).
d, J 15.5 Hz, PhHCH); δC (100 MHz, CDCl3) minor epimer
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
4016.9, 23.3, 23.7, 41.2, 41.6, 44.4, 53.3(2), 59.1, 62.4, 63.6, cyclobutyl-5-(1-bromoprop-2-en-2-yl)-1,3-oxazolidin-2-one (43).
71.8, 73.8, 127.4(2), 128.0, 128.3, 128.4, 129.3, 137.9, 138.1 and Carbon tetrabromide (1.16 g, 3.48 mmol, 1.5 eq.) was added to
158.4; m/z (CI+) 421 (M+ + 1, 100%).
the alcohol 32 (1 g, 2.32 mmol) and triphenylphosphine
(1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-methoxymethyl-4,7- (1.22 g, 4.64 mmol, 2 eq.) in MeCN (26 mL) at 0 °C and the
diaza-9-oxabicyclo[4.3.0]nonan-8-one (8). A solution of formic reaction mixture was warmed to rt then stirred for 2 h. After
acid (93 μL, 0.025 mmol, 0.4 eq.) in MeOH (1 mL) was added concentration under reduced pressure and pre-absorbtion of
to the N-benzylpiperidine 39 (26 mg, 0.062 mmol) and 10% the residue onto the silica, chromatography (ethyl acetate :
Pd/C (41 mg) under N2 and the reaction mixture was stirred at light petroleum = 1 : 25 to 1 : 10) gave the title compound 43
rt for 20 min. Potassium carbonate (50 mg) was added, the (1.15 g, 100%) as a colourless oil, Rf = 0.15 (ethyl acetate : light
reaction mixture was filtered through celite and the residue petroleum = 1 : 10) (Found: M+ + H, 494.1719. C24H37NO379BrSi
was washed with ether. After concentration under reduced requires M, 494.1727); νmax/cm−1 3088, 3063, 3032, 2952, 2932,
pressure, chromatography (MeOH : ether = 1 : 50, saturated in 2897, 2859, 1752, 1496, 1468, 1402, 1355, 1294, 1255, 1211,
ammonia) of the residue gave the title compound 8 (14 mg, 1164, 1102, 1031, 1006, 930, 840 and 779; δH (300 MHz, CDCl3)
71%), Rf = 0.38 (MeOH : ether = 1 : 10 saturated in ammonia) −0.03 and 0.00 (each 3 H, s, SiCH3), 0.86 [9 H, s, SiC(CH3)3],
(Found: M+, 330.1941. C19H26N2O3 requires M, 330.1943); νmax
/
1.61–2.10 (6 H, m, 3 × CH2), 2.82 (1 H, pent, J 9.0 Hz, 4-CH),
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3.45 (2 H, s, 4-CH2), 4.09 and 4.15 (each 1 H, d, J 11.2 Hz, 778; δH (300 MHz, CDCl3) 0.06 and 0.08 (each 3 H, s, SiCH3),
1′-H), 4.44 and 4.54 (each 1 H, d, J 15.7 Hz, PhHCH), 5.14 (1 H, 0.91 [9 H, s, SiC(CH3)3], 1.35–1.94 (6 H, m, 3 × CH2), 2.19 (1 H,
s, 5-H), 5.54 and 5.62 (each 1 H, s, 3′-H) and 7.29–7.39 (5 H, m, br. s, OH), 2.38 (1 H, m, 2′-H), 2.54 (1 H, pent, J 8.7 Hz, 4-CH),
ArH); δC (75 MHz, CDCl3) −6.0, −5.8, 17.3, 18.1, 23.0, 23.6, 2.91 (2 H, t, J 6.7 Hz, 2″-H2), 3.62–3.75 (6 H, m, 4-CH2, 1′-H2,
25.8, 32.9, 39.1, 45.9, 63.0, 68.5, 77.2, 119.8, 127.4, 127.5, 1″-H2), 3.91 (2 H, d, J 4.5 Hz, 3′-H2), 4.18 (1 H, d, J 16.0 Hz,
128.5, 138.4, 140.2 and 158.5; m/z (CI+) 513 (M+ + 18, 25%), PhHCH), 4.49 (1 H, d, J 6.2 Hz, 5-H), 4.69 (1 H, d, J 16.0 Hz,
511 (M+ + 18, 25), 496 (M+ + 1, 5) and 494 (M+ + 1, 5) and 106 PhHCH) and 7.22–7.42 (10 H, m, ArH); δC (75 MHz, CDCl3)
(100).
−5.9, −5.8, 17.2, 17.9, 23.0, 23.2, 25.6, 36.2, 38.6, 40.8, 45.7,
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 61.1, 62.2, 68.5, 71.5, 72.2, 77.3, 126.3, 127.2, 127.5, 128.4(2),
cyclobutyl-5-[1-(2-phenylethoxy)prop-2-en-2-yl]-1,3-oxazolidin- 128.7, 138.4, 138.7 and 159.2; m/z (CI+) 571 (M+ + 18, 2%), 554
2-one (44). Sodium hydride (60% in mineral oil, 176 mg, (M+ + 1, 3) and 102 (100).
4.40 mmol, 2 eq.) was added to 2-phenylethanol (0.26 mL,
2.18 mmol, 0.99 eq.) in THF (15 mL) at 0 °C and the suspen- hydroxy-3-(2-phenylethoxy)prop-2-yl]-1,3-oxazolidin-2-one (46).
sion stirred at rt for 30 min. The bromide 43 (1.09 g, Tetra-n-butylammonium fluoride in THF (1 in THF,
(4SR,5RS)-3-Benzyl-4-cyclobutyl-4-hydroxymethyl-5-[(SR)-1-
M
2.20 mmol) in THF (10 mL) was added and the reaction 1.23 mL, 1.23 mmol, 1.2 eq.) was added to the silyl ether 45
mixture stirred for 3 h. Saturated aqueous ammonium chloride (566 mg, 1.02 mmol) in THF (10 mL) at 0 °C and the reaction
(15 mL) was added and the aqueous phase was extracted with mixture was warmed to rt then stirred for 30 min. After con-
ether (3 × 20 mL). The organic extracts were dried (MgSO4) and centration under reduced pressure and pre-absorbtion onto
concentrated under reduced pressure. Chromatography (ethyl silica, chromatography (ethyl acetate : light petroleum = 1 : 2 to
acetate : light petroleum = 1 : 25) of the residue gave the title neat ethyl acetate) of the residue gave the title compound 46
compound 44 (1.17 g, 99%) as a colourless oil, Rf = 0.56 (ethyl (313 mg, 70%), Rf = 0.16 (ethyl acetate : light petroleum = 3 : 2)
acetate : light petroleum = 1 : 4) (Found: M+ + H, 536.3189. (Found: M+ + H, 440.2435. C26H34NO5 requires M, 440.2431);
C32H46NO4Si requires M, 536.3191); νmax/cm−1 3063, 3029, νmax/cm−1 3396, 3062, 3029, 2942, 2870, 1723, 1604, 1495,
2950, 2928, 2858, 1752, 1603, 1496, 1467, 1404, 1355, 1255, 1432, 1415, 1357, 1297, 1253, 1202, 1167, 1110, 1031, 975 and
1101, 929, 841 and 779; δH (300 MHz, CDCl3) −0.07 and −0.02 911; δH (400 MHz, CDCl3) 1.45–1.90 (6 H, m, 3 × CH2), 2.34–2.50
(each 3 H, s, SiCH3), 0.86 [9 H, s, SiC(CH3)3], 1.51–1.92 (6 H, (2 H, m, 4-CH, 2′-H), 2.88 (4 H, m, 2″-H2, 2 × OH), 3.55 (3 H,
m, 3 × CH2), 2.82 (1 H, pent, J 8.7 Hz, 4-CH), 2.91 (2 H, t, J 7.0 m, 4-HCH, 1′-H, 1″-H), 3.64–3.74 (4 H, m, 4-HCH, 1′-H′, 1″-H′,
Hz, 2″-H2), 3.45 and 3.51 (each 1 H, d, J 10.7 Hz, 4-HCH), 3.62 3′-H), 3.93 (1 H, dd, J 5.75, 11.0 Hz, 3′-H′), 4.35 and 4.55 (each
(1 H, dt, J 9.2, 7.0 Hz, 1″-H), 3.71 (1 H, dt, J 9.2, 7.2 Hz, 1″-H′), 1 H, d, J 16.0 Hz, PhHCH), 4.59 (1 H, d, J 4.2 Hz, 5-H) and
3.99 and 4.14 (each 1 H, d, J 13.0 Hz, 1′-H), 4.37 and 4.60 (each 7.19–7.42 (10 H, m, ArH); δC (100 MHz, CDCl3) 17.4, 22.8, 22.9,
1 H, d, J 15.7 Hz, PhHCH), 4.94 (1 H, s, 5-H), 5.38 (2 H, s, 3′- 36.1, 39.0, 41.0, 45.3, 60.3, 61.1, 68.8, 71.5, 72.2, 77.4, 126.3,
H2) and 7.21–7.39 (10 H, m, ArH); δC (75 MHz, CDCl3) −6.0, 127.6, 127.8, 128.4, 128.7(2), 138.3, 138.6 and 159.4; m/z (CI+)
−5.8, 17.1, 18.1, 22.8, 23.1, 25.8, 36.3, 38.2, 45.8, 62.9, 68.3, 457 (M+ + 18, 3%), 440 (M+ + 1, 10) and 102 (100).
71.2, 71.5, 77.2, 116.9, 126.2, 127.2, 127.5, 128.4(2), 128.9,
138.7, 138.8, 140.6 and 158.9; m/z (CI+) 536 (M+ + 1, 5%) and methyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (48). Freshly
309 (100). distilled methane sulfonyl chloride (0.152 mL, 1.96 mmol,
(1RS,2SR,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-(2-phenylethoxy)
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 4 eq.) and Et3N (0.341 mL, 2.44 mmol, 5 eq.) were added suc-
cyclobutyl-5-[(SR)-1-hydroxy-3-(2-phenylethoxy)prop-2-yl]-1,3- cessively to the diol 46 (215 mg, 0.489 mmol) in DCM (10 mL)
oxazolidin-2-one (45). Borane (1
M in THF, 21.8 mL, at 0 °C and the reaction mixture was allowed to warm to rt
21.8 mmol, 10 eq.) was added dropwise to the alkene 44 then stirred for 1 h. Saturated aqueous ammonium chloride
(1.17 g, 2.18 mmol) in THF (21 mL) at −20 °C and the reaction (10 mL) and ether (15 mL) were added and the aqueous phase
mixture was warmed to 0 °C then stirred for 18 h. Ethanol was extracted with ether (3 × 20 mL). The organic extracts were
(19 mL), saturated aqueous sodium acetate (61 mL) and hydro- dried (MgSO4) and concentrated under reduced pressure to
gen peroxide (30% in water, 22 mL) were added dropwise in give the bis-mesylate 47, Rf
= 0.51 (ethyl acetate : light
that order and the reaction mixture was heated under reflux petroleum = 3 : 2).
for 2.5 h. After cooling the aqueous phase was extracted with
The bis-mesylate 47 (140 mg) was dissolved in benzylamine
ether (3 × 150 mL), and the organic extracts were dried (12 mL) and heated at 95 °C for 15 h. After cooling to rt,
(MgSO4) then concentrated under reduced pressure. Chromato- unreacted benzylamine was removed by distillation under
graphy (ethyl acetate : light petroleum = 1 : 10 to 1 : 4) of the reduced pressure. The residue was dissolved in ether (12 mL)
residue gave the alcohol 45 (870 mg, 72%) as a 3 : 1 mixture of and saturated aqueous potassium carbonate (10 mL) was
2′-epimers. Further chromatography (ethyl acetate : light pet- added. The mixture was stirred vigorously at rt for 30 min and
roleum = 1 : 4) gave the title compound 45 (566 mg, 47%), Rf = then the organic and aqueous phases were separated. The
0.26 (ethyl acetate : light petroleum = 1 : 2) (Found: M+ + NH4, aqueous phase was extracted with ether (3 × 15 mL) and the
571.3569. C32H51N2O5Si requires M, 571.3562); νmax/cm−1 organic extracts were dried (MgSO4) then concentrated under
3442, 3063, 3029, 2969, 2953, 2860, 1733, 1604, 1496, 1468, reduced pressure. Chromatography (ethyl acetate : light pet-
1409, 1357, 1297, 1255, 1206, 1171, 1106, 1032, 980, 841 and roleum = 1 : 10 to 1 : 4) of the residue gave the title compound
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48 (92 mg, 37%), Rf = 0.25 (ethyl acetate : light petroleum = 3.55 (each 1 H, d, J 11.0 Hz, 4-HCH), 4.26 (2 H, s 1′-H2), 4.36
1 : 4) (Found: M+ + H, 511.2966. C33H39N2O3 requires M, and 4.65 (each 1 H, d, J 15.7 Hz, PhHCH), 5.06 (1 H, s, 5-H),
511.2955); νmax/cm−1 3086, 3062, 3028, 2942, 2866, 2808, 1746, 5.28 and 5.44 (each 1 H, s, 3′-H) and 7.23–7.40 (5 H, m, ArH);
1603, 1495, 1454, 1406, 1361, 1171, 1113, 1095, 1064, 1028, δC (75 MHz, CDCl3) −6.1, −5.9, −5.5(2), 16.9, 18.0, 18.2, 22.6,
983, 913, 818 and 748; δH (300 MHz, CDCl3) 1.36–2.00 (6 H, m, 23.0, 25.7, 37.8, 45.8, 62.6, 63.4, 68.1, 77.8, 114.2, 127.1, 127.4,
3 × CH2), 2.09 (1 H, d, J 12.5 Hz, 5-H), 2.21 (1 H, m, 2-H), 2.37 128.3, 138.6, 143.0 and 158.9; m/z (CI) 546 (M+ + 1, 20%) and
(1 H, t, J 10.5 Hz, 3-H), 2.40 (1 H, d, J 12.5 Hz, 5-H′), 2.47 (1 H, 106 (100). The second fraction was the title compound 51
pent, J 9.0 Hz, 6-CH), 2.54 (1 H, dd, J 10.5, 7.2 Hz, 3-H′), 2.88 (333 mg, 43%), Rf = 0.26 (ethyl acetate : light petroleum = 3 : 2)
(2 H, t, J 7.0 Hz, 2′-H2), 3.32 (2 H, s, PhCH2), 3.41 (1 H, dd, (Found: M+ + H, 318.1708. C18H24NO4 requires M, 318.1705);
J 9.2, 6.5 Hz, 2-CH), 3.59–3.73 (3 H, m, 1′-H2, 2-CH′), 3.90 and νmax/cm−1 3409, 3064, 3032, 2942, 2871, 1725, 1496, 1432,
4.28 (each 1 H, d, J 15.7 Hz, PhHCH), 4.46 (1 H, d, J 2.5 Hz, 1414, 1357, 1293, 1254, 1202, 1158, 1068, 1025, 979, 917 and
1-H) and 7.20–7.36 (15 H, m, ArH); δC (75 MHz, CDCl3) 17.6, 817; δH (300 MHz, CDCl3) 1.54–1.97 (6 H, m, 3 × CH2), 2.58
22.9, 23.2, 36.2, 36.8, 39.2, 44.7, 50.6, 52.9, 61.9, 64.4, 70.0, (1 H, pent, J 8.7 Hz, 4-CH), 3.55 and 3.62 (each 1 H, d, J 12.5
72.1, 74.3, 126.2, 127.2, 127.3, 127.9, 128.3(3), 128.9, 138.0, Hz, 4-HCH), 4.06 (2 H, br. s, OH), 4.18 (1 H, d, J 13.0 Hz, 1′-H),
138.3, 138.9 and 159.1; m/z (EI+) 510 (M+, 1%) and 91 (100).
4.34 (1 H, d, J 16.0 Hz, PhHCH), 4.38 (1 H, d, J 13.0 Hz, 1′-H′),
(1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-(2-phenylethoxy)methyl- 4.68 (1 H, d, J 16.0 Hz, PhHCH), 5.11 (1 H, s, 5-H), 5.23 and
4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (49). Following the 5.48 (each 1 H, s, 3′-H) and 7.27–7.44 (5 H, m, ArH);
procedure outlined for the preparation of piperidine 8, the δC (75 MHz, CDCl3) 17.2, 22.8, 22.9, 39.5, 45.8, 60.2, 63.2, 69.7,
benzylamine 48 (105 mg, 0.206 mmol), after chromatography 78.9, 116.7, 127.5, 127.7, 128.6, 138.2, 144.2 and 159.4; m/z (CI)
(ethyl acetate : light petroleum = 3 : 2 with 2% triethylamine to 335 (M+ + 18, 15%) , 318 (M+ + 1, 15) and 88 (100).
neat ethyl acetate) gave the title compound 49 (53 mg, 61%),
(1RS,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-methylene-4,7-diaza-
Rf = 0.24 (1% methanol in ethyl acetate) (Found: M+ + H, 9-oxabicyclo[4.3.0]nonan-8-one (53). Methane sulfonyl chlor-
421.2486. C26H33N2O3 requires M, 421.2486); νmax/cm−1 3348, ide (0.338 mL, 4.36 mmol, 4 eq.) and Et3N (0.761 mL,
3062, 3028, 2938, 2865, 1743, 1603, 1496, 1410, 1259, 1093, 5.45 mmol, 5 eq.) were added to the diol 51 (346 mg,
811 and 755; δH (400 MHz, C6D6) 1.25–1.60 (5 H, m, cyclobutyl 1.09 mmol) in DCM (10 mL) at 0 °C and the reaction mixture
H), 1.74 (1 H, m, cyclobutyl H), 1.95 (1 H, m, 2-H), 2.19 (1 H, d, stirred at rt for 1 h before the addition of saturated aqueous
J 13.6 Hz, 5-H), 2.2 (1 H, pent, J 8.5 Hz, 6-CH), 2.35 (1 H, d, NH4Cl (10 mL) followed by ether (15 mL). The aqueous phase
J 13.6 Hz, 5-H′), 2.44 (1 H, t, J 11.7 Hz, 3-H), 2.73 (1 H, dd, was extracted with ether (3 × 20 cm3) and the organic layer
J 6.4, 11.5 Hz, 3-H′), 2.82 (2 H, t, J 6.9 Hz, 2′-H2), 3.18 (1 H, dd, extracts were dried (MgSO4) then concentrated under reduced
J 6.2, 9.0 Hz, 2-CH), 3.45–3.59 (3 H, m, 2-CH′, 1′-H2), 4.17 and pressure to give the bis-mesylate 52.
4.24 (each 1 H, d, J 15.6 Hz, PhHCH), 4.54, (1 H, d, J 2.7 Hz,
This bis-mesylate 52 was dissolved in benzylamine (12 mL)
1-H), 7.08–7.26 (8 H, m, ArH) and 7.41 (2 H, d, J 7.0 Hz, ArH); and the solution heated at 95 °C for 18 h then allowed to cool
δC (100 MHz, C6D6) 17.5, 22.4, 22.8, 36.3, 36.4, 38.8, 41.4, 44.5, to rt and concentrated under reduced pressure. The residue
45.9, 62.8, 69.7, 71.9, 73.5, 126.1, 127.3, 128.0, 128.3, 128.4, was dissolved in ether (12 mL), saturated aqueous K2CO3
129.0, 139.2(2) and 158.4; m/z (ES+) 421 (M+ + 1, 100%).
(10 mL) was added and the mixture was stirred vigorously at rt
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-5-(1- for 30 min. The aqueous phase was extracted with ether (3 ×
tert-butyldimethylsilyloxyprop-2-en-2-yl)-4-cyclobutyl-1,3-oxa- 15 mL) and the organic extracts were dried (MgSO4) and con-
zolidin-2-one (50) and (4SR,5RS)-3-Benzyl-4-cyclobutyl-4-hydroxy- centrated under reduced pressure. Chromatography of the
methyl-5-(1-hydroxyprop-2-en-2-yl)-1,3-oxazolidin-2-one
(51). residue (ethyl acetate : light petroleum = 1 : 15 to 1 : 9) gave the
Sodium hydride (60% in mineral oil, 195 mg, 4.87 mmol, title compound 53 (254 mg, 60%), Rf = 0.25 (ethyl acetate : light
2 eq.) was added to the alcohol 32 (1.05 g, 2.43 mmol) in THF petroleum = 1 : 4) (Found: M+ + H, 389.2227. C25H29N2O2
(15 mL) and the suspension stired for 30 min. 2-Phenylethyl requires M, 389.2229); νmax/cm−1 3084, 3062, 3028, 2976, 2943,
bromide (0.366 mL, 2.68 mmol, 1.1 eq.) in THF (5 mL) was 2867, 2806, 1746, 1494, 1453, 1402, 1357, 1301, 1169, 1106,
added and the reaction mixture was stirred for 15 h. After 1063, 1024, 919, 818 and 744; δH (300 MHz, CDCl3) 1.36–1.94
adding saturated aqueous NH4Cl (15 mL), the aqueous phase (6 H, m, 3 × CH2), 2.08 (1 H, d, J 12.7 Hz, 5-H), 2.40 (1 H, dd,
was extracted with ether (3 × 20 mL) and the organic extracts J 1.25, 12.7 Hz, 5-H′), 2.47 (1 H, pent, J 8.25 Hz, 6-CH), 3.02
were dried (MgSO4), filtered and concentrated under reduced (1 H, d, J 14.3 Hz, 3-H), 3.27 and 3.46 (each 1 H, d, J 13.0 Hz,
pressure. Chromatography of the residue (ethyl acetate : light PhHCH), 3.71 (1 H, dd, J 1.25, 14.3 Hz, 3-H′), 3.81 and 4.31
petroleum = 1 : 10 to 3 : 2) gave the title compound 50 (501 mg, (each 1 H, d, J 15.7 Hz, PhHCH), 4.84 (1 H, s, 1-H), 5.18 and
38%), Rf = 0.59 (ethyl acetate : light petroleum = 1 : 4) (Found: 5.36 (each 1 H, s, 2-CH) and 7.22–7.42 (10 H, m, ArH);
M+ + H, 546.3430. C30H52NO4Si2 requires M, 546.3435); νmax
/
δC (75 MHz, CDCl3) 17.3, 22.1, 22.2, 38.7, 44.4, 52.1, 55.6, 61.2,
cm−1 3088, 3064, 3031, 2953, 2932, 2889, 2858, 1755, 1496, 65.5, 78.1, 117.4, 127.2, 127.3, 127.9, 128.3(2), 128.9, 137.8,
1467, 1404, 1357, 1291, 1255, 1106, 1005, 934, 917, 840 and 138.3, 139.9 and 158.9; m/z (CI) 389 (M+ + 1, 30%), 196 (50)
778; δH (300 MHz, CDCl3) −0.04, 0.01, 0.09 and 0.10 (each 3 H, and 74 (100).
s, SiCH3), 0.88 and 0.94 [each 9 H, s, SiC(CH3)3], 1.53–2.03
1-Benzyl-5-benzylamino-5-cyclobutyl-3-formyl-1,2,5,6-tetra-
(6 H, m, 3 × CH2), 2.91 (1 H, pent, J 8.5 Hz, 4-CH), 3.49 and hydropyridine (56). Dimethyl sulfoxide (19.6 μL, 0.277 mmol,
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3.2 eq.) in DCM (0.5 mL) was added dropwise to oxalyl chloride 18.0, 22.7, 25.7, 38.3, 45.8, 63.4, 69.0, 74.4, 127.3, 128.4, 130.3,
(14.5 μL, 0.166 mmol, 1.9 eq.) in DCM (0.5 mL) at −78 °C and 135.4, 138.3, 158.8 and 169.7; m/z (CI+) 463 (M+ + 18, 3%), 446
the reaction mixture stirred at this temperature for 20 min. (M+ + 1, 5) and 106 (100).
The alcohol 41 (35 mg, 0.086 mmol) in DCM (0.5 mL) was
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
added and the solution was stirred at −78 °C for 20 min. cyclobutyl-5-[1-(1-hydroxyprop-2-ylaminocarboxy)ethenyl]-1,3-
Hünig’s base (96.0 μL, 0.553 mmol, 6.4 eq.) was added oxazolidin-2-one (59). Isobutyl chloroformate (34 μL,
and, after stirring for 20 min, the reaction mixture was allowed 0.258 mmol, 1.5 eq.) was added to the carboxylic acid 58
to warm to rt. After stirring at rt for 3 h, ether (2.5 mL) and (77 mg, 0.172 mmol) and N-methylmorpholine (57 μL,
saturated aqueous ammonium chloride (5 mL) were added. 0.515 mmol, 3 eq.) in THF (1.5 mL). After stirring at rt for 1 h,
The aqueous phase was extracted with ether (3 × 5 mL) and the 2-aminopropanol (19 mg, 0.258 mmol, 1.5 eq.) in THF
organic extracts were dried (MgSO4) and concentrated under (1.5 mL) was added and the reaction mixture was stirred for
reduced pressure. Chromatography (ethyl acetate : light pet- 12 h. Saturated aqueous sodium bicarbonate (4 mL) was added
roleum = 1 : 4 to 1 : 1) of the residue gave the title compound and the aqueous layer was extracted with ether (3 × 5 mL). The
56 (29 mg, 93%) as a pale yellow oil, Rf = 0.31 (ethyl acetate : organic extracts were dried (MgSO4) and concentrated under
light petroleum = 1 : 1) (Found: M+ + H, 361.2282. C24H29N2O reduced pressure. Chromatography (ethyl acetate : light pet-
requires M, 361.2280); νmax/cm−1 3355, 3060, 3028, 2930, 2856, roleum = 3 : 2) gave the title compound 59 (31 mg, 36%), as a
2808, 2759, 2716, 1685, 1494, 1455, 1363, 1204, 1105, 811 and mixture of epimers, ratio 1 : 1 (Found: M+ + H, 503.2941.
742; δH (400 MHz, C6D6) 1.60–1.95 (6 H, m, 3 × CH2), 2.01 C27H43N2O5Si requires M, 503.2941); νmax/cm−1 3355, 2952,
(1 H, d, J 11.2 Hz, 6-H), 2.44 (1 H, m, 5-CH), 2.51 (1 H, d, J 11.2 2932, 2858, 1739, 1661, 1616, 1536, 1467, 1411, 1359, 1255,
Hz, 6-H′), 3.01 (1 H, dd, J 1.5, 16.5 Hz, 2-H), 3.28 and 3.39 1095, 842 and 780; m/z (CI+) 503 (M+ + 1, 2%) and 106 (100).
(each 1 H, d, J 13.0 Hz, PhHCH), 3.40 (1 H, d, J 16.5 Hz, 2-H′), Samples were partially separated for NMR; 59a Rf = 0.25 (ethyl
3.44 and 3.63 (each 1 H, d, J 12.7 Hz, PhHCH), 6.33 (1 H, s, 4- acetate : light petroleum = 3 : 2); δH (300 MHz, CDCl3) −0.11
H), 7.12–7.42 (10 H, m, ArH) and 9.32 (1 H, s, CHO); and −0.02 (each 3 H, s, SiCH3), 0.83 [9 H, s, SiC(CH3)3], 1.22
δC (100 MHz, C6D6) 18.0, 22.6, 23.6, 41.6, 47.4, 50.5, 55.6, 57.3, (3 H, d, J 6.7 Hz, 3″-H3), 1.57–2.10 (6 H, m, 3 × CH2), 2.95 (1 H,
62.2, 127.0, 127.3, 128.2, 128.4(2), 129.2, 138.5, 141.4, 141.8, pent, J 8.7 Hz, 4-CH), 3.53 (1 H, dd, J 5.5, 11.0 Hz, 1″-H), 3.54
150.8 and 191.3; m/z (CI+) 361 (M+ + 1, 60%) and 108 (100).
and 3.58 (each 1 H, d, J 11.0 Hz, 4-HCH), 3.63 (1 H, dd, J 3.5,
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 11.0 Hz, 1″-H′), 4.10 (1 H, m, 2″-H), 4.31 and 4.68 (each 1 H, d,
cyclobutyl-5-(1-carboxyethenyl)-1,3-oxazolidin-2-one (58). The J = 15.7 Hz, PhHCH), 5.48 (1 H, s, 5-H), 5.81 and 5.88 (each
Dess–Martin periodinane (984 mg, 2.32 mmol, 2 eq.) was 1 H, s, 2′-H), 6.22 (1 H, br. d, J 7.5 Hz, NH) and 7.20–7.38 (5 H,
added to the alcohol 32 (500 mg, 1.16 mmol) in DCM (5 mL) m, ArH); δC (75 MHz, CDCl3) −6.0, −5.8, 16.9(2), 18.1, 22.5,
at rt and the reaction mixture was stirred at rt for 45 min. Satu- 22.7, 25.8, 37.4, 45.7, 47.7, 62.6, 66.5, 68.9, 75.5, 121.4, 127.1,
rated aqueous sodium bicarbonate (5 mL) and saturated 127.2, 128.3, 138.3, 140.3, 158.7 and 167.0; 59b (still a mixture
sodium bisulfite (3 mL) were added, and the aqueous layer with 59a) Rf = 0.19 (ethyl acetate : light petroleum = 3 : 2); δH
was extracted with ether (3 × 10 mL). The organic extracts were (300 MHz, CDCl3) −0.13 and −0.04 (each 3 H, s, SiCH3), 3.50
washed with a saturated aqueous sodium bicarbonate (2 × and 3.54 (each 1 H, d, J 10.5 Hz, 4-HCH), 3.71 (1 H, dd, J 3.5,
2 mL) and brine (2 mL), then dried (MgSO4) and concentrated 11.0 Hz, 1″-H), 5.53 (1 H, s, 5-H), 5.83 and 5.93 (each 1 H, s, 2′-
under reduced pressure to provide aldehyde 57, Rf = 0.44 (ethyl H) and 6.39 (1 H, br. d, J 7.5 Hz, NH). 2-Methylpropyl N-(1-
acetate : light petroleum = 3 : 2).
hydroxyprop-2-yl) carbamate (33 mg) was also isolated, Rf =
3 : 2) (Found: M+,
2-Methyl-2-butene (2 M in THF, 5.8 mL, 11.59 mmol, 0.35 (ethyl acetate : light petroleum
=
10 eq.), sodium chlorite (80% technical, 655 mg, 5.79 mmol, 175.1210. C8H17NO3 requires M, 175.1208); δH (400 MHz,
5 eq.) and sodium dihydrogen phosphate (1.39 g, 11.59 mmol, CDCl3) 0.87 (6 H, d, J 6.8 Hz, 2 × CH3), 1.12 (3 H, d, J 6.8 Hz,
10 eq.) were added to the aldehyde 57 in tert-BuOH and water 3′-H3), 1.86 (1 H, m, 2-H), 3.46 (1 H, dd, J 5.1, 11.0 Hz, 1′-H),
(1 : 1, 15 mL) and the reaction mixture was stirred at rt for 2 h. 3.58 (1 H, dd, J 4.0, 11.0 Hz, 1′-H′), 3.72–3.82 (3 H, m, 2′-H, 1-
Ether (10 mL) and brine (15 mL) were added and the aqueous H2) and 5.8 (1 H, br. s, NH); δC (100 MHz, CDCl3) 17.2, 18.9,
phase was extracted with ether (3 × 20 mL). The organic 27.8, 48.6, 66.4, 71.0 and 157.0; m/z (CI+) 176 (M+ + 1, 100%).
extracts were dried (MgSO4) and concentrated under reduced
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
pressure to give the title compound 58 (516 mg, 100%), Rf = cyclobutyl-5-[1-(4-methyl-1,3-oxazol-2-yl)ethenyl]-1,3-oxazoli-
0.35 (ethyl acetate : light petroleum = 1 : 2) (Found: M+ + H, din-2-one (61). The Dess–Martin periodinane (120 mg,
446.2351. C24H36NO5Si requires M, 446.2363); νmax/cm−1 2953, 0.283 mmol, 2 eq.) was added to the epimeric alcohols 59
2932, 2885, 2859, 1728, 1631, 1469, 1412, 1359, 1255, 1161, (71 mg, 0.142 mmol) in DCM (2 mL) at rt and the reaction
1102, 840 and 779; δH (300 MHz, CDCl3) −0.14 and −0.07 mixture was stirred for 45 min. Saturated aqueous sodium
(each 3 H, s, SiCH3), 0.79 [9 H, s, SiC(CH3)3], 1.41–2.11 (6 H, 3 bicarbonate (2 mL) and saturated aqueous sodium bisulfite
× CH2), 2.82 (1 H, pent, J 8.5 Hz, 4-CH), 3.41 (2 H, s, 4-CH2), (1 mL) were added and the aqueous layer was extracted with
4.34 and 4.59 (each 1 H, d, J 15.7 Hz, PhHCH), 5.40 (1 H, s, 5- ether (3 × 5 mL). The organic extracts were washed with satu-
H), 6.18 and 6.61 (each 1 H, s, 2′-H), 7.22–7.40 (5 H, m, ArH) rated aqueous sodium bicarbonate (2 × 1 mL) and brine
and 9.50 (1 H, br. s, OH); δC (75 MHz, CDCl3) −6.2, −6.0, 16.9, (1 mL), then dried (MgSO4) and concentrated under reduced
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pressure to give the aldehyde 60, Rf = 0.52 (ethyl acetate : light stirred under reflux for 1 h before saturated aqueous NH4Cl
petroleum = 3 : 2). (4 mL) was added. The aqueous phase was extracted with ether
2,6-Di-tert-butyl-4-methylpyridine (87 mg, 0.425 mmol, (3 × 5 mL) and the organic extracts were dried (MgSO4) and
3 eq.) and triphenylphosphine (74 mg, 0.283 mmol, 2 eq.) were concentrated under reduced pressure. Chromatography of the
added to this aldehyde 60 in DCM (1.5 mL). After cooling to residue (light petroleum to 10% ethyl acetate/light petroleum)
0 °C, 1,2-dibromotetrachloroethane (92 mg, 0.283 mmol, 2 eq.) gave the title compound 66 (3.76 g, 79%), Rf = 0.53 (25% ethyl
was added and the solution was stirred at 0 °C for 1 h. Aceto- acetate/light petroleum) (Found: M+
+
H, 416.2619.
nitrile (1.5 mL) and DBU (42 μL, 0.283 mmol, 2 eq.) were C24H38NO3Si requires M, 416.2622); νmax/cm−1 3086, 3065,
added and the reaction mixture was warmed to rt, stirred for 3032, 2952, 2932, 2859, 1754, 1496, 1468, 1402, 1356, 1292,
2.5 h, then concentrated under reduced pressure. Following 1255, 1204, 1162, 1150, 1103, 1004, 906, 840 and 778;
pre-absorbtion onto silica, chromatography (ethyl acetate : δH (400 MHz, CDCl3) −0.08 and −0.03 (3 H, s, SiCH3), 0.85 [9 H,
light petroleum = 1 : 50 to 1 : 4) of the residue gave the title s, SiC(CH3)3], 1.56–2.04 (9 H, m, 3′-H3, 3 × CH2), 2.89 (1 H,
compound 61 (29 mg, 42%), Rf = 0.31 (ethyl acetate : light pent, J 8.7 Hz, 4-CH), 3.47 and 3.51 (each 1 H, d, J 11.0 Hz,
petroleum = 1 : 4) (Found: M+ + H, 483.2674. C27H39N2O4Si 4-HCH), 4.37 and 4.60 (each 1 H, J 15.7 Hz, PhHCH), 4.88 (1 H,
requires M, 483.2680); νmax/cm−1 3062, 3032, 2954, 2929, 2857, s, 5-H), 5.09 (2 H, s, 1′-H2) and 7.21–7.38 (5 H, m, ArH);
1755, 1597, 1530, 1469, 1406, 1358, 1256, 1149, 1100, 1031, δC (100 MHz, CDCl3) −6.1, −5.9, 17.0, 18.1, 19.5, 22.6, 23.0,
1006, 830, 840, 779 and 736; δH (300 MHz, CDCl3) −0.25 and 25.7, 38.0, 45.7, 62.5, 67.7, 80.2, 115.7, 127.1, 127.4, 128.3,
−0.18 (each 3 H, s, SiCH3), 0.75 [9 H, s, SiC(CH3)3], 1.51–1.90 138.6, 139.9 and 158.8; m/z (CI) 433 (M+ + 18, 8%), 416
(6 H, m, 3 × CH2), 2.15 (3 H, d, J 1.2 Hz, 4″-CH3), 2.95 (1 H, (M+ + 1, 10) and 106 (100).
pent, J 8.7 Hz, 4-CH), 3.42 (2 H, s, 4-CH2), 4.40 and 4.61 (each
(4SR,5SR)-5-Acetyl-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-
1 H, d, J 15.7 Hz, PhHCH), 5.70 (1 H, s, 5-H), 5.82 and 6.24 4-cyclobutyl-1,3-oxazolidin-2-one (67). A mixture of ozone and
(each 1 H, s, 2′-H) and 7.19–7.38 (6 H, m, ArH); δC (75 MHz, oxygen was bubbled through the alkene 66 (221 mg,
CDCl3) −6.3, −6.0, 11.5, 17.0, 18.0, 22.7, 22.8, 25.7, 38.1, 45.5, 0.532 mmol) in DCM (5 mL) at −78 °C until a persistent blue
62.6, 68.7, 74.9, 120.2, 127.1, 127.2, 128.3, 131.5, 134.2, 137.5, colour was observed. Triphenylphosphine (167 mg,
138.6, 158.7 and 159.6; m/z (CI+) 483 (M+ + 1, 100%).
0.64 mmmol, 1.2 eq.) was added and the mixture allowed to
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- warm to rt. Chromatography (4% ethyl acetate/light petroleum
cyclobutyl-5-[1-(4-methyl-1,3-oxazol-2-yl)-2-hydroxyethyl]-1,3- to 10% ethyl acetate/light petroleum) gave the title compound
oxazolidin-2-one (62). Borane (1 M in THF, 0.6 mL, 0.6 mmol, 67 (206 mg, 93%) as an oil, Rf = 0.43 (25% ethyl acetate/light
7.75 eq.) was added to the alkene 61 (37 mg, 0.078 mmol) in petroleum) (Found: M+ + H, 418.2411. C23H36NO4Si requires
THF (1 mL) at 0 °C and the reaction mixture was stirred at 0 °C M, 418.2414); νmax/cm−1 3064, 3031, 2953, 2932, 2859, 1756,
for 24 h. Ethanol (0.73 mL), saturated aqueous sodium acetate 1722, 1469, 1408, 1353, 1255, 1162, 1099, 1070, 1005, 936, 896,
(2.5 mL) and H2O2 (30% in water, 0.83 mL) were added and 838, 782 and 755; δH (300 MHz, CDCl3) 0.03 and 0.07 (each
the reaction mixture was warmed to rt and stirred for 18 h. 3 H, s, SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.18 (1 H, m, cyclobutyl
The aqueous phase was extracted with ether (3 × 5 mL), and H), 1.52–1.83 (4 H, m, 2 × CH2), 2.03 (1 H, pent, J 9.8 Hz,
the organic extracts were dried (MgSO4) then concentrated 4-CH), 2.33 (1 H, m, cyclobutyl H), 2.41 (3 H, s, 2′-H3), 3.51 and
under reduced pressure. Chromatography (ethyl acetate : light 3.66 (each 1 H, d, J 11.2 Hz, 4-HCH), 3.86 (1 H, d, J 15.7 Hz,
petroleum = 1 : 10 to 3 : 2) of the residue gave the title com- PhHCH), 4.63 (1 H, s, 5-H), 4.83 (1 H, d, J 15.7 Hz, PhHCH)
pound 62 (8 mg, 20%) as a single diastereoisomer, Rf = 0.34 and 7.25–7.44 (5 H, m, ArH); δC (75 MHz, CDCl3) −5.9, −5.7,
(ethyl acetate : light petroleum = 1 : 2); νmax/cm−1 3446, 2953, 17.1, 18.2, 22.3, 22.6, 25.8, 28.8, 38.0, 44.8, 59.6, 71.4, 78.9,
2932, 2892, 2859, 1750, 1605, 1564, 1467, 1403, 1357, 1295, 127.6, 128.0, 128.4, 137.7, 157.8 and 207.1; m/z (CI) 435
1256, 1169, 1102, 979, 938, 843 and 779; δH (300 MHz, C6D6) (M+ + 18, 100%) and 418 (M+ + 1, 20).
−0.07 and −0.03 (each 3 H, s, SiCH3), 0.90 [9 H, s, SiC(CH3)3],
(4SR,5SR)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
1.42–1.91 (7 H, m, 3 × CH2, 1′-H), 1.93 (3 H, s, 4″-CH3), 2.55 cyclobutyl-5-(1-trifluorosulfonyloxyethenyl)-1,3-oxazolidin-2-
(1 H, pent, J 9.0 Hz, 4-CH), 3.55 (1 H, J 10.7 Hz, 4-HCH), one (68). Potassium hexamethyldisilazide (0.5 M in toluene,
3.55–3.65 (2 H, m, 2′-H2), 3.67 (1 H, d, J 10.7 Hz, 4-HCH), 4.31 0.975 mL, 0.486 mmol, 1.3 eq.) was added to the ketone 67
and 4.39 (each 1 H, d, J 16.0 Hz, PhHCH), 4.46 (1 H, d, J 5.0 (156 mg, 0.374 mmol) in THF (2 mL) at −78 °C and the solu-
Hz, 5-H), 6.80 (1 H, s, 5″-H) and 7.02–7.20 (5 H, m, ArH); tion was stirred at −78 °C for 1 h. N-Phenyltrifluoromethane-
δC (75 MHz, C6D6) −5.8(2), 11.6, 17.5, 17.6, 18.2, 23.4, 23.9, sulfonimide (268 mg, 0.748 mmol, 2 eq.) in THF (1.5 mL) was
25.9, 35.0, 40.1, 45.9, 62.5, 67.2, 80.1, 127.1, 127.2, 128.3, added and the solution was stirred for 5 h at −78 °C then
134.5, 136.5, 139.4, 158.3 and 164.3.
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- (5 mL) were added and the aqueous phase was extracted with
cyclobutyl-5-propen-2-yl-1,3-oxazolidin-2-one (66). Sodium ether (3 × 5 mL). The organic extracts were dried (MgSO4) and
warmed to rt. Ether (5 mL) and saturated aqueous NH4Cl
hydride (60% in mineral oil, 65 mg, 1.60 mmol, 2 eq.) and concentrated under reduced pressure. Chromatography of the
benzyl bromide (0.475 mL, 4.01 mmol, 5 eq.) were added to residue (5% ethyl acetate/light petroleum to 10% ethyl acetate/
the oxazolidinone 25 (261 mg, 0.802 mmol) in THF (4 mL). light petroleum) gave the title compound 68 (145 mg,
The reaction mixture was slowly heated to reflux and was 71%), Rf = 0.48 (25% ethyl acetate/light petroleum) (Found:
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M+ + NH4, 567.2181, C24H38N2O6F3SSi requires M, 567.2172); trated under reduced pressure to yield the oxazolidinone 77 as
νmax/cm−1 2954, 2932, 2860, 1765, 1667, 1600, 1497, 1470, a yellow oil. Sodium hydride (60% dispersion in paraffin,
1426, 1256, 1214, 1141, 1108, 1067, 929, 842, 780 and 754; δH 422 mg, 10.5 mmol) and benzyl bromide (1.4 mL, 15 mmol)
(400 MHz, CDCl3) −0.04 and 0.01 (each 3 H, s, SiCH3), 0.86 were added to the oxazolidinone 77 in tetrahydrofuran (25 mL)
[9 H, s, SiC(CH3)3], 1.53–1.95 (6 H, m, 3 × CH2), 2.73 (1 H, at 0 °C and the reaction mixture heated under reflux for 6 h.
pent, J 9.0 Hz, 4-CH), 3.60 (2 H, s, 4-CH2), 4.25 and 4.68 (each Saturated aqueous NH4Cl (50 mL) was added and the aqueous
1 H, d, J 15.7 Hz, PhHCH), 4.91 (1 H, s, 5-H), 5.50 and 5.70 phase extracted with ether (3 × 50 mL). The organic extracts
(each 1 H, d, J 4.2 Hz, 2′-H) and 7.26–7.39 (5 H, m, ArH); δC were dried (Na2SO4) and concentrated under reduced pressure.
(100 MHz, CDCl3) −6.1, −6.0, 17.0, 18.0, 22.7, 22.8, 25.6, 38.4, Chromatography of the residue (20% ether/light petroleum)
45.8, 61.8, 68.5, 75.4, 107.5, 118.4 (q, J 320 Hz), 127.4, 127.5, gave the title compound 65 (2.7 g, 78% from 10) as a viscous
128.5, 137.8, 149.2 and 157.4; δF (375 MHz, CDCl3) −69.8; m/z oil, Rf 0.24 (20% ether/light petroleum).
(CI) 567 (M+ + 18, 50%), 550 (M+ + 1, 3) and 225 (100).
(4SR,5SR)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- cyclobutyl-5-[1-(2-phenyloxazol-5-yl)ethenyl]-1,3-oxazolidin-2-
cyclobutyl-5-(1-fur-2-ylethenyl)-1.3-oxazolidin-2-one (65). one (69). n-Butyllithium (2.5 M in THF, 0.45 mL, 1.12 mmol,
(4SR,5SR)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
Lithium chloride (11 mg, 0.27 mmol), CuI (9 mg, 6 eq.) was added to 5-bromo-2-phenyl-1,3-oxazole (235 mg,
0.045 mmol), Pd(PPh3)4 (3 mg, 2.5% mol) and 2-tributyl- 1.05 mmol, 6 eq.) in THF (2 mL) at −18 °C and the resulting
stannylfuran (85 μL, 0.27 mmol) were added to the vinyl tri- suspension was stirred for 45 min. Zinc chloride (0.5 M in
flate 68 (50 mg, 0.09 mmol) in THF (2 mL) and the reaction THF, 2.6 mL, 1.30 mmol, 7.5 eq.) was added and the solution
mixture heated under reflux for 3 h. After concentration under was warmed to rt, stirred for 30 min and then added to the
reduced pressure, chromatography of the residue (light pet- enol triflate 68 (95 mg, 0.173 mmol) and PdCl2(PPh3)2 (12 mg,
roleum to 2% ethyl acetate/light pretroleum) gave the title 0.017 mmol, 10 mol%) in THF (1 mL). After being stirred for
compound 65 (27 mg, 65% yield) as a colourless oil, Rf 0.35 48 h at rt, saturated aqueous NH4Cl (5 mL) was added and the
(50% ether/light petroleum) (Found: M+ + Na, 490.2379. aqueous layer was extracted with ether (3 × 10 mL). The
C27H37O4NNaSi requires M, 490.2384); νmax/cm−1 2928, 2853, organic extracts were dried (MgSO4) and concentrated under
2361, 1754, 1254, 1107 and 837; δH (500 MHz, CDCl3) 0.00 and reduced pressure. Chromatography of the residue (2% to 3%
0.05 (each 3 H, s, SiCH3), 0.99 [9 H, s, SiC(CH3)3], 1.77–2.24 ethyl acetate/light petroleum) gave the title compound 69
(6 H, m, 3 × CH2), 3.11 (1 H, pent, J 9.0 Hz, 4-CH), 3.54 and (34 mg, 80%, 45% conversion), Rf = 0.35 (25% ethyl acetate/
3.69 (each 1 H, d, J 11.0 Hz, 4-HCH), 4.60 and 4.85 (each 1 H, light petroleum) (Found: M+ + H, 545.2844. C32H41N2O4Si
d, J 15.8 Hz, PhHCH), 5.59 and 5.70 (each 1 H, d, J 1.0 Hz, requires M, 545.2835); νmax/cm−1 3064, 3032, 2952, 2930, 2858,
2′-H) 5.99 (1 H, s, 5-H), 6.61 (1 H, dd, J 3.5 Hz, 2.0 Hz, 4″-H), 1756, 1693, 1646, 1470, 1404, 1360, 1255, 1101, 1020, 840 and
6.63 (1 H, d, J 3.5 Hz, 3″-H), 7.41–7.54 (5 H, m, ArH) and 7.59 778; δH (300 MHz, CDCl3) −0.13 and −0.09 (each 3 H, s,
(1 H, d, J 1.5 Hz, 5″-H); δC (125 MHz, CDCl3) −6.2, −6.0, 17.0, SiCH3), 0.81 [9 H, s, SiC(CH3)3], 1.58–2.11 (6 H, m, 3 × CH2),
18.0, 22.7, 22.9, 25.8, 37.8, 45.8, 62.7, 68.5, 76.0, 106.9, 111.5, 2.90 (1 H, pent, J 8.7 Hz, 4-CH), 3.49 and 3.56 (each 1 H, d,
114.6, 127.0, 127.2, 128.3, 132.9, 138.6, 142.1, 152.1 and 158.8; J 11.0 Hz, 4-HCH), 4.41 and 4.71 (each 1 H, d, J 16.0 Hz,
m/z (ES+) 490 (M+ + 23, 100%).
PhHCH), 5.31 (1 H, s, 5-H), 5.69 and 5.89 (each 1 H, s, 2′-H),
n-Butyllithium (1.6 M in hexanes, 180 μL, 0.28 mmol) was 7.25–7.57 (9 H, m, ArH) and 8.05–8.12 (2 H, m, ArH); δC
added to methyltriphenylphosphonium bromide (103 mg, (75 MHz, CDCl3) −6.2, −6.0, 16.9, 18.0, 22.8, 23.1, 25.7, 38.2,
0.28 mmol) in THF (1 mL) and the reaction mixture was 46.0, 62.4, 68.7, 76.4, 116.7, 125.0, 126.4, 126.9, 127.3, 127.4,
stirred at room temperature for 1 h. The ketone 74 (90 mg, 128.4, 128.9, 130.7, 133.3, 138.4, 149.3, 158.7 and 161.3; m/z
0.19 mmol) in THF (0.9 mL) was added dropwise and the reac- (CI) 545 (M+ + 1, 2%), 289 (50) and 181 (100).
tion mixture was stirred at room temperature for 15 minutes.
(4SR,5RS)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobutyl-
Saturated aqueous NH4Cl was added and the aqueous phase 5-ethenyl-1,3-oxazolidin-2-one
was extracted with ethyl acetate. The organic extracts were bromide in tetrahydrofuran (0.7
(70). Ethenylmagnesium
M in THF, 26.3 mL,
dried (MgSO4) and concentrated under reduced pressure. 20.24 mmol) was added to the aldehyde 10 (3.6 g, 9.2 mmol)
Chromatography of the residue (10% ethyl acetate/light pretro- in tetrahydrofuran (92 mL) at −78 °C and the solution was
leum) gave the title compound 65 (75 mg, 85% yield).
stirred for 2 h at −78 °C then for 16 h at rt. Saturated aqueous
n-Butyllithium (1.6 M in hexanes, 10.1 mL, 16.2 mmol) was NH4Cl (50 mL) was added and the solution concentrated
added to the vinyl stannane 76 (6.2 g, 16.2 mmol) in tetra- under reduced pressure. The aqueous residue was extracted
hydrofuran (125 mL) dropwise at −78 °C and the reaction with ether (3 × 50 mL) and organic extracts were dried (MgSO4)
mixture was stirred at this temperature for 10 min. The alde- then concentrated under reduced pressure. Chromatography
hyde 10 (2.9 g, 7.4 mmol) in tetrahydrofuran was added drop- of the residue (25% ether/light petroleum) gave the title com-
wise, stirring was continued at −78 °C for 20 min, the reaction pound 70 (2.6 g, 91%) as a clear oil, Rf 0.6 (25% ether/light pet-
mixture was allowed to warm to room temperature, and stir- roleum) (Found: M+ + Na, 334.1812. C16H29O3NNaSi requires
ring was continued for 16 h. Saturated aqueous NH4Cl (50 mL) M, 334.1809); νmax/cm−1 3210, 3132, 2951, 2930, 2858, 1749,
was added and the aqueous layer was extracted with ether (3 × 1472, 1464, 1429, 1370, 1290, 1256, 1108, 1070, 1023, 990, 940
50 mL). The organic extracts were dried (Na2SO4) and concen- and 838; δH (500 MHz, CDCl3) 0.00 and 0.01 (each 3 H, s,
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SiCH3), 0.84 [9 H, s, SiC(CH3)3], 1.67–2.10 (6 H, m, 3 × CH2), mixture was stirred at −78 °C for 5 h, and then saturated
2.50 (1 H, m, 4-CH), 3.36 and 3.39 (each 1 H, d, J 10.5 Hz, aqueous NH4Cl (5 mL) was added. The mixture was concen-
4-HCH), 4.51 (1 H, d, J 7.0 Hz, 5-H), 5.27 (1 H, d, J 10.5 Hz, trated under reduced pressure and the residue extracted with
2′-H), 5.34 (1 H, d, J 17.0 Hz, 2′-H′), 5.95 (1 H, ddd, J, 17.0, ether (3 × 5 mL). The organic extracts were dried (Na2SO4) and
10.5, 6.0 Hz, 1′-H) and 6.42 (1 H, s, NH); m/z (ES−) 310 (M+ − 1, concentrated under reduced pressure. Chromatography of the
100%).
residue (20% ether/light petroleum) gave the alcohol 73
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- (110 mg, 60%) as a mixture of diastereoisomers. Data for the
cyclobutyl-5-ethenyl-1,3-oxazolidin-2-one (71). Sodium hydride less polar title compound 73a, Rf 0.52 (50% ether/light pet-
(60% dispersion in paraffin, 120 mg, 3 mmol) and benzyl roleum) (Found: M+ + H, 472.2505. C26H38O5NSi requires M,
bromide (0.47 mL, 4 mmol) were added at 0 °C to the oxazoli- 472.2514); νmax/cm−1 3385, 2956, 2858, 2351, 2336, 1728, 1411,
dinone 70 (615 mg, 1.97 mmol) in tetrahydrofuran (15 mL) 1256, 1106 and 838; δH (500 MHz, CDCl3) −0.01 and 0.00 (each
and the reaction mixture was heated under reflux for 6 h. Satu- 3 H, s, SiCH3), 0.83 [9 H, s, SiC(CH3)3], 1.54–2.16 (6 H, m, 3 ×
rated aqueous NH4Cl (50 mL) was added and the solution con- CH2), 2.70 (1 H, m, 4-CH), 3.46 (1 H, d, J 4.5 Hz, OH), 3.58 and
centrated under reduced pressure. The residue was extracted 3.66 (each 1 H, d, J 11.4 Hz, 4-HCH), 4.33 and 4.42 (each 1 H,
with ether (3 × 50 mL) and the organic extracts were dried d, J 16.0 Hz, PhHCH), 4.67 (1 H, d, J 8.8 Hz, 5-H), 5.07 (1 H,
(Na2SO4) and concentrated under reduced pressure. Chromato- dd, J 8.8, 4.5 Hz, 5-CH), 6.34 (1 H, dd, J 3.2, 1.5 Hz, 4′-H), 6.38
graphy of the residue (light petroleum to 40% ether/light pet- (1 H, d, J 3.2 Hz, 3′-H), 7.21–7.32 (5 H, m, ArH) and 7.4 (1 H, d,
roleum) gave the title compound 71 (670 mg, 86%) as a J 1.5 Hz, 5′-H); δC (125 MHz, CDCl3) −6.0(2), 17.5, 18.0, 23.2,
viscous oil, Rf 0.25 (15% ether/light petroleum) (Found: M+ + 23.3, 25.7, 39.4, 45.4, 62.3, 66.0, 68.1, 78.0, 108.7, 110.5, 127.6,
Na, 424.2281. C23H35O3NNaSi requires M, 424.2278); νmax
/
127.8, 128.6, 138.5, 142.5, 152.8 and 158.2; m/z (ES−) 470.3
cm−1 2929, 1752, 1402, 1252, 1108, 838 and 777; δH (500 MHz, (M+ − 1, 100%). Data for the more polar title compound 73b Rf
CDCl3) 0.00 (6 H, s, 2 × SiCH3), 0.87 [9 H, s, SiC(CH3)3], 0.37 (50% ether/light petroleum) (Found: M+ + Na, 494.2327.
1.29–1.87 (6 H, m, 3 × CH2), 2.52 (1 H, m, 4-CH), 3.49 (2 H, s, C26H37O5NNaSi requires M, 494.2333); νmax/cm−1 3375, 2956,
4-CH2), 4.03 and 4.65 (each 1 H, d, J 15.8 Hz, PhHCH), 4.82 2853, 2367, 2326, 1742, 1403, 1259, 1096 and 838; δH
(1 H, d, J 7.6 Hz, 5-H), 5.36 (1 H, d, J, 10.5 Hz, 2′-H), 5.48 (1 H, (500 MHz, CDCl3) 0.00 and 0.01 (each 3 H, s, SiCH3), 0.85 [9 H,
d, J 16.0 Hz, 2′-H′), 6.04 (1 H, ddd, J 18.0, 9.8, 7.6 Hz, 1′-H) and s, SiC(CH3)3], 1.38–1.82 (6 H, m, 3 × CH2), 2.29 (1 H, m, 4-CH),
7.2–7.35 (5 H, m, ArH); δC (125 MHz, CDCl3) −5.8, 17.5, 18.0, 3.22 (1 H, d, J 4.5 Hz, OH), 3.64 and 3.66 (each 1 H, d, J 11.4
22.6, 25.7, 38.2, 45.3, 61.7, 67.8, 79.8, 120.8, 127.3, 127.8, Hz, 4-HCH), 4.13 and 4.57 (each 1 H, d, J 16.0 Hz, PhHCH),
128.4, 132.6, 138.5 and 158.9; m/z (ES+) 424 (M+ + 23, 100%).
4.69 (1 H, d, J 4.5 Hz, 5-H), 5.12 (1 H, t, J 4.5 Hz, 5-CH), 6.34
(4RS,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- (1 H, dd, J 3.2, 1.6 Hz, 4′-H), 6.40 (1 H, d, J 3.2 Hz, 3′-H),
cyclobutyl-5-formyl-1,3-oxazolidin-2-one (72). A mixture of O2 7.18–7.30 (5 H, m, ArH) and 7.36 (1 H, d, J 1.0 Hz, 5′-H); δC
and O3 were bubbled through a solution of the alkene 71 (125 MHz, CDCl3) −5.9, −5.8, 17.3, 18.0, 22.8, 23.0, 25.7, 39.2,
(1.87 g, 4.65 mmol) in dichloromethane (50 mL) at −78 °C 45.3, 61.7, 66.2, 67.4, 78.7, 108.3, 110.7, 127.4, 127.5, 128.5,
until the solution assumed a pale blue colour. Triphenyl- 138.1, 142.3, 152.7 and 158.4; m/z (ES−) 470.4 (M+ − 1, 100%).
phosphine (1.36 g, 5.56 mmol) was added immediately and
(4RS,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
reaction mixture was stirred at rt for 3 h. After concentration cyclobutyl-5-furoyl-1,3-oxazolidin-2-one (74). Tetrapropyl per-
under reduced pressure, chromatography of the residue (25% ruthenate (102 mg, 0.29 mmol) was added to a mixture of the
ether/light petroleum to neat ether) gave the title compound epimeric alcohols 73 (1.37 g, 2.9 mmol), N-methylmorpholine
72 (1.7 g, 90%), Rf 0.1 (20% ether/light petroleum) (Found: N-oxide (512 mg, 4.4 mmol) and 4 Å molecular sieves (1.4 g) in
M+ + H, 404.2258. C23H34O4NSi requires M, 404.2252); νmax
/
dichloromethane (29 mL) and the reaction mixture was stirred
cm−1 2929, 2854, 2357, 1755, 1738, 1406, 1101 and 838; δH for 2 h at rt. After filtering through Celite, the filtrate was con-
(500 MHz, CDCl3) 0.00 and 0.01 (each 3 H, s, SiCH3), 0.89 [9 H, centrated under reduced pressure and chromatography of the
s, SiC(CH3)3], 1.20–2.06 (6 H, m, 3 × CH2), 2.39 (1 H, m, 4-CH), residue (light petroleum to 20% ether/light petroleum) gave
3.42 and 3.49 (each 1 H, d, J 11.0 Hz, 4-HCH), 3.94 (1 H, d, title compound 74 (1.21 g, 85%) as a colourless oil, Rf 0.47
J 15.5 Hz, PhHCH), 4.65 (1 H, d, J 1.0 Hz, 5-H), 4.71 (1 H, d, (50% ether/light petroleum) (Found: M+ + Na, 492.2175.
J 15.5 Hz, PhHCH), 7.26–7.38 (5 H, m, ArH) and 9.82 (1 H, d, C26H35O5NNaSi requires M, 492.2177); νmax/cm−1 2929, 2853,
J 1.0 Hz, CHO); δC (125 MHz, CDCl3) −5.8, 17.3, 17.9, 22.4, 1755, 1664, 1464, 1409, 1254, 1104, 838 and 777; δH (500 MHz,
25.6, 37.0, 44.9, 59.3, 72.6, 78.6, 127.8, 128.2, 128.6, 137.5, CDCl3) 0.00 and 0.09 (each 3 H, s, SiCH3), 0.90 [9 H, s, SiC
157.9 and 199.9; m/z (ES−) 402 (M+ − 1, 100%).
(CH3)3], 1.51–2.44 (6 H, m, 3 × CH2), 2.72 (1 H, m, 4-CH), 3.77
(4SR,5SR)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- and 3.97 (each 1 H, d, J 11.4 Hz, 4-HCH), 4.42 and 5.02 (each
cyclobutyl-5-(fur-2-ylhydroxymethyl)-1,3-oxazolidin-2-one (73). 1 H, d, J 15.8 Hz, PhHCH), 5.35 (1 H, s, 5-H), 6.80 (1 H, dd,
n-Butyllithium (1.6 M in hexanes, 0.73 mL, 1.2 mmol) was J 3.5, 2.0 Hz, 4′-H), 7.50–7.63 (5 H, m, ArH), 7.89 (1 H, d, J 2.0
added to furan (85 μL, 1.2 mmol) in tetrahydrofuran (2.4 mL) Hz, 5′-H) and 7.95 (1 H, d, J 3.5 Hz, 3′-H); δC (125 MHz, CDCl3)
at −78 °C. The reaction mixture was warmed to rt and stirred −6.2, −6.0, 17.2, 18.0, 22.7, 22.9, 25.5, 38.6, 45.1, 59.9, 71.7,
for 1.5 h, then cooled to −78 °C and the aldehyde 72 (157 mg, 78.0, 112.6, 122.3, 127.6, 128.0, 128.5, 137.8, 147.0, 150.6,
0.39 mmol) in tetrahydrofuran (1.2 mL) was added. The 157.8 and 184.1; m/z (ES+) 492 (M+ + 23, 100%).
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1-(Fur-2-yl)ethenyl(tributyl)stannane (76). n-Butyllithium in 45.8, 59.7, 64.1, 69.7, 77.6, 108.3, 110.9, 127.0, 127.1, 128.5,
hexanes (1.6 M in hexanes, 31.2 mL, 50 mmol) was added 138.3, 142.0, 152.2 and 159.3.
dropwise to di-isopropylamine (7.1 mL, 50 mmol) in tetra-
(4RS,5SR)-3-Benzyl-4-hydroxymethyl-4-cyclobutyl-5-(1-fur-2-
hydrofuran (244 mL) at 0 °C and the solution was stirred for yl-2-hydroxyethyl)-1,3-oxazolidin-2-ones (80) and (81). Tetra-
30 min. Tributyltin hydride (12.2 mL) was added dropwise and butylammonium fluoride (1 M in THF, 155 μL, 0.155 mmol)
the solution was stirred for a further 30 min. Furyl methyl was added to a mixture of the silyl ethers 78 and 79 (63 mg,
ketone 75 (5.0 g, 45.4 mmol) in tetrahydrofuran (9.1 mL) was 0.13 mmol) in THF (0.5 mL) at 0 °C and the mixture stirred at
added and the solution was warmed to rt and stirred until rt for 30 min. Brine was added and the mixture was extracted
judged complete by TLC (ca. 1 h). Mesyl chloride (14.8 mL, with ethyl acetate. The organic extracts were dried (MgSO4)
182 mmol) and triethylamine (47 mL, 340 mmol) were added and concentrated under reduced presure. Chromatography of
and the reaction mixture stirred at rt overnight. The mixture the residue (60% ethyl acetate/light petroleum) gave the the
was dissolved in MeCN (500 mL) and extracted with pentane title compound 80 (30 mg, 62%) as an oil, Rf 0.28 (60% ethyl
(3
× 500 mL). The pentane extracts were concentrated acetate/light petroleum); δH (500 Mz, CDCl3) 1.50 (2 H, br. s,
under reduced pressure and chromatography of the residue 2 × OH), 1.50–2.00 (6 H, m, 3 × CH2), 2.92 (1 H, pent. J 7.0 Hz,
(pentane) gave the title compound 76 (8.4 g, 59%) a mobile 4-CH), 3.34 (1 H, m, 1′-H), 3.55 and 3.44 (each 1 H, d, J 14.1
yellow oil that was used without delay, Rf 0.95 (pentane); δH Hz, 4-HCH), 3.79 (1 H, dd, J 9.0, 4.7 Hz, 2′-H), 3.92 (1 H, t, J 9.0
(300 MHz, CDCl3) 0.90 (9 H, t, J 7.0 Hz, 3 × CH3), 1.05 (6 H, m, Hz, 2′-H′), 4.12 and 4.44 (each 1 H, d, J 16.8 Hz, PhHCH), 4.97
3 × CH2), 1.35 (6 H, pent, J 7.0 Hz, 3 × CH2), 1.45–1.62 (6 H, m, (1 H, s, 5-H), 6.35 and 6.38 (each 1 H, narrow m, 3″-H and
3 × CH2), 5.22 (1 H, d, J 2.5 Hz, 2-H), 6.15 (1 H, d, J 3.5 Hz, 4″-H), 6.94 (2 H, m, ArH), 6.94–7.23 (3 H, m, ArH) and 7.30
3′-H), 6.19 (1 H, d, J 2.5 Hz, 2-H′), 6.28 (1 H, dd, J 3.5, 1.8 Hz, (1 H, s, ArH); m/z (ES+) 394 (M+ + 23, 100%). The second frac-
4′-H) and 7.27 (1 H, d, J 1.8 Hz, 5′-H); δC (125 MHz, CDCl3) tion was the title compound 81 (12 mg, 28%) as an oil, Rf 0.13
10.1, 13.7, 27.5, 28.9, 106.0, 111.2, 122.6, 139.8, 141.4 and (60% ethyl acetate/light petroleum); δH (500 Mz, CDCl3)
158.6.
1.30–1.80 (6 H, m, 3 × CH2), 2.08 (1 H, pent. J 7.0 Hz, 4-CH),
(4RS,5SR)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 3.29 and 3.44 (each 1 H, d, J 14.1 Hz, 4-HCH), 3.78 (1 H, m,
cyclobutyl-5-(1-fur-2-yl-2-hydroxyethyl)-1,3-oxazolidin-2-ones 1′-H), 3.92 and 3.98 (each 1 H, dd, J 9.0, 13.0 Hz, 2′-H),
(78) and (79). Borane in THF (1 M, 3.85 mL, 3.85 mmol) was 4.34 and 4.47 (each 1 H, d, J 17.1 Hz, PhHCH), 4.69 (1 H, d,
added to the alkene 65 (600 mg, 1.28 mmol) in CH2Cl2 J 10.7 Hz, 5-H), 6.21 and 6.27 (each 1 H, narrow m, 3″-H and
(3.5 mL) at 0 °C. The mixture allowed to warm at room temp- 4″-H) and 7.20–7.39 (6 H, m, ArH); m/z (ES+) 394 (M+ + 23,
erature, stirred 3 h, then was cooled to 0 °C and NaBO3·4H2O 100%).
(590 mg, 3.84 mmol) and water were added carefully. The
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-(1-fur-2-ylethenyl)-4-hydroxy-
mixture was stirred at rt overnight and then the aqueous phase methyloxazolidin-2-one (82). Tetrabutylammonium fluoride
was extracted with ethyl acetate and the organic extracts were (1 M in THF, 0.24 mL, 0.24 mmol) was added to the silyl ether
dried (MgSO4). After concentration under reduced pressure, 65 (108 mg, 0.23 mmol) in tetrahydrofuran (2.3 mL) at rt and
chromatography of the residue (light petroleum to 20% ethyl the solution stirred for 1 h. Saturated aqueous NH4Cl (5 mL) was
acetate/light petroleum) gave a mixture of the title compounds added and the mixture concentrated under reduced pressure.
78 and 79 (390 mg, 60%), 78 : 79 = 2 : 1 (1H NMR), Rf 0.20 (20% The residue was extracted with ether (4 × 5 mL) and the
ethyl acetate/light petroleum); νmax/cm−1 3420, 2953, 2930, organic extracts were dried (Na2SO4) and concentrated under
2858, 1738, 1732, 1411, 1361, 1257, 1104, 1072, 836, 778 and reduced pressure. Chromatography of the residue (50% ether/
733; δH (500 MHz, CDCl3) major isomer 78 −0.17 and −0.19 light petroleum) gave the title compound 82 (82 mg, ca. 100%)
(each 3 H, s, SiCH3), 0.81 [9 H, s, OSi(CH3)3], 1.46–2.00 (6 H, as a viscous oil, Rf 0.12 (50% ether/light petroleum) (Found:
m, 3 × CH2), 2.08 (1 H, br. s, OH), 3.03 (1 H, pent, J 8.8 Hz, M+ + Na, 376.1529. C21H23O4NNa requires M, 376.1519); νmax
/
4-CH), 3.39 (1 H, d, J 10.4 Hz, 4-HCH), 3.43 (1 H, m, 1′-H), 3.46 cm−1 3427, 2944, 2361, 1750, 1495, 1435, 1409, 1358, 1289,
(1 H, d, J 10.4 Hz, 4-HCH), 3.83 (1 H, dd, J 6.3, 10.7 Hz, 2′-H), 1149, 1063, 1017, 918, 885 and 744; δH (500 MHz, CDCl3) 1.26
3.98 (1 H, m, 2′-H′), 4.16 and 4.53 (each 1 H, d, J 15.8 Hz, (1 H, br. s, OH), 1.53–1.98 (6 H, m, 3 × CH2), 2.75 (1 H, pent,
PhHCH), 5.06 (1 H, d, J 1.3 Hz, 5-H), 6.40 (2 H, narrow m, 3″-H J 9 Hz, 4-CH), 3.29 and 3.34 (each 1 H, dd, J 12.5, 4.0 Hz,
and 4″-H), 6.87–6.89 (2 H, m, ArH), 7.15–7.18 (3 H, m, ArH) 4-HCH), 4.45 and 4.49 (each 1 H, d, J 16.5 Hz, PhHCH), 5.32
and 7.34 (1 H, m, ArH); minor isomer 79 −0.09 and −0.14 (1 H, s, 5-H), 5.39 and 5.73 (each 1 H, s, 2′-H), 6.34 (1 H, dd,
(3 H, s, SiCH3), 0.93 [9 H, s, Si(CH3)3], 3.54 (1 H, d, J 11.3 Hz, J 3.5, 2.0 Hz, 4″-H), 6.41 (1 H, d, J 3.5 Hz, 3″-H), 7.17–7.32 (5 H,
4-HCH), 3.68 (1 H, m, 1′-H), 3.72 (1 H, d, J 11.3 Hz, 4-HCH), m, ArH) and 7.33 (1 H, d, J 1.5 Hz, 5″-H); δC (125 MHz, CDCl3)
3.94–4.00 (2 H, m, 2′-H, PhHCH), 4.04 (1 H, dd, J 4.7, 11.0 Hz, 17.2, 22.8, 22.9, 38.2, 45.7, 61.8, 68.7, 76.1, 107.4, 111.6, 114.2,
2′-H′), 4.64 (1 H, d, J 10.7 Hz, 5-H), 4.84 (1 H, d, J 16.1 Hz, 127.6, 128.7, 133.6, 138.4, 142.5, 151.6 and 158.8; m/z (ES+) 371
PhHCH), 6.26 (1 H, d, J 3.1 Hz, 3″-H) and 6.37 (1 H, dd, J 2.2, (M+ + 18, 100%).
3.1 Hz, 4″-H); δC (75 MHz, CDCl3) major isomer 78 −6.1, 17.4,
18.1, 22.6, 23.5, 25.8, 39.4, 41.9, 45.2, 63.6, 63.9, 66.2, 75.0, 2-enylamino)methyl-1,3-oxazolidin-2-one
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-(1-fur-2-ylethenyl)-4-(prop-
(84). The Dess–
108.8, 111.2, 126.9, 127.4, 128.3, 138.0, 141.3, 150.9 and 158.4; Martin periodinane (70 mg, 0.17 mmol) was added to the
minor isomer 79 −5.8, −5.6, 16.8, 17.8, 22.8, 25.6, 37.7, 41.4, alcohol 82 (39 mg, 0.11 mmol) in dichloromethane (1.1 mL) at
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rt and the solution was stirred for 2 h. Concentration under br. s, NH2), 1.47–1.99 (6 H, m, 3 × CH2), 2.51 (2 H, s, 4-CH2),
reduced pressure gave the aldehyde 83 (31 mg, 80%), Rf 0.46 2.74 (1 H, pent, J 8.8 Hz, 4-CH), 4.43 and 4.50 (each 1 H, d, J
(50% ether/light petroleum) (Found: M+ + Na, 374.1369. 15.9 Hz, PhHCH), 5.29 and 5.41 (each 1 H, s, 2′-H), 5.72 (1 H,
C21H21O4NNa requires M, 374.1363); νmax/cm−1 2924, 2846, s, 5-H), 6.34 (1 H, dd, J 3.2, 1.9 Hz, 4″-H), 6.40 (1 H, d, J 3.2 Hz,
1760, 1732, 1393, 1287, 1059, 1018, 920 and 807; δH (500 MHz, 3″-H) and 7.16–7.34 (6 H, m, ArH); δC (125 MHz, CDCl3) 17.2,
CDCl3) 1.40–2.05 (6 H, m, 3 × CH2), 2.90 (1 H, m, 4-CH), 4.31 23.2, 23.4, 30.6, 39.7, 43.0, 45.9, 69.4, 107.6, 111.8, 114.4,
amd 4.45 (each 1 H, d, J 15.0 Hz, PhHCH), 5.35 and 5.40 (each 127.7, 127.8, 128.8, 134.2, 138.7, 142.6, 152.1 and 159.3; m/z
1 H, s, 2′-H), 5.72 (1 H, s, 5-H), 6.30 and 6.34 (each 1 H, s, 3″-H (ES+) 375 (M+ + 23, 100%).
and 4″-H), 7.15–7.30 (6 H, m, ArH) and 8.90 (1 H, s, CHO); δC
(125 MHz, CDCl3) 18.1, 22.7, 23.4, 37.1, 46.3, 73.1, 75.9, 108.6, nitrophenylsulfonylamino)methyl-1,3-oxazolidin-2-one
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-(1-fur-2-ylethenyl)-4-(2-
(86).
111.7, 114.8, 128.1, 128.3, 128.7, 131.8, 137.0, 142.8, 150.0, 2-Nitrophenylsulfonyl chloride (830 mg, 3.7 mmol) was added
158.1 and 197.3; m/z (ES+) 374 (M+ + 23, 100%) and 352 to the amine 85 (1.2 g, 3.4 mmol) and triethylamine (0.47 mL)
(M+ + 1, 40).
in DCM (7.5 mL) and the solution stirred at rt for 2 h. After
This aldehyde 83 was taken up in dry dichloromethane concentration under reduced presure, chromatography of the
(0.3 mL), prop-2-enylamine (12 μL, 1.52 mmol) and oven dried residue (light petroleum to ether) gave the title compound 86
MgSO4 (44 mg, 0.36 mmol) were added, and the mixture was (1.4 g, 76%) as an oil, Rf 0.38 (ether) (Found: M+ + H, 538.1650.
stirred under reflux for 16 h. After filtration through Celite and C27H28N3O7S requires M, 538.1642); νmax/cm−1 3335, 2948,
concentration of the filtrate under reduced pressure, the 2359, 1754, 1542, 1402, 1363, 1257, 1176, 1069, 907 and 734;
residue was immediately dissolved in methanol (0.6 mL) and δH (500 MHz, CDCl3) 1.50–2.00 (6 H, m, 3 × CH2), 2.75–2.85
acetic acid (6.2 μL, 0.106 mmol) and NaCNBH3 (1 M in THF, (3 H, m, 4-CH and 4-CH2), 4.40 and 4.55 (each 1 H, d, J 16.5
122 μL, 0.122 mmol) were added. The reaction mixture was Hz, PhHCH), 5.15 (1 H, m, NH), 5.34 and 5.47 (each 1 H, s,
stirred at rt for 1 h and then saturated aqueous NaHCO3 2′-H), 5.78 (1 H, s, 5-H), 6.28 and 6.37 (each 1 H, narrow m,
(5 mL) was added. The aqueous mixture was extracted with 3″-H and 4″-H), 7.15–7.35 (6 H, m, ArH), 7.52 (1 H, m, ArH),
ether (5 × 5 mL) and the organic extracts were dried (MgSO4) 7.55–7.65 (2 H, m, ArH) and 7.72 (1 H, d, J 7.0 Hz, ArH); δC
and concentrated under reduced pressure. Chromatography of (75 MHz, CDCl3) 17.2, 23.1, 23.5, 39.9, 45.1, 45.7, 53.7, 67.9,
the residue (20% ether/light petroleum) gave the title com- 108.2, 112.0, 115.9, 125.6, 128.0, 129.1, 131.0, 132.9, 133.0,
pound 84 (25 mg, 56%) as a white foam that slowly crystal- 133.7, 134.0, 138.3, 143.0, 148.0, 151.2 and 158.3; m/z (ES+) 560
llised from ether, Rf 0.51 (50% ether/light petroleum) (Found: (M+ + 23, 100%).
M+ + H, 393.2170. C24H29O3N2 requires M, 393.2173); νmax
/
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-(1,2-dihydroxy-1-fur-2-
cm−1 3343, 2945, 2359, 2341, 1744, 1644, 1495, 1456, 1404, ylethyl)-4-(2-nitrophenylsulfonylamino)methyl-1,3-oxazoli-
1360, 1287, 1149, 1061, 1017, 919, 806 and 744; δH (500 MHz, din-2-one (87). The alkene 86 (120 mg, 0.33 mmol) was added
CDCl3) 1.47–1.95 (6 H, m, 3 × CH2), 2.23 and 2.37 (each 1 H, d, to osmium tetraoxide (9 mg) and N-methylmorpholine-N-oxide
J 13.5 Hz, 4-HCH), 2.72 (3 H, m, 4-CH and 1′-H2), 4.41 and 4.54 (118 mg, 1.0 mmol) in water (2.1 mL) and acetone 5.3 mL) and
(each 1 H, d, J 15.8 Hz, PhHCH), 4.86 (1 H, dd, J 16.5, 1.6 Hz, the mixture was stirred at rt for 16 h. An excess of saturated
3′-H), 4.87 (1 H, dd, J 10.0, 1.6 Hz, 3′-H′), 5.28 (1 H, s, 2″-H), aqueous sodium sulfite was added and the mixture partitioned
5.38 (1 H, s, 2″-H′), 5.52 (1 H, ddt, J 16.5, 10.0, 6.0 Hz, 2′-H), between water and ethyl acetate. The organic extracts were
5.70 (1 H, s, 5-H), 6.33 (1 H, dd, J 3.5, 1.5 Hz, 4′′′-H), 6.37 (1 H, dried (Na2SO4) and concentrated under reduced presure.
d, J 3.5 Hz, 3′′′-H) and 7.14–7.32 (6 H, m, ArH); δC (125 MHz, Chromatography of the residue (light petroleum to ether) gave
CDCl3) 17.1, 23.2, 23.4, 39.9, 46.0, 50.0, 53.0, 68.5, 76.9, 107.3, the title compound 87 (898 mg, 64%) as an oil, Rf 0.27 (ether)
111.8, 114.3, 115.9, 127.5, 127.8, 128.7, 134.1, 136.7, 138.9, (Found: M+ + Na, 594.1517. C27H29N3O9NaS requires M,
142.4, 152.3 and 159.1; m/z (ES+) 393 (M+ + 1, 100%).
(4RS,5SR)-4-Aminomethyl-3-benzyl-4-cyclobutyl-5-(1-fur-2- CH2), 2.40 (1 H, br. d, J 12.0 Hz, 4-HCH), 2.82 (1 H, dd, J 12.0,
ylethenyl)-1,3-oxazolidin-2-one (85). Tetrakis-triphenyl- 9.0 Hz, 4-HCH), 3.05 (1 H, pent, J 7.0 Hz, 4-CH), 3.45 (2 H, br.
594.1517); δH (500 MHz, DMSO-d6) 1.80–2.25 (6 H, m, 3 ×
phosphine palladium (2.5 mg, 1 mol%) was added to the pro- s, 2 × OH), 3.45 and 3.98 (each 1 H, d, J 10.0 Hz, 2′-H), 4.18
penylamine 84 (82 mg, 0.23 mmol) and 1,3-dimethylbarbituric and 4.54 (each 1 H, d, J 15.5 Hz, PhHCH), 4.98 (1 H, s, 5-H),
acid (99 mg, 0.69 mmol) in dichloromethane (0.5 mL) at rt 5.91 and 6.14 (each 1 H, narrow m, 3″-H and 4″-H), 7.03 (2 H,
and the reaction mixture was stirred at 35 °C for 2 h. Saturated d, J 7.0 Hz, ArH), 7.18 (1 H, br. d, J 7.0 Hz, ArH), 7.25–7.35
aqueous NaHCO3 (5 mL) and ether (5 mL) were added and the (3 H, m, ArH), 7.40 (1 H, s, 5″-H), 7.75 and 7.94 (each 1 H,
aqueous layer was extracted with ether (3 × 5 mL). The organic t J 7.0 Hz, ArH) and 8.12 (1 H, d, J 7.2 Hz, ArH); δC (100 MHz,
extracts were dried (Na2SO4) then concentrated under reduced DMSO-d6) 17.1, 22.2, 23.7, 41.4, 43.8, 45.6, 66.0, 66.3, 74.5,
pressure. Chromatography of the residue (70% ether/light 75.8, 107.1, 110.1, 125.0, 127.0, 128.3, 129.5, 130.9, 132.7,
petroleum) gave the title compound 85 (48 mg, 74%) as a 134.4, 138.3, 142.3, 147.1, 153.8 and 156.7; m/z (ES+) 594
white foam, Rf 0.31 (ether) (Found: M+ + H, 353.1857. (M+ + 23, 100%).
C21H25O3N2 requires M, 353.1860); νmax/cm−1 3407, 2943,
(3aRS,6aRS)-3-Benzyl-3a-cyclobutyl-6-fur-2-yl-6-hydroxymethyl-5-
2868, 2360, 2342, 1739, 1622, 1496, 1404, 1359, 1286, 1163, (2-nitrophenylsulfonyl)hexahydro-2H-pyrrolo[3,4-d]oxazol-2-one
1061, 1018, 913, 807 and 704; δH (500 MHz, CDCl3) 0.77 (2 H, (89). Di-isopropyl diazodicarboxylate (1.8 μL, 9.1 μmol) was
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added the diol 87 (4 mg, 7 μmol) and triphenylphosphine gave the alcohols 78 and 79 (60 mg, 65%), ratio ca. 1 : 1, Rf 0.24
(2.5 mg, 9.1 μmol) in tetrahydrofuran (70 μL) at rt and the solu- (40% ethyl acetate/light petroleum).
tion was stirred for 16 h and then concentrated under reduced
Trimethylsilylethoxymethyl chloride (0.8 mL, 4.36 mmol),
pressure. Chromatography of the residue (5–10% ether/light 4-dimethylaminopyridine (18 mg, 0.015 mmol), tetrabutyl-
petroleum) gave the title compound 89 (3 mg, 75%) as a pale ammonium iodide (54 mg, 0.015 mmol) and di-isopropyl-
oil, Rf 0.43 (ether) (Found: M+ + H, 554.1599. C27H28O8N3S ethylamine (1.5 mL, 8.7 mmol) were added to a mixture of the
requires M, 554.1592); νmax/cm−1 3343, 2955, 2356, 1742, 1544, alcohols 78 and 79 (706 mg, 1.45 mmol) in dichloromethane
1410, 1360, 1164, 1068, 986, 912, 852 and 734; δH (400 MHz, (15 mL) and the mixture was stirred at room temperature for
CDCl3) 1.19–1.70 (6 H, m, 3 × CH2), 2.55 (1 H, m, 3a-CH), 3.79 16 h. Saturated aqueous NH4Cl (50 mL) was added and the
(1 H, t, J 7.5 Hz, OH), 3.63 and 3.85 (each 1 H, d, J 11.9 Hz, aqueous layer was extracted with ether (3 × 15 mL). The
4-H), 4.15 (1 H, d, J 15.6 Hz, PhHCH), 4.35 and 4.42 (each 1 H, organic extracts were dried (MgSO4) and concentrated under
dd, J 12.6, 7.3 Hz, 6-HCH), 4.43 (1 H, d, J 15.6 Hz, PhHCH), reduced pressure. Chromatography of the residue (20% ether/
5.03 (1 H, s, 6a-H), 6.18 (1 H, dd, J 3.3, 1.8 Hz, 4″-H), 6.40 (1 H, light petroleum) gave the SEM-ethers 93 and 94 (889 mg, 99%)
dd, J 3.5, 0.8 Hz, 3″-H), 7.06 (1 H, dd, J 1.8, 0.8 Hz, 5″-H), as a yellow oil a ca. 1 : 1 mixture, Rf 0.80 (50% ether/light
7.19–7.29 (5 H, m, ArH), 7.42–7.60 (3 H, m, ArH) and 7.67 (1 H, petroleum).
dd, 8.1, 1.3 Hz, ArH); m/z (ES+) 576 (M+ + 23, 100%) and 554
Tetrabutylammonium fluoride (1 M in THF, 0.87 mL,
8.7 mmol) was added to a mixture of the protected diols 93
(M+ + 1, 70).
(1RS,2RS,6SR)-7-Benzyl-6-cyclobutyl-2-fur-2-yl-2-hydroxy-4-(2- and 94 (369 mg, 0.58 mmol) in tetrahydrofuran (6 mL) and the
nitrophenylsulfonyl)-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one solution was stirred for 16 h. Saturated aqueous NH4Cl (5 mL)
(90). Methanesulfonyl chloride (4.8 μL, 0.063 mmol) was was added and the mixture was concentrated under reduced
added to the diol 87 (34 mg, 0.06 mmol) in pyridine (0.5 mL) pressure. The mixture was extracted with ether (3 × 5 mL) and
at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. the organic extracts were dried (Na2SO4). Chromatography of
Water (5 mL) was added and the mixture extracted with ethyl the residue gave gave the title compound 95 (127 mg, 43%) as
acetate (4 × 5 mL). Concentration under reduced pressure gave a yellow oil, Rf 0.84 (ether); νmax/cm−1 3431, 2952, 2351, 1724,
the mesylate 88 as a pale yellow oil that was immediately dis- 1412, 1249, 1059, 836 and 703; δH (500 MHz, CDCl3) 0.00 [9 H,
solved in DMF (0.4 mL) and K2CO3 (10 mg, 0.07 mmol) was s, Si(CH3)3], 0.90–0.95 (2 H, m, CH2Si), 1.06 (1 H, br. s, OH),
added. The reaction mixture was warmed to 45 °C for 1.5 h 1.68–2.03 (6 H, m, 3 × CH2), 2.96 (1 H, pent, J 8.8 Hz, 4-CH),
then added to ethyl acetate (10 mL). The organic layer was 3.41 (1 H, d, J 12.0 Hz, 4-HCH), 3.45 (1 H, dd, J 9.8, 5.7 Hz, 1′-
washed with saturated aqueous NaHCO3 (3 mL) and water (2 × H), 3.49 (1 H, d, J 12.0 Hz, 4-HCH), 3.59 (2 H, m, OCH2CH2Si),
3 mL) than concentrated under reduced pressure. Chromato- 3.67 (1 H, dd, J 9.6, 5.7 Hz, 2′-H), 3.86 (1 H, t, J 9.8 Hz, 2′-H′),
graphy of the residue gave the title compound 90 (14 mg, 42%) 4.15 and 4.49 (each 1 H, d, J 16.1 Hz, PhHCH), 4.69 (2 H, s,
as a yellow syrup, Rf 0.58 (ether) (Found: M+ + H, 554.1586. OCH2O), 5.00 (1 H, s, 5-H), 6.39 (1 H, dd, J 2.8, 1.9 Hz, 4″-H),
C27H28O8N3S requires M, 554.1592); δH (400 MHz, CDCl3) 6.43 (1 H, d, J 3.0 Hz, 3″-H), 6.94–6.99 (2 H, m, ArH), 7.17–7.22
1.41–1.89 (6 H, m, 3 × CH2), 2.54 (1 H, m, 6-CH), 3.30 (1 H, d, (3 H, m, ArH) and 7.33 (1 H, m, 5″-H); δC (125 MHz, CDCl3)
J 12.9 Hz, 5-H), 3.49 (1 H, d, J 12.6 Hz, 3-H), 3.59 (1 H, d, J 12.9 0.00, 19.0, 19.5, 24.2, 24.7, 40.1, 41.2, 46.4, 63.6, 66.9, 67.8,
Hz, 5-H′), 3.60 (1 H, dd, J 12.6, 1.5 Hz, 3-H′), 3.79 (1 H, d, J 1.5 69.9, 76.5, 96.4, 110.5, 112.6, 128.6, 128.7, 130.0, 139.5, 142.9,
Hz, OH), 4.23 and 4.41 (each 1 H, d, J 15.6 Hz, PhHCH), 4.86 152.0 and 159.9; m/z (ES+) 524.3 (M+ + 23, 100%). The second
(1 H, s, 1-H), 6.24 (1 H, dd, J 3.3, 1.8 Hz, 4″-H), 6.39 (1 H, dd, fraction was the title compound 101 (106 mg, 36%) as an oil,
J 3.3, 0.8 Hz, 3″-H), 7.19–7.34 (6 H, m, ArH), 7.56–7.68 (3 H, m, Rf 0.53 (ether) (Found: M+ + Na, 524.2421. C27H39O6NSiNa
ArH) and 7.77 (1 H, m, ArH); δC (125 MHz, CDCl3) 17.3, 22.9 requires M, 524.2444); νmax/cm−1 3425, 2951, 1739, 1497, 1411,
(2), 41.1, 45.1, 46.3, 49.1, 64.1, 70.7, 75.0, 108.7, 110.9, 124.4, 1360, 1249, 1149, 1064, 917, 860, 835 and 733; δH (500 MHz,
128.0, 128.4, 128.7, 130.9, 131.1, 131.9, 134.0, 137.1, 143.0, CDCl3) 0.00 [9 H, s, Si(CH3)3], 0.86–0.92 (2 H, m, CH2Si),
148.2, 152.5 and 157.4; m/z (ES+) 576 (M+ + 23, 100%) and 554 1.45–1.85 (7 H, m, 3 × CH2 and OH), 2.16 (1 H, pent, J 9.1 Hz,
(M+ + 1, 20).
4-CH), 3.36 (1 H, dd, J 12.8, 2.2 Hz, 4-HCH), 3.48 (2 H, t, J 8.5
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[1-fur-2-yl-2-(2-trimethyl- Hz, OCH2CH2Si), 3.52 (1 H, dd, J 13.0, 6.9 Hz, 4-HCH),
silylethoxymethoxy)ethyl]-4-hydroxymethyl-1,3-oxazolidin-2- 3.87–4.01 (3 H, m, 1′-H and 2′-H2), 4.42 and 4.55 (each 1 H, d,
ones (95) and (101). Borane (1 M in THF, 0.54 mL, 0.54 mmol) J 15.8 Hz, PhHCH), 4.61 and 4.64 (each 1 H, d, J 6.8 Hz,
was added to the alkene 65 (85 mg, 0.18 mmol) in tetrahydro- OHCHO), 4.73 (1 H, d, J 10.1 Hz, 5-H), 6.28 (1 H, d, J 3.4 Hz,
furan (2.2 mL) at 0 °C. The solution was warmed to 35 °C and 3″-H), 6.34 (1 H, dd, J 3.2, 1.9 Hz, 4″-H), 7.27–7.38 (4 H, m,
stirred for 3 h. Aqueous NaOH (3 M, 0.5 mL) was added and ArH) and 7.42–7.46 (2 H, m, ArH); δC (125 MHz, CDCl3) 0.00,
the mixture stirred for 30 min before aqueous hydrogen per- 18.7, 19.4, 23.9, 24.3, 40.0, 40.8, 46.6, 61.5, 66.4, 69.2, 70.2,
oxide (30%, 0.54 mL) was added and the mixture stirred for 78.2, 96.3, 109.9, 112.2, 129.2, 129.3, 130.4, 139.8, 142.8, 154.1
30 min. The reaction mixture was poured into water (5 mL) and 160.2; m/z (ES+) 524 (M+ + 23, 100%).
and the aqueous layer extracted with ethyl acetate (3 × 5 mL).
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(SR)-1-fur-2-yl-2-(2-trimethyl-
The organic extracts were dried (Na2SO4) then concentrated silylethoxymethoxy)ethyl]-4-(prop-2-enylaminomethyl)-1,3-oxa-
under reduced pressure and chromatography of the residue zolidin-2-one (96). The Dess–Martin periodinane (420 mg,
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1 mmol) was added to the alcohol 95 (421 mg, 0.81 mmol) in (each 1 H, narrow m, 3″-H and 4″-H), 6.94 (2 H, m, ArH),
dichloromethane (8.0 mL) at rt and the reaction mixture was 7.12–7.20 (3 H, m, ArH) and 7.32 (1 H, s, ArH); δC (100 MHz,
stirred for 2 h. Saturated aqueous NaHCO3 (2 mL) and freshly CDCl3) 0.00, 19.0, 19.5, 24.5, 25.0, 41.0, 41.5, 44.6, 46.3, 66.8,
prepared saturated aqueous Na2S2O3 (2 mL) were added and th 67.8, 70.0, 77.4, 96.3, 110.5, 112.6, 128.5, 129.8, 139.6, 142.7,
mixture was stirred for 20 min. Ether (15 mL) was added and 152.2 and 160.1; m/z (ES+) 523 (M+ + 23, 95%) and 501
the aqueous phase was extracted with ether (4 × 15 mL). The (M+ + 1, 55).
organic extracts were dried (Na2SO4) and concentrated under
This amine 97 was immediately taken up in dichloro-
reduced pressure to leave the crude aldehyde. The residue was methane (0.2 mL) and 2-nitrobenzenesulfonyl chloride (17 mg,
immediately dissolved in dichloromethane (3.2 mL) and prop- 74 μmol) and triethylamine (10 μL, 68 μmol) were added. The
2-enylamine (80 μL, 1.1 mmol) and oven dried MgSO4 solution was stirred at rt for 2 h, saturated aqueous NH4Cl
(253 mg) were added. The reaction mixture was heated under (5 mL) was added and the mixture was extracted with ether
reflux for 16 h then concentrated under reduced pressure. The (4 × 5 mL). The organic extracts were dried (MgSO4) and con-
residue was immediately dissolved in anhydrous methanol centrated under reduced pressure. Chromatography of the
(4.9 mL) and glacial acetic acid (61 μL, 1.1 mmol) and sodium residue (light petroleum to neat ether) gave the title compound
cyanoborohydride (1 M in THF, 1 mL, 1 mmol) were added. 98 (28 mg, 60%) as a clear oil, Rf 0.7 (ether) (Found: M+ + Na,
The mixture was stirred for 1 h at rt before saturated aqueous 708.2384. C33H43O9N3NaSSi requires M, 708.2381); νmax/cm−1
NaHCO3 (10 mL) was added and the mixture was extracted 3323, 2950, 1747, 1541, 1409, 1361, 1249, 1175, 1059, 836 and
with ether (5 × 15 mL). The organic extracts were dried 733; δH (400 MHz, CDCl3) 0.00 [9 H, s, Si(CH3)3], 0.89–0.97
(Na2SO4) and concentrated under reduced pressure. Chromato- (2 H, m, CH2Si), 1.72–2.14 (6 H, m, 3 × CH2), 2.80 (1 H, dd, J 13.6,
graphy of the residue (50% ether/light petroleum) gave the title 5.2 Hz, 4-HCH), 2.85 (1 H, dd, J 13.6, 6.6 Hz, 4-HCH), 2.99
compound 96 (333 mg, 73%), Rf 0.95 (ether) (Found: M+ + Na, (1 H, pent, J 8.4 Hz, 4-CH), 3.39 (1 H, ddd, J 10.2, 5.4 Hz, 0.9 Hz,
563.2906. C30H44O5N2NaSi requires M, 563.2912); νmax/cm−1 1′-H), 3.58–3.63 (2 H, m, OCH2CH2Si), 3.65 (1 H, dd, J 9.8, 5.5
3335, 2950, 1752, 1496, 1402, 1249, 1156, 1030, 919, 860, 835 Hz, 2′-H), 3.87 (1 H, t, J 9.9 Hz, 2′-H′), 3.96 and 4.54 (each 1 H,
and 759; δH (500 MHz, CDCl3) 0.00 [9 H, s, Si(CH3)3], 0.90–0.95 d, J 16.1 Hz, PhHCH), 4.70 (2 H, s, OCH2O), 5.07 (1 H, d, J 1.1
(2 H, m, CH2Si), 1.67–2.02 (6 H, m, 3 × CH2), 2.51 and 2.59 Hz, 5-H), 5.12 (1 H, br. t, J 6.1, NH), 6.33 (1 H, dd, J 3.3, 1.8 Hz,
(each 1 H, d, J 12.7 Hz, 4-HCH), 2.81–2.90 (2 H, m, 4-CH and 4″-H), 6.40 (1 H, dd, J 3.3, 0.7 Hz, 3″-H), 6.90–6.94 (2 H, m,
1′-H), 2.93 (1 H, dd, J 14.2, 6.0 Hz, 1′-H′), 3.56–3.61 (2 H, m, ArH), 7.13 (1 H, dd, J 1.8, 0.7 Hz, 5″-H), 7.14–7.19 (3 H, m,
OCH2CH2Si), 3.62–3.69 (2 H, m, 1″-H and 2″-H), 3.86 (1 H, m, ArH), 7.58–7.72 (3 H, m, ArH) and 7.79 (1 H, dd, J 8.0, 1.3 Hz,
2″-H′), 4.17 and 4.45 (each 1 H, d, J 16.0 Hz, PhHCH), 4.69 ArH); δC (125 MHz, CDCl3) 0.00, 18.9, 19.5, 24.2, 24.9, 40.9,
(2 H, s, OCH2O), 4.94–5.00 (3 H, m, 5-H and 3′-H2), 5.63 (1 H, 41.3, 46.2, 46.8, 66.8, 67.0, 69.6, 76.3, 96.4, 111.0, 112.8, 126.7,
ddt, J 17.8, 9.8, 6.0 Hz, 2′-H), 6.36 (1 H, dd, J 3.3, 1.6 Hz, 128.7, 128.9, 130.1, 132.6, 133.8, 134.0, 135.2, 139.1, 142.9,
4′′′-H), 6.38 (1 H, d, J 3.3 Hz, 3′′′-H), 6.89–6.93 (2 H, m, ArH), 149.4, 151.1 and 159.2; m/z (ES+) 708 (M+ + 23, 100%).
7.13–7.19 (3 H, m, ArH) and 7.31 (1 H, m, 5′′′-H); δC (125 MHz,
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(SR)-1-fur-2-yl-2-hydroxy-
CDCl3) 0.0, 18.8, 19.5, 24.5, 25.0, 40.8, 41.8, 46.4, 51.7, 54.3, ethyl]-4-(2-nitrophenylsulfonylaminomethyl)-1,3-oxazolidin-2-
66.8, 67.1, 69.9, 77.2, 96.2, 110.3, 112.5, 117.3, 128.3, 128.5, one (99). Nitromethane (162 μL, 02.9 mmol) and MgBr2
129.7, 137.9, 139.6, 142.6, 152.3 and 160.0; m/z (ES+) 563 (M+ + (270 mg, 1.45 mmol) were added to the SEM-ether 98 (72 mg,
23, 100%).
0.1 mmol) in anhydrous ether 24 mL) and the reaction mixture
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(SR)-1-fur-2-yl-2-(2-(trimethyl- was stirred at rt for 2 h before dichloromethane (10 mL) and
silylethoxymethoxy)ethyl]-4-(2-nitrophenylsulfonylaminomethyl)- water (10 mL) were added. The aqueous layer was extracted
1,3-oxazolidin-2-one
(98). Tetrakistriphenylphosphinepalla- with dichloromethane (4 × 10 mL), and the organic extracts
dium (1 mg, 0.86 μmol) was added to the prop-2-enylamine 96 were dried (MgSO4) and concentrated under reduced pressure.
(41 mg, 0.076 mmol), and 1,3-dimethylbarbituric acid (35 mg, Filtration through a short pad of silica gave the title compound
0.23 mmol) in dichloromethane (0.2 mL) at rt and the mixture 99 (45 mg, 77%) as a clear oil, Rf 0.3 (ether) (Found: M+ + Na,
was stirred at 35 °C for 2 h. Saturated aqueous NaHCO3 (5 mL) 578.1566. C27H29O8N3NaS requires M, 578.1568); δH (400 MHz,
and ether (5 mL) were added and the aqueous layer was CDCl3) 1.79–2.24 (6 H, m, 3 × CH2), 2.90 (1 H, dd, J 13.6,
extracted with ether (3 × 5 mL). The organic extracts were dried 6.3 Hz 4-HCH), 2.99 (1 H, dd, J 13.6, 8.1 Hz, 4-HCH), 3.09 (1 H,
(Na2SO4) and concentrated under reduced pressure to give the m, 4-CH), 3.44 (1 H, ddd, J 9.3, 5.8, 1.3 Hz, 1′-H), 3.94 and 4.07
amine 97 (34 mg, 90%) as a yellow oil, Rf 0.38 (ether) (Found: (each 1 H, m, 2′-H), 4.07 and 4.64 (each 1 H, d, J 16.1 Hz,
M+ + H, 501.2774. C27H41N2O5Si requires M, 501.2785); νmax
/
PhHCH), 5.20 (1 H, t, J 6.1 Hz, NH), 5.22 (1 H, d, J 1.3 Hz, 5-H),
cm−1 2951, 2346, 1749, 1403, 1246, 1155, 1101, 1029 and 835; 6.46 (1 H, dd, J 3.3, 2.0 Hz, 4″-H), 6.52 (1 H, dd, J 3.3, 0.7 Hz,
δH (400 MHz, CDCl3) 0.00 (9 H, s, 3 × SiCH3), 0.94 (2 H, m, 3″-H), 7.01–7.05 (2 H, m, ArH), 7.24–7.31 (4 H, m, ArH),
CH2Si), 1.55 (2 H, br. s, NH2), 1.65–2.05 (6 H, m, 3 × CH2), 1.64 7.71–7.84 (3 H, m, ArH) and 7.91 (1 H, dd, J 8.0, 1.3 Hz, ArH);
and 1.76 (each 1 H, d, J 15.5 Hz, 4-HCH), 2.92 (1 H, pent, J 7.0 δC (125 MHz, CDCl3) 17.4, 22.8, 23.6, 39.4, 41.9, 44.8, 45.3,
Hz, 4-CH), 3.54–3.68 (4 H, m, OCH2CH2Si, 1′-H and 2′-H), 3.86 63.5, 65.5, 74.9, 109.6, 111.5, 125.2, 127.1, 127.5, 128.9, 131.2,
(1 H, t, J 8.0 Hz, 2′-H′), 4.19 and 4.45 (each 1 H, d, J 18.0 Hz, 132.5, 133.0, 134.4, 137.8, 141.7, 148.1, 150.2 and 158.2; m/z
PhHCH), 4.70 (2 H, s, OCH2O), 4.97 (1 H, s, 5-H), 6.37 and 6.41 (ES+) 578 (M+ + 23, 100%).
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1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-fur-2-yl-4-(2-nitrophenyl- hyde. The residue was immediately dissolved in DCM (1.5 ml)
sulfonyl)-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (91). Tri- and prop-2-enylamine (35 μL, 0.48 mmol) and oven dried
phenylphosphine (19 mg, 72 μmol) and di-isopropyl MgSO4 (114 mg) were added. The reaction mixture was heated
azodicarboxylate (14 μL, 72 μmol) were added to the sulfona- under reflux for 16 h and concentrated under reduced
mide 99 (31 mg, 55 μmol) in tetrahydrofuran (0.5 mL) at rt and pressure. The residue was immediately dissolved in anhydrous
the reaction mixture was stirred for 2 h before concentration methanol (2.2 mL) and glacial acetic acid (27 μL, 0.48 mmol)
under reduced pressure. Chromatography of the residue (light and sodium cyanoborohydride (1
M in THF, 0.44 mL,
petroleum to 50% ether/light petroleum) gave the title com- 0.44 mmol) were added at rt. The reaction mixture was stirred
pound 91 (22 mg, 73%) as a pale oil (Found: M+ + 1, 538.1637. for 1 h before saturated aqueous NaHCO3 (5 mL) was added.
C27H28O7N3S requires M, 538.1642); νmax/cm−1 2919, 1744, The aqueous mixture was extracted with ether (5 × 5 mL) and
1543, 1459, 1406, 1360, 1166, 1061, 909, 852 and 733; δH the organic extracts were dried (Na2SO4). After concentration
(500 MHz, CDCl3) 1.29–1.76 (6 H, m, 3 × CH2), 2.22 (1 H, m, 6- under reduced pressure, chromatography of the residue (50%
CH), 3.04 (1 H, d, J 14.2 Hz, 5-H), 3.33–3.41 (2 H, m, 2-H and 3- ether/light petroleum) gave the title compound 102 (137 mg,
H), 3.63 (1 H, d, J 14.2 Hz, 5-H′), 3.69 (1 H, m, 3-H′), 4.10 and 70%) as an oil, Rf 0.27 (50% ether/light petroleum) (Found: M+
4.62 (each 1 H, d, J 15.5 Hz, PhHCH), 4.79 (1 H, d, J 6.0 Hz, + H, 541.3089. C30H45O5N2Si requires M, 541.3092); νmax/cm−1
1-H), 6.10 (1 H, d, J 3.2 Hz, 3″-H), 6.23 (1 H, dd, J 3.2, 1.9 Hz, 2952, 1744, 1408, 1248, 1111, 1062, 1034, 835 and 708; δH
4″-H), 7.20–7.29 (4 H, m, ArH), 7.32–7.36 (2 H, m, ArH), (500 MHz, CDCl3) 0.00 [9 H, s, Si(CH3)3], 0.86–0.92 (2 H, m,
7.59–7.71 (3 H, m, ArH) and 7.90 (1 H, dd, J 7.6, 1.6 Hz, ArH); CH2Si), 1.38–1.83 (6 H, m, 3 × CH2), 2.17 (1 H, pent, J 8.7, 4-
m/z (ES+) 555.4 (M+ + 18, 100%).
CH), 2.46 and 2.54 (each 1 H, d, J 13.6 Hz, 4-HCH), 2.83 (1 H,
Triethylsilane (9 μL, 60 μmol) and boron trifluoride diethyl dd, J 13.9, 6.3 Hz, 1′-H), 2.90 (1 H, dd, J 13.9, 6.0 Hz, 1′-H′),
etherate (8.3 μL, 65 μmol) were added to the tertiary alcohol 90 3.47 (2 H, t, J 8.5 Hz, OCH2CH2Si), 3.94 (1 H, dd, J 9.5, 3.9 Hz,
(13 mg, 23 μmol) in dichloromethane (0.2 ml) at 0 °C and the 2″-H), 3.97 (1 H, dd, J 9.5, 7.3 Hz, 2″-H′), 4.19 (1 H, ddd, J 11.0,
reaction mixture stirred at 0 °C for 15 min and at rt for 2 h. 7.3, 4.0 Hz, 1″-H), 4.39 and 4.46 (each 1 H, d, J 15.8 Hz,
Saturated aqueous NaHCO3 (5 mL) was added and the PhHCH), 4.60 and 4.63 (each 1 H, d, J 6.8 Hz, OHCHO), 4.65
aqueous mixture extracted with dichloromethane (3 × 5 mL). (1 H, d, J 11.0 Hz, 5-H), 5.02 (1 H, d, J 10.1 Hz, 3′-H), 5.03 (1 H,
The organic extracts were dried (MgSO4) and concentrated d, J 17.6 Hz, 3′-H′), 5.66 (1 H, ddt, J 17.6, 10.1, 6.3 Hz, 2′-H),
under reduced pressure. Chromatography as before gave the 6.22 (1 H, dd, J 3.2 Hz, 3′′′-H), 6.32 (1 H, dd, J 3.2, 1.8 Hz,
title compound 91 (4 mg, 32%), Rf 0.53 (ether).
4′′′-H), 7.26–7.36 (4 H, m, ArH) and 7.42–7.45 (2 H, m, ArH); δC
1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-fur-2-yl-4,7-diaza-9-oxa- (125 MHz, CDCl3) 0.0, 2.4, 18.3, 19.4, 24.0, 24.4, 40.4, 41.8,
bicyclo[4.3.0]nonan-8-one (100). Potassium carbonate (48 mg) 46.6, 49.8, 53.7, 66.3, 69.3, 78.2, 96.3, 110.0, 112.1, 117.5,
and thiophenol (27 μL, 26.2 μmol) were addded to the sufona- 129.1, 129.5, 130.1, 138.0, 139.7, 142.6, 154.4 and 160.0; m/z
mide 91 (47 mg, 87 μmol) in acetonitrile (1.75 mL) and the (ES+) 541.6 (M+ + 1, 100%).
mixture stirred at rt for 2 h. After concentration under reduced
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(RS)-1-fur-2-yl-2-(2-(trimethyl-
pressure, chromatography of the residue (light petroleum to silylethoxymethoxy)ethyl]-4-(2-nitrophenylsulfonylaminomethyl)-
10% methanol in ether) gave the title compound 100 (24 mg, 1,3-oxazolidin-2-one (104). Tetrakistriphenylphosphinepalla-
75%) as an oil, Rf 0.16 (ether) (Found: M+ + H, 353.1851. dium (0.5 mg, 0.45 μmol) was added to the propenylamine 102
C21H25N2O3 requires M, 353.1860); δH (400 MHz, CDCl3) (22 mg, 0.04 mmol), and 1,3-dimethylbarbituric acid (19 mg,
1.65–1.99 (6 H, m, 3 × CH2), 2.45 (1 H, dd, J 2.0, 14.0 Hz, 3-H), 0.12 mmol) in dichloromethane (0.1 mL) at rt and the mixture
2.47 (1 H, d, J 16.2 Hz, 5-H), 2.50 (1 H, m, 6-CH), 2.75 (1 H, m, was stirred at 35 °C for 2 h. Saturated aqueous NaHCO3 (5 mL)
2-H), 2.90 (1 H, dd, J 1.5, 16.2 Hz, 5-H′), 3.00 (1 H, ddd, and ether (5 mL) were added and the aqueous layer was
J 1.0, 6.5 and 16.0 Hz, 3-H′), 4.00 (1 H, d, J 15.4 Hz, PhHCH), extracted with ether (3 × 5 mL). The organic extracts were dried
4.60 (1 H, d, J 8.6 Hz, 1-H), 4.71 (1 H, d, J 15.4 Hz, PhHCH), (Na2SO4) and concentrated under reduced pressure to give the
6.14 (1 H, d, J 4.1 Hz, 3′-H), 6.26 (1 H, dd, J 2.0, 4.1 Hz, amine 103 (16 mg, 79%) as a yellow oil, Rf 0.24 (ether) (Found:
4′-H), and 7.20–7.37 (6 H, m, ArH); m/z (ES+) 353.1 (M+ + 1, M+ + H, 501.2777. C27H41N2O5Si requires M, 501.2779); νmax
100%).
cm−1 3385, 2951, 2358, 1742, 1408, 1249, 1150, 1110, 1062, 835
/
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(RS)-1-fur-2-yl-2-(2-(trimethyl- and 709; δH (400 MHz, CDCl3) 0.00 (9 H, s, 3 × SiCH3),
silylethoxymethoxy)ethyl]-4-(prop-2-enylaminomethyl)-1,3-oxazoli- 0.80–0.95 (2 H, m, CH2Si), 1.28–1.78 (6 H, m, 3 × CH2), 2.05
din-2-one (102). The Dess–Martin periodinane (185 mg, (1 H, pent, J 7.0 Hz, 4-CH), 2.71 and 2.79 (each 1 H, d, J 14.0
0.44 mmol) was added to the alcohol 101 (189 mg, Hz, 4-HCH), 3.45–3.55 (2 H, m, OCH2CH2Si), 3.90–4.00 (3 H,
0.365 mmol) in dichloromethane (3.6 mL) at rt and the reac- m, 1′-H and 2′-H2), 4.35 (1 H, d, J 15.0 Hz, PhHCH), 4.50–4.65
tion mixture was stirred for 2 h. Saturated aqueous NaHCO3 (4 H, m, 5-H, PhHCH and OCH2O), 6.27 and 6.35 (each 1 H,
(1 mL) and freshly prepared saturated aqueous Na2S2O3 (1 mL) narrow m, 3″-H and 4″-H), 7.25–7.58 (5 H, m, ArH) and 7.69
were added and the stirring was continued for 20 min. Ether (1 H, m, ArH); δC (100 MHz, CDCl3) 0.00, 18.2, 19.4, 24.2, 24.4,
(5 mL) was added and the aqueous layer was extracted with 40.7, 41.1, 42.4, 46.8, 66.4, 69.4, 70.3, 96.3, 109.7, 112.2, 128.9,
ether (4 × 5 mL). The organic extracts were dried (Na2SO4) and 129.3, 130.0, 142.7, 154.1 and 160.5; m/z (ES+) 501.5 (M+ + 1,
concentrated under reduced pressure to leave the crude alde- 100%).
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This amine 103 was immediately taken up in dichloro- and the reaction mixture was stirred for 2 h. After concen-
methane (0.1 mL) and 2-nitrobenzenesulfonyl chloride (8 mg, tration under reduced pressure, chromatography of the residue
0.035 mmol) and triethylamine (4.5 μL, 0.032 mmol) were (light petroleum to 50% ether/light petroleum) gave the title
added. The solution was stirred at rt for 2 h, saturated aqueous compound 106 (7 mg, 80%) as a pale oil, that crystallised from
NH4Cl (5 mL) was added and the mixture was extracted with ether on standing, Rf 0.48 (ether) (Found: M+ + Na, 560.1454.
ether (4 × 5 mL). The organic extracts were dried (MgSO4) and C27H27O7N3NaS requires M, 560.1462); δH (500 MHz, CDCl3)
concentrated under reduced pressure. Chromatography of the 1.04–1.89 (6 H, m, 3 × CH2), 2.50 (1 H, pent, J 8.8 Hz, 6-CH),
residue (light petroleum to neat ether) gave title compound 3.25 (1 H, d, J 14.5 Hz, 5-H), 3.38 (1 H, dd, J 12.3, 5.7 Hz, 2-H),
104 (15 mg, 70%) as a white foam, Rf 0.65 (ether) (Found: M+ + 3.55 (1 H, dd, J 10.7, 5.9 Hz, 3-H), 3.66 (1 H, t, J 11.0 Hz, 3-H′),
Na, 708.2389. C33H43O9N3NaSSi requires M, 708.2381); νmax
/
3.68 (1 H, d, J 14.6 Hz, 5-H′), 3.95 and 4.75 (each 1 H, d, J 16.1
cm−1 2949, 1747, 1542, 1405, 1360, 1248, 1173, 1111, 1063, Hz, PhHCH), 4.85 (1 H, s, 1-H), 6.37 (1 H, m, 4′-H), 6.39 (1 H,
917, 853, 836 and 733; δH (500 MHz, CDCl3) 0.00 [9 H, s, Si d, J 3.2 Hz, 3′-H), 7.25–7.39 (6 H, m, ArH), 7.66–7.77 (3 H, m,
(CH3)3], 0.87–0.92 (2 H, m, CH2Si), 1.31–1.84 (6 H, m, 3 × CH2), ArH) and 8.00 (1 H, d, J 7.4 Hz, ArH); m/z (ES+) 560.4 (M+ + 23,
2.19 (1 H, pent, J 9.1 Hz, 4-CH), 3.02 (1 H, dd, J 14.2, 6.0 Hz, 100%).
4-HCH), 3.27 (1 H, dd, J 14.0, 6.9 Hz, 4-HCH), 3.48–3.53 (2 H,
m, OCH2CH2Si), 3.56 (1 H, ddd, J 10.4, 6.3, 4.4 Hz, 1′-H), 3.91 oxabicyclo[4.3.0]nonan-8-one
(1RS,2RS,6SR)-7-Benzyl-6-cyclobutyl-2-fur-2-yl-4,7-diaza-9-
(64). Potassium carbonate
(1 H, dd, J 9.6, 4.4 Hz, 2′-H), 3.96 (1 H, dd, J 9.6, 6.6 Hz, 2′-H′), (45 mg,) and thiophenol (25 μl, 245 μmol) were added to the
4.24 and 4.58 (each 1 H, d, J 16.1 Hz, PhHCH), 4.63 and 4.66 sulfonamide 106 (44 mg, 82 μmol) in acetonitrile (1.7 mL) and
(each 1 H, d, J 6.8 Hz, OHCHO), 4.77 (1 H, d, J 10.1 Hz, 5-H), the reaction mixture stirred at rt for 2 h. After concentration
5.43 (1 H, br. t, J 6.2 Hz, NH), 6.29 (1 H, d, J 3.2 Hz, 3″-H), 6.34 under reduced pressure, chromatography of the residue (light
(1 H, dd, J 3.2, 1.9 Hz, 4″-H), 7.23–7.35 (6 H, m, ArH), petroleum to 10% methanol/ether) gave the title compound 64
7.72–7.79 (2 H, m, ArH), 7.85 (1 H, dd, J 7.6, 1.6 Hz, ArH) and (25 mg, 86%) as a pale oil, Rf 0.38 (10% methanol/ether)
7.95 (1 H, dd, J 7.3, 1.6 Hz, ArH); δC (125 MHz, CDCl3) 0.0, (Found: M+ + H, 353.1861. C21H25O3N2 requires M, 353.1860);
18.0, 19.4, 24.0, 24.1, 40.3, 40.7, 44.5, 46.7, 66.6, 68.8, 78.0, νmax/cm−1 3354, 2931, 1742, 1409, 1164, 1014 and 705; δH
96.3, 110.0, 112.5, 126.8, 129.0, 129.1, 130.2, 132.4, 134.1, (500 MHz, CDCl3) 1.52–1.95 (6 H, m, 3 × CH2), 2.34 (1 H, d,
134.2, 135.3, 139.2, 143.1, 149.5, 153.1 and 159.3; m/z (ES+) J 14.5 Hz, 5-H), 2.62 (1 H, pent, J 8.8 Hz, 6-CH), 2.64 (1 H, d,
708.4 (M+ + 23, 100%).
J 14.5 Hz, 5-H′), 3.02 (1 H, t, J 12.0 Hz, 3-H), 3.12 (1 H, dd,
(4RS,5SR)-3-Benzyl-4-cyclobutyl-5-[(RS)-1-fur-2-yl-2-hydroxy- J 12.0, 6.3 Hz, 3-H′), 3.16 (1 H, ddd, J 12.0, 6.3, 2 Hz, 2-H), 4.14
ethyl]-4-(2-nitrophenylsulfonylaminomethyl)-1,3-oxazolidin-2- and 4.41 (each 1 H, d, J 15.5 Hz, PhHCH), 4.78 (1 H, d, J 2 Hz,
one (105). Nitromethane (34 μL, 0.61 mmol) and MgBr2 1-H), 6.19 (1 H, d, J 3.2 Hz, 3″-H), 6.27 (1 H, dd, J 3.2, 2.0 Hz,
(56 mg, 0.3 mmol) were added to the SEM-ether 104 (15 mg, 4″-H) and 7.18–7.34 (6 H, m, ArH); δC (125 MHz, CDCl3) 17.6,
21 μmol) in anhydrous ether (0.4 mL) and the reaction mixture 22.3, 22.9, 35.5, 38.4, 41.7, 44.7, 64.0, 65.9, 74.9, 106.9, 110.5,
was stirred at rt for 2 h before dichloromethane (5 mL) and 130.0, 128.8, 138.2, 141.6, 152.2 and 158.7; m/z (ES+) 353.3
water (5 mL) were added. The aqueous layer was extracted with (M+ + 1, 100%).
dichloromethane (4 × 5 mL), and the organic extracts were
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
dried (MgSO4) and concentrated under reduced pressure. Fil- cyclobutyl-5-[1-(2-phenyl-1,3-ozaxol-5-yl)prop-2-en-2-yl]-1,3-oxa-
tration through a short pad of silica gave the title compound zolidin-2-one (108). n-Butyllithium (2.5 M in THF, 2.8 mL,
105 (9 mg, 75%) as a pale yellow oil, Rf 0.16 (ether) (Found: M+ 6.96 mmol, 3 eq.) was added to 5-bromo-2-phenyloxazole
+ Na, 578.1580. C27H29O8N3NaS requires M, 578.1568); νmax
/
(1.6 g, 6.96 mmol, 3 eq.) in THF (8 mL) at −18 °C and the
cm−1 3336, 2915, 1739, 1541, 1410, 1360, 1171, 1067, 911, 853 resulting suspension was stirred for 45 min, cooled to −40 °C
and 731; δH (500 MHz, CDCl3) 1.22–1.76 (6 H, m, 3 × CH2), and added to a suspension of CuCN (596 mg, 6.96 mmol,
2.09 (1 H, pent, J 8.6 Hz, 4-CH), 2.97 and 3.22 (each 1 H, d, 3 eq.) and LiCl (590 mg, 13.92 mmol, 6 eq.) in THF (8 mL).
J 13.9 Hz, 4-HCH), 3.49 (1 H, dt, J 10.4, 5.4 Hz, 1′-H), 3.95 (2 H, The reaction mixture was stirred at −40 °C for 1 h and then
m, 2′-H2), 4.18 and 4.52 (each 1 H, d, J 16.1 Hz, PhHCH), 5.75 the bromide 43 (1.15 g, 2.32 mmol) in THF (8 mL) was added.
(1 H, d, J 10.4 Hz, 5-H), 5.42 (1 H, br. s, NH), 6.26 (1 H, d, J 3.3 The mixture stirred for 18 h, warmed to rt, diluted with ether
Hz, 3″-H), 6.30 (1 H, dd, J 3.3, 2.2 Hz, 4″-H), 7.16–7.30 (6 H, m, (15 mL) and saturated aqueous ammonium chloride (15 mL)
ArH), 7.64–7.72 (2 H, m, ArH), 7.78 (1 H, dd, J 7.9, 0.9 Hz, ArH) was added. The aqueous phase was extracted with ether (3 ×
and 7.88 (1 H, dd, J 7.6, 1.2 Hz, ArH); δC (125 MHz, CDCl3) 20 mL) and the organic extracts were dried (MgSO4) and con-
15.3, 16.6, 22.7, 38.9, 41.1, 43.0, 45.4, 63.7, 65.9, 67.5, 109.0, centrated under reduced pressure. Chromatography (ethyl
111.1, 125.4, 127.6, 127.8, 128.9, 131.0, 132.8(2), 134.0, 137.7, acetate : light petroleum = 1 : 25) of the residue gave the title
142.3, 148.1, 151.3 and 157.9; m/z (ES+) 573.4 (M+ + 18, 100%).
compound 108 (1.04 g, 80%) as a colourless oil, Rf = 0.11 (ethyl
(1RS,2RS,6SR)-7-Benzyl-6-cyclobutyl-2-fur-2-yl-4-(2-nitrophenyl- acetate : light petroleum = 1 : 10) (Found: M+ + H, 559.2986.
sulfonyl)-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (106). Tri- C33H43N2O4Si requires M, 559.2993); νmax/cm−1 3087, 3064,
phenylphosphine (5.5 mg, 21 μmol) and di-isopropyl 3033, 2953, 2930, 2898, 2857, 1754, 1648, 1600, 1549, 1486,
azodicarboxylate (4 μL, 21 μmol) were added to the sulfon- 1470, 1401, 1355, 1291, 1256, 1200, 1161, 1104, 1043, 1005,
amide 105 (9 mg, 16 μmol) in tetrahydrofuran (0.16 mL) at rt 915, 840 and 777; δH (400 MHz, CDCl3) 0.00 and 0.03 (each
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3 H, s, SiCH3), 0.88 [9 H, s, SiC(CH3)3], 1.56–2.07 (6 H, m, 3 × 3.61 and 3.71 (each 1 H, d, J 13.0 Hz, 4-HCH), 3.82 (1 H, dd,
CH2), 2.92 (1 H, pent, J 9.0 Hz, 4-CH), 3.55 (1 H, d, J 11.0 Hz, J 4.2, 11.0 Hz, 3′-H), 3.96 (1 H, dd, J 6.2, 11.0 Hz, 3′-H′), 4.31
4-HCH), 3.57 (1 H, d, J 17.5 Hz, 1′-H), 3.62 (1 H, J 11.0 Hz, (1 H, J 16.0 Hz, PhHCH), 4.51 (1 H, d, J 3.5 Hz, 5-H), 4.58 (1 H,
4-HCH), 3.69 (1 H, d, J 17.5 Hz, 1′-H′), 4.40 and 4.64 (each 1 H, d, J 16.0 Hz, PhHCH), 7.00 (1 H, s, 4″-H), 7.25–7.46 (8 H, m,
d, J 15.7 Hz, PhHCH), 4.96 (1 H, s, 5-H), 5.09 and 5.32 (each 1 ArH) and 7.95–7.99 (2 H, m, ArH); δC (75 MHz, CDCl3) 17.2,
H, s, 3′-H), 7.24–7.40 (6 H, m, 4″-H, ArH), 7.44–7.59 (3 H, m, 22.9, 23.0, 27.5, 39.2, 39.3, 45.4, 60.1, 61.5, 68.8, 78.8, 125.8,
ArH) and 7.98–8.02 (2 H, m, ArH); δC (100 MHz, CDCl3) −5.9, 126.0, 127.2, 127.6, 127.7, 128.7, 128.8, 130.3, 138.1, 149.9,
−5.6, 17.0, 18.1, 22.8, 23.3, 25.8, 28.1, 38.3, 46.0, 62.6, 68.2, 159.4 and 161.4; m/z (CI+) 463 (M+ + 1, 100%).
79.3, 115.6, 117.3, 126.2, 126.4, 127.4, 127.5, 128.5, 128.8,
130.9, 138.4, 138.8, 145.7, 158.7 and 161.1; m/z (CI+) 559 oxazol-5-yl)methyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one
(M+ + 1, 1%) and 106 (100).
(112). Freshly distilled methane sulfonyl chloride (0.235 mL,
(1RS,2RS,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-(2-phenyl-1,3-
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 3.03 mmol, 4 eq.) and triethylamine (0.528 mL, 3.78 mmol,
cyclobutyl-5-[(RS)-1-(2-phenyl-1,3-oxazol-5-yl)-3-hydroxyprop-2- 5 eq.) were added successively to the diol 110 (350 mg,
yl]-1,3-oxazolidin-2-one (109). Borane (1 M in THF, 18.6 mL, 0.757 mmol) in DCM (15 mL) at 0 °C and the reaction mixture
18.6 mmol, 10 eq.) was added dropwise to the alkene 108 was allowed to warm to rt and was stirred for 1 h. Saturated
(1.04 g, 1.84 mmol) in THF (18 mL) at 0 °C and the mixture aqueous ammonium choride (15 mL) and ether (15 mL) were
was warmed to rt then stirred for 24 h. Ethanol (16.25 mL), added and the aqueous phase was extracted with ether (3 ×
saturated sodium acetate (51.5 mL) and hydrogen peroxide 20 mL). The organic extracts were dried (MgSO4) and concen-
(30% in water, 18 mL) were added dropwise and the reaction trated under reduced pressure to leave the bis-mesylate 111
mixture was heated under reflux for 1.5 h. After cooling to rt, that was dissolved in benzylamine (25 mL) and the solution
the aqueous phase was extracted with ether (3 × 100 mL), and heated at 90 °C for 18 h. The reaction mixture was allowed to
the organic extracts were dried (MgSO4) and concentrated cool to rt and the excess benzylamine was distilled off under
under reduced pressure. Chromatography (ethyl acetate : light reduced pressure. Chromatography (ethyl acetate : light pet-
petroleum = 1 : 2 to 1 : 1) of the residue gave the title com- roleum = 1 : 20 to 1 : 10 with 1% methanol) of the residue gave
pound 109 (532 mg, 50%) containing small amounts of its the piperidine 112 (327 mg, 81%) containing about 10% of its
2′-epimer, Rf = 0.30 (ethyl acetate : light petroleum = 1 : 2) 2-epimer. Repeated chromatography (ethyl acetate : light pet-
(Found: M+
+ H, 577.3098. C33H45N2O5Si requires M, roleum = 1 : 9 with 1% methanol) gave the title compound 112
577.3098); νmax/cm−1 3414, 3065, 3032, 2951, 2932, 2892, 2859, (176 mg, 44%), as an oil, Rf = 0.28 (ethyl acetate : light pet-
1732, 1602, 1550, 1492, 1408, 1357, 1295, 1255, 1172, 1112, roleum = 1 : 2) (Found: M+ + H, 534.2747. C34H36N3O3 requires
1069, 1032, 983, 913, 840 and 778; δH (300 MHz, CDCl3) 0.04 M, 534.2757); νmax/cm−1 3086, 3062, 3029, 2925, 2855, 1747,
and 0.05 (each 3 H, s, SiCH3), 0.86 [9 H, s, SiC(CH3)3], 1667, 1599, 1550, 1493, 1453, 1405, 1353, 1260, 1154, 1122,
1.24–1.98 (6 H, m, 3 × CH2), 2.10 (1 H, br. s, OH), 2.49–2.61 1064, 1026, 983, 913, 821, 741 and 706; δH (300 MHz, CDCl3)
(2 H, m, 4-CH, 2′-H), 2.93 (1 H, dd, J 7.0, 15.2 Hz, 1′-H), 3.13 1.39–1.55 (2 H, m, cyclobutyl H), 1.61–1.79 (4 H, m, cyclobutyl
(1 H, dd, J 7.2, 15.2 Hz, 1′-H′), 3.65 and 3.71 (each 1 H, d, H), 1.96 (1 H, pent, J 9.5 Hz, 6-CH), 2.10 (1 H, d, J 12.5 Hz, 5-
J 11.2 Hz, 4-HCH), 3.80 (1 H, dd, J 3.0, 11.2 Hz, 3′-H), 3.99 H), 2.38 (1 H, m, 2-H), 2.47–2.54 (2 H, m, 3-H, 5-H′), 2.64 (1 H,
(1 H, dd, J 4.2, 11.2 Hz, 3′-H′), 4.21 (1 H, J 16.0 Hz, PhHCH), J 6.5, 10.5 Hz, 3-H′), 2.83 (1 H, dd, J 6.7, 15.2 Hz, 2-CH), 3.04
4.43 (1 H, d, J 5.2 Hz, 5-H), 4.62 (1 H, J 16.0 Hz, PhHCH), 7.00 (1 H, dd, J 8.0, 15.2 Hz, 2-CH′), 3.32 and 3.40 (each 1 H, d,
(1 H, s, 4″-H), 7.24–7.38 (5 H, m, ArH), 7.42–7.47 (3 H, m, ArH) J 13.0 Hz, PhHCH), 3.94 and 4.31 (each 1 H, d, J 15.7 Hz,
and 7.95–8.01 (2 H, m, ArH); δC (75 MHz, CDCl3) −5.9, −5.8, PhHCH), 4.32 (1 H, d, J 2.5 Hz, 5-H), 6.96 (1 H, s, 4′-H),
17.1, 17.9, 23.2, 23.4, 25.7, 26.1, 39.1, 39.4, 45.9, 61.4, 61.6, 7.21–7.27 (10 H, m, ArH), 7.44–7.48 (3 H, m, ArH) and
68.4, 78.8, 125.9, 126.0, 127.4(2), 127.6, 128.5, 128.7, 130.2, 7.97–8.01 (2 H, m, ArH); δC (75 MHz, CDCl3) 17.6, 23.0, 23.4,
138.3, 150.0, 158.9 and 161.3; m/z (CI+) 577 (M+ + 1, 1%) and 26.4, 35.4, 39.3, 44.9, 53.1, 61.9, 64.5, 75.6, 125.4, 126.0, 127.3,
391 (100).
127.4, 127.5, 127.8, 128.3(2), 128.4, 128.7, 128.9, 130.1, 137.8,
(4SR,5RS)-3-Benzyl-4-cyclobutyl-4-(hydroxymethyl)-5-[(RS)-1- 138.1, 149.7, 158.8 and 161.2; m/z (CI+) 534 (M+ + 1, 10%) and
(2-phenyl-1,3-oxazol-5-yl)-3-hydroxyprop-2-yl]-1,3-oxazolidin-2- 108 (100).
one (110). Following the procedure for the preparation of com-
pound 82, the silyl ether 109 (532 mg, 0.92 mmol), after stir- yl)methyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (113). Fol-
ring for and chromatography (ethyl acetate : light lowing the procedure for the preparation of compound 8, the
(1RS,2RS,6SR)-7-Benzyl-6-cyclobutyl-2-(2-phenyl-1,3-oxazol-5-
1
h
petroleum = 1 : 2 to neat ethyl acetate), gave the title com- N-benzylpiperidine 112 (170 mg, 0.318 mmol), after stirring
pound 110 (352 mg, 83%), Rf = 0.18 (ethyl acetate : light pet- for 20 min and chromatography (ethyl acetate with 1% triethyl-
roleum = 3 : 2) (Found: M+ + H, 463.2225. C27H31N2O5 requires amine to methanol : ethyl acetate = 1 : 10 with 1% triethyl-
M, 463.2234); νmax/cm−1 3387, 3064, 3032, 2942, 2871, 1727, amine), gave the title compound 113 (76 mg, 54%), Rf = 0.16
1600, 1550, 1486, 1433, 1413, 1357, 1294, 1258, 1164, 1069, (methanol : ethyl acetate = 1 : 9) (Found: M+ + H, 444.2285.
982 and 912; δH (300 MHz, CDCl3) 1.24–1.85 (6 H, m, 3 × CH2), C27H30N3O3 requires M, 444.2288); νmax/cm−1 3353, 3063,
2.39 (1 H, pent, J 8.5 Hz, 4-CH), 2.61 (1 H, m, 2′-H), 2.86 (1 H, 3031, 2936, 2865, 1744, 1669, 1598, 1550, 1489, 1432, 1408,
dd, J 7.7, 15.2 Hz, 1′-H), 3.03 (1 H, dd, J 6.2, 15.2 Hz, 1′-H′), 1351, 1258, 1164, 1123, 1063, 982 and 913; δH (400 MHz,
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CDCl3) 1.53–1.96 (6 H, m, 3 × CH2), 2.28 (1 H, m, 2-H), 2.41 0.00 and 0.04 (each 3 H, s, SiCH3), 0.90 [9 H, s, SiC(CH3)3],
(1 H, d, J 14.0 Hz, 5-H), 2.62 (1 H, pent, J 8.5 Hz, 6-CH), 2.69 1.57–2.03 (6 H, m, 3 × CH2), 2.93 (1 H, m, 4-CH), 3.50 (1 H, d,
(1 H, d, J 14.0 Hz, 5-H′), 2.75 (1 H, t, J 12.0 Hz, 3-H), 2.80 (1 H, J 17.0 Hz, 3′-H), 3.55 (1 H, d, J 11.0 Hz, 4-HCH), 3.57 (1 H, d,
dd, J 6.5, 15.5 Hz, 2-CH), 2.97 (1 H, dd, J 5.7, 12.0 Hz, 3-H′), J 17.0 Hz, 3′-H′), 3.62 (1 H, d, J 11.0 Hz, 4-HCH), 4.42 and 4.65
2.99 (1 H, dd, J 8.2, 15.5 Hz, 2-CH′), 4.24 and 4.43 (each 1 H, d, (each 1 H, d, J 16.0 Hz, PhHCH), 4.96 (1 H, s, 5-H), 5.12 and
J 15.5 Hz, PhHCH), 4.51 (1 H, d, J 2.2 Hz, 1-H), 6.97 (1 H, s, 4′- 5.32 (each 1 H, s, 1′-H), 6.15 and 6.36 (each 1 H, br. d, J 3.0 Hz,
H), 7.26–7.39 (5 H, m, ArH), 7.42–7.47 (3 H, m, ArH) and 3″-H and 4″-H) and 7.27–7.41 (6 H, m, ArH); δC (100 MHz,
7.97–8.02 (2 H, m, ArH); δC (100 MHz, CDCl3) 17.4, 22.3, 22.9, CDCl3) −5.9, −5.8, 17.0, 18.2, 22.8, 23.2, 25.8, 31.7, 38.2, 45.9,
26.0, 34.7, 38.6, 43.4, 44.8, 45.0, 63.8, 75.0, 125.4, 126.0, 127.5, 62.9, 68.2, 79.2, 107.4, 110.4, 116.9, 127.2, 127.5, 128.4, 138.6,
127.8, 128.7(2), 130.1, 138.0, 149.6, 158.5 and 161.2; m/z (CI+) 140.7, 141.7, 152.0 and 158.9; m/z (ES+) 504 (M+ + 23, 100%).
444 (M+ + 1, 20%) and 206 (100).
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- cyclobutyl-5-(3-phenylpropen-2-yl)-1,3-oxazolidin-2-one (119).
cyclobutyl-5-[3-(3-methoxyphenyl)propen-2-yl]-1,3-oxazolidin-2- Phenylboronic acid MIDA ester 118 (214 mg, 0.918 mmol) was
one (115). 3-Methoxybenzene boronic acid 114 (4 mg, added to the bromide 43 (227 mg, 0.459 mmol) in tetrahydro-
0.024 mmol) was added to the bromide 43 (10 mg, 0.02 mmol) furan (5 mL) and the solution was de-gassed for 10 min.
in tetrahydrofuran (0.1 mL) and the solution was de-gassed for Bis(triphenylphosphine)palladium(II) dichloride (23 mg,
10 min. Bis(triphenylphosphine)palladium(II) dichloride 0.032 mmol) and de-gassed aqueous sodium carbonate (2 M,
(1 mg, 1 μmol) and de-gassed aqueous sodium carbonate (1 M, 0.92 mL, 1.84 mmol) were added and the reaction mixture was
0.04 mL, 0.04 μmol) were added and the reaction mixture was heated under reflux for 12 h. Water (10 mL) was added and the
heated under reflux for 3 h. Water (5 mL) was added and the mixture was extracted with dichloromethane (3 × 10 mL). The
mixture was extracted with dichloromethane (3 × 10 mL). The organic extracts were dried (MgSO4)and concentrated under
organic extracts were dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue (10% ethyl
reduced pressure. Chromatography of the residue (10% ethyl acetate/light petroleum) gave the title compound 119 (166 mg,
acetate/light petroleum) gave the title compound 115 (8 mg, 73%) as a colourless oil, Rf 0.60 (20% ethyl acetate/light pet-
73%) as a colourless oil, Rf 0.47 (20% ethyl acetate/light pet- roleum) (Found: M+ + Na, 514.2736. C30H41NO3NaSi requires
roleum) (Found: M+ + H, 522.3031, C31H44NO4Si requires M, M, 514.2748); νmax/cm−1 3027, 2949, 2926, 2855, 1744, 1602,
522.3034); νmax/cm−1 2951, 2930, 2857, 1749, 1599, 1585, 1490, 1495, 1453, 1400, 1359, 1291, 1250, 1145, 1098, 1029, 1004,
1464, 1434,1402, 1359, 1259, 1148, 1101, 1051, 837 and 778; δH 909, 834, 775 and 732; δH (400 MHz, CDCl3) −0.03 and 0.01
(400 MHz, CDCl3) 0.00 and 0.04 (each 3 H, s, SiCH3), 0.91 [9 H, (each 3 H, s, SiCH3), 0.87 [9 H, s, SiC(CH3)3], 1.51–1.96 (6 H,
s, SiC(CH3)3], 1.54–2.01 (6 H, m, 3 × CH2), 2.94 (1 H, m, 4-CH), m, 3 × CH2), 2.92 (1 H, m, 4-CH), 3.37 (1 H, d, J 16.0 Hz, 3′-H),
3.38 (1 H, d, J 16.0 Hz, 3′-H), 3.55 (1 H, d, J 11.0 Hz, 4-HCH), 3.54 (1 H, d, J 11.0 Hz, 4-HCH), 3.58 (1 H, d, J 16.0 Hz, 3′-H′),
3.58 (1 H, d, J 16.0 Hz, 3′-H′), 3.62 (1 H, d, J 11.0, 4-HCH), 3.84 3.60 (1 H, d, J 11.0 Hz, 4-HCH), 4.42 and 4.60 (each 1 H, d,
(3 H, s, OCH3), 4.45 and 4.63 (each 1 H, d, J 16.0 Hz, PhHCH), J 16.0 Hz, PhHCH), 4.86 (1 H, s, 5-H), 5.00 and 5.32 (each 1 H,
4.89 (1 H, s, 5-H), 5.07 and 5.35 (each 1 H, s, 1′-H), 6.84–6.77 s, 1′-H) and 7.16–7.37 (10 H, m, ArH); δC (100 MHz, CDCl3)
(3 H, m, ArH) and 7.25–7.40 (6 H, m, ArH); δC (100 MHz, −5.9, −5.8, 17.0, 18.1, 22.7, 23.2, 25.8, 38.2, 39.5, 45.9, 63.0,
CDCl3) −5.9, −5.7, 17.0, 18.2, 22.8, 23.3, 25.9, 38.2, 39.6, 45.9, 68.1, 79.0, 117.0, 126.5, 127.2, 127.4, 128.4, 128.5, 129.2, 138.1,
55.2, 63.0, 68.2, 79.0, 112.0, 114.8, 117.1, 121.6, 127.2, 127.5, 138.6, 143.2 and 158.9; m/z (ES+) 514 (M+ + 23, 100%).
128.4, 129.5, 138.7, 139.7, 143.1, 158.9 and 159.8; m/z (ES+) 544
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-
cyclobutyl-5-[(RS)-3-phenyl-1-hydroxyprop-2-yl]-1,3-oxazolidin-
(M+ + 23, 100%).
(4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4- 2-one (120). Borane (1 M in THF, 2.73 mL, 2.73 mmol) was
cyclobutyl-5-(3-fur-2-ylpropen-2-yl)-1,3-oxazolidin-2-one (117). added dropwise to the alkene 119 (268 mg, 0.545 mmol) in
2-Furylboronic acid MIDA ester 116 (27 mg, 0.12 mmol) was tetrahydrofuran at 0 °C and the mixture was stirred for 16 h at
added to the bromide 43 (30 mg, 0.061 mmol) in tetrahydro- rt. Ethanol (2.5 mL), saturated aqueous NaOAc (8.5 mL) and
furan (2.5 mL) and the solution was de-gassed for 10 min. Bis hydrogen peroxide (30% in water, 3 mL) were added dropwise,
(triphenylphosphine)palladium(II) dichloride (3 mg, 4 μmol) and the mixture was heated under reflux for 1.5 h. After
and de-gassed aqueous sodium carbonate (2 M, 0.12 mL, cooling to rt, the mixture was extracted with ether, and the
0.24 mmol) were added and the reaction mixture was heated organic extracts were dried (MgSO4) and concentrated under
under reflux for 12 h. Water (5 mL) was added and the mixture reduced pressure. Chromatography of the residue (10% ethyl
was extracted with dichloromethane (3 × 10 mL). The organic acetate/light petroleum) gave the title compound 120 (166 mg,
extracts were dried (MgSO4) and concentrated under reduced 73%) as a colourless oil, Rf 0.17 (20% ethyl acetate/light pet-
pressure. Chromatography of the residue (10% ethyl acetate/ roleum) (Found: M+ + Na, 532.2855. C30H43NO4NaSi requires
light petroleum) gave the title compound 117 (21 mg, 72%) as M, 532.2854); νmax/cm−1 3414, 3027, 2927, 2855, 1722, 1603,
a colourless oil, Rf 0.40 (20% ethyl acetate/light petroleum) 1495, 1470, 1453, 1409, 1358, 1293, 1251, 1167, 1100, 1070,
(Found: M+ + H, 482.2710. C28H40NO4Si requires M, 482.2722); 1029, 1003, 980, 835, 775, 745 and 731; δH (500 MHz, CDCl3)
νmax/cm−1 2951, 2929, 2857, 1747, 1609, 1510, 1470, 1403, 0.04 and 0.06 (each 3 H, s, SiCH3), 0.87 [9 H, s, SiC(CH3)3],
1359, 1251, 1103, 909, 837, 777 and 731; δH (400 MHz, CDCl3) 1.46–1.61 (4 H, m, 2 × CH2), 1.72–1.81 (2 H, m, CH2), 2.38
Org. Biomol. Chem.
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