Highly functionalised cyclobutanols by samarium(II) iodide induced radical cyclisations of carbohydrate-derived unsaturated ketones

Article abstract of DOI:10.1002/ejoc.200400220

Certain carbohydrates have been found to be excellent precursors for the samarium diiodide-mediated 4-exo-trig cyclisation reaction of their keto-olefin derivatives, which were readily prepared in a few easy steps. The cyclisation was found to be stereoselective, affording cis products, the diastereoselective excesses of which were influenced by the nature of the protecting group employed at C5-O of the furanose sugar. The major chiral cyclobutane product of the cyclisation step was converted into an advanced intermediate for the synthesis of a nucleoside anti-viral analogue. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400220

FULL PAPER
Highly Functionalised Cyclobutanols by Samarium(II) Iodide Induced Radical
Cyclisations of Carbohydrate-Derived Unsaturated Ketones
D. Bradley G. Williams*[a] and Kevin Blann[a]
Keywords: Carbocycles / Carbohydrates / Radical reactions / Samarium / Small ring systems
Certain carbohydrates have been found to be excellent pre-
cursors for the samarium diiodide-mediated 4-exo-trig cycli-
sation reaction of their keto-olefin derivatives, which were
readily prepared in a few easy steps. The cyclisation was
found to be stereoselective, affording cis products, the dia-
stereoselective excesses of which were influenced by the
nature of the protecting group employed at C5−O of the fur-
anose sugar. The major chiral cyclobutane product of the
cyclisation step was converted into an advanced interme-
diate for the synthesis of a nucleoside anti-viral analogue.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
With the above in mind, and in line with our continued
interest in SmI2-promoted transformations,[13] it was de-
cided to investigate the 4-exo-trig ketyl-olefin cyclisation of
a number of carbohydrate derivatives.
Chiral cyclobutane derivatives are fascinating target mol-
ecules for synthetic chemists. They occur in natural prod-
ucts of diverse origin,[1] are desirable from a pharmaceut-
ical/medicinal chemistry perspective (as antiviral agents[2]
and sedatives[3]), and there is much current interest in the
synthesis of small rings, including cyclobutane derivatives,
due to their remarkable physiological activity. Some ap-
proaches to cyclobutanes make use of [2ϩ2] cycloaddition
reactions,[4] anionic cycloalkylations[5] and ring-opening re-
actions.[6] Accounts of cyclobutanol formation by radical-
induced cyclisation onto activated alkenes are limited.[7]
Few of these make use of samarium() iodide as the radical
initiator,[8] and the preparation of some cyclobutanols
through a SmI2-mediated[9] nucleophilic acyl substitution/
Results and Discussion
Synthesis of Chiral Cyclobutanols
Keto-olefin precursors 3 were readily prepared by stand-
ketyl olefin coupling reaction has recently been reported.[10] ard chemistry in only four steps (two-pot procedure). The
These processes, however, do not allow easy entry to the first two transformations involved selective acetonide pro-
highly functionalised, chiral cyclobutanol derivatives that tection of the cis-diol of the sugar,[14] followed by masking
are essential to physiological activity or to the total syn- of the primary alcohol with various groups (60Ϫ80% over
thesis of a broad spectrum of chiral natural products.
two steps, Scheme 1, R ϭ TBDMS,[14] trityl,[14] pivaloyl[15]).
Until relatively recently, carbohydrates had been neg- The crux of the sequence was the Wittig reaction[16] fol-
lected as synthetic precursors to chiral carbocyclic targets lowed by in situ DessϪMartin oxidation[17] of the resulting
in SmII-mediated chemistry. This has been changed by our alcohol to afford the desired (Z)-α,β-unsaturated esters
efforts,[11aϪ11d] and by those of others,[11eϪ11f] in which the (Scheme 1). (Attempts to isolate the intermediate alcohols
SmI2-induced conversion of carbohydrates into carbocycles, resulted in C-nucleoside formation due to Michael addition
including the synthesis of some chiral cyclopentanes and of the secondary hydroxy group onto the α,β-unsaturated
cyclohexanes, has become well documented. Here we de- ester, a process previously put to good use in the synthesis
scribe what is, to the best of our knowledge, the first record of functionalised tetrahydrofurans.[18]) Lactols 2 were
of a SmI2-mediated process in which carbohydrate deriva- treated with 1.2 equivalents of the triphenylphosphorane re-
tives have been converted into cyclobutanes.[12]
agent in dichloromethane (DCM) for 12 h, after which the
reaction mixture was diluted with DCM and 1.2 equivalents
of DessϪMartin periodinane were added. This procedure
altogether eliminated the unwanted Michael addition, and
allowed the desired ketoalkenes 3 to be isolated in accept-
able yields (40Ϫ60% over two steps).
[a]
Department of Chemistry and Biochemistry, Rand Afrikaans
University,
P.O. Box 524, Auckland Park, 2006, South Africa
Fax: (internat.) ϩ 2711-489-2605
E-mail: dbgw@rau.ac.za
3286
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DOI: 10.1002/ejoc.200400220
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Radical Cyclisations of Carbohydrate-Derived Unsaturated Ketones
FULL PAPER
tanol product 5c in a yield of 6%. The cyclisation yielded
products with cis selectivity[20] (with the exception of the
trace product 5c[21]), differing from the few other reported
stereoselective 4-exo-trig radical cyclisations, in which trans
selectivity was observed.[8,22] The reasons for the observed
selectivity might lie in the bulky nature of the protecting
groups at the primary hydroxy function dominating the
orientation of the α,β-unsaturated ester moiety in the cyclis-
ation transition state.
A study was carried out to establish whether the inclusion
of a fused-ring isopropylidene moiety was a necessary con-
straint for cyclisation to occur, or whether use of a 2,3-
O-dialkyl-protected -arabinose derivative could mimic the
gem-dialkyl effect,[23] the rotational restriction imposed on
a compound due to steric effects when two alkyl groups
are present on the same carbon atom. This effect has been
employed to allow 4-exo-trig cyclisation of suitable non-
carbohydrate precursors into cyclobutane derivatives.[8a]
The substrates 8 were readily accessible by protection of the
anomeric oxygen, perbenzylation, deprotection of the lac-
tol, and subsequent Wittig- and DessϪMartin reactions
(Scheme 4).
Scheme 1
The substrates 3 were dissolved in THF and added to
mixtures of excess SmI2 and HMPA at Ϫ78 °C, smoothly
effecting the 4-exo-trig cyclisations to the desired cyclo-
butane monomers (Scheme 2).
Scheme 2
The outcomes of these reactions were dependent upon
the nature of the protecting groups: substrates func-
tionalised with tert-butyldimethylsilyl (TBDMS, 3a) or with
trityl (3b) protective groups on the primary oxygen under-
went smooth cyclisation to provide the anticipated cyclobu-
tanols. The analogous pivaloyl-protected enone 3c, how-
ever, underwent reductive elimination to afford the Sm-en-
olate and thence the corresponding ketone 6 (Scheme 3),
presumably because the pivaloyl moiety is a relatively good
leaving group.
Scheme 4
Treatment of both the E and Z isomers, of the α,β-un-
saturated esters 8 with SmI2 under a variety of reaction con-
ditions yielded, instead of the cyclobutanols, rather com-
plex and intractable mixtures of products. These experi-
ments showed that the cyclisation is undoubtedly facilitated
by the rotational restriction imposed by the isopropylidene
group. Whereas others have made use of the gem-dialkyl
effect,[8,22] this work neatly demonstrates that such substi-
tutionally restrictive substrates are not essential to a suc-
cessful outcome of the cyclisation step.
Preparation of an Antiviral Precursor
Scheme 3
With the cyclobutane ring formation methodology com-
pleted, an application of the work was initiated, and is cur-
The mechanism for this elimination step could be either rently in progress (vide infra). The design and preparation
a Grob-type fragmentation[19] of the cyclised product or a of novel nucleosides as antiviral agents from carbohydrates
direct anionic or radical elimination at the ketyl radical is well established in medicinal chemistry.[24] Examples of
stage. The said protective groups also played a role in the compounds that are active against HIV and/or herpes vi-
stereocontrol of the reaction: while the TBDMS-protected ruses include deoxy carbohydrate analogues such as AZT
enone 3a provided a 2:1 ratio of diastereomers 4a and 4b (9), acyclic structures such as acyclovir (10), and carbo-
in a total yield of 69%, the cyclisation of the trityl analogue cyclic materials such as the cyclobutyl nucleoside BMS-
was more highly diastereoselective, affording 5a and 5b in 180,194 (11), which has received quite some interest (Fig-
a 4:1 ratio (total yield of 79%), along with a third cyclobu- ure 1).[25]
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D. B. G. Williams, K. Blann
FULL PAPER
perfectly primed for further manipulation towards the syn-
thesis of analogues of BMS-180,194 (11), and results of
these ongoing studies shall be reported in due course.
Conclusion
Figure 1. Examples of anti-viral materials
The results of this project describe an efficient procedure
for the conversion of -ribose into highly functionalised,
chiral, nonracemic cyclobutanes. The linchpin is a tethering
protective group that affords a rotationally restricted sub-
strate suitable for SmI2-mediated radical cyclisation. This
approach nicely complements that making use of the gem-
dialkyl effect. The application of our methodology to the
synthesis of a key intermediate towards a BMS-180,194
analogue further highlights the potential of these cyclo-
butane compounds in the synthesis of novel antiviral mate-
rials.
Preparation of the key direct precursor for the introduc-
tion of a guanine moiety, and a popular route to com-
pounds such as BMS-180,194 (11), involves the selective
triflation of an hydroxy group directly attached to the cyclo-
butane ring and subsequent coupling with a nucleoside de-
rivative.[25] We conceived of a two-pot synthetic pathway to
obtain a similar compound from the protected cyclobutane
5a, which would then be coupled to the guanine and
eventually be manipulated to form the BMS-180,194 (11)
analogue 12 (Scheme 5).[12]
Experimental Section
General Remarks: Thin-layer chromatography (TLC) was conduc-
ted quantitatively with ‘‘Merck GF254 pre-coated silica gel glass
plates’’ (0.25 layer). Aromatic derivatives were viewed under UV
light (254 nm) while carbohydrate substrates were detected after
spraying of the TLC plate with a chromic acid solution followed by
heating. ‘‘Flash column chromatography’’ (FCC) refers to column
chromatography under nitrogen pressure (ca. 50 kPa). The columns
were loaded with Merck Kieselgel 60 (230Ϫ400 mesh) and eluted
with appropriate solvent mixtures in volume per volume ratios.
Acetone was dried over anhydrous K2CO3 for 24 h. The salt was
then filtered off, and the solvent was subsequently distilled from
Scheme 5
Unmasking of the hydroxy groups of 5a was achieved in
acidified methanol, and the tertiary alcohol was reprotected
in situ through an internal lactonisation in THF in the pres-
ence of a catalytic amount of p-toluenesulfonic acid, pro-
ducing the triol 13 in a yield of 63% over the two steps
(Scheme 6). The structure and stereochemistry of the cyclo-
butanetriol 13 were confirmed by single-crystal X-ray crys-
tallography (Figure 2).[20] The key intermediate 13 is now
˚
over 3-A molecular sieves and stored under N2. Benzene and tolu-
ene were dried by heating the respective solvent over sodium-
benzophenone under a N2 atmosphere until the solution turned a
deep blue colour. The solvent was freshly distilled before use. Di-
ethyl ether and THF were pre-dried over freshly ground KOH. The
KOH was then filtered off and the solvent was dried from sodium-
benzophenone. The solvents were distilled under N2 prior to use.
Dichloromethane and dimethylformamide were heated over CaH2
under N2 with subsequent distillation. Ethanol and methanol were
˚
distilled from Mg/I2 and stored over 3-A molecular sieves. Ethyl
acetate was distilled from K2CO3 through a Vigreux distillation
column. Hexanes were distilled prior to use. HMPA was heated
over CaH2 under an argon atmosphere for one week prior to use.
The solvent was only used if freshly distilled. Pyridine was pre-
Scheme 6
˚
dried over anhydrous CaCl2 and was then distilled from 3-A molec-
ular sieves. NMR spectra were recorded on a Varian Gemini 2000,
300 MHz spectrometer. The samples were usually made up in
1
CDCl3 and for more polar samples D2O was used. The H NMR
spectroscopic data are referenced to the residual solvent peak of
CDCl3 (δ ϭ 7.24 ppm). The relative stereochemistry was deter-
mined after study of nuclear Overhauser effect spectra. 13C NMR
spectroscopic data are referenced to the solvent peak of CDCl3
(δ ϭ 77.0 ppm). The compilation of fragmentation determinations
were recorded on a Finnigan Matt 8200 spectrometer at an electron
impact of 70 eV, while FAB-HRMS spectra were recorded on a
Varian E7070 with glycerol or nitrobenzyl alcohol as the matrix. A
Figure 2. X-ray structure of bicyclic lactone 13
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Radical Cyclisations of Carbohydrate-Derived Unsaturated Ketones
FULL PAPER
PerkinϪElmer 881 spectrometer was used to record IR spectra in
dry chloroform as solvent. A Jasco model DIP-730 spectropolari-
meter with a cell with a 10-mm path length was used to determine
optical rotations. The concentration c. indicates the concentration
NMR (300 MHz, CDCl3): δ ϭ 1.27 (t, J ϭ 7.2 Hz, 3 H, CH2CH3),
1.40 (s, 3 H, isopropylidene CH3), 1.61 (s, 3 H, isopropylidene
CH3), 4.16 (qd, J ϭ 0.5, 7.2 Hz, 2 H, CH2CH3), 4.75 (d, J ϭ 18.2
Hz, 1 H, H7b), 4.83 (d, J ϭ 7.7 Hz, 1 H, H5), 4.84 (d, J ϭ 18.2
of the sample in grams per 100 mL of solution. Melting points Hz, 1 H, H7a), 5.90 (td, J ϭ 1.7, 7.7 Hz, 1 H, H4), 5.95 (dd, J ϭ
were determined with a Reichert Thermopan microscope together 1.7, 11.5 Hz, 1 H, H2), 6.20 (dd, J ϭ 7.7, 11.5 Hz, 1 H, H3) ppm.
with a Koffler hot-stage and are uncorrected. All reactions were 13C NMR (75 MHz, CDCl3): δ ϭ 14.2 (CH2CH3), 24.6 (isopro-
performed in flamed out glass apparatus in dry solvents unless
otherwise stated. All samarium diiodide reactions were carried out
pylidene CH3), 26.6 (isopropylidene CH3), 27.2 (CCH3), 38.7
(CCH3), 60.6 (CH2CH3), 67.4 (C7), 75.5 and 81.2 (C4, C5), 111.0
under argon in degassed solvents, while standard chemistry was (acetal C), 123.2 (C2), 142.3 (C3), 165.4 (C1), 177.6 (PivϪCϭO),
performed under an atmosphere of nitrogen. ‘‘Room temperature’’
refers to a temperature ranging from 20Ϫ25 °C. The standard
workup procedure involved addition of water to the reaction mix-
ture and repeated extraction with EtOAc. The organic layer was
then separated and rinsed with brine and finally with water. After
separation and drying of the organic phase with anhydrous MgSO4
the solvent was removed in vacuo at a temperature of ca. 40 °C.
The crude product was then purified by flash column chromatogra-
phy.
201.4 (C6) ppm. FAB-HRMS: calculated for C17H27O7 343.1757,
found 343.1756.
General Cyclisation Procedure: Keto ester 3 (0.21 mmol) was dis-
solved in degassed THF (5 mL), and the solvent was removed by
vacuum distillation to ensure an oxygen-free system. The residue
was then dissolved in THF (20 mL) and was added dropwise over
20 minutes with stirring to a freshly prepared solution of SmI2 in
THF (6.3 mL of a 0.1  solution, 0.63 mmol, 3.0 equiv.) and
HMPA (0.21 mL, 1.43 mmol, 6.8 equiv.) at Ϫ78 °C. The mixture
was stirred at Ϫ78 °C for 2 h, after which it was diluted with EtOAc
(20 mL) and filtered through a thin pad of silica gel. The solvent
was removed in vacuo, and the residue was purified by column
General Procedure for the Preparation of α,β-Unsaturated Esters 3:
(Ethoxycarbonylmethylene)triphenylphosphorane (181 mg, 0.50
mmol) was added to a solution of the protected ribose derivatives
2
[14,15] (0.41 mmol) in dry CH2Cl2 (2 mL), and the reaction mixture chromatography.
was stirred at room temperature for 12 h. The mixture was diluted
with CH2Cl2 (2 mL), treated with DessϪMartin periodinane
(209 mg, 0.50 mmol) and stirred at the same temperature for 12 h.
The solvent was removed in vacuo, and the residue was purified by
chromatography to afford the sugar derivatives 3.
Major Isomer 4a: Colourless oil (36 mg, 0.097 mmol, 46%). Rf ϭ
0.59 (hexanes/EtOAc, 4:1 ). IR (CHCl3): ν˜ ϭ 3040, 2960, 2880,
1790, 1740, 1715, 1660, 1560, 1390, 1270, 1220 cmϪ1. [α]2D0 ϭ Ϫ41.1
(c ϭ 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 0.06 and 0.07
ppm(2 ϫ s, 6 H, SiCH3), 0.88 (s, 9 H, CCH3), 1.23 (t, J ϭ 7.2 Hz,
3 H, CH2CH3), 1.23 (s, 3 H, isopropylidene CH3), 1.51 (s, 3 H,
isopropylidene CH3), 2.34 (ddd, J ϭ 2.1, 7.2, 9.0 Hz, 1 H, H1Ј),
2.45 (dd, J ϭ 7.2, 16.0 Hz, 1 H, H2b), 2.57 (dd, J ϭ 9.0, 16.0 Hz,
1 H, H2a), 3.03 (s, 1 H, OH, D2O exchange), 3.51 (d, J ϭ 9.8 Hz,
1 H, CHaHbOTBDMS), 3.84 (d, J ϭ 9.8 Hz, 1 H, CHaHb-
TBDMS Derivative 3a: Colourless oil (79 mg, 0.21 mmol, 52%).
Rf ϭ 0.58 (hexanes/EtOAc, 6:1). IR (CHCl3): ν˜ ϭ 3040, 2960, 1740,
1
1715, 1660, 1520, 1220 cmϪ1. [α]2D0 ϭ ϩ5.4 (c ϭ 0.4, CHCl3). H
NMR (300 MHz, CDCl3): δ ϭ 0.03 and 0.04 (2 ϫ s, 6 H, SiCH3),
1.28 (t, J ϭ 7.2 Hz, 3 H, CH2CH3), 0.87 (s, 9 H, CCH3), 1.39 (s, 3
H, isopropylidene CH3), 1.58 (s, 3 H, isopropylidene CH3), 4.16 OTBDMS), 4.10 (q, J ϭ 7.2 Hz, 2 H, CH2CH3), 4.37 (s, 1 H, H2Ј),
(qd, J ϭ 1.0, 7.2 Hz, 2 H, OCH2), 4.26 (d, J ϭ 19.1 Hz, 1 H, H7b),
4.38 (s, 1 H, H3Ј) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.29
4.49 (d, J ϭ 19.1 Hz, 1 H, H7a), 4.92 (d, J ϭ 7.8 Hz, 1 H, H5), ppm and Ϫ5.32 (2 ϫ SiCH3), 14.2 (CH2CH3), 18.4 (CCH3), 25.86
6.05Ϫ6.11 and 5.85Ϫ5.92 (m, 3 H, H2, H3, H4) ppm. 13C NMR
(isopropylidene CH3), 25.9 (CCH3), 26.7 (isopropylidene CH3),
(75 MHz, CDCl3): δ ϭ Ϫ5.3 (SiCH3), 14.2 (CH2CH3), 18.5 31.7 (C2), 43.2 (C1Ј), 60.5 (CH2CH3), 64.7 (CH2OTBDMS), 73.2
(CCH3), 24.8 (isopropylidene CH3), 25.9 (CCH3), 26.8 (isopro-
(C4Ј), 75.8 (C2Ј), 80.7 (C3Ј), 114.5 (acetal C), 172.4 (C1) ppm. MS:
pylidene CH3), 60.6 (CH2CH3), 68.6 (C7), 74.8 and 80.7 (C4 and m/z ϭ 375 (75) [Mϩ ϩ 1], 359 (7), 167 (100). FAB-HRMS: calcd.
C5), 110.8 (acetal C), 123.1 (C2), 142.8 (C3), 165.2 (C1), 205.5 (C6) for C18H35O6Si 375.2203, found 375.2202.
ppm. FAB-HRMS: calcd. for C18H33SiO6 373.2046, found
Minor Isomer 4b: Colourless oil (18 mg, 0.048 mmol, 23%). Rf ϭ
373.2044.
0.38 (hexanes/EtOAc, 4:1). IR (CHCl3): ν˜ ϭ 3040, 2960, 2890,
1
Trityl Derivative 3b: Colourless oil (82 mg, 0.16 mmol, 40%). Rf ϭ
1780, 1740, 1715, 1540 cmϪ1. [α]2D0 ϭ Ϫ79.6 (c ϭ 0.5, CHCl3). H
0.73 (hexanes/EtOAc, 4:1). IR (CHCl3): ν˜ ϭ 3040, 3000, 1740, NMR (300 MHz, CDCl3): δ ϭ 0.07 (s, 3 H, SiCH3), 0.89 (s, 9 H,
1715, 1570, 1384, 1260, 1220, 1060 cmϪ1. [α]2D0 ϭ ϩ31.1 (c ϭ 0.9,
CCH3), 1.23 (t, J ϭ 7.2 Hz, 3 H, CH2CH3), 1.31 (s, 3 H, isopro-
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.28 (t, J ϭ 7.2 Hz, pylidene CH3), 1.58 (s, 3 H, isopropylidene CH3), 2.54Ϫ2.71 (m, 3
3 H, CH2CH3), 1.32 (s, 3 H, isopropylidene CH3), 1.37 (s, 3 H, H, H4, H2a, H2b), 2.93 (s, 1 H, OH, D2O exchange), 3.59 (d, J ϭ
isopropylidene CH3), 3.72 (d, J ϭ 18.6 Hz, 1 H, H7b), 4.00 (d, J ϭ 10.1 Hz, 1 H, CHaHbOTBDMS), 3.64 (d, J ϭ 10.1 Hz, 1 H, CHaHb-
18.6 Hz, 1 H, H7a), 4.13 (q, J ϭ 7.2 Hz, 2 H, CH2CH3), 4.84 (d,
OTBDMS), 4.04 (t, J ϭ 4.8 Hz, 1 H, H2Ј), 4.12 (q, J ϭ 7.2 Hz, 2
J ϭ 7.8 Hz, 1 H, H2), 5.77Ϫ5.89 (m, 3 H, H3, H4, H5), 7.22Ϫ7.31 H, CH2CH3), 4.59 (d, J ϭ 4.8 Hz, 1 H, H3Ј) ppm. 13C NMR
(m, 9 H, H3Ј, H4Ј), 7.42Ϫ7.46 (m, 6 H, H2Ј) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.6 (SiCH3), 114.3 (acetal C), 14.3
(75 MHz, CDCl3): δ ϭ 14.2 (CH2CH3), 24.8 (isopropylidene CH3),
26.4 (isopropylidene CH3), 60.6 (CH2CH3), 69.0 (C7), 75.2 and
(CH2CH3), 18.2 (CCH3), 25.8 (CCH3), 26.4 (isopropylidene CH3),
27.4 (isopropylidene CH3), 31.9 (C2), 52.6 (C1Ј), 60.6 (CH2CH3),
81.0 (C4, C5), 87.0 (CPh), 110.8 (acetal C), 123.1 (C2), 127.1 (C4Ј), 64.2 (CH2OTBDMS), 69.0 (C4Ј), 73.6 (C2Ј), 79.4 (C3Ј), 172.4 (C1)
127.9 (C3Ј), 128.4 (C2Ј), 142.6 (C1Ј), 143.2 (C3), 165.1 (C1), 203.6 ppm. MS: m/z ϭ 375 (60) [Mϩ ϩ 1], 359 (4), 167 (100). FAB-
(C6) ppm. FAB-HRMS:, calcd. for C31H33O6 501.2277, found HRMS: calcd. for C18H35O6Si 375.2203, found 375.2203.
501.2277.
Major Isomer 5a: Colourless oil (67 mg, 0.13 mmol, 64%). Rf ϭ
Pivaloyl Derivative 3c: Colourless oil (86 mg, 0.25 mmol, 61%).
0.54 (hexanes/EtOAc, 3:1). IR (CHCl3): ν˜ ϭ 3560, 3040, 2960,
Rf ϭ 0.5 (hexanes/EtOAc, 5:1). IR (CHCl3): ν˜ ϭ 3040, 2960, 1740, 1740, 1715, 1660, 1550, 1460, 1380, 1220, 1080 cmϪ1. [α]2D0 ϭ Ϫ40.0
1
1
1715, 1490, 1384, 1220 cmϪ1. [α]2D0 ϭ ϩ84.0 (c ϭ 1.0, CHCl3). H
(c ϭ 1.5, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.15 (t, J ϭ
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D. B. G. Williams, K. Blann
FULL PAPER
[1] [1a]
7.2 Hz, 3 H, CH2CH3), 1.23 (s, 3 H, isopropylidene CH3), 1.32 (s,
3 H, isopropylidene CH3), 2.24Ϫ2.31 (m, 1 H, H1Ј), 2.45 (dd, J ϭ
6.9, 15.9 Hz, 1 H, H2b), 2.55 (dd, J ϭ 9.2, 15.9 Hz, 1 H, H2a),
3.03 (d, J ϭ 9.3 Hz, 1 H, CHaHbOTrit), 3.12 (s, 1 H, OH, D2O
exchange), 3.52 (d, J ϭ 9.3 Hz, 1 H, CHaHbOTrit), 3.98 (qd, J ϭ
3.6, 7.2 Hz, 1 H, CHaHbCH3), 4.05 (qd, J ϭ 3.6, 7.2 Hz, 1 H,
CHaHbCH3), 4.38 (dd, J ϭ 3.3, 6.0 Hz, 1 H, H2Ј), 4.51 (dd, J ϭ
1.1, 6.0 Hz, 1 H, H3Ј), 7.23Ϫ7.29 (m, 9 H, H3ЈЈ, H4ЈЈ), 7.43Ϫ7.46
(m, 6 H, H2ЈЈ) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.2
(CH2CH3), 25.9 (isopropylidene CH3), 26.4 (isopropylidene CH3),
32.0 (C2), 43.3 (C1Ј), 60.5 (CH2CH3), 65.4 (CH2OTrit), 73.6 (C4Ј),
76.0 (C2Ј), 80.8 (C3Ј), 86.7 (CPh), 114.5 (acetal C), 127.0 (C4ЈЈ),
127.7 (C3ЈЈ), 128.7 (C2ЈЈ), 143.7 (C1ЈЈ), 172.3 (C1Ј) ppm. MS:
m/z ϭ 502 (7) [Mϩ], 243 (100). FAB-HRMS: calcd. for C31H34O6
502.2355, found 502.2361.
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193390 x].
Minor Isomer 5b: Colourless oil (16 mg, 0.32 mmol, 15%). Rf ϭ
0.46 (hexanes/EtOAc, 3:1). IR (CHCl3): ν˜ ϭ 3040, 1740, 1715,
[4a] E. Piers, E. M. Boehringer, J. G. K. Yee, J. Org. Chem. 1998,
[4]
[4b]
63, 8642Ϫ8643.
H. Ito, A. Sato, T. Taguchi, Tetrahedron
1660, 1520, 1220, 1080 cmϪ1. [α]2D0 ϭ Ϫ74.0 (c ϭ 0.5, CHCl3). H
1
Lett. 1999, 40, 3217Ϫ3220.
NMR (300 MHz, CDCl3): δ ϭ 1.14 (t, J ϭ 7.2 Hz, 3 H,
OCH2CH3), 1.32 (s, 3 H, isopropylidene CH3), 1.60 (s, 3 H, isopro-
pylidene CH3), 2.29 (dd, J ϭ 8.7, 16.4 Hz, 1 H, H2b), 2.43 (dd,
J ϭ 7.5, 16.4 Hz, 1 H, H2a), 2.57 (td, J ϭ 5.1, 8.7 Hz, 1 H, H1Ј),
3.05 (s, 1 H, OH, D2O exchange), 3.09 (d, J ϭ 9.5 Hz, 1 H, CHaHb-
OTrit), 3.22 (d, J ϭ 9.5 Hz, 1 H, CHaHbOTrit), 3.99 (dq J ϭ 3.6,
7.2 Hz, 2 H, CHaHbCH3), 4.11 (t, J ϭ 5.0 Hz, 1 H, H2Ј), 4.58 (dd,
J ϭ 0.6, 5.0 Hz, 1 H, H3Ј), 7.23Ϫ7.29 (m, 9 H, H3ЈЈ, H4ЈЈ),
7.41Ϫ7.44 (m, 6 H, H2ЈЈ) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
14.2 (CH2CH3), 26.5 (isopropylidene CH3), 27.3 (isopropylidene
CH3), 32.1 (C2), 52.4 (C1Ј), 60.5 (CH2CH3), 64.5 (CH2OTrit), 69.1
(C4Ј), 73.8 (C2Ј), 78.7 (C3Ј), 87.1 (CPh), 114.6 (acetal C), 127.1
(C4ЈЈ), 127.9 (C3ЈЈ), 128.6 (C2ЈЈ), 143.3 (C1ЈЈ), 172.1 (C1) ppm.
MS: m/z ϭ 503 (10) [Mϩ ϩ 1], 243 (100). FAB-HRMS: calcd. for
C31H35O6 503.2434, found 503.2439.
[5] [5a]
´
G. Frater, U. Müller, W. Günther, Tetrahedron 1984, 40,
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1269Ϫ1277.
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G. A. Molander, C. R. Harris,
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Lactone 13: The cyclobutane derivative 5a (100 mg, 0.199 mmol)
was dissolved in methanol (5 mL), and TsOH (20 mg, 20% m/m)
was added. The reaction mixture was stirred at ambient tempera-
ture for 24 h. Triethylamine (5 drops) was added to neutralise the
reaction (pH paper), and the methanol was then removed in vacuo.
Toluene (5 mL) was added and then removed under reduced press-
ure to ensure that no trace of triethylamine remained. THF (5 mL)
and H2O (3 drops) were added together with TsOH (20 mg), and
the reaction mixture was stirred for a further 24 h. The neutralis-
ation process was repeated as before, and all the solvents were re-
moved. The crude product was subjected to column chromatogra-
phy. White solid (27 mg, 0.155 mmol, 78%). Rf ϭ 0.18 (EtOAc). IR
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[11] [11a]
´
J. J. C. Grove, C. W. Holzapfel, D. B. G. Williams, Tetra-
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´
J. J. C. Grove, C. W.
hedron Lett. 1996, 37, 1305Ϫ1308.
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5817Ϫ5820.
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J. J. C. Grove, C. W. Holzapfel, Carbohydrate
[11d]
´
J. J. C. Grove, C. W. Holzapfel,
[11e]
R. J. Ferrier, S.
[11f]
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Nara, T. Ozawa, H. Shirahama, F. Matsuda, Angew. Chem.
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and references cited therein.
(CHCl3): ν˜ ϭ 3040, 2960, 1745, 1720, 1660, 1520 cmϪ1. [α]2D0
ϭ
[12]
D. B. G. Williams, K. Blann, C. W. Holzapfel, SA Patent Appli-
ϩ4.16 (c ϭ 0.5, H2O). M.p. 140Ϫ142 °C (EtOAc). 1H NMR
(300 MHz, D2O): δ ϭ 2.60 (dd, J ϭ 3.3, 17.7 Hz, 1 H, H4b), 2.66
(dddd, 1 H, J ϭ 1.2, 2.7, 3.3, 9.3 Hz, H5), 2.82 (dd, J ϭ 9.3, 17.7
Hz, 1 H, H4a), 3.77 (d, J ϭ 12.9 Hz, 1 H, H1Јb), 3.88 (d, J ϭ 12.9
Hz, 1 H, H1Јa), 4.10 (dd, J ϭ 2.7, 6.3 Hz, 1 H, H6), 4.24 (dd, J ϭ
1.2, 6.3 Hz, 1 H, H7) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 34.6
(C4), 42.2 (C5), 61.1 (C1Ј), 70.5 (C6), 73.5 (C7), 92.9 (C1), 181.9
(CϭO) ppm. MS: m/z ϭ 174 (3) [Mϩ], 137 (100). FAB-HRMS:
calcd. for C7H10O5 174.0528, found 174.0528.
cation 2002/2457.
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D. B. G. Williams, K. Blann, C. W. Holzapfel, J. Org.
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Acknowledgments
We gratefully recognise the financial support for this project by the
National Research Foundation (GUN2053664), South Africa and
the Rand Afrikaans University.
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3290
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3286Ϫ3291

Radical Cyclisations of Carbohydrate-Derived Unsaturated Ketones
FULL PAPER
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The relative stereochemistries of all the cyclisation products
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The low yield of this material made a full characterisation and
J. Singh, G. S. Bisacchi, J. D. Godfrey Jr., T. Mitt, R. H.
Mueller, R. Zahler, T. P. Kissick (Bristol-Meters Squibb), US
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Received April 2, 2004
Eur. J. Org. Chem. 2004, 3286Ϫ3291
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3291