A novel stereoselective access to substituted L-2-deoxypentono-1,4-lactones and L-2-deoxypentoses

Article abstract of DOI:10.1016/S0040-4020(00)00871-1

A stereoselective method to L-2-deoxypentose or L-2-deoxy-pentono-1,4-lactone units was developed employing the (S)-Hydroxynitrile lyase from Hevea brasiliensis. Additionally a diastereoselective reduction using either (D)- or (L)-tartaric acid in conjuction with sodium borohydride had been applied to control the ultimate stereochemistry of the bioactive compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00871-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9289±9295
A Novel Stereoselective Access to Substituted l-2-Deoxypentono-
1,4-lactones and l-2-Deoxypentoses
*
Dean V. Johnson, Roland Fischer and Herfried Griengl
È È
Spezialforschungsbereich Biokatalyse, Institut fur Organische Chemie der Technischen Universitat Graz, Stremayrgasse 16,
A-8010 Graz, Austria
Received 10 July 2000; accepted 19 September 2000
AbstractÐA stereoselective method to l-2-deoxypentose or l-2-deoxy-pentono-1,4-lactone units was developed employing the
(S)-Hydroxynitrile lyase from Hevea brasiliensis. Additionally a diastereoselective reduction using either (d)- or (l)-tartaric acid in
conjuction with sodium borohydride had been applied to control the ultimate stereochemistry of the bioactive compounds. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
synthetic exploitation of chiral cyanohydrins prepared via
the (S)-Hydroxynitrile lyase from Hevea brasiliensis. With
the development of ef®cient production processes7 these
compounds are now establishing themselves as prepara-
tively useful chiral building blocks in synthesis.8
Methods for gaining access to l-nucleosides and sugars
represent motivating and promising areas of research. As
routes to both enantiomeric series of nucleosides have
emerged, the therapeutic advantages of the l-series
(compared to their corresponding d-counterparts) are
becoming increasingly recognised.1 For example, as their
tendency towards enzymatic metabolism is reduced, an
increase in bio-availability and hence increased potency of
the corresponding drug is observed. This is exempli®ed by
the treatment of the human immunode®ciency virus (HIV)
with the l-nucleoside analogues l-ddC1c±h and l-3TC.1i,2
Indeed, an l-isomer (e.g. (2)-3TC) can also prove less
cytotoxic than its enantiomer.2
Results and Discussion
The chiral cyanohydrin from octenal was chosen as the
starting point for our synthesis, as it is available in optically
pure form and is a versatile chiral material9 in synthesis.
Also in our laboratories it has proven to be the best substrate
from a series of unsaturated aldehydes.7 The silyl protected
cyanohydrin 1 was prepared as previously reported (99%
e.e.),7,10 and then coupled to methyl bromoacetate, in a
zinc mediated reaction,11 to give the g-silyoxy-b-keto
The synthesis of the l-nucleosides can be achieved by estab-
lished procedures, the difference being that the l-sugar is
employed instead of the more normal d-form. Although in
theory this may appear straightforward, the problem
remains that the l-ribose unit (or its derivatives) is not
readily available and must be synthesised from alternative
asymmetric precursors, such as l-xylose3, l-arabinose4 or
d-glutamic acid.5 This challenge has continued to stimulate
efforts in this area, resulting in methods such as that of Trost
et al.6 which elegantly employs a palladium catalysed asym-
metric desymmetrization of cis-2,5-diacyloxy-2,5-dihydro-
furans. With this in mind we set about developing a
synthetic strategy which would allow access to useful
substituted l-2-deoxypentose or l-2-deoxy-pentono-1,4-
lactone units. One of our current research efforts is the
²
ester 2 in good yield (76%). Stereocontrolled reduction of
the ketone functionality was achieved employing the
method of Yatagai et al. for prochiral ketones.12
Treatment of 2 with a mixture of l-tartaric acid and NaBH4
yielded the syn compound 4 in 92% d.e. Alternatively,
treatment with d-tartaric acid and NaBH4 yielded the
corresponding anti compound 3, also in 92% d.e.
Interestingly, both reductions yielded products with a 92%
d.e., which suggests that the pre-existing chirality of the
substrate (i.e. 2) does not in¯uence the stereochemical
outcome of the reduction. To our knowledge13 this aspect
has not been previously observed with this reducing system.
In connection with these results a number of reductions with
Keywords: hydroxynitrile lyase; tartaric acid; cyanohydrin; l-2-deoxypen-
toses.
* Corresponding author. Tel.: 143-316-8738240; fax: 143-316-8738740;
e-mail: sekretariat@orgc.tu-graz.ac.at
The 1H and 13C NMR of compound 2 contained approximately 6% of the
corresponding enol tautomer.
²
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00871-1

9290
D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
Table 1. The reductions of silylester 2 (ratios determined using chiral
HPLC (conditions: Chiralcel OD-H, 99.75:0.25 heptane: 2-propanol,
0.6 mL/min, 254 nm)).
which support the integrity of the structural assignments
of the lactones, i.e. in compound 8, Ha showed an NOE to
Hb (and vice versa) which was not observed in compound 5
(Scheme 1).
Reducing reagent
Ratio 3:4
59:41
NaBH4-d-Tartaric acid diethyl
ester
Conversion of lactone 3 to its corresponding myristoyl ester
6 proceeded in good yield (85%). Cleavage of the exocyclic
alkene to the corresponding alcohol was achieved in one-pot
reaction, employing low temperature ozonolysis followed
by reductive work-up (BH´3Me2S) to yield 7. Compound 7
is the most active of the conformationally restrained
analogues of diacylglycerol which were recently reported
NaBH4-l-Tartaric acid diethyl
ester
64:36
NaBH4-(2R, 3R)-2,3-butanediol
NaBH4
50:50
64:36
NaBH4-Et2BOMe
Bakers' Yeast
75:24
No reduction
Scheme 1. Reagents: (a) Methyl bromoacetate, Zn, TMS-Cl, THF, 76%. (b) d-tartaric acid-NaBH4, THF, 93%. (c) l-tartaric acid-NaBH4, THF, 89%.
(d) tetrabutylammonium ¯uoride, THF, 85%.
structurally related chiral reagents, no chiral reagent or a
biocatalyst were also made (Table 1). The lack of selectivity
achieved when diethyl d-tartrate (as compared to d-tartaric
acid) or diethyl l-tartrate (as compared to l-tartaric acid)
was employed would appear to indicate that the free hy-
droxyl group and carboxylic acid group (in the chiral auxilli-
ary) are important for stereoselective reduction of the
substrate. It can be speculated that hydrogen bonding between
the chiral reagent and the corresponding b-keto ester substrate
(i.e. 2) is important for selectivity in this reaction.
by Teng et al.15and exhibits micromolar (2.5 mM) competi-
tive inhibition of phorbol-12,13-dibutyrate binding to
Protein Kinase C (PKC). This enzyme plays a crucial role
in many cellular processes including cell differentiation and
tumour growth, and has therefore been suggested as a target
enzyme for anticancer therapy.16 This synthesis (7 steps,
32% overall yield) compares favourable to that previously
reported (14 steps, 8% overall yield)16 and represents a
novel stereocontrolled method for the production of
l-ribonolactones (or of l-xylonolactones when diol 4 is
applied).
One pot deprotection and cyclisation of 3 (96:4 ratio of
alcohols) using TBAF afforded the threo-lactone 5 and
erythro-lactone 8 as the major and minor components
respectively, which were separable by preparative chroma-
Next we turned our attention to the synthesis of compounds
useful for the preparation of l-nucleosides. Lactone 8 was
converted to its corresponding silyl ether 9 under standard
conditions.17 DIBALH Reduction followed by acetylation
of the crude lactol yielded 10 as a single diastereomer.
Desilylation (10 to 11) proceeded in moderate yield
(60%), and subsequent conversion of the alcohol to its
corresponding tri¯ate ester facilitate azide introduction
(NaN3/DMF) with inversion to yield 12.
³
tography.14 Analogous lactonisation of compound 4
yielded erythro-lactone 8 and threo-lactone 5 as the major
and minor components. NOE Experiments provided data
Alkene cleavage was achieved using a three step method (i)
conversion to the diol using osmium tetraoxide/NMO (ii)
cleavage of the diol with sodium metaperiodate (iii) reduc-
tion18 of the resultant aldehyde with NaCNBH3 to yield the
azidoalcohol 13 which is the required precursor19 for the
preparation of l-AZT.
b-l-FMAU is one of the more interesting ¯uorinated
l-nucleosides20(20-¯uoro-5-methyl-b-l-arabinofuranosyl-
uracil)21 as it shows anti-viral activity against Hepatitis B
virus (HBV) and Epstein±Barr virus, but does not interfere
with the host system.22 Indeed, b-l-FMAU was con®rmed
³
A model study with compound 17 showed that under the conditions
employed (THF, 2.2 equiv. TBAF) only lactone 18 was obtained. In the
case where toluene was chosen as solvent, or where less TBAF was
employed (1.1 equiv.) a mixture of the lactone 18 and the diol 19 was
obtained.

D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
Table 2. Conditions for the optimal ¯uorination of lactone 14
9291
N-Fluorodibenzene-
sulfonimide
(mmole equiv.)
LiHMDS
(mmole equiv.)
Time
(mins)
14
(% recovered yield)
15
(% yield)
1.00
1.5
2.00
2.00
1.2
1.8
2.4
2.4
270
270
80
70
35
30
0
7
20
49
33
270
of base and ¯uorinating reagent agent (i.e. N-¯uorodi-
benzenesulfonimide), (Table 2, entries 2 and 4) whilst
retaining a relatively short reaction time (Table 2, entry 3)
allowed an optimum yield of 15 to be obtained. Employing
analogous oxidative cleavage conditions to those outlined in
Schemes 2 and 3, followed by desilyation, 15 would easily
furnish the desired lactone 16 (Scheme 4).
Scheme 2. Reagents: (a) C13H27C(O)Cl, pyridine, CH2Cl2, 85%. (b) O3/
CH2Cl2 then BH.3DMS, 40%.
to be the most potent of a series of compounds with anti-
HBV acitvity.23 In contrast the d-enantiomer causes liver
tover toxicity, amongst other side effects.24
Conclusion
In conclusion we have developed a general access to substi-
tuted l-2-deoxypentose or l-2-deoxy-pentono-1,4-lactone
units, in which the stereochemistry at C-4 is developed by
employing the (S)-Hydroxynitrile lyase from Hevea
brasiliensis. Additionally the stereochemistry at C-3 can
be selectively controlled by employing NaBH4 and (d)- or
(l)-tartaric acid. This general chemoenzymatic approach to
these compounds has not previously been reported and
We envisaged an access to the ribono-portion (i.e. l-2-
deoxy-2-¯uoroarabino-pentono-1,4-lactone, 16) of b-l-
FMAU from lactone 5. Protection of the alcohol 5 yielded
silyl ether 14. When 2-¯uorination was attempted under the
conditions of McAtee et al.25, a moderate yield of 15 was
obtained (Table 2, entry 1). However, increasing the amount
Scheme 3. Reagents: (a) tert-butyldiphenylsilyl chloride, imidazole, DMF, 77%. (b) DIBAL, THF, then acetic anhydride, DMAP, CH2Cl2, 66%.
(c) tetrabutylammonium ¯uoride, THF, 60%. (d) tri¯uoroacetic acid anhydride, CH2Cl2, pyridine, then NaN3, DMF, 49% and 29% recovered starting material.
(e) OsO4/N-methyl-N-morpholineoxide, acetone/pH 6.8 phosphate buffer, then NaIO4, acetone/water, then NaCNBH3, pH 3.68 acetate buffer, 38%.
Scheme 4. Reagents: (a) tert-butyldiphenylsilyl chloride, imidazole, DMF, 74%. (b) LiHMDS, N-¯uorodibenzenesulfonimide, THF, 49 % and 30% recovered
starting material.

9292
D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
provides a rapid stereocontrolled access to l-2-deoxy-
pentose or l-2-deoxy-pentono-1,4-lactone building blocks.
(1)-(E,3R,4S)-Methyl
3-hydroxy-4-tert-butylsilyloxy-
undec-5-enoate (3). To a solution of (d)-tartaric acid
(9.60 g, 64.0 mmol) in dry THF (150 mL) was added
sodium borohydride (2.42 g, 64.0 mmol) portionwise and
the suspension was heated at re¯ux for 2.5 h before being
cooled to 2208C. A solution of (4S)-methyl 3-oxo-4-tert-
butylsilyloxyundec-5-enoate (7.54 g, 16.00 mmol) in dry
THF (75 mL) was added dropwise and the temperature
maintained 2208C. After 40 h hydrochloric acid (1 M,
150 mL) was added and stirring continued for 15 min at
rt. Ethyl acetate (500 mL) was added followed by solid
sodium chloride to the point of saturation. The aqueous
phase was separated and further extracted with ethyl acetate
(200 mL). The organic phases were combined, washed with
saturated sodium bicarbonate solution (2£150 mL) then
saturated sodium chloride solution (100 mL), dried over
sodium sulphate, ®ltered and concentrated under reduced
pressure. The crude residue was puri®ed by column chro-
matography (90:10 to 90:20, petroleum ether:ethyl acetate)
to yield the title compound as a colourless oil (6.97 g,
14.70 mmol, 93%). [a]2D0ˆ146.3 (c 1.05, CHCl3);
d.e.ˆ92% (as determined by chiral HPLC, OD-H,
Experimental
General
1H NMR and 13C NMR were recorded on Varian Gemini
200 MHz and Bruker MSL 300 MHz instruments in CDCl3.
Chemical shifts are relative to TMS with CHCl3 as internal
standard [d 7.23 (1H) and d 76.90 (13C)]. Melting points
were determined on a BuÈchi melting point apparatus and
are uncorrected. Optical rotations were measured using a
Perkin Elmer 341 instrument. Tetrahydrofuran was distilled
from potassium benzophenone ketyl, toluene from sodium,
DMF from dibutyltin dilaurate and desmopur-15 (150 mg of
each/100 mL DMF) and dichloromethane from calcium
hydride. All organic layers were dried using anhydrous
sodium sulphate. All products were puri®ed by silica gel
column chromatography using Merck Kieselgel 60 (230±
400 mesh). TLC plates were run on silica gel gel Merck 60
F254, compounds were visualised by spraying with Mo-
reagent [(NH4)6Mo7O´244H2O (100 g/L), Ce(SO4)2´ 4H2O
(4 g/L) in H2SO4 (10% v/v) or KMnO4 reagent [KMnO4
(2.5 g/L), Na2CO3 (20 g/L) in H2O. All reagents were
obtained from Sigma±Aldrich and were used as purchased.
Petroleum ether refers to the fraction of boiling point
60±808C. Elemental analysis was made on EA 1108
CHN-analyser. HPLC enantiomeric separations were
performed using a Jasco 880-PU pump and a Jasco 875
UV/VIS detector connected to a CHIRACEL OD-H chiral
HPLC column (25 cm£0.46 cm).
1
99.75:0.25 heptane:2-propanol, 0.6 mL/min, 254 nm); H
NMR (CDCl3, 200 MHz): d (ppm) 0.88 (t, 3H), 1.07 (s,
9H), 1.13±1.30 (m, 6H), 1.77±1.86 (m, 2H), 2.44 (d, 1H,
Jˆ2.38 Hz), 2.47 (s, 1H), 2.62 (d, 1H, Jˆ3.47 Hz), 3.67
(s, 3H), 4.01±4.12 (m, 2H), 5.14±5.44 (m, 2H), 7.30±7.49
(m, 6H), 7.62±7.73 (m, 4H), 13C NMR (CDCl3, 50 MHz):
d
(ppm), 14.06, 19.41, 22.51, 27.11, 28.45, 31.37,
32.14, 37.07, 51.76, 71.67, 77.61, 127.43, 127.69,
129.66, 129.84, 133.57, 133.81, 135.71, 135.95, 136.08,
172.59.
(1)-(E,3S,4S) Methyl 3-hydroxy-4-tert-butylsilyloxyun-
dec-5-enoate (4). To a solution of (l)-tartaric acid (8.06 g,
53.72 mmol) in dry THF (125 mL) was added sodium boro-
hydride (2.03 g, 53.72 mmol) portionwise and the suspen-
sion was heated at re¯ux for 2.75 h before being cooled to
2208C. A solution of (4S)-methyl-3-oxo-4-tert-butylsilyl-
oxy-undec-5-enoate (5.38 g, 11.55 mmole) in dry THF
(75 mL) was added dropwise and the temperature main-
tained at 2208C. After 43 h hydrochloric acid (1 M,
125 mL) was added and stirring continued for 15 min at
rt. Ethyl acetate (500 mL) was added, followed by solid
sodium chloride to the point of saturation. The aqueous
phase was separated and further extracted with ethyl acetate
(200 mL). The organic phases were combined, washed with
saturated sodium bicarbonate solution (2£150 mL) then
saturated sodium chloride solution (100 mL), dried over
sodium sulphate, ®ltered and concentrated under reduced
pressure. The crude residue was puri®ed by column chro-
matography (90:10 to 90:20, petroleum ether:ethyl acetate)
to yield the title compound as a colourless oil (4.77 g,
10.20 mmol, 89%). [a]2D0ˆ116.0 (c 1.01, CHCl3);
d.e.ˆ92% (as determined by chiral HPLC, OD-H,
(2)-(E,4S)-Methyl 3-oxo-4-tert-butylsilyloxyundec-5-enoate
(2). To a suspension of zinc (7.08 g, 108 mmol) in dry THF
(90 mL) was added trimethylsilyl chloride (1.27 mL,
10.06 mmol). After 20 min (1)-(2S,3E)-2-(tert-butyldiphe-
nylsilyloxy)non-3-enenitrile (1) (15.14 g, 38.72 mmol) was
added and the mixture heated to re¯ux. Methyl bromoace-
tate (120.03 mmol) was then added dropwise over 50 min
and re¯ux continued for a further 70 min thereafter. The
mixture was cooled to 58C, 1 M HCl (175 mL) was added
and then stirred at rt for 2.5 h. The reaction mixture was
poured into sat. NaHCO3 (350 mL), an emulsion formed
which could be broken by the addition of water (300 mL).
The aqueous phase was extracted with ethyl acetate
(2£75 mL), the organic layers combined, dried, ®ltered
and concentrated in vacuo. The crude residue was puri®ed
by column chromatography (92:8 to 98:2, petroleum ether:-
ethyl acetate) to yield the title compound as a colourless oil
(13.60 g, 29.18 mmol, 76%) and unreacted 1 (1.30 g,
3.32 mmol, 8.6%). [a]2D0ˆ229.0 (c 0.10, CHCl3); 1H
NMR (CDCl3, 200 MHz):
d
(ppm) 0.88 (t, 3H,
1
99.75:0.25 heptane:2-propanol, 0.6 mL/min, 254 nm); H
Jˆ7.32 Hz), 1.12 (s, 9H), 1.18±1.37 (m, 6H), 1.88±1.95
(m, 2H), 3.59 (s, 2H), 3.68 (s, 3H), 4.60 (d, 1H,
Jˆ6.3 Hz), 5.39 (dd, 1H, Jˆ15.33, 6.3 Hz), 5.67 (dt, 1H,
Jˆ15.38, 7.57 Hz), 7.30±7.55 (m, 6H), 7.59±7.70 (m, 4H),
13C NMR (CDCl3, 50 MHz): d (ppm), 14.06, 19.33, 22.51,
26.95, 28.41, 31.29, 32.20, 43.88, 52.22, 80.63, 125.74,
127.66, 127.87, 130.12, 132.72, 133.02, 135.85, 135.99,
136.33, 167.79, 202.52.
NMR (CDCl3, 200 MHz): d (ppm) 0.88 (t, 3H), 1.07 (s,
9H), 1.13±1.30 (m, 6H), 1.77±1.86 (m, 2H), 2.36 (dd, 1H,
Jˆ15.63, 8.60 Hz), 2.53 (dd, 1H, Jˆ15.87, 3.23 Hz), 2.76
(d, 1H, Jˆ3.85 Hz), 3.68 (s, 3H), 3.97±4.08 (m, 2H), 5.16±
5.41 (m, 2H), 7.31±7.49 (m, 6H), 7.63±7.71 (m, 4H), 13C
NMR (CDCl3, 50 MHz): d (ppm), 14.06, 19.43, 22.51,
27.11, 28.37, 31.37, 32.14, 37.39, 51.78, 71.74, 77.71,

D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
9293
127.43, 127.71, 129.67, 129.85, 133.51, 133.70, 135.81,
135.92, 136.07, 172.66.
0.07 mmol, 40%). [a]D20ˆ119.0 (c 1.01, CHCl3) (Lit.17
[a]2D0ˆ119.40 (c 1.16, CHCl3)); Mp 60±618C (Lit.17 61±
1
628C); H NMR (CDCl3, 200 MHz): d (ppm) 0.88 (t, 3H,
(2)-(4R,5S)-4-Hydroxy-5-((E)-hept-1-enyl)tetrahydro-
furan-2-one (5). To a cooled (58C) solution of (5E,3R,4S)-
methyl 3-hydroxy-4-tert-butylsilyloxyundec-5-enoate (6.47 g,
13.83 mmol) in THF (165 mL) was added TBAF dropwise
(0.691 M in acetonitrile, 30.0 mL, 20.74 mmol). After 48 h
at rt, ethyl acetate (300 mL) was added and the organic
phase was washed with brine (3£25 mL), then dried, ®ltered
and concentrated in vacuo. The crude residue was puri®ed
by column chromatography (70:30 to 50:50, petroleum
ether:ethyl acetate) to yield the title compound 5 as a colour-
less oil (2.23 g, 11.8 mmol, 85%) and lactone 8 (175 mg,
6%). [a]2D0ˆ267.1 (c 1.21, CHCl3); 1H NMR (CDCl3,
200 MHz): d (ppm) 0.86 (t, 3H, Jˆ7.08 Hz), 1.21±1.43
(m, 6H), 2.04 (q, 2H, Jˆ6.84, 6.54 Hz), 2.47 (dd, 1H,
Jˆ17.82, 3.66 Hz), 2.78 (dd, 1H, Jˆ17.77, 6.16 Hz), 3.12
(bs, 1H), 4.30 (m, 1H), 4.79 (dd, 1H, Jˆ6.34, 2.44 Hz), 5.42
(dd, 1H, Jˆ15.38, 6.57 Hz), 5.83 (dt, 1H, Jˆ15.38,
7.56 Hz); 13C NMR (CDCl3, 50 MHz): d (ppm), 14.04,
22.48, 28.43, 31.34, 32.23, 37.02, 72.21, 87.98, 124.34,
136.34, 172.59.
Jˆ7.08 Hz), 1.23 (s, 20H), 1.55±1.68 (m, 2H), 2.33 (t, 2H,
Jˆ7.32 Hz), 2.55 (dd, 1H, Jˆ18.58, 1.90 Hz), 3.07 (dd, 1H,
Jˆ18.60, 7.54 Hz), 3.93 (m, 2H), 4.50 (m, 1H), 5.36 (dt, 1H,
Jˆ7.43, 1.71 Hz); 13C NMR (CDCl3, 50 MHz): d (ppm),
14.36, 22.94, 24.98, 29.32, 29.46, 29.59, 29.67, 29.88,
32.17, 34.32, 35.68, 62.54, 71.75, 85.73, 173.74, 175.38.
(2)-(4S,5S)-4-Hydroxy-5-(E-hept-1-enyl)tetrahydro-
furan-2-one (8). The title compound was prepared using the
method described for lactone 5, employing (5E,3S,4S)-
methyl-3-hydroxy-4-tert-butylsilyloxy-undec-5-enoate (4.67 g,
9.97 mmol), TBAF (0.691 M in acetonitrile, 21.6 mL,
14.95 mmol), THF (118 mL) and a reaction time of 20 h.
The crude residue was puri®ed by column chromatography
(60:40 to 40:60, petroleum ether:ethyl acetate) to yield the
title compound 8 as a white solid (1.78 g, 8.98 mmol, 90%).
[a]2D0ˆ256.2 (c 1.21, CHCl3); Mp 42±438C; 1H NMR
(CDCl3, 200 MHz): d (ppm) 0.88 (t, 3H, Jˆ7.08 Hz),
1.23±1.53 (m, 6H), 2.04 (q, 2H, Jˆ6.83, 6.73 Hz), 2.27
(bs, 1H), 2.59 (dd, 1H, Jˆ17.63, 1.41 Hz), 2.78 (dd, 1H,
Jˆ17.57, 5.12 Hz), 4.46 (m, 1H), 4.86 (dd, 1H, Jˆ6.84,
3.18 Hz), 5.58 (dd, 1H, Jˆ15.49, 6.89 Hz), 5.97 (dt, 1H,
Jˆ15.49, 6.73 Hz); 13C NMR (CDCl3, 50 MHz): d (ppm),
14.06, 22.51, 28.48, 31.39, 32.49, 38.77, 69.77, 84.88,
121.35, 139.03, 175.58. Anal. calcd for C11H18O3: C,
66.64; H, 9.15; O, 24.21; Found: C, 66.71; H, 9.13.
(2)-(4R,5S)-4-Tetradecanoyl-5-((E)-hept-1-enyl)tetra-
hydrofuran-2-one (6). To a solution of (4R,5S)-4-hydroxy-
5-(E-hept-1-enyl)-tetrahydro-furan-2-one (150 mg, 0.75
mmol) in CH2Cl2 (1 mL) was added a mixture of pyridine
(90 mg, 1.13 mmol) and myristoyl chloride (224 mg,
0.90 mmol) in CH2Cl2 (2 mL) and stirring continued for
20 h at rt. A mixture of CH2Cl2/H2O (15 mL of each) was
then added and organic phase washed with H2O (2£10 mL),
CuSO4 (3% w/v, 10 mL) then brine (10 mL). The organic
phase was separated, dried, ®ltered and concentrated in
vacuo. The crude residue was puri®ed by column
chromatography (95:5, petroleum ether:ethyl acetate) to
yield the title compound 6 as a white solid (249 mg,
0.51 mmol, 85%). [a]D20ˆ216.0 (c 1.08, CHCl3); Mp 28±
(2)-(4S,5S)-4-tert-Butyldiphenylsilyloxy-5-((E)-hept-1-
enyl)tetrahydrofuran-2-one (9). To a cooled solution
(58C) of imidazole (825 mg, 12.12 mmol) in DMF
(0.5 mL) was added tert-butyldiphenylchlorosilane
(2.49 g, 9.09 mmol). After 15 min the alcohol 8 (1.20 g,
6.06 mmol) was added dropwise and the solution warmed
to rt, at which it was stirred for 4 h. Water (100 mL) was
then added and the aqueous phase extracted with CH2Cl2
(3£75 mL). The organic extracts were combined, dried,
®ltered and concentrated in vacuo. The crude residue was
puri®ed by column chromatography (90:10 to 85:15,
petroleum ether:ethyl acetate) to yield the title compound
9 as a white solid (2.04 g, 4.67 mmol, 77%). [a]2D0ˆ257.6
(c 1.07, CHCl3); Mp 37±388C; 1H NMR (CDCl3,
200 MHz): d (ppm) 0.90 (t, 3H, Jˆ6.51 Hz), 1.08 (s, 9H),
1.22±1.46 (m, 6H), 2.07±2.16 (m, 2H), 2.29±2.51 (m, 2H),
4.50±4.54 (m, 1H), 4.67±4.72 (m, 1H), 5.82±5.86 (m, 2H),
7.34±7.49 (m, 6H), 7.59±7.65 (m, 4H); 13C NMR (CDCl3,
50 MHz): d (ppm), 14.08, 19.27, 22.58, 26.85, 28.41, 31.50,
32.48, 38.88, 71.63, 85.63, 123.39, 127.85, 127.98, 130.12,
130.22, 132.58, 133.08, 135.78, 135.89, 138.11, 175.25.
Anal. calcd for C27H36SiO3: C, 74.26; H, 8.31; O, 10.99;
Found: C, 74.12; H, 8.39.
1
298C; H NMR (CDCl3, 200 MHz): d (ppm) 0.86 (t, 3H,
Jˆ7.08 Hz), 1.18±1.45 (m and overlapping s, 26H), 1.53±
1.70 (m, 2H), 2.04 (q, 2H, Jˆ7.82, 6.10 Hz), 2.33 (t, 2H,
Jˆ7.33 Hz), 2.52 (dd, 1H, Jˆ18.31, 1.76 Hz), 2.90 (dd, 1H,
Jˆ18.31, 6.54 Hz), 4.91 (d, 1H, Jˆ5.56 Hz), 5.12 (dt, 1H,
Jˆ6.40, 1.71 Hz), 5.46 (ddt, 1H, Jˆ15.52, 5.70, 1.33 Hz),
5.83 (dt, 1H, Jˆ15.44, 6.72 Hz); 13C NMR (CDCl3,
50 MHz): d (ppm), 14.04, 14.17, 22.49, 22.74, 28.39,
29.10, 29.26, 29.40, 29.47, 29.63, 29.68, 31.33, 31.96,
32.18, 33.74, 34.12, 73.62, 84.76, 123.67, 135.98, 172.97,
174.13. Anal. calcd for C25H44O4: C, 73.48; H, 10.85; O,
15.66; Found: C, 73.60; H, 10.87.
(1)-(4R,5S)-4-Tetradecanoyl-5-hydroxymethyltetrahydro-
furan-2-one (7). Through a solution of (4R,5S)-4-tetra-
decanoyl-5-((E)-hept-1-enyl)-tetrahydrofuran-2-one
(75 mg, 0.18 mmol) in CH2Cl2 (9 mL) at 2788C was passed
ozone for 1 h. The solution was warmed to rt, stirred for
15 min and then under an argon atmopshere BH´3Me2S (1 M
in CH2Cl2, 0.75 mL, 0.75 mmol) was added dropwise over
25 min. After 20 h, MeOH (0.5 mL) was added and stirring
continued for 2 h. The mixture was concentrated in vacuo
and the crude residue was puri®ed by column chromato-
graphy (90:10 to 65:35, petroleum ether:ethyl acetate) to
yield the title compound 7 as a white solid (25 mg,
(2)-(1S,3S,4S)-1-Acetoxy-3-tert-butyldiphenylsilyloxy-
4-((E)-hept-1-enyl)tetrahydrofuran (10). To a solution of
(4S,5S)-4-tert-butyldiphenylsilyloxy-5-(E-hept-1-enyl)-tetra-
hydro-furan-2-one (1.69 g, 3.87 mmol) at 2788 under argon
was added DIBAL (1.0 M in hexane, 11.6 mL, 11.6 mmol)
dropwise over 15 min. After 1.5 h water (2 mL) was added
and stirring continued for a further 15 min at 2788 before
the mixture was allowed to warm to rt, at which it was
stirred for 1.5 h. The mixture was diluted with Et2O

9294
D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
(100 mL) and poured into a saturated solution of disodium
tartrate (110 mL) and stirring continued. After 1 h the
aqueous layer was extracted with Et2O (3£100 mL) and
the organic extracts were combined, dried, ®ltered and
concentrated in vacuo. The crude residue was redissolved
in CH2Cl2 (30 mL), cooled to 58C and a solution containing
acetic anhydride (2.46 mL, 26.13 mmol) and DMAP
(47 mg, 0.387 mmol) was added. The mixture was stirred
for 3.5 h, allowed to warm to rt and then poured into satu-
rated NaHCO3 solution (40 mL). The aqueous layer was
extracted with Et2O (4£40 mL) and the organic phases
combined, dried, ®ltered and concentrated in vacuo. The
crude residue was puri®ed by column chromatography
(90:10 to 85:15, petroleum ether:Et2O) to yield the title
compound 10 as a colourless oil (1.22 g, 2.54 mmol,
200 MHz): d (ppm) 0.89 (t, 3H, Jˆ6.59 Hz), 1.20±1.49
(m, 6H), 2.00±2.18 (m and overlapping s, 6H), 2.60 (ddd,
1H, Jˆ14.5, 8.6, 5.7 Hz), 3.73 (dt, 1H, Jˆ8.6, 5.4, 5.1 Hz),
4.47 (t, 1H, Jˆ6.6 Hz), 5.40 (dd, 1H, Jˆ15.5, 7.41 Hz), 5.86
(dt, 1H, Jˆ15.38, 6.64 Hz), 6.32 (dd, 1H, Jˆ5.69, 1.81 Hz);
13C NMR (CDCl3, 50 MHz): d (ppm), 14.06, 21.32, 22.52,
28.45, 31.36, 32.26, 37.71, 63.64, 84.75, 97.06, 126.12,
136.80, 170.29.
(2)-(1S,3R,4R)-1-Acetoxy-3-azido-4-hydroxymethyltetra-
hydrofuran (13). The compound 12 (24 mg, 0.085 mmol)
was suspended in buffer/acetone mixture (0.5 M, pH
6.8 phosphate, 0.140 mL/1.42 mL), to which was added
NMO (19.9 mg, 0.17 mmol) followed by osmium tertroxide
(2 crystals). After 6 h at rt, sodium sul®te was added and
stirring continued for a further 1.5 h. Ethyl acetate (10 mL)
was added and the organic layer washed with water
(2£1 mL) then brine solution (1 mL). The organic layer
was dried, ®ltered and concentrated in vacuo. The crude
diol was resuspended in acetone/H2O (1.5 mL/0.62 mL),
sodium metaperiodate (30 mg, 0.141 mmol) was added
and after 6 h the mixture ®ltered, diluted with CH2Cl2
(8 mL) and washed with brine solution (2£3 mL). The
combined aqueous layers were back extracted with
CH2Cl2 (5 mL) and thereafter the organic layers combined,
dried, ®ltered and concentrated in vacuo. The crude alde-
hyde was resuspended in THF (1.2 mL), cooled to 08C and
NaBH3CN added in one portion followed by buffer (pH
3.68, NaOAc/HOAc) and the mixture allowed to warm to
rt. After 3.5 h acetone (3 mL) was added to consumed
excess NaBH3CN followed by, after 30 min, ethyl acetate
(10 mL). The organic layer was washed with H2O
(2£3 mL), dried ®ltered and concentrated in vacuo. The
crude residue was puri®ed by column chromatography
(70:30 to 60:40, petroleum ether:EtOAc) to yield the
title compound 13 as a colourless oil (6 mg, 0.030 mmol,
1
66%). [a]2D0ˆ276.7 (c 1.00, CHCl3); H NMR (CDCl3,
200 MHz): d (ppm) 0.89 (t, 3H, Jˆ6.59 Hz), 1.07 (s, 9H),
1.25±1.49 (m, 6H), 1.88±2.24 (m and overlapping s, 7H),
4.37±4.43 (m, 1H), 4.45±4.52 (m, 1H), 5.74±5.77 (m, 2H),
6.37 (dd, 2H, Jˆ5.67, 2.96 Hz), 7.34±7.49 (m, 6H), 7.59±
7.65 (m, 4H); 13C NMR (CDCl3, 50 MHz): d (ppm), 14.07,
19.28, 21.31, 26.90, 28.56, 31.58, 32.51, 42.33, 74.04,
84.54, 97.66, 125.30, 127.76, 127.67, 129.82, 129.89,
133.27, 133.92, 135.84, 135.96, 136.41, 170.36.
(2)-(1S,3S,4S)-1-Acetoxy-4-((E)-hept-1-enyl)-3-hydroxy-
tetrahydrofuran (11). To a cooled solution (58C) of
(2S,4S,5S)-5-acetoxy-3-tert-butyldiphenylsilyloxy-2-(E-hept-
1-enyl)-oxolane (140 mg, 0.296 mmol) in THF (4 mL) was
added TBAF (1.0 M in THF, 0.30 mL, 0.30 mmol) over
10 min. After stirring at rt for 1.5 h, the mixture was poured
into ethyl acetate/water (10 mL/5mL) and the aqueous layer
extracted with ethyl acetate (2£10 mL). The organic layers
were combined, dried, ®ltered and concentrated in vacuo.
The crude residue was puri®ed by column chromatography
(80:20 to 75:25, petroleum ether:EtOAc) to yield the title
compound 11 as a colourless oil (42 mg, 0.174 mmol, 60%).
[a]2D0ˆ265.2 (c 1.01, CHCl3); 1H NMR (CDCl3, 200 MHz):
d (ppm) 0.85 (t, 3H, Jˆ6.59 Hz), 1.22±1.50 (m, 6H), 1.81
(bs, 1H), 2.00±2.14 (m and overlapping s, 5H), 2.35 (ddq,
2H, Jˆ12.51, 5.86, 2.19 Hz), 4.30±4.36 (m, 1H), 4.55 (dd,
1H, Jˆ6.35, 2.69 Hz), 5.51 (ddt, 1H, Jˆ15.63, 6.60,
1.41 Hz), 5.91 (dt, 1H, Jˆ15.57, 6.59 Hz), 6.42 (dd, 1H,
Jˆ5.86, 2.25 Hz); 13C NMR (CDCl3, 50 MHz): d (ppm),
14.03, 21.32, 22.51, 28.64, 31.43, 32.54, 41.98, 72.42,
83.62, 97.64, 122.93, 137.43, 170.38.
1
38%). [a]2D0ˆ2117.8 (c 0.60, CHCl3); H NMR (CDCl3,
200 MHz): d (ppm) 2.11 (s, 3H), 2.19 (ddd, 1H, Jˆ14.64,
4.57, 3.17 Hz), 2.57 (ddd, Jˆ14.63, 8.66, 5.47 Hz), 3.70
(bd, 1H, Jˆ12.22 Hz), 3.89 (dd, 1H, Jˆ12.33, 2.83 Hz),
4.10 (m, 1H), 4.20 (m, 1H); 13C NMR (CDCl3, 50 MHz):
d (ppm) 21.41, 38.50, 59.66, 62.29, 84.94, 97.06, 170.49.
(2)-(4R,5S)-4-tert-butyldiphenylsilyloxy-5-((E)-hept-1-
enyl)tetrahydrofuran-2-one (14). To a cooled solution
(58C) of imidazole (343 mg, 5.05 mmol) in DMF (0.2 mL)
was added tert-butyldiphenylchlorosilane (1.04 g, 3.78
mmol). After 15 min the alcohol 5 (0.50 g, 2.52 mmol)
was added dropwise and the solution warmed to rt, at
which it was stirred for 2 h. Water (10 mL) was then
added and the aqueous phase extracted with CH2Cl2
(4£10 mL). The organic extracts were combined, dried,
®ltered and concentrated in vacuo. The crude residue was
puri®ed by column chromatography (95:5 to 90:10, petro-
leum ether:ethyl acetate) to yield the title compound 14 as a
white solid (891 mg, 1.86 mmol, 74%). [a]2D0ˆ28.10 (c
(2)-(1S,3R,4S)-1-Acetoxy-3-azido-4-((E)-hept-1-enyl)-
tetrahydrofuran (12). To a cooled (2508C) solution of
(2S,4S,5S)-5-Acetoxy-2-(E-hept-1-enyl)-3-hydroxy-oxolane
(42 mg, 0.176 mmol) in CH2Cl2 (0.5 mL) was added pyri-
dine (42 mg, 0.530 mmol) followed by tri¯ic anhydride
(74 mg, 0.352 mmol) in one portion and stirring continued
for 45 min. Sodium azide (114 mg, 1.76 mmol) followed by
DMF (1 mL) was added and the mixture allowed to warm to
rt, at which it was stirred overnight. After the addition of
CH2Cl2 (10 mL), the organic phase was washed with water
(3£5 mL), dried, ®ltered and concentrated in vacuo. The
crude residue was puri®ed by column chromatography
(90:10 to 70:30, petroleum ether:EtOAc) to yield the title
compound 12 as a colourless oil (24 mg, 0.085 mmol, 49%)
and recovered starting material 11 (10 mg, 0.041 mmol,
1
0.67, CHCl3); Mp 47±488C; H NMR (CDCl3, 300 MHz):
d (ppm) 0.87 (t, 3H, Jˆ6.35 Hz), 1.08 (s, 9H), 1.20±1.39
(m, 6H), 1.88±2.02 (m, 2H), 2.40±2.62 (m, 2H), 4.19±4.25
(m, 1H), 4.72 (dd, Jˆ6.59, 2.01 Hz, 1H), 5.10 (ddt, 1H,
Jˆ15.38, 6.68, 1.38 Hz), 5.59 (ddt, 1H, Jˆ15.38, 8.11,
1.03 Hz), 7.35±7.50 (m, 6H), 7.60±7.70 (m, 4H); 13C
NMR (CDCl3, 200 MHz): d (ppm), 14.05, 19.07, 22.51,
1
24%). [a]2D0ˆ290.9 (c 2.00, CHCl3); H NMR (CDCl3,

D. V. Johnson et al. / Tetrahedron 56 (2000) 9289±9295
9295
W.-B.; Yeola, S.; Liotta, D. C. Antimicrob. Agents Chemother.
1992, 36, 672±676.
26.82, 28.38, 31.33, 32.16, 37.38, 73.71, 87.90, 124.45,
127.96, 128.01, 130.24, 132.83, 135.71, 135.80, 136.08,
175.11. Anal. calcd for C27H36SiO3: C, 74.26; H, 8.31; O,
10.99; Found: C, 74.25; H, 8.37.
2. Coates, J. A. V; Cammack, N.; Jenkinson, H. J.; Mutton, I. M.;
Pearson, B. A.; Storer, R.; Cameron, J. M.; Penn, C. R. Antimicrob.
Agents Chemother. 1992, 36, 202±205. (b) Coates, J. A. V;
Cammack, N.; Jenkinson, H. J.; Jowett, A. J.; Jowett, M. I.;
Pearson, B. A.; Penn, C. R.; Rouse, P. L.; Viner, C. K.; Cameron,
J. M. Antimicrob. Agents Chemother. 1992, 36, 733±739.
3. Gosselin, G.; Mathe, C.; Bergogne, M.-C.; Aubertin, A.-M.;
Kirn, A.; Sommadossi, J.-P.; Schinazi, R.; Imbach, J.-L.
Nucleosides Nucleotides 1995, 14, 611±617.
(2)-(2R,4R,5S)-4-tert-butyldiphenylsilyloxy-2-¯uoro-5-
((E)-hept-1-enyl)tetrahydrofuran-2-one (15). A solution
of lactone 14 (280 mg, 0.583 mmol) and N-¯uorodibenze-
nesulfonimide (367 mg, 1.16 mmol) in THF (2.8 mL) was
cooled to 2788C, to which was added LiHMDS (3.4 mL,
0.41 M in THF, 1.4 mmol) dropwise over 50 min. The
mixture was stirred for a further 30 min, afterwhich satu-
rated ammonium chloride was added (9 mL) and the cooling
bath removed. After 30 min at rt, the mixture was diluted
with ethyl acetate (60 mL) and the organic phase washed
with saturated sodium bicarbonate (2£10 mL). The organic
phase was dried, ®ltered and concentrated in vacuo and
the mixture puri®ed by column chromatography (toluene
as eluent). Recrystallisation from petroleum ether
yielded the title compound as a colourless oil (132 mg,
2.65 mmol, 49%) and recovered lactone 15 (84 mg,
0.175 mmol, 30%). [a]2D0ˆ290.9 (c 2.00, CHCl3); 1H
4. Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Zhu, Y.-L.; Gullen, E.;
Dutschman, G. E.; Cheng, Y.-C. J. Med. Chem. 1996, 39, 1754±1759.
5. Lin, T.-S.; Luo, M. Z.; Liu, M.-C. Tetrahedron 1995, 51, 1055±
1068.
6. Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64, 5427±5435.
È
7. Griengl, H.; Klempier, N.; Pochlauer, P.; Schmidt, M.; Shi, N.;
Zabelinska-Mackova, A. A. Tetrahedron 1998, 54, 14477±14486.
8. (a) Effenberger F. Chimia 1999, 53, 3±10; (b) Johnson, D. V.;
Griengl, H. Adv. Biochem. Eng. Biotechnol. 1999, 63, 32±53.
9. Johnson, D. V.; Griengl, H. Tetrahedron 1997, 53, 617±624.
10. Johnson, D. V.; Felfer, U.; Griengl, H. Tetrahedron 2000, 56,
781±790.
NMR (CDCl3, 200 MHz)
d
(ppm) 0.88 (t, 3H,
11. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833±3835.
12. Yatagai, M.; Ohnuki, T. J. Chem. Soc., Perkin Trans. 1 1990,
1826±1828.
Jˆ6.55 Hz), 1.08 (s, 9H), 1.20±1.33 (m, 6H), 1.86±1.93
(m, 2H), 4.24 (dt, 1H, Jˆ17.0, 7.71 Hz), 4.57 (t, 1H,
Jˆ7.84 Hz), 5.00 (dd, 1H, Jˆ15.38, 8.35 Hz) 5.21 (d, 1H,
Jˆ51.4, 7.81 Hz), 5.82 (dt, 1H, Jˆ15.14, 6.81 Hz), 7.34±
7.51 (m, 6H), 7.52±7.65 (m, 4H); 13C NMR (CDCl3,
50 MHz): d (ppm), 14.01, 19.28, 22.49, 26.82, 28.02,
31.35, 32.18, 77.76 (d, Jˆ19.4 Hz), 81.60 (d, Jˆ11.0 Hz),
91.4 (d, Jˆ200 Hz), 123.39, 127.81, 127.91, 130.40,
131.86, 132.21, 135.92, 135.80, 140.39, 168.44
(Jˆ22.1 Hz).
13. The other reported uses of this reagent are: (a) Hirao, A.;
Mochizkui, H.; Ali Zoorob, H. H.; Igarashi, I.; Itsuno, S.; Ohwa,
M.; Nakaham, S.; Yamazaki, N. Agric. Biol. Chem. 1981, 45 (3),
693±697; (b) Adams, C. Synth. Commun. 1984, 14 (10), 955±959;
(c) Iwagami, H.; Yatagai, M.; Nakazawa, M.; Orita, H.; Honda, Y.;
Ohnuki, T.; Yukawa, T. Bull. Chem. Soc. Jpn. 1991, 64, 175±182.
14. `Anhydrous' TBAF was employed in this reaction and was
prepared by the method described by Cox, D. P.; Terpenski, J.;
Lawrynowicz J. Org. Chem. 1984, 49, 3216±3219
15. Teng, K.; Marquez, V. E.; Milne, G. W. A.; Barchi, J. J.;
Kazanietz; Lewin, N. E.; Blumberg, P. M.; Abushanab J. Am.
Chem. Soc. 1992, 114, 1059±1070.
Acknowledgements
È
The authors wish to thank Carina Illaszewicz, Hansjorg
16. (a) Gescher, A.; Dale, I. L. Anti-cancer Drug Des. 1989, 4,
93±105; (b) Weinstein, I. B. Mutat. Res. 1988, 202, 413±420.
17. Brussee, J.; Roos, E. C.; Kruse, C. G. Tetrahedron 1990, 46,
979±986.
Weber and Lothar Brecker for measuring the NMR spectra.
The authors would like to thank DSM-Chemie Linz and the
European Union (Project No: ERBBIO4CT960112) for
®nancial support.
18. Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am.
Chem. Soc. 1997, 119, 4856±4865.
19. (a) Chu, C. K.; Warren Beach, J.; Ullas, G. V.; Kosugi, Y.
Tetrahedron Lett. 1988, 29, 5349±5352; (b) Wengel, J.; Lau, J.;
Pedersen, E. B.; Nielsen, C. M. J. Org. Chem. 1991, 56, 3591±
3594.
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