Studies towards the total synthesis of solanoeclepin A: Synthesis of the 7-oxabicyclo[2.2.1]heptane moiety and attempted seven-membered ring formation

Article abstract of DOI:10.1039/b201987f

This paper details studies towards the total synthesis of solanoeclepin A (1), the most active natural hatching agent of potato cyst nematodes. The first goal was the preparation of the tetracyclic left-handed substructure 2 in enantiopure form. The 7-oxabicyclo[2.2.1]heptane moiety was obtained via a diastereoselective intramolecular Diels-Alder strategy by using (R)-phenylglycinol as a chiral auxiliary as pioneered by Mukaiyama. A chromium-mediated nickel-catalysed coupling of aldehyde 5 with vinyl triflate 6 gave α,β-unsaturated lactone 18 as a single stereoisomer. The seven-membered ring was expected to arise from a McMurry coupling of dialdehyde 4. Surprisingly, oxidation of diol 24 did not lead to the desired dialdehyde 4, but to the eight-membered ring lactone 25.

Full text of DOI:10.1039/b201987f

View Article Online / Journal Homepage / Table of Contents for this issue
Studies towards the total synthesis of solanoeclepin A:
synthesis of the 7-oxabicyclo[2.2.1]heptane moiety
and attempted seven-membered ring formation
1
Jorg C. J. Benningshof, Richard H. Blaauw, Angeline E. van Ginkel, Jan H. van Maarseveen,
Floris P. J. T. Rutjes and Henk Hiemstra*
Institute of Molecular Chemistry, Universiteit van Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands. E-mail: hiemstra@science.uva.nl
Received (in Cambridge, UK) 26th February 2002, Accepted 24th May 2002
First published as an Advance Article on the web 24th June 2002
This paper details studies towards the total synthesis of solanoeclepin A (1), the most active natural hatching
agent of potato cyst nematodes. The first goal was the preparation of the tetracyclic left-handed substructure 2 in
enantiopure form. The 7-oxabicyclo[2.2.1]heptane moiety was obtained via a diastereoselective intramolecular Diels–
Alder strategy by using (R)-phenylglycinol as a chiral auxiliary as pioneered by Mukaiyama. A chromium-mediated
nickel-catalysed coupling of aldehyde 5 with vinyl triflate 6 gave α,β-unsaturated lactone 18 as a single stereoisomer.
The seven-membered ring was expected to arise from a McMurry coupling of dialdehyde 4. Surprisingly, oxidation
of diol 24 did not lead to the desired dialdehyde 4, but to the eight-membered ring lactone 25.
Introduction
Potato cyst nematodes (PCN) are responsible for major losses
in potato crops. The quest for an environmentally benign
method to control PCN has resulted in the isolation1 and
structure elucidation2 of the most active hatching agent,
solanoeclepin A (1, Fig. 1). Its complex heptacyclic structure
Fig. 1
Scheme 1
features nine stereogenic centres and all ring sizes ranging from
solanoeclepin A. An obvious way to prepare such a bicyclic
structure is via a Diels–Alder reaction of a furan. In order to
obtain both a favourable rate and regioselectivity this cyclo-
addition should be carried out in an intramolecular fashion.6–9
However, it is well-known10 that such a process usually fails
when an ester function is in the tether between the diene and
the dienophile. On the other hand, a tertiary amide can be
an excellent linking functional group.8,10 In 1981 an elegant
example was published by Mukaiyama and Iwasawa in the
synthesis of (ϩ)-farnesiferol C.11 ‡ The intramolecular Diels–
Alder reaction of the enantiopure tertiary amide 8 provided the
tricyclic lactam 7 in high yield and excellent diastereoselectivity
(Scheme 2). (R)-Phenylglycinol served as the source of chirality
in this synthesis.
three to seven. The extreme scarcity of the natural material,
its fascinating structure, and its potential role in the search for
a benign way to control PCN make 1 a challenging target for
total synthesis.3
Both this paper and the following paper in this issue detail
studies directed at the synthesis of the left-handed substructure
2 (Scheme 1). An obvious approach to arrive at tetracycle 2
would be the closure of the seven-membered ring via an acyloin
condensation. However, both the drastic conditions required
and unfavourable literature reports regarding the use of α,β-
unsaturated esters in this reaction4 led us to take a different
approach. The McMurry type pinacol coupling5 of dialdehyde
4 to diol 3 was deemed a more promising approach in view of
its proven utility in total synthesis.5 It was further assumed
that diol 3 could be readily converted into 2. Dialdehyde 4
should be available via a chromium-mediated coupling reaction
of aldehyde 5 with vinyl triflate † 6, followed by partial
reduction of the two ester groups.
The structural resemblance between lactam 7 and aldehyde
5 is obvious. The desired aldehyde 5 should be available,
successively, via hydroboration of the double bond of 7,
removal of the N-substituent and opening of the γ-lactam to an
aldehyde ester.
This strategy made aldehyde 5, containing the 7-oxabicyclo-
[2.2.1]heptane skeleton, the first goal in the synthetic route to
‡ The IUPAC name for farnesiferol C is 7-{[3-methyl-5-(1,3,3-trimethyl-
7-oxabicyclo[2.2.1]hept-2-yl)penten-2-yl]oxy}coumarin.
† The IUPAC name for triflate is trifluoromethanesulfonate.
DOI: 10.1039/b201987f
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700
This journal is © The Royal Society of Chemistry 2002
1693

View Article Online
Table 1 Hydroboration of oxabicyclic alkene 14
Hydroborating agent
Selectivity 15a : 15b
Yield 15a (%)
Diborane
Thexylborane
9-BBN
Dicyclohexylborane
Disiamylborane
50 : 50
50 : 50
91 : 9
95 : 5
92 : 8
36%
35%
56%
63%
76%
Scheme 2
Results and discussion
Synthesis of aldehyde 5
Although a literature procedure for the synthesis of the Diels–
Alder precursor 8 was available,11,12 the need for multigram
amounts required an improved route (Scheme 3). The synthesis
Scheme 3 Reagents and conditions: a, (R)-phenylglycinol, toluene,
reflux; b, NaBH4, isopropanol; c, TMSCl, pyridine, THF; d, 3,3-
dimethylacryloyl chloride then 5% HCl, H2O; e, n-BuMgCl, Et2O,
Ϫ60 ЊC then toluene reflux, 16 h; f, Hg(OAc)2, THF–H2O then NaOH,
NaBH4.
Scheme 4 Reagents and conditions: a, p-TsCl, pyridine, CH2Cl2; b,
DBU, MeCN; c, 5 M HCl; d, NaNO2, AcOH, Ac2O; e, KOH (1 equiv.),
EtOH; f, NaHCO3 (aq); g, TBDMSCl, imidazole, DMF; h, disiamyl-
borane, THF, 0 ЊC; i, NaOH, H2O2; j, TDBPSCl, imidazole, CH2Cl2;
k, HCl (cat.), EtOH; l, TPAP, NMO, acetone.
started with the condensation of freshly distilled furfural
with (R)-phenylglycinol.13 Reduction of the resulting imine
with sodium borohydride in isopropanol gave the amine 9. All
attempts to perform selective N-acylation of 9 without compet-
ing O-acylation resulted in mixtures of mono- and di-acylated
products. To circumvent this problem the hydroxy group was
first silylated leaving the amine unprotected. The latter was then
acylated with 3,3-dimethylacryloyl chloride. Acidic removal of
the silyl ether and column chromatographic purification
afforded the Diels–Alder precursor 8 in excellent overall
yield (79%, 3 steps). The intramolecular Diels–Alder reaction
employing the Mukaiyama protocol11,12 furnished lactam 7 in
both satisfactory yield and diastereoselectivity (90 : 10) on a
50 g scale. The pure diastereomer 7 was obtained in 69% yield
after recrystallisation of the reaction product and subsequent
column chromatography of the mother liquor.
At this point the introduction of a hydroxy group via
hydroboration of the double bond was investigated. To attain
good regioselectivity in this reaction the use of bulky boranes
was deemed necessary. Unfortunately, alkene hydroboration14
of the Diels–Alder product 7 by several different reagents,
including diborane and dicyclohexylborane, did not proceed in
the desired fashion. In all cases competing reduction of the
lactam carbonyl was observed. Oxymercuration with mercuric
acetate,15 however, did enable the desired chemical transform-
ation, but a 1 : 1 mixture of products 10a and 10b was obtained.
Because of this low regioselectivity it was decided to functional-
ise the double bond at a later stage of the synthesis.
by intramolecular nucleophilic attack of nitrogen.18 DBU-
mediated dehydrohalogenation gave the enamide, which upon
acidic hydrolysis yielded lactam 12 as a crystalline solid
[mp 154 ЊC; [α]2D2 = ϩ52.4 × 10Ϫ1 deg cm2 gϪ1 (c = 0.82, CHCl3)].
Hydroboration of the alkene of 12 at this point still failed
due to the vulnerability of the lactam carbonyl towards reduc-
tion. Therefore, lactam 12 was first converted into the protected
hydroxy ester 14. It is known that an N-nitrosolactam can be
converted into a γ-hydroxyester with loss of nitrogen gas.17
Thus, lactam 12 was nitrosated with sodium nitrite in acetic
acid in the presence of acetic anhydride. Then, an ethanolic
solution of the N-nitroso compound was made alkaline with
ethanolic potassium hydroxide. Neutralisation using workup by
aqueous sodium bicarbonate produced the hydroxy ester 13,
which was then protected as a silyl ether.
Gratifyingly, chemoselective hydroboration15 of the double
bond of 14 appeared to be successful (Table 1). Hydroboration
with diborane resulted in a clean reaction, but the regioselectiv-
ity was poor. Increasing the steric bulk by using thexylborane§
did not lead to better selectivity. Fortunately, 9-borabicyclo-
[3.3.1]nonane, dicyclohexyl- and disiamylborane§ gave good
regioselectivity. The desired isomer 15a was obtained in good
yield after separation from its regioisomer 15b by column
chromatography. The highest yield of 15a was obtained by
using disiamylborane, because in this case the alcohol
byproduct resulting from the borane substituent could be best
separated by column chromatography.
Removal of the N-substituent in 7 was then attempted.
Because of the presence of the allylic oxygen bridge, reductive
methods16 were expected to fail, therefore a new non-reductive
one-pot procedure had to be developed.17 The first step was
transformation of the hydroxy group into a good leaving group
by treatment with toluene-p-sulfonyl chloride (Scheme 4).
Under these conditions chloride 11 was obtained. The form-
ation of this chloride can be explained by invoking an azirid-
inium intermediate, which was formed after tosylation followed
To complete the synthesis of aldehyde 5 the secondary
hydroxy group was protected with the large and robust tert-
butyldiphenylsilyl protecting group. Selective deprotection
§ The IUPAC name for thexyl is 1,1,2-trimethylpropyl. The IUPAC
name for disiamyl is 1,2-dimethylprop-1-yl.
1694
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700

View Article Online
of the primary hydroxy group with a catalytic amount of
hydrochloric acid in ethanol and subsequent TPAP–NMO
oxidation19 furnished the enantiopure aldehyde 5, which was
synthesised in 11 steps with an overall yield of 13% from
furfural.
Attempted seven-membered ring formation
A chromium-mediated nickel-catalysed coupling20 of aldehyde
5 with vinyl triflate 621 using the conditions of Knochel and
Rao 22 afforded a γ-hydroxy ester, which lactonised under
the reaction conditions to give the α,β-unsaturated lactone
18 (Scheme 5). This lactone was isolated as a stable crystalline
Fig. 2 ORTEP plot of the crystal structure of 20.
Scheme 5 Reagents and conditions: a, CrCl2 (4 equiv.), NiCl2 (cat.),
DMF, 50 ЊC, 18 h; b, HFؒpyridine, THF; c, TPAP, NMO, acetone.
solid (mp 101 ЊC; [α]2D2 = ϩ8.57 × 10Ϫ1 deg cm2 gϪ1 (c = 1.21,
CHCl3)). Surprisingly, only a single isomer was found where
a mixture of diastereomers was expected. Possibly some type
of chromium chelation is responsible for the stereoselective
result of this reaction.
It was not possible to determine the relative configuration of
the new stereogenic centre by 1H NMR experiments. Therefore,
an X-ray crystal structure of lactone 18 was desired. However,
the crystals of lactone 18 appeared to be unsuitable for X-ray
measurements. Removal of the silyl protecting group and
subsequent TPAP, NMO oxidation of alcohol 19 afforded the
highly crystalline ketone 20 (mp 168.5–169.5 ЊC; [α]1D9 = ϩ98.0 ×
10Ϫ1 deg cm2 gϪ1 (c = 1.25, CHCl3)). The X-ray analysis of this
latter compound revealed an (S)-configuration for the newly
formed centre in the lactone ring, based on the known absolute
configuration of the remaining three stereocentres originally
derived from the starting material, (R)-phenylglycinol11 (see
Fig. 2).
Knowing that lactone 18 possesses the correct stereo-
chemistry the synthesis of dialdehyde 4 was investigated. The
two ester groups of 18 were cleanly reduced (Scheme 6) by rapid
addition of lithium aluminium hydride to the lactone in diethyl
ether at room temperature. The solvent and temperature
appeared crucial to achieve a good yield of triol 21. Before the
primary hydroxy groups in 21 could be oxidised, the secondary
hydroxy group had to be protected. The following three-step
procedure was used for this purpose. First, both primary
hydroxy groups of 21 were protected as TBDMS ethers. Then
the secondary alcohol in 22 was acetylated and finally acidic
cleavage of the two primary silyl ethers of 23 with camphor-
sulfonic acid (CSA) in methanol yielded diol 24 in good overall
yield.
Scheme 6 Reagents and conditions: a, LiAlH4, Et2O, rt, 15 min;
b, TBDMSCl, pyridine, DMF; c, Ac2O, pyridine; d, CSA, MeOH, rt;
e, TPAP, NMO, acetone.
remaining hydroxy groups then resulted in the eight-membered
ring lactol and this process is apparently faster than oxidation
of the second primary hydroxy group. The oxidising agent then
converted the lactol into lactone 25. Alternative oxidative
methods such as pyridinium chlorochromate and activated
manganese dioxide could not circumvent this problem as these
oxidizing agents gave the same lactone as the sole product.
An attempted Swern oxidation led to a complex mixture of
products.
Having established that the synthesis of dialdehyde 4 could
not be readily realised, our plan to construct the desired
seven-membered ring via 4 was abandoned. A different and
successful approach to close the seven-membered ring was then
investigated, which will be reported in the next article in this
issue.24
Conclusion
In this paper, the synthesis of aldehyde 5 in enantiopure form
has been reported. A chromium-mediated nickel-catalysed
coupling reaction of 5 with vinyl triflate 6 produced lactone 18
with perfect stereocontrol. Unfortunately, further transform-
ation of 18 to prepare the seven-membered ring failed, because
it was not possible to prepare the dialdehyde 4 required for a
McMurry coupling. A new approach has been developed which
will be discussed in the following paper.24
Surprisingly, perruthenate oxidation of diol 24 did not give
the expected dialdehyde. Instead, the eight membered ring
lactone 25 was rapidly formed in a surprisingly good yield.23
The allylic alcohol was probably oxidised first to give the
corresponding allylic aldehyde. Intramolecular attack of the
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700
1695

View Article Online
extracted with Et2O (3 × 400 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (2 × 400 mL)
followed by brine. Evaporation of the solvent and column
chromatography (petroleum ether–Et2O (1 : 5)) afforded amide
9 (139 g, 464 mmol, 87%, 2 steps) as a yellow oil. Rf = 0.21
(petroleum ether–Et2O (1 : 5)); [α]2D2 Ϫ89.1 (c = 1.03, CHCl3);
(lit.12 [α]2D2 Ϫ88.5 (c = 0.853, CHCl3)); IR 3383 (br), 3030,
2935, 1608, 1452; 1H NMR (400 MHz, 360 K, toluene-d6)
δ 7.14–6.95 (6H, m), 5.97 (2H, m), 5.89 (1H, s), 5.35 (1H, m),
4.36 (1H, d, J = 16.7 Hz), 4.07 (1H, d, J = 16.6 Hz), 3.99–3.87
(2H, m), 1.93 (3H, s), 1.57 (3H, s); HRMS (EI) calcd for
C18H21NO3: 299.1521, found: 299.1526.
Experimental
General
All reactions involving oxygen or moisture sensitive compounds
were carried out under a dry nitrogen atmosphere. THF and
Et2O were distilled from sodium and CH2Cl2 was distilled from
CaH2. DMF and toluene were distilled from CaH2 and stored
over 4 Å molecular sieves. Triethylamine was stored over KOH
pellets and DMSO was dried and stored over 4 Å molecular
sieves. Column chromatography was performed using Acros
silica gel (0.030–0.075 mm). Petroleum ether (60–80) used for
chromatography was distilled prior to use. TLC analyses were
performed on Merck F-254 silica gel plates. IR spectra were
measured as thin films on NaCl plates unless otherwise noted
using a Bruker IFS 28 FT-spectrophotometer and wavelengths
(؊)-(1R,5S,7S)-3-[(1R)-2-Hydroxy-1-phenylethyl]-6,6-
dimethyl-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-en-4-one (7)
(ν) are reported in cmϪ1. H NMR spectra were recorded on a
1
A solution of alcohol 8 (45.5 g, 152 mmol) in Et2O (850 mL)
was cooled to Ϫ60 ЊC. To the reaction mixture was added
freshly prepared n-butylmagnesium chloride (176 mL of a
0.95 M solution in Et2O, 167 mol, 1.1 equiv.). After 45 min the
cooling bath was removed and the yellow suspension was
allowed to warm to rt. Then the solvent Et2O was replaced
by toluene by distilling off the Et2O while toluene was continu-
ously added (650 mL). After all the Et2O had been removed
(approximately 2 h) the clear solution was refluxed for 16 h.
After cooling to rt HCl (650 mL of a 5% aqueous solution, 0.86
mol) was added and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 500 mL). The combined
organic layers were washed with saturated aqueous NaHCO3
followed by brine and subsequently dried over Na2SO4. The
solvent was removed in vacuo. Recrystallisation (CH2Cl2–
petroleum ether) afforded the Diels–Alder product 7 (19.8 g,
66.2 mmol, 44%) as a yellow crystalline solid. To collect an
extra portion of the Diels–Alder product, the mother liquor
was concentrated and purified by column chromatography
(EtOAc) (11.6 g, 38.8 mmol, 25%) (and its diastereoisomer
(3.6 g, 12,1 mmol, 8%)). (Combined yield of 7: 31.4 g, 104
mmol, 69%.) Rf = 0.13 (EtOAc); mp 154.1 ЊC; [α]2D2 Ϫ83.6 (c =
1.30, MeOH)); (lit.11 mp 155.5–156.5 ЊC; [α]2D5 Ϫ85.1 (c = 6.61,
MeOH); IR (KBr) 3469 (br), 2960, 1676, 1355, 1060; 1H NMR
(400 MHz) δ 7.36–7.28 (2H, m), 7.27–7.23 (3H, m), 6.45–6.41
(2H, m), 5.19 (1H, dd, J = 8.8, 4.2 Hz), 4.40 (1H, d, J = 1.2 Hz),
4.17 (1H, dd, J = 11.9, 4.3 Hz), 4.06 (1H, dd, J = 11.9, 8.8 Hz),
3.88 (1H, d, J = 11.7 Hz), 3.48 (1H, d, J = 11.7 Hz), 2.77 (1H,
br s), 2.17 (1H, s), 1.42 (3H, s), 1.04 (3H, s); 13C NMR (50
MHz) δ 174.3, 136.7, 136.2, 134.0, 128.8, 127.6, 126.8, 90.2,
88.1, 62.6, 57.6, 57.3, 46.7, 41.9, 25.4, 25.3; HRMS (FAB)
[M ϩ Hϩ] calcd for C18H22NO3: 300.1600, found: 300.1608.
Bruker AC 200 (200 MHz), a Bruker ARX 400 (400 MHz) and
a Varian Inova (500 MHz). The latter machines were also used
for 13C NMR spectra (50, 100 and 125 MHz respectively).
Unless otherwise indicated, CDCl3 was used as the solvent.
Chemical shifts are given in ppm (δ) relative to an internal
1
standard of chloroform (7.26 ppm for H-NMR and 77.0 for
13C-NMR). Mass spectra and accurate mass determinations
were performed on a JEOL JMS SX/SX102A, coupled to a
JEOL MS-MP7000 data system. Elemental analyses were per-
formed by Dornis u. Kolbe Mikroanalytisches Laboratorium,
Mülheim an der Ruhr, Germany. Optical rotations were
measured with a Perkin-Elmer 241 polarimeter in a 1 dm cell in
the indicated solvent, and are given in units of 10Ϫ1 deg cm2 gϪ1
.
(؊)-(2R)-2-[(Furan-2-ylmethyl)amino]-2-phenylethanol (9)
To a solution of (R)-2-phenylglycinol13 (84 g, 0.61 mol) in tolu-
ene (575 mL) was added furfural (60.9 mL, 0.74 mol, 1.2 equiv.)
in toluene (150 mL) and the reaction mixture was refluxed
under Dean–Stark conditions for 2 h. After evaporation of the
toluene the crude imine was dissolved in isopropanol (900 mL)
and cooled to 0 ЊC. Then NaBH4 (51.2 g, 1.35 mol, 2.2 equiv.)
was added in portions (4–5 g) over 15 min and the reaction
mixture was allowed to warm to rt. The mixture was stirred for
16 h followed by acidification with HCl (290 mL of a 5 M
aqueous solution, 1.45 mol) and most of the organic solvents
were evaporated. After neutralisation of the aqueous layer with
NaOH (5% solution in water) the aqueous layer was extracted
with Et2O (3 × 400 mL). The combined organic layers were
washed with brine and subsequently dried over Na2SO4.
Removal of the solvent afforded crude aminoalcohol 9 (121 g,
0.56 mol, 91%) as a solid, which was used in the next step
without purification. Rf = 0.80 (petroleum ether–Et2O (1 : 5));
mp 52.0–52.5 ЊC; [α]2D2 Ϫ99.8 (c = 0.88, CHCl3); (lit.12 mp 50.5–
51.5 ЊC; [α]2D2 Ϫ100 (c = 0.97, CHCl3)); IR 3340 (br), 2925, 2869,
1451, 1028; 1H NMR (400 MHz) δ 7.40–7.25 (6H, m), 6.29 (1H,
d, J = 2.0 Hz), 6.12 (1H, d, J = 2.9 Hz), 3.80 (1H, dd, J = 8.4, 4.3
Hz), 3.78 (1H, dd, J = 10.7, 4.4 Hz), 3.71–3.67 (1H, m), 3.62
(1H, dd, J = 11.8, 3.0 Hz), 3.59 (1H, dd, J = 10.8, 8.1 Hz), 2.50–
2.20 (2H, br s); 13C NMR (100 MHz) δ 153.4, 141.8, 140.0,
128.6, 127.6, 127.3, 110.0, 107.0, 66.7, 63.4, 43.6; HRMS (FAB)
[M ϩ Hϩ] calcd for C13H16NO2: 218.1181, found: 218.1177.
(1R,5S,7R,8R)-8-Hydroxy-3-[(1R)-2-hydroxy-1-phenylethyl]-
6,6-dimethyl-10-oxa-3-azatricyclo[5.2.1.01,5]decan-4-one (10a)
and (1R,5S,7S,9S)-9-hydroxy-3-[(1R)-2-hydroxy-1-phenyl-
ethyl]-6,6-dimethyl-10-oxa-3-azatricyclo-[5.2.1.01,5]-decan-4-one
(10b)
The Diels–Alder product 7 (202 mg, 0.68 mmol) and mercuric
acetate (216 mg, 0.68 mmol, 1 equiv.) were dissolved in THF
(1 mL) and water (1 mL). The colourless reaction mixture was
stirred for 16 h at rt. To the yellow mixture was added NaOH
(1.0 mL of a 3 M aqueous solution) followed by NaBH4 (51 mg,
1.3 mmol, 2 equiv.). The gray solution was saturated with NaCl,
extracted with THF (3 × 5 mL) and dried over Na2SO4. Evap-
oration afforded diol 10a and its regioisomer 10b as a 50 : 50
mixture (168 mg, 0.53 mmol, 78%), which was separated by
(؊)-(2R)-N-Furan-2-ylmethyl-N-(2-hydroxy-1-phenylethyl)-3-
methylbut-2-enamide (8)
To a solution of crude aminol 9 (116 g, 534 mmol) in THF (800
mL) was added chlorotrimethylsilane (74.9 mL, 867 mmol, 1.6
equiv.) and pyridine (47.5 mL, 587 mmol, 1.1 equiv.). The
reaction mixture was stirred for 1 h. To the reaction mixture
was added pyridine (95.0 mL, 1.17 mol, 2 equiv.) followed by
3,3-dimethylacryloyl chloride (74.4 mL, 668 mmol, 1.3 equiv.)
and stirring was continued for 16 h. The mixture was cooled to
0 ЊC, acidified to pH = 2 with HCl (1 M aqueous solution) and
1
chromatography. 10a: H NMR (400 MHz) δ 7.37–7.20 (5H,
m), 5.15 (1H, m), 4.15–3.87 (4H, m), 3.67 (1H, d, J = 10.2 Hz),
3.34 (1H, d, J = 10.2 Hz), 2.43 (1H, dd, J = 13.2, 6.5 Hz),
2.35–2.15 (1H, br s), 2.14 (1H, s), 1.56 (1H, m), 1.23 (3H, s),
1
1.12 (3H, s). 10b: H NMR (400 MHz) δ 7.35–7.19 (5H, m),
5.13 (1H, m), 4.15–3.99 (4H, m), 3.95–3.92 (2H), 2.45–2.41
(1H, m), 2.13 (1H, s), 1.54 (1H, m), 1.26 (3H, s), 1.13 (3H, s).
1696
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700

View Article Online
(1R,5S,7S)-3-[(1R)-2-Chloro-1-phenylethyl]-6,6-dimethyl-10-
oxa-3-azatricyclo[5.2.1.01,5]dec-8-en-4-one (11)
dried over Na2SO4. Evaporation of the solvent afforded
hydroxy ester 13 (7.2 g, 32 mmol, 58%) as a brown oil, which
was protected in the next step without purification. IR 3453,
2977, 2873, 1736, 1179, 1160, 1023; 1H NMR (400 MHz) δ 6.49
(1H, dd, J = 5.7, 1.8 Hz), 6.38 (1H, d, J = 5.7 Hz), 4.39 (1H, d,
J = 1.7 Hz), 4.35 (1H, d, J = 11.5 Hz), 4.21–4.11 (2H, m),
4.03 (1H, d, J = 11.5 Hz), 2.30 (1H, br s), 2.22 (1H, s), 1.27 (3H,
t, J = 7.1 Hz), 1.17 (3H, s), 1.06 (3H, s); 13C NMR (50 MHz,
C6D6) δ 172.9, 138.4, 136.2, 93.1, 87.7, 61.8, 60.8, 56.5, 45.6,
26.9, 25.8, 15.1; HRMS (FAB) [M ϩ Hϩ] calcd for C12H19O4:
227.1283, found: 227.1288.
To a solution of Diels–Alder product 7 (61.4 g, 0.21 mol) in
CH2Cl2 (400 mL) was added toluene-p-sulfonyl chloride (77.8 g,
0.41 mol, 2 equiv.) followed by pyridine (42 mL, 0.52 mol, 2.5
equiv.). The brown solution was stirred at rt for 16 h. To achieve
complete conversion the reaction mixture was heated at 50 ЊC
for another 3 h. Then water was added (500 mL) and the
aqueous layer was extracted with CH2Cl2 (3 × 500 mL). The
combined organic layers were washed with brine and sub-
sequently dried on Na2SO4. Evaporation of the solvent gave
chloride 11 as a brown oil, which was used crude in the next
(؉)-(1R,2S,4S)-1-(tert-Butyldimethylsilyloxymethyl)-3,3-
dimethyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid ethyl
ester (14)
1
reaction. Rf = 0.55 (EtOAc); H NMR (400 MHz) δ 7.41–7.37
(2H, m), 7.35–7.27 (3H, m), 6.46 (2H, m), 5.56 (1H, dd,
J = 10.0, 4.8 Hz), 4.41 (1H, d, J = 1.2 Hz), 4.10 (1H, dd, J = 11.8,
4.9 Hz), 3.95 (1H, dd, J = 11.7, 10.0 Hz), 3.90 (1H, d, J = 11.3
Hz), 3.51 (1H, d, J = 11.3 Hz), 2.18 (1H, s), 1.42 (3H, s), 1.05
(3H, s).
Hydroxy ester 13 (468 mg, 2.12 mmol) was dissolved in CH2Cl2
(5 mL). To this solution was added TBDMSCl (477 mg,
3.16 mmol, 1.5 equiv.) and imidazole (288 mg, 4.2 mmol,
2.0 equiv.). The reaction mixture was stirred for 16 h and
poured into water (15 mL). After separation of the organic
layer the water layer was extracted with CH2Cl2 (2 × 15 mL).
Evaporation of the solvent and purification by column chroma-
tography (petroleum ether–Et2O (9 : 1)) afforded protected
alcohol 14 (646 mg, 1.93 mmol, 91%) as a colourless oil. Rf =
0.46 (petroleum ether–Et2O (2 : 1)); [α]2D1 ϩ19.4 (c = 1.08,
CHCl3); 1H NMR (400 MHz) δ 6.44–6.41 (2H, m), 4.33 (1H, d,
J = 1.4 Hz), 4.30 (1H, d, J = 9.8 Hz), 4.19–4.07 (2H, m), 3.97
(1H, d, J = 9.8 Hz), 2.21 (1H, s), 1.26 (3H, t, J = 7.1 Hz), 1.14
(؉)-(1R,5S,7S)-6,6-Dimethyl-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-en-4-one (12)
To a solution of chloride 11 (65.9 g, 0.21 mol) in acetonitrile
(225 mL) was added DBU (64 mL, 0.42 mol, 2 equiv.) and the
dark reaction mixture was stirred at rt for 16 h. Then the
reaction mixture was poured into water (200 mL) and after
separation of the organic layer the water layer was extracted
with CH2Cl2 (2 × 300 mL). The combined organic layers were
washed with brine, dried over Na2SO4 and the solvent was
removed in vacuo. The dark crude product was dissolved in
CH2Cl2 (100 mL) and HCl (160 mL of a 5 M aqueous solution)
was added to hydrolyse the enamide. After 30 min of vigorous
stirring the layers were separated and the aqueous layer was
extracted with chloroform (4 × 200 mL). The combined organic
layers were washed with brine and subsequently dried over
Na2SO4 and the solvent was removed in vacuo. Column
chromatography (EtOAc–MeOH (19 : 1)) afforded lactam
12 (33.8 g, 0.19 mol, 90%) as a light yellow solid. Rf = 0.31
(EtOAc–MeOH (19 : 1)); mp 154.2 ЊC; [α]2D2 ϩ52.4 (c = 0.82,
(3H, s), 1.04 (3H, s), 0.88 (9H, s), 0.06 (3H, s), 0.04 (3H, s); 13
C
NMR (100 MHz) δ 172.0, 137.3, 135.2, 91.1, 86.9, 61.1, 59.8,
54.7, 44.2, 26.4, 25.7, 25.0, 18.0, 14.3, Ϫ5.5, Ϫ5.7.
(؉)-(1R,2S,4R,5S)-1-(tert-Butyldimethylsilyloxymethyl)-5-
hydroxy-3,3-dimethyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic
acid ethyl ester (15a) and (؉)-(1R,2S,4S,6R)-1-(tert-butyldi-
methylsilyloxymethyl)-6-hydroxy-3,3-dimethyl-7-oxabicyclo-
[2.2.1]heptane-2-carboxylic acid ethyl ester (15b)
A solution of 2-methylbut-2-ene (2.0 mL of a 2.0 M solution in
THF, 4 mmol, 2 equiv.) was cooled to 0 ЊC. To this solution was
added dropwise a borane–methyl sulfide complex (2.0 mL,
2.0 mmol). The reaction mixture was allowed to warm to rt and
stirring was continued for 4 h resulting in a 1.0 M solution of
disiamylborane in THF. A solution of 14 (96 mg, 0.29 mmol) in
THF (1.0 mL) was cooled to 0 ЊC. To this solution was added
disiamylborane (0.6 mL of a 1.0 M solution in THF, 0.6 mmol,
2.0 equiv.). The colourless reaction mixture was stirred at 0 ЊC
for 3 h. Then NaOH (1.0 mL of a 2.0 M solution, 2.0 mmol,
6.8 equiv.) was carefully added followed by H2O2 (2.0 mL of a
35 wt% solution in water, 20 mmol, excess) and stirring was
continued at rt for 2 h. NH4Cl (5 mL) was added and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with brine and then dried
over Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (1 : 3)) furnished
alcohol 15a (79 mg, 0.22 mmol, 76%) and its regioisomer 15b
(7.5 mg, 0.02 mmol, 7%) as colourless oils. 15a: Rf = 0.18
(petroleum ether–EtOAc (6 : 4)); [α]2D0 ϩ14.3 (c = 1.12, CHCl3);
1
CHCl3); IR 3288 (br), 2959, 1698, 1666, 1356, 1070; H NMR
(400 MHz) δ 6.47–6.44 (2H, m), 6.43 (1H, br s), 4.39 (1H, d, J =
1.2 Hz), 3.82 (1H, d, J = 11.6 Hz), 3.62 (1H, d, J = 11.5 Hz), 2.16
(1H, s), 1.41 (3H, s), 1.02 (3H, s); 13C NMR (50 MHz) δ 176.3,
136.2, 134.1, 93.1, 88.2, 55.7, 44.6, 41.6, 26.4, 25.1; HRMS (EI)
calcd for C10H13NO2: 179.0946, found: 179.0942; anal. calcd
for C10H13NO2: C 67.02, H 7.31, N 7.82, found: C 66.85, H 7.27,
N 7.76%.
(1R,2S,4S)-1-Hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]-
hept-5-ene-2-carboxylic acid ethyl ester (13)
To a solution of lactam 12 (10.0 g, 55.8 mmol) in HOAc (78
mL) and acetic anhydride (225 mL) was added sodium nitrite
(11.5 g, 167 mmol, 3 equiv.). The reaction mixture turned
yellow immediately and a brown gas escaped. After stirring at
rt for 30 min the solvents were evaporated and the remaining
solid was dissolved in EtOAc (200 mL) followed by washing
with saturated aqueous NaHCO3 (4 × 250 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. To
remove residual acetic acid from the crude product the reaction
mixture was concentrated after the addition of toluene pro-
viding sufficiently pure N-nitrosolactam.
A solution of this N-nitrosolactam (11.5 g, 55.3 mmol) in
EtOH (250 mL) was cooled to Ϫ20 ЊC. To this ethanolic
solution was added 67 mL of a 5% potassium hydroxide
solution in ethanol (59.3 mmol, 1.05 equiv.). The resulting dark
brown reaction mixture was stirred for 20 min at Ϫ20 ЊC and
then poured into saturated aqueous NaHCO3 (200 mL) at 0 ЊC.
The aqueous layer was extracted with EtOAc (3 × 250 mL) and
the organic layers were washed with brine and subsequently
1
IR 3383 (br), 2926, 2851, 1740, 1110; H NMR (400 MHz)
δ 4.29 (1H, dd, J = 6.7, 1.5 Hz), 4.22 (1H, d, J = 9.8 Hz), 4.12–
4.07 (2H, m), 3.94 (1H, d, J = 9.8 Hz), 3.82 (1H, d, J = 1.5 Hz),
2.30 (1H, s), 2.13 (1H, dd, J = 13.8, 6.8 Hz), 1.95–1.72 (1H,
br s), 1.62 (1H, d, J = 13.8 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.18
(3H, s), 10.4 (3H, s), 0.86 (9H), 0.05 (3H, s), 0.02 (3H, s). 15b: Rf
= 0.43 (petroleum ether–EtOAc (6 : 4)); [α]2D2 ϩ17.3 (c = 1.21,
1
CHCl3); H NMR (400 MHz) δ 4.40 (1H, dd, J = 9.6 Hz),
4.15–3.99 (3H, m), 3.96–3.94 (2H, m), 2.45–2.41 (1H, m), 2.29–
2.21 (1H, br s), 2.12 (1H, s), 1.55–1.45 (1H, m), 1.26 (3H, t, J
= 7.2 Hz), 1.12 (3H, s), 1.01 (3H, s), 0.87 (9H, s), 0.06 (3H, s),
0.03 (3H, s, SiCH3).
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700
1697

View Article Online
(؉)-(1R,2S,4R,5S)-1-(tert-Butyldimethylsilyloxymethyl)-5-
(tert-butyldiphenylsilyloxy)-3,3-dimethyl-7-oxabicyclo[2.2.1]-
heptane-2-carboxylic acid ethyl ester (16)
135.8, 135.6, 134.8, 133.8, 133.4, 129.9, 129.8, 129.6, 127.8,
127.7, 91.8, 90.6, 70.9, 62.2, 60.8, 44.2, 43.4, 26.8, 24.5, 24.1,
19.0, 14.2; HRMS (FAB) [M ϩ Hϩ] calcd for C28H37O5Si:
481.2410, found: 481.2372.
To a solution of alcohol 15a (585 mg, 1.63 mmol) in CH2Cl2
(25 mL) was added TBDPSCl (636 µL, 2.44 mmol, 1.5 equiv.)
and imidazole (222 mg, 3.26 mmol, 2.0 equiv.). The mixture was
stirred at rt for 16 h. Then the reaction mixture was poured
in water (25 mL) and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic layers were washed with brine and sub-
sequently dried over Na2SO4 and the solvent was removed in
vacuo. Column chromatography (petroleum ether–EtOAc
(9 : 1)) afforded protected alcohol 16 (831 mg, 1.50 mmol, 92%)
as a colourless oil. Rf = 0.73 (petroleum ether–Et2O (1 : 1)); [α]2D0
(؉)-(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-3,3-dimethyl-
1-[(1S)-3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-1-yl]-7-
oxabicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (18)
To a solution of aldehyde 5 (1.03 g, 2.14 mmol) in DMF (8 mL)
was added vinyl triflate 621 (1.60 g, 5.30 mmol, 2.5 equiv.)
followed by CrCl2 (1.33 g, 10.8 mmol, 5 equiv.) and NiCl2 (7.4
mg, 57 µmol, ca. 2 mol%). The resulting green suspension was
stirred at 50 ЊC for 16 h. After cooling the mixture to 0 ЊC, the
reaction was quenched by adding saturated aqueous NH4Cl
(5 mL) followed by water (15 mL). The aqueous mixture was
extracted with EtOAc (3 × 40 mL). The combined organic
layers were washed with brine and subsequently dried over
Na2SO4 and the solvent was removed in vacuo. Column
chromatography (petroleum ether–Et2O (4 : 1)) afforded
lactone 18 (873 mg, 1.48 mmol, 69%) as a white solid. Rf = 0.23
(petroleum ether–Et2O (1 : 1)); mp 101.5 ЊC; [α]2D2 ϩ 8.57 (c =
1.2, CHCl3); IR 3070, 2935, 2858, 1760, 1737, 1111, 1066, 1024;
1H NMR (400 MHz) δ 7.64 (2H, d, J = 6.7 Hz), 7.55 (2H, d, J =
6.7 Hz), 7.56–7.36 (6H, m), 5.91 (1H, s), 4.30 (1H, d, J = 6.0
Hz), 4.12–4.07 (2H, m), 3.6 (1H, s), 2.83–2.77 (1H, m), 2.44–
2.39 (1H, m), 2.27–2.24 (3H, m), 1.77–1.72 (6H, m), 1.22 (3H, t,
J = 7.1 Hz), 1.03 (9H, s), 0.86 (3H, s), 0.78 (3H, s); 13C NMR
(100 MHz) δ 173.2, 170.4, 164.0, 135.6, 135.4, 133.6, 133.1,
129.8, 127.8, 127.7, 127.6, 127.6, 91.6, 86.6, 80.3, 71.2, 60.1,
60.0, 43.0, 41.5, 26.6, 24.9, 24.5, 24.2, 21.5, 21.6, 20.0, 18.8,
14.1; HRMS (FAB) [M ϩ Hϩ] calcd for C35H45O6Si: 589.2985,
found: 589.2983; anal. calcd for C35H44O6Si: C 71.39, H 7.53,
found: C 71.30, H 7.42.
1
ϩ11.0 (c = 1.31, CHCl3); IR 3018, 2958, 2858, 1740, 1111; H
NMR (400 MHz) δ 7.68 (2H, d, J = 7.9 Hz), 7.64 (2H, d, 7.9
Hz), 7.44–7.35 (6H, m), 4.34 (1H, dd, J = 6.9, 2.4 Hz), 4.26 (1H,
d, J = 9.7 Hz), 4.11–3.99 (2H, m), 3.95 (1H, d, J = 9.7 Hz), 3.62
(1H, s), 2.11 (1H, s), 1.98 (1H, dd, J = 12.8, 7.0 Hz), 1.77 (1H,
dd, J = 12.8, 1.9 Hz), 1.20 (3H, t, J = 7.1 Hz), 1.06 (9H, s), 0.86
(9H, s), 0.84 (3H, s), 0.72 (3H, s), 0.05 (3H, s), 0.02 (3H, s); 13
C
NMR (100 MHz) δ 170.9, 135.8, 135.7, 134.1, 133.9, 129.7,
129.6, 127.6, 91.8, 88.1, 71.9, 63.4, 59.6, 59.0, 47.0, 42.9, 26.9,
25.7, 25.1, 24.6, 19.1, 18.1, 14.3, Ϫ5.5, Ϫ5.6; HRMS (FAB)
[M ϩ Hϩ] calcd for C34H53O5Si2: 597.3432, found: 597.3437.
(؉)-(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-1-hydroxy-
methyl-3,3-dimethyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic
acid ethyl ester (17)
Compound 16 (831 mg, 1.5 mmol) was dissolved in EtOH
(25 mL) and concentrated HCl (250 µL) was added. After
60 min saturated aqueous NaHCO3 (50 mL) was added to
quench the reaction. The aqueous layer was extracted with
CH2Cl2 (3 × 75 mL). The combined organic layers were washed
with brine and subsequently dried over Na2SO4. Evaporation
of the solvents and column chromatography (petroleum ether–
Et2O (1 : 1)) afforded alcohol 17 (622 mg, 1.3 mmol, 86%) as a
colourless oil. Rf = 0.22 (petroleum ether–Et2O (1 : 1)); [α]2D0
ϩ14.5 (c = 0.91, CHCl3); IR 3469 (br), 3070, 2958, 2857, 1738,
1110, 1068; 1H NMR (400 MHz) δ 7.68 (2H, d, J = 8.0 Hz), 7.63
(2H, d, J = 8.0 Hz), 7.45–7.36 (6H, m), 4.37 (1H, dd, J = 6.6, 2.8
Hz), 4.20 (1H, d, J = 11.8 Hz), 4.12–4.02 (2H, m), 3.94 (1H, d,
J = 11.8 Hz), 3.67 (1H, s), 2.23 (1H, br s), 2.12 (1H, s), 1.91 (1H,
dd, J = 12.8, 2.7 Hz), 1.85 (1H, dd, J = 12.7, 6.6 Hz), 1.21 (3H, t,
J = 7.1 Hz), 1.06 (9H, s), 0.88 (3H, s), 0.75 (3H, s); 13C NMR
(100 MHz) δ 171.6, 135.8, 135.7, 134.0, 133.8, 129.8, 129.7,
127.7, 91.7, 88.0, 72.1, 62.5, 60.2, 59.6, 46.0, 43.8, 26.8, 24.8,
(؉)-(1R,2S,4R,5S)-5-Hydroxy-3,3-dimethyl-1-[(1S)-3-oxo-
1,3,4,5,6,7-hexahydroisobenzofuran-1-yl]-7-oxabicyclo[2.2.1]-
heptane-2-carboxylic acid ethyl ester (19)
A solution of lactone 18 (52 mg, 88 µmol) in THF (1 mL) was
cooled to 0 ЊC. To this solution was added HFؒpyridine (70%
HF, 30% pyridine, 0.2 mL). The mixture was allowed to warm
to rt and stirring was continued for 8 h. The reaction was care-
fully quenched by adding saturated aqueous NaHCO3 (3 mL)
and water (5 mL) and was extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with brine and
subsequently dried over Na2SO4 and the solvent was removed
in vacuo. Column chromatography (petroleum ether–Et2O
(7 : 1 3 : 1)) afforded alcohol 19 (29 mg, 83 µmol, 94%) as a
white solid. Rf = 0.13 (petroleum ether–Et2O (1 : 3)); [α]2D0 ϩ17.3
(c = 1.37, CHCl3); IR 3470 (br), 2941, 1756, 1738, 1670, 1159,
24.3, 19.0, 14.3; HRMS (FAB) [M
C28H38NaO5 Si: 505.2386, found: 505.2372.
ϩ
Naϩ] calcd for
1
1008; H NMR (400 MHz) δ 5.92 (1H, s), 4.37 (1H, d, J = 6.2
Hz), 4.19–4.10 (2H, m), 3.89 (1H, s), 2.47–2.43 (3H, m), 2.30–
2.18 (2H, m), 1.87 (1H, dd, J = 13.7, 6.7 Hz), 1.75–1.61 (5H, m),
1.27 (3H, t, J = 7.1 Hz), 1.20 (3H, s), 1.12 (1H, d, J = 13.8 Hz),
1.06 (3H, s); 13C NMR (100 MHz) δ 173.0, 170.5, 163.0, 128.1,
92.2, 87.0, 80.3, 70.2, 60.3, 60.2, 43.1, 41.8, 25.1, 25.0, 24.5,
21.5, 21.5, 20.1, 14.3; HRMS (FAB) [M ϩ Hϩ] calcd for
C19H27O6: 351.1808, found: 351.1813.
(؉)-(1R,2S,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-1-formyl-3,3-
dimethyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid ethyl
ester (5)
To a solution of alcohol 17 (1.25 g, 2.59 mmol) in acetone
(4 mL) was added NMO (465 mg, 3.97 mmol, 1.5 equiv.) and
TPAP (36 mg, 0.10 mmol, 4 mol%). The dark mixture was
stirred for 90 min and the reaction mixture was filtered over a
thin pad of silica followed by exhaustive rinsing with EtOAc.
After evaporation of the solvent, crude aldehyde 5 (1.08 g, 2.25
mmol, 87%) was obtained as a colourless oil and was used
without further purification in the next reaction. Rf = 0.35
(petroleum ether–EtOAc (8 : 2)); [α]2D0 ϩ25.6 (c = 2.10, CHCl3);
(؉)-(1R,2S,4R)-3,3-Dimethyl-5-oxo-1-[(1S)-3-oxo-1,3,4,5,6,7-
hexahydroisobenzofuran-1-yl]-7-oxabicyclo[2.2.1]heptane-2-
carboxylic acid ethyl ester (20)
To a solution of alcohol 19 (29 mg, 83 µmol) in acetone (2 mL)
was added NMO (15 mg, 128 µmol, 1.5 equiv.) and TPAP
(2.2 mg, 6.3 µmol, 7.5 mol%). The dark mixture was stirred for
2 h and was filtered over a thin pad of silica followed by
exhaustive rinsing with EtOAc. Evaporation of the solvent and
purification by column chromatography (CH2Cl2) afforded
ketone 20 (24 mg, 69 µmol, 83%) as a white solid, which was
1
IR 3071, 2931, 2856, 1732, 1107; H NMR (400 MHz) δ 10.13
(1H, s), 7.69 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz), 7.47–
7.36 (6H, m), 4.38 (1H, dd, J = 6.7, 2.4 Hz), 4.09–4.03 (2H, m),
3.77 (1H, s), 2.45 (1H, s), 2.03 (1H, dd, J = 12.9, 6.7 Hz), 1.78
(1H, dd, J = 12.9, 1.9 Hz), 1.20 (3H, t, J = 7.1 Hz), 1.07 (9H, s),
0.92 (3H, s), 0.76 (3H, s); 13C NMR (100 MHz) δ 200.1, 170.7,
1698
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700

View Article Online
recrystallised from Et2O to give colourless crystals. Rf = 0.30
(petroleum ether–Et2O (1 : 1)); mp 168.5–169.5 ЊC; [α]2D1 ϩ98.0
(c = 1.25, CHCl3); IR 3022, 2942, 2865, 1753, 1212, 1018;
1H NMR (400 MHz) δ 5.94 (1H, s), 4.22–4.17 (2H, m), 3.86
(1H, s), 2.71 (1H, s), 2.45–2.39 (2H, m), 2.30–2.18 (2H, m), 1.97
(1H, d, J = 17.7 Hz), 1.91 (1H, d, J = 17.8 Hz), 1.78–1.67 (4H,
m), 1.30 (3H, t, J = 7.2 Hz), 1.22 (3H, s), 1.15 (3H, s); 13C NMR
(100 MHz) δ 207.5, 172.2, 169.7, 162.3, 128.9, 89.6, 82.0, 79.9,
60.8, 59.6, 43.3, 43.2, 24.6, 24.5, 24.0, 21.5, 21.5, 20.1, 14.3;
anal. calcd for C19H24O6: C 65.50, H 6.94, found: C 65.17,
H 6.82%.
Crystallographic data for 20:¶ C19H24O6, Mr = 348.3903,
monoclinic, P21, a = 8.5854(7), b = 8.3775(7), c = 12.428(1) Å, β
= 103.395Њ, V = 869.56(13) Å3, Z = 2, Dx = 1.33 g cmϪ3, λ-
(Cu-Kα) = 1.5481 Å, µ(Cu-Kα) = 8.2 cmϪ1, F(000) = 372, 253 K,
final R = 0.060 for 1655 reflections.
61.4, 56.8, 43.9, 41.0, 31.9, 27.2, 26.8, 26.1, 25.9, 24.8, 22.8,
22.7, 19.0, 18.5, 18.2, 14.0, Ϫ5.1, Ϫ5.6; HRMS (FAB) [M ϩ
Hϩ] calcd for C45H76O5Si3: 779.4922, found: 779.4922.
(؊)-(S)-Acetic acid [(1R,2R,4R,5S)-2-(tert-butyldimethylsilyl-
oxymethyl)-5-(tert-butyldiphenylsilyloxy)-3,3-dimethyl-7-oxa-
bicyclo[2.2.1]heptan-1-yl][2-(tert-butyldimethylsilyloxymethyl)-
cyclohex-1-enyl]methyl ester (23)
To a solution of alcohol 22 (150 mg, 0.18 mmol) in CH2Cl2
(2 mL) was added acetic anhydride (0.2 mL, 2.1 mmol,
12 equiv.) and pyridine (2 mL). The reaction mixture was stirred
at 40 ЊC for 16 h. The brown solution was concentrated in vacuo
and the product was purified by column chromatography
(petroleum ether–EtOAc (98 : 2)) to afford protected triol
23 (132 mg, 0.16 mmol, 89%) as a colourless oil. Rf = 0.45
(petroleum ether–EtOAc (19 : 1)); [α]2D0 Ϫ6.51 (c = 0.97, CHCl3);
1
IR 2932, 2858, 1760, 1112, 1068; H NMR (400 MHz) δ 7.64
(؊)-(S)-[(1R,2R,4R,5S)-5-(tert-Butyldiphenylsilyloxy)-2-
hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]heptan-1-yl]-
(2-hydroxymethylcyclohex-1-enyl)methanol (21)
(2H, d, J = 7.9 Hz), 7.61 (2H, d, J = 7.9 Hz), 7.44–7.34 (6H, m),
5.75 (1H, s), 4.41 (1H, d, J = 12.6 Hz), 4.32 (1H, dd, J = 6.6, 1.9
Hz), 4.16 (1H, d, J = 12.6 Hz), 3.68 (1H, dd, J = 10.0, 4.3 Hz),
3.51 (1H, dd, J = 10.6, 10.0 Hz), 3.46 (1H, d, J = 1.8 Hz), 2.36
(1H, s), 2.29–2.24 (1H, m), 2.11–2.06 (2H, m), 2.04 (3H, s), 1.83
(1H, dd, J = 12.6, 6.8 Hz), 1.66 (1H, d, J = 12.6 Hz), 1.58–1.50
(4H, m), 1.37 (1H, dd, J = 10.8, 4.3 Hz), 1.04 (9H, s), 0.96 (3H,
s), 0.91 (9H, s), 0.83 (9H, s), 0.67 (3H, s), 0.09 (3H, s), 0.09 (3H,
s), Ϫ0.02 (3H, s), Ϫ0.04 (3H, s); 13C NMR (100 MHz) δ 169.2,
136.7, 135.8, 135.7, 134.3, 134.1, 129.6, 127.5, 127.0, 92.3, 88.2,
72.6, 71.5, 62.9, 60.9, 57.1, 45.9, 41.6, 26.8, 26.7, 26.1, 25.8,
25.5, 23.1, 22.7, 22.4, 20.9, 19.1, 18.5, 18.0, Ϫ5.3, Ϫ5.4, Ϫ5.6,
Ϫ5.7; HRMS (EI) calcd for C47H76O6Si3: 820.4950, found:
820.4888.
To a solution of lactone 18 (723 mg, 1.23 mmol) in Et2O
(10 mL) was added lithium aluminium hydride (3.8 mL of a 1.0
M solution in Et2O, 3.8 mmol, 5 equiv.) in one portion at rt.
After 10 min the reaction mixture was cooled to 0 ЊC and
quenched by adding aqueous saturated NaHCO3. After separ-
ation of the organic layer the water layer was extracted with
Et2O (2 × 20 mL). The combined organic layers were washed
with brine and subsequently dried over Na2SO4. Evaporation
of the solvent afforded triol 21 (415 mg, 0.75 mmol, 61%) as a
colourless oil. Triol 21 was used unpurified in the next reaction.
Rf = 0.18 (petroleum ether–Et2O (1 : 3)); [α]2D1 Ϫ5.21 (c = 1.6,
1
CHCl3); IR 3427 (br), 2929, 2856, 1245, 1110, 1069; H NMR
(؊)-(S)-Acetic acid [(1R,2R,4R,5S)-5-(tert-butyldiphenyl-
silyloxy)-2-hydroxymethyl-3,3-dimethyl-7-oxabicyclo[2.2.1]-
heptan-1-yl](2-hydroxymethylcyclohex-1-enyl)methyl ester (24)
(400 MHz) δ 7.63–7.60 (4H, m), 7.44–7.36 (6H, m), 5.20 (1H, s),
4.41 (1H, d, J = 10.7 Hz), 4.31 (1H, d, J = 6.7 Hz), 3.78 (1H, dd,
J = 10.9, 10.8 Hz), 3.63 (1H, dd, J = 10.7, 2.7 Hz), 3.57–3.54
(1H, m), 3.48 (1H, s), 3.46–3.38 (1H, m), 2.58–2.54 (1H, m),
2.33–2.28 (1H, m), 2.17–2.12 (1H, m), 2.03–1.99 (1H, m), 1.96
(1H, dd, J = 12.9, 6.8 Hz), 1.78 (1H, d, J = 12.6 Hz), 1.66–1.48
(5H, m), 1.04 (9H, s), 0.77 (3H, s), 0.72 (3H, s).
To a solution of diol 23 (42 mg, 51 µmol) in MeOH (1 mL) were
added a few crystals of CSA. The reaction mixture turned
yellow immediately and decolourised after stirring for 4 h. Then
water was added (5 mL) and the aqueous layer was extracted
with Et2O (4 × 5 mL). The combined organic layers were
washed with brine and subsequently dried on Na2SO4 and
the solvent was removed in vacuo. Column chromatography
(petroleum ether–Et2O (1 : 3)) afforded diol 24 (23 mg, 39 µmol,
76%) as a colourless oil. Rf = 0.27 (petroleum ether–Et2O
(1 : 3)); [α]2D0 Ϫ14.3 (c = 1.53, CHCl3) IR 3385 (br), 2932, 2824,
(؊)-(S)-[(1R,2R,4R,5S)-2-(tert-Butyldimethylsilyloxymethyl)-
5-(tert-butyldiphenylsilyloxy)-3,3-dimethyl-7-oxabicyclo[2.2.1]-
heptan-1-yl][2-(tert-butyldimethylsilyloxymethyl)cyclohex-1-
enyl]methanol (22)
To a solution of triol 21 (415 mg, 0.75 mmol) in CH2Cl2 (5 mL)
was added pyridine (0.61 mL, 7.6 mmol, 10 equiv.) and
TBDMSCl (343 mg, 2.28 mmol, 3 equiv.). The reaction mixture
was stirred at rt for 16 h. Then the solution was poured into
water (30 mL) and extracted with Et2O (3 × 25 mL). The com-
bined organic layers were washed with brine and subsequently
dried over Na2SO4 and the solvent was removed in vacuo.
Column chromatography (petroleum ether–EtOAc (97 : 3))
afforded protected alcohol 22 (496 mg, 0.64 mol, 85%) as a
colourless oil. Rf = 0.41 (petroleum ether–EtOAc (19 : 1)); [α]2D1
Ϫ7.11 (c = 1.00, CHCl3); IR 3425 (br), 2929, 2856, 1254, 1110,
1068; 1H NMR (400 MHz) δ 7.65 (2H, d, J = 7.9 Hz), 7.61 (2H,
d, J = 7.9 Hz), 7.43–7.34 (6H, m), 4.95 (1H, s), 4.50 (1H, d, J =
12.4 Hz), 4.28–4.24 (2H, m), 4.09 (1H, d, J = 12.4 Hz), 3.70 (1H,
dd, J = 10.6, 10.5 Hz), 3.51 (1H, dd, J = 10.7, 3.5 Hz), 3.37 (1H,
s), 2.36–2.31 (2H, m), 2.17–1.98 (2H, m), 1.91 (1H, dd, J = 12.7,
6.8 Hz), 1.75 (1H, d, J = 12.8 Hz), 1.68–1.58 (4H, m), 1.45 (1H,
dd, J = 10.5, 3.4 Hz), 1.03 (9H, s), 0.92 (9H, s), 0.88 (9H, s), 0.74
(3H, s), 0.67 (3H, s), 0.08 (3H, s), 0.08 (3H, s), 0.08 (3H, s), 0.07
(3H, s); 13C NMR (50 MHz) δ 135.7, 135.7, 134.5, 134.3, 134.1,
130.5, 129.6, 129.5, 127.6, 127.5, 91.5, 91.3, 71.4, 69.4, 63.4,
1
1757, 1111, 1069; H NMR (400 MHz) δ 7.64–7.57 (4H, m),
7.49–7.35 (6H, m), 5.07 (1H, s), 4.34–4.30 (2H, m), 4.28–4.15
(2H, m), 3.58 (1H, d, J = 11.5 Hz), 3.51 (1H, s), 2.59–2.54
(1H, m), 2.33–2.26 (1H, m), 2.16–2.09 (1H, m), 2.03 (3H, s),
2.02–1.98 (1H, m), 1.93 (1H, dd, J = 13.0, 6.7 Hz), 1.79 (1H, d,
J = 12.8 Hz), 1.66–1.55 (5H, m), 1.04 (9H, s), 0.87 (3H, s), 0.71
(3H, s); 13C NMR (50 MHz) δ 170.1, 136.4, 135.7, 135.7, 133.9,
133.7, 132.3, 129.7, 127.7, 127.7, 92.2, 89.6, 71.1, 68.8, 62.8,
60.2, 53.4, 43.6, 41.4, 29.7, 29.4, 26.8, 26.2, 25.0, 23.5, 22.8,
21.0, 19.0; HRMS (FAB) [M ϩ Naϩ] calcd for C35H48NaO6Si:
615.3118, found: 615.3068.
(؉)-(2S,3R,5R,10R,19S)-Lactone 25
To a solution of diol 24 (12 mg, 20 µmol) in acetone (1 mL)
were added NMO (7.0 mg, 60 µmol, 3 equiv.) and TPAP
(2.1 mg, 6.0 µmol, 0.3 equiv.). The dark mixture was stirred for
90 min followed by filtration over a thin pad of silica and
exhaustive rinsing with EtOAc. Evaporation of the solvent and
column chromatography (petroleum ether–Et2O (1
: 1))
afforded lactone 25 (8.3 mg, 14 µmol, 70%) as a colourless oil.
Rf = 0.60 (petroleum ether–Et2O (1 : 3)); [α]2D1 ϩ26.7 (c = 1.29,
CHCl3); IR 3070, 2935, 2859, 1761, 1744, 1671, 1235, 1112,
¶ CCDC reference number 180411. See http://www.rsc.org/suppdata/
p1/b2/b201987f/ for crystallographic files in .cif or other electronic
format.
1
1025; H NMR (400 MHz, C6D6) δ 7.68 (2H, d, J = 7.9 Hz),
7.62 (2H, d, J = 7.9 Hz), 7.20–7.11 (6H, m), 4.60 (1H, s), 4.40
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700
1699

View Article Online
7 W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1977, 16, 10;
W. Oppolzer, Synthesis, 1978, 793; W. Oppolzer, Heterocycles, 1980,
14, 1615; G. Brieger and J. N. Bannet, Chem. Rev., 1980, 80, 63.
8 For examples of intramolecular Diels–Alder reactions of furyl-
substituted α,β-unsaturated amides, see K. A. Parker and
M. R. Adamchuk, Tetrahedron Lett., 1978, 19, 1689; T. Mukaiyama,
T. Tsuji and N. Iwasawa, Chem. Lett., 1979, 697; M. E. Jung and
L. J. Street, J. Am. Chem. Soc., 1984, 106, 8327; D. Prajapati
and J. S. Sandhu, Heterocycles, 1985, 23, 17; D. Prajapati,
D. R. Borthakur and J. S. Sandhu, J. Chem. Soc., Perkin Trans. 1,
1993, 1197; J. Zylber, A. Tubul and P. Brun, Tetrahedron:
Asymmetry, 1995, 6, 377.
(1H, dd, J = 11.2, 4.6 Hz), 4.23 (1H, dd, J = 6.6, 1.4 Hz), 4.10
(1H, dd, J = 11.2, 8.4 Hz), 3.52 (1H, s), 2.89–2.78 (1H, m),
2.21–2.14 (1H, m), 2.09–2.00 (2H, m), 1.95 (3H, s), 1.57 (1H,
m), 1.49 (1H, dd, J = 13.0, 6.7 Hz), 1.40–1.21 (5H, m), 1.13 (9H,
s), 0.76 (3H, s), 0.46 (3H, s); 13C NMR (100 MHz, C6D6)
δ 172.8, 170.8, 163.1, 136.8, 136.6, 135.0, 135.5, 134.5, 130.9,
130.9, 129.2, 129.1, 93.7, 88.0, 80.7, 72.6, 63.0, 54.3, 42.7, 41.9,
27.7, 24.1, 23.5, 22.7, 22.6, 22.6, 21.3, 21.3, 19.8; HRMS (FAB)
[M ϩ Hϩ] calcd for C35H45O6Si: 589.2985, found: 589.2971.
9 For recent examples of intramolecular Diels–Alder reactions
between furan and unactivated double bonds, see A. D. Mance,
M. Sindler-Kulyk, K. Jakopcic, A. Hergold-Brundic and A. Nagl,
J. Heterocycl. Chem., 1997, 34, 1315; N. Choony, A. Dadabhoy
and P. G. Sammes, Chem. Commun., 1997, 513; N. Choony,
A. Dadabhoy and P. G. Sammes, J. Chem. Soc., Perkin Trans. 1,
1998, 2017; C. Andrés, J. Nieto, R. Pedrosa and M. Vicente, J. Org.
Chem., 1998, 68, 8570; R. Pedrosa, C. Andrés and J. Nieto, J. Org.
Chem., 2000, 65, 831.
Acknowledgements
J. Fraanje and K. Goubitz of the same Institute are kindly
acknowledged for the X-ray crystal structure determination.
The DSM company (Geleen, the Netherlands) provided gener-
ous quantities of (R)-phenylglycine. These investigations were
supported (in part) by the Netherlands Research Council for
Chemical Sciences (CW/NWO) with financial aid from the
Netherlands Technology Foundation (STW).
10 K. A. Parker and M. R. Adamchuk, Tetrahedron Lett., 1976, 19,
1689.
11 T. Mukaiyama and N. Iwasawa, Chem. Lett., 1981, 29.
12 M. R. Gmünder and C. H. Eugster, Helv. Chim. Acta, 1990, 73,
1954.
13 (R)-Phenylglycinol was prepared by reduction of (R)-phenylglycine
using the procedure of A. Abiko and S. Masamune, Tetrahedron
Lett., 1992, 33, 5517.
Notes and references
1 J. G. Mulder, P. Diepenhorst, P. Plieger and I. E. M. Brüggemann-
Rotgans, CT Int. Appl. WO 93 02 083, 1992 (Chem. Abstr., 1993,
118, 185844z).
2 H. Schenk, R. A. J. Driessen, R. de Gelder, K. Goubitz, H. Nieboer,
I. E. M. Brüggemann-Rotgans and P. Diepenhorst, Croat. Chem.
Acta, 1999, 72, 593.
14 H. C. Brown, A. K. Mandal and S. U. Kulkarni, J. Org. Chem., 1977,
42, 1844.
15 H. C. Brown and P. J. Geoghegan Jr., J. Org. Chem., 1970, 33,
1844.
16 R. Julina, T. Herzig, B. Bernet and A. Vasella, Helv. Chim. Acta,
1986, 69, 368; L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992,
57, 1656.
17 For comparable methods, see V. Nyzam, C. Belaud, F. Zammattio
and J. Villiéras, Tetrahedron: Asymmetry, 1996, 7, 1835; O. Fains and
J. M. Vernon, Tetrahedron Lett., 1997, 38, 8265; C. Agami, F. Couty
and G. Evano, Tetrahedron Lett., 1999, 40, 3709.
18 S. E. de Sousa and P. O’Brien, Tetrahedron Lett., 1997, 38, 4885;
K. Heyns and O.-F. Woyrsch, Chem. Ber., 1953, 86, 76;
T. Mukaiyama, N. Iwasawa, T. Tsuji and K. Narasaka, Chem. Lett.,
1979, 1175.
19 For a review on TPAP, NMO oxidations, see S. V. Ley, J. Norman,
W. P. Griffith and S. P. Marsden, Synthesis, 1994, 639.
20 For reviews on chromium() and chromium()-mediated couplings,
see L. A. Wessjohann and G. Scheid, Synthesis, 1999, 1; A. Fürstner,
Chem. Rev., 1999, 99, 991.
3 R. H. Blaauw, J.-F. Brière, R. de Jong, J. C. J. Benningshof, A. E. van
Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk and
H. Hiemstra, Chem. Commun., 2000, 1463; J. C. J. Benningshof,
R. H. Blaauw, A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje,
K. Goubitz, H. Schenk and H. Hiemstra, Chem. Commun., 2000,
1465; R. H. Blaauw, J.-F. Brière, R. de Jong, J. C. J. Benningshof,
A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk
and H. Hiemstra, J. Org. Chem., 2001, 66, 233; J.-F. Brière,
R. H. Blaauw, J. C. J. Benningshof, A. E. van Ginkel, J. H.
van Maarseveen and H. Hiemstra, Eur. J. Org. Chem., 2001, 2371;
R. H. Blaauw, J. C. J. Benningshof, A. E. van Ginkel, J. H.
van Maarseveen and H. Hiemstra, J. Chem. Soc., Perkin Trans. 1,
2001, 2250.
4 For reviews on the acyloin condensation, see S. M. McElvain, Org.
React., 1948, 4, 256; K. Rühlmann, Synthesis, 1971, 23, 236;
J. J. Bloomfield, D. C. Owsley and J. M. Nelke, Org. React., 1976, 23,
259.
5 For reviews on the McMurry coupling, see J. E. McMurry, Chem.
Rev., 1989, 89, 1513; D. Lenoir, Synthesis, 1989, 883; A. Fürstner
and B. Bogdanovic, Angew. Chem., Int. Ed., 1996, 35, 630. For
application in total synthesis, see N. Kato, H. Takeshita,
H. Kataoka, S. Ohbuchi and S. Tanaka, J. Chem. Soc., Perkin Trans.
1, 1989, 165; K. C. Nicolaou, Z. Yang, J. J. Liu, P. G. Nantermet,
C. F. Claiborne, J. Renaud, R. K. Guy and K. Shibuyama, J. Am.
Chem. Soc., 1995, 117, 645.
21 For the synthesis of 6 see E. Piers and H. L. A. Tse, Can. J. Chem.,
1993, 71, 983.
22 P. Knochel and C. J. Rao, Tetrahedron, 1993, 49, 29.
23 This remarkable result is not unusual for oxidations of diols.
For a similar oxidation process to a 6-membered lactone, see M. Lee,
I. Ikeda, T. Kawabe, S. Mori and K. Kanematsu, J. Org. Chem.,
1996, 61, 3406.
24 J. C. J. Benningshof, M. IJsselstijn, S. R. Wallner, Anne L. Koster,
R. H. Blaauw, A. E. van Ginkel, J.-F. Brière, J. H. van Maarseveen,
F. P. J. T. Rutjes and H. Hiemstra, J. Chem. Soc., Perkin Trans. 1,
2002, (DOI 10.1039/b202020n).
6 For reviews on intramolecular furan Diels–Alder reactions,
see B. H. Lipshutz, Chem. Rev., 1986, 86, 795; C. O. Kappe,
S. S. Murphree and A. Padwa, Tetrahedron, 1997, 53, 14179.
1700
J. Chem. Soc., Perkin Trans. 1, 2002, 1693–1700