Synthesis of (+)-goniothalesdiol and (+)-7-epi-goniothalesdiol

Article abstract of DOI:10.1016/j.tet.2005.01.004

A total synthesis of (+)-goniothalesdiol, a 3,4-dihydroxy-2,5-disubstituted tetrahydrofuran isolated from Goniothalamus borneensis (Annonaceae), and its 7-epimer is reported using oxycarbonylation methodology for construction of polyhydroxylated substitut

Full text of DOI:10.1016/j.tet.2005.01.004

Tetrahedron 61 (2005) 2471–2479
Synthesis of (C)-goniothalesdiol and (C)-7-epi-goniothalesdiol
*
´
Matej Babjak, Peter Kapitan and Tibor Gracza
´
Department of Organic Chemistry, Slovak University of Technology, Radlinskeho 9, SK-812 37 Bratislava, Slovakia
Received 23 June 2004; revised 22 November 2004; accepted 5 January 2005
Available online 25 January 2005
Dedicated to Prof. Peter Stanetty on his 60th birthday.
Abstract—A total synthesis of (C)-goniothalesdiol, a 3,4-dihydroxy-2,5-disubstituted tetrahydrofuran isolated from Goniothalamus
borneensis (Annonaceae), and its 7-epimer is reported using oxycarbonylation methodology for construction of polyhydroxylated substituted
heterocycles. Diastereoselectivity of addition of organometallic reagents to 2,3-O-isopropylidene-D-threose derivatives using theoretical
calculations based on the semiempirical PM5 was studied.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
structure and relative stereochemistry of 1 was assigned on
1
the basis of H, 13C NMR spectroscopy and the absolute
configuration was confirmed by semi-synthesis from natural
(C)-goniothalenol (altholactone).
The palladium(II)-catalysed oxycarbonylation1 of unsatu-
rated polyols2 or/and aminopolyols3 represents a powerful
methodology4 for construction of 5-/6-membered saturated
oxa/azaheterocycles. In our long term program directed
towards the application of carbonylation methodology
to natural product synthesis, we have described the
syntheses of both enantiomers of cytotoxic styryl-lactones
goniofufurone,5a,b 7-epi-goniofufurone,5a,b erythro-
skyrine,5c homo-DLX,5d homo-DMDP,5d homo-DNJ5e,f
and homo-L-ido-DNJ.5e,f Herein, we report experimental
details of the optimised synthesis of goniothalesdiol 1 and
7-epi-goniothalesdiol 2 (Fig. 1) starting with D-mannitol.6
Meanwhile, growing attention is given to this class of
compounds, as demonstrated by development of new
syntheses of unnatural enantiomer of goniothalesdiol (K)-
1,8 and its 7-epimer (C)-2.9 Both syntheses started from
chiral pool, D-glucuronolactone or D-tartaric acid, respect-
ively, using Grignard addition followed by Lewis acid
promoted hydrogenation of the corresponding lactone, the
latter setting the cis configuration at C6-C7 of the epimer,
and thus were not applicable for natural goniothalesdiol.
Recently, preparation of 3,6-anhydro-2-deoxy-6-C-phenyl-
D-gluco-1,4-hexonolactone 9, an intermediate in our
synthetic route,6 was described from an erythrulose
derivate10 via an aldol reaction.
2. Results and discussion
We report herein details of the optimised synthesis6 of
natural goniothalesdiol (C)-1 and its 7-epimer (C)-2. The
strategy followed is shown in Scheme 1. In both routes the
phenyl moiety is introduced by diastereoselective addition
of organometallic reagents at C1 of the aldose 6, to allow for
an entry into both diastereomers. For the second crucial
step, oxycarbonylating bicyclisation of pentenitols, advan-
tage is taken of recent progress in Pd(II)-catalysed
carbonylations of unsaturated polyols or aminopolyols,
that have turned out bicyclic lactones/lactams with high
regio-control and excellent stereoselectivity, without neces-
sity of OH-protection.4,5
Figure 1. Goniothalesdiol 1 and 7-epi-goniothalesdiol 2.
Goniothalesdiol was isolated from the bark of the Malaysian
tree Goniothalamus borneensis (Annonaceae), and has been
revealed to have significant cytotoxicity against P388
mouse leukaemia cells, and insecticidal activities.7 The
Keywords: Palladium(II) catalysis; Stereoselective oxycarbonylation;
Diastereoselective addition to carbonyl; Goniothalesdiol; Natural products;
PM5 calculations.
* Corresponding author. Tel.: C421 2 593 25 167; fax: C421 2 529 68
560; e-mail: tibor.gracza@stuba.sk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.004

2472
M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
of the second terminal acetonide was achieved with
Zn(NO3)2$6H2O in acetonitrile.15
With aldose 6 in our hands the synthesis was set up for the
first key reaction of the sequence—Grignard addition with
phenylmagnesium bromide (Scheme 3). A diastereomeric
mixture of D-arabino 7 and L-xylo 8 partially protected
pentenitols in the ratio 50:50 and 70% yield was obtained.
The diastereomers could be readily separated by flash
chromatography.
The unexpected lack of diastereocontrol observed in the
Scheme 3. Reagents and conditions: (a) PhMgBr, THF.
Scheme 1. Retrosynthetic analysis of 1 and 2.
addition led us to study the reactions of organometallic
reagents with aldehyde 6 in more detail.16
The first key intermediate, aldose 6, was obtained from
D-mannitol by a standard carbohydrate chemistry pro-
cedure.11,12 Following the reaction sequence, acetonisation
of D-mannitol,13 selective hydrolysis of the terminal
acetonide,13 O-mesylation of both unprotected hydroxyl
groups, reductive elimination with sodium iodide14 and
subsequent selective hydrolysis of the next terminal
acetonide with HCl in ethanol, the diol 5 was readily
prepared, however, in poor yield (3% overall4a,6).
Generally, the design of addition of C-nucleophiles to
aldehyde 6 could be based on models of either chelation-
control: 1,2- (Cram) versus 1,3-asymmetric induction
(Reetz) or non-chelation-control (Felkin-Anh), leading to
alcohols 8 (1,2-syn, Cram) or 7 (1,2-anti, Reetz and Felkin-
Anh).
Table 1 summarises the results of a series of micro scale
experiments with several organometallics. The best results
were noted with the Seebach reagent (entry 6, non-chelation
control) and with PhCeCl2 in diethyl ether at K10 8C,
affording the requisite D-arabino diastereomer (1,2-anti) in
62% de (entry 1, chelation control). General anti-
diastereoselectivity, observed in this set of reactions, in
concert with literary references,16 called for a new model of
the transition state for these reactions. In the case of hard
Lewis acids, such as MgBr2 (entry 4), the convenient
Cram’s chelating model favored 1,2-syn-diastereomer
(L-xylo, 8), whereas dominance of 1,2-anti-diastereomer
was found in practice. Our model considers a 1,2-chelation
of the subsidiary Lewis acid along with the chelation of
organometallic reagent, causing the Re face of carbonyl
group to be the preferred one for a nucleophilic attack
(model B, Fig. 2). The activation energy for this model of
TS (model B, 4 kcal/mol), was considerably lower, than that
predicted by the modified Cram’s model (model A,
w8 kcal/mol) or classical Cram’s model (15 kcal/mol).
Transition state candidates were determined using saddle-
point calculations and potential energy surfaces. PM5
semiempirical method was chosen as well balanced
compromise between speed and accurancy,17 even though
it is still a novelty in the field of metal complex
calculations.18 Transition states were subsequently verified
by vibrational and IRC analysis.
In order to improve the efficiency of the synthesis of the
requisite aldose 6 various reaction conditions for dioxolane
ring hydrolysis and work up of reactions were examined. An
effort that culminated in development of a four-step
protocol for synthesis of C5-aldose 6 with 14% yield,
starting from cheap D-mannitol. (Scheme 2). The major
improvement is the one pot conversion of D-mannitol to
bismesylate 3, which was isolated by simple crystallisation
in 35% yield together with 30% of tris-O-acetonide-D-
mannitol; the latter can be recycled. A selective hydrolysis
Predictions made by the suggested bis-chelation model of
the transition state for addition of organometallic reagents to
2,3-O-isopropylidene-D-threose derivatives matched the
Scheme 2. Reagents and conditions: (a) 1, H2SO4, acetone; 2, H2O; 3,
NaOH; 4, MsCl, pyridine; (b) Lit.14 NaI, acetone; (c) Lit.15 Zn(NO3)2$
6H2O, acetonitrile; (d) NaIO4, H2O.

M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
Table 1. Addition of organometallics to aldehyde 6
2473
Entry
Reagent
Temp 8C
Solvent
anti-7:syn-8
1
2
3
4
5
6
7
8
9
10
PhCeCl2
K10
rt
K80
K80
rt
K80
K80
K80
K80
K80
Et2O
CH2Cl2
THF
81:19
79:21
72:28
69:31
79:21
O98:!2
68:32
44:56
63:37
52:48
PhMgBr/18-crown-6
PhMgBr/LiCl
PhMgBr/MgBr2
PhLi
THF
Et2O
CH2Cl2
THF
THF
THF
a
PhTi(OiPr)3
PhMgBr/SnCl4
PhMgBr/TiCl4
PhMgBr/ZnBr2
PhMgBr/ZnBr2
Et2O
a Low conversion.
with (methoxymethylene)-triphenylphosphonium chloride
and tert-butyllithium in THF (60 and 59% as the mixtures of
E/Z-isomers, 60:40).
Finally, the E/Z-isomeric mixtures of 15 and 16 were
subjected to a three-step, in one-pot sequence to convert the
vinyl ether to the methyl carboxylate (Scheme 5). Ether
cleavage with sulphuric acid in THF–H2O, followed by
Ag2O oxidation of the aldehyde and an acidic esterification
with methanol afforded target compounds (C)-1 and (C)-2,
respectively. Final purification by Kugelrohr-distillation in
vacuo (190 8C, 0.05 Torr), followed by repeated treatment
with acidic Amberlyst in the case of (C)-1, because of
lactonisation by heating to 17, provided the target
goniothalesdiol (C)-1 and its 7-epimer (C)-2 in 42 and
75% yields, respectively over three steps.
Figure 2. Models of transition states, calculated by PM5 method.
experimental results and clarified the discrepancies in
stereochemical outcomes of additions to erythro-19 versus
threo-16 configured aldehydes. In fact, the goniothalesdiol-
precursor 7 was obtained by the addition of PhCeCl2 to
aldehyde 6 in 55% yield.
The NMR data, mp, and specific rotations of (C)-1 and
(C)-2 were in good agreement with the reported data for the
The second crucial step of both syntheses, which were run in
parallel with the pure diastereomers 7 (D-arabino) and 8
(L-xylo) is oxycarbonylating bicyclisation. Firstly, the
acetonide group was removed in acidic ethanol and
pentenitols 9 and 10 were exposed to oxycarbonylation
conditions (Scheme 4). The reaction was carried out under
standard conditions with palladium(II) chloride as catalyst
(0.1 equiv), copper(II) chloride as oxidant (3 equiv), sodium
acetate (3 equiv) in acetic acid as buffer under a carbon
monoxide atmosphere (balloon) at room temperature. As
expected only the required lactones 11 and 12, were formed
with high regio- and threo-selectivity.4,5 After work-up of
the reaction mixture and flash chromatography the key
intermediates were isolated, 11 in 90% and 12 in 85% yield,
after recrystallisation. The configuration of both lactones,
D-gluco for 11 (intermediate with correct stereochemistry
for the natural product) and L-ido for 12 (precursor of 2) was
established by comparison of 1H NMR data with the
literature data of 3,6-anhydro-2-deoxy-1,4-heptonolactones
of the same configuration.4a The final confirmation of the
absolute stereochemistry came from the single crystal X-ray
analysis of 12.20
The syntheses continued with smooth partial reduction of
the lactones using diisobutylaluminium hydride in CH2Cl2
affording a mixture of anomeric lactols 13 and 14 (exo:endo,
75:25) in very good yields, which were transformed to
tetrahydrofuran derivatives 15 and 16 by the Wittig reaction
Scheme 4. Reagents and conditions: (a) HCl, aqueous EtOH; (b) PdCl2,
CuCl2, AcONa, AcOH, CO; (c) DIBAL-H, CH2Cl2; (d) Ph3PCH2OCH3Cl,
tBuLi, THF.

2474
M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
dipping the plates in an aqueous H2SO4 solution of cerium
sulphate/ammonium molybdate followed by charring with a
heat-gun. HPLC analyses were performed on Varian
Dynamax system with variable wavelength UV detector.
Melting points were obtained using a Boecius apparatus and
are uncorrected. Optical rotations were measured with a
POLAR L-mP polarimeter (IBZ Messtechnik) with a water-
jacketed 10,000 cm cell at the wavelength of sodium
line D (lZ589 nm). Specific rotations are given in units of
10K1 deg cm2 gK1 and concentrations are given in
g/100 mL. Elemental analyses were run on FISONS
EA1108 instrument, HRMS on Finnigan MAT 8230.
Infrared spectra were recorded either on a Philips Analytical
PU9800 FTIR spectrometer or a Perkin–Elmer 1750 FTIR
spectrophotometer as KBr discs (KBr) or as thin films on
KBr plates (film). NMR spectra were recorded on a Tesla
BS 487 (80 MHz) and a Varian VXR-300 spectrometers.
Chemical shifts (d) are quoted in ppm and are either
referenced to the tetramethylsilane (TMS) as internal
standard. Compounds are numbered according to carbo-
hydrate naming scheme.
Scheme 5. Reagents and conditions: (a) 1, H2SO4, THF–H2O; 2, Ag2O,
NaOH, THF–H2O; 3, Amberlyst 15, MeOH; (b) distillation,
190 8C/0.05 Torr; (c) Amberlyst 15, MeOH.
natural product,7 and/or unnatural antipode8 {[a]2D7ZK7.1
(c 0.15, EtOH)} and its 7-epimer.9
3. Conclusions
In conclusion, (C)-goniothalesdiol and (C)-7-epi-
goniothalesdiol have been synthesised in 10 steps from
cheap D-mannitol using an oxycarbonylation strategy for
construction of tetrahydrofuran ring in two key steps,
namely diastereoselective addition of organometallics
to aldose 6 followed by a palladium(II)-catalysed
oxycarbonylation of the appropriate unsaturated triols 9,
10. The synthesis of D-threose derivative, a very useful
C5-chiron, was developed from D-mannitol.
4.1.1. 1,2:3,4-Di-O-isopropylidene-5,6-di-O-mesyl-D-
mannitol (3). To the suspension of D-mannitol (25 g,
0.137 mol) in dry acetone (300 mL) was concd H2SO4
(3.5 mL) added dropwise and the mixture was stirred for 6 h
at room temperature. At this point, the reaction could be
scaled up by addition of discretionary amount of acetone
solution of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol (c,
13.8 g/100 mL). Water was added (3.3 mL/100 mL of
reaction solution) and the mixture was additionally stirred
for 1 h (TLC monitoring). The mixture was neutralised with
10% aqueous sol NaOH and boiled-down to half of volume
in vacuo. Resulting aqueous slurry was extracted with
CH2Cl2 (4!50 mL) and combined extracts were dried over
Na2CO3 and evaporated in vacuo. Oily residue, containing
mixture of 1,2:3,4-di-O-isopropylidene-D-mannitol and
1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol was dissolved
in pyridine (35 mL) and cooled to 0 8C. A solution of MsCl
(6.4 mL, 9.6 g, 82 mmol) in pyridine (15 mL) was added
dropwise with vigorous stirring, keeping the reaction
temperature below 10 8C. After 10 h stirring at rt the
mixture was poured on ice/water (350 mL) to form a brown-
yellow precipitate, which was filtered and dissolved in
boiling AcOEt (150 mL). The solution was dried over
Na2SO4 an concentrated in vacuo. The residue was slurried
in cold hexanes (100 mL) and filtered to provide crude
product. The procedure was repeated twice and obtained
white powder was recrystallised from MeOH; yield 20 g
(35%) of 3, colourless crystals, mp 120–122 8C, [a]2D5Z
C22.5 (c 2.3, CH2Cl2); {lit.14: mp 118–120 8C,
[a]D20ZC25.1 (c 2.0, CHCl3); lit.4a: mp 117–118 8C,
[a]2D3ZC24.7 (c 2.18, CHCl3)}. Combined hexanes
extracts were evaporated and the solid residue crystallised
from Et2O to give 1,2:3,4:5,6-tri-O-isopropylidene-D-
mannitol (12 g, 30%), mp 68–70 8C, [a]2D5ZC16 (c 1.4,
MeOH); {lit.4a: mp 66–67 8C, [a]2D3ZC16.5 (c 1.395,
MeOH)}.
The diastereoselectivity of addition of organometallic
reagent to aldose 6 was studied and model for transition
state was designed using theoretical calculations based on
the semiempirical PM5.
4. Experimental
4.1. General methods
Commercial reagents were used without further purifi-
cation. All solvents were distilled before use. Hexanes refer
to the fraction boiling at 60–65 8C. Lewis acids for
diastereoselectivity studies were prepared as follows:
CeCl3, ZnBr2 and LiCl as commercial hydrates (Fluka)
were heated in tube oven at 150 8C under pressure of 2 Torr
for 5 h, then stored under argon gas. MgBr2$THF: 1 equiv
of Mg turnings and few crystals of iodine were heated in the
flask covered with reflux condenser and dropping funnel,
cooled, charged with Ar and under vigorous stirring solution
1.05 equiv of 1,2-dibromoethane in THF was added and
refluxed until no Mg remained. Ti(OiPr)3Cl: at K10 8C,
1 equiv of TiCl4 was added dropwise to 3 equiv of Ti(OiPr)4
and stirred for 2 h, then distilled under reduced pressure (bp
65–70 8C/0.1 Torr). TiCl4 and SnCl4 were used without
further treatment. Flash column liquid chromatography
(FLC) was performed on silica gel Kieselgel 60 (40–63 mm,
230–400 mesh) and analytical thin-layer chromatography
(TLC) was performed on aluminum plates pre-coated with
either 0.2 mm (DC-Alufolien, Merck) or 0.25 mm silica gel
60 F254 (ALUGRAMw SIL G/UV254, Macherey-Nagel).
The compounds were visualised by UV fluorescence and by
4.1.2. 3,4:5,6-Di-O-isopropylidene-D-arabino-1-hexenitol
(4).14 The dimesylate 3 (8 g, 16.6 mmol) and dry NaI (24 g,
160 mmol were dissolved in dry acetone (100 mL) and
heated at 100 8C for 6 h in an autoclave. The resulting

M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
2475
brown suspension was distributed between Na2S2O3
solution (10% in H2O, 100 mL) and AcOEt (100 mL).
Inorganic phase was extracted with AcOEt (3!50 mL) and
combined organic phases were dried over Na2SO4. Con-
centrated crude mixture was distilled under reduced
pressure on a microscale distillation apparatus equipped
with 15 cm Vigreux column. Analytically pure product 4
was isolated (3.52 g, 80%) as a colourless oil, bp 40–
45 8C/0.05 Torr, [a]2D5ZK4.8 (c 3.25, CH2Cl2); {lit.12:
[a]2D3ZK3.6 (c 4.23, CHCl3); lit.14: [a]2D1ZK5.5 (c 2.4,
CHCl3); lit.4a: bp 70–80 8C/1 mbar, [a]2D1ZK5.3 (c
2.98, CHCl3)}.
THF (20 mL) was added dropwise to start a vigorous
exothermic reaction. Reaction was left to reflux for 1 h, until
no Mg particles remained in the flask, and subsequently
cooled to 0 8C. Aldehyde 6 (1.5 g, 9.6 mmol) in THF
(15 mL) was added and solution was left to stand overnight
(12 h), and then quenched with saturated solution of NH4Cl
(20 mL), Et2O (30 mL) was added and the separated
aqueous phase extracted with AcOEt (4!30 mL). Organic
phases were dried over Na2SO4 and concentrated. Crude oil
was separated on silica gel column (100 g, 4 cm i.d. of
column, 4% AcOEt and 0.3% THF in hexanes) to afford 7
(750 mg, 33%), 8 (600 mg, 27%) and 200 mg fraction
containing both isomers. Overall yield of isolated products
was 70%.
4.1.3. 3,4-O-isoPropylidene-D-arabino-1-hexenitol (5).
According to lit.15 a solution of bisacetonide 4 (5 g,
26.6 mmol) and Zn(NO3)2$6H2O (39 g, 133 mmol) in
acetonitrile (30 mL) was stirred at rt for 24 h. After
concentration in vacuo the remainder was distributed
between CH2Cl2 (200 mL) and water (200 mL) and
separated water layer was extracted with CH2Cl2 (2!
50 mL). Combined organic extracts were dried over
Na2CO3 and after solvent removal separated by flash
column chromatography on silica (50% AcOEt in hexanes).
Yield of 5 as a colourless oil: 2.3 g (55%), Rf 0.21 (50%
AcOEt in hexanes), [a]2D5ZC6.4 (c 0.47, CH2Cl2); {lit.12:
[a]2D3ZC16.1 (c 3.25, EtOH)}. IR (film, cmK1): n 3391
Preparative procedure with PhCeCl2$MgBrCl: The alde-
hyde 6 (500 mg, 3.21 mmol) in Et2O (10 mL) was added to
the freshly prepared reagent [875 mg, 2.35 mmol of dry
CeCl3 was sonicated for 10 min in dry Et2O (10 mL), then
2.35 mmol of freshly prepared PhMgBr in Et2O (10 mL)
was added and suspension was stirred for 2 h at K10 8C and
the resulting suspension was left to stir overnight. Reaction
was quenched by addition of 5% HCl (15 mL) and extracted
with Et2O. Organic phases were dried over Na2SO4 and
concentrated. Crude oil was separated on silica gel column
(25 g, 2.5 cm i.d. of column, 4% AcOEt and 0.3% THF in
hexanes) to afford 7 (410 mg, 55%), 8 (105 mg, 14%) and
80 mg fraction containing both isomers. Overall yield of
isolated products was 79%.
1
(bs), 2936 (s), 2985 (s), 1732 (s), 1647, 1559 (all m); H
NMR (300 MHz, CDCl3): d 1.42, 1.43 (2! s, 6H,
C(CH3)2), 3.25 (broad s, 2H, OH), 3.64–3.90 (m, 4H, H-1,
H-2, H-3), 4.42 (‘t’, 1H, J4,5Z7 Hz, J3,4Z7 Hz, H-4), 5.25
(d, 1H, J5,6ZZ10.3 Hz, H-6Z) 5.41 (d, 1H, J5,6EZ17.5 Hz,
H-6E), 5.88 (ddd, 1H, J4,5Z7 Hz, J5,6ZZ10.3 Hz, J5,6E
Z
4.2.1. Compound 7. Rf 0.49 (23% AcOEt in hexanes),
[a]D21ZC4.4 (c 0.21, CH2Cl2). IR (film, cmK1): n 3467 (s),
2987 (s), 1455, 1381, 1240, 1217, 1167, 1057, 701 (all s). 1H
NMR (300 MHz, CDCl3): d 1.43, 1.45 (all s, 6H, C(CH3)2),
17.5 Hz, H-5); 13C NMR (75 MHz, CDCl3): d 26.9, 27.0 (all
q, C(CH3)2), 63.5 (t, C-1), 72.1, 79.3, 81.0 (all d, C-2, C-3,
C-4), 109.4 (s, C(CH3)2), 118.6 (t, C-6), 135.9 (d, C-5).
Anal. calcd for C9H16O4 (188.2): C, 57.43; H, 8.57. Found:
C, 57.72; H, 8.55.
2.68 (broad s, 2H, OH), 4.02 (dd, 1H, J4,5Z4.0 Hz, J3,4
Z
8.1 Hz, H-4), 4.42 (dd, 1H, J2,3Z6.2 Hz, J3,4Z8.1 Hz,
H-3), 4.88 (ddd, 1H, J1Z,2Z10.5 Hz, H-1Z), 4.99 (d, 1H,
J1E,2Z17.3 Hz, H-1E), 5.03 (bd, 1H, J4,5Z4.0 Hz, H-5),
4.1.4. 2,3-O-isoPropylidene-D-threo-4-pentenose (6). A
solution of NaIO4 (3.4 g, 14.6 mmol) in water (35 mL) was
added dropwise to the suspension of 5 (2.3 g, 12.2 mmol) in
water (9 mL) at 0 8C. After 90 min (TLC monitoring) of
vigorous stirring (white precipitate had been created) NaCl
(3 g) was added and mixture was extracted with AcOEt (4!
50 mL). Extracts were dried over K2CO3 and concentrated.
After removal of the traces of solvent (0.05 Torr for 30 min
at rt) a colourless viscous oil of 6 (1.7 g, 90%) was obtained
in satisfactory purity for the next reaction step. Rf 0.58 (50%
AcOEt in hexanes), [a]2D5ZK24.1 (c 0.21, CHCl3). 1H
NMR (80 MHz, CDCl3): d 1.46 (s, 6H, C(CH3)2), 3.80–4.48
(m, 2H, H-2, H-3), 5.00–5.50 (m, 2H, H-5E, H-5Z), 5.65–
6.20 (m, 1H, H-4), 9.72 (d, 1H, J1,2Z2 Hz, H-1). The aldose
6 can be stored for 1 month at 0–10 8C without loss of
quality.
5.28 (ddd, 1H, J2,3Z6.2 Hz, J1Z,2Z10.5 Hz, J1E,2
Z
17.3 Hz, H-2), 7.20–7.40 (m, 5H, Ph); 13C NMR
(75 MHz, CDCl3): d 26.9 (‘q’, 2! q C(CH3)2), 71.8, 77.0,
84.2 (all d, C-3, C-4, C-5), 109.4 (s, C(CH3)2), 117.1 (t,
C-1), 126.1, 128.3, 129.7 (all d, Ph), 135.7 (d, C-2), 138.5 (s,
Ph). Anal. calcd for C14H18O3 (234.3): C, 71.77; H, 7.74;
Found: C, 72.12; H, 7.55.
4.2.2. Compound 8. Rf 0.57 (23% AcOEt/hexanes),
[a]D21ZC14.4 (c 0.25, CH2Cl2). IR (film, cmK1): n 3466
(s), 2987 (s), 1458, 1381, 1240, 1218, 1166, 701 (all s). 1H
NMR (300 MHz, CDCl3): d 1.44, 1.48 (2! s, 6H,
C(CH3)2), 2.81 (broad s, OH), 3.93 (dd, 1H, J4,5Z5.3 Hz,
J3,4Z8.1 Hz, H-4), 4.31 (dd, 1H, J2,3Z6.8 Hz, J3,4
Z
8.1 Hz, H-3), 4.62 (bd, 1H, J4,5Z5.3 Hz, H-5), 5.00 (d,
1H, J1Z,2Z10.5 Hz, H-1Z), 5.08 (d, 1H, J1E,2Z17.3 Hz,
4.2. 2,3-O-isoPropylidene-5-C-phenyl-D-arabino-1-
pentenitol (7) and 2,3-O-isopropylidene-5-C-phenyl-L-
xylo-1-pentenitol (8)
H-1E), 5.44 (ddd, 1H, J2,3Z6.2 Hz, J1Z,2Z10.5 Hz, J1E,2
Z
17.3 Hz, H-2), 7.26–7.29 (m, 5H, Ph); 13C NMR (75 MHz,
CDCl3): d 25.2, 27.1 (both q, C(CH3)2), 74.0, 79.1, 84.5 (all
d, C-3, C-4, C-5), 109.7 (s, C(CH3)2), 118.1 (t, C-1), 125.3,
126.8, 128.4 (all d, Ph), 134.7 (d, C-2), 139.8 (s, Ph). Anal.
calcd for C14H18O3 (234.3): C, 71.77; H, 7.74; Found: C,
71.92; H, 7.95.
Preparative procedure with PhMgBr: a dry flask was
charged with Mg turnings (260 mg, 10.7 mmol) and a few
particles of iodine, heated under Ar until the iodine started
to sublime. The solution of PhBr (1.7 g, 10.8 mmol) in dry

2476
M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
4.3. Typical procedure for addition of organometallics to
aldehyde 6
chromatography (50% AcOEt in hexanes) afforded pure
10 (472 mg, 95%) as colourless oil, Rf 0.15 (50% AcOEt/
hexanes), [a]2D1ZC29.4 (c 0.35, MeOH). IR (film, cmK1): n
3386 (s), 3064, 3032, 2914, 1718 (all m), 1494, 1454, 1401
Freshly prepared phenylating reagent (1.1 mmol PhMgBr,
PhLi, PhCeCl2) in 10 mL of corresponding solvent was set
up to chosen temperature. Aldehyde 6 (156 mg, 1 mmol)
was added dropwise in solvent (5 mL) and mixture was kept
at initial temperature for additional 3 h, then kept to reach rt.
Reaction was left until no 6 was observed, but no longer
than 24 h (Table 1).
1
(all s), 1198, 1042 (all m). H NMR (300 MHz, CDCl3): d
2.96 (broad s, 3H, OH), 3.59 (dd, 1H, J3,4Z3.3 Hz, J4,5
5.5 Hz, H-4), 4.04 (dd, 1H, J3,4Z3.3 Hz, J2,3Z5.5 Hz,
H-3), 4.79 (d, 1H, J4,5Z5.5 Hz, H-5), 5.20 (d, 1H, J1Z,2
Z
Z
10.5 Hz, H-1Z), 5.29 (d, 1H, J1E,2Z17.2 Hz, H-1E), 5.87
(ddd, 1H, J2,3Z5.5 Hz, J1Z,2Z10.5 Hz, J1E,2Z17.2 Hz,
H-2), 7.26–7.40 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3):
d 72.6, 74.5, 77.4 (all d, C-3, C-4, C-5), 116.8 (t, C-1),
126.6, 128.0, 128.5 (all d, Ph), 137.6 (d, C-2), 140.7 (s, Ph).
Anal. calcd for C11H14O3 (194.2): C, 68.02; H, 7.27. Found:
C, 68.31; H, 7.52.
4.4. Typical procedure for addition of organometallics to
aldehyde 6 in the presence of Lewis acid
Lewis acid (1.1 mmol) was dissolved or suspended in
corresponding solvent (10 mL) and cooled to chosen
temperature. Aldehyde 6 (156 mg, 1 mmol) in solvent
(5 mL) was added and mixture was left to stir for 30 min.
Phenylating agent (1.1 mL, 1.1 mmol PhLi or PhMgBr, 1 M
soln) was added dropwise within 10 min, and mixture was
stirred at initial temperature for 2 h, then left to reach rt;
until no 6 was observed, but no longer than 24 h.
4.6.3. 3,6-Anhydro-2-deoxy-6-C-phenyl-D-gluco-1,4-hex-
onolactone; [(1S, 5S, 7R, 8R)-8-hydroxy-7-phenyl-2,6-
dioxabicyclo[3.3.0]octan-3-one] (11). A 25 mL-flask with
stopcock equipped side inlet was charged with PdCl2 (9 mg,
0.05 mmol, 0.1 equiv), CuCl2 (207 mg, 1.55 mmol, 3 equiv)
and AcONa (127 mg, 1.55 mmol, 3 equiv). Alkenol 9
(100 mg, 0.52 mmol) in AcOH (10 mL) was added and
the flask was purged with CO from balloon (residual air was
removed through side inlet with water aspirator). The
mixture was vigorously stirred at rt until colour of the
mixture changed from green to pale brown (approx. 10 h).
Inorganic material was removed on Cellitew pad and the
filtrate was concentrated in vacuo. Residue was dissolved in
AcOEt (25 mL) and washed with 10% NaHCO3 (10 mL).
Separated organic phase was dried over Na2SO4 and
concentrated. Crude product was purified on silica gel
column (50% AcOEt in hexanes). Spectroscopically pure
lactone 11 was isolated as pale brown oil (102 mg, 90%), Rf
0.44 (50% AcOEt/hexanes), [a]2D1ZK75 (c 0.38, CH2Cl2).
IR (film, cmK1) n 3438, 2930, 1782, 1194, 1154, 1048,
1003, 760, 701. 1H NMR (300 MHz, DMSO-d6): d 2.64 (d,
1H, J2A,2BZ18 Hz, H-2), 2.97 (dd, 1H, J2A,2BZ18 Hz,
4.5. Procedure for addition of organometallics to
aldehyde 6 in the presence of crown-ether
Freshly prepared PhMgBr in Et2O (1.2 mmol in 10 mL) was
concentrated under Ar. Syrupy brown residue was dissolved
in CH2Cl2 (10 mL), 18-crown-6 (4 equiv) was added and
mixture was left to stir until all crown-ether dissolved.
Aldehyde 6 (156 mg, 1 mmol) in CH2Cl2 (5 mL) was added
during 10 min and mixture was left overnight.
4.6. General workup procedure for all reactions above
Reactions were quenched with satd NH4Cl (10 mL),
extracted with Et2O and dried over Na2SO4. Crude oils
were analysed on n-phase HPLC (Separon SGX 250!4 mm
column, lZ254 nm, 17% AcOEt in i-hexane, flow rate
0.7 mL/min, 25 8C); TrZ7.8 min for 7 and 11.7 min for 8.
J2,3Z2.7 Hz, H-2), 4.06 (dd, 1H, J5,OHZ5.1 Hz, J4,5
Z
5.4 Hz, H-5), 4.66 (d, 1H, J4,5Z5.7 Hz, H-4), 4.87 (bs, 2H,
H-3, H-6), 5.97 (d, 1H, J5,OHZ5.1 Hz, OH), 7.26–7.40 (m,
5H, Ph); 13C NMR (75 MHz, DMSO-d6): d 35.7 (t, C-2),
77.4 (d, C-5), 81.8 (d, C-3), 86.8 (d, C-4), 90.1 (d, C-6),
125.8, 127.7, 128.3 (all d, Ph), 139.4 (s, Ph), 175.5 (s, C-1).
HR MS: 220.0733G5 ppm (calcd 220.0736 for C12H12O4).
4.6.1. 5-C-Phenyl-D-arabino-1-pentenitol; [(1R, 2S, 3R)-
1-phenyl-pent-4-ene-1,2,3-triol] (9). A suspension of
protected triol 7 (600 mg, 2.56 mmol) in 70% EtOH
(10 mL) and concd HCl (1 mL) was stirred for 3 h at rt.
Solvents were removed in vacuo and residue was purified by
flash chromatography on silica (50% AcOEt in hexanes).
Yield of 9 (450 mg, 90%), colourless crystals; mp 143–
144 8C, Rf 0.21 (50% AcOEt/hexanes), [a]2D1ZC11.9 (c
0.08, MeOH). 1H NMR (300 MHz, CDCl3): d 2.46 (broad s,
3H, OH), 3.67 (dd, 1H, J3,4Z2.6 Hz, J4,5Z5.4 Hz, H-4),
4.28 (dd, 1H, J3,4Z2.6 Hz, J2,3Z5.4 Hz, H-3), 4.88 (d, 1H,
J4,5Z5.4 Hz, H-5), 5.21 (d, 1H, J1Z,2Z10.6 Hz, H-1Z), 5.30
(d, 1H, J1E,2Z17.2 Hz, H-1E), 5.90 (ddd, 1H, J2,3Z5.4 Hz,
J1Z,2Z10.6 Hz, J1E,2Z17.2 Hz, H-2), 7.27–7.43 (m, 5H,
Ph); 13C NMR (75 MHz, CDCl3): d 71.4, 75.7, 75.9 (all d,
C-3, C-4, C-5), 116.2 (t, C-1), 126.4, 127.7, 128.4 (all d,
Ph), 137.4 (d, C-2), 140.8 (s, Ph). Anal. calcd for C11H14O3
(194.2): C, 68.02; H, 7.27. Found: C, 68.22; H, 7.31.
4.6.4. 3,6-Anhydro-2-deoxy-6-C-phenyl-L-ido-1,4-hexo-
nolactone; [(1S, 5S, 7S, 8R)-8-hydroxy-7-phenyl-2,6-
dioxabicyclo[3.3.0]octan-3-one] (12). Procedure as
above; alkenol 10 (100 mg, 0.52 mmol). Lactone 12 was
obtained in pure form by crystallisation of the crude product
from AcOEt. Yield of 12 (97 mg, 85%), as colourless
crystals, mp 177–180 8C, Rf 0.44 (50% AcOEt/hexanes),
[a]D21ZC38 (c 0.31, CH2Cl2). IR (KBr, cmK1): n 3499,
1
1774, 1188, 1158, 1052, 1037, 742. H NMR (300 MHz,
DMSO-d6): d 2.47 (d, 1H, J2A,2BZ18.3 Hz, H-2), 2.86 (dd,
1H, J2A,2BZ18.3 Hz, J2,3Z6.6 Hz, H-2), 4.20 (dd, 1H,
J5,OHZ5.1 Hz, J5,6Z3.6 Hz, H-5), 4.88 (2! d, 2H, J3,4
Z
3.8 Hz, J5,6Z3.6 Hz, H-4, H-6), 4.94 (dd, 1H, J2,3Z6.0 Hz,
J3,4Z3.8 Hz, H-3), 5.19 (d, 1H, J5,OHZ5.4 Hz, OH), 7.15–
7.32 (m, 5H, Ph)); 13C NMR (75 MHz, DMSO-d6): d 35.7 (t,
C-2), 74.4 (d, C-5), 76.4 (d, C-3), 82.2 (d, C-4), 88.1 (d, C-6)
127.1, 127.3, 127.4 (all d, Ph), 136.7 (s, Ph), 176 (s, C-1)).
4.6.2. 5-C-Phenyl-L-xylo-1-pentenitol; [(1S, 2S, 3R)-1-
phenyl-pent-4-ene-1,2,3-triol] (10). Procedure as above;
protected triol 8 (600 mg, 2.56 mmol). Flash column

M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
2477
Anal. calcd for C12H12O4 (220.2): C, 65.45; H, 5.49. Found:
C, 65.28; H, 5.50.
to afford 15 (81 mg, 60%, pale yellow oil), as a mixture of
E/Z isomers (E: ZZ60:40).
E-15: 1H NMR (300 MHz, DMSO-d6): d 2.20 (dd, 2H,
J2,3Z5.9 Hz, J3,4Z7.5 Hz, H-3), 3.45 (s, 3H, Me), 3.90–
4.6.5. 3,6-Anhydro-2-deoxy-6-C-phenyl-a/b-D-gluco-
furanose (13). A flame dried 25 mL-flask with stopcock
equipped side inlet was flushed with Ar, charged with
lactone 11 (130 mg, 0.6 mmol) in dry CH2Cl2 (5 mL) and
cooled to K80 8C. Diisobutylaluminiumhydride solution
(0.8 mL, 1.2 mmol, 2 equiv, 1.5 M soln in toluene) was
added dropwise under vigorous stirring. The mixture was
kept at K80 8C for 90 min and subsequently quenched with
1 M HCl (5 mL). Water phase was separated and extracted
with AcOEt (3!10 mL). Combined organic extracts were
washed with satd NaCl, dried over Na2SO4 and evaporated.
Crude aldose 13 was isolated in 95% purity as colourless oil
(125 mg, 94%) and therefore no purification was necessary,
Rf 0.24 (50% AcOEt/hexanes). IR (KBr, cmK1): n 3455,
4.02 (m, 2H, H-5, H-6), 4.10 (dd, 1H, J3,4Z7.5 Hz, J4,5
Z
4.1 Hz, H-4), 4.38 (dd, 1H, J1,2Z13.0 Hz, J2,3Z5.9 Hz,
H-2), 4.74 (s, 1H, H-7), 5.01 (d, 1H, J5,OHZ3.6 Hz, OH),
5.15 (d, 1H, J6,OHZ4.2 Hz, OH), 6.43 (d, 1H, J1,2
Z
12.9 Hz, H-1), 7.16–7.35 (m, 5H, Ph); 13C NMR (75 MHz,
DMSO-d6): d 27.2 (t, C-3), 55.5 (q, Me), 76.7 (d, C-5), 78.3
(d, C-6), 81.6 (d, C-4), 81.7 (d, C-7), 99.0 (d, C-2), 126.5,
127.2, 127.3 (all d, Ph), 139.3 (s, Ph), 148.2 (d, C-1).
Z-15: 1H NMR (300 MHz, DMSO-d6): d 2.15–2.26 (m, 2H,
H-3), 3.55 (s, 3H, Me), 3.92 (m, 2H, H-5, H-6), 4.05–4.14
(m, 1H, J6,7Z7.5 Hz, H-7), 4.77 (d, 1H, J4,5Z4.2 Hz, H-4),
4.79 (d, 1H, J1,2Z6.3 Hz, H-2), 5.00 (d, 1H, J5,OHZ3.6 Hz,
1
3410, 2938, 1247, 1101, 1074, 1059, 996, 958 (all s). H
NMR (300 MHz, DMSO-d6, mixture of anomers in 1:8
ratio, following spectra are for major anomer): d 2.03 (dd,
OH), 5.09 (d, 1H, J6,OHZ4.5 Hz, OH), 6.03 (d, 1H, J1,2
Z
6.3 Hz, H-1), 7.16–7.35 (m, 5H, Ph); 13C NMR (75 MHz,
DMSO-d6): d 23.9 (t, C-3), 59.0 (q, Me), 77.0 (d, C-5), 78.3
(d, C-6), 80.6 (d, C-4), 81.6 (d, C-7), 102.2 (d, C-2), 126.5,
127.2, 127.3 (3! d, Ph), 139.3 (s, Ph), 147.3 (d, C-1).
2H, J1,2Z3.6 Hz, J2,3Z4.5 Hz, H-2), 4.02 (dd, 1H, J5,6
2.5 Hz, J5,OHZ5.1 Hz, H-5), 4.47 (d, 1H, J3,4Z4.5 Hz,
H-4), 4.81 (d, 1H, J5,6Z2.4 Hz, H-6), 4.85 (d, 1H, J5,OH
Z
Z
5.4 Hz, OH), 4.98 (‘q’, 1H, J2,3Z4.8 Hz, J3,4Z4.5 Hz,
H-3), 5.51 (‘q’, 1H, J1,2Z3.6 Hz, J1,OHZ4.3 Hz, H-1), 6.24
(d, 1H, J1,OHZ4.8 Hz, OH), 7.14–7.37 (m, 5H, Ph); 13C
NMR (75 MHz, DMSO-d6): d 41.5 (t, C-2), 76.2 (d, C-5),
80.7 (d, C-3), 81.7 (d, C-6), 87.0 (d, C-4), 98.8 (d, C-1),
126.8, 127.3, 127.5 (3! d, Ph), 137.6 (s, Ph).
4.6.8. (E/Z)-4,7-Anhydro-2,3-dideoxy-1-O-methyl-7-C-
phenyl-L-ido-1-heptenitol (16). Following the above pro-
cedure heptenitol 16 was obtained (80 mg, 59%) as a
mixture of E/Z isomers (E: ZZ62:38 by NMR) from
idofuranose 14 (120 mg, 0.54 mmol).
E-16: 1H NMR (300 MHz, DMSO-d6): d 2.20–2.35 (m, 2H,
4.6.6. 3,6-Anhydro-2-deoxy-6-C-phenyl-a/b-D-idofura-
nose (14). The same procedure as above was used for the
preparation of idofuranose 14 (127 mg, 95%), colourless oil,
Rf 0.24 (50% AcOEt/hexanes). 1H NMR (300 MHz,
DMSO-d6, only one anomer was detected): d 1.85 (dt, 1H,
J2A,2BZ9.0 Hz, J1,2ZJ2,3Z4.5 Hz, H-2A), 2.23 (d, 1H,
J2A,2BZ9.0 Hz, H-2B), 3.87 (dd, 1H, J5,OHZ5.1 Hz, H-5),
4.42 (d, 1H, J5,6Z2.4 Hz, H-6), 4.54 (d, 1H, J3,4Z5.7 Hz,
H-4), 4.73 (dd, 1H, J2,3Z4.5 Hz, J3,4Z5.1 Hz, H-3), 5.49
(dd, 1H, J1,2Z4.5 Hz, J1,OHZ5.1 Hz, H-1), 5.61 (d, 1H,
J5,OHZ5.1 Hz, OH), 6.25 (d, 1H, J1,OHZ5.4 Hz, OH),
7.14–7.38 (m, 5H, Ph); 13C NMR (75 MHz, DMSO-d6): d
40.8 (t, C-2), 81.8 (d, C-5), 82.9 (d, C-3), 87.9 (d, C-6), 89.0
(d, C-4), 99.1 (d, C-1), 125.9, 127.4, 128.1 (3! d, Ph),
140.6 (s, Ph).
H-3), 3.44 (s, 3H, Me), 3.80 (dd, 1H, J5,OHZ4.5 Hz, J4,5
Z
4.8 Hz, H-5), 3.84 (2! d, 2H, J6,OHZ3.6 Hz, J6,7Z3.6 Hz,
H-6, H-7), 4.46 (d, 1H, J3,4Z5.7 Hz, J4,5Z4.2 Hz, H-4),
4.76 (dd, 1H, J1,2Z12.9 Hz, H-2), 4.90 (d, 1H, J6,OH
Z
3.6 Hz, OH), 5.40 (d, 1H, J5,OHZ4.5 Hz, OH), 6.43 (d, 1H,
J1,2Z12.9 Hz, H-1), 7.20–7.44 (m, 5H, Ph); 13C NMR
(75 MHz, DMSO-d6): d 27.0 (t, C-3), 55.4 (q, Me), 77.9 (d,
C-5), 82.0 (d, C-6), 84.8 (d, C-4), 86.7 (d, C-7), 99.0 (d,
C-2), 126.4, 128.7, 128.8 (all d, Ph), 141.1 (s, Ph), 148.2 (d,
C-1).
Z-16: 1H NMR (300 MHz, DMSO-d6): d 2.30–2.40 (m, 2H,
H-3), 3.55 (s, 3H, Me), 3.80 (t, 1H, J5,OHZ4.5 Hz, J4,5
Z
4.8 Hz, H-5), 3.84 (2! d, 2H, J6,OHZ3.6 Hz, J6,7Z3.6 Hz,
H-6, H-7), 4.46 (dd, 1H, J3,4Z5.7 Hz, J4,5Z4.2 Hz, H-4),
4.76 (d, 1H, J1,2Z6.3 Hz, H-2), 4.90 (d, 1H, J6,OHZ4.2 Hz,
4.6.7. (E/Z)-4,7-Anhydro-2,3-dideoxy-1-O-methyl-7-C-
phenyl-D-gluco-1-heptenitol (15). A flame dried 100 mL-
flask with stopcock equipped side inlet was flushed with Ar,
charged with methoxymethylene–triphenyl–phosphonium
chloride (1.27 g, 3.78 mmol, 7 equiv) in dry THF (20 mL)
and cooled to K80 8C. tert-Butyllithium (2.5 mL,
3.75 mmol, 6.9 equiv, 1.5 M in pentane) was added in two
portions and the mixture was stirred at K80 8C for 1 h.
Properly prepared reagent has bright red colour. Furanose
13 (120 mg, 0.54 mmol) in THF (5 mL) was added and the
temperature was kept under K60 8C for additional 2 h.
After overnight stirring at rt water (20 mL) and diethyl ether
(50 mL) was added and separated water layer was extracted
with diethyl ether. Combined organic layers were washed
with water (30 mL) and dried over Na2SO4. Crude brown oil
was purified by flash chromatography (20 g of silica-gel,
20%, then 35% and 50% ethyl acetate in toluene as eluent)
OH), 5.40 (d, 1H, J5,OHZ4.5 Hz, OH), 6.02 (d, 1H, J1,2
Z
6.3 Hz, H-1), 7.20–7.44 (m, 5H, Ph); 13C NMR (75 MHz,
DMSO-d6): d 23.7 (t, C-3), 59.1 (q, Me), 77.6 (d, C-5), 81.0
(d, C-6), 84.7 (d, C-4), 86.5 (d, C-7), 102.2 (d, C-2), 126.4,
127.9, 128.8 (all d, Ph), 141.7 (s, Ph), 147.4 (d, C-1).
4.6.9. (C)-Goniothalesdiol (1). A solution of D-gluco-
heptenitol 15 (100 mg, 0.4 mmol) in THF (7 mL) and water
(3 mL) was acidified with H2SO4 (96%, 1 mL) and left to
stir at rt, until no starting material was detected by TLC
(approx. 3 h). The mixture was carefully neutralised with
10% NaOH solution (pHZ8) and the entire content of the
reaction flask was introduced into the freshly prepared
suspension of Ag2O (250 mg, 1.5 mmol of AgNO3 and
130 mg, 3.25 mmol of NaOH in 5 mL of deionised water,
stirred for 30 min to prepare brown suspension). After 1 h of

2478
M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
vigorous stirring colour of the suspension turned to black
and TLC detected no spots with RfO0.05 (50% AcOEt in
hexanes). The precipitate of Ag/Ag2O was filtered off
(Cellite pad) and the filtrate neutralised with 1 M HCl.
Solvents were replaced with dry MeOH (25 ml) and acidic
catex (1 g, Amberlyst 15, previously washed three times
with MeOH) was added. After 1 h of stirring at rt, catex and
inorganic salts were removed by filtration on Celitew and
the filtrate was concentrated. Crude yellow oil (100 mg),
containing mixture of methylester 1, nonesterified acid and
impurities, was distilled on Kugelrohr apparatus (190 8C/
0.05 Torr) to provide colourless oil (50 mg), a mixture of
required product 1 and lactone 17 (50:50, determined by 1H
NMR). Another esterification this mixture (10 mL of dry
MeOH, 300 mg of Amberlyst 15, 1 h at rt) afforded
analytically pure goniothalesdiol 1 (45 mg, 42%) as a
colourless oil, Rf 0.20 (50% AcOEt/hexanes), [a]2D1ZC6.9
(c 0.38, MeOH) {lit.7:[a]2D5ZC7.5 (c 0.23, EtOH), (K)-
goniothalesdiol lit.8: [a]2D7ZK7.1 (c 0.15, EtOH)}. IR
(film, cmK1): n 3448 (bs), 2956 (m), 2929 (m), 1736, 1449,
1375, 1236, 1176, 1070, 757, 700 (all s). 1H NMR
(300 MHz, CDCl3): d 2.03–2.15 (m, 2H, H-3), 2.42–2.70
(m, 2H, H-2), 3.68 (s, 3H, OMe), 4.03–4.07 (m, 3H, H-4,
H-5, H-6), 4.59 (d, 1H, J6,7Z4.5 Hz, H-7), 7.25 (d, 1H, JZ
7.0 Hz, H-40), 7.33 (t, 2H, JZ7.0 Hz, H-30, H-50), 7.41 (d,
2H, JZ7.0 Hz, H-20, H-60); 13C NMR (75 MHz, CDCl3): d
23.7 (t, C-3), 30.6 (t, C-2), 51.9 (q, OMe), 79.0 (d, C-5), 800.7
(d, C-4), 85.3 (d, C-6), 86.1 (d, C-7), 126.1 (d, C-30, C-5 ),
127.9 (d, C-40), 128.7 (d, C-20, C-60), 139.9 (s, C-10), 174.7
(s, C-1). Anal. calcd for C14H18O5 (266.3): C, 63.15; H,
6.81. Found: C, 63.38; H, 6.60.
References and notes
1. For reviews see: (a) Colquhoun, H. M.; Thompson, D. J.;
Twigg, M. V. Carbonylation; Plenum: New York, 1991. (b)
Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G.
Principles and Applications of Organotransition Metal
Chemistry; University Science Books/Oxford University
Press: Mill Valley, CA, 1987. (c) Heck, R. F. Palladium
Reagents in Organic Synthesis; Academic: London, 1990. (d)
Falbe, J. In Falbe, J., Ed.; Houben-Weyl, Methoden der
Organischen Chemie; Thieme: Stuttgart, 1986; Vol. E 18/2; 4.
Aufl. (e) Tsuji, J. Palladium Reagents and Catalyst; Wiley:
Chichester, 1995. (f) Eilbracht, P. In Helmchen, G., Hofmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Houben-Weyl,
Methoden der Organischen Chemie; Thieme: Stuttgart, 1996;
Vol. E 18/2, pp 2488–2734; 4. Aufl.. (g) Hegedus, L. S.
¨
Organische Synthese mit Ubergangsmetalle; VCH: Weinheim,
1995.
2. (a) Tamaru, Y.; Kobayashi, T.; Kawamura, S.-i.; Ochiai, H.;
Hojo, M.; Yoshida, Z.-i. Tetrahedron Lett. 1985, 26,
3207–3210. (b) Tamaru, Y.; Hojo, M.; Yoshida, Z.-i. J. Org.
Chem. 1991, 56, 1099–1105. (c) Semmelhack, M. F.;
Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496–1498. (d)
Semmelhack, M. F.; Zhang, N. J. J. Org. Chem. 1989, 54,
4483–4485. (e) Semmelhack, M. F.; Kim, C.; Zhang, N.;
Bodurow, C.; Sanner, M.; Dobler, W.; Meier, M. Pure Appl.
Chem. 1990, 62, 2035–2040.
3. (a) Tamaru, Y.; Kobayashi, T.; Kawamura, S.-i.; Ochiai, H.;
Yoshida, Z.-i. Tetrahedron Lett. 1985, 26, 4479–4482. (b)
Tamaru, Y.; Hojo, M.; Yoshida, Z.-i. J. Org. Chem. 1988, 53,
5731–5741. (c) Tamaru, Y.; Kimura, M. Synlett 1997,
749–757.
¨
4. (a) Gracza, T.; Hasenohrl, T.; Stahl, U.; Jager, V. Synthesis
¨
4.6.10. (C)-7-epi-Goniothalesdiol (2). Prepared as above
from 16 (100 mg, 0.4 mmol). In this case the second
esterification was not needed, because Kugelrohr distillation
afforded pure target compound 2 (80 mg, 75%) as colourless
oil, Rf 0.21 (50% AcOEt/hexanes), [a]2D1ZC70.3 (c 0.23,
EtOH) {lit.9:[a]2D5ZC66.6 (c 0.74, EtOH)}. IR (film, cmK1):
n 3456 (s), 2926 (m), 1717 (s), 1452, 1369, 1253, 1173,
1067, 742, 704 (all s). 1H NMR (300 MHz, CDCl3): d 2.07
(dd, 2H, J2,3ZJ3,4Z7.2 Hz, H-3), 2.40–2.65 (m, 2H, H-2),
3.70 (s, 3H, OMe), 4.16 (d, 1H, J6,7Z3.0 Hz, H-6), 4.21 (d,
1991, 1108–1118. (b) Jager, V.; Gracza, T.; Dubois, E.;
Hasenohrl, T.; Hu¨mmer, W.; Kautz, U.; Kirschbaum, B.;
Lieberknecht, A.; Remen, L.; Shaw, D.; Stahl, U.; Stephan, O.
Pd(II)-catalyzed carbonylation of unsaturated polyols and
aminopolyols. In Organic Synthesis via Organometallics OSM
5; Helmchen, G., Dibo, J., Flubacher, D., Wiese, B., Eds.;
Vieweg: Braunschweig, 1997; pp 331–360.
¨
5. (a) Gracza, T.; Jager, V. Synlett 1992, 191–193. (b) Gracza, T.;
¨
Jager, V. Synthesis 1994, 1359–1368. (c) Dixon, D. J.; Ley,
´
S. V.; Gracza, T.; Szolcsanyi, P. J. Chem. Soc., Perkin Trans 1
1999, 839–841. (d) Hu¨mmer, W.; Dubois, E.; Gracza, T.;
1H, J4,5Z2.9 Hz, H-5), 4.31 (dt, 1H, J3,4Z7.2 Hz, J4,5
Z
2.9 Hz, H-4), 5.32 (d, 1H, J6,7Z3.0 Hz, H-7), 7.25–7.43 (m,
5H, Ph); 13C NMR (75 MHz, CDCl3): d 23.5 (t, C-3), 30.6
(t, C-2), 52.0 (q, OMe), 76.9 (d, C-5), 79.1 (d, C-4), 81.4 (0d,
C-6), 82.3 (d, C-7), 126.7 (d, C-30, C-50), 127.9 (d, C-4 ),
128.6 (d, C-20, C-60), 136.8 (s, C-10), 175.1 (s, C-1). Anal.
calcd for C14H18O5 (266.3): C, 63.15; H, 6.81. Found: C,
63.42; H, 6.93.
´
Jager, V. Synthesis 1997, 6, 634–642. (e) Szolcsanyi, P.;
¨
´
Gracza, T.; Koman, M.; Pronayova, N.; Liptaj, T. Chem.
´
Commun. 2000, 471–472. (f) Szolcsanyi, P.; Gracza, T.;
´
Koman, M.; Pronayova, N.; Liptaj, T. Tetrahedron:
Asymmetry 2000, 11, 2579–2597.
6. Preliminary communication: Babjak, M.; Kapitan, P.; Gracza,
´
T. Tetrahedron Lett. 2002, 43, 6983–6985.
7. Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. H.; Pereira,
J. T.; Goh, S.-H. Tetrahedron 1998, 54, 2143–2148.
8. Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 1532–1534.
9. Yoda, H.; Shimojo, T.; Takabe, K. Synlett 1999, 1969–1971.
10. Murga, J.; Ruiz, P.; Falomir, E.; Carda, M.; Peris, G.; Marco,
J.-A. J. Org. Chem. 2004, 69, 1987–1992.
Acknowledgements
This work was supported by Slovak Grant Agencies
(VEGA, Slovak Academy of Sciences and Ministry of
Education, Bratislava, project No. 1/7314/20, and APVT,
Bratislava, project No. APVT-27-030202). The authors are
grateful to Dr. Zalupsky (Department of Organic Chemistry,
STU Bratislava) for helpful discussions and fy. TauChem
Ltd (Bratislava) for supplying chemicals.
11. Synthesis of 6 starting with D-sorbitol: Bourne, E. J.;
McSweeney, G. P.; Stacey, M.; Wiggins, L. F. J. Chem. Soc.
1952, 1408–1414.
12. Saunders, R. M.; Ballou, C. E. J. Org. Chem. 1965, 30,
3219–3220.
13. Wiggins, L. F. J. Chem. Soc. 1946, 13.

M. Babjak et al. / Tetrahedron 61 (2005) 2471–2479
2479
14. Bladon, P.; Owen, L. N. J. Chem. Soc. 1950, 591, 598.
15. Vijayasaradhi, S.; Singh, J.; Aidhen, I. S. Synlett 2000,
110–112.
Tetrahedron 1990, 46, 265–276. (g) Lee, W. W.; Chang, S.
Tetrahedron: Asymmetry 1999, 10, 4473–4476.
17. Stewart, J. J. P. J. Mol. Model. 2004, 10, 6–12.
16. For diastereoselectivity of organometallic reagents additions
to 2,3-O-isopropylidene-D-threose derivatives see: (a) Akita,
H.; Uchida, K.; Kato, K. Heterocycles 1998, 47, 157–162. (b)
Wong, T.; Wilson, P. D.; Woo, S.; Fallis, A. G. Tetrahedron
Lett. 1997, 38, 7045–7048. (c) Wu, W.-L.; Yao, Z.-J.; Li,
Y. L.; Li, J.-C.; Xia, Y.; Wu, Y.-L. J. Org. Chem. 1995, 60,
3257–3259. (d) Marco-Contelles, J.; Bernabe, M.; Ayala, D.;
Sanchez, B. J. Org. Chem. 1994, 59, 1234–1235. (e) Kanger,
T.; Liiv, M.; Pehk, T.; Lopp, M. Synthesis 1993, 91–93. (f)
Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
18. Lyapchenko, N.; Eitner, K.; Schroeder, G.; Brzezinski, B.
J. Mol. Struct. 2004, 690, 45–51.
19. For diastereoselectivity of organometallic reagents additions
to 2,3-O-isopropylidene-D-erythrose derivatives see: (a)
Fujisawa, T.; Kojima, E.; Itoh, T.; Sato, T. Tetrahedron Lett.
1985, 26, 6089–6092. (b) Corey, E. J.; Pan, B.-Ch.; Hua, D. A.;
Deardorff, D. R. J. Am. Chem. Soc. 1982, 104, 6816–6818.
20. Langer, V.; Gyepesova, D.; Koman, M.; Kapitan, P.; Babjak,
M.; Gracza, T.; Koos, M. Molecules 2003, 8, 599–606.