Asymmetric synthesis of (4R,5R)-cytoxazone and (4R,5S)-epi-cytoxazone.

Article abstract of DOI:10.1039/b402437k

(4R,5R)-Cytoxazone has been prepared in four steps and in 61% overall yield and >98% ee. Conjugate addition of lithium (R)-N-benzyl-N-[small alpha]-methylbenzylamide to tert-butyl (E)-3-(p-methoxyphenyl)prop-2-enoate and subsequent in situ diastereoselect

Full text of DOI:10.1039/b402437k

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Asymmetric synthesis of (4R,5R)-cytoxazone and
(4R,5S )-epi-cytoxazone
Stephen G. Davies,* Deri G. Hughes, Rebecca L. Nicholson, Andrew D. Smith and
Angela J. Wright
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA
Received 18th February 2004, Accepted 30th March 2004
First published as an Advance Article on the web 27th April 2004
(4R,5R)-Cytoxazone has been prepared in four steps and in 61% overall yield and >98% ee. Conjugate addition of
lithium (R)-N-benzyl-N-α-methylbenzylamide to tert-butyl (E)-3-(p-methoxyphenyl)prop-2-enoate and subsequent
in situ diastereoselective enolate oxidation with (ϩ)-(camphorsulfonyl)oxaziridine gave tert-butyl (2R,3R,αR)-2-
hydroxy-3-(p-methoxyphenyl)-3-(N-benzyl-N-α-methylbenzylamino)propanoate in >98% de. Subsequent N-benzyl
deprotection to the primary β-amino ester via hydrogenolysis, oxazolidinone formation with C(2)-retention by
treatment with diphosgene and chemoselective ester reduction furnishes (4R,5R)-cytoxazone. The synthesis of the
C(5)-epimer, (4R,5S)-epi-cytoxazone in 44% overall yield, has also been completed via a protocol involving N-Boc
protection of the primary β-amino ester, utilization of the N-Boc group to facilitate simultaneous C(2)-inversion and
oxazolidinone formation, and subsequent reduction.
The realisation of this strategy, and the extension of this
protocol to the synthesis of (4R,5S)-epi-cytoxazone 5 is
described herein.
Introduction
Cytoxazone 1 is a microbial metabolite1 isolated from Strepto-
myces sp.,2 which has been identified as a selective modulator of
TH2 cytokine secretion. Due to its potent biological activity and
relatively simple structure, the development of efficient asym-
metric routes to cytoxazone and its stereoisomers has been the
Results and discussion
Asymmetric synthesis of (4R,5R)-cytoxazone
subject of intense synthetic interest. A variety of synthetic
routes to 1 have been reported in 10% to 51% overall
yield, including chemoenzymatic resolution,3 imino 1,2-Wittig
rearrangement,4 addition of Grignard reagents to a protected
imine,5 Sharpless asymmetric dihydroxylation and regio- and
stereoselective introduction of azide,6,7 asymmetric amino-
hydroxylation8 and asymmetric aldol reactions.9 We have pre-
viously demonstrated that conjugate addition of a homochiral
lithium amide to α,β-unsaturated esters and subsequent enolate
oxidation with electrophilic oxygen sources allows the efficient
synthesis of a range of anti-α-hydroxy-β-amino acid derivatives
with high diastereoselectivity.10 It was envisaged that this
methodology would allow an efficient and stereoselective
asymmetric synthesis of (4R,5R)-cytoxazone 1 via synthetic
elaboration of the α-hydroxy-β-amino ester 2 derived from
conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzyl-
amide 3 to a β-4-methoxyphenyl-α,β-unsaturated ester 4 and
enolate hydroxylation (Fig. 1).
Following the literature protocol,10 conjugate addition of
lithium amide (R)-3 to tert-butyl (E)-3-(p-methoxyphenyl)-
prop-2-enoate 6 and subsequent in situ diastereoselective enol-
ate oxidation with (ϩ)-(camphorsulfonyl)oxaziridine gave anti-
α-hydroxy-β-amino ester (2R,3R,αR)-7 in 79% yield and 98%
de on a >3 mmol scale. The C(2)–C(3)-anti-configuration
within α-hydroxy-β-amino ester 7 was assigned by analogy to
the known anti-selectivity noted upon hydroxylation of related
β-amino enolates. Having successfully installed the desired
stereogenic centres required for the synthesis of cytoxazone,
and with >3 mmol quantities of β-amino ester (2R,3R,αR)-7 in
hand, functional group manipulation of β-amino ester 7 to
furnish the natural product was investigated. Initial attention
was turned towards the efficient removal of the N-benzyl and
N-α-methylbenzyl protecting groups, with hydrogenolysis using
palladium hydroxide on carbon under 5 atmospheres of H2 in
MeOH affording the desired anti-α-hydroxy-β-amino ester-
(2R,3R)-8 in 96% yield and 98% de (Scheme 1).
Installation of the oxazolidinone functionality within
cytoxazone was next investigated, with direct cyclisation of
aminoalcohol 8 upon treatment with carbonyldiimidazole
giving >70% conversion to oxazolidinone (4R,5R)-9 on a trial
scale, but less than 40% conversion on a mmol scale, furnishing
(4R,5R)-9 in 36% isolated yield. However, use of diphosgene for
oxazolidinone formation proved satisfactory, giving oxazol-
idinone (4R,5R)-9 in 88% isolated yield and in 98% de on a 2
mmol scale (Scheme 2).
With oxazolidinone (4R,5R)-9 in hand, chemoselective
reduction of the ester functionality to the alcohol was required
to complete the synthesis of cytoxazone. Initial investigations
utilised varying equivalents of LiAlH4 over a range of temper-
atures for the reduction, with starting material being returned
in each case. A broad range of reducing agents (LiBH4,11 Super-
hydride,12 Red-Al13 and DIBAL-H14) that have previously
been shown to reduce tert-butyl esters were therefore screened
Fig. 1 Retrosynthetic analysis for 1 and 5.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 4 9 – 1 5 5 3
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5-epi-cytoxazone. As the introduction of the hydroxyl func-
tionality into anti-α-hydroxy-β-amino ester 7 via conjugate add-
ition/hydroxylation is substrate controlled, the syn-epimer can-
not be synthesised via direct oxidation of the β-amino enolate
formed in situ from conjugate addition. Epimerisation of the
existing hydroxyl stereocentre of anti-α-hydroxy-β-amino ester
7 was therefore investigated for the synthesis of 5-epi-cytox-
azone. Anoxidation/reductionprotocolwasfirstattempted, with
stereoselective reduction of an α-keto-β-amino ester proposed
as a route to the required syn-α-hydroxy-β-amino ester. Oxid-
ation of anti-α-hydroxy-β-amino ester 7 under standard Swern
conditions16 returned only starting material, while oxidation
with o-iodooxybenzoic acid proved successful, giving the
desired α-keto-β-amino ester 10. However, α-keto-β-amino
ester 10 underwent rapid tautomerisation to enol (αR)-11, limit-
ing the synthetic utility of this strategy (Scheme 4).
Scheme 1 Reagents and conditions: (i). lithium (R)-N-benzyl-N-α-
methylbenzylamide 3, THF, Ϫ78 ЊC; then (ϩ)-CSO, THF, Ϫ78 ЊC to rt;
(ii). Pd(OH)2 on C, H2 (5atm.), MeOH.
Scheme 2 Reagents and conditions: (i). CDI, DMAP, THF, rt; (ii).
Cl3COCOCl, activated charcoal, toluene, rt (1 hour) then ∆ (4 hours).
for their suitability in this transformation. Reduction with
LiBH4 and Red-Al showed 20% and 50% conversion respect-
ively to cytoxazone 1, while Superhydride and DIBAL-H gave
complete conversion to the cytoxazone 1 by 1H NMR spectro-
scopic analysis of the crude reaction mixture, with chromato-
graphic purification furnishing (4R,5R)-cytoxazone 1 in 70%
and 75% yield respectively. As an alternative protocol, in situ
conversion of the ester to the mixed anhydride and subsequent
reduction, based upon the procedure reported by Boojamra
et al., was evaluated.15 Oxazolidinone ester 9 was treated suc-
cessively with TFA, ethyl chloroformate and NaBH4 in diglyme,
giving cytoxazone 1 in 92% isolated yield and 98% de with
spectroscopic properties consistent with those reported in the
literature {[α]2D5 Ϫ72.0 (c 1.0, MeOH), lit.6 [α]2D5 Ϫ75.7 (c 1.0,
MeOH)}. The ee of synthetic 1 was determined as >98% ee by
19F NMR spectroscopic analysis of the esters derived from 1
and homochiral and racemic Mosher’s acid chloride (Scheme
3). The formation of (4R,5R)-1 as predicted is consistent with
the initial anti-amino hydroxylation followed by oxazolidinone
formation with retention of configuration at C(2).
Scheme
4
Reagents and conditions: (i). o-iodooxybenzoic acid,
DMSO, rt.
As an alternative approach, a procedure for the inversion of
the C(2)-hydroxyl stereocentre within anti-α-hydroxy-β-amino
ester 7 was examined. Although direct C(2)-inversion of
anti-α-hydroxy-β-amino ester 7 under Mitsunobu conditions17
returned only starting material, it was proposed that intra-
molecular inversion using neighbouring group participation of
an N-Boc protected anti-α-hydroxy-β-amino ester would lead
directly to oxazolidinone formation.18 Following this hypo-
thesis, secondary N-Boc species 12 was prepared by selective
N-protection of primary amino anti-α-hydroxy-β-amino ester 8
in 90% yield. Treatment of 12 with methanesulfonyl chloride in
DCM allowed formation of the C(2)-mesylate 13 in 90% yield,
which upon heating in DMF gave the desired trans-(4R,5S)-
oxazolidinone 14 as a single diastereoisomer in 77% isolated
yield. Subsequent reduction with Superhydride gave (4R,5S)-
epi-cytoxazone 5 in 94% yield and 98% de, with comparable
spectroscopic properties to those described in the literature
{[α]D20 ϩ28.6 (c 1.0, MeOH), lit.6 [α]2D5 ϩ28.8 (c 0.59, MeOH)}
(Scheme 5).
Conclusions
In conclusion, we have shown that homochiral (4R,5R)-cytox-
azone 1 may be prepared in four steps and in 61% overall yield
via an efficient protocol that compares well to the other pub-
lished synthetic routes (10% to 51% yield) to this natural prod-
uct. The synthesis of (4R,5R)-cytoxazone 1 involves a protocol
involving conjugate addition of lithium (R)-N-benzyl-N-α-
methylbenzylamide 3 and subsequent in situ diastereoselective
enolate oxidation, followed by hydrogenolysis, oxazolidinone
formation and reduction. (4R,5S)-epi-Cytoxazone has been
prepared in 44% overall yield by a strategy involving intra-
molecular N-Boc participation to facilitate oxazolidinone
Scheme 3 Reagents and conditions: (i). Superhydride, THF, 0 ЊC to rt;
(ii). DIBAL-H, DCM, 0 ЊC to rt; (iii) TFA, DCM, rt, 1 h; then ClCO2Et
(1.5 eq.), THF, NEt3, rt, 2 h; then NaBH4, AcOH, diglyme, 0 ЊC.
Synthesis of (4R,5S )-epi-cytoxazone
With the asymmetric synthesis of (4R,5R)-cytoxazone 1 com-
plete, further investigations focused upon the preparation of
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 4 9 – 1 5 5 3
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Transform spectrophotometer using either a CHCl3 cell
(CHCl3) or a KBr disc (KBr). Only the characteristic peaks are
quoted. Low-resolution mass spectra (m/z) were recorded on
VG MassLab 20–250 or Micromass Platform 1 spectrometers
and high-resolution mass spectra (HRMS) on a Micromass
Autospec 500 OAT spectrometer. Techniques used were chem-
ical ionisation (CI, NH3), atmospheric pressure chemical
ionisation (APCI) using partial purification by HPLC with
methanol : acetonitrile : water (40 : 40 : 20) as eluent or electro-
spray ionisation (ESI). Optical rotations were recorded on a Per-
kin-Elmer 241 polarimeter with a path length of 1 dm. Concen-
trations are quoted in g 100 mLϪ1. Melting points were recorded
on a Leica VMTG Galen III apparatus and are uncorrected.
Elemental analyses were performed by the microanalysis service
of the Inorganic Chemistry Laboratory, Oxford.
Preparation
of
(2R,3R,ꢀR)-tert-butyl
2-hydroxy-3-
(p-methoxyphenyl)-3-(N-benzyl-N-ꢀ-methylbenzylamino)-
propanoate 7. BuLi (2.5 M in hexanes, 2.6 mL, 6.4 mmol) was
added dropwise to a stirred solution of the (R)-α-N-methyl-
benzyl-N-benzylamine (1.4 g, 6.8 mmol) in THF (40 mL) at
–78 ЊC. After thirty minutes a solution of (E)-6 (1.0 g, 4.2
mmol) in THF (40 mL) at Ϫ78 ЊC was added dropwise via can-
nula. After a further two hours solid (ϩ)-CSO (1.6 g, 6.8 mmol)
was added and the mixture warmed to rt overnight before being
partitioned between 10% aqueous citric acid solution and
DCM. The combined organic layers were dried, filtered and
concentrated in vacuo. Purification via flash column chromato-
graphy on silica (30–40 petroleum : Et2O, 9 : 1) gave (2R,3R,
Scheme 5 Reagents and conditions: (i). Boc2O, NaHCO3, MeOH,
rt, sonication; (ii). MsCl, NEt3, DCM, 0 ЊC to rt; (iii). DMF, 60 ЊC;
(iv). Superhydride, DCM, 0 ЊC to rt.
formation and simultaneous C(2)-hydroxyl inversion, and sub-
sequent deprotection. The synthetic strategy detailed herein is
equally applicable to the synthesis of the (4S,5S)- and (4S,5R)-
stereoisomers of cytoxazone using the conjugate addition of
lithium (S)-N-benzyl-N-α-methylbenzylamide, and the appli-
cation of this strategy to a variety of related natural products is
currently underway.
25
αR)-7 as a colourless oil (1.54 g, 79%). [α]D Ϫ2.5 (c 1.9,
CHCl3); νmax (CHCl ) 3020 (O–H), 1720 (C᎐O); δ (400 MHz,
᎐
3
H
CDCl3) 1.21 (3H, d, J 6.8, C(α)Me), 1.22 (9H, s, C(Me)3), 2.76
(1H, br s, OH ), 3.79 (1H, d, J 15.0, NCHA), 3.80 (3H, s, OMe),
4.11 (1H, d, J 15.0, NCHB), 4.16 (1H, d, J 3.3, C(3)H ), 4.20
(1H, q, J 6.8, C(α)H ), 4.38 (1H, d, J 3.3, C(2)H ), 6.85 (2H, d,
J 8.9, ArorthoH ), 7.40 (2H, d, J 8.9, ArmetaH ), 7.17–7.49 (10H, m,
PhH ); δC (100 MHz, CDCl3) 13.9 (C(α)Me), 27.7 (C(Me)3),
52.2 (C(α)H), 55.2 (CH2), 57.1 (OMe), 65.2 (C(3)H), 73.4
(C(Me)3), 82.1 (C(2)H), 113.2, 113.3 (Arortho, C6H4–OMe),
Experimental
General
126.6, 126.8 (Phpara), 127.9, 128.0, 128.1, 128.2, 130.2 (Phortho
,
All reactions involving organometallic or other moisture
sensitive reagents were performed under an atmosphere of dry
nitrogen using standard vacuum line techniques. All glassware
was flame-dried and allowed to cool under vacuum. In all cases,
the reaction diastereoselectivity was assessed by peak inte-
gration in the 1H NMR spectrum of the crude reaction mixture.
THF was distilled under an atmosphere of dry nitrogen from
sodium benzophenone ketyl. DCM was distilled under an
atmosphere of dry nitrogen from calcium hydride. Et2O was
distilled under an atmosphere of dry nitrogen from sodium
benzophenone ketyl. Water was distilled. All other solvents
were used as supplied (Analytical or HPLC grade), without
prior purification. All organometallic reagents were used as
supplied. All other reagents were used as supplied, without
prior purification. Reactions were dried with MgSO4. Thin
layer chromatography (TLC) was performed on aluminium
sheets coated with 60 F254 silica. Sheets were visualised using
UV light, iodine, phosphomolybdic acid (PMA) solution, or
KMnO4 solution. Flash column chromatography was per-
formed on Kieselgel 60 silica. Nuclear Magnetic Resonance
(NMR) spectra were recorded on a Bruker DPX 400 (1H: 400
MHz and 13C: 100 MHz), Bruker AV 400 (1H: 400 MHz and
13C: 100 MHz), or where stated on a Bruker DPX 200 (1H: 200
MHz and 13C: 50 MHz) or AMX 500 (1H: 500 MHz and 13C:
125 MHz) in the deuterated solvent stated. All chemical
shifts (δ) are quoted in ppm and coupling constants (J) in Hz.
Coupling constants are quoted twice, each being recorded as
observed in the spectrum without averaging. Residual signals
from the solvents were used as an internal reference. Infrared
spectra were recorded on a Perkin-Elmer 1750 IR Fourier
Phmeta, Arpara, C6H4–OMe) 130.9, 131.0 (Armeta, C6H4–OMe),
141.9, 144.2 (Phipso), 158.9 (Aripso, C6H4–OMe), 172.1 (CO); m/z
ϩ
(APCIϩ) 462 (MHϩ, 2%), 195 (100); HRMS (CI) C29H36NO4
requires 462.2644; found 462.2642.
Preparation of (2R,3R)-tert-butyl 2-hydroxy-3-amino-3-
(p-methoxyphenyl)propanoate 8. Pearlman’s catalyst (0.5 g) was
added to a solution of 7 (1.5 g, 3.0 mmol) in degassed MeOH
(10 mL) and stirred vigorously under five atmospheres of H2
gas for 24 hours. The reaction mixture was then filtered through
Celite® (eluent MeOH) and concentrated in vacuo to afford the
crude product as a yellow solid. Purification via flash column
chromatography on silica (Et2O : MeOH, 9 : 1) gave (2R,3R)-8
as a colourless solid (0.77 g, 96%); C14H21NO4 requires C, 62.90;
H, 7.92; N, 5.24%; found C, 63.00; H, 7.79; N, 5.54%; [α]2D5 Ϫ1.2
(c 2.1, CHCl3); mp 111–114 ЊC; νmax (KBr) 3366 (N–H), 3287
(O–H), 1734 (C᎐O); δ (500 MHz, CDCl3), 1.35 (9H, s,
᎐
H
C(Me)3), 2.28 (3H, br s, NH2 and OH ), 3.77 (3H, s, OMe), 4.21
(1H, d, J 3.6, C(2)H ), 4.31 (1H, d, J 3.6, C(3)H ), 6.83 (2H, d,
J 8.9, ArorthoH ), 7.24 (2H, d, J 8.9, ArmetaH ); δC (125MHz,
CDCl3) 27.8 (CMe3), 57.4 (OMe), 74.8 (CMe3), 77.2 (C(3)H),
82.5 (C(2)H), 113.4, 113.6 (Arortho), 128.3, 128.4 (Armeta), 132.8
(Arpara), 158.9 (Aripso), 171.6 (CO); m/z (APCIϩ) 268 (MHϩ,
ϩ
12%), 195 (100); HRMS (CI) C14H22NO4 requires 268.1549,
found 268.1542.
Preparation of (4R,5R)-4-(p-methoxyphenyl)-5-tert-butoxy-
carbonyl oxazolidin-2-one 9. (i). With CDI; to a solution of 8
(100 mg, 0.40 mmol) in THF (3 mL) were added carbonyl
diimidazole (100 mg, 0.60 mmol) and DMAP (10 mg, 0.08
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 4 9 – 1 5 5 3
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mmol). The reaction mixture was stirred for 24 h at rt before
addition of saturated aqueous NH4Cl (2 mL). The aqueous
phase was extracted with EtOAc (3 × 5 mL), washed with brine
(10 mL), dried, filtered and concentrated in vacuo. Purification
via flash column chromatography (Et2O) gave (4R,5R)-9 as a
colourless solid (42 mg, 36%).
ꢀ-methylbenzylamino)prop-2-enoate 11. Compound 7 (100 mg,
0.22 mmol) and IBX (67 mg, 0.24 mmol) were stirred in DMSO
(5 mL) for 16 h. H2O (10 mL) was added and the mixture
extracted with DCM (3 × 5 mL), washed with H2O (5 × 5 mL)
dried, filtered and concentrated in vacuo to yield a crude
1
product. H 400 MHz NMR spectroscopic analysis obtained
(ii). With diphosgene; diphosgene (0.29 mL, 2.39 mmol)
was added dropwise to a stirred suspension of 8 (580 mg,
2.17 mmol) and activated charcoal (100mg) in toluene (20 mL)
and the mixture stirred for 1 h at rt before refluxing for 4 h.
After recooling to rt, the mixture was filtered through Celite®
and concentrated in vacuo to yield a crude product which was
washed with saturated aqueous NH4Cl (20 mL), extracted with
EtOAc (3 × 20 mL), dried, filtered and concentrated in vacuo.
Purification via flash column chromatography (Et2O) gave
(4R,5R)-9 as a colourless solid (550 mg, 88%); [α]2D5 Ϫ1.3
immediately after work-up showed the predominance of
ketone 10; δH (400 MHz, CDCl3) 1.21 (3H, d, J 6.8, C(α)Me),
1.29 (9H, s, C(Me)3), 3.79 (3H, s, OMe), 3.97 (1H, d, J 15.5,
NCHA), 4.14 (1H, d, J 15.5, NCHB), 4.20 (1H, q, J 6.8,
C(α)H ), 5.33 (1H, s, C(3)H ), 7.14–7.50 (14H, m, ArH, PhH );
δC (100 MHz, CDCl3) 19.4 (C(α)Me), 27.5 (C(Me)3), 51.2
(C(α)H), 55.2 (CH2), 59.6 (OMe), 67.4 (C(3)H), 73.4 (C(Me)3),
114.0, 114.3 (Arortho), 126.3, 126.4, 126.7, 127.0, 127.2, 127.5,
128.0, 128.1, 128.2, 128.4 (Phortho, Phmeta, Phpara, Arpara) 131.0,
131.3 (Armeta), 142.2, 144.3 (Phipso), 159.4 (CO), 160.9 (Aripso),
196.5 (C(2)O); After standing for 2.5 h the ketone 10 had
tautomerised to the enol form 11; δH (400 MHz, CDCl3) 1.06
(9H, s, C(Me)3), 1.60 (3H, d, J 6.9, C(α)Me), 3.80 (3H, s, OMe),
3.97 (1H, d, J 15.7, NCHA),4.05 (1H, d, J 15.7, NCHB), 4.87
(1H, q, J 6.9, C(α)H ), 6.75–7.50 (14H, m, ArH, PhH ); δC (100
MHz, CDCl3) 18.4 (C(α)Me), 27.6 (C(Me)3), 48.3 (C(α)H), 55.3
(CH2), 58.7 (OMe), 73.4 (C(Me)3), 112.9 (C2), 114.0, 114.3
(Arortho), 127.0, 127.1, 127.2, 127.4, 127.5, 127.7, 127.9, 128.3,
(c 1.8, CHCl3), mp 153–155 ЊC; νmax (KBr) 1778 (C᎐O, oxazol-
᎐
idinone), 1744 (C᎐O, ester); δ (400 MHz, CDCl ) 1.07 (9H, s,
᎐
H
3
CMe3), 3.80 (3H, s, OMe), 5.11 (1H, d, J 9.3, C(5)H ), 5.15 (1H,
d, J 9.3, C(4)H ), 5.99 (1H, br s, NH ), 6.88 (2H, d, J 8.8,
ArorthoH ), 7.24 (2H, d, J 8.8, ArmetaH ); δC (100 MHz, CDCl3)
29.0 (CMe3), 50.6 (C(4)H), 55.4 (OMe), 77.9 (CMe3), 83.0
(C(5)H), 114.1 (Arortho), 127.9 (Armeta), 128.7 (Arpara), 158.4
(Aripso), 160.4 (NCO), 165.3 (CO); m/z (APCIϩ) 294 (MHϩ,
ϩ
90%), 238 (100); HRMS (CI) C15H20NO5 requires 294.1341,
128.4, 128.5, 128.6, 128.9, 129.0 (Phortho, Phmeta, Phpara, Armeta,
found 294.1352.
Arpara) 132.6 (C3), 140.7, 143.4 (Phipso), 159.6 (Aripso), 166.8
(CO).
Preparation of (4R,5R)-4-(p-methoxyphenyl)-5-hydroxy-
methyl oxazolidin-2-one 16. (i). DIBAL-H (1.0 M in hexanes,
0.85 mL, 0.85 mmol) was added dropwise to a solution of 9 (25
mg, 0.09 mmol) in DCM (2 mL) at 0 ЊC. The resulting solution
was allowed to warm to rt over 6 h before the addition of satur-
ated aqueous NH4Cl. The aqueous layer was extracted with
EtOAc (3 × 5 mL), dried, filtered and concentrated in vacuo.
Purification via flash column chromatography on silica (Et2O :
MeOH, 99 : 1) gave 1 as a colourless solid (15 mg, 75%).
(ii). Superhydride (1.0 M in THF, 0.85 mL, 0.85 mmol) was
added dropwise to a solution of 9 (25 mg, 0.09 mmol) in THF
(2 mL) at 0 ЊC. The resulting solution was allowed to warm to rt
over 6 h before the addition of saturated aqueous NH4Cl. The
aqueous layer was extracted with EtOAc (3 × 5 mL), dried,
filtered and concentrated in vacuo. Purification via flash column
chromatography on silica (Et2O : MeOH, 99 : 1) gave 1 as a
colourless solid (14 mg, 70%).
(iii). Mixed anydride route; 9 (50 mg, 0.17 mmol) was treated
with TFA (1.8 mL) in DCM (0.2 mL) at rt for 1 h before the
volatiles were removed in vacuo to yield a colourless solid. The
residue was coevaporated with DCM–toluene (1 : 1) and
MeOH–toluene (1 : 1). The residue (50 mg, 0.28 mmol) was
treated with ethyl chloroformate (28 mg, 0.26 mmol) and NEt3
(26 mg, 0.26 mmol) in THF (5 mL) at rt and allowed to warm to
rt for 2h, before the addition of NaBH4 (1.02 mL, 0.5 M in
diglyme, 0.51 mmol) at 0 ЊC. The resulting solution was allowed
to warm to rt over 6 h before the addition of saturated aqueous
NH4Cl. The aqueous layer was extracted with EtOAc (3 ×
5 mL), dried, filtered and concentrated in vacuo. Purification via
column chromatography on silica (Et2O : MeOH, 99 : 1) gave 1
as a colourless solid (35 mg, 92%) with spectroscopic data com-
parable to the literature; [α]2D5 Ϫ72.0 (c 1.0, MeOH) {lit.6 [α]D25
Ϫ75.7 (c 1.0, MeOH)}; δH (400 MHz, acetone) 3.17–3.27 (2H,
br m, CH2), 3.81 (3H, s, OMe), 3.86 (1H, br s, OH ), 4.82 (1H,
ddd, J 4.2, J 8.2, J 8.4, C(5)H ), 5.03 (1H, d, J 8.2, C(4)H ), 6.95
(2H, d, J 8.8, ArorthoH ), 6.97 (1H, br s, NH ), 7.25 (2H, d, J 8.8,
ArmetaH ); δC (125 MHz, acetone) 55.6 (OMe), 57.8 (C5), 62.5
(CH2), 81.5 (C4), 114.7 (Arortho), 129.1 (Armeta), 130.3 (Arpara),
159.6 (CO), 160.7 (Aripso).
Preparation of (2R,3R)-tert-butyl 2-hydroxy-3-(p-methoxy-
phenyl)-3-(N-tert-butoxy-carbonylamino)propanoate 12. A solu-
tion of 8 (0.30 g, 1.1 mmol), Boc2O (0.26 g, 1.2 mmol) and
NaHCO3 (0.19 g, 2.2 mmol) in MeOH (5 mL) was sonicated for
12h. The reaction mixture was concentrated in vacuo and par-
titioned between saturated aqueous NH4Cl and Et2O, the com-
bined organic extracts were dried, filtered and concentrated
in vacuo to yield a crude product. Purification via flash column
chromatography on silica (30–40 petroleum : Et2O, 1 : 1)
afforded (2R,3R)-12 as a colourless oil (0.37 g, 90%); [α]2D5 Ϫ1.5
(c 3.8, CHCl3); νmax (CHCl ) 3020 (O–H), 1710 (br, 2 × C᎐O); δ
᎐
3
H
(400 MHz, CDCl3) 1.37 (9H, s, N–Boc), 1.47 (9H, s, C(Me)3),
3.30 (1H, br s, OH ), 3.78 (3H, s, OMe), 4.46 (1H, br s, NH ),
5.01 (1H, d, J 8.8, C(2)H ), 5.57 (1H, d, J 8.8, C(3)H ), 6.83 (2H,
d, J 8.7, ArorthoH ), 7.26 (2H, d, J 8.7, ArmetaH ); δC (100 MHz,
CDCl3) 27.9 (Boc–CMe3), 28.4 (CMe3), 55.2 (C(3)H), 55.7
(OMe), 73.1 (Boc–CMe3), 79.7 (CMe3), 83.4 (C(2)H), 113.6,
113.8 (Arortho), 129.0, 129.1 (Armeta), 129.4 (Arpara), 154.9 (Boc-
CO), 159.3 (Aripso), 171.0 (CO); m/z (APCIϩ) 368 (MHϩ 2%) 195
(100); HRMS (CI) C19H28NO6Naϩ requires 390.1893, found
390.1881.
Preparation of (2R,3R)-tert-butyl 2-methanesulfonyloxy-3-
(p-methoxyphenyl)-3-(N-tert-butoxy-carbonylamino)propanoate
13. Methanesulfonyl chloride (0.09 mL, 1.13 mmol) was added
to a stirred solution of 12 (395 mg, 1.08 mmol) and NEt3
(0.21 mL, 1.51 mmol) in DCM (20 mL) at 0 ЊC and stirred for
40 minutes, before warming to rt. After stirring for 24 h, the
reaction mixture was quenched with H2O (10 mL), extracted
with DCM (4 × 20 mL), washed with brine, dried, filtered and
concentrated in vacuo to yield the crude product. Purifi-
cation via flash column chromatography on silica (30–40 ЊC
petroleum : Et2O, 1 : 1) afforded 13 as a pale yellow oil (432 mg,
0.97 mmol, 90%); [α]2D5 Ϫ18.2 (c 2.0, CHCl3); νmax (thin film)
1749 (C᎐O ester), 1712 (C᎐O carbamate); δ (400 MHz, CDCl )
᎐
᎐
H
3
1.32 (9H, s, N-Boc), 1.43 (9H, s, C(Me)3), 3.14 (3H, s, SO2Me),
3.78 (3H, s, OMe), 5.21–5.22 (2H, m, NH & C(2)H ), 5.43 (1H,
d, J 3.2, C(3)H ), 6.82–6.86 (2H, m, ArorthoH ), 7.28 (2H, d, J 8.3,
ArmetaH ); δC (100 MHz, CDCl3) 27.8 (Boc-CMe3), 28.3 (CMe3),
39.1 (SO2Me), 54.6 (C(3)H), 55.2 (OMe), 79.2 (C(2)H), 80.3
(Boc-CMe3), 83.8 (CMe3), 113.9 (Arortho), 127.9 (Arpara), 129.3
(Armeta), 154.8 (Aripso), 159.6 (Boc-CO), 165.5 (CO); m/z (CIϩ)
Preparation of (3R,ꢀR)-tert-butyl 2-oxo-3-(p-methoxy-
phenyl)-3-(N-benzyl-N-ꢀ-methylbenzylamino)propanoate 10 and
(ꢀR)-tert-butyl 2-hydroxy-3-(p-methoxyphenyl)-3-(N-benzyl-N-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 4 9 – 1 5 5 3
1552

View Article Online
468 (MNaϩ, 100%), 366 (25), 334 (40), 273 (40); HRMS (CI)
C20H31NO8SNaϩ requires 468.1668, found 468.1662.
Acknowledgements
The authors wish to acknowledge New College, Oxford, for a
Junior Research Fellowship (A. D. S).
Preparation of (4R,5S )-4-(p-methoxyphenyl)-5-tert-butoxy-
carbonyl oxazolidin-2-one 14. A solution of 13 (370 mg,
0.83 mmol) in DMF (20 mL) was warmed to 60 ЊC for 18 h,
then cooled to rt. After stirring for a further 24 h, the reaction
mixture was diluted with water, extracted with DCM (5 ×
20 mL), dried, filtered and concentrated in vacuo to yield a
crude product (330 mg). Purification by column chromato-
graphy on silica (30–40 ЊC petroleum : Et2O, 1 : 1) afforded 14
as a white solid (187 mg, 0.64 mmol, 77%); mp 104–105 ЊC
(pentane–Et2O); [α]2D2 ϩ94.7 (c 0.55, MeOH); νmax (KBr disc)
References and notes
1 H. Kakeya, M. Morishita, H. Koshino, T. Morita, K. Kobayashi
and H. Osada, J. Org. Chem., 1999, 64, 1052.
2 H. Kakeya, M. Morishita, K. Kobinata, M. Osono, M. Ishizuka and
H. Osada, J. Antibiot., 1998, 51, 1126.
3 Z. Hamersak, E. Ljubovic, M. Mercep, M. Mesic and V. Sunjic,
Synthesis, 2001, 13, 1989.
4 O. Miyata, H. Asai and T. Naito, Synlett, 1999, 12, 1915.
5 A. Madham, A. R. Kumar and B. V. Rao, Tetrahedron: Asymmetry,
2001, 12, 2009.
1771 (C᎐O ester), 1726 (C᎐O oxazolidin-2-one); δ (400 MHz,
᎐
᎐
H
CDCl3) 1.51 (9H, s, C(Me)3), 3.81 (3H, s, OMe), 4.58 (1H, d,
J 5.7, C(2)H ), 4.86 (1H, d, J 5.7, C(3)H ), 6.66 (1H, s, NH ),
6.90–6.93 (2H, m, ArorthoH ), 7.26–7.28 (2H, m, ArmetaH ); δC
(100 MHz, CDCl3) 27.9 (CMe3), 55.3 (OMe), 58.9 (C(3)H),
80.9 (C(2)H), 83.6 (CMe3), 114.5 (Arortho), 127.3 (Armeta), 131.1
(Arpara), 15.83 (NCO), 160.0 (CO), 167.3 (Aripso); m/z (ESϪ) 292
(M Ϫ Hϩ, 100%); HRMS (ESϪ) C15H19NO5 Ϫ Hϩ requires
292.1185, found 292.1177.
6 Y. Sakamoto, A. Shiraishi, J. Seonhee and T. Nakata, Tetrahedron
Lett., 1999, 40, 4203.
7 M. Seki and K. Mori, Eur. J. Org. Chem., 1999, 2965.
8 S. Milicevic, R. Matovic and R. N. Saicic, Tetrahedron Lett., 2004,
45, 955.
9 P. H. Carter, J. R. LaPorte, P. A. Scherle and C. P. Decicco, Bioorg.
Med. Chem. Lett., 2003, 13, 1237.
10 A. N. Chernaga, M. E. Bunnage, S. G. Davies and C. J. Goodwin,
J. Chem. Soc., Perkin Trans. 1, 1994, 2373.
11 D. Ma, T. Zhang, G. Wang, A. P. Kozikowski, N. E. Lewin and
P. M. Blumberg, Bioorg. Med. Chem. Lett., 2001, 10, 99.
12 P. Deprez, J. Royer and H-P. Husson, Tetrahedron, 1993, 49,
3781.
13 S. Harashima, O. Oda, S. Amemiya and L. Kojima, Tetrahedron,
1991, 47, 2773.
14 M. M. Kabat, L. M. Garofalo, A. R. Daniewski, S. D. Hutchings,
W. Liu, M. Okabe, R. Radinov and Y. Zhou, J. Org. Chem., 2001, 66,
6141.
15 C. G. Boojamra, R. C. Lemoine, J. C. Lee, R. Léger, K. A. Stein,
N. G. Vernier, A. Magon, O. Lomovskaya, P. K. Martin,
S. Chamberland, M. D. Lee, S. J. Hecker and V. J. Lee, J. Am. Chem.
Soc., 2001, 123, 870.
16 T. T. Tidwell, Org. React., 1990, 39, 297.
17 M. E. Bunnage, S. G. Davies and C. J. Goodwin, J. Chem. Soc.,
Perkin Trans. 1, 1994, 2385.
18 For another recent application of this strategy see : M. E. Bunnage,
A. J. Burke, S. G. Davies, N. L. Millican, R. L. Nicholson, P. M.
Roberts and A. D. Smith, Org. Biomol. Chem., 2003, 3708. For a
related protocol for C(2)-inversion of α-hydroxy-β-amino esters see
reference 17.
Preparation of (4R,5S )-4-(p-methoxyphenyl)-5-hydroxy-
methyl oxazolidin-2-one 5. Superhydride (1.0 M in THF,
2.05 mL, 2.05 mmol) was added dropwise to a solution of 14
(150 mg, 0.51 mmol) in THF (20 mL) at 0 ЊC. The resulting
solution was allowed to warm to rt over 6 h before the addition
of saturated aqueous NH4Cl. The aqueous layer was extracted
with EtOAc (3 × 15 mL), dried, filtered and concentrated in
vacuo. Purification via flash column chromatography on silica
(Et2O : MeOH, 99 : 1) gave 5 (107 mg, 94%) as a colourless
solid; mp 158–160 ЊC (MeOH–Et2O); [α]2D3 ϩ28.6 (c 1.0,
MeOH); δH (500 MHz, CD3OD) 3.69 (1H, dd, J 4.5, J 12.5,
CHA), 3.79 (3H, s, OMe), 3.82 (1H, dd, J 3.5, J 12.5, CHB), 4.32
(1H, ddd, J 3.5, J 4.5, J 6.5, C(5)H ), 4.75 (1H, d, J6.5, C(4)H ),
6.96 (2H, d, J 8.5, ArorthoH ), 7.30 (2H, d, J 8.5, ArmetaH );
δC (125MHz, CD3OD) 55.9 (OMe), 58.7 (C5), 62.6 (CH2), 87.0
(C4), 115.6 (Arortho), 128.8 (Armeta), 133.7 (Arpara), 160.8 (CO),
161.5 (Aripso).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 4 9 – 1 5 5 3
1553