Synthetic studies towards the total synthesis of providencin

Article abstract of DOI:10.1055/s-2007-990883

A synthetic approach to assemble the uncommon furylcyclobutane substructure in providencin has been developed starting from a commercially available cyclobutane precursor. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990883

PAPER
3807
Synthetic Studies towards the Total Synthesis of Providencin
S
ynthetic Studie
l
s
towa
i
rds the
a
T
otal Synth
n
esis of Prov
e
idencin Schweizer, Tanja Gaich, Lothar Brecker, Johann Mulzer*
Institut für Organische Chemie, Universität Wien, Währinger Straße 38, 1090 Vienna, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 17 July 2007; revised 24 September 2007
cal access to the furylcyclobutane segment of 1.7 We also
envisaged a ‘furan first’ strategy for the synthesis of 1
starting from a readily available cyclobutane. Thus, the
deoxy compound 2 would serve as a late-stage key inter-
mediate, which might be accessible via metathesis and
Horner–Wadsworth–Emmons (HWE) olefination from
the cyclobutylfuran 4 (Scheme 1). Fragment 4 can be fur-
ther disconnected to aldehyde 5, in turn obtainable from
Abstract: A synthetic approach to assemble the uncommon furyl-
cyclobutane substructure in providencin has been developed start-
ing from a commercially available cyclobutane precursor.
Key words: furans, cyclizations, natural products, stereoselective
synthesis, total synthesis
The abundance of variably functionalized furans in bio-
logically active compounds has stimulated considerable
synthetic interest.1 Hence, a variety of methods have been
devised to assemble furan intermediates.2 Furanocem-
branes (Figure 1) have received particular attention, be-
cause they are effective against various cancer types,
reveal analgesic or anti-inflammatory activity, or display
potent neuro- and cytotoxic properties.3 Most notable con-
tributions came from the groups of Paquette, Marshall,
Wipf, and Pattenden,4 who developed ‘furan first’5 or ‘fu-
ran last’ strategies, depending on the stage at which the fu-
ran moiety was introduced into the carbon skeleton.
the commercially available bicycloheptenone
(Scheme 1).
6
CO2Me
CO2Me
CM or
RCM
O
O
1
OBz
OBz
OAc
HWE
reaction
OAc
PMBO
PMBO
2
3
Quite recently, the diterpene providencin [(+)-1]6 was iso-
lated from the gorgonian octocoral Pseudopterogorgia
kallos, featuring an uncommon furylcyclobutane ring sys-
tem. Bray and Pattenden recently reported a photochemi-
CO2Me
H
CHO
O
rac
OPMB
OBz
O
CHO
CO2Me
H
OBz
OTr
OTr
4
5
6
O
O
O
Scheme 1 Retrosynthetic considerations for the total synthesis of
providencin [(+)-1]
O
O
OAc
O
O
First we had to develop methodology for attaching a high-
ly substituted furan ring to the cyclobutane moiety present
in 5. After extensive experimentation, a Paal–Knorr-type
reaction turned out to be the method of choice. Therefore,
in a preliminary model study, ethyl ester 7, obtained by a
Roskamp reaction8 from 2-methylbutyraldehyde and
commercially available ethyl diazoacetate, was alkylated
with chloroacetone, leading to 1,4-diketone 8 (Scheme 2).
Microwave-assisted cyclization led to furan 9 in excellent
yield (Scheme 2). Further functionalization by selective
bromination at the less substituted a-position afforded
furans 10–12 (Scheme 2) as versatile intermediates for a
variety of potential coupling reactions.
O
O
lophotoxin
acerosolide
CO2Me
CO2Me
12 13
11
10
14
OH
O
O
1
2
O
O
9
3
8
O
4
7
6
OAc
5
O
O
O
O
pukalide
providencin [(+)-1]
Figure 1 Examples of furanocembranolides isolated from marine
invertebrates
For the synthesis of furylcyclobutane 19 (Scheme 3), ra-
cemic bicycloheptenone 6 (see Scheme 1) was stereose-
lectively reduced to the alcohol and converted into the
corresponding benzoate 13. Ozonolysis of the double
bond by reductive workup with sodium borohydride fol-
SYNTHESIS 2007, No. 24, pp 3807–3814
x
x.
x
x
.
2
0
0
7
Advanced online publication: 13.11.2007
DOI: 10.1055/s-2007-990883; Art ID: T10907SS
© Georg Thieme Verlag Stuttgart · New York

3808
E. Schweizer et al.
PAPER
CO2Et
tained can be benzoylated and further transformed as de-
O
scribed for the racemate 13 (Scheme 3).
a
b
CHO
CO2Et
To validate our approach towards the total synthesis of the
providencin macrolide [(+)-1], (R)-glycidol was tritylated
O
O
7
8
CO2Et
CO2Et
a
O
OH
b
c
e
(R)-glycidol
c
OTr
OTr
20
21
OPMB
O
O
R
d
X
OPMB
OTr
d
OH
11 X = O
9 R = H
f
12 X = CH2
10 R = Br
22
23
Scheme 2 Synthesis of furans 9–12. Reagents and conditions: (a)
N2CHCO2Et, SnCl2, CH2Cl2, 25 °C, 4 h (97%); (b) chloroacetone,
NaH, THF, 25 °C, 36 h (63%); (c) concd HCl, EtOH, MW, 100 °C, 8
min (98%); (d) NBS, AIBN, CCl4, 76 °C, 1 h (79%); (e) DMSO,
190 °C, 10 min (45%); (f) Ph3PMe+Br–, n-BuLi, THF, 0–25 °C, 12 h
(55%).
OPMB
e
O
H
(–)-24
TrO
TrO
g
f
16
OBz
O
rac
lowed, affording diol 14, which was tritylated with trityl
chloride to give both monoprotected regioisomers 15 and
16, which are separable by column chromatography, in a
4:1 ratio (Scheme 3). The bis-tritylated diol and un-
changed starting material were recovered and recycled.
Alcohol 15 was oxidized to aldehyde 17, which was
isomerized at C1 with aqueous potassium carbonate and
then converted into the 1,4-diketone 18 (Scheme 3). Mi-
crowave irradiation led, finally, to the desired furan 19,
under cleavage of the trityl protecting group (Scheme 3).
OBz
MeO
MeO
P
OH
OHC
25
26
TrO
TrO
i
h
OBz
O
OBz
MeO
MeO
P
O
O
OPMB
27
28
TrO
j
TrO
k
1
1
H
OBz
OBz
R1O
a, b
c
6
OH
OAc
rac
rac
R2O
OBz
OBz
OPMB
HO
H
OPMB
29
30
R1
14 R1 = H R2 = Tr
13
d
15 R1 = H R2 = Tr
16 R1 = Tr R2 = H
1
R2
OBz
m
l
OBz
CO2Et
CO2Et
OAc
OAc
O
OPMB
OPMB
O
i
O
1
2
rac
1
2
rac
e
f
g, h
31
32 (R1 = H, R2 = CHO
33 (R1 = CHO, R2 = H)
15
17
5
n
O
OBz
OBz
18
19
EtO2CH2C
OPMB
TrO
HO
o
Scheme 3 Synthesis of the 1,2-trans-substituted furylcyclobutane
19. Reagents and conditions: (a) NaBH4, MeOH, –78 °C, 1 h; (b)
BzCl, py, 0–25 °C, 4 h (97%, over 2 steps); (c) 1. O3, CH2Cl2, –78 °C,
20 min; 2. NaBH4, 0 °C, 2 h (85%); (d) TrCl, Et3N, DMAP, CH2Cl2,
25 °C, 18 h (15: 35%; 16: 9%); (e) DMP, NaHCO3, CH2Cl2, 25 °C, 3
h (87%); (f) 0.1 M K2CO3, MeOH, CH2Cl2, 25 °C, 15 min (87%); (g)
N2CHCO2Et, SnCl2, CH2Cl2, 25 °C, 2 h (73%); (h) chloroacetone,
NaH, THF, 25 °C, 50 h (46%); (i) concd HCl, MeOH, CH2Cl2, MW,
100 °C, 10 min (90%).
OBz
33
OAc
34
Scheme 4 Synthesis of fragment 34. Reagents and conditions: (a)
TrCl, Et3N, DMAP, CH2Cl2, 0–25 °C, 24 (100%); (b)
h
H2C=C(Me)MgBr, CuI, THF, –78 to –40 °C, 2 h (100%); (c) PMBCl,
NaH, TBAB, THF, 25 °C, 1 h, then 60 °C, 24 h; (d) TsOH, MeOH,
25 °C, 30 min (71%); (e) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 1
h, then 0 °C, 2 h (88%); (f) DMP, NaHCO3, CH2Cl2, 25 °C, 3 h
(95%); (g) MeP(O)(OMe)2, n-BuLi, THF, –78 °C, 6 h (84%); (h)
DMP, NaHCO3, CH2Cl2, 25 °C, 2 h (78%); (i) NaH, (–)-24, THF,
–10 °C, 10 min, then 25 °C, 2 h (92%); (j) NaBH4, CeCl3·7H2O,
MeOH, –78 °C, 3 h (78%); (k) Ac2O, Et3N, DMAP, CH2Cl2, 25 °C,
2 h (97%); (l) TsOH, MeOH, 25 °C, 2 h (81%); (m) DMP, NaHCO3,
CH2Cl2, 25 °C, 2 h (85%); (n) 0.1 M K2CO3, MeOH, 25 °C, 15 min
(66%); (o) N2CHCO2Et, SnCl2, CH2Cl2, 25 °C, 2 h (79%).
For the synthesis of enantiomerically pure compounds, bi-
cycloheptenone 6 was reduced with sodium borohydride
and converted into the corresponding acetate. Digestion
with the lipase SAM-II afforded the undesired alcohol and
the desired enantiomer as unchanged acetate, which was
hydrolyzed with lithium hydroxide. The alcohol thus ob-
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards the Total Synthesis of Providencin
Ethyl Furan-3-carboxylate 9
3809
to 20 (Scheme 4), and then treated with isopropenylmag-
nesium bromide in the presence of copper(I) iodide to
give alcohol 21, which was protected as the p-methoxy-
benzyl ether 22. After detritylation, alcohol 23 formed,
and was oxidized to aldehyde 24 (Scheme 4). In a parallel
sequence, alcohol 16 was oxidized to aldehyde 25, which
was converted into b-keto phosphonate 27 and coupled
with aldehyde 24 to give ketone 28, which was reduced to
alcohol 29 and acetylated (Scheme 4). After detritylation,
alcohol 31 was obtained, and was oxidized to aldehyde
32. Base-catalyzed epimerization delivered aldehyde 33
(Scheme 4), which corresponds to the C14–C9 fragment
of (+)-1. The Roskamp reaction finally led to keto ester 34
(Scheme 4).
A mixture of a 60% suspension of NaH in mineral oil (650 mg, 16.3
mmol) and keto ester 7 (2.80 g, 16.3 mmol) in THF (20 mL) was
stirred at 25 °C for 1 h. Chloroacetone (1.2 mL, 15.5 mmol) was
added dropwise, and the mixture was stirred at 25 °C for 50 h.
Workup with H2O and Et2O followed by chromatography (silica
gel, hexane–EtOAc, 20:1) furnished diketone 8 as a colorless oil,
which was used in the next step without further purification; yield:
2.24 g (63%).
A mixture of diketone 8 (400 mg, 1.75 mmol), EtOH (3 mL), and
concd HCl (30 mL) was subjected to microwave-assisted furan cy-
clization as described by the general procedure above. The residue
was purified by column chromatography (silica gel, hexane–
EtOAc, 20:1); this gave 9.
Yield: 360 mg (98%); pale yellow oil.
IR (film): 2968, 2930, 1709, 1580, 1383, 1277, 1231, 1201, 1064
cm–1.
1H NMR (250 MHz, CDCl3): d = 0.84 (t, J = 7.5 Hz, 3 H), 1.23 (d,
J = 6.9 Hz, 3 H), 1.33 (t, J = 6.9 Hz, 3 H), 1.49–1.79 (m, 2 H), 2.24
(d, J = 0.9 Hz, 3 H), 3.45–3.61 (m, 1 H), 4.24 (q, J = 6.9 Hz, 2 H),
6.20 (d, J = 0.9 Hz, 1 H).
In conclusion, we have described the synthesis of the
trans-fused furylcyclobutane moiety 34 of providencin
[(+)-1], starting from the commercially available cyclo-
butane derivative 6. Functionalization of the substituents
at both the C1 and C2 positions of the cyclobutane ring
was possible, thus corroborating our strategy. Moreover,
the synthesis of highly functionalized furan derivatives
provided versatile intermediates, which might be em-
ployed in a variety of coupling reactions.
13C NMR (63 MHz, CDCl3): d = 12.3, 13.5, 14.7, 18.9, 28.9, 34.2,
60.1, 106.4, 113.7, 150.1, 164.6, 165.2.
HRMS (EI): m/z calcd for C12H18O3: 210.1256; found: 210.1258.
Ethyl 5-(Bromomethyl)-2-sec-butylfuran-3-carboxylate (10)
Methylfuran 9 (360 mg, 1.71 mmol), NBS (320 mg, 1.80 mmol),
and AIBN (32 mg, 0.19 mmol) were dissolved in CCl4 (10 mL) and
the mixture was refluxed for 1 h. The succinimide was removed by
filtration and the filtrate was concentrated in vacuo. Purification of
the residue by column chromatography (silica gel, hexane–EtOAc,
10:1) afforded 10.
All 1H NMR (250 MHz or 400 MHz) and 13C NMR (63 MHz or 100
MHz) spectra were recorded on Bruker Avance DPX 250 or DRX
400 spectrometers. The chemical shifts d are reported relative to the
solvent peaks. IR spectra were recorded of samples prepared as
films on NaCl plates on a Perkin-Elmer Spectrum 1600 Series FTIR
spectrometer. MS spectra were recorded on a Finnigan MAT 8230
apparatus with a resolution of 10000. Products were purified by
flash column chromatography (silica gel from Merck, 40–63 mm,
240–400 mesh). THF was distilled from sodium/benzophenone.
Yield: 390 mg (79%); pale yellow oil.
IR (film): 2968, 2930, 1709, 1611, 1558, 1216, 1057 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.85 (t, J = 7.4 Hz, 3 H), 1.26 (d,
J = 6.9 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.56–1.84 (m, 2 H), 3.49–
3.62 (m, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.44 (s, 2 H), 6.63 (s, 1 H).
Microwave-Assisted Furan Cyclization; General Procedure
The diketone (1.75 mmol) was dissolved in MeOH or EtOH (3 mL),
then concd HCl (30 mL) was added, and the mixture was subjected
to microwave irradiation (Biotage Initiator) for 4–15 min at 100–
120 °C. Sat. aq NaHCO3 (5 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 10 mL). The combined organic phases were
washed with H2O (30 mL) and brine (30 mL), dried (MgSO4), and
concentrated in vacuo.
13C NMR (63 MHz, CDCl3): d = 12.4, 14.6, 18.8, 23.6, 28.8, 34.5,
60.5, 110.9, 114.6, 148.3, 167.1, 167.7.
HRMS (EI): m/z calcd for C12H17O3Br: 288.0361; found: 288.0332.
Ethyl 2-sec-Butyl-5-formylfuran-3-carboxylate (11)
Bromide 10 (40 mg, 0.14 mmol) was dissolved in anhyd DMSO (5
mL) and the soln was heated under reflux at 190 °C for 10 min; then
H2O (20 mL) was added and the mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were washed with H2O
(60 mL) and brine (60 mL), dried (MgSO4), and concentrated in
vacuo. Purification of the residue by column chromatography (silica
gel, hexane–EtOAc, 5:1) yielded 11.
Ethyl 2-sec-Butyl-5-methylfuran-3-carboxylate (9)
Keto Ester 7
SnCl2 (38 mg, 0.2 mmol), N2CHCO2Et (126 mL, 1.2 mmol), and s-
BuCHO (107 mL, 1.0 mmol) in CH2Cl2 (2 mL) were stirred for 4 h.
The mixture was quenched with sat. aq NH4F and extracted with
Et2O (3 × 5 mL). The organic layer was dried (MgSO4) and evapo-
rated, and the residue was purified by chromatography (silica gel,
hexane–EtOAc, 3:1); this gave 7.
Yield: 14 mg (45%); pale yellow oil.
IR (film): 2968, 2930, 1721, 1688, 1586, 1535, 1459, 1216, 1057
cm–1.
Yield: 171 mg (97%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 7.6 Hz, 3 H), 1.31 (d,
J = 7.2 Hz, 3 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.61–1.86 (m, 2 H), 3.62–
3.71 (m, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 7.47 (s, 1 H), 9.57 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.3, 14.6, 18.5, 28.7, 34.9, 60.8,
110.6, 116.2, 150.7, 163.0, 172.3, 177.6.
IR (film): 2961, 2930, 2870, 1740, 1709, 1649, 1626, 1459, 1406,
1368, 1307, 1224, 1171, 1148, 1125, 1095, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.93 (t, J = 7.4 Hz, 3 H, H–C1),
1.13 (d, J = 7.0 Hz, 3 H, H–C4), 1.30 (t, J = 7.2 Hz, 3 H, H–C7),
1.38–1.55 (m, 1 H, H–C2), 1.62–1.84 (m, 1 H, H–C2), 2.53–2.68
(m, 1 H, H–C3), 3.49 (s, 2 H, H–C5), 4.22 (q, J = 7.2 Hz, 2 H, H–
C6).
HRMS (EI): m/z calcd for C12H16O4: 224.1049; found: 224.1047.
13C NMR (63 MHz, CDCl3): d = 11.8, 14.5, 15.8, 26.0, 48.1, 48.4,
61.6, 167.7, 206.8.
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PAPER
Ethyl 2-sec-Butyl-5-vinylfuran-3-carboxylate (12)
1H NMR (250 MHz, CDCl3): d = 1.70–2.07 (m, 3 H, H–C2, H–C6),
2.38–2.59 (m, 2 H, H–C2, H–C3), 2.83–2.99 (m, 1 H, H–C7), 3.52–
3.67 (m, 2 H, H–C4), 3.73–4.00 (m, 4 H, H–C5, OH), 5.25–5.37 (m,
1 H, H–C1), 7.38–7.48 (m, 2 H, Ph), 7.51–7.60 (m, 1 H, Ph), 7.99–
8.06 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 26.4, 30.9, 34.4, 40.6, 62.8, 62.9,
69.4, 128.8, 129.9, 130.5, 133.5, 166.5.
Ph3PMe+Br– (96 mg, 0.27 mmol) was dissolved under argon in an-
hyd THF (2 mL) and the suspension was cooled to 0 °C. A 2.5 M
soln of n-BuLi in hexane (0.1 mL, 0.25 mmol) was added, and the
mixture was warmed to 25 °C and stirred for 1 h before aldehyde 11
(50 mg, 0.22 mmol) in THF (3 mL) was added. Then the mixture
was stirred for 12 h at 25 °C, treated with sat. aq NaHCO3 (10 mL),
and extracted with Et2O (3 × 10 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification of the
residue by column chromatography (silica gel, hexane–EtOAc,
20:1) gave 12.
ESI-MS: m/z [M + Na]+ calcd for C14H18O4Na: 273.1103; found:
273.1105.
(1SR,2RS,3RS)-2-(2-Hydroxyethyl)-3-[(trityloxy)methyl]cyclo-
butyl Benzoate (16) and (1SR,2RS,3RS)-3-(Hydroxymethyl)-2-
[2-(trityloxy)ethyl]cyclobutyl Benzoate (15)
Yield: 27 mg (55%); pale yellow oil.
IR (film): 2961, 2930, 2877, 1717, 1588, 1535, 1451, 1375, 1209,
1057 cm–1.
TrCl (4.66 g, 16.6 mmol) in CH2Cl2 (15 mL) at 0 °C was treated
with Et3N (5.1 mL, 36.8 mmol) and DMAP (22 mg, 0.18 mmol).
Diol 14 (4.60 g, 18.4 mmol) in CH2Cl2 (60 mL) was added dropwise
and the mixture was stirred for 18 h at 25 °C. The mixture was
quenched with aq NH4Cl (200 mL) and extracted with Et2O (3 × 50
mL), and the organic layer was washed with brine (3 × 100 mL),
dried (MgSO4), and concentrated. Purification of the residue by
chromatography (silica gel, hexane–EtOAc, 5:1, then 1:1) gave 15
and 16 as colorless oils.
1H NMR (250 MHz, CDCl3): d = 0.89 (t, J = 7.5 Hz, 3 H), 1.30 (d,
J = 7.1 Hz, 3 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.56–1.89 (m, 2 H), 3.52–
3.68 (m, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 5.19 (d, J = 11.3 Hz, 1 H),
5.66 (d, J = 17.5 Hz, 1 H), 6.45 (dd, J = 17.5, 11.3 Hz, 1 H), 6.51 (s,
1 H).
13C NMR (100 MHz, CDCl3): d = 12.4, 14.7, 18.9, 29.0, 34.4, 60.4,
108.7, 113.0, 114.6, 124.9, 151.1, 164.3, 166.3.
ESI-HRMS: m/z calcd for C13H18O3: 222.1256; found: 222.1245.
Compound 15
Yield: 1.63 g (35%); colorless oil.
(1SR,5RS,6SR)-Bicyclo[3.2.0]hept-2-en-6-yl Benzoate (13)
A suspension of NaBH4 (870 mg, 23.0 mmol) in MeOH (75 mL) at
–78 °C was treated dropwise with racemic bicycloheptenone 6 (4.9
mL, 46.0 mmol) in MeOH (25 mL). The mixture was stirred for 1 h
at –78 °C, warmed to 25 °C, and diluted with Et2O (100 mL) and 2
M HCl (70 mL). The organic layer was dried (MgSO4), concentrat-
ed, and diluted with CH2Cl2 (50 mL) and py (7.5 mL, 92.0 mmol).
BzCl (7.5 mL, 64.4 mmol) was added dropwise and the mixture was
stirred at 25 °C for 4 h, quenched with H2O (200 mL) and extracted
with CH2Cl2 (5 × 20 mL). The organic layer was washed with brine
(3 × 10 mL), dried (MgSO4), and concentrated; chromatography of
the residue (silica gel, hexane–EtOAc, 10:1) gave benzoate 13.
IR (film): 1716, 1490, 1449, 1314, 1275, 1176, 1112, 1070, 1026
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 5.1 Hz, 1 H, OH),
1.77–2.01 (m, 3 H, H–C2, H–C6), 2.23–2.34 (m, 1 H, H–C3), 2.43–
2.52 (m, 1 H, H–C2), 2.78–2.86 (m, 1 H, H–C7), 3.02 (dd, J = 15.0,
7.7 Hz, 1 H, H–C5), 3.13 (dd, J = 15.0, 7.7 Hz, 1 H, H–C5), 3.52–
3.60 (m, 1 H, H–C4), 3.63–3.71 (m, 1 H, H–C4), 5.17 (q, J = 7.0 Hz,
1 H, H–C1), 7.07–7.19 (m, 9 H, CPh3), 7.29–7.35 (m, 8 H, Ph,
CPh3), 7.47 (t, J = 8.1, 1 H, Ph), 7.85 (d, J = 8.1 Hz, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 25.1, 31.5, 34.0, 39.2, 63.2, 63.7,
69.1, 87.1, 127.4, 128.1, 128.8, 129.0, 130.0, 130.6, 133.3, 144.6,
166.3.
Yield: 9.6 g (97% over 2 steps); colorless oil.
IR (film): 3056, 2939, 2850, 1716, 1602, 1585, 1491, 1452, 1347,
1314, 1271, 1176, 1113, 1070, 1046 cm–1.
ESI-HRMS: m/z [M + Na]+ calcd for C33H32O4Na: 515.2198; found:
515.2196.
1H NMR (CDCl3, 250 MHz): d = 1.90–2.01 (m, 1 H, H–C2), 2.50
(dd, J = 17.1 Hz, 9.8, 1 H, H–C6), 2.60–2.73 (m, 1 H, H–C6), 2.88
(dt, J = 8.0, 2.2 Hz, 1 H, H–C2), 3.10–3.23 (m, 1 H, H–C3), 3.36–
3.50 (m, 1 H, H–C7), 5.41–5.52 (m, 1 H, H–C1), 5.88 (s, 2 H, H–
C4), H–C5), 7.46 (t, J = 7.6 Hz, 2 H, Ph), 7.59 (t, J = 7.6 Hz, 1 H,
Ph), 8.07 (d, J = 7.6 Hz, 2 H, Ph).
Compound 16
Yield: 600 mg (9%); colorless oil.
IR (film): 3456, 3060, 2938, 1717, 1699, 1601, 1490, 1451, 1314,
1276, 1113, 1069, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (t, J = 5.7 Hz, 1 H, OH),
1.60–1.81 (m, 2 H, H–C6), 1.85–2.00 (m, 1 H, H–C2), 2.57–2.71
(m, 2 H, H–C2, H–C3), 2.91–3.03 (m, 1 H, H–C7), 3.21 (dd,
J = 9.4, 7.8 Hz, 1 H, H–C4), 3.32 (dd, J = 9.4, 5.3, 1 H, H–C4),
4.83–4.64 (m, 2 H, H–C5), 5.29–5.40 (m, 1 H, H–C1), 7.20–7.38
(m, 9 H, CPh3), 7.39–7.51 (m, 8 H, Ph, CPh3), 7.53–7.63 (m, 1 H,
Ph), 7.90–7.96 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 27.7, 31.7, 32.3, 39.2, 62.3, 64.3,
69.8, 87.2, 127.4, 128.2, 128.8, 129.0, 129.9, 130.5, 133.4, 144.4,
166.3.
13C NMR (63 MHz, CDCl3): d = 33.1, 37.1, 41.3, 41.7, 69.8, 128.7,
130.0, 130.1, 132.6, 133.2, 134.6, 144.4.
HRMS (EI): m/z [M+] calcd for C14H14O2: 214.0994; found:
214.0991.
(1SR,2RS,3RS)-2-(2-Hydroxyethyl)-3-(hydroxymethyl)cyclo-
butyl Benzoate (14)
Olefin 13 (4.60 g, 21.5 mmol) in CH2Cl2 (30 mL) was treated at
–78 °C with O3 for 20 min, then warmed to 0 °C and diluted with
MeOH (30 mL). Solid NaBH4 (3.25 g, 85.9 mmol) was added in
small portions and the mixture was stirred for 2 h at 0 °C, quenched
with 2 M HCl (300 mL) and extracted with CH2Cl2 (5 × 20 mL). The
organic layer was washed with brine (3 × 100 mL), dried (MgSO4),
and evaporated; purification of the residue by chromatography (sil-
ica gel, EtOAc) gave 14.
ESI-HRMS: m/z [M + Na]+ calcd for C33H32O4Na: 515.2198; found:
515.2189.
(1SR,2RS,3RS)-3-Formyl-2-[2-(trityloxy)ethyl]cyclobutyl Ben-
zoate (17)
Alcohol 15 (1.63 g, 3.31 mmol) was treated with NaHCO3 (1.3 g,
14.9 mmol) and DMP (2.1 g, 4.96 mmol) in CH2Cl2 (30 mL) for 2
h. The mixture was quenched with aq Na2S2O4 (100 mL) and ex-
tracted with Et2O (3 × 100 mL). The organic layer was washed with
Yield: 4.6 g (85% over 2 steps); colorless oil.
IR (film): 3339, 2944, 2874, 1720, 1699, 1278, 1177, 1115, 1071,
1050, 1025 cm–1.
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards the Total Synthesis of Providencin
3811
brine (3 × 100 mL), dried (MgSO4), and concentrated. Purification
of the residue by chromatography (silica gel, hexane–EtOAc, 10:1)
gave aldehyde 17.
Ethyl 2-[(1SR,2RS,3SR)-3-(Benzoyloxy)-2-(2-hydroxyethyl)cy-
clobutyl]-5-methylfuran-3-carboxylate (19)
A mixture of diketone 18 (63 mg, 0.1 mmol), MeOH (1 mL),
CH2Cl2 (0.5 mL), and concd HCl (30 mL) was subjected to micro-
wave-assisted furan cyclization as described by the general proce-
dure above. Purification of the residue by column chromatography
(silica gel, hexane–EtOAc, 3:1) afforded 19.
Yield: 1.41 g (87%); colorless oil.
IR (film): 3060, 3032, 2937, 2870, 2723, 1716, 1601, 1490, 1449,
1386, 1314, 1274, 1224, 1177, 1153, 1115, 1070, 1026, 1002 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.86–2.08 (m, 2 H, H–C6), 2.43–
2.55 (m, 1 H, H–C2), 2.65–2.78 (m, 1 H, H–C2), 3.03–3.16 (m, 3
H, H–C3, H–C5), 3.35–3.53 (m, 1 H, H–C7), 5.29–5.43 (m, 1 H, H–
C1), 7.18–7.36 (m, 9 H, CPh3), 7.38–7.47 (m, 8 H, Ph, CPh3), 7.55–
7.61 (m, 1 H, Ph), 7.95–7.97 (m, 2 H, Ph), 9.71 (d, J = 1.9 Hz, 1 H,
CHO).
13C NMR (100 MHz, CDCl3): d = 25.9, 27.9, 42.0, 43.0, 62.5, 68.3,
87.1, 127.4, 128.2, 128.8, 129.0, 130.0, 130.3, 133.5, 144.5, 166.2,
202.0.
Yield: 27 mg (90%); pale yellow oil.
IR (film): 3515, 2946, 1717, 1580, 1451, 1375, 1315, 1277, 1209,
1110, 1057 cm–1.
1H NMR (CDCl3, 400 MHz): d = 1.33 (t, J = 7.1 Hz, 3 H), 1.83 (br
s, 1 H), 1.88–2.02 (m, 2 H), 2.29 (s, 3 H), 2.51–2.62 (m, 1 H), 2.74–
2.85 (m, 1 H), 3.02–3.12 (m, 1 H), 3.66 (t, J = 6.4 Hz, 2 H), 4.16–
4.23 (m, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 5.55–5.61 (m, 1 H), 6.23 (s,
1 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.58 (t, J = 7.7 Hz, 1 H), 8.08 (d,
J = 7.7 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): d = 13.7, 14.7, 32.3, 32.6, 34.8, 43.8,
60.6, 61.1, 70.8, 106.9, 122.8, 128.8, 130.0, 130.6, 133.5, 150.9,
161.4, 164.7, 166.7.
ESI-HRMS: m/z [M + Na]+ calcd for C33H30O4Na: 513.2042; found:
513.2053.
(1SR,2RS,3SR)-3-Formyl-2-[2-(trityloxy)ethyl]cyclobutyl Ben-
zoate (5)
HRMS (EI): m/z calcd for C21H24O6: 372.1573; found: 372.1584.
Aldehyde 17 (290 mg, 0.59 mmol) in CH2Cl2 (2 mL) was treated
with 0.1 M K2CO3 in MeOH (10 mL) and CH2Cl2 (5 mL) for 15 min
at 25 °C. Purification of the residue by column chromatography (sil-
ica gel, hexane–EtOAc, 7:1) furnished 5.
(S)-2-[(Trityloxy)methyl]oxirane [(–)-20]9
A soln of TrCl (2.46 g, 8.8 mmol) in CH2Cl2 (8 mL) was treated un-
der argon at 0 °C with Et3N (2.2 mL, 16.0 mmol) and (R)-glycidol
(540 mL, 8.0 mmol) in CH2Cl2 (4 mL). DMAP (10 mg, 0.08 mmol)
was added and the mixture was stirred for 24 h at 25 °C. The mix-
ture was quenched with NH4Cl (50 mL) and extracted with Et2O (3
× 50 mL). The organic phase was washed with brine (3 × 100 mL),
dried (MgSO4), and concentrated; this gave white crystals which
were recrystallized from MeOH.
Yield: 252 mg (87%); colorless oil.
IR (film): 3059, 2946, 1709, 1595, 1489, 1451, 1307, 1277, 1178,
1155, 1110, 1072, 1027 cm–1.
1H NMR (CDCl3, 250 MHz): d = 1.84–2.19 (m, 2 H), 2.24–2.37 (m,
1 H), 2.63–2.81 (m, 1 H), 2.98–3.16 (m, 3 H), 3.17–3.24 (m, 1 H),
5.27–5.39 (m, 1 H), 7.20–7.33 (m, 9 H), 7.41–7.48 (m, 8 H), 7.50–
7.60 (m, 1 H), 8.01–8.09 (m, 2 H), 9.64 (d, J = 1.6 Hz, 1 H).
13C NMR (CDCl3, 63 MHz): d = 27.6, 29.0, 39.3, 47.2, 61.3, 69.3,
86.7, 127.0, 127.8, 128.4, 128.6, 129.6, 129.9, 133.1, 144.0, 165.8,
201.4.
Yield: 2.5 g (100%); mp 94–96 °C (MeOH) (Lit.9 100 °C); [a]D
25
–9.7 (c 1.0, CHCl3) {Lit.9 [a]D25 –10.5 (c 1, CHCl3)}.
IR (film): 3023, 2925, 2874, 1595, 1490, 1448, 1158, 1071, 1032,
1002 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.68 (dd, J = 4.9, 2.2 Hz, 1 H, H–
C3), 2.82 (dd, J = 4.9, 3.9 Hz, 1 H, H–C3), 3.17–3.28 (m, 2 H, H–
C1), 3.38–3.48 (m, 1 H, H–C2), 7.26–7.45 (m, 9 H, CPh3), 7.51–
7.62 (m, 6 H, CPh3).
ESI-HRMS: m/z [M + Na]+ calcd for C33H30O4Na: 513.2042; found:
513.2053.
(1SR,2RS,3SR)-3-[2-(Ethoxycarbonyl)-4-oxopentanoyl]-2-[2-
(trityloxy)ethyl]cyclobutyl Benzoate (18)
(S)-4-Methyl-1-(trityloxy)pent-4-en-2-ol [(–)-21]9
As described for the preparation of 7, reaction of SnCl2 (62 mg),
N2CHCO2Et (206 mL, 1.96 mmol), and aldehyde 5 (800 mg, 1.64
mmol) in CH2Cl2 (6 mL) gave the corresponding b-keto ester; yield:
690 mg (73%). The crude ester was transformed into diketone 18 as
described for the preparation of 8 from 7. Purification of the crude
product by chromatography (silica gel, hexane–EtOAc, 10:1, then
5:1) furnished 18.
CuI (121 mg, 0.63 mmol) under argon in THF (2 mL) was treated
dropwise at –78 °C with 0.5 M H2C=C(Me)MgBr in THF (13.3 mL,
6.64 mmol). After 30 min, (–)-20 (1.0 g, 3.16 mmol) in THF (1 mL)
was added and the mixture was stirred for 2 h at –40 °C, quenched
with NH4Cl, and stirred for 30 min at 25 °C. Workup with H2O and
Et2O followed by chromatography (silica gel, hexane–EtOAc, 5:1)
furnished (–)-21.
Yield: 1.14 g (100%); colorless oil; [a]D25 –3.8 (c 0.6, CHCl3) {Lit.9
Yield: 138 mg (46%); colorless oil.
[a]D25 –3.0 (c 1.15, CHCl3)}.
IR (film): 3059, 2984, 2946, 2870, 1740, 1717, 1599 (w), 1489,
1448, 1398, 1364, 1311, 1269, 1228, 1178, 1155, 1114, 1068, 1023
cm–1.
IR (film): 3058, 3020, 2926, 2875, 1595, 1489, 1449, 1220, 1103,
1071 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.18–1.33 (m, 3 H, CH2CH3),
1.84–2.10 (m, 1 H, H–C6), 2.10–2.54 (m, 2 H, H–C2, H–C6), 2.18
(s, 3 H, H–C11), 2.66–2.80 (m, 1 H, H–C2), 2.85–3.29 (m, 5 H, H–
C3, H–C5, H–C7, H–C9), 3.38–3.57 (m, 1 H, H–C9), 3.88–4.03 (m,
1 H, H–C8), 4.05–4.42 (m, 2 H, CH2CH3), 5.27–5.38 (m, 1 H, H–
C1), 7.14–7.32 (m, 9 H, CPh3), 7.36–7.52 (m, 8 H, Ph, CPh3), 7.56–
7.66 (m, 1 H, Ph), 7.99–8.09 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 14.4, 29.8, 30.0, 31.0, 31.6, 40.8,
42.0, 47.6, 52.7, 62.1, 69.5, 87.1, 127.3, 128.1, 128.8, 129.0, 130.0,
130.6, 133.4, 144.6, 166.2, 168.9, 205.0, 205.5.
1H NMR (250 MHz, CDCl3): d = 1.74 (s, 3 H, H–C5), 2.19 (d,
J = 6.7 Hz, 2 H, H–C3), 2.25 (d, J = 3.3 Hz, 1 H, OH), 3.11–3.24
(m, 2 H, H–C1), 3.87–4.00 (m, 1 H, H–C2), 4.75 (s, 1 H, H–C6),
4.82 (s, 1 H, H–C6), 7.23–7.38 (m, 9 H, CPh3), 7.44–7.50 (m, 6 H,
CPh3).
(S)-2-[(4-Methoxybenzyl)oxy]-4-methylpent-4-en-1-ol [(+)-23]
A 60% suspension of NaH in mineral oil (633 mg, 15.8 mmol) in
THF (15 mL) was treated dropwise at 0 °C with (–)-21 (3.78 g, 10.6
mmol) in THF (5 mL). The mixture was stirred at 25 °C for 1 h, then
PMBCl (2.14 mL, 15.8 mmol) and TBAB (68 mg, 0.21 mmol) were
added and the mixture was stirred for 24 h at 60 °C. Usual workup
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York

3812
E. Schweizer et al.
PAPER
(1SR,2RS,3RS)-2-[3-(Dimethoxyphosphoryl)-2-hydroxypro-
with NH4Cl, H2O, and Et2O furnished 22 after chromatography (sil-
ica gel, hexane–EtOAc, 20:1). Compound 22 was detritylated in
MeOH (20 mL) with TsOH·H2O (200 mg, 1.1 mmol) for 30 min at
25 °C. Usual workup and chromatography (silica gel, hexane–
EtOAc, 5:1, then 0:1) gave 23.
Yield: 1.77 g (71%, 2 steps); colorless oil; [a]D25 +14.7 (c 0.3,
CHCl3).
pyl]-3-[(trityloxy)methyl]cyclobutyl Benzoate (26)
MeP(O)(OMe)2 (138 mL, 1.16 mmol) in THF (7 mL) was treated
dropwise at –78 °C under argon with 2.5 M n-BuLi in hexane (464
mL, 1.16 mmol). After 30 min, aldehyde 25 (570 mg, 1.16 mmol) in
THF (3 mL) was added and the mixture was stirred for 6 h at
–78 °C. Workup with NaHCO3, H2O, and Et2O followed by chro-
matography (silica gel, hexane–EtOAc, 5:1, 0:1) furnished 26 as an
inseparable diastereomeric mixture. The NMR data provided below
are for the major diastereomer [Rf = 0.21 (hexane–EtOAc, 5:1)].
IR (film): 3401, 2929, 1738, 1713, 1613, 1514, 1455, 1301, 1249,
1173, 1103, 1035 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.79 (s, 3 H, H–C5), 1.94 (dd,
J = 6.9, 5.6 Hz, 1 H, OH), 2.22 (dd, J = 14.1, 7.2 Hz, 1 H, H–C3),
2.42 (dd, J = 14.1, 5.6 Hz, 1 H, H–C3), 3.47–3.59 (m, 1 H, H–C2),
3.64–3.76 (m, 2 H, H–C1), 3.84 (s, 3 H, OCH3), 4.50, 4.64 (AB,
J = 11.2 Hz, 2 H, CH2C6H4CH3), 4.81 (s, 1 H, H–C6), 4.85 (s, 1 H,
H–C6), 6.91, 7.30 (AA¢BB¢, J = 8.5 Hz, 4 H, C6H4CH3).
13C NMR (63 MHz, CDCl3): d = 23.2, 39.9, 55.7, 64.7, 71.6, 78.1,
113.6, 114.3, 129.8.
EI-HRMS: m/z [M+] calcd for C14H20O3: 236.1412; found:
236.1417.
Yield: 380 mg (84%, based on recovered starting material).
IR (film): 3392, 3058, 3033, 2953, 2874, 1716, 1601, 1490, 1450,
1449, 1360, 1314, 1275, 1223, 1178, 1154, 1113 (s), 1064, 1032
cm–1.
1H NMR (250 MHz, CDCl3): d = 1.57–1.97 (m, 3 H, H–C2, H–C6),
2.59–2.75 (m, 2 H, H–C2, H–C3), 3.02–3.42 (m, 4 H, H–C4, H–C5,
H–C7), 3.57–3.85 (m, 8 H, H–C8, 2 × OCH3), 3.86–4.09 (br s, 1 H,
OH), 5.30–5.42 (m, 1 H, H–C1), 7.20–7.36 (m, 9 H, CPh3), 7.39–
7.49 (m, 8 H, Ph, CPh3), 7.50–7.65 (m, 1 H, Ph), 7.86–8.06 (m, 2 H,
Ph).
13C NMR (63 MHz, CDCl3): d = 31.8, 32.7, 34.2, 38.5, 39.0, 52.6,
52.7, 64.4, 65.5, 70.2, 87.1, 127.4, 128.2, 128.8, 129.1, 129.9,
130.6, 133.3, 144.4, 166.2.
ESI-HRMS: m/z [M + Na]+ calcd for C36H39O7PNa: 637.2331;
found: 637.2344.
(S)-2-[(4-Methoxybenzyl)oxy]-4-methylpent-4-enal [(–)-24]
Oxalyl chloride (100 mL, 1.18 mmol) under argon in CH2Cl2 (3 mL)
was treated at –78 °C with DMSO (167 mL, 2.36 mmol). After 15
min, (+)-23 (254 mg, 1.07 mmol) in CH2Cl2 (2 mL) was added, and
the mixture was stirred for 1 h at –78 °C. Et3N (748 mL, 5.37 mmol)
was added and the mixture was warmed to 0 °C and stirred for 2 h.
Usual workup with H2O and Et2O followed by chromatography (sil-
ica gel, hexane–EtOAc, 5:1) furnished aldehyde (–)-24.
(1SR,2RS,3RS)-2-[3-(Dimethoxyphosphoryl)-2-oxopropyl]-3-
[(trityloxy)methyl]cyclobutyl Benzoate (27)
A mixture of alcohol 26 (472 mg, 0.77 mmol), NaHCO3 (291 mg,
3.47 mmol), and DMP (489 mg, 1.15 mmol) in CH2Cl2 (20 mL) was
stirred for 2 h at 25 °C. Workup as before including chromatogra-
phy (silica gel, EtOAc) furnished keto phosphonate 27.
Yield: 220 mg (88%); colorless oil; [a]D25 –44.9 (c 2.0, CHCl3).
IR (film): 3078, 2936, 2839, 1733, 1700, 1652, 1613, 1514, 1464,
1456, 1375, 1303, 1250, 1174, 1103, 1035 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.76 (s, 3 H, H–C5), 2.43 (d,
J = 6.6 Hz, 2 H, H–C3), 3.84 (s, 3 H, OCH3), 3.92 (dt, J = 6.6, 2.2
Hz, 1 H, H–C2), 4.55, 4.63 (AB, J = 11.3 Hz, 2 H, CH2C6H4CH3),
4.83 (s, 1 H, H–C6), 4.89 (s, 1 H, H–C6), 6.91, 7.30 (AA¢BB¢,
J = 8.5 Hz, 4 H, C6H4CH3), 9.65 (d, J = 2.2 Hz, 1 H, CHO).
13C NMR (63 MHz, CDCl3): d = 23.1, 38.8, 55.6, 72.6, 82.0, 114.2,
114.3, 129.7, 129.9, 140.8, 160.0, 203.6.
Yield: 370 mg (78%); colorless oil.
IR (film): 3058, 2953, 1716, 1600, 1490, 1449, 1399, 1314, 1274,
1179, 1112, 1028 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.83–1.96 (m, 1 H, H–C2), 2.59–
2.77 (m, 2 H, H–C2, H–C3), 2.87 (s, 1 H, H–C8), 2.96 (s, 1 H, H–
C8), 3.13 (dd, J = 9.6, 8.4 Hz, 1 H, H–C4), 3.26 (dd, J = 9.6, 5.4 Hz,
1 H, H–C4), 3.34–3.46 (m, 1 H, H–C7), 5.32–5.42 (m, 1 H, H–C1),
7.21–7.37 (m, 9 H, CPh3), 7.39–7.48 (m, 8 H, Ph, CPh3), 7.53–7.62
(m, 1 H, Ph), 7.83–7.89 (m, 2 H, Ph).
EI-HRMS: m/z [M+] calcd for C14H18O3: 234.1261; found:
234.1261.
13C NMR (63 MHz, CDCl3): d = 31.3, 31.9, 37.2, 39.7, 42.5, 64.3,
69.4, 88.0, 127.4, 128.2, 128.8, 129.0, 129.9, 130.5, 133.4, 144.4,
166.1, 201.9.
ESI-HRMS: m/z [M + Na]+ calcd for C36H37O7PNa: 635.2175;
found: 635.2182.
(1SR,2RS,3RS)-2-(2-Oxoethyl)-3-[(trityloxy)methyl]cyclobutyl
Benzoate (25)
A mixture of alcohol 16 (600 mg, 1.22 mmol), NaHCO3 (460 g,
5.48 mmol), and DMP (776 mg, 1.83 mmol) in CH2Cl2 (10 mL) was
stirred at 25 °C for 3 h. Usual workup and chromatography (silica
gel, hexane–EtOAc, 10:1) furnished aldehyde 25.
(1SR,2RS,3RS)-2-{(E,5S)-5-[(4-Methoxybenzyl)oxy]-7-methyl-
2-oxoocta-3,7-dienyl}-3-[(trityloxy)methyl]cyclobutyl Benzoate
(28)
Yield: 570 mg (95%); colorless oil.
IR (film): 3060, 2935, 1721, 1601, 1490, 1450, 1314, 1275, 1154,
1112, 1069, 1026 cm–1.
A 60% suspension of NaH in mineral oil (26 mg, 0.66 mmol) in
THF (6 mL) was treated dropwise at –10 °C with 27 (370 mg, 0.60
mmol) in THF (2 mL). After 10 min, aldehyde (–)-24 (155 mg, 0.66
mmol) in THF (2 mL) was added and the mixture was stirred for 2
h at 25 °C. Usual workup with H2O and Et2O including chromatog-
raphy (silica gel, hexane–EtOAc, 5:1) furnished 28 as an insepara-
ble diastereomeric mixture. The NMR data provided below are for
the major diastereomer [Rf = 0.38 (hexane–EtOAc, 5:1)].
1H NMR (250 MHz, CDCl3): d = 1.88–2.05 (m, 1 H, H–C2), 2.59
(d, J = 9.1 Hz, 2 H, H–C6), 2.64–2.78 (m, 2 H, H–C2, H–C3), 3.02–
3.17 (m, 1 H, H–C4), 3.22–3.33 (m, 1 H, H–C4), 3.37–3.57 (m, 1
H, H–C7), 5.33–5.46 (m, 1 H, H–C1), 7.21–7.37 (m, 9 H, CPh3),
7.40–7.49 (m, 8 H, Ph, CPh3), 7.54–7.63 (m, 1 H, Ph), 7.86–7.93
(m, 2 H, Ph), 9.69 (t, J = 1.4 Hz, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 31.2, 31.6, 36.7, 39.2, 64.0, 68.6,
87.2, 127.5, 128.2, 128.8, 129.0, 129.9, 130.5, 133.5, 144.3, 166.1,
201.8.
Yield: 400 mg (92%); colorless oil.
IR (film): 2934, 1718, 1684, 1654, 1560, 1512, 1448, 1274, 1148,
1068 cm–1.
ESI-HRMS: m/z [M+] calcd for C33H30O4Na: 513.2042; found:
513.2028.
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards the Total Synthesis of Providencin
3813
1H NMR (400 MHz, CDCl3): d = 1.65 (s, 3 H, H–C13), 1.84–1.93
(m, 1 H, H–C2), 2.05–2.13 (m, 1 H, H–C11), 2.25–2.34 (m, 1 H, H–
C11), 2.60–2.76 (m, 3 H, H–C2, H–C3, H–C6), 2.77–2.87 (m, 1 H,
H–C6), 3.09 (t, J = 8.9 Hz, 1 H, H–C4), 3.26 (dd, J = 9.4, 5.0 Hz, 1
H, H–C4), 3.42–3.52 (m, 1 H, H–C7), 3.80 (s, 3 H, OCH3), 3.95–
4.01 (m, 1 H, H–C10), 4.20, 4.39 (AB, J = 11.6 Hz, 2 H,
CH2C6H4CH3), 4.65 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14), 5.34–
5.40 (m, 1 H, H–C1), 6.13 (ddd, J = 16.0, 4.5, 1.1 Hz, 1 H, H–C8),
6.51 (dt, J = 16.0, 6.0 Hz, 1 H, H–C9), 6.81–6.86 (m, 2 H,
C6H4CH3), 7.13–7.18 (m, 2 H, C6H4CH3), 7.19–7.25 (m, 9 H,
CPh3), 7.33–7.39 (m, 2 H, Ph), 7.41–7.45 (m, 6 H, CPh3), 7.48–7.53
(m, 1 H, Ph), 7.78–7.83 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 23.2, 31.5, 31.6, 35.8, 37.2, 43.8,
55.7, 64.2, 69.3, 71.1, 76.9, 86.9, 113.8, 114.2, 127.4, 128.2, 128.7,
129.0, 129.7, 129.9, 130.3, 130.4, 130.6, 133.2, 141.6, 144.4, 145.8,
159.6, 166.1, 198.8.
ESI-HRMS: m/z [M + Na]+ calcd for C38H48O6Na: 743.3349; found:
743.3343.
C11), 2.28–2.43 (m, 1 H, H–C11), 2.57–2.77 (m, 2 H, H–C2, H–
C3), 2.84–3.00 (m, 1 H, H–C4), 3.17–3.39 (m, 2 H, H–C4, H–C7),
3.78–3.92 (m, 1 H, H–C10), 3.83 (s, 3 H, OCH3), 4.24, 4.46 (AB,
J = 11.6 Hz, 2 H, CH2C6H4CH3), 4.71 (s, 1 H, H–C14), 4.77 (s, 1 H,
H–C14), 5.25–5.58 (m, 4 H, H–C1, H–C5, H–C8, H–C9), 6.83–
6.91 (m, 2 H, C6H4CH3), 7.18–7.38 (m, 11 H, C6H4CH3, CPh3),
7.40–7.54 (m, 8 H, Ph, CPh3), 7.55–7.64 (m, 1 H, Ph), 7.90–7.99
(m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 21.6, 23.3, 29.5, 31.7, 32.9, 38.4,
44.4, 55.7, 64.5, 70.2, 70.3, 73.4, 77.7, 87.1, 113.2, 114.1, 127.4,
128.2, 128.8, 129.1, 129.7, 130.0, 130.6, 131.0, 131.5, 133.3, 134.0,
142.4, 144.5, 159.5, 166.3, 170.6.
ESI-HRMS: m/z [M + Na]+ calcd for C50H52O7Na: 787.3611; found:
787.3626.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-(hydroxymethyl)cyclobutyl Ben-
zoate (31)
Trityl ether 30 (72 mg, 0.094 mmol) in MeOH (2 mL) was detrity-
lated with TsOH (4 mg, 0.019 mmol) for 2 h at 25 °C. Workup as
described for 22 followed by chromatography (silica gel, hexane–
EtOAc, 1:2) gave 31 as an inseparable diastereomeric mixture. The
NMR data provided below are for the major diastereomer [Rf = 0.45
(hexane–EtOAc, 1:2)].
(1SR,2RS,3RS)-2-{(E,5S)-2-Hydroxy-5-[(4-methoxyben-
zyl)oxy]-7-methylocta-3,7-dienyl}-3-[(trityloxy)methyl]cyclo-
butyl Benzoate (29)
Ketone 28 (91 mg, 0.13 mmol) and CeCl3·H2O (48 mg, 0.13 mmol)
were stirred for 30 min in MeOH (4 mL) at –78 °C. NaBH4 (6 mg,
0.14 mmol) was added and the mixture was stirred for 3 h at –78 °C.
Usual workup with NH4Cl, H2O, and Et2O followed by chromatog-
raphy (silica gel, hexane–EtOAc, 1:1) gave 29 as an inseparable
diastereomeric mixture. The NMR data provided below are for the
major diastereomer [Rf = 0.38 (hexane–EtOAc, 1:1)].
Yield: 40 mg (81%); colorless oil.
IR (film): 3467, 2935, 2870, 1718, 1612, 1513, 1452, 1371 (m),
1275, 1248, 1175, 1111, 1071, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.70 (s, 3 H, H–C13), 1.86–2.03
(m, 3 H, H–C2, H–C6), 2.02 (s, 3 H, CH3CO), 2.11–2.27 (m, 1 H,
H–C11), 2.33–2.68 (m, 3 H, H–C2, H–C3, H–C11), 2.81–2.96 (m,
1 H, H–C7), 3.70–3.99 (m, 3 H, H–C4, H–C10), 3.82 (s, 3 H,
OCH3), 4.31, 4.49 (AB, J = 11.4 Hz, 2 H, CH2C6H4CH3), 4.72 (s, 1
H, H–C14), 4.78 (s, 1 H, H–C14), 5.28–5.40 (m, 1 H, H–C1), 5.41–
5.53 (m, 1 H, H–C5), 5.59–5.68 (m, 2 H, H–C8, H–C9), 6.83–6.92
(m, 2 H, C6H4CH3), 7.20–7.31 (m, 2 H, C6H4CH3), 7.42–7.52 (m, 2
H, Ph), 7.55–7.65 (m, 1 H, Ph), 8.02–8.13 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 21.6, 23.3, 29.7, 31.3, 34.3, 38.4,
44.4, 55.7, 63.5, 69.0, 70.4, 73.2, 77.7, 113.3, 114.2, 126.9, 128.8,
129.7, 130.0, 130.5, 131.2, 133.5, 134.0, 142.4, 159.5, 170.9.
ESI-HRMS: m/z [M + Na]+ calcd for C31H38O7Na: 545.2515; found:
545.2498.
Yield: 73 mg (78%); colorless oil.
IR (film): 3468, 3061, 2934, 2862, 1717, 1612, 1514, 1490, 1450,
1368, 1314, 1276, 1249, 1174, 1111, 1069, 1033 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.58–1.76 (m, 2 H, H–C6, OH),
1.70 (s, 3 H, H–C13), 1.76–1.96 (m, 2 H, H–C2, H–C6), 2.11–2.24
(m, 1 H, H–C11), 2.29–2.45 (m, 1 H, H–C11), 2.59–2.78 (m, 2 H,
H–C2, H–C3), 2.98–3.14 (m, 1 H, H–C4), 3.17–3.30 (m, 1 H, H–
C4), 3.31–3.41 (m, 1 H, H–C7), 3.82 (s, 3 H, OCH3), 3.84–3.95 (m,
1 H, H–C10), 4.06–4.21 (m, 1 H, H–C5), 4.31, 4.50 (AB, J = 11.4
Hz, 2 H, CH2C6H4CH3), 4.73 (s, 1 H, H–C14), 4.78 (s, 1 H, H–C14),
5.29–5.65 (m, 3 H, H–C1, H–C8, H–C9), 6.83–6.93 (m, 2 H,
C6H4CH3), 7.17–7.38 (m, 11 H, C6H4CH3, CPh3), 7.39–7.53 (m, 8
H, Ph, CPh3), 7.54–7.64 (m, 1 H, Ph), 7.87–7.97 (m, 2 H, Ph).
13C NMR (63 MHz, CDCl3): d = 23.3, 31.8, 32.0, 32.8, 38.5, 44.6,
55.7, 64.6, 70.2, 70.4, 71.3, 78.0, 87.2, 113.1, 114.1, 127.4, 128.2,
128.8, 129.0, 129.7, 129.9, 130.6, 131.2, 131.8, 133.4, 136.1, 142.5,
144.4, 159.5, 166.3.
ESI-HRMS: m/z [M + Na]+ calcd for C48H50O6Na: 745.3505; found:
745.3489.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-formylcyclobutyl Benzoate (32)
Alcohol 31 (14 mg, 0.027 mmol) was oxidized with NaHCO3 (10
mg, 0.122 mmol) and DMP (17 mg, 0.040 mmol) in CH2Cl2 (1 mL)
as described above for the synthesis of 17 from 15. Purification by
chromatography (silica gel, hexane–EtOAc, 2:1) gave aldehyde 32.
Yield: 12 mg (85%); colorless oil.
(1SR,2RS,3RS)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-[(trityloxy)methyl]cyclobutyl Ben-
zoate (30)
IR (film): 2930, 2855, 1717, 1649, 1611, 1512, 1451, 1375, 1315,
1277, 1246, 1178, 1118, 1072, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.66 (s, 3 H, H–C13), 1.88–1.99
(m, 2 H, H–C6), 2.04 (s, 3 H, CH3CO), 2.15 (dd, J = 13.9, 6.4 Hz,
1 H, H–C11), 2.36 (dd, J = 13.9, 7.3 Hz, 1 H, H–C11), 2.46–2.68
(m, 2 H, H–C2), 3.05–3.31 (m, 2 H, H–C3, H–C7), 3.79 (s, 3 H,
OCH3), 3.82–3.93 (m, 1 H, H–C10), 4.27, 4.45 (AB, J = 11.5 Hz, 2
H, CH2C6H4CH3), 4.69 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14),
5.21–5.32 (m, 1 H, H–C1), 5.33–5.44 (m, 1 H, H–C5), 5.53–5.59
(m, 2 H, H–C8, H–C9), 6.84, 7.20 (AA¢BB¢, J = 8.5 Hz, 4 H,
C6H4CH3), 7.40–7.50 (m, 2 H, Ph), 7.53–7.63 (m, 1 H, Ph), 8.00–
8.09 (m, 2 H, Ph), 9.99 (s, 1 H, CHO).
Alcohol 29 (82 mg, 0.11 mmol) in CH2Cl2 (5 mL) was treated with
Ac2O (32 mL, 0.34 mmol), Et3N (63 mL, 0.45 mmol), and DMAP (3
mg, 0.02 mmol) for 2 h at 25 °C. Usual workup and chromatogra-
phy (silica gel, hexane–EtOAc, 5:1) gave 30 as an inseparable dia-
stereomeric mixture. The NMR data provided below are for the
major diastereomer [Rf = 0.32 (hexane–EtOAc, 5:1)].
Yield: 84 mg (97%); colorless oil.
IR (film): 3061, 2934, 1737, 1717, 1612, 1514, 1490, 1450, 1370,
1314, 1274, 1247, 1174, 1155, 1111, 1069, 1027 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.66–1.96 (m, 3 H, H–C2, H–C6),
1.69 (s, 3 H, H–C13), 2.02 (s, 3 H, CH3CO), 2.07–2.21 (m, 1 H, H–
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York

3814
E. Schweizer et al.
PAPER
13C NMR (63 MHz, CDCl3): d = 21.6, 23.3, 28.1, 30.1, 41.1, 43.3,
44.4, 55.7, 68.5, 70.4, 72.6, 77.7, 113.3, 114.2, 128.9, 129.7, 130.0,
130.5, 130.9, 133.7, 134.1, 142.3, 202.1.
ESI-HRMS: m/z [M + Na]+ calcd for C35H42O9Na: 629.2727; found:
629.2723.
ESI-MS: m/z [M + Na]+ calcd for C31H36O7Na: 543.2359; found:
543.2361.
Acknowledgment
We thank Susanne Felsinger and Hanspeter Kählig for NMR analy-
sis. E.S. gratefully acknowledges a postdoctoral fellowship from the
Swiss National Science Foundation (Schweizerischer National-
fonds, SNF).
(1SR,2RS,3SR)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-formylcyclobutyl Benzoate (33)
Aldehyde 32 (160 mg, 0.31 mmol) in CH2Cl2 (3 mL) was stirred
with 0.1 M K2CO3 in MeOH–H2O (10:1, 5 mL) for 15 min at 25 °C.
Usual workup followed by chromatography (silica gel, hexane–
EtOAc, 5:1) gave aldehyde 33 as an inseparable diastereomeric
mixture. The NMR data provided below are for the major diastereo-
mer [Rf = 0.33 (hexane–EtOAc, 5:1)].
References
(1) For recent reviews, see: (a) Keay, B. A.; Dibble, P. W. In
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1997, 395. (b) Hou, X.-L.; Yang, Z.;
Wong, H. N. C. In Progress in Heterocyclic Chemistry, Vol.
15; Gribble, G. W.; Joule, J. A., Eds.; Pergamon: Oxford,
2003, 167. (c) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong,
H. N. C. In Progress in Heterocyclic Chemistry, Vol. 17;
Gribble, G. W.; Joule, J. A., Eds.; Pergamon: Oxford, 2005,
142.
(2) For recent reviews, see: (a) Lipshutz, B. H. Chem. Rev.
1986, 86, 795. (b) Cacchi, S. J. Organomet. Chem. 1999,
576, 42. (c) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209.
(d) Wong, H. N. C.; Yu, P.; Yick, C.-Y. Pure Appl. Chem.
1999, 71, 1041. (e) Brown, R. C. D. Angew. Chem. Int. Ed.
2005, 44, 850; Angew. Chem. 2005, 117, 872. (f) Lee, H.-
K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.; Wong,
H. N. C. Pure Appl. Chem. 2005, 77, 139. (g) Wright, D. L.
In Progress in Heterocyclic Chemistry, Vol. 17; Gribble, G.
W.; Joule, J. A., Eds.; Pergamon: Oxford, 2005, 1.
(h) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. For
recent furan syntheses, see, for example: (i) Pridmore, S. J.;
Slatford, P. A.; Williams, J. M. Tetrahedron Lett. 2007, 48,
5111. (j) Peng, L.; Zhang, X.; Ma, W.; Wang, J. Angew.
Chem. Int. Ed. 2007, 46, 1905; Angew. Chem. 2007, 119,
1937.
(3) (a) Fenical, W.; Okuda, R. K.; Bandurraga, M. M.; Culver,
P.; Jacobs, R. S. Science 1981, 212, 1512. (b) Fenical, W. J.
Nat. Prod. 1987, 50, 1001. (c) Wright, A. E.; Burres, N. S.;
Schulte, G. K. Tetrahedron Lett. 1989, 30, 3491.
(d) Abramson, S. N.; Trischman, J. A.; Tapiolas, D. M.;
Harold, E. E.; Fenical, W.; Taylor, P. J. Med. Chem. 1991,
34, 1798. (e) Gutiérrez, M.; Capson, T. L.; Guzmán, H. M.;
González, J.; Ortega-Barría, E.; Quiñoá, E.; Riguera, R. J.
Nat. Prod. 2005, 68, 614.
(4) (a) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J. Am.
Chem. Soc. 1992, 114, 3910. (b) Marshall, J. A.; Van
Devender, E. A. J. Org. Chem. 2001, 66, 8037. (c) Wipf,
P.; Soth, M. J. Org. Lett. 2002, 4, 1787. (d) Cases, M.;
Gonzalez-Lopez de Turiso, F.; Hadjisoteriou, M. S.;
Pattenden, G. Org. Biomol. Chem. 2005, 3, 2786.
(5) This expression is coined after the ‘furan last’ approach
described by: Marshall, J. A.; DuBay, W. J. J. Org. Chem.
1994, 59, 1703.
Yield: 106 mg (66%); colorless oil.
IR (film): 2995, 2976, 2938, 1769, 1757, 1720, 1612, 1513, 1452,
1375, 1247, 1112, 1057 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.67 (s, 3 H, H–C13), 1.91–2.08
(m, 2 H, H–C6), 2.04 (s, 3 H, CH3CO), 2.09–2.22 (m, 1 H, H–C11),
2.30–2.42 (m, 2 H, H–C2, H–C11), 2.65–2.81 (m, 1 H, H–C2),
2.97–3.26 (m, 2 H, H–C3, H–C7), 3.79 (s, 3 H, OCH3), 3.83–3.96
(m, 1 H, H–C10), 4.28, 4.47 (AB, J = 11.6 Hz, 2 H, CH2C6H4CH3),
4.69 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14), 5.24–5.44 (m, 2 H, H–
C1, H–C5), 5.57–5.62 (m, 2 H, H–C8, H–C9), 6.85, 7.21 (AA¢BB¢,
J = 8.5 Hz, 4 H, C6H4CH3), 7.42–7.51 (m, 2 H, Ph), 7.54–7.64 (m,
1 H, Ph), 8.01–8.09 (m, 2 H, Ph), 9.79 (d, J = 1.7 Hz, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 21.5, 23.3, 28.4, 33.7, 37.8, 44.4,
47.7, 55.7, 69.6, 70.5, 71.9, 77.7, 113.4, 114.1, 128.9, 129.7, 130.0,
130.5, 130.6, 130.9, 133.8, 134.1, 142.3, 159.5, 166.3, 170.5, 203.0.
ESI-MS: m/z [M + Na]+ calcd for C31H36O7Na: 543.2359; found:
543.2358.
(1SR,2RS,3SR)-2-{(E,5S)-2-Acetoxy-5-[(4-methoxybenzyl)oxy]-
7-methylocta-3,7-dienyl}-3-(3-ethoxy-3-oxopropanoyl)cyclobu-
tyl Benzoate (34)
A mixture of SnCl2 (8 mg, 0.04 mmol), N2CHCO2Et (25 mL, 0.24
mmol), and aldehyde 33 (106 mg, 0.20 mmol) in CH2Cl2 (8 mL)
was treated as described for 5 (in the preparation of 18). Chroma-
tography (silica gel, hexane–EtOAc, 2:1) gave 34 as an inseparable
diastereomeric mixture. The NMR data provided below are for the
major diastereomer [Rf = 0.29 (hexane–EtOAc, 2:1)].
Yield: 96 mg (79%); colorless oil.
IR (film): 2976, 2938, 2862, 2839, 1740, 1717, 1650, 1611, 1512,
1451, 1368, 1315, 1277, 1239, 1178, 1110, 1072, 1034 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.67 (s, 3 H, H–C13), 1.80–1.96 (m, 1 H, H–C6), 2.04 (s, 3 H,
CH3CO), 2.06–2.20 (m, 2 H, H–C6, H–C11), 2.31–2.46 (m, 2 H, H–
C2, H–C11), 2.58–2.69 (m, 1 H, H–C2), 2.91–3.14 (m, 1 H, H–C7),
3.30–3.42 (m, 1 H, H–C3), 3.43, 3.48 (AB, J = 15.4 Hz, 2 H, H–
C15), 3.79 (s, 3 H, OCH3), 3.85–3.92 (m, 1 H, H–C10), 4.20 (q,
J = 7.2 Hz, 2 H, CH2CH3), 4.27, 4.47 (AB, J = 11.6 Hz, 2 H,
CH2C6H4CH3), 4.69 (s, 1 H, H–C14), 4.75 (s, 1 H, H–C14), 5.25–
5.41 (m, 2 H, H–C1, H–C5), 5.56–5.63 (m, 2 H, H–C8, H–C9),
6.84, 7.21 (AA¢BB¢, J = 8.0 Hz, 4 H, C6H4CH3), 7.42–7.49 (m, 2 H,
Ph), 7.55–7.62 (m, 1 H, Ph), 8.01–8.10 (m, 2 H, Ph).
(6) Marrero, J.; Rodríguez, A. D.; Baran, P.; Raptis, R. G. Org.
Lett. 2003, 5, 2551.
(7) Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 3937.
(8) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258.
(9) Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.;
Kaehlig, H.; Öhler, E.; Mulzer, J. J. Org. Chem. 2003, 68,
3026.
13C NMR (100 MHz, CDCl3): d = 21.5, 23.2, 31.3, 33.7, 38.8, 44.3,
47.4, 48.4, 55.7, 61.9, 69.4, 70.4, 71.9, 77.7, 113.3, 114.1, 128.9,
129.7, 130.0, 130.3, 130.6, 130.9, 133.6, 134.5, 142.3, 159.5, 166.3,
167.4, 170.5, 203.0.
Synthesis 2007, No. 24, 3807–3814 © Thieme Stuttgart · New York