Sulfur-ylide-mediated synthesis of functionalized and trisubstituted epoxides with high enantioselectivity; Application to the synthesis of CDP-840

Article abstract of DOI:10.1002/anie.200350968

Benzyl and substituted allyl sulfonium salts react with a broad range of simple and functionalized aldehydes and ketones to give epoxides with high diastereoselectivity and high enantioselectivity (see scheme). The process has been applied to a short synthesis of the phosphodiesterase-IV inhibitor CDP-840. R¹, R² = hydrogen, alkyl, alkenyl, alkynyl, aryl, or pyridyl.

Full text of DOI:10.1002/anie.200350968

Communications
example, in the a, b, and g positions. Direct transformations
into other versatile functional groups, such as alkenes and
epoxides, further increase the importance of carbonyl groups
in synthesis. The ability to conduct such transformations
enantioselectively would be extremely useful, and toward this
goal we recently reported a practical, catalytic, and asym-
metric conversion of aldehydes into epoxides by using the
sulfide 1 (Scheme 1).[1] The sulfide 1, which is readily
available in both enantiomeric forms, was obtained in four
steps in 48% overall yield from camphorsulfonyl chloride.
Scheme 1. Catalytic and asymmetric epoxidation of aldehydes; condi-
tions: Rh2(OAc)4 (1 mol%), BnEt3N+ ClÀ (10 mol%), CH3CN, 408C.
However, attempts to apply our catalytic process to the
synthesis of CDP-840, through an epoxidation reaction with
4-pyridinecarboxaldehyde, were unsuccessful. In mapping out
the scope of the catalytic process we discovered that, as well
as the reactions of heteroaromatic aldehydes that bear basic
groups, those of n-alkyl aliphatic aldehydes, a,b-unsaturated
aldehydes, acetylenic aldehydes, and ketones gave either low
yields, low diastereomeric ratios, or low enantioselectivities.[2]
A further limitation of the catalytic process emerged when we
attempted to use a,b-unsaturated hydrazones with the chiral
sulfide 1, as only low yields were observed. As unsaturated
epoxides[3] and epoxides that contain a basic nitrogen
functionality are difficult to prepare by oxidative methods,
we were keen to find a solution to this problem. Indeed, a
common limitation in catalytic asymmetric synthesis is
substrate specificity and one solution to the problem is to
devise a stoichiometric process with good recovery of the
chirality-transfer agent. An outstanding example is the Evans
auxiliary, which, even though it is used in stoichiometric
amounts, is widely employed as a result of its broad
applicability, reliability, and recyclability. Although enantio-
selective epoxidations with stoichiometric quantities of sul-
fide have been described, their scope is limited. SolladiØ-
Cavallo et al. have only described the reaction of Eliel's
oxathiane benzyl sulfonium salt with aromatic,[4] heteroaro-
matic,[5] and a,b-unsaturated aldehydes.[6] Metzner and co-
workers have reported moderate to high enantioselectivities
in reactions of trans-2,5-dimethylthiolane benzyl sulfonium
salt with aromatic and heteroaromatic aldehydes[7] and
moderate enantioselectivities in related allyl sulfonium salt
reactions.[8] Furthermore, it is not possible to access both
enantiomers of these sulfides easily, which further limits their
practical applications.
Asymmetric Synthesis of Epoxides
Sulfur-Ylide-Mediated Synthesis of
Functionalized and Trisubstituted Epoxides with
High Enantioselectivity; Application to the
Synthesis of CDP-840**
Varinder K. Aggarwal,* Imhyuck Bae, Hee-Yoon Lee,*
Jeffery Richardson, and David T. Williams
The carbonyl group occupies a position of central importance
in organic synthesis as it allows ready functionalization, for
[*] Prof. Dr. V. K. Aggarwal, J. Richardson, D. T. Williams
School of Chemistry, University of Bristol
Cantock's Close, Bristol BS8 1TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Prof. Dr. H.-Y. Lee, I. Bae
Centre for Molecular Design and Synthesis
Department of Chemistry and School of Molecular Science (BK21)
Korea Advanced Institute of Science and Technology
Daejon 305-701 (Republic of Korea)
Fax: (+82)42-869-2810
E-mail: leehy@kaist.ac.kr
Herein we describe a process for the epoxidation of a very
broad range of carbonyl compounds, including ketones, in
high yields and with high selectivities. Although stoichiomet-
ric quantities of sulfide were required, the resulting high
[**] We thank the BBSRC and the EPSRC for studentships (D.T.W. and
J.R.), and the Brain Korea-21 project for financial support (I.B.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200350968
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enantioselectivities, diastereoselectivities, and yields, together
with the increase in scope, now allow this process to be
employed in the synthesis of complex and challenging targets,
which is also exemplified herein.
acetophenone) with moderate to high enantioselectivity. The
full scope of the reaction with ketones is currently being
investigated. These are the first examples of both the
desymmetrization of a carbonyl group and the asymmetric
synthesis of trisubstituted epoxides with chiral sulfur ylides.
The process was also extended to a,b-unsaturated sulfo-
nium salts, which were prepared either by the reaction of the
sulfide with the corresponding alcohol and HBF4, or by
alkylation with the appropriate unsaturated bromide.
Although the use of allyl and methallyl sulfonium salts led
to moderate yields of the epoxides (perhaps because of
competing g attack), high diastereoselectivities and high
enantioselectivities were nevertheless observed. However,
with the more substituted substrates 2d and 2e high yields
were once again observed and the high selectivities main-
tained. Interestingly, considerably higher diastereoselectivi-
ties are observed with a-substituted (d.r. > 99:1) than with a-
unsubstituted (d.r. = 91:9) a,b-unsaturated sulfonium salts.
Metzner and co-workers made a similar observation.[8]
Although a,b-unsaturated sulfonium salts have been
employed in epoxidation reactions,[13] it has been reported
that [2,3] sigmatropic rearrangements often compete.[14] No
such rearrangements were observed in our case, thus indicat-
ing that ylide equilibration did not occur.
Initial studies were carried out with the benzyl sulfonium
salt 2a. This salt was originally prepared from the sulfide 1,
BnBr, and AgBF4, but we have since found that the reaction
of 1 with BnOH in the presence of HBF4 in Et2O is also
effective. Although the use of ROH/HX has been reported
previously for the synthesis of sulfonium salts, a large excess
of the sulfide is invariably required.[9] We have found
conditions under which the sulfonium salt is formed in high
yield in the presence of just 1equivalent of the sulfide. This
process is more economical and gives cleaner products, as the
salt simply precipitates from the solution in diethyl ether
(Scheme 2).
Although in all cases the use of the phosphazene base at
low temperature (method B) provided superior results to
KOH at room temperature (method A), the fact that high
enantioselectivities were also observed under the latter
conditions will render this the method of choice for industrial
applications in many cases. However, high selectivities could
only be obtained by using the phosphazene base at low
temperature in some cases (Table 1, entries 4 and 13). As the
use of this phosphazene base is undesirable for large-scale
operations, a lower cost, lower-molecular-weight base that
would perform as effectively was sought. A number of cheap
and readily available bases were tested and we discovered
that potassium hexamethyldisilazide (KHMDS) was indeed
equally effective (method C).
The high yields and selectivities observed, coupled with
the recyclable nature of the sulfide, render this process
practical for these especially difficult substrates. This feature
was demonstrated in a short synthesis of the anti-inflamma-
tory agent CDP-840.[15] We envisaged that CDP-840 could be
obtained from the alcohol 3, which could itself be prepared by
a copper-catalyzed regioselective ring opening of the diaryl
epoxide 4 with a Grignard reagent (Scheme 4).
As the alcohol was to be removed in the final step, we
could tolerate a mixture of cis and trans epoxides, provided
that both were obtained with high enantioselectivity and with
the same configuration (S) at C3. These requirements led us
to consider the coupling of the sulfonium salt 5 with 4-
pyridinecarboxaldehyde. The sulfonium salt 5 was prepared
by treating the aryl alcohol 6 and ent-1 with HBF4 in Et2O.
Again, this direct method for sulfonium salt formation was
found to be cleaner, higher yielding, and more economical
than the standard two-step procedure involving formation of
the bromide followed by alkylation in the presence of AgBF4.
Subsequent treatment of the salt with the phosphazene base
and the aldehyde furnished the epoxide in high yield with
Scheme 2. Preparation of the chiral sulfonium salt.
Subsequent treatment of the salt with a carbonyl com-
pound and either a phosphazene base[5,10] at low temperature
or KOH[11] at room temperature furnished the corresponding
epoxides (Table 1). Following an initial reaction with benzal-
dehyde, in which the corresponding epoxide was produced
with very high selectivity (Table 1, entry 1), only substrates
that performed poorly in the catalytic reaction were exam-
ined. The reactions of pyridine carboxaldehydes (Table 1,
entries 2 and 3) gave the desired epoxides in high yields and
with high diastereoselectivities and almost perfect (> 99%)
enantioselectivities under both sets of conditions. A series of
unsaturated aldehydes were tested (Table 1, entries 5–7) and
although reactions with acrolein proceeded in low yields, the
use of methacrolein and crotonaldehyde both led to yields of
up to 90%. In all cases the selectivities were exceptionally
high. High enantioselectivities were also observed with
acetylenic aldehydes (e.g. Table 1, entry 8), although diaster-
eoselectivities were poor. In the cases in which the epoxide
was stable to chromatography, the sulfide was recovered in
essentially quantitative yield.
Ketones,[12] which have never been employed previously
in asymmetric sulfur-ylide-mediated epoxidations, performed
remarkably well in this system to furnish epoxides with high
enantioselectivities. Cyclohexanone and 4-tert-butylcyclohex-
anone (Table 1, entries 9 and 10) provide dramatic examples
of the effectiveness of the epoxidation process. In the latter
case the epoxide was obtained as a single diastereomer and a
single enantiomer in high yield (Scheme 3). Furthermore, the
method was found to be applicable to nonsymmetrical
ketones, although in these cases the cis diastereomer was
formed preferentially (exclusively in the case of p-nitro-
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Table 1: Reactions of sulfonium salts with various electrophiles
Entry
1
Salt
Electrophile
Major product
Method[a]
A
Yield [%][b]
75
d.r.[c]
98:2
ee[d]
98
2a[e]
benzaldehyde
2
3
2a
2a
2-pyridine-
carboxaldehyde
A
B88
91
91:9
99
95(80[f])
98:2
3-pyridine-
carboxaldehyde
A
B59
74
97:3
>99:1
98
>99
4
2a
valeraldehyde
A
B64
C
58
92:8
87
60:40
97
90:10
91
>99
5
6
2a
2a
acrolein
A
B19
30[g],[h]
90:10
>99:1
97
>99
[g],[h]
methacrolein
A
B52
51[g]
96:4
>99:1
96
99
[g]
7
8
2a
2a
crotonaldehyde
A
B90
72[g]
98:2
>99:1
90
95
[g]
TIPS-propargyl
aldehyde
A
B51
50
60:40
99
95
>99
71
63:37
9
2a
2a
cyclohexanone
B85
B93
–
92
10
4-tert-butyl-
cyclohexanone
99:1
[f]
11
12
2a
2a
acetophenone
B77
B73
33:67
93(50
)
p-nitro-
>1:99
acetophenone
13
14
15
2b[e]
2c[e]
2d[i]
benzaldehyde
benzaldehyde
benzaldehyde
A
B43
C
33[g]
71:29
91:9
82:18
84
89
90
[g]
28[g]
A
B26
37[g]
97:3
>99:1
97
97
[g]
A
B93
96[g]
96:4
>99:1
90
93
[g]
[g]
16
2e[i],[j]
benzaldehyde
B69
91:9
90
[a] Method A: carbonyl compound, KOH, MeCN/H2O (9:1), room temperature; method B: P2 base, CH2Cl2, À788C, 10 min, followed by addition of
the carbonyl compound; method C: KHMDS (0.5m in toluene), THF, À788C, 2 h, followed by addition of the carbonyl compound. [b] Yield of isolated
product. [c] Trans/cis. [d] In all cases the major enantiomer has the R configuration at the benzylic position. [e] Prepared from the alkyl bromide
followed by counterion exchange. [f] The ee value for the cis isomer. [g] The yield was determined by 1H NMR spectroscopy against an internal standard
(the epoxide is unstable on silica gel). [h] Aldehyde: 5 equiv. [i] Prepared from the alcohol and HBF4. [j] We thank Mamta Patel for carrying out this
experiment.
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the ylide conformation and its face selectivity.[17] The
high enantioselectivity observed is a consequence of
ylide conformer 7B being strongly favored over
conformer 7A owing to 1,4-steric interactions and
essentially complete preference for Si-face attack, as
the Re face of the ylide is hindered by the bulky
camphor moiety. As the aldehyde can approach in
different orientations, both betaine diastereomers
and thereby the two epoxide diastereomers are
formed. The ylide is less stable than a benzyl-
substituted ylide and the betaines are formed non-
reversibly, which accounts for the low diastereose-
lectivity observed. Crucially, the epoxide stereocen-
ter at C3 has the S configuration in both isomers. To
preserve the integrity of the C3 stereogenic center
the method of purification of the epoxide turned out
to be critical. Purification on silica gel resulted in
some decomposition but also changed the diastereo-
meric ratio from 7:3 to 9:1. Furthermore, the
enantiomeric excess of the purified trans epoxide
was much lower. Presumably silica-gel-promoted
ring opening at C3 of the acid-sensitive cis epoxide,
and following bond rotation and ring closure the
trans epoxide was obtained with the opposite stereo-
chemistry at C3, thus eroding the enantiomeric
excess. However, purification on basic alumina gave
Scheme 3. Desymmetrization of 4-tert-butylcyclohexanone. P2 base=N,N,N’,N’-
tetramethyl-N’’-(tris(dimethylamino)phosphoranylidene)phosphoric triamide
ethylimine.
Scheme 4. Retrosynthetic analysis of CDP-840.
essentially complete control of enantioselectivity (Scheme 5).
Furthermore, the sulfide was recovered in quantitative yield.
The diastereoselectivity of the epoxidation was low, but as
expected this proved inconsequential for our total synthesis.
The origin of the enantioselectivity for both diastereomers is
explained in Scheme 6.[16] The reaction of the ylide 7 with 4-
pyridinecarboxaldehyde to give the intermediate betaine is
not reversible as the ylide is destabilized by the p-methoxy
substituent. The enantioselectivity is therefore determined by
Scheme 6. The origin of the enantioselectivity. py=pyridyl.
the epoxide in high yield and high enantioselectivity, and in
the same diastereomeric ratio as observed in the crude
reaction mixture, thus indicating that no equilibration had
occurred. Ring opening of the epoxide with PhMgBr occurred
with complete regioselectivity and with clean inversion of
stereochemistry at C3. Finally, removal of the hydroxy group
furnished CDP-840 in enantiomerically pure form. Compar-
ison of the optical rotation of our sample of CDP-840 with the
literature value[18] not only confirmed its absolute configu-
ration but also lent further weight to our model for the source
of the enantioselectivity.
Scheme 5. Synthesis of CDP-840. Reagents and conditions: a) K2CO3,
cyclopentyl bromide, DMF, 608C, 12 h, 97%; b) NaBH4, MeOH, room
temperature, 1 h, 99%; c) ent-1, HB F, Et2O, room temperature, 4 h,
4
80%; d) P2 base, CH2Cl2, À788C, 15 min, then 4-pyridinecarboxalde-
hyde, À788C, 1 h, 89% (trans/cis=7:3), >98% ee; e) PhMgBr
(2.5 equiv), CuI (0.25 equiv), THF, À408C, 15 h, 85%; f) Et3N, MsCl,
CH2Cl2, 08C, 30 min; g) Zn, AcOH, room temperature, 5 h, 80%
(2 steps). DMF=N,N-dimethylformamide; Ms=methanesulfonyl.
In summary, we have described the highly enantio- and
diastereoselective reaction of aldehydes and ketones with
chiral sulfonium ylides to generate di- and trisubstituted
epoxides. The scope of the epoxidation reaction was further
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demonstrated by its application to the synthesis of a target
compound (CDP-840) with significant functionality.
Received: January 20, 2003
Revised: April 29, 2003 [Z50968]
Keywords: asymmetric synthesis · epoxidation · sulfur ·
.
synthetic methods · ylides
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