Practical radical cyclisations leading to the construction of near-stereopure quaternary carbon stereogenic centres

Article abstract of DOI:10.1039/a807930g

The 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl auxiliary is effective in directing bromopropargyloxy additions to the olefinic bonds of vinylogous esters/carbonates; in the presence of AIBN and 1-ethylpiperidinium hypophosphite, the adducts undergo highly stereoselective reductive radical cyclisations in which quaternary carbon stereogenic centres are generated.

Full text of DOI:10.1039/a807930g

Practical radical cyclisations leading to the construction of near-stereopure
quaternary carbon stereogenic centres
Raymond McCague,a Robin G. Pritchard,b Richard J. Stoodley*b and Douglas S. Williamsonb
a Chirotech Technology Ltd., Cambridge Science Park, Milton Road, Cambridge, UK CB4 4WE
b Department of Chemistry, UMIST, PO Box 88, Manchester, UK M60 1QD. E-mail: richard.stoodley@umist.ac.uk
Received (in Liverpool, UK) 12th October 1998, Accepted 2nd November 1998
The 2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl auxiliary is
from which the major diastereomer, mp 151–152 °C, [a]D +40
(c 0.25, CH2Cl2), was isolated by fractional crystallisation. The
product possessed the stereostructure 8 on the basis of the X-ray
analysis§ (Fig. 1). Clearly, the radical 5a had undergone a
reductive cyclisation to give 6a rather than 7a. Moreover, there
was a preference for hydrogen addition to 6a to occur syn to the
acyl group. Finally, the presumed stereochemical outcome of
the initial bromopropargyloxylation reaction was substan-
tiated.
Numerous attempts were made to improve the efficiency of
the 4a?6a transformation and to avoid the handling of toxic
tin-based reagents. The use of AIBN and tris(trimethylsilyl)-
silane4 in toluene under reflux provided a cleaner raw product
but chromatography was still required to remove impurities; 6a
was then isolated in 65% yield. However the best result was
achieved when 4a was heated with AIBN and 1-ethylpiper-
idinium hypophosphite5 in toluene under reflux; the crude
product, obtained in essentially quantitative yield after work-up,
was very largely 6a.
The effectiveness of the overall technology was demon-
strated further by its application to the vinylogous ester 1b.
Thus, subjection of 1b to the action of NBS and propargyl
alcohol gave 4b‡ (47% yield after crystallisation), mp 133–134
°C, [a]D 282 (c 0.25, CH2Cl2), which underwent the hypophos-
phite-induced reductive radical cyclisation to give largely 6b
almost quantitatively; crystallisation provided 6b,ঠmp
133–134 °C, [a]D 228 (c 0.28, CH2Cl2), in 61% yield.
The excellent stereoselectivity observed in the aforecited
radical cyclisations can be accommodated by an extension of a
stereoinduction model proposed by Giese.6 Thus, it is envisaged
that the cyclisation occurs by way of the conformer 9 in which
the acetal hydrogen atom is syn to the olefinic bond of the
delocalised radical. A prediction of this model is that the
stereochemical outcome is determined solely by the acetal
configuration and that the auxiliary plays no direct role in the
stereoinduction process.
effective in directing bromopropargyloxy additions to the
olefinic bonds of vinylogous esters/carbonates; in the pres-
ence of AIBN and 1-ethylpiperidinium hypophosphite, the
adducts undergo highly stereoselective reductive radical
cyclisations in which quaternary carbon stereogenic centres
are generated.
The control of the absolute stereochemical outcome of reactions
that generate quaternary carbon stereogenic centres is an
important requirement in synthesis which is receiving much
attention.1 For radical methodology to provide a contribution, it
is necessary to effect stereoselective additions of tertiary carbon
radicals to carbon-based radical acceptors or of carbon radicals
to tertiary olefinic acceptors. The ability to direct such radical
additions by the use of temporarily attached auxiliaries† would
offer notable synthetic versatility. To date, however, very few
examples of such processes have been reported.2
Recently, we have shown that vinylogous esters/carbonates
bearing the 2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl auxiliary
react with NBS and primary alcohols with excellent re-
gioselectivity, high anti stereoselectivity and reasonable facial
selectivity.3 For example, in reactions involving PrOH, the
olefins 1a–c gave rise to ca. 6:1 mixtures of the bromopropoxy
derivatives 2a–c and 3a–c (Scheme 1), from which the major
products 2a–c could be isolated in near-stereopure states and
satisfactory yields by fractional crystallisation. Seeking to
stereoselectively replace the bromine atoms by functional
carbon substituents, we have studied the radical reactivity of
bromides of type 4. We now report our findings.
As outlined in Scheme 2, it was envisaged that, in the
presence of a radical reducing agent, bromides of type 4 would
afford tertiary radicals of type 5 which would undergo 5-exo-dig
cyclisations and acceptance of hydrogen atoms to give products
of types 6 and/or 7. In an initial experiment, it was found that the
vinylogous ester 1a was converted into a 4:1 mixture of the
requisite bromide 4a and a diastereomer by the action of NBS
and propargyl alcohol; fractional crystallisation provided 4a,‡
mp 169–170 °C, [a]D 268 (c 0.54, CH2Cl2), in 54% yield.
When heated in toluene under reflux with AIBN and Bu3SnH,
4a was transformed into one major product (35% yield after
chromatography and crystallisation), mp 94–95 °C, [a]D 223
(c 0.25, CH2Cl2), that clearly possessed the structure 6a or 7a on
the basis of its analytical and spectral properties.
The vinylogous ester 10a∑ was converted into the acetylenic
bromide rac-11a‡ (73% yield after chromatography) which
O
R
O
R
NBS
CH2OH
Br
Me
O
H
Me
That the radical cyclisation product possessed the stereo-
structure 6a was established by an X-ray crystallographic
analysis of a derivative. Thus, catalytic hydrogenation (H2, 5%
Pd–C, EtOAc) afforded a 3:1 mixture of dihydro derivatives,
OR*
OR*
1
4
O
R
O
R
O
R
O
R
Me
R
Me
R
OAc
OAc
O
O
H
O
Br
Me
Br
Me
O
X
NBS
Me
+
PrO
H
PrO
H
R* =
PrOH
Me
OR*
OR*
OR*
O
O
OR*
OR*
OR*
6
7
ca. 6:1
5
OAc OAc
2
3
1
a R = Et b R = Me
a R = Et b R = Me c R = OEt
Scheme 1
Scheme 2
Chem. Commun., 1998, 2691–2692
2691

of the precursors 4a and 4b were high. When a crystallised
sample of 6b was employed, the derived g-lactone 14b
possessed an ee of > 99%.
Me
R
Me
Me
Et
O
O
The aforecited findings are significant in the following
respects. In the presence of AIBN, 1-ethylpiperidinium hypo-
phosphite offers marked advantages over Bu3SnH or tris-
(trimethylsilyl)silane in effecting 5-exo-dig reductive radical
cyclisations‡‡ of acetylenic bromides. The high stereoselectiv-
ities observed in the radical cyclisations are striking; they can be
accommodated by a simple stereoinduction model dictated by
allylic strain considerations. As well as providing a further
illustration of the versatility of vinylogous esters/carbonates of
type 1 in asymmetric synthesis, the technology enables units
featuring quaternary carbon stereogenic centres with three
functional arms to be assembled in multigram quantities.
We thank the DTI and EPSRC for subsidisation of a
studentship (to D. S. W.) under the Link Asymmetric Synthesis
Programme. We are also grateful to P. D. Tiffin for relevant
preliminary studies and to Dr G. Potter for helpful advice.
O
H
OR*
OR*
O
9
8
O
R
O
R
Br
Me
R
O
H
O
Me
Me
OMe
OMe
OMe
O
10 a R = Et
b R = Me
11 a R = Et
b R = Me
12 a R = Et
b R = Me
Me
Me
O
O
R
R
OMe
O
Notes and references
O
O
† For examples of the use of chiral auxiliaries in radical reactions, see ref.
8.
13 a R = Et
b R = Me
14 a R = Et
b R = Me
‡ This compound displayed analytical and spectral properties that supported
its assigned structure.
underwent radical cyclisation to give compound rac-12a‡ (77%
yield after chromatography) [a comparative NOE difference
spectroscopic study on rac-12a and rac-13a (obtained by
equilibration of rac-12a using TsOH and MeOH) left little
doubt about the stereochemical assignments]. Similarly, 11b‡
(obtained in 78% yield after chromatography by bromopro-
pargyloxylation of 10b∑) afforded rac-12b‡ (74% yield after
chromatography). Clearly, the configuration of the acetal
stereocentre of the reactants rac-11a and rac-11b determines
the configuration of the quaternary carbon stereocentre of the
products rac-12a and rac-12b, providing strong support for the
stereoinduction model 9.
To complete the study, it was appropriate to remove the sugar
auxiliary from 6a and 6b and to determine the enantiomeric
purities of the products. In preliminary experiments, it was
shown that rac-12a and rac-12b could be oxidised (CrO3,
H2SO4, Me2CO, ultrasound)7 to the g-lactones rac-14a and rac-
14b,** the enantiomers of which were separable by GC.††
Under methanolysis conditions (TsOH, MeOH), 6a was
transformed into a 1:1 mixture of the methoxy derivatives 12a
and 13a‡ (84% yield after chromatography), [a]D 2110 (c 0.16,
CH2Cl2), whereas 6b afforded a 3:1 mixture of the methoxy
derivatives 12b and 13b‡ (79% yield after chromatography),
[a]D 2142 (c 0.30, CH2Cl2). Following Jones’ oxidation of the
mixtures, the g-lactones 14a and 14b** were isolated, each with
96% ee. Since the ee analyses were conducted on products that
had been obtained from raw samples of 6a and 6b, it is clear that
the hypophosphite-induced radical cyclisations displayed ex-
cellent stereoselectivities; moreover, the diastereomeric purities
§ Crystal data for 8: C23H34O12, M = 502.5, monoclinic, space group P21,
a = 6.425(6), b = 23.566(7), c = 17.545(7) Å, b = 90.36(4)°, Z = 4 (2
molecules per asymmetric unit), Dc = 1.256 g cm–3, F(000) = 1072,
m(Mo–Ka) = 1.05 cm–1, crystal size 0.30 3 0.25 3 0.25 mm. A total of
4328 reflections were measured, 4315 of which were unique (Rint = 0.067),
on a Siemens R3m/V diffractometer using the w/2q scan method (l =
0.71073 Å) at 293(2) K. The structure was solved by direct methods and
refined by full-matrix least-squares based on F2, with all non-hydrogen
atoms anisotropic and hydrogen atoms constrained in calculated positions.
The final cycle converged to R = 0.1280 and wR2 = 0.2431. CCDC
182/1081. The crystallographic data is available as a .cif file; see
http://www.rsc.org/suppdata/cc/1998/2691
¶ A solution of 4b (5.61 g, 10 mmol), 1-ethylpiperidinium hypophosphite
(8.99 g, 50 mmol) and AIBN (0.34 g, 2.0 mmol) in toluene (150 cm3) was
heated under reflux for 1 h. The resulting olive-green mixture was
concentrated and the residue was dissolved in CH2Cl2. The solution was
filtered through a pad of Celite and the filtrate washed with water (32) and
brine. Evaporation of the dried (MgSO4) organic phase left a white solid
(5.05 g) which was largely 6b. After crystallisation from PriOH, 6b (2.99 g,
61%) was isolated in a pure state.
∑ Compounds 10a and 10b were prepared by methylation (MeOTs, Me2SO)
of the corresponding sodium enolates [obtained by the method of Kaushal
et al. (ref. 9)].
** The yields of these products were low (10–18%).
†† The enantiomers were separated on
trifluoroacetyl column (heated from 100 to 160 °C at a rate of 1.5 °C
min21).
a Chiraldex g-cyclodextrin
‡‡ This appears to be the first report of the use of 1-ethylpiperidinium
hypophosphite to effect such reactions.
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37, 388.
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M. S. Biggers, M. L. Caspar and D. G. Davis, Tetrahedron Lett., 1992,
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Q. Zhang, R. M. Mohan, L. Cook, S. Kazanis, D. Peisach, B. M. Foxman
and B. B. Snider, J. Org. Chem., 1993, 58, 7640.
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Fig. 1 Molecular structure of 8.
Communication 8/07930G
2692
Chem. Commun., 1998, 2691–2692