A Lewis acid promoted oxidative cyclization

Article abstract of DOI:10.1021/jo901243y

(Chemical Equation Presented) Replacing trifluoroacetic acid with a catalytic amount of Lewis acid in the osmium mediated oxidative cyclization results in higher yielding reactions that can proceed nearly an order of magnitude faster. The osmium loading c

Full text of DOI:10.1021/jo901243y

pubs.acs.org/joc
SCHEME 1. The Osmium-Mediated Oxidative Cyclization
A Lewis Acid Promoted Oxidative Cyclization
Timothy J. Donohoe,* Paul C. M. Winship, and
Daryl S. Walter
Department of Chemistry, University of Oxford, Chemistry
Research Laboratory, Mansfield Road, Oxford, OX1 3TA,
United Kingdom, and Pain & Neuroexcitability DPU,
Neurosciences CEDD, GlaxoSmithKline, New Frontiers
Science Park North, Harlow, Essex, CM19 5AW,
United Kingdom
of the starting material. As a consequence of this, PNO
combinedwith citric acid (which stabilizes Os(VI) with respect
to disproportion in acidic media)4 has been incorporated as a
replacement to the trimethylamine N-oxide/trans-cinnamic
acid system in the amino-alcohol series to give higher yielding
reactions (Scheme 1). As previously shown, the cyclization
reactions are stereospecific (with syn addition of both het-
eroatoms across the tethered alkene) and stereoselective
(forming cis-2,5-pyrrolidines exclusively).
timothy.donohoe@chem.ox.ac.uk
Received June 11, 2009
Initial attempts to apply these improved conditions, using
PNO/citric acid, to the more challenging diol cyclization to
afford the corresponding tetrahydrofurans were unsuccess-
ful, however, with more catalyst and TFA being required for
the reaction to proceed cleanly. While still being a substantial
improvement on the previous TMO/TFA conditions, the
very acidic environment required for the cyclization to occur,
both in the diol and the amino-alcohol series, leads to
complications during workup, especially on a large scale.
As a result, a wide range of functional groups were still not
compatible with the reaction.
The exact role of acid in the cyclization step is unknown.
However, it has been suggested that protonation of an oxo
ligand on the osmium center results in the metal becoming
electron deficient, which allows an inverse electron demand
[4þ2] cycloaddition to take place with an electron-rich alkene.5
It was envisaged that in order to make the cyclization condi-
tions less acidic, a catalytic amount of an oxophilic Lewis acid
could be used in place of a Brønsted acid in the cyclization
procedure. After screening a range of Lewis acids, we can now
report that a range of metal triflates are capable of replacing the
Brønsted acid, and cyclizing vicinal diols to THF rings.
Initial investigations concentrated on the cyclization of
diol 4. Under previous conditions the reaction proceeded to
furnish 5 in 72% yield in 20 h (Table 1). Initial improve-
ments to this were observed by changing the reoxidant to
PNO, with the addition of citric acid. Furthermore, repla-
cing TFA with an excess of Lewis acid in the form of
Sc(OTf)3 saw a further improvement in the yield; however,
when used catalytically, Sc(OTf)3 in acetone encouraged
the formation of acetonide side products, and therefore, the
Replacing trifluoroacetic acid with a catalytic amount of
Lewis acid in the osmium mediated oxidative cyclization
results in higher yielding reactions that can proceed
nearly an order of magnitude faster. The osmium loading
can also be reduced to as little as 0.2 mol %. Furthermore,
these mildly acidic conditions are capable of tolerating a
wide range of acid sensitive protecting groups that are
incompatible with previous cyclization conditions.
The oxidative cyclization of 1,5-dienes to the correspond-
ing THFs has been known for almost 50 years. Previously,
reports from our group showed that vicinal diols derived
from 1,5-dienes will cyclize to form 2,5-cis-THFs in good
yields under the action of osmium tetraoxide and an acid.1
This system used trimethylamine N-oxide (TMO) as a reox-
idant, and utilized an excess of a “sacrificial alkene”, usually
trans-cinnamic acid, in order to afford a source of Os(VI) in
situ. This methodology has also been applied to unsaturated
N-Ts amino-alcohols, which cyclize to give the correspond-
ing 2,5-cis-pyrrolidines.2
Recently, it was also noted that pyridine N-oxide (PNO)
could be used as a novel reoxidant for osmium in the oxidative
cyclization of N-protected amino-alcohols.3 It is speculated
that PNO is capable of oxidizing Os(IV) to Os(VI) (this being
the more active catalyst for the cyclization process) but not to
unwanted Os(VIII);which can result in the dihydroxylation
(4) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B.
Adv. Synth. Catal. 2002, 344, 421–433.
(1) Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed. 2005, 44,
4766–4768.
(2) Donohoe, T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop,
P. A. Angew. Chem., Int. Ed. 2006, 45, 8025–8028.
(3) Donohoe, T. J.; Wheelhouse, K. M. P.; Lindsay-Scott, P. J.; Glossop,
P. A.; Nash, I. A.; Parker, J. S. Angew. Chem., Int. Ed. 2008, 47, 2872–2875.
(5) Previous attempts to heat the reactions in TFA saw an increase in the
rate of reaction, but yields were generally lower: e.g., treating 6 under the
PNO/TFA cyclization conditions with 1 mol % of K2OsO2(OH)4 at rt
furnished 7 in 74% after 24 h; however, at 60 °C the yield was only 51%
after 14 h.
6394 J. Org. Chem. 2009, 74, 6394–6397
Published on Web 07/08/2009
DOI: 10.1021/jo901243y
r
2009 American Chemical Society

Donohoe et al.
JOCNote
TABLE 1. Optimization of Conditions
entry
conditions
5 mol % of K2OsO4 2H2O, TMO, trans-cinnamic acid, TFA, acetone:water (9:1)a
yield of 5
1
2
3
4
5
6
7
72% (20 h)
78% (16 h)
84% (16 h)
87% (8 h)
89% (8 h)
92% (6 h)
90% (72 h)
3
5 mol % of K2OsO4 2H2O, PNO, citric acid, TFA, acetone:water (9:1)a
3
5 mol % of K2OsO4 2H2O, PNO, citric acid, 6 equiv of Sc(OTf)3, acetone:water (9:1)a
3
5 mol % of K2OsO4 2H2O, PNO, citric acid, 0.5 equiv of Cu(OTf)2, MeCN:water (4:1), 60 °C
3
5 mol % of K2OsO4 2H2O, PNO, citric acid, 0.5 equiv of Zn(OTf)2, MeCN:water (4:1), 60 °C
3
1 mol % of K2OsO4 2H2O, PNO, citric acid, 0.5 equiv of Zn(OTf)2, MeCN:water (3:2), 60 °C
3
0.2 mol % of K2OsO4 2H2O, PNO, citric acid, 0.5 equiv of Zn(OTf)2, MeCN:water (3:2), 60 °C
3
aReaction carried out at room temperature
SCHEME 3. Unhindered Substratesa
SCHEME 2. Triflate Source
use of acetone as a solvent was abandoned. After screening
various solvents and temperatures, an acetonitrile/water
solvent system was found to be most effective. In addition
to this, the reaction could be heated to 60 °C, resulting in an
increase of the rate of reaction, with no loss in yield. This is
completely unlike the previous TFA conditions, where
heating led to deleterious side reactions.5 Screening various
metal triflates also revealed that Cu(OTf)2 and Zn(OTf)2
were cheaper, milder, and equally reliable alternatives to
Sc(OTf)3. Both Cu(OTf)2 and Zn(OTf)2 give similar yields
(Table 1, entries 4 and 5), and are essentially interchange-
able. Rates of reaction were also found to be much quicker
when more water was added. Following the large increase in
rate and comparatively mild nature of these new conditions,
a
2
When attempted with 1 mol % K OsO4 2H2O less than 50% conversion
3
was observed after 96 h
used in a standard cyclization reaction on geraniol benzyl ether
6, glycolic acid (with an R-hydroxy carboxylic acid group) and
acetic acid. The standard reaction with citric acid proceeded to
completion in just 3.5 h. It was found that when replacing citric
acid with glycolic acid (0.75 equiv) and adjusting the reaction
to pH 2 with acetic acid, the reaction proceeded to completion
in 9 h. Furthermore, when citric acid was replaced with just
acetic acid at pH 2, the reaction took 96 h, thus allowing us to
conclude that the most important role of the citric acid is the
ligating effect of the R-hydroxy carboxylic acid, as originally
suggested by Sharpless.4
the loading of K2OsO4 2H2O can now be reduced to as low
as 0.2 mol % (Table 1, entry 7).
3
When applying these new Lewis acid/citric acid conditions
to relatively unsubstituted diol substrates, the cyclization
proceeds with excellent yields to produce the corresponding
THF, even in the case of 1,3 diols, which have previously
been more reluctant to cyclize due to the slow formation of
the intermediate osmate ester (Scheme 3).
With these new conditions available, a range of challen-
ging substrates that had previously cyclized in relatively low
yields or did not cyclize at all were examined (Scheme 4).
Despite the PNO/TFA conditions proving a substantial
improvement from the previous TMO/TFA system, cycliz-
ing the same substrates by using the new Lewis acid condi-
tions saw another increase in yield and in most cases the
rate of reaction was also accelerated. However, a loading of
5 mol % was required to cyclize 14, as polymerization of
the diene occurs slowly on a time scale comparable to the
cyclization reaction.
To establish the role of the M(OTf)x species, a series of
trial reactions were conducted. Initially, it was unclear as to
whether the Lewis acid acted by interacting with the inter-
mediate osmate ester, or simply as a mild in situ source of
TfOH. The pH of the Lewis acid-promoted cyclization was
measured to be pH 2. Therefore, in an analogous reaction,
the Lewis acid was omitted, and the reaction adjusted to pH 2
by addition of TfOH. After several hours, however, signifi-
cant amounts of decomposition were seen, with only a trace
of desired THF recovered (Scheme 2).
Investigations into the exact role of citric acid were con-
ducted, as it was unclear whether the cyclization was facilitated
due to a pH effect of the added acid, or due to the ligating R-
hydroxy carboxylic acid moiety of the citrate species, which
stabilizes the metal and encourages the cyclization by assisting
product release.4 To determine the importance of the two
processes, two acids with similar pKa values to citric acid were
J. Org. Chem. Vol. 74, No. 16, 2009 6395

Donohoe et al.
JOCNote
SCHEME 4. Substrates That Were Difficult To Cyclize
dihydrate (0.01 mmol) and the metal trifluoromethansulfonate
(0.5 mmol). The resulting solution was warmed to 60 °C and the
mixture was left to stir until all starting material had reacted.
Sodium sulfite (5 mg) and water (10 mL) were added and the
reaction was cooled to room temperature. The mixture was
extracted with ethyl acetate (3 ꢀ 50 mL) and the combined
organic layers were washed with 2 M HCl (20 mL), 3 M NaOH
(20 mL), and brine (20 mL), dried over sodium sulfate, and
filtered, then the solvent was removed in vacuo. The crude
product was purified as specified.
(1R,10S)-1,10-((2R,5S)-Tetrahydrofuran-2,5-diyl)dipentan-1-
ol, 5. Diol 4 (50mg, 0.18 mmol) was subjected toprocedure1 (8 h).
The crude product was purified by flash column chromatography
[SiO2, acetone-petrol, 20:80] to give THF 5 (various yields) as an
oil. 1H NMR (400 MHz, CDCl3) δH 3.86-3.79 (2H, m), 3.43-
3.39 (2H, m), 3.00 (2H, br s), 1.97-1.88 (2H, m), 1.77-1.69 (2H,
m), 1.48-1.28 (12H, m), 0.90 (6H, t, J=10.8 Hz); 13C NMR (100
MHz, CDCl3) δC 82.9, 74.3, 33.7, 28.1, 27.8, 22.7, 14.1.
(R)-1-((2R,5S)-5-(Hydroxymethyl)tetrahydrofuran-2-yl)hex-
an-1-ol, 9. Diol 8 (50 mg, 0.27 mmol) was subjected to procedure 1
(6 h). The crude product was purified by flash column chroma-
tography [SiO2, acetone-petrol, 20:80] to give THF 9 (51 mg,
94%) as a colorless oil. IR (thin film, cm-1) 3385, 1651, 1463,
1054; 1H NMR (400 MHz, CDCl3) δH 4.14-4.06 (1H, m), 3.83
(1H, dd, J=6.6, 12.6Hz), 3.75 (1H, dd, J=11.6, 2.8 Hz), 3.51 (1H,
dd, J=11.6, 5.2 Hz), 3.46-3.40 (1H, m), 3.07 (2H, br. s), 1.99-
1.88 (2H, m), 1.84-1.67 (2H, m), 1.57-1.17 (8H, m), 0.89 (3H, t,
J=6.8Hz); 13C NMR (100 MHz, CDCl3) δC 83.1, 80.0, 74.4, 65.1,
34.0, 31.9, 28.2, 27.2, 25.4, 22.6, 14.1; HRMS (ESþ, m/z) calcd
SCHEME 5. Acid-Sensitive Substrates
225.1461 (C11H22NaO3), found 225.1462; [R]22 þ9.5 (c 0.5,
D
CH2Cl2).
(R)-1-((2R,5S)-5-(2-Hydroxyethyl)tetrahydrofuran-2-yl)hex-
an-1-ol, 11. Diol 10 (50 mg, 0.18 mmol) was subjected to proce-
dure 1 (30 h). The crude product was purified by flash column
chromatography [SiO2, acetone-petrol, 15:85] to give THF 11
(49 mg, 88%) as a colorless oil. IR (thin film, cm-1) 3386, 1464,
1067; 1H NMR (400 MHz, CDCl3) δH 4.07 (1H, dtd, J=7.6, 7.2,
4.8 Hz), 3.81-3.76 (3H, m), 3.39 (1H, q, J=5.6 Hz), 2.89 (1H, br
The main benefit, however, of removing TFA from the
osmium-mediated oxidative cyclization procedure was to
make the reaction compatible with a wide range of functional
groups that would otherwise react under the harshly acidic
conditions. It was found that the use of a phosphate buffer at
pH 6.5 instead of water6 was sufficient to tolerate a range of
acid-sensitive N- and O-protecting groups (Scheme 5). De-
spite longer reaction times, the reactions proceeded cleanly in
good to excellent yields. In each case, attempting to cyclize
the same substrates under PNO/TFA conditions led to
complete deprotection within 1 h, with no oxidative cycliza-
tion products being observed.
To conclude, replacing trifluoroacetic acid with a cata-
lytic amount of a Lewis acid has afforded a mild procedure
capable of forming both tetrahydrofurans and pyrrolidines
in high yields. Furthermore, due to the mildly acidic con-
ditions, the osmium loading can be reduced as low as
0.2 mol %. These conditions are now compatible with a
wide range of acid-sensitive protecting groups.
s), 2.67 (1H, br s), 2.06-1.22 (14H, m), 0.87 (3H, t, J=6.8Hz);13
C
NMR(100 MHz, CDCl3) δC 82.9, 79.1, 74.1, 61.1, 37.7, 34.1, 31.9,
31.6, 27.5, 25.4, 22.6, 14.1; HRMS:(ESþ, m/z) calcd 239.1618
(C12H24NaO3), found 239.1617.
2-((2R,5S)-5-((S)-Benzyloxy(hydroxy)methyl)-5-methyltetra-
hydrofuran-2-yl)propan-2-ol, 7. Diol 61 (50 mg, 0.18 mmol) was
subjected to procedure 1 (8 h). The crude product was purified
by flash column chromatography [SiO2, acetone-petrol, 20:80]
1
to give THF 7 (44 mg, 83%) as a colorless oil. H NMR (400
MHz, CDCl3) δH 7.39-7.26 (5H, m), 4.62-4.53 (2H, m), 3.85
(1H, t, J=7.1 Hz), 3.74 (1H, dd, J=8.5, 3.3 Hz), 3.69-3.63 (1H,
m), 3.61-3.54 (1H, m), 3.20 (2H, br s), 2.28-2.17 (1H, m),
2.06-1.85 (2H, m), 1.65-1.58 (1H, m), 1.23 (3H, s), 1.15 (3H, s),
1.09 (3H, s); 13C NMR (100 MHz, CDCl3) δC 137.8, 128.5,
127.8, 85.8, 83.9, 75.4, 73.5, 71.7, 71.1, 35.1, 27.8, 26.3, 25.0,
23.3; [R]22D -15.0 (c 1.0, CH2Cl2).
2-((2R,5S)-5-((R)-Benzyloxy(hydroxy)methyl)-5-methyltetra-
hydrofuran-2-yl)propan-2-ol, 13. Diol 12 (50 mg, 0.18 mmol)
was subjected to procedure 1 (16 h). The crude product was
purified by flash column chromatography [SiO2, acetone-
petrol, 20:80] to give THF 13 (45 mg, 85%) as a colorless oil.
IR (thin film, cm-1) 3398, 1071; 1H NMR (400 MHz, CDCl3)
δH 7.39-7.26 (5H, m), 4.56 (2H, s), 3.88-3.80 (2H, m), 3.62
(1H, dd, J=9.7, 3.2 Hz), 3.41 (1H, dd, J=9.7, 7.8 Hz), 2.98 (2H,
br s), 2.23-2.15 (1H, m), 2.05-1.85 (2H, m), 1.53 (1H, ddd, J=
12.4, 8.3, 6.8 Hz), 1.24 (3H, s), 1.16 (3H, s), 1.10 (3H, s); 13C
NMR (100 MHz, CDCl3) δC 138.8, 128.5, 127.8, 84.9, 84.4,
75.5, 73.4, 71.8, 71.2, 32.7, 27.7, 26.6, 25.1, 23.6; HRMS (ESþ,
Experimental Section
Representative Procedure 1. To a solution of diol (1 mmol) in
acetonitrile (12 mL) and water (8 mL) was added pyridine
N-oxide (2 mmol), citric acid (0.75 mmol), potassium osmate
(6) The sodium phosphate buffer consisted of a 1:1 mixture of 0.67 M
NaH2PO4 and 0.67 M Na2HPO4 (pH 6.5 at 22 °C): Zhao, M. M.; Li, J.;
Mano, E.; Song, Z. J.; Tschaen, D. M. Org. Synth. 2005, 81, 195–203.
m/z) calcd 317.1729 (C17H26NaO4), found 317.1733; [R]22
þ3.1 (c 1.0, CH2Cl2).
D
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Donohoe et al.
JOCNote
2-((2R,5R)-5-(Hydroxymethyl)-5-vinyltetrahydrofuran-2-yl)-
propan-2-ol, 15. Diol 147 (50 mg, 0.29 mmol) was subjected to
procedure 1 (5 mol % Os, 16 h). The crude was purified by flash
column chromatography [SiO2, acetone-petrol, 20:80] to give 15
(39 mg, 78%) as a colorless oil. IR (thin film, cm-1) 3375, 2967,
1056; 1H NMR (400 MHz, CDCl3) δH 5.80 (1H, dd, J=17.2, 10.8
Hz), 5.31 (1H, dd, J=17.2, 1.6 Hz), 5.13 (1H, dd, J=10.8, 1.6 Hz),
3.84 (1H, t, J=11.2 Hz), 3.59 (1H, d, J=11.2 Hz), 3.49 (1H, d, J=
11.2 Hz), 3.10 (1H, br s), 2.94 (1H, br s), 2.11 (1H, ddd, J=12.0,
8.8, 6.0 Hz), 1.97-1.82 (2H, m), 1.81-1.72 (1H, m), 1.29 (3H, s),
1.14 (3H, s); 13C NMR (100 MHz, CDCl3) δC 140.3, 114.0, 86.2,
85.7, 71.9, 67.5, 32.2, 27.6, 26.3, 25.1; HRMS (ESþ, m/z) calcd
(400 MHz, CDCl3) δH 4.66 (2H, s), 3.84 (1H, t, J=7.2 Hz), 3.77
(1H, dd, J=10.2, 2.8 Hz), 3.70-3.66 (1H, m), 3.55 (1H, dd, J=
10.2, 8.6 Hz), 3.38 (3H, s), 3.29 (1H, s), 3.22 (1H, s), 2.20 (1H, ddd,
J = 12.4, 9.2, 6.0 Hz), 2.04-1.85 (2H, m), 1.62 (1H, ddd, J =
12.4, 8.6, 7.2Hz), 1.23 (3H, s), 1.17 (3H, s), 1.09 (3H, s); 13C NMR
(100 MHz, CDCl3) δC 96.9, 85.7, 83.9, 75.7, 71.7, 69.5, 55.4, 35.2,
27.7, 26.3, 25.0, 23.2; HRMS (ESþ, m/z) calcd 271.1516
(C12H24NaO5), found 271.1514; [R]22D -5.2 (c 1.0, CH2Cl2).
2-((2R,5S)-5-((S)-2-(tert-Butyldimethylsilyloxy)-1-hydroxy-
ethyl)-5-methyltetrahydrofuran-2-yl)propan-2-ol, 21. Diol 20 (50 mg,
0.17 mmol) was subjected to procedure 2. The crude product was
purified by flash column chromatography [SiO2, acetone-petrol,
20:80] to give THF 21 (35 mg, 67%) as a colorless oil. IR (thin
film, cm-1) 3396, 2958, 1471, 1257, 1115, 1069; 1H NMR
(400 MHz, CDCl3) δH 3.87 (1H, dd, J=7.2, 6.2 Hz), 3.79 (1H,
dd, J=9.2, 3.8 Hz), 3.69 (1H, ∼t, J=9.2 Hz), 3.60 (1H, dd, J=9.2,
3.8Hz), 3.45 (1H, brs), 3.02 (1H, brs), 2.31 (1H, ddd, J=12.4, 9.0,
7.2 Hz), 2.09-2.00 (1H, m), 1.97-1.87 (1H, m), 2.31 (1H, ddd, J=
12.0, 8.4, 6.2 Hz), 1.25 (3H, s), 1.16 (3H, s), 1.10 (3H, s), 0.92-0.90
(9H, m), 0.10-0.08 (6H, m); 13C NMR (100 MHz, CDCl3) δC
85.9, 83.5, 76.4, 71.8, 63.6, 35.1, 27.9, 26.0, 25.9, 25.0, 23.4, 18.3, -
5.4, -5.3; HRMS (ESþ, m/z) calcd 341.2119 (C16H34NaO4Si),
found 341.2118; [R]22D -7.4 (c 1.0, CH2Cl2).
2-((2R,5S)-5-((S)-1-Hydroxy-2-(4-methoxybenzyloxy)ethyl-
5-methyltetrahydrofuran-2-yl)propan-2-ol, 23. Diol 22 (100 mg,
0.32 mmol) was subjected to procedure 2. The crude product
was purified by flash column chromatography [SiO2, acetone-
petrol, 20:80] to give THF 23 (74 mg, 70%) as a colorless oil. IR
(thin film, cm-1) 2971, 2872, 1712, 1612, 1514, 1249; 1H NMR
(400 MHz, CDCl3) δH 7.29-7.24 (2H, m), 6.91-6.86 (2H, m),
4.50 (2H, m), 3.85 (1H, t, J=7.2 Hz), 3.81 (3H, s), 3.72 (1H, dd,
J=8.4, 3.2 Hz), 3.64 (1H, dd, J=9.6, 3.2 Hz), 3.55 (1H, dd, J=
9.6, 8.4 Hz), 3.20 (1H, br s), 3.03 (1H, br s), 2.24 (1H, ddd, J=
12.4, 9.0, 6.4 Hz), 2.06-1.96 (1H, m), 1.94-1.85 (1H, m), 1.60
(1H, ddd, J=12.4, 8.4, 7.2 Hz), 1.23 (3H, s), 1.15 (3H, s), 1.09
(3H, s); 13C NMR (100 MHz, CDCl3) δC 159.3, 129.9, 129.5,
113.9, 85.8, 83.9, 75.4, 73.1, 71.7, 70.7, 55.3, 35.1, 27.8, 26.3,
25.0, 23.3; HRMS (ESþ, m/z) calcd 347.1829 (C18H28O5Na),
found 347.1819; [R]22D -9.8 (c 1.0, CH2Cl2).
22
209.1151 (C10H18NaO3), found 209.1154; [R]D þ1.3 (c 1.0,
CH2Cl2).
Representative Procedure 2. To a stirred solution of diol
(1.0 mmol) in acetonitrile/pH 6.5 phosphate buffer (20 mL,
3:2 mixture) was added pyridine N-oxide (2.0 mmol), citric acid
(0.75 mmol), and metal trifluoromethanesulfonate (0.5 mmol)
before potassium osmate dihydrate (as specified) was added.
The mixture was heated to 60 °C and left to stir until all starting
material had reacted. The resulting mixture was then quenched
with sodium sulfite (50 mg) and stirred for 0.5 h before ethyl
acetate (50 mL) and water (20 mL) were added. The two layers
were separated and the aqueous layer was extracted with ethyl
acetate (3ꢀ50 mL). The combined organic layers were washed
with brine (20 mL), dried over sodium sulfate, and filtered, then
the solvent was removed in vacuo. The crude product was
purified as specified.
(2R,5S)-tert-Butyl 2,5-Bis(hydroxymethyl)pyrrolidine-1-car-
boxylate, 17. Amino-alcohol 168 (50 mg, 0.23 mmol) was sub-
jected to procedure 2. The crude product was purified by flash
column chromatography [SiO2, acetone-petrol,20:80] to give
pyrrolidine 179 (44 mg, 82%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δH 4.54 (1H, br s), 4.04-3.72 (4H, m),
3.51 (2H, dd, J=11.2, 4.8 Hz), 3.23 (1H, br s), 2.24-1.72 (4H,
m), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3) δC 155.4, 80.7,
64.4, 60.5, 28.5, 26.9.
2-((2R,5S)-5-((S)-1-Hydroxy-2-(methoxymethoxy)ethyl)-5-
methyltetrahydrofuran-2-yl)propan-2-ol, 19. Diol 18 (50 mg, 0.22
mmol) was subjected to procedure 2. The crude product was
purified by flash column chromatography [SiO2, acetone-petrol,
35:65] to give THF 19 (48 mg, 91%) as a colorless oil. IR (thin
Acknowledgment. We thank the EPSRC/Pharma Organic
Synthetic Chemistry Studentships program for supporting
this project and GlaxoSmithKline for financial support.
1
film, cm-1) 3418 (br), 2972, 1464, 1378, 1151, 1035; H NMR
(7) Hioki, H.; Ooi, H.; Hamano, M.; Mimura, Y.; Yoshio, S.; Kodama,
M.; Ohta, S.; Yanai, M.; Ikegami, S. Tetrahedron 2001, 57, 1235–1246.
(8) Anada, M.; Sugimoto, T.; Watanabe, N.; Nakajima, M.; Hashimoto,
S. Heterocycles 1999, 50, 969–980.
Supporting Information Available: Preparation of com-
pounds 4, 8, 10, 12, 18, 20, 24, and H NMR of all oxidative
cyclization products are available. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
^
ꢀ
(9) Chenevert, R.; Jacques, F.; Giguere, P.; Dassar, M. Tetrahedron:
Asymmetry 2008, 19, 1333–1338.
J. Org. Chem. Vol. 74, No. 16, 2009 6397