A stereoselective anti-aldol route to (3R,3aS,6aR)-hexahydrofuro[2,3-b] furan-3-ol: A key ligand for a new generation of HIV protease inhibitors

Article abstract of DOI:10.1055/s-2006-942547

A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P₂-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942547

PAPER
3015
A Stereoselective Anti-Aldol Route to (3R,3aS,6aR)-Hexahydrofuro[2,3-b]
furan-3-ol: A Key Ligand for a New Generation of HIV Protease Inhibitors
Stereoselective
Sy
r
nthesis
o
u
f
(3R,3a
S
,6a
n
R
)
-Hexahydrofuro[
K
2,3-
b
]furan-3-ol . Ghosh,* Jianfeng Li, Ramu Sridhar Perali
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
Fax +1(765)4961612; E-mail: akghosh@purdue.edu
Received 27 April 2006; revised 25 May 2006
Abstract: A stereoselective synthesis of (3R,3aS,6aR)-hexahydro-
furo[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high
enantiomeric excess (>99%) is reported. The synthesis features an
ester-derived titanium enolate based highly stereoselective anti-al-
dol reaction as the key step.
NH2
OH
H
H
N
O
H
N
S
O
O
O
O
H
Ph
O
1 (TMC-114 or Darunavir)
Key Words: antiviral agents, asymmetric synthesis, chiral auxilia-
ry, aldol reactions, fused-ring systems
O
OH
H
H
N
O
H
N
The AIDS epidemic has become one of the most serious
medical problems of our time.1 The highly active antiret-
roviral therapy (HAART) with HIV protease inhibitors
and reverse transcriptase inhibitors continues to be a ma-
jor treatment option.2 However, more effective HAART
with new generation inhibitors is in critical need to com-
bat drug-resistant HIV and reduce serious drug side ef-
fects.3 As part of our continuing studies aimed at
developing novel inhibitors to combat drug resistance, we
have designed and synthesized a series of nonpeptidyl
HIV protease inhibitors that are exceedingly potent both
against wild-type and resistant viruses.4 One of these in-
hibitors (1, Ki = 16 pM, and ID50 = 3 nM, Figure 1) has
been under advanced clinical development.4,5 It was re-
cently approved by the U.S. Food and Drug Administra-
tion for treatment of drug-resistant HIV. This inhibitor
incorporates a very important structure-based designed
and stereochemically defined bis-tetrahydrofuran (bis-
THF) derived urethane as the P2-ligand. This ligand is de-
signed to hydrogen bond with the backbone of HIV-1 pro-
tease. The significance of this ligand particularly for
withstanding potency against drug-resistant HIV is now
well documented.4 Inhibitor 2, which also incorporates
the same bis-THF ligand, is currently undergoing phase II
clinical trials.7
O
S
O
O
O
O
H
O
2 (GW0385 or Brecanavir)
N
S
O
Me
Figure 1 Structure of inhibitors 1 and 2
THF ligand.8b We have also investigated a stereoselective
photochemical addition of 1,3-dioxolane to a chiral furan-
one derivative which was prepared by a lipase-catalyzed
enzymatic resolution as the key step.8c Both these proce-
dures provided access to quantities of optically active bis-
THF ligand alcohol. However, optical purity was in the
range of 92–96% ee. Recently, Quaedflieg and co-work-
ers have reported the synthesis of this ligand utilizing a
diastereoselective Michael addition as the key step.9 For
our continued interest in optically pure bis-THF ligand,
we have investigated the feasibility of ester-derived titani-
um enolate based anti-aldol reaction to prepare bis-THF
ligand in high optical purity. Herein, we report a stereo-
controlled synthesis of bis-THF utilizing an ester-derived
titanium enolate based anti-aldol reaction as the key step.
The overall route is amenable to quantities of bis-THF
ligand in high optical purity.
The bis-THF ligand has also been utilized in the design
and synthesis of a number of other very potent HIV-1 pro-
tease inhibitors. Our initial synthesis of optically active
bis-THF involved (3R)-diethyl malate as the key starting
material.8a This route provided optically pure bis-THF
ligand but the overall process was not very efficient. Sub-
sequently, we developed an efficient racemic synthesis of
bis-THF ligand followed by a lipase-catalyzed enzymatic
resolution to provide quantities of optically active bis-
As shown in Scheme 1, our plan was to carry out an acid-
catalyzed cyclization of intermediate 4 to provide the de-
sired (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (3). A
logical precursor to intermediate 4 would be the anti-aldol
product 5. Thus, asymmetric anti-aldol reaction would
provide a convenient access to two key stereocenters of
bis-THF enantioselectively. For stereoselective genera-
tion of this anti-aldol, we elected to utilize an ester-de-
rived titanium enolate-mediated asymmetric anti-aldol
reaction developed in our laboratory.10 For stereoselective
generation of anti-aldol product 5, we planned to utilize
readily available optically pure amino-indanol derived
SYNTHESIS 2006, No. 18, pp 3015–3018
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.08.2006
DOI: 10.1055/s-2006-942547; Art ID: M02806SS
© Georg Thieme Verlag Stuttgart · New York

3016
A. K. Ghosh et al.
PAPER
Ts
chiral auxiliary. Accordingly, acylation of commercially
available (1S,2R)-1-tosylamido-2-indanol (6) with pent-
4-enoic acid in the presence of EDC and DMAP furnished
ester 7 in nearly quantitative yield (Scheme 2).11 Expo-
sure of ester 7 to TiCl4 (1.2 equiv) and N,N-diisopropyl-
ethylamine (3.8 equiv) in CH2Cl2 at 0 °C generated the
corresponding titanium enolate. Treatment of the result-
ing enolate with TiCl4 (1 equiv) pre-complexed cinnamal-
dehyde (2 equiv) at –78 °C furnished anti-aldol product 8
and its diastereomer in 60% yield as a 8:2 diastereomeric
mixture. In order to improve the diastereomeric ratio and
yield we examined a number of other reaction conditions.
As shown in Table 1, we examined the additive effect es-
pecially with MeCN and NMP as additives. Both of these
additives showed good improvement in diastereoselectiv-
ity and yield. However, diastereomeric excess of these al-
dol reactions appeared to be very sensitive to small
changes in the Lewis acid stoichiometry. The use of one
equivalent of TiCl4 and two equivalents of TMEDA pro-
vided reproducible results with good diastereomeric ex-
cess but the observed yield was not satisfactory (Table 1,
entry 4). Subsequently we investigated the effect of one
equivalent of TiCl4 and two equivalents of DIPEA on
anti-aldol diastereoselectivity (Table 1, entry 5).
Ts
NH
NH
O
pent-4-enoic
acid
O
OH
EDCI, HOBt
(99%)
6
7
TiCl4, i-Pr2NEt
cinnamaldehye
(70%)
Ts
NH
O
OR
OTHP
LiAlH4
O
HO
THF
Ph
Ph
(99%)
10
8 R = H
DHP
9 R = THP
PPTS
1. Swern Ox
2. CH(OMe)3
(89%)
MeO
92%
MeOH, CSA
1. ozonolysis
Me2S
then NaBH4
H
OH
OTHP
O
H
H
MeO
Ph
2. aq HCl
(60%)
O
11
3
Scheme 2 Synthesis of bis-THF ligand
duction of 9 afforded the alcohol 10 in excellent yield.
The chiral auxiliary 6 was also recovered in near-quanti-
tative yield. Swern oxidation of 10 gave the correspond-
ing aldehyde which was protected as methyl acetal 11 in
89% yield in a two-step sequence. Ozonolysis of 11 fol-
lowed by reduction with dimethyl sulfide and NaBH4 pro-
vided the corresponding diol. Exposure of the resulting
diol to aqueous HCl effected deprotection of THP group
and acid-catalyzed cyclization to the desired bis-THF al-
cohol 3. The optical purity of bis-THF alcohol was deter-
mined to be >99% by Mosher ester analysis.12,13
OH
H
H
OH
H
OH
H
O
OH
O
H
Xc
Ph
H
O
O
5
4
3
OH
Scheme 1 Anti-aldol strategy to bis-THF ligand
Table 1 Aldol Reaction with Cinnamaldehyde
Entry
Additivea
none
Yield (%)
Anti/Syn
80:20
96:4
In conclusion,
a
stereoselective synthesis of
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (3), an im-
portant P2-ligand for TMC-114 and GW0385 has been
achieved. The key step involves a diastereoselective ester-
derived Ti-enolate based anti-aldol reaction utilizing to-
sylamidoindanol as the chiral auxiliary. This anti-aldol
route provides an easy access to bis-THF 3 in high optical
purity (>99% ee).
1
2
3
4
5
60
60
55
30
70
MeCN
NMP
90:10
96:4
TMEDA
DIPEA
96:4
a One equiv of TiCl4 and 2 equiv of additive.
Anhydrous solvents were obtained as follows: CH2Cl2, distillation
over CaH2; THF, distillation from sodium/benzophenone under N2.
Flash chromatography was performed using 230–400 mesh silica
gel under low pressure of 5–10 psi. TLC was performed on silica gel
These conditions have provided the best result. The titani-
um enolate was generated as described above. In a sepa-
rate flask, cinnamaldehyde was pre-complexed with one
equivalent of TiCl4 and two equivalents of DIPEA at
–78 °C. This enolate was added dropwise to the above
pre-complexed cinnamaldehyde at –78 °C for 30 min. The
mixture was stirred for 3.5 h at –78 °C and then quenched
by saturated aqueous NH4Cl solution. This protocol con-
sistently provided excellent diastereoselectivity and good
yield.
60F 254 plates. All melting points are uncorrected. 1H NMR and 13
C
NMR spectra were recorded on Bruker 300 MHz and Varian 300
MHz instruments. IR spectra were recorded on a ATI Mattson Gen-
esis series FT-IR spectrometer. Optical rotation was measured using
a PerkinElmer 241 spectropolarimeter with a sodium lamp (589
nm). Mass spectra were recorded on a Finnigan Mat 90 mass spec-
trometer.
(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-ylpent-4-
enoate (7)
To a solution of N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-
yl]-4-methylbenzenesulfonamide (6; 6.85 g, 22.6 mmol) in CH2Cl2
(100 mL) were added EDCI (4.32 g, 22.6 mmol), pent-4-enoic acid
To convert the aldol product 8 to bis-THF 3, the hydroxyl
group was first protected as the THP ether 9. LiAH4 re-
Synthesis 2006, No. 18, 3015–3018 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol
3017
(2.26 g, 22.6 mmol) and DMAP (2.76 g, 22.6 mmol) and stirred for
3 h. The mixture was quenched with H2O and the organic layer was
washed with aq sat. NaHCO3 solution. The aqueous layer was ex-
tracted with CH2Cl2 (2 ×) and the combined organic layers were
dried (Na2SO4), filtered and then concentrated in vacuo. Flash col-
umn chromatography of the crude product over silica gel (Rf 0.27,
25% EtOAc in hexanes) afforded product 7 (8.6 g, 99%) as a white
solid; mp 120–121 °C.
mmol) dropwise and stirred for 5 min. The mixture was stirred for
3 h while allowing it to warm up to 23 °C. The reaction was
quenched by the addition of brine and the aqueous layer was ex-
tracted with CH2Cl2 (2 ×). The combined organic layers were dried
(Na2SO4) and filtered. Removal of solvent under reduced pressure
followed by purification by flash column chromatography using
25% EtOAc–hexanes afforded compound 9 (9.18 g, 92%, mixture
of diastereomers) as a colorless gum in 92% yield.
IR (neat): 3283, 1738 cm–1.
IR (neat): 2942, 1737 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (d, J = 8.4 Hz, 2 H), 7.17–
7.27 (m, 6 H), 5.76 (m, 1 H), 5.18 (m, 2 H), 4.98 (m, 3 H), 3.06–3.13
(dd, J = 17.1 Hz, 1 H), 2.90 (d, J = 17.1 Hz, 1 H), 2.46 (s, 3 H), 2.27
(m, 4 H).
13C NMR (75 MHz, CDCl3): d = 171.9, 143.9, 139.7, 138.6, 137.8,
136.4, 129.9, 128.7, 127.4, 127.0, 125.0, 124.3, 115.8, 74.9, 59.5,
37.5, 33.2, 28.6, 21.6.
1H NMR (300 MHz, CDCl3): d (polar diastereomer) = 7.85 (d,
J = 8.4 Hz, 2 H), 7.17–7.45 (m, 11 H), 6.66 (d, J = 10.2 Hz, 1 H),
6.53 (d, J = 16.2 Hz, 1 H), 5.84 (dd, J = 8.7, 15.6 Hz, 1 H), 5.57–
5.65 (m, 1 H), 5.33 (t, J = 4.5 Hz, 1 H), 4.91–5.02 (m, 3 H), 4.44 (t,
J = 5.1 Hz, 1 H), 4.37 (t, J = 9.3 Hz, 1 H), 3.93 (br d, J = 10.8 Hz, 1
H), 3.34 (t, J = 9.3 Hz, 1 H), 3.01 (dd, J = 4.2, 17.1 Hz, 1 H), 2.84
(br d, J = 17.1 Hz, 1 H), 2.59–2.66 (m, 1 H), 2.43 (s, 3 H), 2.04–2.30
(m, 2 H), 1.74–1.78 (m, 2 H), 1.60–1.61 (m, 2 H), 1.40–1.44 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 172.3, 143.2, 140.6, 138.5, 138.4,
138.2, 135.8, 134.2, 129.6 128.6, 128.2, 128.1, 127.1, 126.6, 126.2,
124.7, 124.0, 117.5, 97.1, 76.8, 75.3, 64.9, 59.7, 50.9, 37.6, 33.9,
30.6, 24.5, 21.5, 21.2.
HRMS-ESI: m/z [M + Na]+ calcd for C21H23NO4S + Na: 408.1246;
found: 408.1256.
(2S)-(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-yl-2-
[(S,E)-1-hydroxy-3-phenylallyl]pent-4-enoate (8)
To a stirred solution of 7 (7.89 g, 20.5 mmol) in CH2Cl2 (210 mL)
at 0 °C was added a 1.8 M solution of TiCl4 (13.8 mL, 24.8 mmol)
under N2 and the resulting solution was stirred for an additional 5
min. To this solution was added N,N-diisopropylethylamine (13.9
mL, 79.7 mmol) dropwise. The mixture was allowed to warm to
23 °C and stirred for 2 h. To a separate flask charged with cinnam-
aldehyde (5.30 mL, 42 mmol) and CH2Cl2 (320 mL) at –78 °C was
added a 1.8 M solution of TiCl4 (11.5 mL, 20.7 mmol) dropwise.
After stirring for 5 min at the same temperature, N,N-diisopropyl-
ethylamine (7.3 mL, 41.9 mmol) was added dropwise and mixture
was stirred for further 5 min. After this period, the above titanium
enolate solution was added to cinnamaldehyde solution dropwise
via an insulated cannula over 30 min. The mixture was stirred at
–78 °C for 3.5 h and quenched by addition of aq NH4Cl. The result-
ing mixture was allowed to warm to 23 °C and the layers were sep-
arated. The aqueous layer was extracted with CH2Cl2 (2 ×). The
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated to afford the crude aldol product. Silica gel chro-
matography (15% and then 20% EtOAc–hexanes; (Rf 0.13, 20%
EtOAc in hexanes) yielded diastereomerically pure anti-aldol prod-
Anal. Calcd for C35H37NO6S: C, 69.86; H, 6.53; N, 2.33. Found: C,
69.77; H, 6.57; N, 2.20.
(2R,3S,E)-2-Allyl-5-phenyl-3-(tetrahydro-2H-pyran-2-yl-
oxy)pent-4-en-1-ol (10)
To a solution of compound 9 (9.12 g, 15.2 mmol) in THF (140 mL)
at 0 °C was added LiAlH4 (1.12 g, 29.5 mmol) in three portions and
the mixture was stirred first at 0 °C for 10 min and then at 23 °C for
1 h. The reaction was quenched by aq sat. potassium sodium tartrate
solution. The aqueous layer was extracted with CH2Cl2 (2 ×) and
EtOAc (2 ×). The combined organic layers were dried (Na2SO4), fil-
tered and concentrated under reduced pressure. Flash chromatogra-
phy of the crude compound using EtOAc–hexanes (1:2) afforded
product 10 (4.46 g, 99%) as a colorless oil (Rf 0.47, 40% EtOAc in
hexanes). N-Tosylamidoindanol 6 was recovered quantitatively
(4.47 g).
IR (neat): 3455, 2939, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d (polar diastereomer) = 7.22–7.40
(m, 5 H), 6.56 (d, J = 16.2 Hz, 1 H), 6.30 (dd, J = 8.4, 15.9 Hz, 1 H),
5.70–5.90 (m, 1 H), 5.01–5.13 (m, 2 H), 4.79 (d, J = 2.7 Hz, 1 H),
4.28 (t, J = 8.4 Hz, 1 H), 3.93 (dd, J = 2.7, 11.1 Hz, 2 H), 3.66 (dd,
J = 5.1, 11.4 Hz, 1 H), 3.49–3.57 (m, 1 H), 2.53 (br s, 1 H), 2.30 (m,
1 H), 2.12 (m, 1 H), 1.40–1.91 (m, 7 H).
uct 8 (7.43 g, 70%) as a gummy solid; [a]23 –18.3 (c = 1.26,
D
CHCl3).
IR (neat): 3477, 3283, 1738, 1232 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.78 (d, J = 8.5 Hz, 2 H), 7.35 (m,
1 H), 7.15–7.30 (m, 10 H), 7.04 (m, 1 H), 6.48 (d, J = 16 Hz, 1 H),
6.38 (d, J = 9.5 Hz, 1 H), 6.08 (dd, J = 7, 16 Hz, 1 H), 5.50–5.70 (m,
1 H), 5.34 (t, J = 5 Hz, 1 H), 4.98 (dd, J = 10.5, 18 Hz, 2 H), 4. 80
(dd, J = 5, 9.5 Hz, 1 H), 4.25 (t, J = 7.5 Hz, 1 H), 2.98 (dd, J = 5, 17
Hz, 1 H), 2.80 (d, J = 17 Hz, 1 H), 2.60 (m, 1 H), 2.38 (s, 3 H), 2.14–
2.25 (m, 2 H).
13C NMR (CDCl3, 75 MHz): d = 171.7, 143.5, 140.2, 138.4, 137.6,
135.9, 134.3, 133.3, 129.7, 128.6, 128.5, 128.4, 128.2, 127.4, 127.2,
126.7, 124.8, 124.5, 117.7, 75.1, 73.6, 59.6, 51.9, 37.4, 33.5, 21.6.
13C NMR (75 MHz, CDCl3): d = 136.9, 136.7, 134.5, 129.1, 128.4,
127.0, 117.0, 96.6, 79.8, 64.0, 62.8, 45.3, 33.0, 31.2, 25.7, 20.7.
2-[(3S,4S,E)-4-(Dimethoxymethyl)-1-phenylhepta-1,6-dien-3-
yloxy]tetrahydro-2H-pyran (11)
To a solution of oxalyl chloride (2.61 mL, 29.9 mmol) in CH2Cl2
(170 mL) at –78 °C, was added DMSO (3.18 mL, 44.8 mmol) drop-
wise. The mixture was stirred for 15 min and a solution of alcohol
10 (4.25 g, 14 mmol) in CH2Cl2 (20 mL) was added via a syringe.
The mixture was stirred for 30 min and Et3N (12.5 mL, 89.4 mmol)
was added. The reaction was quenched with brine after 1 h. The
aqueous layer was extracted with CH2Cl2 (2 ×). The combined or-
ganic layers were dried (Na2SO4), filtered and concentrated under
reduced pressure. Flash column chromatography (Rf 0.30, 0.25 for
THP diastereomers; 20% EtOAc in hexanes) afforded the corre-
sponding aldehyde (3.80 g, 90%) as a colorless oil.
LRMS-ESI: m/z [M – H]– calcd for C30H30NO5S: 516; found: 516.
Anal. Calcd for C30H30NO5S: C, 69.61; H, 6.04; N, 2.71. Found: C,
69.47; H, 6.19; N, 2.55.
(2S)-(1S,2R)-1-(Tosylamino)-2,3-dihydro-1H-inden-2-yl-2-
[(S,E)-3-phenyl-1-(tetrahydro-2H-pyran-2-yloxy)allyl]pent-4-
enoate (9)
To an ice cold (0 °C) solution of anti-aldol product 8 (8.52 g, 16.5
mmol) and pyridinium p-toluenesulfonate (0.41 g, 1.65 mmol) in
CH2Cl2 (150 mL) was added 3,4-dihydro-2H-pyran (4.50 mL, 49.4
Precursor Aldehyde
IR (neat): 2941, 1727 cm–1.
Synthesis 2006, No. 18, 3015–3018 © Thieme Stuttgart · New York

3018
A. K. Ghosh et al.
PAPER
1H NMR (300 MHz, CDCl3): d (polar diastereomer) = 9.65 (d,
J = 3.3 Hz, 1 H), 7.05–7.30 (m, 5 H), 6.50 (d, J = 15.9 Hz, 1 H),
6.13 (dd, J = 8.4, 15.9 Hz, 1 H), 5.60 (m, 1 H), 4.89–4.98 (m, 2 H),
4.61 (t, J = 2.7 Hz, 1 H), 4.47 (t, J = 8.1 Hz, 1 H), 3.70 (m, 1 H),
3.26 (m, 1 H), 2.56 (m, 1 H), 2.14–2.33 (m, 2 H), 1.30–1.75 (m, 6
H).
13C NMR (75 MHz, CDCl3): d = 203.9, 136.3, 135.7, 134.9, 129.0,
128.6, 127.0, 126.6, 117.7, 94.8, 76.0, 62.5, 56.3, 31.1, 30.8, 25.8,
19.4.
References
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To a stirred solution of the above aldehyde (3.12 g, 10.4 mmol) in
trimethyl orthoformate (34 mL) at 0 °C, were added anhydrous
MeOH (0.84 mL, 20.8 mmol) and camphorsulfonic acid (0.24 g,
1.04 mmol). The resulting mixture was stirred for 1 h at 0 °C and
quenched with aq sat. NaHCO3 solution (30 mL). The aqueous layer
was carefully extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and concentrated. The
crude product was purified by flash column chromatography
(Rf 0.31, 0.25 for THP diastereomers, 25% EtOAc in hexanes) using
a mixture (1:70) of Et2O and CH2Cl2 as the eluent to afford acetal
11 (3.57 g, 99%) as colorless liquid.
11
1H NMR (300 MHz, CDCl3): d (polar diastereomer) = 7.22–7.40
(m, 5 H), 6.54 (d, J = 15.6 Hz, 1 H), 6.12 (dd, J = 7.2, 15.9 Hz, 1 H),
5.90–5.99 (m, 1 H), 4.97 (dd, J = 9.3, 17.1 Hz, 1 H), 4.70 (d, J = 3.3
Hz, 1 H), 4.42–4.47 (m, 2 H), 3.86–3.93 (m, 1 H), 3.50–3.54 (m, 1
H), 3.39 (s, 6 H), 2.26–2.30 (m, 2 H), 2.13–2.19 (m, 1 H), 1.55–1.85
(m, 6 H).
(5) (a) De Meyer, S.; Peeters, M. Conference on Retroviruses
and Opportunistic Infections (11th CROI), Feb 8-11; San
Francisco, USA, 2004, Abstracts 533 and 620.
(b) Surleraux, D. L. N. G.; Tahri, A.; Verschueren, W. G.;
Pille, G. M. E.; de Kock, H. A.; Jonckers, T. H. M.; Peeters,
A.; De Meyer, S.; Azijn, H.; Pauwels, R.; de Bethune, M.-P.;
King, N. M.; Prabu-Jeyabalan, M.; Schiffer, C. A.;
Wigerinck, P. B. T. P. J. Med. Chem. 2005, 48, 1813.
(c) Sorbera, L. A.; Castaner, J.; Bayes, M. Drugs Future
2005, 30, 441.
13C NMR (75 MHz, CDCl3): d = 138.4, 138.6, 133.0, 128.4, 128.0,
127.5, 126.4, 114.9, 105.4, 94.9, 75.7, 62.1, 54.3, 53.8, 46.0, 30.7,
30.2, 25.5, 19.4.
HRMS-EI: m/z [M + Na]+ calcd for C21H30O4 + Na: 369.2036;
found: 369.2034.
(6) On June 23, 2006, the FDA approved a new HIV treatment
for patients who do not respond to existing drugs; see:
www.fda.gov/bbs/topics/NEWS/2006/NEW01395.html.
(7) Miller, J. F.; Andrews, C. W.; Brieger, M.; Furfine, E. S.;
Hale, M. R.; Hanlon, M. H.; Hazen, R. J.; Kaldor, I.;
McLean, E. W.; Reynolds, D.; Sammond, D. M.;
Spaltenstein, A.; Tung, R.; Turner, E. M.; Xu, R. X.; Sherrill,
R. G. Bioorg. Med. Chem. Lett. 2006, 16, 1788.
(8) (a) Ghosh, A. K.; Kincaid, J. F.; Walters, D. E.; Chen, Y.;
Chaudhuri, N. C.; Thompson, W. J.; Culberson, C.;
Fitzgerald, P. M. D.; Lee, H. Y.; McKee, S. P.; Munson, P.
M.; Duong, T. T.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.;
Axel, M. G.; Lin, J.; Huff, J. R. J. Med. Chem. 1996, 39,
3278. (b) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995,
36, 505. (c) Ghosh, A. K.; Leshchenko, S.; Noetzel, M. J.
Org. Chem. 2004, 69, 7822.
(9) Quaedflieg, P. J. L. M.; Kesteleyn, B. R. R.; Wigerinck, P.
B. T. P.; Goyvaerts, N. M. F.; Vijn, R. J.; Liebregts, C. S. M.;
Kooistra, J. H. M. H.; Cusan, C. Org. Lett. 2005, 7, 5917.
(10) For recent ester enolate-based anti-aldol procedures, see:
(a) Ghosh, A. K.; Kim, J. Org. Lett. 2003, 5, 1063.
(b) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2, 2405.
(c) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118,
2527.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol (3)
Compound 11 (2.8 g, 8.08 mmol) was dissolved in CH2Cl2 (210
mL) and the clear solution was cooled to –78 °C. A stream of ozone
(generated by PCI ozone generator) was bubbled through the solu-
tion at –78 °C until the solution turned light blue (~50 min). Excess
of ozone was displaced by bubbling argon through the mixture at
–78 °C until the blue color disappeared (~30 min). Me2S (4.0 mL,
54.5 mmol) was then added to the solution and the mixture was
stirred for 1 h and then warmed up to 0 °C. MeOH (50 mL) and
NaBH4 (1.40 g, 37 mmol) were added respectively to the mixture
and stirring was continued for further 2 h. After this period, the mix-
ture was allowed to warm up to 23 °C. The mixture was concentrat-
ed under reduced pressure and the residue was dissolved in aq THF.
The mixture was cooled to 0 °C and aq 6 M HCl was added until pH
2. The mixture was stirred for 3 days and then solid NaHCO3 was
added. The mixture was stirred for 30 min and filtered and concen-
trated under reduced pressure. Purification of compound by flash
column chromatography using EtOAc in hexanes (1:1) afforded the
bis-THF 3 as a colorless oil (0.63 g, 60% in 3 steps); Rf 0.31(75%
EtOAc in hexane); [a]D23 –12.2, (c = 2.4, MeOH).
1H NMR (300 MHz, CDCl3): d = 5.48 (d, J = 5 Hz, 1 H), 4.21 (dd,
J = 6.5, 14.2 Hz, 1 H), 3.65–3.85 (m, 4 H), 3.38 (t, J = 7.5 Hz, 1 H),
2.65 (dd, J = 6.5, 9 Hz, 1 H), 2.11 (m, 1 H), 1.60–1.74 (m, 1 H).
13C NMR (CHCl3, 75 MHz): d = 109.5, 73.1, 71.1, 69.9, 46.6, 24.8.
(11) (a) Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org.
Chem. 2003, 821. (b) Ghosh, A. K.; Bischoff, A.; Cappiello,
J. J. Org. Lett. 2001, 3, 2677.
HRMS-EI: m/z [M + H]+ calcd for C6H10O3: 131.0709; found:
131.0710.
(12) The Mosher ester was formed by the reaction of Mosher acid
and alcohol 3 with EDCI in the presence of DMAP. The 19
NMR analysis of the Mosher ester13 revealed an
enantiomeric purity of >99%.
F
Acknowledgment
(13) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
Financial support of this work by the National Institutes of Health
(GM 53386) is gratefully acknowledged.
Synthesis 2006, No. 18, 3015–3018 © Thieme Stuttgart · New York