Towards a simplified peloruside A: Synthesis of C1-C11 of a dihydropyran analogue

Article abstract of DOI:10.1016/j.tet.2011.09.131

A simplified analogue of the C1-C11 fragment of peloruside A has been synthesised starting from a monoprotected 2,2-dimethylpropane-1,3-diol. Oxidation, asymmetric allylation and acryloylation provided a substrate for ring-closing metathesis to a δ-lacton

Full text of DOI:10.1016/j.tet.2011.09.131

Tetrahedron 67 (2011) 9376e9381
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Towards a simplified peloruside A: synthesis of C1eC11 of a dihydropyran
analogue
,
,
*
Emma M. Casey a y, Febly Tho a, Joanne E. Harveya, Paul H. Teesdale-Spittle b
a Centre for Biodiscovery, School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
b Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2011
Received in revised form 11 September 2011
Accepted 26 September 2011
Available online 6 October 2011
A simplified analogue of the C1eC11 fragment of peloruside A has been synthesised starting from
a monoprotected 2,2-dimethylpropane-1,3-diol. Oxidation, asymmetric allylation and acryloylation
provided a substrate for ring-closing metathesis to a d-lactone. Reduction, acylation and homologation
with trimethyl(vinyloxy)silane provided a protected C3eC11 analogue in a stereoisomer manner. In-
troduction of the C1eC2 fragment and incorporation of the 2,3-syn stereochemistry was achieved by
a boron-mediated Evans aldol reaction.
Keywords:
Peloruside A
Laulimalide
Ó 2011 Elsevier Ltd. All rights reserved.
Analogue synthesis
Metathesis
Aldol reaction
1. Introduction
glycoprotein-mediated efflux,5 synergistic activity with taxoid site
binders,6 interactions with a previously uncharacterised binding
Microtubule stabilisers such as the taxanes and epothilones are
among the most successful anti-cancer drugs in current use.1 With
one in four deaths in the United States during 2010 attributed to
cancer,2 there is an ongoing need for improved clinical agents.
Peloruside A (1, Fig. 1) is a microtubule stabilising agent3 that was
first reported by Northcote et al. in 20004 and has sparked a flurry
of biological and chemical endeavour. It has high potency against
cancer cells, low susceptibility towards resistance through P-
site on tubulin,5 and a unique mode of microtubule stabilisation.7
In vivo animal study data show that peloruside A has good phar-
macokinetic and pharmacodynamic profiles,8 indicating that
compounds based on its structure will be especially useful agents in
cases where resistance to existing drugs forces the termination of
treatment.
To date there have been six total syntheses of peloruside A,9e15
along with a number of syntheses of fragments and analogues,
including the C1eC1116,17 and C12eC24 fragments,18 the un-
expected synthesis of (ꢀ)-2-epi-peloruside A,19 a monocyclic ana-
logue,20 and the naturally occurring congener peloruside B (2,
Fig. 1).21
There is experimental evidence pointing to a peloruside A
binding site on b-tubulin that coincides with that of laulimalide (3,
Fig. 1),5 a highly potent macrolide isolated from the sponge Caco-
spongia mycofijiensis that also stabilises microtubules.22 However,
uncertainty remains about the exact binding mode of peloruside A
within this site.7
There are a number of structural changes that might be explored
in seeking an analogue that is as potent as, and synthetically more
tractable than, peloruside A. It is noticeable that with existing an-
alogues or congeners of peloruside A, removal or modification of
the pyran impacts severely on cytotoxicity, suggesting that the
presence and position of the pyran ring are crucial to the binding/
activity.20,23 In order to probe this further, we have chosen to
Fig. 1. Structures of peloruside A (1), peloruside B (2) and laulimalide (3).
* Corresponding author. Tel.: þ64 4 463 6094; fax: þ64 4 463 5339; e-mail ad-
dress: paul.teesdale-spittle@vuw.ac.nz (P.H. Teesdale-Spittle).
y
Current address: Department of Pharmacy and Pharmacology, University of
Bath, Bath BA2 7AY, UK.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.131

E.M. Casey et al. / Tetrahedron 67 (2011) 9376e9381
9377
replace the pyranose ring of peloruside A with the dihydropyran of
laulimalide, leading conceptually to analogue 4 (Scheme 1). The
laulimalide-like dihydropyran presents the advantages over the
peloruside A tetrahydropyran of having two fewer chiral centres
and no hemiacetal functionality, thereby allowing greater ease of
synthesis and higher metabolic stability. Several syntheses of lau-
limalide have been undertaken, with the most relevant to our work
being that of Ghosh and Wang who prepared the dihydropyran
using ring-closing methathesis.24
a reliably high yield under Swern conditions to provide aldehyde
13. Allylation using Brown’s boron-mediated asymmetric meth-
odology provided secondary alcohol 10. Although removal of
magnesium salts created during the standard preparation of the
allyldiisopinocampheylborane has been reported to improve
enantioselectivity,26 we found this to be unnecessary and we were
able to obtain an ee of at least 95% according to Mosher ester
analysis. Alcohol 10 was esterified with acryloyl chloride; sub-
sequent ring-closing metathesis of the resulting diene 9 using
Grubbs’ second generation catalyst provided lactone 14. Although
a single step conversion equivalent to transformation of aldehyde
13 to lactone 14 via a vinylogous aldol reaction has been achieved,27
our three-step approach allowed us to obtain good stereochemical
control and a higher overall yield than reported for the single step
transformation.
Scheme 1. Retrosynthetic strategy for the synthesis of simplified peloruside A ana-
logue, 4.
For optimal convergence in a synthetic strategy, precedent has
shown it to be ideal to disconnect the macrocycle of peloruside A at
both the lactone and a bond in the C9eC13 region. Two of the prior
total syntheses have selected the C11eC12 bond for this latter
purpose,12,14 and the same strategy was implicit in the reported
synthesis of the C12eC24 fragment by Stocker, Hoberg and our-
selves.18,25 We have thus targeted the synthesis of a C1eC11 ana-
logue in the work presented here.
Our retrosynthetic analysis of the C1eC11 fragment of analogue
4 (viz. compound 5) is shown in Scheme 1. A 1,2-syn-aldol reaction
between aldehyde 6 and an Evans oxazolidinone 7 was envisaged
to set the C2eC3 stereochemistry. Aldehyde 6 would be obtained by
substitution of lactol acetate 8 with a vinyl enol ether nucleophile.
Lactol acetate 8 would be synthesised by ring-closing metathesis of
diene 9, followed by reduction and acetylation. Diene 9 would ul-
timately be derived from acryloyl chloride and alcohol 10, the
product of an asymmetric Brown allylation of an unsymmetrically
oxidised 1,3-propanediol.
Scheme 2. Synthesis of C3eC11 fragment 6 via lactone 14.
Synthesis of the C3eC11 fragment was completed in three fur-
ther steps without purification of the intermediates in order to
minimise degradation. Thus, careful reduction of 14 with DIBAL-H
provided the hemiacetal 15 as a ca. 5:1 mixture of diastereomers,
accompanied by about 10% of the ring-open aldehyde congener.
This material was immediately acetylated under mild conditions to
provide lactol acetate 8, again as a mixture of diastereomers.
Treatment with trimethyl(vinyloxy)silane under Lewis acidic con-
ditions provided the C3eC11 aldehyde 6 in good overall yield, now
as a single diastereomer. The laulimalide-like trans substitution
across the dihydropyran of aldehyde 6 was confirmed by the ob-
servation of NOE correlations between H9 and H4a (Fig. 2). This
stereochemical control presumably arises from steric shielding of
one face of the conjugated oxonium intermediate by the bulky C9
substituent.
2. Results and discussion
The synthesis of the C5eC11 fragment of analogue 4 proceeded
as described in Scheme 2. Synthesis of allylic alcohol 10 began with
monoprotection of 1,3-propanediol (11) to provide 12 in reasonable
yield. Formation of the accompanying bis-protected product was
minimised by using a slight excess of 11 over the protecting group.
While several possible protecting groups were considered, ulti-
mately the TBS group was chosen to provide stability through the
synthesis of the C1eC11 fragment, whilst allowing orthogonal
deprotection prior to oxidation and subsequent aldol coupling to
a C12eC24 fragment. Alcohol 12 was subsequently oxidised in
Fig. 2. NOE correlations within
substituents.
6 confirming the trans-orientation of the ring
The required syn-relationship between the C2 and C3 sub-
stituents was set using an Evans’ oxazolidinone-directed 1,2-syn-
aldol reaction.28 Oxazolidinone glycolate
7
is well known.29

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E.M. Casey et al. / Tetrahedron 67 (2011) 9376e9381
However, we found the literature preparation via a pivaloyl mixed
anhydride was prone to formation of the undesired pivaloylated
Evans auxiliary as a persistent contaminant. For this reason, 7 was
generally prepared by acylation of the lithium salt of benzyl oxa-
zolidinone through HBTU-mediated coupling with commercially
available glycolic acid derivative 16, albeit in modest yield (Scheme
3). Reaction of the boron enolate of 7 with aldehyde 6 proceeded
smoothly to give the 1,2-syn-adduct in excellent yield with a di-
astereomeric ratio of 10:1 (according to NMR analysis of the crude
material). We noted a tendency for 17 to undergo a retro-aldol
reaction, so although 17 could be synthesised in yields of up to
90%, methyl ether 5 was most reliably prepared when the resulting
alcohol was methylated without significant delay using Meerwein’s
salt to produce the fully protected C1eC11 fragment 5. The use of
no more than 2 equiv of fresh, high grade Meerwein’s salt was
optimal for this transformation. Retro-aldol products were noted
when using older bottles of reagent, while loss of the auxiliary and
formation of the methyl ester provided a competing reaction that
was promoted by use of larger excesses of Meerwein’s salt.
depending on scale (ca. 70e75%). However, use of TEMPO and the
co-oxidant PhI(OAc)2 at room temperature appears to provide the
desired aldehyde in high yield (ca. 85%) without the requirements
for inert atmosphere, anhydrous conditions or low temperatures.
Scheme 4. Completion of the C1-C11 fragment 20.
3. Conclusion
The C1eC11 fragment of a novel peloruside A-laulimalide ana-
logue has been completed. Successful synthesis of the C3eC11
fragments using a ring-closing metathesis reaction was followed by
incorporation of the C1eC2 moiety, utilising a boron-mediated
Evans aldol reaction to set the desired 1,2-syn stereochemistry at
C2 and C3. Protecting group manipulation allowed the synthesis of
the C1eC11 alcohol, oxidation of which completed the fragment.
4. Experimental section
4.1. General
Scheme 3. Synthesis of protected C1eC11 oxazolidinone 5.
Unless otherwise stated, the following conditions apply. All re-
actions were performed under argon in oven-dried or flame-dried
glassware using dry solvents and standard syringe techniques.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were distilled from
the sodium benzophenone ketyl radical ion. Dichloromethane
(CH2Cl2), triethylamine (Et3N), and acetonitrile (MeCN) were by
Stocker, Hoberg and ourselves distilled from calcium hydride. Tol-
uene, hexanes and methanol (MeOH) were distilled from sodium.
Diisopropylethylamine (i-Pr2NEt) and pyridine were distilled from
sodium hydroxide. Acetone was distilled from potassium carbon-
ate. Anhydrous dimethylformamide (DMF) and dimethylsulfoxide
(DMSO) were purchased from Aldrich Chemical Company and were
used without further purification. Sodium hydride (NaH) was ob-
tained as a 60% suspension in mineral oil, washed three times with
dry hexanes and dried under vacuum immediately prior to use. All
other reagents were of commercial quality and distilled prior to use
if necessary.
Reaction progress was monitored using aluminium-backed thin
layer chromatography (TLC) plates pre-coated with silica UV254
and visualised by either UV radiation (254 nm), ceric ammonium
molybdate dip or potassium permanganate dip. Purification of
products via flash chromatography was conducted using a column
filled with silica gel 60 (220e240 mesh) with solvent systems as
indicated. 1H and 13C NMR spectra were recorded on either a Varian
Unity Inova 300 (300 MHz for 1H and 75 MHz for 13C), a Varian
Unity Inova 500 (500 MHz for 1H and 125 MHz for 13C), or a Varian
DirectDrive 600 (600 MHz for 1H and 150 MHz for 13C) spectrom-
Conversion of oxazolidinone 5 into a C11 aldehyde that would
undergo aldol reaction with the C12eC24 portion of the analogue 4
was then explored. It was deemed necessary at this stage to remove
the Evans auxiliary, in order to improve the solubility of the C1eC11
fragment for further reactions. Unfortunately, formation of the
methyl ester from the above-mentioned reaction of 5 with excess
Meerwein’s salt was not sufficiently reliable or high yielding to be
useful. Instead, conversion of the auxiliary-bound 5 into the methyl
ester 18 was achieved with sodium methoxide in the presence of
dimethyl carbonate following the methodology of Kanomata et al.
(Scheme 4).30 Formation of methyl ester 18 was typically accom-
panied, in yields of around 30%, by the methyl carbonate produced
from ring opening of the Evans auxiliary. This competing reaction is
likely to result from nucleophile attack at the carbamate carbonyl
due to hindered access for the methoxide to the desired carbonyl
group. Nonetheless, the Kanomata method provided significantly
better results than those obtained without dimethyl carbonate and
reasonable to good yields of 18 were obtained (typically ranging
between 59 and 69%). Removal of the silyl protecting group with
methanolic HCl afforded alcohol 19. The reaction time was critical
as concurrent loss of the PMB group was observed if left longer than
5 min. Thus alcohol 19 has been prepared and is ready for future
coupling studies with the C12eC24 fragment. Preliminary studies
on oxidation of 19 to aldehyde 20, which will be required for aldol
coupling with an appropriate C12eC24 fragment, suggest that the
DesseMartin periodinane oxidation gives variable yields
eter. All chemical shifts (d) were referenced to solvent peaks

E.M. Casey et al. / Tetrahedron 67 (2011) 9376e9381
9379
(1Hdresidual CHCl3, 13CdCDCl3). Infrared spectra were obtained
on either a Biorad FTS-7 spectrometer or a Bruker Tensor 27 FTIR
spectrometer. High-resolution mass spectrometry (HRMS) was
recorded on a Mariner 5158 time of flight spectrometer. Diaster-
eoselectivies were determined by averaging the 1H NMR peak
heights for the diastereotopic signals of the crude product.
Compounds 12 and 13 were prepared following the methodol-
ogy of Richter et al.31 and compound 10 was prepared as described
by Zhan et al.32
1H), 3.34 (d, J¼9.5 Hz, 1H), 2.17e2.09 (m, 1H), 1.92e1.87 (m, 1H),
0.89 (s, 9H), 0.85 (s, 6H), 0.03 (s, 6H). The resulting lactol was
redissolved in CH2Cl2 (104 mL) and Et3N (4.5 mL, 32.3 mmol) was
added followed by Ac2O (2.0 mL, 31.2 mmol) and catalytic DMAP
(0.02 g, 0.16 mmol). The mixture was stirred at rt overnight then
washed successively with satd aq KHSO4 (25 mL), NaHCO3 (25 mL)
and satd aq brine (25 mL). The organic fraction was dried (MgSO4),
filtered and the solvent removed under reduced pressure to pro-
vide the acetate 8. The crude material was dried under vacuum
(0.2 mmHg, 2 h) to remove excess Ac2O; Rf (10:1 hexane/ethyl ac-
4.2. (3S)-1-tert-Butyldimethylsilyloxy-2,2-dimethylhex-5-ene-3-
etate) 0.19; 1H NMR (300 MHz, CDCl3)
d 6.27e6.26 (m, 1H),
yl propenoate (9)
6.18e6.13 (m, 1H), 5.75e5.74 (m, 1H), 3.82 (dd, J¼3.3, 11.6 Hz, 1H),
3.42 (d, J¼9.5 Hz, 1H), 3.30 (d, J¼9.5 Hz, 1H), 2.22e2.18 (m, 1H), 2.12
(s, 3H), 1.97e1.93 (m, 1H), 0.89 (s, 9H), 0.87 (s, 3H), 0.83 (s, 3H), 0.02
(s, 6H). The crude acetate was then redissolved in MeCN (130 mL)
and trimethyl(vinyloxy)silane (2.9 mL, 19.4 mmol) was added fol-
lowed by BF3$OEt2 (0.16 mL, 1.3 mmol). The resulting solution was
stirred at rt for 3.5 h and was then quenched with satd aq NaHCO3
(100 mL). The phases where separated and the aqueous phase was
extracted with CH2Cl2 (3ꢂ100 mL). The organic fractions were
combined, dried (MgSO4), filtered and the solvent removed under
reduced pressure. Flash chromatography (20:1 hexanes/EtOAc)
provided aldehyde 6 (2.39 g, 53% over four steps from diene 9) as
a colourless oil; Rf (10:1 hexane/EtOAc) 0.35; 1H NMR (500 MHz,
To a solution of the allylic alcohol (4.52 g, 17.5 mmol) in CH2Cl2
(96 mL) at 0 ꢁC was added i-Pr2NEt (7.6 mL, 46.6 mmol) followed by
acryloyl chloride (2.8 mL, 34.5 mmol). The reaction mixture was
warmed to rt, stirred overnight and then quenched with satd aq
NH4Cl (50 mL). The phases were then separated, the aqueous phase
was extracted with CH2Cl2 (3ꢂ50 mL) and the organic fractions
combined. The organic fractions were then washed with satd aq
brine (100 mL), dried (MgSO4), filtered and the solvent removed
under reduced pressure. Flash chromatography (20:1 hexanes/
EtOAc) of the crude orange product provided diene 9 as a colourless
oil (4.50 g, 82%); Rf (10:1 hexane/EtOAc) 0.64; 1H NMR (500 MHz,
CDCl3)
d
6.37 (dd, J¼17.3, 1.5 Hz, 1H), 6.10 (dd, J¼17.3, 10.5 Hz, 1H),
CDCl3)
d
9.82 [dd (app. t), J¼2.7, 2.2 Hz, 1H, H-15], 5.96e5.89 (m,
5.79 (dd, J¼10.5, 1.5 Hz, 1H), 5.77e5.70 (m, 1H), 5.09 (dd, J¼10.3,
2.9 Hz, 1H), 5.02 (d, J¼18.6 Hz, 1H), 4.97 (d, J¼10.3 Hz, 1H), 3.33 (d,
J¼5.6 Hz, 2H), 2.46e2.41 (m, 1H), 2.29e2.22 (m, 1H), 0.91 (s, 6H),
0.89 (s, 12H), 0.01 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz, CDCl3)
1H), 5.71e5.65 (m, 1H), 4.79e4.77 (m, 1H), 3.57 (dd, J¼11.0, 3.2 Hz,
1H), 3.43 (d, J¼9.5 Hz, 1H), 3.24 (d, J¼9.5 Hz, 1H), 2.82 (ddd, J¼16.4,
9.5, 2.7 Hz, 1H), 2.45 (ddd J¼16.4, 4.4, 2.2 Hz, 1H), 2.18e2.05 (m,
1H), 1.91e1.83 (m, 1H), 0.89 (s, 9H), 0.83 (s, 3H), 0.82 (s, 3H), 0.02 (s,
d
165.7, 135.3, 130.2, 128.9, 116.8 76.7, 69.2, 39.5, 34.7, 25.8, 20.9,
6H). 13C NMR (125 MHz, CDCl3)
d
201.5, 127.9, 126.4, 70.3, 69.2, 68.9,
20.6, 18.2, ꢀ5.6, ꢀ5.7. IR (KBr disc) 2957, 2930, 2897, 2858, 1728,
1642, 1473, 1404, 1266, 1191, 1100, 984, 850, 775, 669 cmꢀ1. HRMS
(ESI) calcd for C17H33O3Siþ (MþHþ) 313.2199, found 313.2189.
47.3, 38.5, 25.9, 24.8, 20.9, 19.5, 18.3, ꢀ5.5, ꢀ5.6. IR (neat) 2956,
2857, 1724, 1472, 1390, 1362, 1252, 1216, 1094, 906, 837, 730 cmꢀ1
.
HRMS (ESI) calcd for C17H33O3Siþ (MþHþ) 313.2199, found
313.2195.
4.3. (2S,6R)-2-(2-tert-Butyldimethylsilyloxy-1,1-dimethylethyl)-
6-oxoethyl-2,3-dihydro-6H-pyran (6)
4.4. (4S)-3-[1-Oxo-2-(4-methoxybenzyloxy)ethyl]-4-benzyl-2-
oxazolidinone (7)
To a solution of diene 9 (4.50 g, 14.4 mmol) in CH2Cl2 (1440 mL)
was added Grubbs’ second generation catalyst (0.63 g, 0.74 mmol)
at rt. The reaction mixture was stirred overnight at rt then the
solvent was removed under reduced pressure. The resulting residue
was then redissolved in a 10:1 hexanes/EtOAc solvent mixture and
filtered through a short pad of silica gel. The solvent was removed
under reduced pressure and flash chromatography (10:1 hexanes/
EtOAc) provided lactone 14 as a pale yellow oil (3.68 g, 90%); Rf
To a solution of acid 16 (3.87 g, 19.7 mmol) in MeCN (159 mL)
was added Et3N (3.50 mL, 25.1 mmol) at rt. HBTU (8.24 g,
21.7 mmol) was then added and the resulting solution was stirred
for 30 min. In
a separate flask, (S)-4-benzyloxazolidin-2-one
(3.50 g, 19.8 mmol) was dissolved in THF (20 mL), cooled to
ꢀ78 ꢁC and n-BuLi (11.0 mL of a 2.0 M solution in cyclohexane,
22 mmol) was added dropwise. This mixture was stirred for 15 min
and the activated acid mixture was cannulated into the lithium salt
of the oxazolidinone. The reaction mixture was warmed to rt and
stirred for 2 h before being quenched with satd aq brine (50 mL).
The phases were separated and the aqueous was extracted with
CH2Cl2 (3ꢂ50 mL). The organic fractions were combined and
washed with 10% HCl (100 mL), satd aq NaHCO3 (100 mL) and water
(100 mL), then dried (MgSO4), filtered and the solvent removed
under reduced pressure. The resulting oil was purified by gradient
flash chromatography (5:1 to 1:1 hexanes/EtOAc) to provide 7 as
a white solid (3.34 g, 48%); Rf (2:1 hexane/EtOAc) 0.21; spectral data
matched those reported in the literature.33
(10:1 hexane/EtOAc) 0.18; 1H NMR (500 MHz, CDCl3)
d 6.92 (ddd,
J¼9.8, 6.6, 2.2 Hz, 1H), 6.01 (dd, J¼9.8, 1.0 Hz), 4.36 (dd, J¼12.9,
3.9 Hz), 3.54 (d, J¼9.8 Hz, 1H), 3.37 (d, J¼9.8 Hz, 1H), 2.44 (ddd,
J¼18.3,12.9, 2.2 Hz,1H), 2.27 (dddd, J¼18.3, 6.6, 3.9,1.0 Hz,1H), 0.98
(s, 3H), 0.91 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H). 13C NMR (125 MHz,
CDCl3)
d 166.5, 145.9, 121.2, 81.3, 68.4, 38.6, 25.8, 24.5, 20.5, 19.9,
18.2, ꢀ5.6. IR (neat) 2955, 2930, 2884, 2857, 1721, 1200e600.
Freshly prepared lactone 14 (3.68 g, 12.9 mmol) was then dissolved
in CH2Cl2 (182 mL) at ꢀ23 ꢁC and DIBAL-H was added dropwise
(20.0 mL of a 1.0 M solution in hexanes, 20.0 mmol). The resulting
mixture was stirred for 45 min then quenched with methanol
(10 mL) and warmed to rt. A saturated solution of Rochelle’s salt
(100 mL) was added to the reaction mixture. The phases were
separated and the aqueous layer was extracted with CH2Cl2
(3ꢂ50 mL). The organic fractions were combined and dried
(MgSO4), filtered and the solvent removed under reduced pressure
to provide the lactol 15 as well as the corresponding ring opened
aldehyde (10:1 by 1H NMR analysis) and was used directly without
further purification; Rf (10:1 hexane/ethyl acetate) 0.22; 1H NMR
4.5. (4S)-4-Benzyl-3-{(2S,3R)-4-[(2S,6R)-2-(2-tert-
butyldimethylsilyloxy-1,1-dimethylethyl)-2,3-dihydro-6H-pyran-
6-yl]-3-methoxy-2-(4-methoxybenzyloxy)-1-oxobutyl}-
oxazolidin-2-one (5)
To a solution of the acylated oxazolidinone 7 (3.34 g, 9.4 mmol)
in toluene (50 mL) at ꢀ50 ꢁC was added Et3N (1.5 mL, 10.8 mmol),
causing the solution to turn orange. This was followed by the ad-
dition of Bu2BOTf (10.0 mL of a 1 M solution in CH2Cl2, 10.0 mmol),
(500 MHz, CDCl3)
5.37e5.35 (m, 1H), 3.87 (dd, J¼3.0, 11.5 Hz, 1H), 3.45 (d, J¼9.5 Hz,
d
6.07e6.04 (m, 1H), 5.79 (d, J¼10.0 Hz, 1H),

9380
E.M. Casey et al. / Tetrahedron 67 (2011) 9376e9381
upon which the orange colour disappeared. The solution was stir-
red at ꢀ50 ꢁC for 1.5 h, then a solution of the aldehyde 6 (2.39 g,
7.65 mmol) in toluene (23 mL) was added by cannula and the re-
action mixture was warmed to ꢀ30 ꢁC over 30 min. The solution
was stirred at ꢀ30 ꢁC for a further 2 h and the reaction was
quenched with pH 7.0 sodium phosphate buffer (0.5 mL), MeOH
(5.0 mL) and THF (5.0 mL). The resulting mixture was stirred for
5 min then a 30% solution of H2O2 was added (5.0 mL), the mixture
was warmed to 0 ꢁC and stirred for a further 1 h. The solvent was
removed under reduced pressure and the resulting residue was
dissolved in satd aq NaHCO3 (50 mL) and EtOAc (50 mL). The phases
were separated and the aqueous layer was extracted with EtOAc
(3ꢂ50 mL). The organic fractions were combined, dried (MgSO4),
filtered and the solvent removed under reduced pressure to pro-
vide a yellow oil. Flash chromatography (1% Et3N in 2:1 hexane/
EtOAc) provided alcohol 17 (2.66 g, 52%) as a colourless oil in
a mixture of diastereoisomers, dr¼10:1 (by 1H NMR analysis); Rf
(2:1 hexane/EtOAc) 0.31 and used without delay for conversion to
The phases were separated and the aqueous fraction was extracted
with CH2Cl2 (3ꢂ20 mL). The organic fractions were combined and
acidified with 10% aq HCl (20 mL), then dried (MgSO4), filtered and
the solvent removed under reduced pressure. Gradient flash
chromatography (5:1 hexanes/EtOAc to neat EtOAc) provided
methyl ester 18 (0.59 g, 69%) as a colourless oil; Rf (2:1 hexane/
EtOAc) 0.53; 1H NMR (500 MHz, CDCl3)
d 7.28e7.23 (m, 2H),
6.87e6.83 (m, 2H), 5.85e5.80 (m, 1H), 5.65e5.62 (m, 1H), 4.69 (d,
J¼11.6 Hz, 1H), 4.39e4.34 (m, 1H), 4.36 (d, J¼11.6 Hz, 1H), 3.91e3.89
(m, 1H), 3.86e3.80 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.44 (s, 3H),
3.45e3.42 (m, 1H), 3.39e3.36 (m, 1H), 3.30e3.29 (m, 1H), 2.17e2.05
(m, 1H), 1.86e1.80 (m, 1H), 1.69e1.60 (m, 2H), 0.90 (s, 3H), 0.86 (s,
9H), 0.81 (s, 3H), 0.00 (s, 6H, H-3). 13C NMR (125 MHz, CDCl3)
d
171.5,159.3,130.0,129.7,129.4,129.3,124.8,124.9,113.7, 79.5, 78.6,
78.1, 72.4, 71.1, 69.6, 69.3, 59.7, 55.2, 51.8, 38.8, 34.7, 25.9, 25.2, 20.7,
20.5, 18.2, 14.2, ꢀ5.6. IR (neat) 2954, 2930, 2856, 1751, 1613, 1514,
1463, 1249, 1091, 835, 730 cmꢀ1. HRMS (ESI) calcd for C29H52NO7Siþ
(MþNHþ4 ) 554.3513, found 554.3506.
5. 1H NMR (500 MHz, CDCl3)
d 7.47e7.27 (m, 5H), 7.22e7.11 (m, 2H),
6.91e6.87 (m, 2H), 5.83e5.80 (m, 1H), 5.68 (br d, J¼9.4 Hz, 1H), 5.18
(d, J¼2.7 Hz, 1H), 4.67e4.64 (m, 1H), 4.64 (d, J¼11, 1H), 4.50 (d,
J¼11 Hz, 1H), 4.49e4.45 (m, 1H), 4.19e4.16 (m, 1H), 4.16e4.11 (m,
2H), 3.78 (s, 3H), 3.43 (d, J¼9.8 Hz, 1H), 3.41 (dd, J¼10.5, 2.9 Hz, 1H),
3.30 (d, J¼9.8 Hz, 1H), 3.25 (dd, J¼13.4, 3.2 Hz, 1H), 2.67 (dd, J¼13.4,
9.8 Hz, 1H), 2.17e2.07 (m, 1H), 1.90e1.83 (m, 2H), 1.68 (ddd, J¼13.9,
10.3, 3.7 Hz,1H), 0.91 (s, 3H), 0.87 (s, 9H), 0.82 (s, 3H), 0.01 (d, J¼4.2,
4.7. Methyl (2S,3R)-4-[(2S,6R)-(2-hydroxy-1,1-dimethylethyl)-
2,3-dihydro-6H-pyran-6-yl]-3-methoxy-2-(4-methoxybenzyloxy)
butyrate (19)
To a solution of silyl ether 18 (560 mg, 1.0 mmol) in MeOH
(10 mL) at rt was added HCl (1 mL of a 1 mmol solution in CH2Cl2,
1 mmol). The resulting solution was stirred for 10 min, then
quenched with satd aq NaHCO3 (10 mL) and extracted with CH2Cl2
(3ꢂ10 mL). The organic fractions were combined, dried (MgSO4),
filtered and the solvent removed under reduced pressure. Flash
chromatography was used to purify the residue. Flash chromatog-
raphy (2:1 hexanes/EtOAc) provided 19 (270 mg, 62%) as a colour-
less oil; Rf (2:1 hexane/EtOAc) 0.16; 1H NMR (500 MHz, CDCl3)
6H, H-3). 13C NMR (125 MHz, CDCl3)
d 170.8, 159.6, 153.3, 135.1,
130.1, 129.8, 129.4, 129.3, 129.1, 129.0, 127.4, 124.9, 113.9, 79.2, 72.8,
71.7, 69.7, 69.2, 69.1, 66.8, 55.6, 55.2, 38.8, 37.7, 37.0, 25.9, 25.3, 21.3,
20.2, 18.2, ꢀ5.5, ꢀ5.6. IR (neat) 3750, 3649, 2900, 1772, 1701, 1513,
1392, 1361, 1246, 1210, 1071, 1031, 908, 833, 728, 647 cmꢀ1. To
a solution of freshly prepared 17 (2.66 g, 3.98 mmol) in CH2Cl2
(100 mL) at 0 ꢁC was added 1,8-bis(dimethylamino)naphthalene
(proton sponge) (1.71 g, 7.96 mmol) followed by Me3OþBF4ꢀ (1.18 g,
8.0 mmol). The resulting suspension was stirred for 3 h at 0 ꢁC,
quenched with satd aq NaHCO3 (50 mL) and the two phases were
separated. The aqueous phase was extracted with CH2Cl2
(3ꢂ50 mL), the organic fractions were combined, washed with satd
aq brine (75 mL), dried (MgSO4), filtered and the solvent removed
under reduced pressure. Gradient flash chromatography (5:1 to 2:1
hexanes/EtOAc) provided 5 (2.37 g, 87% from 17) as a colourless oil;
d
7.28e7.26 (m, 2H), 6.89e6.86 (m, 2H), 5.84e5.81 (m, 1H), 5.61
(dtd, J¼10.3, 2.9, 1.2 Hz, 1H), 4.70 (d, J¼11.7 Hz, 1H), 4.40 (d,
J¼11.7 Hz, 1H), 4.41e4.39 (m, 1H), 4.03 (d, J¼4.6 Hz, 1H), 3.80 (s,
3H), 3.80e3.73 (m, 1H), 3.76 (s, 3H), 3.68 (d, J¼10.9 Hz, 1H), 3.51
(dd, J¼10.9, 2.9 Hz, 1H), 3.44 (s, 3H), 3.26 (d, J¼11.0 Hz, 1H), 2.78 (br
s, 1H), 2.17e2.11 (m, 1H), 1.87e1.82 (m, 2H), 1.45 (ddd, J¼14.9, 11.0,
2.4 Hz, 1H), 0.96 (s, 3H), 0.83 (s, 3H). 13C NMR (125 MHz, CDCl3)
d
171.4, 159.4, 129.9, 129.2, 128.9, 124.5, 113.7, 78.1, 77.9, 72.8, 72.3,
70.0, 69.9, 59.3, 55.2, 51.9, 37.8, 34.4, 25.1, 22.5, 19.4. IR (neat) 3488,
Rf (10:1 hexane/EtOAc) 0.52; 1H NMR (500 MHz, CDCl3)
d 7.33e7.28
3033, 2953, 2836, 1740, 1612, 1514, 1247, 1092, 1030, 909, 728 cmꢀ1
.
HRMS (ESI) calcd for C23H35O7þ (MþHþ) 423.2383, found 423.2375.
(m, 5H), 7.20 (d, J¼7.0 Hz, 2H), 6.86 (dd, J¼6.8, 2.1 Hz, 2H),
5.84e5.79 (m, 1H), 5.64 (d, J¼10.3 Hz, 1H), 5.50 (d, J¼4.7 Hz, 1H),
4.61e4.54 (m, 1H), 4.57 (s, 2H), 4.36 (br d, J¼10.3 Hz, 1H), 4.16e4.11
(m, 2H), 3.86e3.80 (m, 1H), 3.76 (s, 3H), 3.50 (d, J¼9.4 Hz, 1H), 3.45
(s, 3H), 3.41 (dd, J¼10.5, 2.7 Hz, 1H), 3.30 (d, J¼9.4 Hz, 1H), 3.18 (dd,
J¼13.2, 3.2 Hz, 1H), 2.58 (dd, J¼13.2, 10.0 Hz, 1H), 2.17e2.07 (m, 1H),
2.02e1.92 (m, 1H), 1.86 (dd, J¼17.0, 2.7 Hz, 1H), 1.52e1.42 (m, 1H),
0.95 (s, 3H), 0.88 (s, 9H), 0.84 (s, 3H), 0.02 (s, 3H), 0.015 (s, 3H). 13C
Acknowledgements
Financial support from the Foundation for Research, Science and
Technology, New Zealand is gratefully acknowledged.
Supplementary data
NMR (75 MHz, CDCl3)
d 171.3, 159.4, 153.1, 135.3, 130.1, 129.6,
129.44, 129.37, 129.9, 127.3, 124.8, 113.7, 78.2, 76.3, 72.9, 71.7, 69.4,
66.5, 59.9, 55.8, 55.2, 38.8, 37.8, 33.6, 30.9, 25.9, 25.3, 21.2, 20.2,18.3,
ꢀ5.5, ꢀ5.6. IR (neat) 2837, 1780, 1705, 1626, 1596, 1574, 1510, 1462,
1421, 1379, 1303, 1246, 1194, 1162, 1105, 1031, 977, 834, 776, 732,
703, 596. HRMS (ESI) calcd for C38H55O8NSiNaþ (MþNaþ) 704.3595,
found 704.3547.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.09.131.
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