Chiral cyclobutanols and cyclopentane dimers via samarium(II) iodide induced keto-olefin cyclisations of carbohydrate-derived unsaturated ketones

Article abstract of DOI:10.1055/s-0029-1216824

Some pentose and hexose sugars were converted into unsaturated ketone derivatives, which themselves served as substrates for 4-exo-trig radical cyclisation reactions mediated by SmI₂. Depending on the order of addition of reagents, the keto-olefins could also be made to undergo a surprising tandem 5-endo-trig cyclisation/dimerisation reaction to a cyclopentane dimer or a cyclobutane monomer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216824

PAPER
2009
Chiral Cyclobutanols and Cyclopentane Dimers via Samarium(II) Iodide
Induced Keto-Olefin Cyclisations of Carbohydrate-Derived Unsaturated
Ketones
C
D
yclobutanols and
.
Cyclopentan
B
e
D
imers radley G. Williams,* Judy Caddy, Kevin Blann, J. J. Cronjé Grové, Cedric W. Holzapfel
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park, Johannesburg 2006, South Africa
Fax +27(11)4892819; E-mail: bwilliams@uj.ac.za
Received 18 February 2009
O
O
N
Abstract: Some pentose and hexose sugars were converted into un-
saturated ketone derivatives, which themselves served as substrates
N
N
O
N
HN
HN
O
for 4-exo-trig radical cyclisation reactions mediated by SmI . De-
2
N
N
HN
pending on the order of addition of reagents, the keto-olefins could
also be made to undergo a surprising tandem 5-endo-trig cyclisa-
tion/dimerisation reaction to a cyclopentane dimer or a cyclobutane
monomer.
H2N
HO
N
HO
O
H2N
HO
O
N3
: AZT
HO
Key words: carbocycles, carbohydrates, radical reactions, samari-
um, ring closure
1
2: Acyclovir
3: BMS-180,194
Figure 1 Bioactive compounds 1–3 containing thymine or guanine
moieties
Carbohydrates are ubiquitous in nature and chemists have
recognised the potential of these flexible starting materi-
als, applying them to their use as starting materials in the
O
O
OEt
O
O
O
O
1
synthesis of chiral products. The use of carbohydrates as
O
O
OH
precursors for the synthesis of cyclopentane derivatives
1. Wittig
. Dess–Martin
2
H
was recognised some time ago. Since then, significant at-
2
O
tention has been paid to this strategy, resulting in many
O
O
new syntheses of substituted stereodefined cyclopen-
1
tanes. In addition to the SmI -mediated synthesis of cy-
5a: trans (major)
2
4
3
clopentanes in our group, we have also recently reported
on the synthesis of cyclobutanes, using that reagent. A
number of routes toward the synthesis of compounds 1–3
+
4
O
O
O
OEt
(
Figure 1), which contain thymine or guanine moieties
and which are bioactive (antiviral agents), have been de-
vised. It is the synthesis of analogues of the guanine-con-
O
5
O
O
taining cyclobutane derivative 3 that our strategy attempts
to address. Therefore, we decided to utilise the methodol-
ogy developed in our laboratories, revolving around
5b: cis (minor)
4
,6
Scheme 1
SmI , a selective single-electron reductant, towards the
2
synthesis of functionalised cyclobutanes from carbohy-
drate precursors in 4-exo-trig ‘keto-olefin’ cyclisation re- Reaction of 5a with SmI by slow dropwise addition of
2
actions of some carbohydrate derivatives.
the sugar substrate to the SmI /HMPA–THF mixture at
2
–
78 °C gave the desired chiral cyclobutane products 6a
Our previous work has shown that a conformationally re-
stricted system is required before cyclisations to small
rings will take place. With this in mind, 2,3:5,6-di-O-iso-
(
50%) and 6b (33%), arising from a favoured 4-exo-trig
10
4
cyclisation according to Baldwin’s rules, in good yields
Figure 2). Reversal of the mode of addition, that is, addi-
(
propylidene-D-mannofuranose (4) was subjected to a
7
tion of the SmI solution to the keto-olefin substrate, again
2
Wittig reaction and in situ (to prevent unwanted Michael
8
9
afforded products 6a and 6b, but also allowed the isola-
tion of a third isomer 7c in trace amounts. The keto-olefin
coupling reaction11 has been used in many guises, to ef-
addition reactions ) Dess–Martin oxidation to provide
keto-olefins 5a (63%) and 5b (5%) (Scheme 1).
12
4
5
fect, for example, 3-exo-trig, 4-exo-trig , and 5-exo-trig
cyclisation reactions. For unactivated alkene systems and
for most a,b-unsaturated ester substrates, the mechanism
SYNTHESIS 2009, No. 12, pp 2009–2014
x
x.
x
x
.
2
0
0
9
is generally held to proceed via the ketyl radical
cyclising onto the alkene, although there is
some evidence that the process may proceed via initial re-
anion3
,4,11–13
Advanced online publication: 19.05.2009
DOI: 10.1055/s-0029-1216824; Art ID: P02909SS
Georg Thieme Verlag Stuttgart · New York
©

2
010
D. B. G. Williams et al.
PAPER
O
O
OH
OH
EtO2C
OH
EtO2C
OH
EtO2C
OH
TBDMSO
TBDMSO
O
O
O
O
O
O
OEt
OEt
O
O
O
O
O
O
O
O
O
O
11a
11b
6a
6b
6c
O
O
OH
OH
Figure 2 Cyclobutane derivatives 6a–c prepared from keto-enoate
TBDMSO
TBDMSO
5a
OEt
OEt
O
O
O
O
duction of the enoate system followed by cyclisation onto
the keto moiety in certain instances.1
2
1
1c
11d
The diastereoselectivity observed presumably relates to
the steric bulk of the two acetonide protecting groups pre- Figure 3 Cyclobutane derivatives 11a–d prepared from enoate 10
ferring a trans set-up in the transition state, which would
select 6a as the major product with 6b as the minor. In the
event, the 4-exo-trig cyclisation reactions typically pro-
ceed such that the hydroxyl group and the ester function
maintain a trans relative stereochemistry in the prod-
In all of the cases shown above, the stereochemistry of the
isomers obtained was deduced and assigned on the basis
of extensive NOE NMR experiments. A single crystal X-
ray structure determination14 of the fully deprotected lac-
tone 12 (Scheme 3), derived from 11c by acid-catalysed
hydrolysis, offered conclusive evidence of the stereo-
4
c,d,11c
uct.
We have previously observed analogous cyclisations
14
4
chemistry of this product. Indeed, triol 12 (and its
based on ribose-derived materials. Here, identical reac-
15
ribose-derived analogue ) is now perfectly set up for fur-
ther manipulation towards a nucleoside, which is part of
our ongoing studies in this area.
tions could be carried out to prepare cyclobutane deriva-
tives of opposite stereochemistry, when making use of D-
lyxose (7) as starting material. Synthesis of the lyxose de-
rivative 10 for treatment with SmI was carried out with
2
O
OH
ease, using known chemistry (Scheme 2) (53% total yield
OH
4
TBDMSO
over three steps, cis/trans = 2:7).
CHCl3, HCl
HO
OEt
O
O
HO
HO
O
O
HO
O
OH
O
OH
acetone
H2SO4
11c
12
HO
OH
O
O
Scheme 3
7
8
A remarkable change in the selectivity of the reaction oc-
curred, for some substrates, when the order of the addition
of reagents was reversed. As already stated, keto-olefin 5b
provided essentially identical product distributions, irre-
spective of whether the substrate was added to the SmI2
TBDMSCl
py
O
O
OEt
TBDMSO
O
OH
O
TBDMSO
1. Wittig
. Dess–Martin
solution or the SmI solution was added to the substrate.
2
2
O
O
O
However, when the SmI solution was added to either the
2
4a
ribose-derived substrate 13 or the lyxose-derived ana-
logue 10, we unexpectedly isolated dimeric materials 14
10
9
(
Scheme 4).
Scheme 2
Even more surprising was the fact that these products
were not dimeric cyclobutanes (i.e., simple dimers of, for
example, 11b), but were dimeric cyclopentanes, the prod-
ucts of a tandem cyclisation/dimerisation reaction. This
was unexpected in the face of Baldwin’s rules of cycli-
sation, under which it is anticipated that a 4-exo-trig cycli-
Carrying out the SmI -mediated ring-closing reaction by
2
adding the trans substrate to the SmI /HMPA–THF mix-
2
ture gave four monomers 11a–d in a total yield of 65%
10
(
5%:30%:13%:17%) (Figure 3), the major products hav-
ing the alcohol and ester groups cis with respect to each
other, as anticipated from our previous work.4 The
change in the selectivity from trans to cis in the present in-
stance presumably relates to the large size of the TBDMS
group dominating steric interactions in the cyclisation
transition state.
sation dominates over
a
5-endo-trig competing
a
possibility. The structure of one of the ribose-derived
dimeric products 14a was confirmed by X-ray crystallog-
16
raphy.
Synthesis 2009, No. 12, 2009–2014 © Thieme Stuttgart · New York

PAPER
Cyclobutanols and Cyclopentane Dimers
2011
O
O
OEt
EtO2C
HO
O
CO2Et
OH
O
O
RO
SmI2, THF, HMPA
RO
OR
and/or isomer
add dropwise to 13
O
H
H
O
O
1
3a: R = Piv
3b: R = TDBMS
14a: R = Piv
14b: R = Piv, isomer
14c: R = TBDMS, isomer
14d: lyxose analogue, isomer
1
or lyxose analogue 10
Scheme 4
Interestingly, the ribose-derived trityl-protected keto-ole- tailed study by Flowers22 indicates that the keto-olefin
4
a
fin 15 failed to afford the dimeric product (Scheme 5), reaction, particularly the role of HMPA therein, is diffi-
instead producing only the monomeric cyclobutane prod- cult to predict. In the present case, it is quite possible that
4
a
ucts already described elsewhere, regardless of the order the mechanism switches from the usual ketyl radical cy-
of addition. This was also the case for the mannose deriv- clisation to an anion cyclisation/radical dimerisation or
ative 5, as described above.
similar mechanism of the enoate moieties to produce 16
and 17 and so generate the five-membered rings
(Scheme 6). In this way, the preferred 5-exo-trig cyclisa-
tion is followed.
O
O
OEt
O
TritO
SmI2, THF, HMPA
cyclobutane
monomers only
O
OEt
standard or
reverse addition
O
OEt
CO2Et
O
O
O
O
R
R
SmI2
R
15
O
O
O
O
O
O
Scheme 5
16
From these data, it appears as if the outcome of the reac-
tion is dependent on two factors. Firstly, the reaction is
sensitive to the order of addition of substrate and reagent:
CO2Et
O
addition of the keto-olefin substrates to SmI facilitates
final product
2
2
R
monomer formation only, in all cases, while the reverse
addition allows the possibility of generating dimers. Sec-
ondly, in instances in which dimerisation is at all a possi-
O
O
17
bility, namely when the SmI is slowly added to the keto-
2
olefin substrate, steric factors may inhibit the dimerisation Scheme 6
reaction altogether, as was found to be the case with the
sterically demanding enoate substrates 5 and 15. The rea-
son why dimer formation occurs probably lies in a change
in the mechanism of the reaction. Literature reports have
indicated that the cyclisation of keto-enoate substrates
In summary, chiral cyclobutane derivatives can be readily
prepared from chiral carbohydrate precursors of varying
carbon number and chirality using a reductive cyclisation
protocol. Furthermore, depending on the steric bulk
around the ketone functionality and the order of addition
of reagents, cyclopentane dimers may also be prepared
from common intermediates. Excessive steric bulk pre-
vents the formation of such dimers, regardless of the order
of addition of the reagents, producing cyclobutane deriv-
atives in all instances. We are currently in the process of
preparing analogues of 3, from products of this study,
with the view to their biological evaluation, the results of
which will be disclosed in due course.
1
2,13
may also be initiated at the enoate group.
Since the re-
duction of the ketone to the ketyl radical is reversible,17
and the fact that 4-exo-trig reactions are held to be rela-
1
8
tively slow, the reaction may well favour reaction at the
enoate under the particular reaction conditions cited here.
Such cyclisations to monomeric systems have previously
been observed when the reactions are performed in the
1
9
presence of a proton source. (Proton sources have been
shown to dramatically effect SmI -mediated reactions,
2
also permitting stereoselective reactions to be secured
2
0
from chiral alcohols. ) Furthermore, such reactions at the
enoate are also known to lead to dimerisation products in
TLC was conducted quantitatively on Merck GF254 precoated silica
gel glass plates (0.25 mm layer). Various solvent mixtures were
used to elute the chromatograms with the mixture of hexanes and
EtOAc usually being the eluent of choice. Aromatic derivatives
2
1
some instances. Here, the process is generally believed
to proceed via radical addition, but one different mecha-
2
1c
nism has also been proposed. In any case, a recent de- were visualised by their fluorescence under UV light (254 nm)
Synthesis 2009, No. 12, 2009–2014 © Thieme Stuttgart · New York

2
012
D. B. G. Williams et al.
PAPER
while carbohydrate substrates were detected after spraying the TLC
plate with a chromic acid solution and then heating it over an open
flame. Flash column chromatography refers to column chromatog-
mL) and added dropwise over 20 min with stirring to a freshly pre-
pared solution of SmI in THF (8.8 mL of a 0.1 M solution, 0.88
2
mmol, 4.2 equiv) and HMPA (0.21 mL, 1.43 mmol, 6.8 equiv) at
–78 °C. The mixture was stirred at –78 °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 flash column chromatography (3:1 hexanes–EtOAc). Two iso-
meric monomers 6a and 6b were obtained as oils (total yield: 83%).
Reversed addition allowed 6c to be isolated in a separate reaction as
a colourless oil.
raphy under N pressure (ca. 50 kPa). The columns were loaded
2
with Merck Kieselgel 60 (230–400 mesh) and eluted with appropri-
ate solvent mixtures in a volume per volume ratio. THF was pre-
dried over freshly ground KOH. The KOH was then filtered off and
the solvent distilled from sodium-benzophenone under N immedi-
2
ately prior to use, and once a sustained blue colour was present.
HMPA was heated over CaH under argon for one week prior to its
2
use. The solvent was only used if freshly distilled. NMR-spectra
were recorded using a Varian Gemini 2000, 300 MHz spectrometer.
Cyclobutane 6a
The samples were usually made up in CDCl and for more polar
Yield: 35 mg (50%); R = 0.47 (2:1 hexanes–EtOAc); [a] +61.1 (c
1.0, CHCl3).
3
f
D
1
samples D O was used. The H NMR data are listed in order: Chem-
2
ical shift (d, reported in ppm and referenced to the residual solvent
–1
IR (CHCl ): 3568, 2949, 1733, 1730, 1066 cm .
3
peak of CDCl [d = 7.24]), the multiplicity, the coupling constant J
3
1
H NMR (300 MHz, CDCl ): d = 4.46 (t, J = 6.9 Hz, 1 H), 4.41 (s,
H), 4.40 (s, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.99 (dd, J = 8.4, 6.9
Hz, 1 H), 3.75 (dd, J = 8.4, 6.9 Hz, 1 H), 2.61–2.48 (m, 2 H), 2.53
d, J = 6.0 Hz, 1 H, OH), 2.47–2.38 (m, 1 H), 1.56 (s, 3 H), 1.42 (s,
expressed in Hz, the proton integration, and finally the specific hy-
drogen allocation. Spin-decoupling experiments aided in the deter-
mination of the coupling constants and hydrogen allocation. The
relative stereochemistry was determined after studying nuclear
3
1
(
1
3
3 H), 1.37 (s, 3 H), 1.25 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).
Overhauser effect spectra (1D NOE difference). C NMR data are
listed in the order: chemical shift (d, reported in ppm referenced to
13
C NMR (75 MHz, CDCl ): d = 172.1, 114.9, 109.3, 81.0, 76.2,
75.9, 71.9, 63.9, 60.7, 42.1, 31.5, 26.5, 26.3, 25.6, 24.9, 14.2.
3
the solvent peak of CDCl [(d = 77.0]) and the specific carbon atom
3
allocation. DEPT and HETCOR spectroscopy were used to assist in
the allocation of difficult spectra where necessary. Mass spectra
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 using glycerol or nitrobenzyl alcohol as the matrix. A
PerkinElmer 881 spectrometer was used to record IR spectra using
MS (FAB): m/z = 331 ([M + 1]+).
+
HRMS-FAB: m/z calcd for C16
H
O
: 331.1757 ([M] ); found:
26
7
331.1756.
Cyclobutane 6b
anhyd CHCl as the solvent. The data are listed with characteristic
Yield: 23 mg (33%); R
0.5, CHCl ).
f
= 0.29 (2:1 hexanes–EtOAc); [a] +19.5 (c
D
3
–
1
peaks indicated in wavenumbers (cm ). A Jasco model DIP-730
spectropolarimeter having a cell with a 10 mm path length was used
to determine optical rotations. The concentration (c) indicates the
concentration of the sample in grams per 100 mL of solution. All re-
actions were performed in flamed out glass apparatus using anhyd
3
–1
IR (CHCl ): 3429, 3033, 2935, 1735, 1222 cm .
3
1
H NMR (300 MHz, CDCl ): d = 4.84 (dd, J = 6.3, 5.4 Hz, 1 H),
3
4
.43 (t, J = 7.2 Hz, 1 H), 4.38 (dd, J = 5.4, 2.1 Hz, 1 H), 4.13 (q,
J = 7.2 Hz, 2 H), 3.92 (dd, J = 7.5, 7.2 Hz, 1 H), 3.77 (dd, J = 7.5,
solvents unless otherwise stated. All SmI reactions were carried
2
7
2
1
.2 Hz, 1 H), 2.77–2.66 (m, 1 H), 2.55 (dd, J = 16.2, 11.4 Hz, 1 H),
.55 (br s, 1 H, OH), 2.13 (dd, J = 16.2, 5.9 Hz, 1 H), 1.54 (s, 3 H),
.45 (s, 3 H), 1.37 (s, 3 H), 1.26 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H).
out under argon using degassed solvents while standard chemistry
was done under N2.
1
3
Keto-Enoate 5a
C NMR (75 MHz, CDCl ): d = 171.3, 113.9, 108.9, 81.2, 75.9,
3
To a solution of 2,3:5,6-di-O-isopropylidene-D-mannofuranose (4;
74.5, 71.3, 63.9, 60.7, 39.5, 29.7, 26.2, 25.3, 25.2, 24.5, 14.2.
4
a
1
00 mg, 0.37 mmol) in anhyd CH Cl (1.5 mL) was added eth-
2 2
+
MS (FAB): m/z = 331 ([M + 1] , 100%).
yl(triphenylphosphoranylidene)acetate (157 mg, 0.45 mmol) and
the reaction mixture stirred at r.t. Upon completion of the reaction
+
HRMS-FAB: m/z calcd for C16
331.1753.
H
O
: 331.1757 ([M] ); found:
26
7
(
6 d, TLC), the mixture was diluted with CH Cl (1.5 mL), treated
2
2
with Dess–Martin periodinane (191 mg, 0.45 mmol) and stirred at
r.t. for 3 h. The solvent was removed in vacuo and the residue was
purified by flash column chromatography (5:1 hexanes–EtOAc) to
afford the trans title compound as a colourless oil; yield: 76 mg
Cyclobutane 6c
Yield: 11 mg (16%); R
0.5, CHCl ).
= 0.56 (2:1 hexanes–EtOAc); [a] +17.4 (c
D
f
3
(
63%); R = 0.67 (2:1 hexanes–EtOAc).
–1
f
IR (CHCl ): 3400, 3026, 2942, 1702, 1045 cm .
3
–
1
IR (CHCl ): 3026, 1723, 1664 cm .
1
3
H NMR (300 MHz, CDCl ): d = 4.77 (dd, J = 5.7, 5.4 Hz, 1 H),
3
1
H NMR (300 MHz, CDCl ): d = 6.76 (dd, J = 15.2, 3.4 Hz, 1 H),
4.33 (dd, J = 8.4, 6.6 Hz, 1 H), 4.28–3.99 (m, 5 H, 4 × CH, OH),
3.69 (t, J = 8.6 Hz, 1 H), 2.91 (dd, J = 12.6, 6.6 Hz, 1 H), 2.27 (ddd,
J = 13.2, 12.6, 5.4 Hz, 1 H), 2.09 (dd, J = 13.2, 6.6 Hz, 1 H), 1.41
(s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.26
3
6
.09 (d, J = 15.2 Hz, 1 H), 5.03 (s, 2 H), 4.71 (dd, J = 8.1, 6.3 Hz, 1
H), 4.21–4.11 (m, 3 H), 3.87 (dd, J = 8.7, 6.3 Hz, 1 H), 1.59 (s, 3 H),
1
.42 (s, 3 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
(
s, 3 H).
13C NMR (75 MHz, CDCl
8.9, 78.6, 65.3, 61.2, 42.8, 35.3, 26.0, 25.9, 25.3, 23.7, 14.0.
1
3
C NMR (75 MHz, CDCl ): d = 204.1, 165.2, 141.5, 123.3, 110.7,
3
1
10.6, 81.2, 75.6, 75.8, 64.9, 60.5, 26.6, 25.5, 24.7, 24.5, 14.1.
3
): d = 174.5, 110.3, 107.9, 85.6, 82.9,
7
+
MS (FAB): m/z = 329 ([M + 1] , 100%).
+
MS (FAB): m/z = 331 ([M + 1] , 100%).
HRMS-FAB: m/z calcd for C16 : 331.1757 ([M] ); found:
31.1757.
+
HRMS-FAB: m/z calcd for C H O : 329.1600 ([M] ); found:
3
1
6
24
7
+
29.1611.
H O
26 7
3
Mannofuranose Monomers 6a–c
Keto-enoate 5a (69 mg, 0.21 mmol) was dissolved in degassed THF
5 mL) and the solvent removed by vacuum distillation to ensure an
Keto-Enoate 10
The general procedure to perform a Wittig reaction with ethyl(tri-
(
4
a
oxygen-free system. The residue was then dissolved in THF (20
phenylphosphoranylidene)acetate in CH
2
Cl
2
was carried out on
protected lyxose derivative 8 (1.050 mg, 3.44 mmol) followed by in
Synthesis 2009, No. 12, 2009–2014 © Thieme Stuttgart · New York

PAPER
Cyclobutanols and Cyclopentane Dimers
2013
situ Dess–Martin oxidation. The solvent was removed in vacuo and
the residue was purified by flash column chromatography (7:1 hex-
anes–EtOAc) to afford the trans title compound as a colourless oil;
IR (CHCl ): 3040, 2960, 2880, 1780, 1740, 1715, 1660, 1390, 1272,
1230 cm .
3
1
–
1
H NMR (300 MHz, CDCl ): d = 4.76 (t, J = 5.5 Hz, 1 H, H-5¢), 4.41
3
yield: 749 mg (56%); R = 0.57 (5:1 hexanes–EtOAc). The cis iso-
f
(
dd, J = 5.5, 1.7 Hz, 1 H, H-1¢), 4.11 (q, J = 7.2 Hz, 2 H,), 3.71 (d,
mer (224 mg, 17%) was obtained as a by-product.
J = 10.2 Hz, 1 H,), 3.57 (d, J = 10.2 Hz, 1 H), 3.18 (br s, 1 H, OH),
2.64–2.56 (m, 2 H), 2.50 (dd, J = 5.7, 3.9 Hz, 1 H), 1.47 (s, 3 H),
1.24 (s, 3 H), 1.23 (t, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H),
0.05 (s, 3 H).
IR (CHCl ): 1723, 1386, 1313, 1267, 1191, 1111, 1080, 1034, 982,
3
–
1
8
47 cm .
1
H NMR (300 MHz, CDCl ): d = 6.73 (dd, J = 15.6, 4.5 Hz, 1 H),
3
1
3
6
.07 (dd, J = 15.6, 1.7 Hz, 1 H), 5.02–4.94 (m, 2 H), 4.42 (d,
J = 18.8 Hz, 1 H), 4.13 (d, J = 18.8 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2
H), 1.59 (s, 3 H), 1.37 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9
H), 0.05 (s, 3 H), 0.03 (s, 3 H).
C NMR (75 MHz, CDCl ): d = 172.2, 113.6, 80.5, 71.9, 63.1, 60.5,
3
40.6, 28.8, 25.9, 25.3, 25.2, 18.3, 14.2, –5.4.
+
HRMS-FAB: m/z calcd for C H O Si: 375.2203 ([M + 1] );
1
8
35
6
found: 375.2212.
1
3
C NMR (75 MHz, CDCl ): d = 205.7, 165.2, 140.9, 123.5, 110.8,
3
8
1.6, 75.9, 68.3, 60.5, 26.8, 25.8, 24.8, 18.3, 14.2, –5.5.
Cyclobutane 11d
Yield: 12 mg (17%); [a]
anes–EtOAc).
+
+61.7 (c 5.0, CHCl ); R = 0.27 (4:1 hex-
D 3 f
HRMS-FAB: m/z calcd for C H SiO : 373.2046 ([M + 1] );
found: 373.2037.
1
8
33
6
IR (CHCl ): 3040, 2960, 2880, 1790, 1740, 1715, 1660, 1560, 1390,
3
–
1
Lyxose Monomers 11a–d
1270, 1220 cm .
The general procedure to form monomers with SmI in THF in the
1
2
H NMR (300 MHz, CDCl ): d = 4.58 (d, J = 4.8 Hz, 1 H), 4.12 (q,
3
presence of HMPA via normal addition was used to form monomers
from enoate 10 (78 mg, 0.21 mmol). The residue was purified by
flash column chromatography (3:1 hexanes–EtOAc). Four mono-
mer isomers were obtained as oils; total yield: 55%.
J = 7.2 Hz, 2 H), 4.04 (t, J = 4.8 Hz, 1 H), 3.64 (d, J = 10.1 Hz, 1
H), 3.59 (d, J = 10.1 Hz, 1 H), 2.92 (br s, 1 H, OH), 2.71–2.55 (m,
3
H), 1.58 (s, 3 H), 1.31 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.89 (s, 9
H), 0.06 (s, 3 H), 0.05 (s, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 172.4, 114.3, 79.4, 73.6, 69.0, 64.2,
Cyclobutane 11a
Yield: 4 mg (5%); [a] –28.2 (c 2.0, CHCl ); R = 0.56 (5:1 hex-
anes–EtOAc).
3
6
0.5, 52.6, 31.9, 27.4, 26.4, 25.8, 18.2, 14.2, –5.6.
D
3
f
+
HRMS-FAB: m/z calcd for C H O Si: 3754.2203 ([M + 1] );
1
8
35
6
found: 375.2205.
IR (CHCl ): 3040, 2960, 2870, 1790, 1740, 1660, 1540, 1390, 1270
cm .
3
–
1
Dimers 14a–d; General Procedure
The keto ester 10 or 13 (0.21 mmol) was dissolved in degassed THF
5 mL) and the solvent removed by vacuum distillation to ensure an
oxygen-free system. The residue was then dissolved in THF (20
mL) and HMPA (0.21 mL, 1.43 mmol, 6.8 equiv) and subsequently
1
H NMR (300 MHz, CDCl ): d = 4.75 (t, J = 5.6 Hz, 1 H), 4.21 (d,
3
J = 5.7 Hz, 1 H), 4.20–4.06 (m, 2 H), 3.97 (br s, 1 H, OH), 3.80 (d,
J = 1.5 Hz, 2 H), 2.80 (dd, J = 12.5, 6.6 Hz, 1 H), 2.26 (td, J = 13.5,
5
3
H).
1
(
.1 Hz, 1 H), 2.03 (dd, J = 13.6, 6.6 Hz, 1 H), 1.41 (s, 3 H), 1.24 (s,
H), 1.25 (t, J = 6.9 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3
cooled to –78 °C. A freshly prepared solution of SmI in THF (6.3
2
mL of a 0.1 M solution, 0.63 mmol, 3.0 equiv) was then added drop-
wise over 20 min with stirring. The stirring was continued at –78 °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 purified by flash column chromatography.
3
C NMR (75 MHz, CDCl ): d = 173.9, 110.0, 85.4, 83.1, 78.9, 66.1,
3
6
0.7, 45.7, 34.8, 26.2, 25.9, 23.8, 18.4, 14.1, –5.40.
+
+
MS (EI, 70 eV): m/z (%) = 375 ([M + 1] , 4), 359 ([M – CH ] , 31),
3
5
3
+
+
+
29 ([M – OEt] , 40), 317 ([M – C H ] , 72), 259 ([M – TBDMS] ,
4 9
3), 28 (100).
Ribose-Derived Pivaloyl Dimer 14a16
+
HRMS-FAB: m/z calcd for C H O Si: 3754.2203 ([M + 1] );
found: 375.2202.
1
8
35
6
Yield: 24 mg (0.035 mmol, 33%); colourless oil; R = 0.37 (2:1 hex-
f
anes–EtOAc).
IR (CHCl ): 3520, 3040, 3000, 2960, 1740, 1715, 1570, 1220, 1170
cm .
3
Cyclobutane 11b
Yield: 27 mg (30%); [a] –138.9 (c 16.0, CHCl ); R = 0.46 (5:1
hexanes–EtOAc).
–
1
D
3
f
1
H NMR (300 MHz, CDCl ): d = 4.88 (dd, J = 6.8, 2.8 Hz, 2 H),
3
4
.50 (d, J = 6.8 Hz, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.22 (d, J = 12.2
Hz, 2 H), 4.10 (d, J = 12.2 Hz, 2 H), 4.05 (q, J = 7.2 Hz, 2 H), 3.80
br s, 2 H, OH), 3.04 (m, 2 H), 2.67 (t, J = 2.8 Hz, 2 H), 1.43 (s, 6
H), 1.28 (s, 6 H), 1.26 (t, J = 7.2 Hz, 6 H), 1.20 (s, 18 H).
IR (CHCl ): 3040, 2960, 2880, 1790, 1740, 1715, 1660, 1560, 1390,
3
–
1
1
270, 1220 cm .
(
1
H NMR (300 MHz, CDCl ): d = 4.37 (s, 1 H), 4.36 (s, 1 H), 4.10
3
(
q, J = 7.2 Hz, 2 H), 3.84 (d, J = 9.9 Hz, 1 H), 3.51 (d, J = 9.9 Hz, 1
1
3
C NMR (75 MHz, CDCl ): d = 178.4, 172.6, 111.9, 85.5, 83.1,
3
H), 3.02 (br s, 1 H, OH), 2.56 (dd, J = 16.2, 9.0 Hz, 1 H), 2.44 (dd,
J = 16.2, 6.9 Hz, 1 H), 2.34 (ddd, J = 9.0, 6.9, 1.8 Hz, 1 H), 1.50 (s,
3
8
1.2, 67.1, 61.1, 51.6, 46.8, 38.9, 27.1, 26.4, 24.3, 14.1.
+
H), 1.22 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H), 0.87 (s, 9 H), 0.60 (s, 3
HRMS-FAB: m/z calcd for C H O : 688.3670 ([M + 2] ); found:
3
4
56 14
H), 0.56 (s, 3 H).
688.3672.
1
3
C NMR (75 MHz, CDCl ): d = 172.4, 114.4, 80.7, 75.8, 73.2, 64.7,
3
Ribose-Derived Pivaloyl Dimer 14b
Yield: 20 mg (0.030 mmol, 28%); white needle-like, gummy crys-
6
0.4, 43.2, 31.7, 26.4, 25.9, 25.8, 18.4, 14.2, –5.31, –5.33.
+
HRMS-FAB: m/z calcd for C H O Si: 375.2203 ([M + 1] );
found: 375.2203.
1
8
35
6
tals; R = 0.25 (2:1 hexanes–EtOAc).
f
–
1
IR (CHCl ): 3600, 3040, 2960, 1740, 1715, 1390, 1220, 1170 cm .
3
1
Cyclobutane 11c
H NMR (300 MHz, CDCl ): d = 4.56 (dd, J = 6.8, 4.2 Hz, 2 H),
3
Yield: 15 mg (13%); [a] +57.7 (c 2.0, CHCl ); R = 0.31 (5:1 hex-
anes–EtOAc).
4.44 (d, J = 6.8 Hz, 2 H), 4.36 (d, J = 11.7 Hz, 2 H), 4.23 (d,
J = 11.7 Hz, 2 H), 4.16 (q, J = 7.2 Hz, 4 H), 2.87–2.76 (m, 6 H,
D
3
f
Synthesis 2009, No. 12, 2009–2014 © Thieme Stuttgart · New York

2
014
D. B. G. Williams et al.
PAPER
4
6
× CH, 2 × OH), 1.42 (s, 6 H), 1.258 (s, 6 H), 1.264 (t, J = 7.2 Hz,
H), 1.19 (s, 18 H).
(4) (a) Williams, D. B. G.; Blann, K. Eur. J. Org. Chem. 2004,
3286. (b) Williams, D. B. G.; Caddy, J. Carbohydr. Res.
2005, 340, 1301. (c) Edmonds, D. J.; Muir, K. W.; Procter,
D. J. J. Org. Chem. 2003, 68, 3190. (d) Weinges, K.;
Schmidbauer, S. B.; Schick, H. Chem. Ber. 1994, 127, 1305.
(5) (a) Brown, B.; Hegedus, L. S. J. Org. Chem. 1998, 63, 8012.
1
3
C NMR (75 MHz, CDCl ): d = 178.2, 170.3, 113.0, 86.0, 81.2,
3
8
1.0, 65.3, 61.1, 56.4, 48.4, 38.9, 27.2, 26.2, 24.9, 14.2.
+
HRMS-FAB: m/z calcd for C H O : 687.3592 ([M + 1] ); found:
6
3
4
55 14
87.3588.
(
b) Martín-Vilà, M.; Minguillón, C.; Ortuño, R. M.
Tetrahedron: Asymmetry 1998, 9, 4291. (c) Godfrey, J. D.
Jr.; Mueller, R. H. (Bristol-Myers Squibb Co.) US Patent
5773614, 1998; Chem. Abstr. 1998, 129, 122668.
Ribose-Derived OTBDMS Dimer 14c
Yield: 47 mg (0.063 mmol, 60%); colourless oil; R = 0.37 (4:1 hex-
anes–EtOAc).
f
(
d) Maruyama, T.; Hanai, Y.; Sato, Y.; Snoeck, R.; Andrei,
–
1
G.; Hosoya, M.; Balzarini, J.; De Clercq, E. Chem. Pharm.
Bull. 1993, 41, 516. (e) Collins, P. W.; Djuric, S. W. Chem.
Rev. 1993, 93, 1533. (f) Slusarchyk, W. A.; Young, M. G.;
Bisacchi, G. S.; Hockstein, D. R.; Zahler, R. Tetrahedron
Lett. 1989, 30, 6453. (g) Jacobs, G. A.; Tino, J. A.; Zahler,
R. Tetrahedron Lett. 1989, 30, 6955.
IR (CHCl ): 3040, 2960, 1740, 1715, 1660, 1570, 1220, 1100 cm .
3
1
H NMR (300 MHz, CDCl ): d = 4.50 (dd, J = 6.7, 4.4 Hz, 2 H),
3
4
2
.42 (d, J = 6.7 Hz, 2 H), 4.20–4.02 (m, 4 H), 3.84 (d, J = 10.2 Hz,
H), 3.72 (d, J = 10.2 Hz, 2 H), 3.39 (br s, 2 H, OH), 2.78 (d, J = 9.3
Hz, 2 H), 2.55–2.71 (m, 2 H), 1.39 (s, 6 H), 1.24 (s, 6 H), 1.23 (t,
J = 7.2 Hz, 6 H), 0.88 (s, 18 H), 0.06 (s, 6 H), 0.04 (s, 6 H).
(
6) (a) Williams, D. B. G.; Caddy, J.; Blann, K.; Holzapfel, C.
W. Synth. Commun. 2002, 32, 3755. (b) Williams, D. B. G.;
Blann, K.; Holzapfel, C. W. Synth. Commun. 2001, 31, 203.
(c) Williams, D. B. G.; Blann, K.; Holzapfel, C. W. J. Chem.
Soc., Perkin Trans. 1 2001, 219. (d) Williams, D. B. G.;
Blann, K.; Holzapfel, C. W. J. Org. Chem. 2000, 65, 2834.
7) Zhou, Z.; Bennet, S. Tetrahedron Lett. 1997, 38, 1153.
8) (a) Wanner, M. J.; Koomen, G. J. Tetrahedron Lett. 1990,
1
3
C NMR (75 MHz, CDCl ): d = 170.6, 112.6, 85.3, 81.1, 80.7, 63.3,
3
6
0.5, 55.9, 47.9, 26.3, 25.9, 24.9, 18.5, 14.2, –5.5, –5.3.
+
HRMS-FAB: m/z calcd for C H Si O : 747.4171 ([M + 1] );
3
6
67
2
12
found 747.4171.
(
(
Lyxose-Derived OTBDMS Dimer 14d
Yield: 34 mg (0.045 mmol, 43%); colourless oil; [a] +29.5 (c 0.5,
D
31, 907. (b) Barrett, A. G. M.; Broughton, H. B.; Attwood,
CHCl ); R = 0.32 (4:1 hexanes–EtOAc).
3
f
S. V.; Gunatilaka, L. A. A. J. Org. Chem. 1986, 51, 495.
–
1
IR (CHCl ): 3041, 2960, 1740, 1714, 1662, 1220, 1100 cm .
3
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
(10) Baldwin, J. J. Chem. Soc., Chem. Commun. 1976, 734.
(11) (a) Molander, G. A.; Czakó, B.; Rheam, M. J. Org. Chem.
2007, 72, 1755. (b) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321. (c) Molander, G. A.; Harris, C.
R. Chem. Rev. 1996, 96, 307.
1
H NMR (300 MHz, CDCl ): d = 4.81 (t, J = 5.6 Hz, 1 H), 4.73 (t,
3
J = 5.6 Hz, 1 H), 4.36 (d, J = 5.4 Hz, 1 H), 4.19 (d, J = 5.7 Hz, 1 H),
4
.16–4.10 (m, 4 H), 3.88 (d, J = 9.6 Hz, 1 H), 3.75 (d, J = 9.6 Hz, 1
H), 3.46 (d, J = 1.2 Hz, 2 H), 3.17 (br s, 1 H, OH), 2.99 (d, J = 12.9
Hz, 1 H), 3.02–2.91 (m, 1 H), 2.73–2.64 (m, 1 H), 2.68 (d, J = 12.0
Hz, 1 H), 1.56 (br s, 1 H, OH), 1.52 (s, 3 H), 1.39 (s, 3 H), 1.35 (s,
(12) Bezzenine-Lafollée, S.; Guibé, F.; Villar, H.; Zriba, R.
Tetrahedron 2004, 60, 6931.
3
H), 1.25 (s, 3 H), 1.26 (t, J = 6.6 Hz, 3 H), 1.24 (t, J = 6.8 Hz, 3
H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.06 (s, 6 H), 0.04 (s, 6 H).
(13) Johnston, D.; Couché, E.; Edmonds, D. J.; Muir, K. W.;
Procter, D. J. Org. Biomol. Chem. 2003, 1, 328.
1
3
C NMR (75 MHz, CDCl ): d = 172.3, 171.3, 110.3, 109.6, 84.3,
3
(
14) Caddy, J.; Williams, D. B. G.; Roodt, A.; Muller, A. Acta
Crystallogr., Sect. E 2003, 59, o1095.
8
4
–
2.6, 80.5, 80.4, 80.3, 80.2, 66.1, 63.8, 60.6, 60.5, 54.8, 50.5, 42.4,
0.3, 26.5, 26.4, 25.9, 25.8, 24.8, 24.3, 18.4, 18.3, 14.2, 14.1, –5.54,
5.52, –5.37, –5.30.
(
15) Blann, K.; Williams, D. B. G.; Roodt, A.; Muller, A. Acta
Crystallogr., Sect. E 2003, 59, o1551.
+
HRMS-FAB: m/z calcd for C H O Si : 747.4171 ([M] ); found:
(16) CCDC 294062.
(17) Prasad, E.; Flowers, R. A. II J. Am. Chem. Soc. 2002, 124,
3
6
66 12
2
7
47.4172.
6
357.
18) Park, S.-U.; Varick, T. R.; Newcomb, M. Tetrahedron Lett.
990, 31, 2975.
(
(
(
Acknowledgment
1
19) Johnston, D.; McCusker, C. M.; Muir, K.; Procter, D. J.
The authors thank the NRF and the University of Johannesburg for
funding this project.
J. Chem. Soc., Perkin Trans. 1 2000, 681.
20) A recent review details the use of SmI in numerous
2
asymmetric syntheses: Gopalaiah, K.; Kagan, H. B. New J.
Chem. 2008, 32, 607.
References
(
21) (a) Cabrera, A.; Le Lagadec, R.; Sharma, P.; Arias, J. L.;
Toscano, R. A.; Velasco, L.; Gaviño Alvarez, C.; Salmon,
M. J. Chem. Soc., Perkin Trans. 1 1998, 3609. (b) Cabrera,
A.; Alper, H. Tetrahedon Lett. 1992, 33, 5007. (c) Howells,
D. M.; Barker, S. M.; Watson, F. C.; Light, M. E.;
Hursthouse, M. B.; Kilburn, J. D. Org. Lett. 2004, 6, 1943.
22) Sadasivam, D. V.; Antharjanam, P. K. S.; Prasad, R. J.;
Flowers, R. A. II J. Am. Chem. Soc. 2008, 130, 7228.
(
(
1) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779.
2) Verheyden, J. P. H.; Richardson, A. C.; Bhatt, R. S.; Grant,
B. D.; Fitch, W. L.; Moffat, J. G. Pure Appl. Chem. 1978, 50,
1363.
(
3) (a) Grové, J. J. C.; Holzapfel, C. W.; Williams, D. B. G.
Tetrahedron Lett. 1996, 37, 1305. (b) Grové, J. J. C.;
Holzapfel, C. W.; Williams, D. B. G. Tetrahedron Lett.
(
1996, 37, 5817.
Synthesis 2009, No. 12, 2009–2014 © Thieme Stuttgart · New York