Synthesis of 2,3-dihydroxyhex-4-enoates by palladium-catalyzed allylic alkylations of carbohydrate derived vinyl lactones

Article abstract of DOI:10.1055/s-0028-1083203

D-Gulonic lactone or its L-isomer is easily converted to the vinyl lactone 1 via three convenient reactions in an overall 69% yield. Reaction of the D isomer of 1 with a variety of carbon, oxygen, sulfur, and nitrogen nucleophiles and a palladium catalyst produced carboxylic acids that were esterified with methyl iodide to give the esters 2. Alternatively, reaction of L-lactone 1 with Ph₃P=CHCO₂Et provided the Wittig product that underwent palladium-catalyzed rearrangement to give the cyclopentanone 3. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083203

3682
PAPER
Synthesis of 2,3-Dihydroxyhex-4-enoates by Palladium-Catalyzed Allylic
Alkylations of Carbohydrate Derived Vinyl Lactones
P
alladium
a
Chemistry
m
of Carbohydrate
V
i
i
nyl
L
ac
e
tones Singleton, Krishna Sahteli, John O. Hoberg*
Department of Chemistry, University of Wyoming, 1000 East University Ave., Laramie, WY 82071, USA
Fax +1(307)7662807; E-mail: hoberg@uwyo.edu
Received 1 July 2008; revised 12 August 2008
romethane can be omitted and replaced by precipitation
with water to give the diacetonide as a white solid. The
subsequent C5–C6 deprotection to give 4 has also been
greatly enhanced from initial reports of 59–79%, with one
Abstract: D-Gulonic lactone or its L-isomer is easily converted to
the vinyl lactone 1 via three convenient reactions in an overall 69%
yield. Reaction of the D isomer of 1 with a variety of carbon, oxy-
gen, sulfur, and nitrogen nucleophiles and a palladium catalyst pro-
duced carboxylic acids that were esterified with methyl iodide to such report using chloroform–methanol12 mixtures as sol-
give the esters 2. Alternatively, reaction of L-lactone 1 with
Ph3P=CHCO2Et provided the Wittig product that underwent palla-
dium-catalyzed rearrangement to give the cyclopentanone 3.
vents for flash chromatography. Rather, the use of a 95%
solution of acetic acid with several days of stirring fol-
lowed by azeotropic removal of the acetic acid with tolu-
ene provides 4 as a highly pure solid. Finally, we were
unable to reproduce the synthesis of 1 from 4 as reported
by Chakravarthy.13 Additionally, the authors report 1 as
an oil, when in fact it exists as a solid. Thus, we have mod-
ified this reaction to produce 1 in good yield. However,
this reaction is fraught with purification difficulties as the
by-products are difficult to remove and hence greatly
hinder acquiring pure solid 1. Thus, Soxhlet extraction
with hexanes was used on the crude mixture prior to flash
chromatography to obtain pure material. In light of the
ease and scalability of the first two steps and the removal
of any column chromatography in their purification, im-
provements to the final step would be desirable and are
being addressed. However, this overall sequence current-
ly enables the construction of 1 on the multi-gram scale.
Key words: gulonic lactone, rearrangement, p-allyl, allylic alkyla-
tion, palladium
A common motif found in a variety of natural products
consists of an acid derivative with either a 2,3-dihydroxy,
2,3-diether, or hydoxyl ether moiety. Examples of this in-
clude peloruside A,1 mycalamide A,2 onnamide A,3 theo-
pederin,4 pederin,5 and the enterocins.6 These natural
products have displayed potent biological activity in a va-
riety of cell lines and have therefore become targets for to-
tal synthesis. In view of their activity, the diverse
stereochemical nature of this motif, and the interest by the
synthetic community, a general synthetic route for the
construction of this fragment would be desirable. We en-
visioned that such a route was available via functionalized
vinyl lactones, such as 1, and transition metal catalyzed
allylic alkylations. Ample precedence exists for the con-
version of 1 to 2 dating back to an initial report by Trost,7
and more recently by others.8–10 The required lactones,
such as the gulonic lactone enantiomers used in this work,
are obtainable from commercially available carbohydrate
lactones as four isomers (Figure 1) or can easily be syn-
thesized in one step when cost and/or availability becomes
an issue. These gulono- and galactono-lactones are ame-
nable to two- or three-step protection/deprotection strate-
gies, making the total synthetic sequence presented herein
highly efficient and practical.
O
O
OH
OH
OH OH
OH
OH OH
O
O
OH
D-gulono-1,4-lactone
L-gulono-1,4-lactone
HO
OH
O
OH
OH
O
O
O
OH
OH
HO
OH
D-galactono-1,4-lactone
L-galactono-1,4-lactone
Figure 1 Commercially available carbohydrate lactones
Synthesis of diol 411,12 and the required lactone 113 have
been described in various reports, however improved
yields and more environmentally benign conditions can
be obtained with slight modifications (Scheme 1). The
yield of the initial diacetonation of the 2,3- and 5,6-diol
groups of gulono lactone can be improved from 79 to 87%
by simply stirring for 3 days versus overnight. Further-
more, extraction of the reaction mixture with dichlo-
HO
H
O
O
O
O
O
O
iii
i, ii
HO
OH OH
OH
H
5
O
O
O
O
6
HO
D-gulono-1,4-lactone
4
1
Scheme 1 Reagents and conditions: (i) (MeO)2CMe2, acetone,
p-TsOH, MeCN–DMF 10:1, r.t., 87%; (ii) 95% aq AcOH, r.t., 95%;
(iii) Ph3P, imidazole, I2, toluene, MeCN, 83%.
SYNTHESIS 2008, No. 22, pp 3682–3686
Advanced online publication: 23.10.2008
x
x.
x
x
.
2
0
0
8
DOI: 10.1055/s-0028-1083203; Art ID: M03408SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Palladium Chemistry of Carbohydrate Vinyl Lactones
3683
Table 1 Reaction of Vinyl Lactone 1 with Nucleophiles
With vinyl lactone 1 in hand, the reaction with dimethyl
malonate anion and various catalysts were studied. Of the
catalysts used, Pd(PPh3)4, Pd2(dba)3, and [C3H5PdCl]2 at 2
mol% loadings, only the allylpalladium dimer produced
unacceptable results. Purification of the resulting acid was
generally problematic and usually required highly polar
solvents for chromatography that resulted in impure prod-
ucts. This issue was resolved by filtration of the acid prod-
uct through silica gel and then esterification with MeI to
give the methyl ester. Reactions with a variety of nucleo-
philes were next undertaken to test the generality of this
sequence (Table 1). As expected, the reaction of vinyl lac-
tone 1 with a range of carbon, oxygen, sulfur, and nitrogen
nucleophiles is very general (entries 1, 5, 7, and 8 as ex-
amples). In all cases, mild conditions and good overall
yields were observed. Reaction times of the initial alkyla-
tion reaction are especially convenient with entry 4 being
the only outlier.
H
O
Nuc
O
CO2Me
1. Nuc, PdLn
2. MeI, K2CO3
O
O
O
O
2
1
Entrya
Nucleophile
Time
15 min
15 min
3 h
Yield (%) of 2b
75 (2a)c
67 (2b)
1
2
3
4
5
6
7
8
NaCH(CO2Et)2
NaCH(CO2Me)2
NaCMe(CO2Et)2
NaCH(CO2Me)SO2Ph
NaOCH2C6H5
NaOCH2C6H4OMe
NaTs
67 (2c)d
55 (2d)
48 h
4 h
76 (2e)
2 h
57 (2f)
4 h
66 (2g)
Given the propensity for this system towards palladium
allylic alkylations, we suspected that other metal-cata-
lyzed reactions leading to cyclopentyl systems could be
used with it. In 1981, Trost reported on the rearrangement
of 5-vinyl-2-alkylidenetetrahydrofurans (Scheme 2).14,15
In this report, alkylidene 5 was constructed in nine steps
and a series of rearrangements products were reported.
These products included pentanone 6, the decarboxylation
product of 6 (loss of CO2t-Bu), and a cycloheptene struc-
ture, in which the isolated yields and product distribution
were modest to good. Furthermore, Gree16 recently pub-
lished the synthesis of cyclopentenones from vinylic fura-
noses using Fe(CO)5 and light. In view of these, we felt
that a more facile and synthetically shorter entry into the
Trost system and an expansion of Gree’s chemistry to
multiple isomers would be readily available from vinyl
lactone 1 and its isomers.
NaN3
1 h
63 (2h)
a Step 1 performed with 2 mol% Pd(PPh3)4 and 3 mol% PPh3 in THF
at r.t. for the time indicated in Table 1. Esterification reactions per-
formed in acetone with MeI and K2CO3.
b Yields reported for combined two steps.
c A 25:1 ratio of E/Z isomers was obtained.
d A 2 h reflux period was required for completion of step 1.
to 0 °C, rather, the starting material was recovered un-
changed. We have not yet used 9 in the chemistry reported
by Gree, although it is simply a diastereomer of that re-
ported; however, heating of 8 at 90 °C in DMSO with a
variety of palladium catalysts and ligands does result in
the formation of cyclopentanone 3. Although cyclopen-
tanone formation was observed, low yields (40–50%) and
a difficult purification plagued this reaction making it syn-
thetically unusable in our opinion. Thus, further studies on
this rearrangement are currently required and are being
pursued.
In conclusion, D-gulonic lactone and its enantiomer19 are
easily converted to vinyl lactones 1 and 7, respectively.
These have been shown to be useful intermediates in pal-
ladium-catalyzed allylic alkylation reactions. Additional-
ly, any of the four isomers of the esters 2 can be obtained
by simply choosing the appropriate starting lactone shown
in Figure 1. As the protection schemes of the galactono
lactones are established, entry into a myriad of isomeric
esters and cyclopentyl systems using the isomers of 8 and
9 are potentially available.
In the synthesis of 5, it was reported that all attempts at its
formation from a lactone using Wittig or Emmons–
Wadsworth–Horner reagents failed. However, since then
reports on the Wittig reaction of lactones have appeared.17
Given that Ph3P=CHCO2Et18 is a stable, easily formed
Wittig reagent that has been used in the reaction with lac-
tones, its use appeared to be ideal. Gratifyingly, reaction
of 7, the enantiomer of 1, with Ph3P=CHCO2Et in a sealed
tube gave an excellent yield of 8 as a 1:1 mixture of E/Z
isomers (Scheme 3). Additionally, reduction of 7 gave vi-
nyl lactol 9 in again excellent yield. It should also be noted
that the use of DIBAL-H in the reduction of 7 did not pro-
duce the desired lactol at temperatures ranging from –78
CO2t-Bu
CO2t-Bu
H
H
CO2t-Bu
O
O–
O
PdLn
+
LnPd
100 °C
O
O
O
O
O
O
5
6
Scheme 2
Synthesis 2008, No. 22, 3682–3686 © Thieme Stuttgart · New York

3684
J. Singleton et al.
PAPER
CO2Et
O
O
O
OH
O
H
H
H
NaBH4
Ph3P=CHCO2Et
O
O
O
O
O
O
MeCN–MeOH
85%
toluene, 144 °C
86%
9
7
8
Pd cat.
DMSO
90 °C
H
O
O
O
3
Scheme 3
1H and 13C NMR spectra were recorded at 400 and 100 MHz, re-
spectively, in the indicated solvent. Chemical shifts are reported in
d units, parts per million (ppm) relative to CDCl3 (7.27 ppm for 1H
NMR and 77.0 ppm for 13C NMR). THF was distilled from NaK and
acetone was distilled from anhyd CaSO4. Toluene and MeCN were
distilled from CaH2. NaH was washed with hexane before use and
dried. Flash chromatography was performed using Silicycle ultra
pure silica gel 60 Å (230–400 mesh). All the TLC analyses were
performed on Merck Silica gel 60 F precoated plates for TLC (layer
thickness 250 mm). Standard syringe techniques were employed for
handling air-sensitive reagents, glassware for experiments requiring
anhydrous conditions were flame dried, and all reactions were car-
ried out under argon.
D or l-2,3-O-Isopropylidene-5-vinylgulonolactone (1 or 7)
PPh3 (2.00 g, 27.5 mmol) was added to a solution of I2 (6.98 g, 27.5
mmol) in toluene (30 mL)–MeCN (15 mL) and the mixture stirred
for 0.5 h at 60 °C. Imidazole (1.87 g, 27.5 mmol) was added in one
portion and the mixture boiled for 0.5 h. The mixture was cooled to
r.t. and solid 2,3-O-isopropylidenegulonolactone (2.00 g, 9.17
mmol) was added and stirred at 50 °C for 8 h. After cooling to r.t.,
the volume was reduced and the resulting solid was dissolved in
CH2Cl2 (20 mL). The organic layer was washed with aq sat.
NaHCO3 (100 mL), dried (Na2SO4), filtered, and concentrated. The
solid was loaded into a glass Soxhlet thimble and extracted, using a
500 mL Soxhlet extractor, with hexane (500 mL) until ca. 40–42
turns were achieved; usually about 10–12 h. Concentration and gra-
dient flash chromatography with cyclohexane–EtOAc (10:1, 5:1,
then elution with 2:1) gave 1.40 g (83%) of a white solid; mp 97–
99 °C.
2,3,5,6-Di-O-isopropylidenegulonolactone
MeCN–DMF (22.0 mL of a 10:1 ratio) was added to either D- or L-
gulono-1,4-lactone (6.00 g, 33.7 mmol), followed by acetone (40.0
mL), 2,2-dimethoxypropane (25.0 mL), and PTSA (320 mg, 5
mol%). The mixture was stirred at r.t. for 3 days and then concen-
trated (40 °C rotovap bath temperature) to a thick, cloudy syrup.
H2O (40 mL) was added to the syrup producing a white solid that
was stirred for 20 min at r.t. The mixture was cooled for 1 h by plac-
ing in a refrigerator (~5 °C), filtered, washed with cold H2O (10
mL), and dried under vacuum to give 7.57 g (87%) of a white solid
that needed no further purification; mp 150–152 °C.
1H NMR (CDCl3): d = 4.85 (d, J = 5.6 Hz, 1 H), 4.75 (dd, J = 3.4,
5.6 Hz, 1 H), 4.45 (m, 2 H), 4.24 (m, 1 H), 3.82 (m, 1 H), 1.50 (s, 3
H), 1.48 (s, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H).
13C NMR (CDCl3): d = 173.3, 114.7, 110.5, 80.9, 76.0, 75.7, 75.2,
65.1, 26.5, 25.7, 25.0.
IR (neat): 2990, 2930, 1770, 1325 cm–1.
1H NMR (CDCl3): d = 5.99 (ddd, J = 17.0, 10.4, 7.3 Hz, 1 H), 5.53
(dd, J = 16.9, 0.9 Hz, 1 H), 5.47 (dd, J = 10.5, 0.9 Hz, 1 H), 4.91
(ddd, J = 7.3, 2.3, 0.9 Hz, 1 H), 4.84 (d, J = 5.3 Hz, 1 H), 4.80 (dd,
J = 5.2, 2.3 Hz, 1 H), 1.48 (s, 3 H), 1.40 (s, 3 H).
13C NMR (CDCl3): d = 173.9, 130.2, 121.2, 114.4, 80.2, 77.9, 76.3,
26.9, 26.0.
HRMS: m/z calcd for C9H12O4: 184.0736; found: 184.0731.
Esters 2a–h; Diethyl 2-{(E)-3-[(4R,5R)-5-(Methoxycarbonyl)-
2,2-dimethyl-1,3-dioxolan-4-yl]prop-2-enyl}malonate (2a);
Typical Procedure
Lactone 1 (100.0 mg, 0.540 mmol), Ph3P (4 mg, 0.01 mmol), and
Pd(PPh3)4 (12 mg, 0.01 mmol) were stirred in THF (5 mL) at r.t. for
20 min. In a separate flask, a solution of diethyl malonate (206 mL,
1.36 mmol) in THF (1 mL) was slowly added to a slurry of hexane-
washed NaH (32 mg, 1.33 mmol) in THF (4 mL) and stirred for 30
min (1 h stirring in the case of p-methoxybenzyl alcohol). The re-
sulting clear solution was added in one portion to the former and the
combined mixture was stirred at r.t. for 15 min. The mixture was
cooled to 0 °C and acidified with 5% aq HCl. The yellow mixture
was partitioned between CH2Cl2 (20 mL) and H2O (20 mL), the
aqueous phase was extracted with CH2Cl2 (3 × 30 mL), and the
CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo.
Gradient flash chromatography/filtration using a plug of silica gel
with cyclohexane–EtOAc (3:1), then cyclohexane–EtOAc–AcOH
(2:1:0.1) gave the carboxylic acid (150 mg) as an oil. Indicative res-
onances in the in the IR included, (neat): 3510 1725, 1710 cm–1 and
in 1H NMR (CDCl3): d = 10.30 (br s, 1 H). To a solution of the acid
D or l-2,3-O-Isopropylidenegulonolactone (4)
2,3,5,6-Di-O-isopropylidenegulonolactone (3.30 g, 12.8 mmol)
was added to 95% aq AcOH (40 mL) and stirred at r.t. for 3 d. Tol-
uene (30 mL) was added to the mixture and the volume concentrat-
ed at a bath temperature of 46 °C. Additional toluene was added 2–
3 times until the majority of the AcOH was removed from the crude
material. The resulting solid was placed under vacuum (0.001
mmHg at 45 °C for 8 h) to yield 2.65 g (95%) of a white solid; mp
100–102 °C.
1H NMR (D2O): d = 5.14 (d, J = 5.3 Hz, 1 H), 5.04 (dd, J = 5.3, 3.5
Hz, 1 H), 4.68 (dd, J = 8.4, 3.5 Hz, 1 H), 4.07 (m, 1 H), 3.79 (dd,
J = 12.2, 3.3 Hz, 1 H), 3.71 (dd, J = 12.2, 5.4 Hz, 1 H), 1.34 (s, 3 H),
1.30 (s, 3 H).
13C NMR: see reference 13.
Synthesis 2008, No. 22, 3682–3686 © Thieme Stuttgart · New York

PAPER
Palladium Chemistry of Carbohydrate Vinyl Lactones
3685
(150 mg) in acetone (6 mL) at r.t. was added anhyd Na2CO3 (120
mg, 0.84 mmol) and MeI (390 mL, 6.3 mmol). The mixture was
stirred at r.t. for 4 h, then cooled to 0 °C and acidified with dilute
HCl. The mixture was partitioned between CH2Cl2 (20 mL) and
H2O (20 mL), the aqueous phase was extracted with CH2Cl2 (2 × 20
mL), and the CH2Cl2 extracts were dried (Na2SO4), and concentrat-
ed in vacuo. Gradient flash chromatography with cyclohexane–
EtOAc (5:1 to 2:1) gave 2a (144.3 mg, 75% overall yield) as an oil.
1H NMR (CDCl3): d = 7.35 (m, 5 H), 5.98 (dtd, J = 15.2, 5.4, 1.0
Hz, 1 H), 5.66 (ddt, J = 15.5, 7.3, 1.5 Hz, 1 H), 4.86 (t, J = 7.2 Hz,
1 H), 4.69 (d, J = 7.1 Hz, 1 H), 4.5 (s, 2 H), 4.03 (d, J = 5.3, 2 H),
3.70 (s, 3 H), 1.6 (s, 3 H), 1.40 (s, 3 H).
13C NMR (CDCl3): d = 169.9, 138.1, 132.0, 128.3, 127.7, 127.5,
126.1, 111.1, 77.9, 77.7, 72.0, 69.4, 51.8, 26.9, 25.5.
HRMS: m/z calcd for C17H22O5: 306.1467; found: 306.1461.
IR (neat): 2990, 2940, 1725 cm–1.
2f
1H NMR (CDCl3): d = 5.81 (dtd, J = 14.0, 6.9, 0.7 Hz, 1 H), 5.43
(ddt, J = 14.6, 7.6, 1.3 Hz, 1 H), 4.74 (dd, J = 7.5, 2.2 Hz, 1 H), 4.62
(d, J = 7.1 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 4 H) 3.35 (t, J = 7.5 Hz, 1
H), 2.64 (ddd, J = 7.4, 7.2, 1.3 Hz, 2 H), 1.6 (s, 3 H), 1.35 (s, 3 H),
1.25 (t, J = 7.1 Hz, 6 H).
13C NMR (CDCl3): d = 169.7, 168.9, 131.5, 127.1, 111.0, 78.1, 77.5,
52.6, 52.5, 51.8, 51.0, 31.0, 26.9, 25.5.
Gradient flash chromatography with cyclohexane–EtOAc (5:1 to
2:1) gave 2f as an oil.
IR (neat):2995, 2940, 2850, 1750 cm–1.
1H NMR (CDCl3): d = 7.17 (m, 2 H), 7.68 (m, 2 H), 5.89 (dt,
J = 15.5, 5.7 Hz, 1 H), 5.56 (ddt, J = 15.5, 7.3, 1.5 Hz, 1 H), 4.77
(dd, J = 7.2, 7.2 Hz, 1 H), 4.61 (d, J = 7.1 Hz, 1 H), 4.34 (s, 2 H),
3.92 (d, J = 5.4 Hz, 2 H), 3.72 (s, 3 H), 3.6 (s, 3 H), 1.6 (s, 3 H), 1.35
(s, 3 H).
HRMS: m/z calcd for C17H26O8: 358.1627; found: 358.1638.
13C NMR (CDCl3): d = 169.9, 159.1, 132.1, 130.1, 129.4, 126.1,
2b
113.7, 111.1, 77.9, 77.7, 71.6, 69.1, 55.2, 51.8, 26.9, 25.5.
Gradient flash chromatography with cyclohexane–EtOAc (5:1 to
2:1) gave 2b as an oil.
HRMS: m/z calcd for C18H24O6: 336.1573; found: 336.1581.
IR (neat): 2995, 2950, 1740 cm–1.
2g
1H NMR (CDCl3): d = 5.79 (ddt, J = 15.4, 7.0, 0.8 Hz, 1 H), 5.42
(dd, J = 15.4, 7.5 Hz, 1 H), 4.72 (dd, J = 7.3 Hz, 1 H), 4.61 (d,
J = 7.1 Hz, 1 H), 3.75 (s, 3 H), 3.70 (s, 6 H), 3.40 (t, J = 7.5 Hz, 1
H), 2.64 (ddd, J = 7.5, 7.5 0.8 Hz, 2 H), 1.6 (s, 3 H), 1.35 (s, 3 H).
A solution of p-toluenesulfinic acid sodium salt hydrate (1.5 equiv)
in MeOH (1.5 mL, 0.54 mmol of 1) was added to a mixture of 1 and
the palladium catalyst. The mixture was stirred at r.t. for 4 h prior to
treatment as described above. Gradient flash chromatography of
crude 2g with cyclohexane–EtOAc (5:1 to 2:1) gave 2g as an oil.
13C NMR (CDCl3): d = 169.7, 168.9, 131.5, 127.1, 111.0, 78.1, 77.5,
52.6, 52.5, 51.8, 51.0, 31.0, 26.9, 25.5.
IR (neat): 2995, 2950, 2940, 1750 cm–1.
HRMS: m/z calcd for C15H22O8: 330.1315; found: 330.1314.
1H NMR (CDCl3): d = 7.75 (m, 2 H), 7.35 (m, 2 H), 5.78 (dt,
J = 15.4, 7.3 Hz, 1 H), 5.63 (dd, J = 15.4, 6.4 Hz, 1 H), 4.80 (dd,
J = 7.0, 6.7 Hz, 1 H), 4.70 (d, J = 7.2 Hz, 1 H), 3.76 (dd, J = 3.8, 3.9
Hz, 2 H), 3.72 (s, 3 H), 2.45 (s, 3 H), 1.58 (s, 3 H), 1.37 (s, 3 H).
2c
Gradient flash chromatography with cyclohexane–EtOAc (5:1 to
2:1) gave 2c as an oil.
IR (neat): 2990, 2940, 1725 cm–1.
13C NMR (CDCl3): d = 169.4, 144.8, 141.0, 135.7, 134.1, 129.9,
128.4, 127.8, 120.9, 111.4, 77.9, 77.6, 59.4, 52.2, 27.0, 25.5, 21.6.
1H NMR (CDCl3): d = 5.71 (dt, J = 15.0, 7.0 Hz, 1 H), 5.44 (dd,
J = 15.0, 7.2 Hz, 1 H), 4.72 (dd, J = 7.2 Hz, 1 H), 4.60 (d, J = 7.0
Hz, 1 H), 4.15 (q, J = 7.1 Hz, 4 H) 3.68 (s, 1 H), 2.57 (m, 2 H), 1.57
(s, 3 H), 1.34 (s, 3 H), 1.32 (s, 3 H), 1.22 (t, J = 7.1 Hz, 6 H).
13C NMR (CDCl3): d = 171.6, 171.5, 169.8, 130.6, 128.4, 110.9,
78.3, 77.3, 61.3, 53.1, 51.7, 38.4, 29.6, 26.9, 25.5, 19.6, 13.9.
HRMS: m/z calcd for C17H12O6S: 344.0355; found: 344.0354.
2h
A solution of NaN3 (2.5 equiv) in H2O (1.5 mL, 0.65 mmol 1) was
added to a mixture of 1 and the palladium catalyst and the mixture
was stirred at r.t. for 1 h prior to treatment as described above. Gra-
dient flash chromatography of crude 2h with cyclohexane–EtOAc
(5:1 to 1:1) gave 2h as a white solid; mp 84–86 °C.
HRMS: m/z calcd for C18H28O8: 372.1784; found: 372.1780.
IR (neat): 3200, 2990, 2940, 2050, 1750 cm–1.
2d
Gradient flash chromatography with cyclohexane–EtOAc (5:1 to
2:1) gave 2d as an oil.
IR (neat): 2990, 2950, 1740 cm–1.
1H NMR (CDCl3): d = 7.88–7.60 (m, 5 H), 5.72 (dt, J = 15.8, 6.8
Hz, 1 H), 5.46 (dd, J = 15.4, 7.8 Hz, 1 H), 4.64 (dd, J = 7.4, 7.2 Hz,
1 H), 4.00 (d, J = 7.3 Hz, 1 H), 3.70 (s, 3 H), 3.63 (s, 3 H), 2.8 (m,
2 H), 1.6 (s, 3 H), 1.40 (s, 3 H).
1H NMR (CDCl3): d = 5.95 (dtd, J = 15.4, 6.0, 1.0 Hz, 1 H), 5.76
(ddt, J = 15.4, 6.8, 1.3 Hz, 1 H), 4.85 (dd, J = 7.0, 7.1 Hz, 1 H), 4.71
(d, J = 7.3 Hz, 1 H), 3.8 (d, J = 6.0 Hz, 2 H), 1.64 (s, 3 H), 1.47 (s,
3 H).
13C NMR (CDCl3): d = 173.9, 128.5, 128.2, 111.5, 77.3, 77.2, 51.7,
26.8, 25.3.
HRMS: m/z calcd for C9H13O4N3: 227.0901; found: 227.0901.
13C NMR (CDCl3): d = 169.7, 164.4, 136.5, 133.8, 129.2, 128.9,
128.3, 111.1, 78.8, 77.5, 69.7, 63.0, 53.1, 51.8, 29.3, 26.9, 25.5.
2,3-O-Isopropylidene-5-vinyl-l-gulose (9)
NaBH4 (20.5 mg, 0.543 mmol) was added to a 1:1 MeCN–MeOH
(2 mL) solution of 7 (100.0 mg, 0.543 mmol) at 0 °C and stirred for
5 min. The ice bath was removed and the mixture was stirred at r.t.
until TLC indicated the disappearance of the starting material (~1
h). Aq sat. NH4Cl (5 mL) was added and stirred for 10 min, then the
mixture was extracted with CH2Cl2 (3 × 10 mL), dried (Na2SO4), fil-
tered, and concentrated. Flash chromatography with cyclohexane–
EtOAc (2:1) gave 9 as a colorless oil (86.0 mg, 85%).
HRMS: m/z calcd for C19H24O8S: 412.1192; found: 412.1200.
2e
Gradient flash chromatography with cyclohexane–EtOAc (5:1 to
2:1) gave 2e as an oil.
IR (neat): 2995, 2940, 2850, 1750 cm–1.
IR (neat): 3316, 2982 cm–1.
Synthesis 2008, No. 22, 3682–3686 © Thieme Stuttgart · New York

3686
J. Singleton et al.
PAPER
1
1H NMR (CDCl3): d = 6.0 (ddd, J = 16.4, 10.3, 6.9 Hz, 1 H), 5.4 (m,
3 H), 4.8 (dd, J = 6.0, 4.5 Hz, 1 H), 4.61 (d, J = 6 Hz, 1 H), 4.6 (m,
1 H), 3.4 (br s, 1 H), 1.5 (s, 3 H), 1.3 (s, 3 H).
13C NMR (CDCl3): d = 132.0, 119.3, 112.6, 101.0, 85.7, 81.5, 81.4,
26.8, 24.8.
3. Comparison of the H NMR to a literature1 diastereomer con-
firmed the structure and stereochemistry.
1H NMR (CDCl3): d = 6.0 (ddd, J = 18.2, 7.4, 4.9, 1 H), 5.24 (m, 2
H), 4.77 [dd, J = 4.5 Hz (identical coupling), 1 H], 4.25 [dd, J = 4.9
(J3,4), 1.4 Hz, 1 H], 2.91 (m, 1 H), 2.58 (ddd, J = 18.2, 12.3, 1.2 Hz,
1 H), 2.37 (dddd, J = 18.2, 8.0, 1.7, 0.6 Hz, 1 H), 1.45 (s, 3 H), 1.38
(s, 3 H).
HRMS: m/z calcd for C9H14O4: 186.0892; found: 186.0888.
Vinylalkylidene 8
Ph3P=CHCO2Et (1.80 g, 5.10 mmol) was added to a solution of 7
(375 mg, 2.04 mmol) in toluene (10 mL) and heated to 144 °C in a
sealed flask for 24 h. The mixture was cooled, the volume reduced
to a thick syrup and subjected to gradient flash chromatography
with cyclohexane–EtOAc (4:1 then 2:1) to give a 1:1 E/Z mixture
of 8, which separated on the column (combined 86% yield).
References
(1) West, L. M.; Battershill, C. N.; Northcote, P. T. J. Org.
Chem. 2000, 65, 445.
(2) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K.
J. Am. Chem. Soc. 1988, 110, 4850.
(3) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T.
J. Am. Chem. Soc. 1988, 110, 4851.
(4) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem.
1992, 57, 3828.
First Isomer
IR (neat): 2987, 1711, 1657, 1117 cm–1.
1H NMR (CDCl3): d = 6.0 (ddd, J = 17.8, 7.4, 3.0 Hz, 1 H), 5.75 (dd,
J = 6.0, 1.3 Hz, 1 HH), 5.40 (m, 3 H), 4.75 (dd, J = 6.0, 4.3 Hz, 1
H), 4.59 (dd, J = 8.2, 4.2 Hz, 1 H), 4.19 (m, 2 H), 1.41 (s, 3 H), 1.39
(s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3): d = 171.8, 166.9, 131.0, 120.6, 113.2, 94.6, 85.0,
80.0, 79.1, 59.8, 26.6, 25.7, 14.3.
(5) Fursaki, A.; Watanabe, T.; Matsumoto, T.; Yanagiya, M.
Tetrahedron Lett. 1968, 6301.
(6) Kang, H.; Jensen, P. R.; Fenical, W. J. Org. Chem. 1996, 61,
1543.
(7) Trost, B. M.; Klun, T. P. J. Am. Chem. Soc. 1979, 79, 6756.
(8) Tarver, J. E. Jr.; Joullie, M. M. J. Org. Chem. 2004, 69, 815.
(9) Aggarwal, V. K.; Monteiro, N.; Tarver, G. J.; McCague, R.
J. Org. Chem. 1997, 62, 4665.
(10) Ashfeld, B. L.; Martin, S. F. Org. Lett. 2005, 7, 4535.
(11) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron
1989, 45, 319.
(12) Nishimura, Y.; Adachi, H.; Satoh, T.; Shitara, E.; Nakamura,
H.; Kojima, F.; Takeuchi, T. J. Org. Chem. 2000, 65, 4871.
(13) Banda, G.; Chakravarthy, I. E. Tetrahedron: Asymmetry
2006, 17, 1684.
(14) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103,
2485.
Second Isomer
1H NMR (CDCl3): d = 6.05 (ddd, J = 17.3, 7.4, 3.0 Hz, 1 H), 5.5
(ddd, J = 17.2, 10.4, 1.2 Hz, 2 H), 5.15 (dd, J = 5.5, 1 Hz, 1 H), 5.1
(d, J = 1.1 Hz, 1 H), 5.5 Hz), 4.89 (m, 1 H), 4.69 (dd, J = 5.9 Hz, 1
H), 4.19 (m, 2 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3
HH).
13C NMR (CDCl3): 169.1, 165.4, 130.7, 120.8, 114.0, 92.0, 86.4,
81.8, 78.5, 59.5, 27.1, 26.1, 14.3.
HRMS: m/z calcd for C13H18O5, 254.1154; found: 254.1139.
(15) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103,
7559.
(16) Petrignet, J.; Prathap, I.; Chandrasekhar, S.; Yadav, J. S.;
Gree, R. Angew. Chem. Int. Ed. 2007, 46, 6297.
(17) Lakhrissi, M.; Chapleur, Y. Angew. Chem., Int. Ed. Engl.
1996, 35, 750.
Attempts at Cyclopentanone 3
Vinyl alkylidene 8 was heated at 60–100 °C in a combination of the
following solvents, catalysts, and ligands: Solvents: DMSO, DMF,
THF, or dioxane; Catalyst: Pd2(dba)3·CHCl3, [Pd(allyl)Cl]2,
(PPh3)2NiCl2, Mo(CO)6, (COD)2IrCl2; Ligands: DIPHOS, Trost’s,
PPh3, DPPF, and 1,3-bis[2,6-(i-Pr)2phenyl]imidazolium chloride.
Pd2(dba)3.CHCl3 was the only catalyst to produce any of the cyclo-
pentanone, with either DIPHOS or Trost’s ligand with DMSO as
solvent. The use of Trost ligand gave only 10% conversion and
DIPHOS a complex mixture of products that after multiple flash
chromatography with cyclohexane–EtOAc gave 40–50% yields of
(18) Chow, S. Y.; Williams, H. J.; Huang, Q.; Nanda, S.; Scot,
A. I. J. Org. Chem. 2005, 70, 9997.
(19) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J. Org. Chem.
1981, 46, 2976.
Synthesis 2008, No. 22, 3682–3686 © Thieme Stuttgart · New York