Dihydroxylation-based approach for the asymmetric syntheses of hydroxy-γ-butyrolactones

Article abstract of DOI:10.1021/jo2021289

A method of preparing enantiopure hydroxy-γ-butyrolactones containing multiple contiguous stereocenters in high yield with good diastereoselectivity has been developed. Osmium tetroxide mediated dihydroxylation of a range of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in formation of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones. The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxylation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-d-ribonolactone. Published 2011 by the American Chemical Society.

Full text of DOI:10.1021/jo2021289

Article
pubs.acs.org/joc
Dihydroxylation-Based Approach for the Asymmetric Syntheses
of Hydroxy-γ-butyrolactones
Jennifer Peed,† Iwan R. Davies,† Lucy R. Peacock,† James E. Taylor,† Gabriele Kociok-Kohn,‡
̈
and Steven D. Bull*,†
†Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom
‡Department of Chemical Crystallography, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom
S
* Supporting Information
ABSTRACT: A method of preparing enantiopure hydroxy-γ-
butyrolactones containing multiple contiguous stereocenters in
high yield with good diastereoselectivity has been developed.
Osmium tetroxide mediated dihydroxylation of a range of
β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in forma-
tion of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones.
The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that
1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxy-
lation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this
methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-D-ribonolactone.
reduction of the resulting ketone functionality to afford the
desired γ-butyrolactones with high levels of diastereocontrol.5f
Another common method of forming highly substituted
hydroxy-γ-butyrolactones is through dihydroxylation of γ,δ-
unsaturated carbonyl systems, with spontaneous intramolecular
ring-closure then occurring to afford a γ-butyrolactone skeleton.
For example, Woerpel et al. carried out osmium tetroxide
(OsO4) catalyzed directed dihydroxylation reactions of α-
hydroxy-γ,δ-unsaturated acids to afford hydroxy-γ-butyrolac-
INTRODUCTION
■
Enantiomerically pure trisubstituted γ-butyrolactones are found
as fragments in a large number of natural products that display
a broad range of biological activities1 and a wide range of meth-
odology has been developed for their asymmetric synthesis.2
Hydroxy-γ-butyrolactones represent an important subset of this
type of natural product3 and they have also been shown to be
important chiral building blocks for natural product synthesis.4
For example, Nicolaou et al. have employed a substituted
5-hydroxy-γ-butyrolactone as an intermediate for the synthesis
of the antibiotic abyssomicin C.4c Shioiri et al. also employed a
trisubstituted γ-butyrolactone as a key intermediate for the
stereoselective synthesis of the C20-C25 subunit of calyculin A.4f
Chamberlin et al. used functionalized hydroxy-γ-butyrolactones
as key chiral building blocks for the enantioselective synthesis
of the polyketide 9S-dihydroerythronolide A seco acid.4g
A number of asymmetric methods exist for the synthesis of
highly substituted hydroxy-γ-butyrolactones,5 with a number of
these approaches based upon the diastereoselective reaction of
substituted enolates with appropriately substituted electro-
philes. For example, Johnson et al. prepared substituted silyl-
protected 3-hydroxy-γ-butyrolactones via double Reformatsky
reactions, which involved reaction of a zinc propionate enolate
with silyl glyoxylates to afford a new zinc enolate intermediate
that then reacts further with an aryl ketone electrophile.5d Baba
et al. have shown that indium enolates of α-substituted-α-bromo
esters undergo diastereoselective Reformatsky reactions with
α-hydroxy ketones to form 3-hydroxy-γ-butyrolactones that
contain three contiguous stereocenters in good yield and with
high diastereoselectivity.5i Luo and Gong et al. prepared tri-
substituted 2-hydroxy-γ-butyrolactones by performing enantio-
selective aldol reactions between ketones and α-keto acids using a
proline derived organocatalyst, with subsequent diastereoselective
tones as single diastereoisomers in good yield.5c Bruckner et al.
̈
have used Sharpless asymmetric dihydroxylation reactions of
disubstituted5m and trisubstituted5g β,γ-unsaturated esters to
prepare substituted 3-hydroxy-γ-butyrolactones in reasonable
yield with low to moderate levels of enantiomeric excess (ee).
Jenkinson et al. prepared synthetically useful and highly fun-
ctionalized sugar-lactones using directed osmium dihydrox-
ylations of chain extended ribulose and erythrose derivatives.5b
We have previously reported that β-alkenyl-β-hydroxy-N-
acyloxazolidin-2-ones (1) undergo efficient epoxidation/lacto-
nization reactions with catalytic VO(acac)2 and a stoichiometric
equivalent of tert-butylhydroperoxide to afford hydroxy-γ-
butyrolactones (3) (Scheme 1). It is proposed that an unstable
epoxide (2) is generated with high levels of diastereocontrol,
which is then ring-opened by intramolecular nucleophilic attack
of the exocyclic carbonyl fragment, resulting in clean inversion
of configuration at the C4 position of epoxide 2. Hydrolysis of
the resulting iminium species affords a highly functionalized
hydroxy-γ-butyrolactone skeleton containing multiple contiguous
stereocenters.6
Received: October 18, 2011
Published: November 12, 2011
Published 2011 by the American Chemical
Society
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unsaturated aldol 1a7 was treated under standard Upjohn
conditions8 with 10 mol % OsO4 and N-methylmorpholine-N-
oxide (NMO) in acetone:H2O (8:1) at room temperature to
produce a new hydroxy-γ-butyrolactone 6a in 69% yield and in
Scheme 1. Epoxidation/Lactonization Sequence with Inversion
of Configuration at C4 of Epoxide 2 to Form a Hydroxy-γ-
butyrolactone 3 Containing Three Contiguous Stereocenters
1
>49:1 dr (Scheme 3a). H NOE spectroscopic analysis of 6a
showed a strong interaction between the C3 proton and the
methylene protons of the C5 ethyl group, as well as a strong in-
teraction between the C4 proton and the C5 CH2OH methylene
protons (Scheme 3b), indicating a (3S,4S,5R) configuration.
This assignment is consistent with the expected suprafacial di-
hydroxylation of unsaturated aldol 1a with anti-diastereose-
lectivity with respect to its β-hydroxyl group. Thus, while our
previously reported epoxidation/lactonization sequence pro-
duces (3S,4S,5S)-hydroxy-γ-butyrolactone 3, this dihydroxyla-
tion/lactonization sequence provides its complementary C5
diastereoisomer (6a) in high dr.
To further investigate the scope and effect of the alkene sub-
stitution pattern on the stereochemical outcome of this dihy-
droxylation/lactonization protocol, a series of syn-aldols (1b−j)
was prepared in good yield and high dr by reaction of the boron
enolate of 5,5-dimethyl-N-propionyl-oxazolidin-2-one (7a) with
the corresponding α,β-unsaturated aldehydes (Scheme 4).7
As this epoxidation/lactonization sequence leads to inversion
of configuration at the C4 position, it was decided to investigate
an osmium-catalyzed dihydroxylation/lactonization protocol to
access complementary diastereoisomers of this type of hydroxy-
γ-butyrolactone (Scheme 2). For example, it was predicted that
Scheme 4. SuperQuat Auxiliary Directed Synthesis of
Unsaturated syn-Aldols (1)
Scheme 2. Proposed Dihydroxylation/Lactonization of
Unsaturated Aldols (1) to Produce Hydroxy-γ-
butyrolactones (6)
dihydroxylation of the alkene fragment of the generic aldol
substrate 1 with anti-diastereoselectivity to its β-hydroxyl group
would afford a triol (5), which would spontaneously lactonise
to afford a diastereomeric hydroxy-γ-butyrolactone.
Therefore, we now report herein a highly diastereoselective
dihydroxylation based approach for the synthesis of function-
alized hydroxy-γ-butyrolactones containing multiple contiguous
stereocenters, where the major diastereoisomer of the lactone
produced is controlled by the alkene substitution pattern.
These syn-aldols (1b−j) were then treated with 10 mol % OsO4
and NMO in acetone/H2O (8:1) at room temperature to afford
a series of hydroxy-γ-butyrolactones (6b−j) in good yield and
generally high diastereoselectivity (Table 1, entries 1−9).
Reaction of 1,1-disubstituted aldol 1b, which contains a terminal
O-benzyl substituent, with 10 mol % OsO4 and NMO proceeded
with good levels of anti-diastereoselectivity to form hydroxy-γ-
butyrolactone 6b in high yield (Table 1, entry 1). The stereo-
chemistry of hydroxy-γ-butyrolactone 6b was unequivocally assigned
as (3S,4S,5R) via X-ray crystallographic analysis (see Supporting
Information). The terminal O-benzyl fragment of this type of
lactone makes it particularly useful as a bifunctional synthetic
building block for the synthesis of polyketide inspired synthetic
targets.9 The stereochemistry of the remaining lactones (6) was
RESULTS AND DISCUSSION
■
The configuration of hydroxy-γ-butyrolactone 3, formed from
the epoxidation/lactonization reaction of aldol 1a had
previously been unequivocally assigned as (3S,4S,5S) using
X-ray crystallographic analysis. Consequently, it was decided to
investigate the corresponding dihydroxylation/lactonization
reaction of aldol 1a to confirm that a different diastereoisomer
of hydroxy-γ-butyrolactone would be produced. Therefore,
1
determined by H NOE spectroscopic analysis as well as by
comparison with literature precedent for dihydroxylations of each
of the different alkene substitution patterns (see below).
Scheme 3. (a) Dihydroxylation/Lactonization of Unsaturated Aldol 1a to Form Hydroxy-γ-butyrolactone 6a and (b) Strong 1H
NOE Interactions in γ-Butyrolactone 6a Confirm a (3S,4S,5R) Configuration
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Table 1. Dihydroxylation of Aldols 1b−k to Afford Hydroxy-γ-butyrolactones 6b−k
a
b
c
Major diastereoisomer formed. Configuration of hydroxyl-γ-butyrolactones confirmed by 1H NOE spectroscopic analysis. Determined by analysis
d
1
of the crude H NMR spectra. Yields after purification by column chromatography.
The dihydroxylation/lactonization reaction of acrolein aldol
1c was less diastereoselective, giving a 3:1 mixture of diaste-
reoisomers, with the major diastereoisomer (6c) being formed
from dihydroxylation with anti-diastereocontrol in 79% yield
(Table 1, entry 2). It was found that (E)-1,2-disubstituted
aldols derived from cinnamaldehyde and crotonaldehyde
(1d and 1e respectively) underwent dihydroxylation with
greater levels of anti-diastereoselectivity to give hydroxy-γ-
butyrolactones 6d (9:1 dr) and 6e (5:1 dr) in good yields
(Table 1, entries 3 and 4). Pleasingly, the (E)-1,2-disubstituted
aldol 1f containing an O-benzyl group also underwent
dihydroxylation/lactonization under standard Upjohn condi-
tions to form the hydroxy-γ-butyrolactone 6f in 77% yield with
4:1 diastereoselectivity (Table 1, entry 5). The related (Z)-1,2-
disubstituted O-benzyl aldol 1g was found to undergo
dihydroxylation with poor levels of anti-diastereoselectivity
(2:1 dr), with the corresponding hydroxy-γ-butyrolactone 6g
being formed with the opposite C6 configuration to that
observed for (E)-1,2-disubstituted aldol 1f (Table 1, entry 6).
Reaction of (E)-1,1,2-trisubstituted aldol 1h under standard
dihydroxylation/lactonization conditions proceeded with ex-
cellent levels of anti-diastereoselectivity to afford hydroxy-γ-
butyrolactone 6h in 82% yield as a single diastereoisomer
(Table 1, entry 7). The related O-benzyl (E)-1,1,2-trisubstituted
aldol 1i also underwent dihydroxylation/lactonization with similar
levels of high anti-diastereoselectivity, providing the synthetically
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Scheme 5. Effect of using Sharpless Asymmetric Dihydroxylation Conditions
useful O-benzyl-γ-butyrolactone 6i in 93% yield as a single
diastereoisomer (Table 1, entry 8). However, the reaction of
1,2,2-trisubstituted aldol 1j derived from 3-methyl-2-butenal
proceeded with reduced diastereoselectivity, with the major
hydroxy-γ-butyrolactone 6j diastereoisomer having the opposite
configuration at C5 to that observed for the previous examples.
Therefore, it follows that the 1,2,2-trisubstituted aldol 1j must
preferentially undergo dihydroxylation syn to its β-hydroxyl
group (5:1 dr) before lactonization to afford (3S,4S,5R)-
hydroxy-γ-butyrolactone 6j in 41% yield (Table 1, entry 9).
We then decided to investigate the effect of varying the
α-substituent of the unsaturated aldol on the dihy-
droxylation/lactonization reaction. The α-phenyl 1,1-disubsti-
tuted aldol 1k was prepared using our standard boron aldol
protocol and subjected to the standard dihydroxylation/
lactonization conditions. It was found that α-phenyl aldol 1k
underwent dihydroxylation with good levels of anti-diaste-
reoselectivity (9:1 dr), allowing the corresponding hydroxy-γ-
butyrolactone 6k to be isolated in 75% yield (Table 1, entry 10).
While the vast majority of alkene substitution patterns gave
high levels of diastereoselectivity for our dihydroxylation/
lactonization sequence, the (Z)-1,2-disubstituted aldol 1g gave
a 2:1 mixture of lactone diastereoisomers. In an attempt to
improve the diastereoselectivity, (Z)-1,2-disubstituted aldol 1g
was reacted under Sharpless asymmetric dihydroxylation
conditions using both AD-mix-α and AD-mix-β (Scheme 5a
and b).10 Remarkably, the ‘mismatched’ reaction of (Z)-1,2-
disubstituted aldol 1g with AD-mix-α resulted in dihydroxy-
lation/lactonization with reversal of diastereoselectivity com-
pared with the reaction using the standard Upjohn conditions.
The hydroxy-γ-butyrolactones (6g and 8) were obtained in
95% yield as a 4:1 mixture of diastereoisomers, with the major
lactone (8) being formed as the result of dihydroxylation with
syn-diastereoselectivity with respect to the β-hydroxyl group of
1g (Scheme 5a). This facial selectivity is consistent with that
observed previously by Sharpless et al. for reaction of a sim-
plified (Z)-O-benzyl allylic alcohol with AD-mix-α.11 Pleasingly,
the use of AD-mix-β resulted in “matched” enhancement
of the diastereoselectivity observed for dihydroxylation under
Upjohn conditions, affording the hydroxy-γ-butyrolactones
(6g and 8) in 95% yield as a 17:1 mixture of diastereoisomers
(Scheme 5b). In this case, the major diastereoisomer
(6g) obtained is the result of dihydroxylation with anti-
diastereoselectivity relative to the β-hydroxyl group of 1g,
which is again consistent with the results obtained by Sharpless
et al. using AD-mix-β on related substrates.11
Finally, to demonstrate the synthetic utility of our dihydroxylation/
lactonization protocol, we decided to apply it to the synthesis of
2-deoxy-D-ribonolactone (11),12 which is a byproduct of
oxidatively damaged DNA.13 2-Deoxy-D-ribonolactone (11)
has also been shown to be a useful synthetic precursor,14 while
its nucleoside derivatives are of structural interest because
they can potentially act as universal bases and non-hydrogen
bonding isosteres of nucleobases for chemical biology
applications.15 Therefore, the boron enolate of α-chloropro-
pionyl-N-acyl-oxazolidin-2-one 7c was reacted with acrolein to
afford syn-aldol 9 in a 45% yield and in >95% de. Treatment of
the α-chloro-β-vinyl-aldol 9 with zinc dust and ammonium
chloride in methanol resulted in dechlorination, providing the
desired allylic alcohol 10 in 82% yield.16 The dechlorinated
alcohol 10 was then subjected to the standard Upjohn
dihydroxylation/lactonization conditions, to afford 2-deoxy-D-
ribonolactone (11) as a 9:1 mixture of diastereoisomers in 87%
yield (Scheme 6).17
Assignment of Stereochemistry. There are many
literature examples of directed dihydroxylation reactions of
Scheme 6. Asymmetric Synthesis of 2-Deoxy-D-
ribonolactone (11)
allylic alcohols, with selected examples of dihydroxylations of allylic
alcohols with various substitution patterns shown in Scheme 7.18
Several stereochemical models have been proposed to ration-
alize the observed diastereoselectivity in these dihydroxylation
reactions, most notably the models described by Kishi, Houk
and Vedejs.19−22
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The configuration of each of the hydroxyl-γ-butyrolactone
(6a−k) prepared in this study has been determined by H
Scheme 7. Literature Examples of Dihydroxylation Reactions
of Allylic Alcohols with Different Alkene Substitution
Patterns
1
NOE spectroscopic analysis (Figure 1) and the conclusions
compared with the literature precedent for dihydroxylation of
each of the alkene substitution patterns shown in Scheme 7.
The results from dihydroxylation/lactonization of 1,1-disub-
stituted (1a and 1b), 1-substituted (1c), and (E)-1,2-disub-
stituted allylic alcohols (1d−f) are consistent with the anti-
diastereoselectivity observed in catalytic osmylation reactions of
related substrates with the same alkene substitution patterns
1
(Scheme 7a−c). The H NOE spectrum of the O-benzyl hy-
droxy-γ-butyrolactone 6b, derived from dihydroxylation/
lactonization of 1,1-disubstituted aldol 1b, shows a strong
interaction between the C3 proton and the C5 methylene pro-
tons of the O-benzyl substituent that confirms the configuration
of the C5 stereocenter (Figure 1b). The 1H NOE spectra of the
hydroxy-γ-butyrolactones 6c-f also show strong interaction
between the C3 proton and the C5 proton, confirming that
these protons lie on the same face of the lactone ring (Figure
1c−f).
The modest levels of anti-diastereoselectivity (2:1) observed
for the reaction of (Z)-1,2-disubstituted aldol 1g are in contrast
with the observations of Donohoe et al., who found that simple
(Z)-1,2-disubstituted allylic alcohols gave low levels (2:1) of
syn-diastereoselectivity when dihydroxylation was carried out
under Upjohn conditions (Scheme 7d).23b In our case, the con-
figuration of the C5 stereocenter of the major diasteroisomer of
hydroxy-γ-butyrolactone 6g was confirmed by analysis of the
1H NOE spectrum, which showed a strong interaction between
the C3 proton and the C5 proton (Figure 1g). However, the low
levels of diastereoselectivity observed in both cases suggest that
the directing effect of the allylic alcohol in (Z)-1,2-disubstituted
systems is limited; therefore, it is unsurprising that different
1
Figure 1. Strong interactions in the H NOE spectra of the hydroxyl-γ-butyrolactones (6a−k).
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substrates result in different diastereoisomers being formed
with poor dr.
methyl protons on C3 and the C5 proton (Figure 1j), while a
vicinal coupling constant between the protons on C4 and C5 of
3J = 7.4 Hz is indicative of a syn-relationship between these
protons.25
The high levels of anti-diastereoselectivity observed for the
(E)-1,1,2-trisubstututed aldols (1h and 1i) were consistent with
the results of Fronza et al. who found that an acetonide pro-
tected allylic alcohol gave dihydroxylation with anti-diaste-
reoselectivity when reacted under Sharpless conditions in the
absence of a chiral ligand (Scheme 7e).24 The configuration of
the hydroxy-γ-butyrolactones (6h and 6i) was confirmed by
The α-substituent of the aldol product was shown not to
affect the stereochemical outcome of the dihydroxylation reac-
tion unduly, with α-phenyl 1,1-disubstituted aldol 1k under-
going dihydroxylation with the expected anti-diastereoselectiv-
ity (Scheme 7a) to afford hydroxy-γ-butyrolactone 6k, which
1
analysis of the H NOE spectra, which showed strong interac-
1
exhibited the same characteristic interactions in its H NOE
tions between the proton on C3 and the C5 methyl protons as
well as strong interactions between the C3 methyl group and
the C5 CHOH proton in both cases (Figure 1h and i).
The dihydroxylation/lactonization of 1,2,2-trisubstituted aldol
1j proceeded with syn-diastereoselectivity, which is consistent
spectrum as the previous examples (Figure 1k).
Of particular relevance to the results described is the pre-
vious report of Dias et al., who reported the dihydroxylation/
lactonization of a small series of closely related Evans derived
β-alkenyl-O-silyl aldol products (14a−d). Surprisingly, the
configuration of the resulting O-silyl-γ-butyrolactones (16a−d)
was reported as (3S,4S,5S), which was different to the results
we had obtained, with lactones 16b and 16d reported to have
arisen from an unprecedented antarafacial dihydroxylation reac-
tion occurring with syn-diastereoselectivity to the β-O-silyl
hydroxyl group (Scheme 9).5h,26 Therefore, in order to inves-
tigate the effect of the O-silyl group on these dihydroxylation/
lactonization reactions, unsaturated aldol 1a was O-TBS pro-
tected using TBS-OTf and 2,6-lutidine and subjected to the
standard Upjohn dihydroxylation/lactonization conditions,
which gave O-TBS γ-butyrolactone 13 in a 3:1 dr. This mixture
was then deprotected using TBAF to give hydroxy-γ-butyro-
Scheme 8. Dihydroxylation/Lactonization of Unprotected
Aldol 1a and O-TBS Aldol 12 Afford the Same Major
Diastereoisomer of Hydroxy-γ-butyrolactone (6a)
with the syn-diastereoselectivity previously observed by
Donohoe et al. for dihydroxylation of 1,2,2-trisubstituted allylic
alcohols (Scheme 7f).23b The 5R stereochemistry of the major
diastereoisomer of hydroxy-γ-butyrolactone 6j was confirmed
1
lactone 6a in 65% yield and 3:1 dr (Scheme 8), whose H,
13C{1H}, and NOE spectra were identical to those of the lactone
we had previously formed from dihydroxylation/lactonization
of the unprotected aldol 1a.
1
by a strong interaction in the H NOE spectra between the
Scheme 9. (a) Dias et al.’s Dihydroxylation/Lactonization of O-TBS Protected Unsaturated Aldols (14a−d) and (b) Proposed
Reassignment of Configuration of the Reported O-Silyl-γ-butyrolactones (17a−d)
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to afford (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one 7a
(3.52 g, 13.4 mmol, 92%) as a white solid. H NMR (300 MHz,
In light of this result, we propose that both the free hydroxyl
and O-silyl protected unsaturated aldol derivatives of 1a and 12 un-
dergo dihydroxylation with anti-diastereoselectivity to the
stereodirecting group. It is therefore suggested that the stereo-
chemical assignments of the O-silyl-γ-butyrolactones (16a−d)
previously reported by Dias et al.5h are incorrect and that the
configuration of these lactones should be reassigned as shown
in Scheme 9.
1
CDCl3): δH 7.31−7.17 (5H, m, Ph), 4.48 (1H, dd, J = 9.6, 3.9 Hz,
CHN), 3.12 (1H, dd, J = 14.3, 3.9 Hz, CHHAHBPh), 2.94−2.81 (3H,
m, CHAHBPh, COCH2), 1.34 (3H, s, C(CH3)(CH3)), 1.33 (3H, s,
C(CH3)(CH3)), 1.12 (3H, t, J = 7.33 Hz, CH2CH3); 13C{1H} NMR
(75 MHz, CDCl3): δC 174.4, 152.8, 137.1, 129.2, 128.8, 126.9, 82.3,
63.6, 35.5, 29.5, 28.7, 22.4, 8.5; IR cm−1 ν = 1766 (COox), 1703
(CO); HRMS: m/z (ES) 262.1446, C15H20NO3 [M + H]+ requires
262.1443; [α]D21 = −42.0 (c = 0.50 g/100 mL in CHCl3).
(S)-4-Benzyl-5,5-dimethyl-3-(2-phenylacetyl)oxazolidin-2-
one, 7b. The title compound was prepared according to the general
procedure from n-BuLi (1.71 mL, 4.3 mmol, 2.5 M solution in hexane),
(S)-4-benzyl-5,5-dimethyloxazolidin-2-one (0.80 g, 3.9 mmol) and
phenylacetyl chloride (0.56 mL, 4.3 mmol) in THF (30 mL). The
crude product was purified using flash silica chromatography [CH2Cl2,
Rf 0.61] to afford (S)-4-benzyl-5,5-dimethyl-3-(2-phenylacetyl)oxazolidin-
2-one 7b (0.96 g, 3.0 mmol, 76%) as a colorless oil, which solidified on
CONCLUSIONS
■
We have developed a method of preparing enantiomerically
pure hydroxy-γ-butyrolactones (6a−k) containing multiple
contiguous stereocenters through directed dihydroxylation/
lactonization reactions of β-alkenyl-β-hydroxy-N-acyloxazoli-
din-2-ones (1a−k). The configurations of the resulting
1
hydroxy-γ-butyrolactones (6a−k) have been confirmed by H
1
standing. H NMR (300 MHz, CDCl3): δH 7.33−7.15 (10H, m, Phox,
NOE spectroscopic analysis, which revealed that the diaste-
reoselectivity of these directed dihydroxylation reactions is
dependent on the alkene substitution pattern. It was found that
1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-
disubstituted, and 1,1,2-trisubstituted alkenes undergo dihy-
droxylation with anti-diastereoselectivity to their β-hydroxyl
groups, whereas a 1,2,2-trisubstituted alkene gave the syn-
diastereoisomer. The poor levels of diastereoselectivity obser-
ved for the dihydroxylation/lactonization of the (Z)-1,2-
disubstituted aldol (1g) could be improved using Sharpless’
asymmetric dihydroxylation conditions, with the “matched” and
“mismatched” diastereoisomers being formed dependent on the
enantiomer of ligand used. The synthetic utility of this directed
dihydroxylation/lactonization methodology has been demon-
strated with a short synthesis of 2-deoxy-D-ribonolactone (11).
Ph), 4.46 (1H, dd, J = 9.6, 3.8 Hz, CHN), 4.25 (2H, s, COCH2Ph),
3.11 (1H, dd, J = 14.4, 3.8 Hz, CHAHBPh), 2.82 (1H, dd, J = 14.4, 9.6
Hz, CHAHBPh), 1.34 (3H, s, C(CH3)(CH3)), 1.29 (3H, s,
C(CH3)(CH3)); 13C{1H} NMR (75 MHz, CDCl3): δC 171.6, 152.7,
137.0, 133.8, 129.8, 129.2, 128.8, 128.7, 127.3, 126.9, 82.5, 63.9, 41.9,
35.3, 28.7, 22.4; IR cm−1 ν = 1765 (COox), 1712 (CO); HRMS:
m/z (ES) 324.1605, C20H22NO3 [M + H]+ requires 324.1599; [α]D21
−36.0 (c = 0.50 g/100 mL in CHCl3).
=
Non-Commercially Available Aldehydes. (E)-4-(Benzyloxy)-
but-2-enal. Based on a literature procedure,27 oxalyl chloride (0.26
mL, 3.1 mmol) was dissolved in dry dichloromethane (10 mL) at
−55 °C under nitrogen. Dimethylsulfoxide (0.39 mL, 5.6 mmol) was
added and the resulting solution was stirred for 2 min. (Z)-4-(Benzyloxy)-
but-2-en-1-ol (0.50 g, 2.8 mmol) in dichloromethane (1 mL) was added
dropwise to the solution to form a light yellow cloudy mixture, which was
stirred for 15 min at −55 °C. Triethylamine (1.96 mL, 14.0 mmol) was
then added and the resulting solution was stirred for a further 15 min at
−55 °C. The thick white slurry was warmed to room temperature and
was quenched with the addition of water (10 mL). The layers were
separated and the aqueous layer was extracted three times with
dichloromethane (20 mL). The combined organic layers were washed
with 1 M HCl (10 mL) and saturated NaHCO3 before being dried over
MgSO4 and concentrated. The crude product was purified using flash
silica chromatography [1:8 EtOAc/Petroleum ether, Rf 0.25] to
predominantly afford the cis alkene (0.42 g, 2.4 mmol, 84%) as a
colorless liquid. The pure material was dissolved in dichloromethane
(1 mL) with a catalytic amount of p-TSA and left at room temperature
overnight to isomerize to the trans isomer (E)-4-(benzyloxy)but-2-enal
EXPERIMENTAL SECTION
■
General. All reactions were performed using starting materials and
solvents obtained from commercial sources without further puri-
fication using dry solvents under an atmosphere of nitrogen. 1H NMR
spectra were recorded at 250, 300, 400, and 500 MHz and 13C{1H}
NMR spectra were recorded at 75 MHz. Chemical shifts δ are quoted
in parts per million and are referenced to the residual solvent peak.
1
NMR peak assignments were confirmed using 2D H COSY where
necessary. Chemical shift is reported in parts per million (ppm) and all
coupling constants, J, are reported in Hertz (Hz). Infrared spectra
were recorded as thin films or were recorded with internal background
calibration in the range 600−4000 cm−1, using thin films on NaCl plates
(film), or KBr discs (KBr) as stated. High resolution mass spectra were
recorded in either positive or negative mode using electrospray (ES)
ionization. Optical rotations were recorded with a path length of 1 dm;
concentrations (c) are quoted in g/100 mL.
General Procedure for the Acylation of (S)-4-Benzyl-5,5-
dimethyloxazolidin-2-one. n-BuLi (1.1 equiv, 2.5 M solution in
hexane) was added to a solution of (S)-4-benzyl-5,5-dimethylox-
azolidin-2-one (1 equiv) in dry THF at −78 °C under nitrogen and
was stirred for 30 min. The appropriate acid chloride (1.1 equiv) was
added in one portion and the resulting solution was stirred for a
further 2 h. The reaction was quenched with saturated ammonium
chloride and allowed to warm to ambient temperature. The THF was
evaporated under reduced pressure, and the resulting oil was
redissolved in dichloromethane and extracted with brine. The com-
bined organic extracts were dried over MgSO4 and concentrated to
afford the crude product.
1
in a 99:1 ratio. H NMR (300 MHz, CDCl3): δH 9.58 (1H, d, J =
7.9 Hz, CHO), 7.39−7.28 (5H, m, Ph), 6.85 (1H, dt, J = 15.8, 4.1 Hz,
CHCHCHO), 6.41 (1H, ddt, J = 15.8, 7.9, 1.9 Hz, CHCHO), 4.60
(2H, s, OCH2Ph), 4.29 (2H, dd, J = 4.1, 1.9 Hz, CH2OBn); 13C{1H}
NMR (75 MHz, CDCl3): δC 193.4, 153.2, 137.5, 131.9, 128.6, 128.1,
127.8, 73.1, 68.7; IR cm−1 ν = 1682 (CO); HRMS: m/z (ES)
199.0737, C11H12NaO2 [M + Na]+ requires 199.0734.
4-(Benzyloxy)butanal. Oxalyl chloride (1.03 mL, 12.2 mmol) was
dissolved in dry dichloromethane (50 mL) at −55 °C under nitrogen.
Dimethylsulfoxide (1.58 mL, 22.2 mmol) was added and the resulting
solution was stirred for 2 min. 4-(Benzyloxy)butan-1-ol
(2.00 g, 11.1 mmol) in dichloromethane (5 mL) was added dropwise
to the solution to form a light yellow cloudy mixture, which was stirred
for 15 min at −55 °C. Triethylamine (7.73 mL, 55.5 mmol) was then
added and the resulting solution was stirred for a further 15 min at
−55 °C. The thick white slurry was warmed to room temperature and
was quenched with the addition of water (50 mL). The layers were
separated and the aqueous layer was extracted three times with
dichloromethane (50 mL). The combined organic layers were washed
with 1 M HCl (10 mL) and saturated NaHCO3 before being dried
over MgSO4 and concentrated. The crude product was purified using
flash silica chromatography [1:9 EtOAc/Petroleum ether, Rf 0.63] to
afford 4-(benzyloxy)butanal (1.48 g, 8.3 mmol, 75%) as a colorless
(S)-4-Benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one, 7a. The
title compound was prepared according to the general procedure from
n-BuLi (6.43 mL, 16.1 mmol, 2.5 M solution in hexane), (S)-4-benzyl-
5,5-dimethyloxazolidin-2-one (3.00 g, 14.6 mmol) and pro-
pionyl chloride (1.40 mL, 16.1 mmol) in THF (90 mL). The crude
product was purified by recrystallization from diethyl ether and hexane
549
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Article
1
liquid. H NMR (300 MHz, CDCl3): δH 9.68 (1H, s, CHO), 7.30−
ethylamine (0.36 mL, 2.1 mmol) and 4-(benzyloxy)-2-methylenebu-
tanal (0.40 g, 2.1 mmol) in dichloromethane (5 mL) to afford a crude
product as a pale-yellow oil. The crude product was purified using flash
silica chromatography [1:4 EtOAc/Petroleum ether, Rf 0.27] to afford
(S)-4-benzyl-3-((2S,3S)-6-(benzyloxy)-3-hydroxy-2-methyl-4-methyl-
enehexanoyl)-5,5-dimethyloxazolidin-2-one 1b (0.57 g, 1.3 mmol,
7.18 (5H, m, Ph), 4.41 (2H, s, OCH2Ph), 3.43 (2H, t, J = 6.1 Hz,
CH2OBn), 2.45 (2H, t, J = 7.1 Hz, CHOCH2), 1.87 (2H, app. quintet,
J = 6.6 Hz, CH2CH2CH2OBn); 13C{1H} NMR (75 MHz, CDCl3): δC
202.1, 138.3, 128.3, 127.5, 72.8, 69.0, 40.8, 22.5; IR cm−1 ν = 1721
(CO); HRMS: m/z (ES) 201.0894, C11H14NaO2, [M + Na]+
requires 201.0891.
1
78%) as a colorless oil. H NMR (300 MHz, CDCl3): δH 7.27−7.16
4-(Benzyloxy)-2-methylenebutanal. 4-(Benzyloxy)butanal (0.50
g, 2.8 mmol) was dissolved in 37% aqueous formaldehyde solution
(0.27 mL, 3.7 mmol). Dimethylamine hydrochloride (0.30 g, 3.7
mmol) was added and the mixture was heated at 70 °C for 24 h. The
reaction was cooled to room temperature, quenched with satu-
rated NaHCO3, extracted into hexane and the combined organic frac-
tions were washed with water, dried over MgSO4 and concentrated.
The crude product was purified using flash silica chromatography [1:9
EtOAc/Petroleum ether, Rf 0.31] to afford 4-(benzyloxy)-2-methyl-
(10H, m, Ph, Phox), 5.11 (1H, s, CCHAHB), 4.95 (1H, s, C
CHAHB), 4.45−4.40 (3H, m, OCH2Ph, CHN), 4.32 (1H, br. d, J = 5.8
Hz, CHOH), 4.00 (1H, app. quintet, J = 6.6 Hz, CHCH3), 3.62−3.48
(2H, m, CH2OBn), 3.18 (1H, br. s, OH), 2.99 (1H, dd, J = 14.4, 4.3
Hz, CHAHBPh), 2.83 (1H, dd, J = 14.1, 8.7 Hz, CHAHBPh), 2.44−2.35
(1H, m, CHAHBOBn), 2.29−2.21 (1H, m, CHAHBOBn), 1.31 (3H, s,
C(CH3)(CH3)), 1.26 (3H, s, C(CH3)(CH3)), 1.12 (3H, d, J = 6.9 Hz,
CHCH3); 13C{1H} NMR (75 MHz, CDCl3): δC 176.3, 152.2, 146.8,
137.9, 136.7, 129.1, 128.6, 128.4, 127.7, 127.6, 126.8, 113.3, 82.2, 74.5,
73.0, 70.0, 63.3, 41.5, 35.3, 32.7, 28.2, 22.1, 12.0; IR cm−1 ν = 3467
(OH), 1770 (COox), 1694 (CO); HRMS: m/z (ES) 452.2458,
C27H34NO5 [M + H]+ requires 452.2436; [α]D17 = −30.0 (c = 0.50
g/100 mL in CHCl3).
1
enebutanal (0.41 g, 2.2 mmol, 78%) as a colorless liquid. H NMR
(300 MHz, CDCl3): δH 9.46 (1H, s, CHO), 7.30−7.19 (5H, m, Ph),
6.31 (1H, s, CCHAHB), 6.00 (1H, s, CCHAHB), 4.43 (2H, s,
OCH2Ph), 3.53 (2H, t, J = 6.4 Hz, CH2OBn), 2.51 (2H, t, J = 6.4 Hz,
CH2CCH2); 13C{1H} NMR (75 MHz, CDCl3): δC 194.4, 146.9,
138.2, 135.7, 128.4, 127.6, 127.5, 72.8, 67.9, 28.2; IR cm−1 ν = 1686
(CO); HRMS: m/z (ES) 213.0912, C12H14NaO2, [M + Na]+
requires 213.0886.
(S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2-methylpent-4-enoyl)-5,5-di-
methyloxazolidin-2-one, 1c. The title compound was prepared
according to the general procedure from 9-BBN-OTf (3.78 mL, 1.9
mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one 7a
(0.40 g, 1.7 mmol), N,N-diisopropylethylamine (0.43 mL,
2.5 mmol) and acrolein (0.16 mL, 2.5 mmol) in dichloromethane
(90 mL) to afford a crude product as a pale-yellow oil. The crude
product was purified using flash silica chromatography to afford (S)-4-
benzyl-3-((2S,3R)-3-hydroxy-2-methylpent-4-enoyl)-5,5-dimethyloxa-
General Procedure for the Synthesis of β-Alkenyl-β-hydroxy-N-
acyloxazolidin-2-ones. Acylated (S)-4-benzyl-5,5-dimethyloxazoli-
din-2-one 7a or 7b (1 equiv.) was dissolved in dry dichloromethane
at 0 °C under nitrogen and was stirred for 30 min. 9-Borabicyclo-
[3.3.1]nonyl trifluoromethanesulfonate (9-BBN-OTf) (1.1 equiv,
0.5 M solution in hexanes) or dibutylboron triflate (1.1 equiv.,
1.0 M in dichloromethane) was added dropwise. After 30 min, N,N-
diisopropylethylamine (1.3 equiv) was added and the resulting solution
was stirred for 30 min before the reaction was cooled to −78 °C. The
appropriate aldehyde (1.3 equiv) was added in one portion and the
reaction was allowed to warm to ambient temperature overnight. The
reaction was quenched with pH 7 buffer solution (Na2PO4/NaH2PO4)
(10 mL) and was stirred for 10 min. Hydrogen peroxide (4 mL) and
methanol (8 mL) were then added and the solution was stirred for a
further 2 h. The methanol was evaporated, the solution diluted with
dichloromethane and washed with saturated NaHCO3 and brine. The
combined organic extracts were dried over MgSO4 and concentrated
to afford crude product.
1
zolidin-2-one 1c (0.26 g, 0.9 mmol, 53%) as a colorless oil. H NMR
(300 MHz, CDCl3): δH 7.26−7.12 (5H, m, Ph), 5.83−5.70 (1H, ddd,
J = 10.5, 5.5, 5.3 Hz, CHCH2), 5.25 (1H, dt, J = 1.5 Hz, CHcisHtrans

C), 5.13 (1H, dt, J = 10.5, 1.5 Hz, CHcisHtransC), 4.49 (1H, dd, J =
9.0, 4.5 Hz, CHN), 4.38 (1H, m, CHOH), 3.85 (1H, dq, J = 7.0, 4.0 Hz,
CHCH3), 3.0 (1H, dd, J = 14.5, 4.5 Hz, CHAHBPh), 2.85 (1H, dd,
J = 14.5, 9.0 Hz, CHAHBPh), 2.65 (1H, br. s, OH), 1.33 (3H, s,
(CH3)C(CH3)), 1.31 (3H, s, (CH3)C(CH3)), 1.10 (3H, d, J = 7.0 Hz,
CH3CH); 13C{1H} NMR (75 MHz, CDCl3): δC 176.9 152.8, 137.7,
137.0, 129.5, 129.1, 127.3, 116.8, 82.8, 73.2, 63.8, 42.85, 35.9, 28.8, 22.6,
11.7; IR cm−1 ν = 3501 (br. OH), 1754 (CO), 1702 (COox);
HRMS: m/z (ES) 340.1577, C18H23NNaO4 [M + Na]+ requires
340.1519; [α]D22 = −26.0 (c = 0.60 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3S)-3-hydroxy-2-methyl-4-methylenehexano-
yl)-5,5-dimethyloxazolidin-2-one, 1a. The title compound was
prepared according to the general procedure from 9-BBN-OTf (9.46
mL, 4.7 mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-
one 7a (1.08 g, 4.3 mmol), N,N-diisopropylethylamine (0.94 mL, 5.4
mmol) and ethacrolein (0.45 g, 5.4 mmol) in dichloromethane (90
mL) to afford a crude product as a pale-yellow oil. The crude product
was purified using flash silica chromatography to afford (S)-4-benzyl-
3-((2S,3S)-3-hydroxy-2-methyl-4-methylenehexanoyl)-5,5-
dimethyloxazolidin-2-one 1a (1.19 g, 3.4 mmol, 80%) as a colorless
(S)-4-Benzyl-3-((2S,3R,E)-3-hydroxy-2-methyl-5-phenylpent-4-
enoyl)-5,5-dimethyloxazo lidin-2-one, 1d. The title compound was
prepared according to the general procedure from 9-BBN-OTf (10.10
mL, 5.0 mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-
one 7a (1.20 g, 4.6 mmol), N,N-diisopropylethylamine (1.03 mL, 5.9
mmol) and (E)-cinnimaldehyde (0.76 mL, 5.9 mmol) in dichloro-
methane (30 mL) to afford a crude product as a pale-yellow oil. The
crude product was purified using flash silica chromatography to afford
(S)-4-benzyl-3-((2S,3R,E)-3-hydroxy-2-methyl-5-phenylpent-4-enoyl)-
5,5-dimethyloxazolidin-2-one 1d (1.41 g, 3.6 mmol, 78%) as a
colorless oil. mp = 147−149 °C (Et2O); 1H NMR (300 MHz,
CDCl3): δH 7.36−7.13 (10H, m, Ph), 6.59 (1H, dd, J = 16.0, 1.5 Hz,
CHCHPh), 6.12 (1H, dd, J = 16.0 Hz, 6.0 Hz, CHCHPh), 4.54
(1H, m, CHOH), 4.47 (1H, dd, J = 9.0, 5.0 Hz, CHN), 3.94 (1H, qd,
J = 7.0, 4.0 Hz, COCH), 3.00 (1H, dd J = 14.0, 5.0 Hz, CHAHBPh),
2.84 (1H, dd, J = 14.0, 9.0 Hz, CHACHBPh), 2.74 (1H, br. s, OH),
1.32 (3H, s, (CH3)C(CH3)), 1.30 (3H, s, (CH3)C(CH3)), 1.13 (3H,
d, J = 7.0 Hz, CH3CH); 13C{1H} NMR (75 MHz, CDCl3): δC 177.1,
152.6, 137.7, 134.1, 129.3, 129.2, 129.1, 127.3, 82.7, 73.4, 63.8, 43.3,
35.9, 32.7, 32.2, 29.6, 29.5, 23.1, 14.5, 12.0; IR cm−1 ν = 3443 (OH),
1768 (CO), 1684 (COox); HRMS: m/z (ES) 416.1821,
C24H27NNaO4 [M + Na]+ requires 416.1838; [α]D23 = +6.0 (c =
0.89 g/100 mL in CHCl3).
1
oil. H NMR (300 MHz, CDCl3): δH 7.34−7.20 (5H, m, Ph), 5.16
(1H, app. t, J = 1.0 Hz, CHcisHtransC), 4.98 (1H, app. t, J = 1.0 Hz,
CHcisHtransC), 4.53 (1H, dd, J = 9.0, 4.0 Hz, CHN), 4.40 (1H, d,
J = 3.5 Hz, CHOH), 3.96 (1H, qd, J = 7.0, 3.5 Hz, CHCO), 3.08
(1H, dd, J = 14.0, 4.0 Hz, CHAHBPh), 2.91 (1H, dd, J = 14.0, 9.5 Hz,
CHAHBPh), 2.91 (1H, br. s, OH), 2.02 (2H, m, CH2CH3) 1.40 (3H, s,
(CH3)C(CH3)), 1.38 (3H, s, (CH3)C(CH3)), 1.11 (3H, d, J = 7.0 Hz,
CH3CH), 1.07 (3H, t, J = 7.0, CH3CH2); 13C{1H} NMR (75 MHz,
CDCl3): δC 177.5, 152.6, 150.3, 137.0, 129.5, 129.1, 127.3, 109.9, 82.7,
74.1, 63.8, 41.1, 35.8, 28.8, 25.7, 22.6, 12.5, 11.1; IR cm−1 ν = 3497 (br.
OH), 1773 (COox), 1700 (CO); HRMS: m/z (ES) 346.2014,
C20H28NO4 [M + H]+ requires 346.2013; [α]D21 = −36.0
(c = 1.00 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3S)-6-(benzyloxy)-3-hydroxy-2-methyl-4-
methylenehexanoyl)-5,5-di methyloxazolidin-2-one, 1b. The title
compound was prepared according to the general procedure from
dibutylboron triflate (1.78 mL, 1.8 mmol), (S)-4-benzyl-5,5-dimethyl-
3-propionyloxazolidin-2-one 7a (0.423 g, 1.6 mmol), N,N-diisopropyl-
(S)-4-Benzyl-3-((2S,3R,E)-3-hydroxy-2-methylhex-4-enoyl)-5,5-di-
methyl-oxazolidin-2-one, 1e. The title compound was prepared
according to the general procedure from 9-BBN-OTf (5.56 mL, 2.8
mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one 7a
(0.61 g, 2.3 mmol), N,N-diisopropylethylamine (0.53 mL, 3.0
550
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1
mmol) and (E)-crotonaldehyde (0.25 mL, 3.0 mmol) in dichloro-
methane (50 mL) to afford a crude product as a pale-yellow oil.
The crude product was purified using flash silica chromatography to
afford (S)-4-benzyl-3-((2S,3R,E)-3-hydroxy-2-methylhex-4-enoyl)-5,5-
dimethyloxazolidin-2-one 1e (0.70 g, 2.1 mmol, 91%) as a clear oil. 1H
NMR (300 MHz, CDCl3): δH 7.39−7.17 (5H, m, Ph), 5.74 (1H, dqd,
J = 15.5, 6.5, 1.0 Hz, CHCHCH3), 5.48 (1H, ddd, J = 15.5, 6.5, 1.0
Hz, CHCHCH3), 4.60 (1H, dd, J = 9.0, 4.5 Hz, CHN), 4.53 (1H,
m, CHOH), 3.91 (1H, qd, J = 7.0, 4.5 Hz, COCH), 3.05 (1H, dd J =
14.5, 4.5 Hz, CHAHBPh), 2.90 (1H, dd. J = 14.5, 9.0 Hz, CHAHBPh),
2.60 (1H, d, J = 2.5 Hz, OH), 1.70 (3H, d, J = 7.0 Hz, CH3CHCH),
1.39 (3H, s, (CH3)C(CH3)), 1.38 (3H, s, (CH3)C(CH3)), 1.15 (3H,
d, J = 7.0 Hz, CH3CH); 13C{1H} NMR (75 MHz, CDCl3): δC 176.9,
152.9, 137.1, 130.5, 129.5, 129.1, 128.9, 127.3, 82.7, 73.6, 63.8, 43.2,
35.9, 28.7, 22.5, 18.2, 12.1; IR cm−1 ν = 3508 (br. OH), 1775 (C
Oox), 1696 (CO); HRMS: m/z (ES) 332.1855, C19H26NO4 [M +
H]+ requires 332.1856; [α]D21 = −14.0 (c = 0.84 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3R,E)-6-(benzyloxy)-3-hydroxy-2-methylhex-
4-enoyl)-5,5-dimethyl-oxazolidin-2-one, 1f. Based on a literature
procedure,27 (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one
7a (1.95 g, 7.5 mmol) was dissolved in dry dichloromethane (50
mL) at −10 °C under nitrogen and was stirred for 20 min.
Dibutylboron triflate (8.97 mL, 9.0 mmol, 1.0 M in dichloromethane)
was added dropwise followed by triethylamine (1.35 mL, 9.7 mmol)
and the resulting solution was stirred for 30 min at 0 °C. The reaction
was cooled to −78 °C and (E)-4-(benzyloxy)but-2-enal (1.45 g, 8.2
mmol) was added dropwise. The solution was stirred at −78 °C for
45 min and then warmed to 0 °C and stirred for a further 3 h. The
reaction was cooled to −10 °C and pH 7 buffer solution (Na2PO4/
NaH2PO4) (30 mL) was added followed by methanol (24 mL) and
hydrogen peroxide (12 mL). The methanol was evaporated, the
solution diluted with dichloromethane and washed with saturated
NaHCO3 and brine. The combined organic extracts were dried over
MgSO4 and concentrated. The crude product was purified using flash
silica chromatography [1:4 EtOAc/Petroleum ether, Rf 0.19] to afford
(S)-4-benzyl-3-((2S,3R,E)-6-(benzyloxy)-3-hydroxy-2-methylhex-4-
enoyl)-5,5-dimethyloxazolidin-2-one 1f (2.91 g, 6.7 mmol, 89%) as a
colorless gum, which crystallized on standing. H NMR (300 MHz,
CDCl3): δH 7.29−7.12 (10H, m, Ph), 5.71−5.52 (2H, m, CHCH),
4.63−4.49 (1H, m, CHOH), 4.44−4.39 (3H, m, CH2OBn, CHN),
4.10 (1H, ddd, J = 12.7, 6.5, 1.3 Hz, CHAHBOBn), 4.00 (1H, ddd, J =
12.6, 5.5, 1.3 Hz, CHAHBOBn), 3.87 (1H, m, CHCH3), 2.97 (1H, dd,
J = 14.3, 4.5 Hz, CHAHBPh), 2.81 (1H, dd, J = 14.3, 9.0 Hz,
CHAHBPh), 2.73 (1H, broad s, OH), 1.30 (3H, s, C(CH3)(CH3)), 1.26
(3H, s, C(CH3)(CH3)), 1.11 (3H, d, J = 7.0 Hz, CHCH3); 13C{1H}
NMR (75 MHz, CDCl3): δC 175.9, 152.6, 138.1, 136.7, 132.1, 129.6,
129.2, 128.7, 128.5, 127.9, 127.8, 126.9, 82.4, 72.5, 69.0, 66.2, 63.4, 43.1,
35.5, 28.4, 22.2. 12.4; IR cm−1 ν = 3477 (OH), 1771 (COox), 1692
(CO); HRMS: m/z (ES) 460.2097, C26H31NNaO5 [M + Na]+
requires 460.2099; [α]D25 = −12.0 (c = 0.50 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3S,E)-3-hydroxy-2,4-dimethylhept-4-enoyl)-
5,5-dimethyloxazolidin-2-one, 1h. The title compound was prepared
according to the general procedure from 9-BBN-OTf (7.08 mL, 3.5
mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one 7a
(0.84 g, 3.2 mmol), N,N-diisopropylethylamine (0.73 mL, 4.2
mmol) and 2-methyl-pentenal (0.48 mL, 4.2 mmol) in dichloro-
methane (100 mL) to afford a crude product as a pale-yellow oil. The
crude product was purified using flash silica chromatography to afford
(S)-4-benzyl-3-((2S,3S,E)-3-hydroxy-2,4-dimethylhept-4-enoyl)-5,5-di-
methyloxazolidin-2-one 1h (0.95 g, 2.6 mmol, 82%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δH 7.27−7.12 (5H, m, Ph), 6.51 (1H, tt,
J = 7.0, 1.5 Hz, CCH), 4.45 (1H, dd, J = 9.0, 4.5 Hz, CHN), 4.23
(1H, br. s, CHOH), 3.91 (1H, dq, J = 7.0, 4.0 Hz, COCH), 3.10 (1H,
dd
J = 14.5, 4.5 Hz, CHA CHB Ph), 2.84 (1H, dd,
J = 14.5, 9.0 Hz, CHACHBPh), 2.84 (1H, br. d, OH), 2.10−1.92
(2H, m, CH2CH3), 1.53 (3H, s, CH3CCH), 1.32 (3H, s,
(CH3)C(CH3)), 1.29 (3H, s, (CH3)C(CH3)), 1.00 (3H, d, J = 7.0
Hz, CH3CH), 0.90 (3H, t, J = 7.5 Hz, CH2CH3); 13C{1H} NMR (75
MHz, CDCl3): δC 177.3, 152.7, 137.1, 133.4, 129.5, 129.0, 128.8,
127.2, 82.67, 76.1, 63.8, 41.1, 35.8, 28.7, 22.5, 21.3, 14.4, 13.5, 11.5; IR
cm−1 ν = 3493 (br. OH), 1777 (CO), 1680 (CO); HRMS: m/z
(ES) 382.1977, C21H29NNaO4 [M + Na]+ requires 382.1994; [α]D25
−5.0 (c = 1.00 g/100 mL, CHCl3).
=
(S)-4-Benzyl-3-((2S,3S,E)-6-(benzyloxy)-3-hydroxy-2,4-dimethyl-
hex-4-enoyl)-5,5-dimeth yloxazolidin-2-one, 1i. The title compound
was prepared according to the general procedure from dibutylboron
triflate (1.50 mL, 1.5 mmol), (S)-4-benzyl-5,5-dimethyl-3-propiony-
loxazolidin-2-one 7a (0.36 g, 1.4 mmol), N,N-diisopropyl-
ethylamine (0.31 mL, 1.8 mmol) and (E)-4-(benzyloxy)-2-methyl-
but-2-enal28 (0.34 g, 1.8 mmol) in dichloromethane (3 mL) to afford a
crude product as a pale-yellow oil. The crude product was purified
using flash silica chromatography [1:9 EtOAc/Petroleum ether, Rf
0.24] to afford (S)-4-benzyl-3-((2S,3S,E)-6-(benzyloxy)-3-hydroxy-
2,4-dimethylhex-4-enoyl)-5,5-dimethyloxazolidin-2-one 1i (0.28 g,
1
yellow oil. H NMR (300 MHz, CDCl3): δH 7.27−7.15 (10H, m, Ph,
Phox), 5.83 (1H, dtd, J = 15.6, 5.4, 1.0 Hz, CHCHCH2OBn), 5.68
(1H, dd, J = 15.6, 5.4 Hz, CHCHCH2OBn), 4.48−4.38 (4H, m,
CH2OBn, CHN, CHOH), 3.96 (2H, d, J = 5.4 Hz, CH2OBn), 3.86
(1H, qd, J = 7.0, 4.2 Hz, CHCH3), 2.99 (1H, dd, J = 14.2, 4.6 Hz,
CHAHBPh), 2.82 (1H, dd, J = 14.4, 9.0 Hz, CHAHBPh), 2.76 (1H,
broad s, OH), 1.30 (3H, s, C(CH3)(CH3)), 1.28 (3H, s, C(CH3)-
(CH3)), 1.10 (3H, d, J = 7.1 Hz, CHCH3); 13C{1H} NMR (75 MHz,
CDCl3): δC 176.3, 152.4, 138.2, 136.6, 132.0, 129.1, 128.7, 128.6,
128.3, 127.7, 127.6, 126.8, 82.3, 72.2, 72.1, 70.0, 63.3, 42.7, 35.4, 28.3,
22.1, 11.6; IR cm−1 ν = 3474 (OH), 1771 (COox), 1693 (CO);
HRMS: m/z (ES) 460.2064, C26H31NNaO5 [M + Na]+ requires
460.2099; [α]D25 = −28.0 (c = 0.50 g/100 mL in CHCl3).
1
0.6 mmol, 46%) as a colorless oil. H NMR (300 MHz, CDCl3): δH
7.27−7.15 (10H, m, Ph, Phox), 5.71 (1H, br. t, J = 6.3 Hz, CCH),
4.46−4.43 (3H, m, OCH2Ph, CHN), 4.28 (1H, d, J = 3.7 Hz, CHOH),
4.02 (2H, d, J = 6.6 Hz, CH2OBn), 3.96−3.91 (1H, m, CHCH3), 3.01
(1H, dd, J = 14.3, 4.0 Hz, CHAHBPh), 2.82 (2H, dd, broad s, J = 14.3,
9.1 Hz, CHAHBPh, OH), 1.57 (3H, s, CH3CCH), 1.30 (3H, s,
C(CH3)(CH3)), 1.26 (3H, s, C(CH3)(CH3)), 1.05 (3H, d, J = 7.4 Hz,
CHCH3); 13C{1H} NMR (75 MHz, CDCl3): δC 176.6, 152.3, 138.3,
138.1, 136.7, 129.1, 128.6, 128.4, 127.8, 127.6, 126.9, 122.9, 82.4, 75.2,
72.1, 66.2, 63.5, 40.6, 35.3, 28.3, 22.1, 13.6, 10.9; IR cm−1 ν = 3481
(OH), 1771 (COox), 1698 (CO); HRMS: m/z (ES) 452.2446,
C27H34NO5 [M + H]+ requires 452.2436; [α]D20 = −42.0 (c = 0.50
g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2,5-dimethylhex-4-enoyl)-5,5-
dimethyloxazolidin-2- one, 1j. The title compound was pre-
pared according to the general procedure from 9-BBN-OTf (8.05
mL, 4.0 mmol), (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-
one 7a (0.96 mg, 3.7 mmol), N,N-diisopropylethylamine (0.83 mL, 4.8
mmol) and 3-methyl-2-butenal (0.46 mL, 4.8 mmol) in dichloro-
methane (100 mL) to afford a crude product as a pale-yellow oil. The
crude product was purified using flash silica chromatography to afford
(S)-4-benzyl-3-((2S,3R)-3-hydroxy-2,5-dimethylhex-4-enoyl)-5,5-di-
methyloxazolidin-2-one 1j (1.28 g, 3.7 mmol, 92%) as a white solid.
(S)-4-Benzyl-3-((2S,3R,Z)-6-(benzyloxy)-3-hydroxy-2-methylhex-
4-enoyl)-5,5-dimethyl oxazolidin-2-one, 1g. Based on a literature
procedure,27 (S)-4-benzyl-5,5-dimethyl-3-propionyloxazolidin-2-one
7a (0.50 g, 1.9 mmol) was dissolved in dry dichloromethane (20
mL) at −10 °C under nitrogen and was stirred for 20 min.
Dibutylboron triflate (2.29 mL, 2.3 mmol, 1.0 M in dichloromethane)
was added dropwise followed by triethylamine (0.35 mL, 2.5 mmol)
and the resulting solution was stirred for 30 min at 0 °C. The reaction
was cooled to −78 °C and (Z)-4-(benzyloxy)but-2-enal (0.37 g, 2.1
mmol) was added dropwise. The solution was stirred at −78 °C for
45 min and then warmed to 0 °C and stirred for a further 3 h. The
reaction was cooled to −10 °C and pH 7 buffer solution (Na2PO4/
NaH2PO4) (10 mL) was added followed by methanol (8 mL) and
hydrogen peroxide (4 mL). The methanol was evaporated, the solu-
tion diluted with dichloromethane and washed with saturated NaHCO3
and brine. The combined organic extracts were dried over MgSO4
and concentrated. The crude product was purified using flash silica
chromatography [1:2 EtOAc/Petroleum ether, Rf 0.63] to afford (S)-
4-benzyl-3-((2S,3R,Z)-6-(benzyloxy)-3-hydroxy-2-methylhex-4-
enoyl)-5,5-dimethyloxazolidin-2-one 1g (0.74 g, 1.7 mmol, 88%) as a
551
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Article
1H NMR (300 MHz, CDCl3): δH 7.35−7.17 (5H, m, Ph), 5.23
7.4 Hz, CHCH3), 2.07−1.91 (2H, m, CH2CH2OBn), 1.20 (3H, d, J =
7.4 Hz, CHCH3); 13C{1H} NMR (75 MHz, CDCl3): δC 177.4, 136.5,
128.8, 128.5, 128.3, 87.8, 76.5, 73.9, 66.4, 64.8, 42.9, 30.3, 13.7; IR
cm−1 ν = 3402 (OH), 1754 (CO); HRMS: m/z (ES) 303.1210,
C15H20NaO5, [M + Na]+ requires 303.1208; [α]D24 = +18.0 (c = 0.50 g/
100 mL in CHCl3).
(1H, d, J = 9.0 Hz, CHCC), 4.60 (1H, m, CHOH), 4.52 (1H,
dd, J = 9.0, 4.5 Hz, CHN), 3.93 (1H, qd, J = 7.0, 5.0 Hz, COCH),
3.05 (1H, dd J = 14.5, 4.5 Hz, CHACHBPh), 2.90 (1H, dd, J = 14.5,
9.0 Hz, CHACHBPh), 2.35 (1H, br. s, OH), 1.72 (3H, s, C
C(CH3)A(CH3)B), 1.68 (3H, s, CC(CH3)A(CH3)B), 1.39 (3H,
s, (CH3)C(CH3)), 1.37 (3H, s, (CH3)C(CH3)), 1.18 (3H, d, J =
7.0 Hz, CH3CH); 13C{1H} NMR (75 MHz, CDCl3): δC 176.7,
153.0, 137.2, 137.1, 129.5, 129.1, 127.3, 124.5, 82.6, 69.9,
63.8, 43.4, 35.9, 28.6, 26.4, 22.5, 18.8, 12.6; IR cm−1 ν = 3479
(br. OH), 1769 (CO), 1681 (CO); HRMS: m/z (ES)
346.2011, C20H28NO4 [M + H]+ requires 346.2013; [α]D21 = −27.0
(c = 1.00 g/100 mL in CHCl3).
(3S,4S,5R)-4-Hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-
2(3H)-one, 6c. OsO4 (15 mg, 0.06 mmol) was added to a solution of
1c (150 mg, 0.52 mmol) in acetone/water (8:1, 5 mL) followed by
addition of NMO (60% by weight in water, 0.09 mL, 0.52 mmol)
according to the general procedure to afford the crude product as
black oil. Purification via column chromatography afforded a dia-
stereomeric mixture of 6c major and 6c minor (60 mg, 0.41 mmol,
79%, 3:1 dr). The two diastereoisomers were analyzed as a mixture.
(3S,4S,5R)-major: 1H NMR (500 MHz, MeOD): δH 4.19−4.17 (1H,
m, CHCH2OH), 4.02 − 3.99 (1H, m, CHOH), 3.94 (1H, dd, J = 12.8,
2.5 Hz, CHACHBOH), 3.72 (1H, dd, J = 12.8, 4.8 Hz, CHACHBOH),
2.66 (1H, dq, J = 8.9, 7.1 Hz, CHCH3), 1.30 (3H, d, J = 7.3 Hz, CH3);
13C{1H} NMR (75 MHz, MeOD): δC 180.0, 86.8, 75.6, 62.0, 45.7,
(S)-4-Benzyl-3-((2S,3S)-3-hydroxy-4-methyl-2-phenylpent-4-
enoyl)-5,5-dimethyloxazolid in-2-one, 1k. The title compound was
prepared according to the general procedure from 9-BBN-OTf (0.45
mL, 0.9 mmol), (S)-4-benzyl-5,5-dimethyl-3-(2-phenylacetyl)-
oxazolidin-2-one 7b (0.27 g, 0.8 mmol), N,N-diisopropylethylamine
(0.17 mL, 1.0 mmol) and methacrolein (0.08 mL, 1.0 mmol) in
dichloromethane (70 mL) to afford a crude product as a pale-yellow
oil. The crude product was purified using flash silica chromatography
to afford (S)-4-benzyl-3-((2S,3S)-3-hydroxy-4-methyl-2-phenylpent-4-
enoyl)-5,5-dimethyloxazolidin-2-one 1k (0.24 g, 0.6 mmol, 75%) as a
colorless oil. 1H NMR (300 MHz,CDCl3): δH 7.42−7.20 (5H, m, Ph),
7.14−6.98 (5H, m, Ph), 5.27 (1H, d, J = 7.0 Hz, PhCH) 4.92 (1H, m,
CHcisHtransC), 4.85 (1H, br. app. pent., J = 1.5 Hz, CHcisHtransC),
4.69 (1H, d, J = 8.0 Hz, CHOH), 4.43 (1H, dd, J = 9.0, 4.0 Hz, CHN),
2.82 (1H, dd J = 14.0, 4.0 Hz, CHAHBPh), 2.63 (1H, dd, J = 14.0, 9.0
Hz, CHACHBPh), 2.05 (1H, br. s, OH), 1.74 (3H, s, CH2CCH3),
1.27 (3H, s, (CH3)C(CH3)), 1.24 (3H, s, (CH3)C(CH3)); 13C{1H}
NMR (75 MHz, CDCl3): δC 172.9, 152.5, 144.8, 136.9, 134.7, 130.26,
129.4, 129.1, 128.9, 128.4, 127.1, 114.2, 82.5, 63.7, 53.4, 35.3, 28.7,
22.5, 18.7; IR cm−1 ν = 3489 (OH), 1768 (CO), 1671 (COox);
HRMS: m/z (ES) 394.2019, C24H28NO4 [M + H]+ requires 394.2018;
[α]D25 = −89.9 (c = 1.00 g/100 mL, CHCl3).
General Procedure for the Synthesis of (3S,4S)-Hydroxy-γ-
lactones (6a-6k, 11). Osmium tetroxide (OsO4) (0.1 equiv) was
added in one portion to a stirring solution of the appropriate β-alkenyl-
β-hydroxy-N-acyloxazolidin-2-one 1a−1k (1.0 equiv) in acetone/water
(8:1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine
N-oxide, 60% by weight in water, 1.1 equiv) was added in one portion
and stirred for 24 h. The resulting reaction mixture was concentrated
under reduced pressure and immediately purified via column chro-
matography.
(3S,4S,5R)-5-Ethyl-4-hydroxy-5-(hydroxymethyl)-3-methyldihy-
drofuran-2(3H)-one, 6a. OsO4 (22 mg, 0.09 mmol) was added to a
solution of 1a (305 mg, 0.88 mmol) in acetone/water (8:1, 3 mL)
followed by addition of NMO (60% by weight in water, 0.16 mL, 0.97
mmol) according to the general procedure to afford the crude product
as a black oil. Purification via column chromatography afforded 6a
(120 mg, 0.61 mmol, 69%, 49:1 dr). 1H NMR (500 MHz, MeOD): δH
4.24 (1H, d, J = 9.4 Hz, CHOH), 3.74 (1H, d, J = 12.1 Hz,
CHAHBOH), 3.52 (1H, d, J = 12.2 Hz, CHAHBOH), 2.68 (1H, qd, J =
9.4, 7.1 Hz, CHCO), 1.81 (1H, dq, J = 15.0, 7.5 Hz, CHAHBCH3),
1.71 (1H, dq, J = 15.0, 7.5 Hz, CHAHBCH3), 1.28 (3H, d, J = 7.5 Hz,
CH3), 1.01 (3H, t, J = 7.5 Hz, CH2CH3); 13C{1H} NMR (75 MHz,
MeOD): δC 179.6, 90.2, 76.5, 64.7, 44.2, 25.0, 13.9, 8.6; IR cm−1 ν =
3368 (br. OH), 1751 (CO); HRMS: m/z (ES) 175.0957, C8H15O4
[M + H]+ requires 175.0970; [α]D24 = −3.4 (c = 0.88 g/100 mL in
CHCl3).
1
13.6; (3S,4S,5S)-minor: H NMR (500 MHz, CDCl3): δH 4.57 (1H,
dt, J = 5.8, 3.7 Hz, CHCH2OH), 4.27 (1H, t, J = 6.0 Hz, CHOH), 3.90
(2H, d, J = 3.7 Hz, CHACHBOH), 2.71 (1H, dt, J = 13.6, 7.6 Hz,
CHCH3), 1.29 (3H, d, J = 7.5 Hz, CH3); 13C{1H} NMR (75 MHz,
MeOD): δC 181.6, 84.1, 76.2, 62.2, 45.5, 14.4; IR cm−1 ν = 3377 (br.
OH), 2934 (br. OH), 1763 (CO); HRMS: m/z (ES) 147.0650,
C6H11O4 [M+H]+ requires 147.0657; [α]D24 = +4.0 (c = 0.50 g/100 mL
in MeOH).
(3S,4S,5S)-4-Hydroxy-5-((S)-hydroxy(phenyl)methyl)-3-methyldi-
hydrofuran-2(3H)-one, 6d. OsO4 (13 mg, 0.05 mmol) was added to
a solution of 1d (198 mg, 0.50 mmol) in acetone/water (8:1, 3 mL)
followed by addition of NMO (60% by weight in water, 0.1 mL, 0.55
mmol) according to the general procedure to afford the crude product
as black oil. Purification via column chromatography afforded 6d (90
mg, 0.41 mmol, 81%, 9:1 dr). 1H NMR (500 MHz, CDCl3): δH 7.41−
7.25 (5H, m, Ph), 4.76 (1H, d, J = 5.7, CHPh), 4.22 (1H, dd, J = 9.2,
7.5 Hz, CHCHPh), 3.95 (1H, dd, J = 9.2, 7.5 Hz, CHOH), 2.56 (1H,
dq, J = 9.2, 7.2 Hz, CHCO), 1.19 (3H, d, J = 6.9 Hz, CH3CH);
13C{1H} NMR (75 MHz, CDCl3): δC 178.4, 134.5, 129.1, 128.7,
127.4, 80.1, 74.9, 70.9, 43.1, 14.1; IR cm−1 ν = 3358 (br. OH), 1753
(CO); HRMS: m/z (ES) 223.0964, C12H15O4 [M+H]+ requires
223.0970; [α]D23 = +44.0 (c = 1.62 g/100 mL in CHCl3).
(3S,4S,5R)-4-Hydroxy-5-((S)-1-hydroxyethyl)-3-methyldihydrofur-
an-2(3H)-one, 6e. OsO4 (13 mg, 0.05 mmol) was added to a solution
of 1e (164 mg, 0.50 mmol) in acetone/water (8:1, 3 mL) followed by
addition of NMO (60% by weight in water, 0.09 mL, 0.54 mmol)
according to the general procedure to afford the crude product as a
black oil. Purification via column chromatography afforded a
diastereomeric mixture of 6e major and 6e minor (66 mg, 0.41
mmol, 83%, 5:1 dr). The two diastereoisomers were analyzed as a
1
mixture. (3S,4S,5R)-major: H NMR (500 MHz, CDCl3): δH 4.11
(1H, dd, J = 8.8, 7.0 Hz, CHOH), 4.04−3.95 (2H, m, CHOCO,
CHOHCH3), 2.68 (1H, dq, J = 9.1, 7.1 Hz, CHCO), 1.37 (3H, d, J =
6.5 Hz, CH3CHOH), 1.32 (3H, d, J = 7.1 Hz, CH3CH); 13C{1H}
NMR (75 MHz, CDCl3): δC 176.8, 86.4, 74.9, 66.6, 44.2, 19.9, 12.8;
1
(3S,4S,5S)-minor: H NMR (500 MHz, CDCl3) δH 4.35−4.32 (1H,
m, CHOH), 4.32 − 4.27 (2H, m, CHOCO, CHOHCH3), 2.76 (1H,
dq, J = 7.7, 5.3 Hz, CHCO), 1.39 (3H, d, J = 6.7 Hz, CH3CHOH),
1.32 (3H, d, J = 7.5 Hz, CH3CH); 13C{1H} NMR (75 MHz, CDCl3)
δC 177.3, 82.9, 76.3, 67.1, 44.6, 19.8, 14.0; IR cm−1 ν = 3356 (br. OH),
1754 (CO); HRMS: m/z (ES) 183.0613, C7H12NaO4 [M + Na]+
requires 183.0628.
(3S,4S,5R)-5-(2-(Benzyloxy)ethyl)-4-hydroxy-5-(hydroxymethyl)-
3-methyldihydrofuran-2(3H)-one, 6b. OsO4 (8 mg, 0.03 mmol) was
added to a solution of 1b (140 mg, 0.31 mmol) in acetone/water (8:1,
1.5 mL) followed by addition of NMO (60% by weight in water, 0.07
mL, 0.34 mmol) according to the general procedure to afford the
crude product as a black oil. Purification via column chromatography
(3S,4S,5S)-5-((S)-2-(Benzyloxy)-1-hydroxyethyl)-4-hydroxy-3-
methyldihydrofuran-2(3H)-one, 6f. OsO4 (6 mg, 0.02 mmol) was
added to a solution of 1f (100 mg, 0.22 mmol) in acetone/water (8:1,
1.2 mL) followed by addition of NMO (60% by weight in water, 0.04
mL, 0.25 mmol) according to the general procedure to afford the
crude product as a black oil. Purification via column chromatography
1
afforded 6b (80 mg, 0.28 mmol, 93%, 10:1 dr). H NMR (300 MHz,
1
CDCl3): δH 7.31−7.18 (5H, m, Ph), 4.43 (2H, s, OCH2Ph), 4.12 (1H,
br. s, OH), 3.96 (1H, d, J = 8.4 Hz, CHOH), 3.59−3.49 (4H, m,
CH2OBn, CH2OH), 2.80 (1H, br. s, OH), 2.49 (1H, app. quintet, J =
afforded 6f (47 mg, 0.17 mmol, 77%, 4:1 dr). H NMR (300 MHz,
CDCl3): δH 7.33−7.20 (5H, m, Ph), 4.50 (2H, s, OCH2Ph), 4.04−
3.90 (3H, m, CH3CHCHOH, COOCH, OCH2CHOH), 3.63−3.52
552
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Article
(3H, m, CH2OBn, OH), 2.95 (1H, d, J = 4.3 Hz, OH), 2.61−2.51
(1H, m, CHCH3), 1.22 (3H, d, J = 7.0 Hz, CHCH3); 13C{1H} NMR
(75 MHz, CDCl3): δC 176.6, 137.1, 128.8, 128.4, 128.1, 84.3, 74.6,
74.0, 71.1, 69.3, 43.2, 12.4; IR cm−1 ν = 3396 (OH), 1760 (CO);
HRMS: m/z (ES) 289.1041, C14H18NaO5, [M + Na]+ requires
289.1051; [α]D24 = +4.0 (c = 0.50 g/100 mL in CHCl3).
12.7; IR cm−1 ν = 3420 (OH), 1761 (CO); HRMS: m/z (ES)
281.1368, C15H21O5, [M + H]+ requires 281.1388; [α]D23 = −12.0
(c = 0.50 g/100 mL in CHCl3).
(3S,4S,5R)-4-Hydroxy-5-(2-hydroxypropan-2-yl)-3-methyldihy-
drofuran-2(3H)-one, 6j. OsO4 (14 mg, 0.05 mmol) was added to a
solution of 1j (184 mg, 0.53 mmol) in acetone/water (8:1, 3 mL)
followed by addition of NMO (60% by weight in water, 0.10 mL, 0.59
mmol) according to the general procedure to afford the crude product
as a black oil. Purification via column chromatography afforded 6j (38
(3S,4S,5S)-5-((R)-2-(Benzyloxy)-1-hydroxyethyl)-4-hydroxy-3-
methyldihydrofuran-2(3H)-one, 6g. OsO4 (6 mg, 0.02 mmol) was
added to a solution of 1g (100 mg, 0.22 mmol) in acetone/water (8:1,
1.2 mL) followed by addition of NMO (60% by weight in water, 0.04
mL, 0.25 mmol) according to the general procedure to afford the
crude product as a black oil. Purification via column chromatography
afforded the product in 74% yield, 2:1 dr, 6g major (28 mg, 0.11
mmol, 45%), 6g minor (13 mg, 0.05 mmol, 21%) and a mixture of
6g major and 6g minor (4 mg, 0.15 mmol, 7%). (3S,4S,5R)-5-(S)-
1
mg, 0.22 mmol, 41%, 5:1 dr) as a pale oil. H NMR (300 MHz,
CDCl3): δH 4.94 (1H, d, J = 4.1 Hz, OH), 4.26 (1H, app. dt, J = 3.9,
1.5 Hz, CHOH), 4.09 (1H, d, J = 4.1 Hz, CHOCO), 2.96 (1H, br. s,
OH), 2.68 (1H, qd, J = 7.8, 1.5 Hz, CHC(CH3)2OH), 1.38 (3H, s,
(CH3)C(CH3)), 1.36 (3H, s, (CH3)C(CH3)), 1.19 (3H, d, J = 7.8 Hz,
CH3CH); 13C{1H} NMR (75 MHz, CDCl3): δC 179.5, 84.0, 76.3,
73.0, 46.9, 28.7, 25.0, 13.5; IR cm−1 ν = 3295 (br. OH), 1754 (CO);
HRMS: m/z (ES) 175.0970, C8H15O4 [M + H]+ requires 175.0970;
[α]D23 = −55.6 (c = 0.99 g/100 mL in CHCl3).
1
major: H NMR (300 MHz, 50:50 CDCl3:C6H6): δH 7.32−21 (5H,
m, Ph), 4.43 (1H, d, J = 11.6 Hz, OCHAHBPh), 4.36 (1H, d, J = 11.6
Hz, OCHAHBPh), 4.03 (1H, dd, J = 9.9, 7.3 Hz, CH3CHCHOH), 3.85
(1H, dd, J = 7.3, 5.1 Hz, COOCH), 3.79−3.75 (1H, m,
OCH2CHOH), 3.51 (1H, dd, J = 10.3, 3.3 Hz, CHAHBOBn), 3.46
(1H, dd, 10.3, 4.2 Hz, CHAHBOBn), 3.21 (1H, br. s, OH), 2.59 (1H,
br. s, OH), 2.50 (1H, dq, 9.9, 7.1 Hz, CHCH3), 1.25 (3H, d, J = 7.1
Hz, CHCH3); 13C{1H} NMR (75 MHz, CDCl3): δC 176.5, 136.9,
128.8, 128.5, 128.2, 83.1, 74.5, 74.3, 70.9, 70.4, 42.7, 12.6; IR cm−1 ν =
3418.67 (OH), 1759.65 (CO); HRMS: m/z (ES) 289.1042,
C14H18NaO5, [M + Na]+ requires 289.1051; [α]D24 = −2.0 (c = 0.50
g/100 mL in CHCl3). (3S,4S,5S)-5-(R)-minor: 1H NMR (300 MHz,
CDCl3): δH 7.40−7.30 (5H, m, Ph), 4.59 (2H, s, OCH2Ph), 4.43 (1H,
dd, J = 8.0, 4.7 Hz, COOCH), 4.32 (1H, dd, J = 4.7, 2.6 Hz,
CH3CHCHOH), 4.18−4.13 (1H, m, OCH2CHOH), 3.79 (1H, dd, J =
9.9, 3.3 Hz, CHAHBOBn), 3.69 (1H, dd, J = 9.9, 5.0 Hz, CHAHBOBn),
3.11 (1H, br. s, OH), 2.87 (1H, br. s, OH), 2.68 (1H, qd, J = 7.8, 2.5
Hz, CHCH3), 1.30 (3H, d, J = 7.8 Hz, CHCH3); 13C{1H} NMR (75
MHz, CDCl3): δC 178.4, 137.3, 128.8, 128.3, 128.1, 79.2, 75.0, 73.9,
71.0, 69.1, 43.8, 13.8; IR cm−1 ν = 3421 (OH), 1774 (CO); HRMS:
m/z (ES) 289.1032, C14H18NaO5, [M + Na]+ requires 289.1051;
[α]D24 = −6.0 (c = 0.50 g/100 mL in CHCl3).
(3S,4S,5R)-4-Hydroxy-5-(hydroxymethyl)-5-methyl-3-phenyldihy-
drofuran-2(3H)-one, 6k. OsO4 (6 mg, 0.03 mmol) was added to a
solution of 1k (94 mg, 0.25 mmol) in acetone/water (8:1,
3 mL) followed by addition of NMO (60% by weight in water, 0.06
mL, 0.26 mmol) according to the general procedure to afford the
crude product as a black oil. Purification via column chromatography
1
afforded 6k (42 mg, 0.19 mmol, 75%, 9:1 dr) as a pale oil. H NMR
(400 MHz, CDCl3): δH 7.29−7.23 (3H, m, Ph), 7.18−7.13 (2H, m,
Ph), 4.62 (1H, d, J = 10.5 Hz, CHOH), 3.80 (1H, d, J = 10.5 Hz,
CHCO), 3.70 (1H, d, J = 12.6 Hz, CHAHBOH), 3.58 (1H, d, J = 12.6
Hz, CHAHBOH), 1.32 (3H, s, CH3); 13C{1H} NMR (75 MHz,
CDCl3): δC 174.3, 135.1, 129.4, 129.0, 128.4, 86.5,75.3, 65.5, 53.8,
16.9; IR IR cm−1 ν = 3308 (br. OH), 1745 (CO); HRMS: m/z (ES)
223.0961, C12H15O4 [M + H]+ requires 223.0970; [α]D23 = −9.1
(c = 0.83 g/100 mL in MeOH).
(3S,4S,5S)-5-((R)-2-(benzyloxy)-1-hydroxyethyl)-4-hydroxy-3-
methyldihydrofuran-2(3H)-one, 6g. AD-mix-β (252 mg, 1.4 g/mmol
t
of allylic alcohol) was dissolved in a 1:1 mixture of BuOH and water
(1.8 mL, 10 mL/mmol of allylic alcohol). MeSO2NH2 (17 mg, 0.18
mmol) was added and the biphasic suspension was cooled to
0 °C. (S)-4-Benzyl-3-((2S,3R,Z)-6-(benzyloxy)-3-hydroxy-2-methyl-
hex-4-enoyl)-5,5-dimethyloxazolidin-2-one (80 mg, 0.18 mmol)
dissolved in CH2Cl2 (1 mL) was added dropwise via syringe to the
stirring suspension followed by OsO4 (4.5 mg, 0.18 mmol). The
suspension was stirred vigorously while slowly warming to room
temperature. After 48 h, the reaction was quenched with solid sodium
sulfite (100 mg) at room temperature. The suspension was filtered
through a pad of Celite/Florisil, eluting with ethyl acetate before the
solution was dried over MgSO4 and concentrated. The crude product
was purified via column chromatography [1:1 EtOAc/Petroleum
ether, Rf 0.15] to afford (3S,4S,5S)-5-((R)-2-(benzyloxy)-1-hydroxy-
ethyl)-4-hydroxy-3-methyldihydrofuran-2(3H)-one 6g (46 mg, 0.17
mmol, 95%, 17:1 dr) as a white oil.
(3S,4S,5R)-4-Hydroxy-5-((S)-1-hydroxypropyl)-3,5-dimethyldihy-
drofuran-2(3H)-one, 6h. OsO4 (15 mg, 0.06 mmol) was added to a
solution of 1h (209 mg, 0.58 mmol) in acetone/water (8:1, 3 mL)
followed by addition of NMO (60% by weight in water, 0.11 mL, 0.64
mmol) according to the general procedure to afford the crude product
as a black oil. Purification via column chromatography afforded
(3S,4S,5R)-4-hydroxy-5-((R)-1-hydroxypropyl)-3,5-dimethyl-dihydro-
1
furan-2(3H)-one, 6h (89 mg, 0.48 mmol, 82%, >49:1 dr). H NMR
(300 MHz, CDCl3): δH 4.12 (1H, dd, J = 9.8, 5.4 Hz, CHOH), 3.93
(1H, d, J = 5.4 Hz, OH), 3.57 (1H, d, J = 8.5 Hz, OH), 3.37 (1H, ddd,
J = 10.8, 8.8, 2.2 Hz, CHOHCH2), 2.62 (1H, dq, J = 9.9, 7.1 Hz,
CHCH3) 1.67 (1H, dqd, J = 15.1, 7.5, 2.4 Hz, CHAHBCH3) 1.45−1.28
(1H, m, CHAHBCH3), 1.23 (3H, s, CH3CO), 1.18 (3H, d, J = 7.1 Hz,
CHCH3), 0.97 (3H, t, J = 7.3 Hz, CH2CH3); 13C{1H} NMR (75
MHz, CDCl3): δC 178.0, 89.1, 75.6, 75.2, 41.6, 24.1, 16.4, 12.8, 11.3;
IR cm−1 ν = 3356 (br. OH), 1748 (CO); HRMS: m/z (ES)
189.1120, C9H17O4 [M + H]+ requires 189.1127; [α]D23 = −5.4 (c =
1.30 g/100 mL in CHCl3).
(3S,4S,5R)-5-((S)-2-(Benzyloxy)-1-hydroxyethyl)-4-hydroxy-3-
methyldihydrofuran-2(3H)-one, 8. AD-mix-α (252 mg, 1.4
t
g/mmol of allylic alcohol) was dissolved in a 1:1 mixture of BuOH
and water (1.8 mL, 10 mL/mmol of allylic alcohol). MeSO2NH2 (17
mg, 0.18 mmol) was added and the biphasic suspension was cooled to
(3S,4S,5S)-5-((S)-2-(Benzyloxy)-1-hydroxyethyl)-4-hydroxy-3,5-di-
methyldihydrofuran-2(3H)-one, 6i. OsO4 (4 mg, 0.02 mmol) was
added to a solution of 1i (75 mg, 0.17 mmol) in acetone/water (8:1,
0.7 mL) followed by addition of NMO (60% by weight in water, 0.03
mL, 0.18 mmol) according to the general procedure to afford the
crude product as a black oil. Purification via column chromato-
̊
0 C. (S)-4-Benzyl-3-((2S,3R,Z)-6-(benzyloxy)-3-hydroxy-2-methylhex-
4-enoyl)-5,5-dimethyloxazolidin-2-one (80 mg, 0.18 mmol) dissolved
in CH2Cl2 (1 mL) was added dropwise via syringe to the stirring sus-
pension followed by OsO4 (4.5 mg, 0.18 mmol). The suspension was
stirred vigorously while slowly warming to room temperature. After
48 h, the reaction was quenched with solid sodium sulfite (100 mg) at
room temperature. The suspension was filtered through a pad of Celite/
Florisil, eluting with ethyl acetate before the solution was dried over
MgSO4 and concentrated. The crude product was purified using via
column chromatography [1:1 EtOAc/Petroleum ether, Rf 0.15] to
afford (3S,4S,5R)-5-((S)-2-(benzyloxy)-1-hydroxyethyl)-4-hydroxy-3-
methyldihydrofuran-2(3H)-one 8 (46 mg, 0.17 mmol, 95%, 4:1 dr)
as a white oil.
1
graphy afforded 6i (43 mg, 0.15 mmol, 93%, >49:1 dr). H NMR
(300 MHz, CDCl3): δH 7.31−7.17 (5H, m, Ph), 4.49 (1H, d, J =
11.6 Hz, OCHAHBPh), 4.43 (1H, d, J = 11.6 Hz, OCHAHBPh), 3.86
(1H, d, J = 10.5 Hz, CHCH3CHOH), 3.77 (1H, dd, J = 7.6, 6.2 Hz,
CHOHCH2OBn), 3.54 (1H, dd, J = 10.0, 6.2 Hz, CHAHBOBn), 3.47
(1H, dd, J = 9.8, 7.8 Hz, CHAHBOBn), 3.42 (1H, br. s, OH), 2.90
(1H, br. s, OH), 2.65−2.53 (1H, m, CHCH3), 1.20−1.16 (6H, m,
CHCH3, CCH3); 13C{1H} NMR (75 MHz, CDCl3): δC 175.9,
136.6, 128.9, 128.6, 128.3, 87.7, 76.8, 74.3, 74.0, 70.0, 40.6, 13.9,
553
dx.doi.org/10.1021/jo2021289 | J. Org. Chem. 2012, 77, 543−555

The Journal of Organic Chemistry
Article
Synthesis of 2-Deoxy-D-ribonolactone. (S)-4-Benzyl-3-(2-
chloroacetyl)-5,5-dimethyloxazolidin-2-one, 7c. The title com-
pound was prepared according to the general procedure from n-BuLi
(10.7 mL, 26.8 mmol, 2.5 M solution in hexane), (S)-4-benzyl-5,5-
dimethyloxazolidin-2-one (5.00 g, 24.3 mmol) and chloroacetyl chloride
(2.07 mL, 26.8 mmol) in THF (150 mL). The crude product was
purified using flash silica chromatography [1:9 EtOAc/Petroleum
ether, Rf 0.50] to afford (S)-4-benzyl-3-(2-chloroacetyl)-5,5-dimethy-
loxazolidin-2-one 7c (5.69 g, 20.1 mmol, 83%) as a colorless oil that
CHAHBOH), 3.72 (1H, dd, J = 12.4, 3.7 Hz, CHAHBOH), 2.94 (1H,
dt, J = 17.9, 6.8 Hz, CHAHBCO), 2.40 (1H, dd, J = 17.9, 2.5 Hz,
CHAHBCO); 13C{1H} NMR (75 MHz, MeOD): δC 179.5, 91.0,
1
70.6, 63.4, 40.0; (4S,5S)-minor: H NMR (500 MHz, MeOD): δH
4.63−4.50 (2H, m, CHOH and CHCH2OH), 3.90 (2H, dd, J = 5.4,
1.6 Hz, CH2OH), 2.93 (1H, dd, J = 17.6, 5.9 Hz, CHAHBCO), 2.45
(1H, dd, J = 17.7, 1.6 Hz, CHACHBCO); 13C{1H} NMR (75 MHz,
MeOD): δC 179.5, 87.4, 69.8, 62.1, 40.9; IR cm−1 ν = 3356 (OH),
1749 (CO); HRMS: m/z (ES) 155.0333, C5H8NaO4, [M + Na]+
requires 155.0320; [α]D25 = +4.0 (c = 0.50 g/100 mL in MeOH) [lit:
[α]D25 = +2.17 (c = 0.6 g/100 mL in MeOH)].12a
1
solidified on standing. H NMR (300 MHz, CDCl3): δH 7.32−7.20
(5H, m, Ph), 4.76 (1H, d, J = 15.8 Hz, COCHAHBCl), 4.64 (d, J =
15.8 Hz, COCHAHBCl), 4.49 (1H, dd, J = 9.7, 3.9 Hz, CHN), 3.20
(1H, dd, J = 14.4, 3.8 Hz, CHHAHBPh), 2.88 (1H, dd, J = 14.4, 9.8 Hz,
CHAHBPh), 1.38 (3H, s, C(CH3)(CH3)), 1.36 (3H, s, C(CH3)(CH3));
13C{1H} NMR (75 MHz, CDCl3): δC 166.4, 152.4, 136.5, 129.1, 128.9,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C{1H}, spectra of all aldol products (1a−k, 9) and
127.1, 83.7, 64.1, 44.0, 35.0, 28.7, 22.4; IR cm−1 ν = 1769 (COox), 1709
(CO); HRMS: m/z (ES) 304.0722, C14H16ClNNaO3 [M + Na]+
requires 304.0716; [α]D25 = −32.0 (c = 0.50 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((2S,3R)-2-chloro-3-hydroxypent-4-enoyl)-5,5-di-
methyloxazolidin −2-one, 9. The title compound was pre-
pared according to the general procedure from dibutylboron triflate
(7.70 mL, 7.7 mmol), (S)-4-benzyl-3-(2-chloroacetyl)-5,5-dimethylox-
azolidin-2-one 7c (1.97 g, 7.0 mmol), N,N-diisopropylethylamine
(1.58 mL, 9.1 mmol) and acrolein (0.61 mL, 9.1 mmol) in dichloro-
methane (15 mL) to afford a crude product as a pale-yellow oil. The
crude product was purified using flash silica chromatography [1:4
EtOAc/Petroleum ether, Rf 0.27] to afford (S)-4-benzyl-3-((2S,3R)-2-
chloro-3-hydroxypent-4-enoyl)-5,5-dimethyloxazolidin-2-one 9 (1.07
g, 3.2 mmol, 45%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δH
7.31−7.17 (5H, m, Ph), 5.88 (1H, ddd, J = 17.3, 10.5, 5.8 Hz, CH
CH2), 5.72 (1H, d, J = 5.1 Hz, CHCl), 5.40 (1H, dt, J = 17.3, 1.3 Hz,
CHCHAHB), 5.28 (1H, dt, J = 10.5, 1.2 Hz, CHCHAHB), 4.59
(1H, app. t, J = 5.5 Hz, CHOH), 4.48 (1H, dd, J = 9.5, 3.8 Hz, CHN),
3.14 (1H, dd, J = 14.4, 3.8 Hz CHAHBPh), 3.00 (1H, br. s, OH), 2.88
(1H, dd, J = 14.4, 9.5 Hz, CHAHBPh), 1.36 (3H, s, C(CH3)(CH3)),
1.33 (3H, s, C(CH3)(CH3)); 13C{1H} NMR (75 MHz, CDCl3): δC
167.9, 152.0, 136.4, 135.0, 129.1, 128.8, 127.0, 118.9, 83.3, 72.9, 64.0,
59.1, 34.9, 28.5, 22.2; IR cm−1 ν = 3496 (OH), 1771 (COox), 1703
(CO); HRMS: m/z (ES) 338.1149, C17H21ClNO4 [M + H]+
requires 338.1159; [α]D24 = −12.0 (c = 1.00 g/100 mL in CHCl3).
(S)-4-Benzyl-3-((S)-3-hydroxypent-4-enoyl)-5,5-dimethyloxazoli-
din-2-one, 10. (S)-4-Benzyl-3-((2S,3R)-2-chloro-3-hydroxypent-4-
enoyl)-5,5-dimethyloxazolidin-2-one 9 (1.08 g, 3.2 mmol) was
dissolved in dry methanol (12 mL) under nitrogen. Zinc dust (0.83
g, 12.8 mmol) and ammonium chloride (0.69 g, 12.8 mmol) were
added and the reaction was stirred for 1 h. The suspension was filtered
through Celite and concentrated to afford the crude product as a
yellow oil. The crude product was purified using flash silica chro-
matography [1:4 EtOAc/Petroleum ether, Rf 0.18] to afford (S)-4-
benzyl-3-((S)-3-hydroxypent-4-enoyl)-5,5-dimethyloxazolidin-2-one
1
hydroxy-γ-butyrolactones (6a−k, 8, 11) as well as H NOE
spectra of all lactones. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*S.D.Bull@bath.ac.uk
■
ACKNOWLEDGMENTS
We thank the University of Bath (J.P.) and the EPSRC (I.R.D.)
for funding.
■
REFERENCES
■
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1
10 (0.79 g, 2.6 mmol, 82%) as a colorless oil. H NMR (300 MHz,
CDCl3): δH 7.33−7.24 (5H, m, Ph), 5.89 (1H, ddd, J = 17.3, 10.5, 5.4
Hz, CHCH2), 5.32 (1H, d, J = 17.3 Hz, CHCHAHB), 5.15 (1H,
d, J = 10.5 Hz, CHCHAHB), 4.58−4.50 (2H, m, CHOH, CHN),
3.16−3.09 (3H, m, CHACHBPh, CH2CHOH), 2.93−2.85 (2H, m,
CHACHBPh, CHOH), 1.39 (3H, s, C(CH3)(CH3)), 1.37 (3H, s,
C(CH3)(CH3)); 13C{1H} NMR (75 MHz, CDCl3): δC 172.3, 152.7,
138.8, 136.8, 129.1, 128.9, 127.0, 115.5, 82.7, 68.9, 63.5, 42.6, 35.6,
28.6, 22.3; IR cm−1 ν = 3483 (OH), 1771 (CO), 1694 (COox);
HRMS: m/z (ES) 304.1511, C17H22NO4, [M + H]+ requires
304.1548; [α]D20 = −52.0 (c = 0.50 g/100 mL in CHCl3).
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6621−6624.
2-Deoxy-D-ribonolactone (4S,5R)-4-Hydroxy-5-(hydroxymethyl)-
dihydrofuran-2(3H)-one, 11. OsO4 (16 mg, 0.06 mmol) was added
to a solution of 10 (200 mg, 0.66 mmol) in acetone/water (8:1, 2.5
mL) followed by addition of NMO (60% by weight in water, 0.12 mL,
0.73 mmol) according to the general procedure to afford the crude
product as a black oil. Purification via column chromatography
1
afforded 11 (76 mg, 0.57 mmol, 87%, 9:1 dr). (4S,5R)-major: H
(4) (a) Pena-Lopez, M.; Martinez, M. M.; Sarandeses, L. A.; Sestelo,
J. P. Chem.Eur. J. 2009, 15, 910−916. (b) Habrant, D.; Stewart,
A. J. W.; Koskinen, A. M. P. Tetrahedron 2009, 65, 7927−7934.
NMR (500 MHz, MeOD): δH 4.46 (1H, dt, J = 6.7, 2.3 Hz, CHOH),
4.40−4.39 (1H, m, CHCH2OH), 3.79 (1H, dd, J = 12.4, 3.3 Hz,
554
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(c) Nicolaou, K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129, 429−
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5055−5072.
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