The first practical approach to optically pure cyclopropanes derived from trans γ-hydroxy enones

Article abstract of DOI:10.1039/b001973i

The optically pure cyclopropanes derived from trans γ-hydroxy enones were discussed. The trans γ-hydroxy enones were found to be prepared from reaction of stabilized ketoylides on optically pure α hydroxy aldehydes. The analysis showed that the use of light and a triplet sensitizer lead to a dramatic increase in reaction rate and isolated yield.

Full text of DOI:10.1039/b001973i

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The first practical approach to optically pure cyclopropanes derived
from trans ꢀ-hydroxy enones
Francine N. Palmer and Dennis K. Taylor*
1
Department of Chemistry, The University of Adelaide, Australia, 5005.
E-mail: dennis.taylor@adelaide.edu.au
Received (in Cambridge, UK) 14th December 1999, Accepted 13th March 2000
Published on the Web 11th April 2000
A new approach for the synthesis of optically pure
cyclopropanes from trans ꢀ-hydroxy enones and stabilised
phosphorus ylides is presented; the use of light and a triplet
sensitiser leads to a dramatic increase in reaction rate and
isolated yield.
sion of triphenylphosphine oxide and proton transfer from the
reaction manifold afford the observed cyclopropanes in excel-
lent diastereomeric excess. A minor amount of the “all cis”
isomer 5b is occasionally formed. While cyclopropanation is
favored by the use of ester stabilised ylides 2, the use of keto or
aldo stabilised ylides results in a preference for 1,4-dicarbonyl
6 formation through a competing Kornblum–De La Mare
rearrangement of the intermediate hemiacetals.4 The trans
γ-hydroxy enones 7 were also shown to be a possible entry point
into the cyclopropanation manifold, however, reaction times
were excessive (weeks at ambient temp.) and yields were poor
due to the position of the cis–trans equilibrium favoring the
trans form.
The most noticeable current strategies for the construction of
the cyclopropyl motif include, i) the direct carbene transfer
(both stoichiometric and catalytic) from a diazo precursor to
an olefin utilising transition metals (Rh, Cu, Zn and Pd)1 and
ii) Michael addition of nucleophiles (usually sulfur ylides) to
α,β-unsaturated ketones and esters followed by intramolecular
cyclisation.2 Despite the great advances in these areas, the
efficient synthesis of diversely functionalised enantiopure
cyclopropanes containing greater than di-substitution still
remains a considerable challenge. We recently reported on
a new approach to diastereomerically pure diversely function-
alised cyclopropanes 5a which utilised 1,2-dioxines 1 and
stabilised phosphorus ester ylides as the key precursors
(Scheme 1).3 Key features of the cyclopropanation sequence
According to Scheme 1, in order to allow for the preparation
of enantiomerically pure cyclopropanes one would need to pre-
pare either the cis or trans γ-hydroxy enones in an optically pure
form. Synthesis of optically pure cis γ-hydroxy enones is
unattractive as they are highly sensitive to acid and base,
rearranging rapidly to furan or 1,4-diketone 6 respectively.3
Therefore, we decided to embark on developing a practical
strategy for the synthesis of optically pure trans γ-hydroxy
enones 7, which could be utilised for the construction of optic-
ally pure cyclopropanes. Additionally, we report herein the first
practical approach to the shifting of the cis–trans γ-hydroxy
enone equilibrium which allows for a dramatic acceleration in
the rate of the cyclopropanation sequence along with an
increase in overall yield.
Retrosynthetically, we envisaged that the trans γ-hydroxy
enones 7 could be prepared from reaction of stabilised keto
ylides on optically pure α-hydroxy aldehydes. The latter alde-
hydes themselves could be prepared from reduction of optically
pure α-hydroxy esters. In order to test this general approach we
first utilised the commercially available glycolaldehyde dimer 8,
which being optically inactive would result in the formation of
only diastereomerically pure cyclopropanes (Scheme 2).†
Reaction of the glycolaldehyde dimer 8 with keto ylides 10
resulted in the smooth generation of the trans γ-hydroxy enones
11 which were judged to be of >90% purity by 1H NMR. Direct
Scheme 1
included the ylide acting as a mild base inducing ring opening
of the 1,2-dioxines 1 to their isomeric cis γ-hydroxy enones 3,
Michael addition of the ylide to the cis γ-hydroxy enones 3
and attachment of the electrophilic phosphorus pole of the
ylide to the hydroxy moiety afford the intermediate 1,2λ5-
oxaphospholanes 4 and sets up the observed cis stereochemistry
between H1 and H3. Cyclisation of the resultant enolate, expul-
Scheme 2
DOI: 10.1039/b001973i
J. Chem. Soc., Perkin Trans. 1, 2000, 1323–1325
This journal is © The Royal Society of Chemistry 2000
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Table 1 Formation of cyclopropanes from glycolaldehyde dimer 8 under thermal and photolytic conditionsa
Thermal conditions
Photolytic conditions
Entry
R1
R2
Cyclopropane (yield, %)
Time/h
Cyclopropane (yield, %)
Time/h
1
2
3
CH2Ph
CH3
CH3
Ph
Ph
CH3
12a (35) 12b (0)
120
—
192
12a (68) 12b (0)
12a (64) 12b (0)
12a (41) 12b (3)
30
30
96
b
—
12a (26) 12b (6)
a Yields quoted refer to isolated yields starting from 8. The trans γ-hydroxy enones 11 were prepared under an inert atmosphere by heating a mixture
of glycolaldehyde dimer 8 in CH2Cl2 (0.5 g in 32 mL) with ylide 10 (1.05 equiv.) under reflux. After 4 hours ylide 2 (1.5 equiv.) was then introduced
and the mixture heated under reflux for the time indicated. The volatiles were then removed in vacuo and the residue subjected to column chroma-
tography. The reactions performed under photolytic conditions were carried out in an identical manner except after the introduction of ylide 2, the
mixture was irradiated with light from 2 sun lamps (300 W) at a distance of 10 cm in the presence of benzophenone (10 mol%). b Complex mixture of
unidentified products.
Table 2 Formation of enantiomerically pure cyclopropanes 18 from optically pure ethyl lactate 13a
Thermal conditions
Photolytic conditions
Entry
R1
R2
Ent.b
Cyclopropane (yield, %)
Time/h
Cyclopropane (yield, %)
Time/h
1
2
3
4
5
6
CH2Ph
CH2Ph
CH3
(Ϫ)-Menthol
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Ph
Ph
Ph
Ph
p-Br-Ph
CH3
t-Bu
Ph
Ϫ
ϩ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
18a (29) 18b (4)
18a (34) 18b (2)
180
120
—
18a (50) 18b (12)
40
—
27
27
27
—
—
25
c
—
d
—
18a (41) 18b (9)
18a (40) 18b (10)
18a (65) 18b (6)
c
—
—
18a (48) 18b (3)
18a (21) 18b (0)
18a (13) 18b (5)
144
448
358
—
c
—
—
c
7
8a
—
18a (54) 18b (8)
c
a Yields quoted refer to isolated yields starting from 16. Time refers to overall reaction time. Both the trans γ-hydroxy enones 17 and the cyclopro-
panes 18 were prepared in an analogous manner to those described within Table 1 except the reaction time for enone formation was 5 hours. b Refers
to the enantiomer of 13 utilised. c Not attempted. d Complex mixture of unidentified products. e DCA utilised as sensitiser.
addition of the ester stabilised ylides 2 to the reaction mixture
resulted in the formation of the desired cyclopropanes 12
(entries 1–3, Table 1). Under thermal conditions the formation
of the desired cyclopropanes was extremely slow due to the
cis–trans γ-hydroxy enone equilibrium favouring the thermo-
dynamically more stable trans isomers. Furthermore, the isol-
ated yields were poor due to base induced Kornblum–De La
Mare competing rearrangement of the resultant hemiacetals
in solution and the formation of unidentified decomposition
products. Previous studies showed that the cyclopropane yield
is essentially quantitative when starting from the cis γ-hydroxy
enones 3.3 Therefore, it seemed only reasonable to expect that if
we could in some way shift the equilibrium away from the trans
γ-hydroxy enones 11 and towards the cis γ-hydroxy enones, then
we would expect an increase in overall cyclopropane yield
coupled with an increase in reaction rate. Thus, we repeated the
same three experiments in Table 1 under photolytic conditions
utilising benzophenone as the sensitiser. As can be seen, not
only did the yield of desired cyclopropane dramatically increase
but also the overall reaction rate.
With the validity of this new approach to cyclopropane
formation now established, we turned our attention to the
preparation of optically pure cyclopropanes utilising optically
pure α-hydroxy aldehydes (Scheme 3). Thus, protection of (Ϫ)-
ethyl lactate 13 as the TBDMS ether proceeded in 89% yield.
Scheme 3 Reagents and conditions: i, TBDMSCl, imidazole (1.5
DIBAL-H reduction afforded aldehyde (Ϫ)-15 in 81% yield
which was deprotected with aqueous HF to afford (Ϫ)-16. This
α-hydroxy aldehyde was immediately treated with keto ylides 10
to afford the intermediate optically pure trans γ-hydroxy enones
(Ϫ)-17. Subsequent addition of ester ylides 2 gave rise to optic-
ally pure cyclopropanes, (Table 2) which were determined to be
of >98% ee by 1H NMR analysis in the presence of [Eu(hfc)3].‡§
In a similar fashion, the opposite enantiomeric series (ϩ)-17
was prepared from (ϩ)-methyl lactate. As can be seen by inspec-
tion of the data collated in Table 2, the yields are poor and
reaction times excessive under thermal conditions. However,
under photolytic conditions the overall reaction rate was once
again dramatically accelerated, while the isolated yields of
optically pure cyclopropanes were extremely good considering
equiv.), DMF, 25 ЊC, 1.5 h, 98%; ii, DIBAL-H (1.5 equiv.), ether,
Ϫ78 ЊC, 10 min, then MeOH–H2O (dropwise) to 25 ЊC, 1 h, 81%;
iii, aq. HF (48%), CH3CN, 15 min, 82%.
they represent several synthetic transformations (i.e. 16 to 18).
Finally, we report that the use of benzophenone as the sensitiser
in these reactions can be exchanged for dicyanoanthracene
(DCA). While the use of DCA failed to dramatically increase
cyclopropane yield, comparison of entries 1 and 8 within Table
2 reveals that it was effective in lowering the overall reaction
time.
As the cyclopropanation can accommodate a wide range of
substituents (e.g. H, alkyl and aryl) at the hydroxy terminus of
the trans γ-hydroxy enones, we envisage that the approach
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J. Chem. Soc., Perkin Trans. 1, 2000, 1323–1325

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1 See for example: S. E. Denmark, B. L. Christenson, S. P. O’Conner
highlighted here will find application in the construction of a
wide range of diversely functionalised optically pure cyclo-
propanes. We are currently evaluating the use of optically pure
α-hydroxy aldehydes derived from ethyl mandelate and also
from the sugar chiral pool which will be reported in due course
along with a more thorough investigation of how other types of
sensitisers influence the cyclopropanation sequence.
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2 See for example: J. Salaun, Chem. Rev., 1989, 89, 1247; M. Calmes,
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Acknowledgements
Financial support from the Australian Research Council
(ARC) is gratefully acknowledged.
3 T. D. Avery, T. D. Haselgrove, T. J. Rathbone, D. K. Taylor and E. R.
T. Tiekink, Chem. Commun., 1998, 333; T. D. Avery, D. K. Taylor and
E. R. T. Tiekink, J. Org. Chem., 1999, submitted.
4 N. Kornblum and H. E. De La Mare, J. Am. Chem. Soc., 1951, 73,
881; M. E. Sengül, Z. Ceylan and M. Balci, Tetrahedron, 1997, 53,
10401 and references cited therein.
Notes and references
† All new compounds have been fully characterised by elemental
analysis, spectroscopy and mass spectrometry.
‡ (ϩ)-Camphorate utilised.
§ hfc = tris[3-(heptafluoropropylhydroxymethylene)-(ϩ)-camphorate].
J. Chem. Soc., Perkin Trans. 1, 2000, 1323–1325
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