Asymmetric cyclopropanations and cycloadditions of dioxocarbenes

Article abstract of DOI:10.1055/s-2006-926452

Methods for enantioselective transfer of carbenes starting from precursors carrying two carbonyl groups have been elaborated. A one-pot procedure for olefin cyclopropanation with CH-acidic precursors via intermediate phenyliodonium ylides has been develop

Full text of DOI:10.1055/s-2006-926452

SPECIAL TOPIC
1689
Asymmetric Cyclopropanations and Cycloadditions of Dioxocarbenes
Asymmetric
C
a
yclopropa
n
u
ations l Müller,* Yves F. Allenbach, Sabrina Chappellet, Ashraf Ghanem
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland
Fax +41(22)3793215; E-mail: paul.muller@chiorg.unige.ch
Received 16 February 2006
O
O
N2
Abstract: Methods for enantioselective transfer of carbenes start-
ing from precursors carrying two carbonyl groups have been elabo-
rated. A one-pot procedure for olefin cyclopropanation with CH-
acidic precursors via intermediate phenyliodonium ylides has been
developed. The structure of the [Rh2{(S)-nttl}4] catalyst was opti-
mized to produce up to 98% ee in olefin cyclopropanations with
dimethyl malonate or Meldrum’s acid. Highly selective Rh(II)-cat-
alyzed olefin cyclopropanations could be observed upon replace-
ment of methyl diazoacetoacetate by methyl (silyloxy-
vinyl)diazoacetate. Enantioselective dipolar cycloadditions of diazo-
pyruvate to polar olefins have been realized with Ru(II)-pybox cat-
alysts.
N2
X
X
H
OEt
X
OMe
N2
H
X
N2
O
O
O
O
4
1a X = OR
1b X = NR2
2a X = COOR
2b X = COCH3
2c X = CH=CH2
2d X = Ar
3a X = CH2
3b X = O
Figure 1 Diazo compounds 1–4
stituted carbenes differ obviously from those of their
mono-substituted counterparts, so that the need for differ-
ent catalysts is not surprising.
Key words: carbenoids, catalysis, diazo decomposition, phenyl-
iodonium ylides, rhodium
This paper summarizes efforts which we have carried out
during the past years with the objective to tune Rh(II) cat-
alysts in order to achieve enantioselective carbene transfer
with diazo esters carrying a second electron-attracting
substituent 2a, 2b, 3 and 4 (Figure 1) or the corresponding
phenyl iodonium ylides. Alternatively, vinyl diazoace-
tates were used as synthetic equivalents of diazo acetoac-
etates in cyclopropanations and formal cycloadditions.
Asymmetric carbene transfer has seen spectacular devel-
opment during the recent years thanks to the development
of highly efficient and selective catalysts.1 The reaction
involves the transition-metal-induced decomposition of a
diazo compound2 to afford an intermediate metallocar-
bene, which subsequently transfers the carbene moiety to
an appropriate substrate. The enantioselectivity of the re-
action may be controlled by the chiral ligands surrounding
the metal. Exceptional enantioselectivities have been re-
ported for asymmetric transfer of diazoacetate esters 1a
and amides 1b, having a single substituent on the diazo
group. In contrast, the enantioselectivity of diazo com-
pounds carrying two substituents of type 2 and 3 is more
difficult to control (Figure 1). A notable exception to this
is provided by vinyl- and aryl-substituted diazo esters 2c
and 2d, respectively, with which impressive selectivities
have been achieved.3 Davies proposed that the unusual se-
lectivity of the metallocarbenes derived from these latter
precursors should be ascribed to a transition state occur-
ring late on the reaction coordinate, as evidenced by the
high negative r-value of –1.0 for cyclopropanation of sty-
rene with Rh(II) catalysts.4
A One-Pot Carbene Transfer with in situ Generated
Phenyliodonium Ylides
The transition-metal-catalyzed decomposition of dimeth-
yl diazomalonate (2a, X = CO2Me) and of the diazo deriv-
ative of Meldrum’s acid 3b presents difficulties owing to
the high stability of the diazo precursors. In addition, the
carbene transfer is characterized by disappointingly low
enantioselectivities.5 Phenyliodonium ylides derived from
CH-acidic compounds may be used as substitutes for di-
azo compounds in catalytic carbene-transfer reactions,6 in
analogy to phenyliodonium ylides derived from carbam-
ates, sulfonamides, and sulfamates (iminophenyliodanes)
which may be applied to catalytic nitrene transfer.7 The
ylide 5 derived from Meldrum’s acid is isolable and de-
composes under mild conditions in the presence of Rh(II)
catalysts, but the reactions proceed with only modest
enantioselectivity.8 In general, however, such ylides are
amorphous, often unstable and difficult to purify. Proto-
cols for in situ generation and decomposition of imi-
nophenyliodanes have been developed which offer
significant improvement over procedures using isolable
ylides.9 Based on previous work of Dauban,10 and in par-
allel with Charette,11 we have adapted the in situ proce-
dure for carbene transfer with dimethyl malonate (7) and
In contrast, diazo esters having a second electron-with-
drawing substituent such as diazomalonate (2a) or 2-dia-
zodimedone (3a) exhibit low selectivity. The
corresponding metallocarbenes are highly electrophilic,
and the transition state for carbene transfer occurs early on
the reaction coordinate. Typically, a r-value of –0.3 has
been reported for cyclopropanation of styrene with diazo-
malonate 2a. In addition, the steric requirements of disub-
SYNTHESIS 2006, No. 10, pp 1689–1696
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Advanced online publication: 27.04.2006
DOI: 10.1055/s-2006-926452; Art ID: C00206SS
© Georg Thieme Verlag Stuttgart · New York

1690
P. Müller et al.
SPECIAL TOPIC
O
O
O
O
O
O
O
[Rh2{(S)–4-X-nttl}4]
PhIO, MgO, MS
O
O
O
O
IPh
+
R
H
R
O
O
6a,b,c,d
10a,b,c,d
7
8
O
O
[Rh2{(S)–4-X-nttl}4]
O
O
O
O
O
+
IPh
PhI(OAc)2, Al2O3
MS
R
O
R
O
O
H
O
5
6a,d
9
11a,b
Scheme 1
Meldrum’s acid 9.12 The intermediate ylides 8 and 5, re- Cyclopropanation with Methyl (Silyloxyvinyl)diazo-
spectively, were generated either with iodosylbenzene acetate 13
(PhI=O) in the presence of MgO and molecular sieves (for
7), or with diacetoxyiodobenzene [PhI(OAc)2] in the pres- The decomposition of diazoacetoacetates (2b) results in
ence of aluminum oxide and molecular sieves (for 9). the formation of carbenes which are destabilized by two
Good yields of cyclopropanes 11 were obtained when the electron withdrawing carbonyl substituents and which
reaction was carried out with a tenfold excess of olefin are, therefore, unselective. (Silyloxyvinyl)diazoacetates,
(Scheme 1). In addition, an unexpected substituent effect their synthetic equivalents, have been used with some suc-
on the enantioselectivity was observed when Rh(II)-based cess by Davies for enantioselective carbene transfer with
catalysts (Figure 2) with 4-substituted 1,8-napthanoyl-de- [Rh2{(S)-dosp}4] as catalyst.13 We observed that the
rivatized tert-leucine ligands were screened. The ee for [Rh2(S)-nttl}4]-catalyst8 is particularly adapted for diazo
cyclopropanation of styrene (6a) with 7 increased from transfer with the TIPS-enol ether 13 derived from methyl
37% with [Rh2{(S)-nttl}4] to 82% with [Rh2{4-Br-(S)- diazoacetoacetate (2b).
nttl}4] (Table 1). This compares favorably with the 40%
ee reported for cyclopropanation of styrene with dimethyl
diazomalonate in the presence of Doyle’s [Rh2{(S)-
Cyclopropanation of Styrene14
bnaz}4] catalyst.5 [Rh2{4-Br-(S)-nttl}4] led to 98% ee in The cyclopropanation of styrene (6a) with methyl diaz-
the cyclopropanation of pentene (6d) with 7. A similar oacetoacetate (2b) in the presence of [Rh2{(S)-nttl}4] pro-
trend was observed in cyclopropanations starting with ceeded in 68% yield to a mixture of racemic trans-adduct
Meldrum’s acid (9), where enantioselectivities of up to 12 and enantio-enriched cis-12 of 16% ee in a 1:8 ratio
92% were achieved.
(Scheme 2). Replacement of 2b by its silyl enol ether 13
resulted in a dramatic increase in selectivity. Under opti-
mized conditions [Rh2{(S)-nttl}4] afforded the cis isomer
of the adduct 14a with 95% diastereoselectivity and 95%
H
COOH
H
COOH
O
O
N
O
O
O
O
N
P
OH
O
X
X = H [Rh2{(S)-nttl}4]
[Rh2{(S)-bnp}4]
[Rh2{(R)-ntv}4]
O
O
R
OMe
O
N
H
N
R
S
N
H
COOH
O
O
HOOC
O
H
[Rh2{(2S)-mepy}4]
R = PhCH2 [Rh2{(S)-ptpa}4]
R = t-Bu [ Rh2{(S)-pttl}4]
R = C12H25 [Rh2{(S)-dosp}4]
R = t-Bu [Rh2{(S)-tbsp}4]
Figure 2 Structures of some rhodium catalysts
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cyclopropanations
1691
Table 1 One-Pot Asymmetric Cyclopropanations with in situ Gen-
Table 2 Cyclopropanation of Substituted Styrenes with (Silyl-
oxyvinyl)diazoacetate 13 in the Presence of Rh(II) Catalystsa
erated Phenyliodonium Ylidesa
Olefin R
Pre-
Catalyst
Product, ee
Olefin X
Catalyst
Solvent Product, ee
de
cursor
yield (%) (%)
yield (%) (%) (%)
toluene 14a, 77 94 91
styreneb 14a, 72 94 nd
toluenec 14a, 76 98 95
CH2Cl2 14a, 84 95 nd
styreneb 14a, 77 94d 92d
toluene 14a, 86 94 93
6a
6a
6a
6a
6a
6b
6c
6d
6a
6d
6a
6d
Ph
7
[Rh2{(S)-nttl}4]
10a, 72 37
10a, 77 66
10a, 75 82
10a, 75 82
6a
6a
6a
6a
6a
6a
6a
6a
6b
6e
6f
H
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-ntv}4]
[Rh2{(S)-pttl}4]
Ph
7
[Rh2{(S)-4-Cl-nttl}4]
[Rh2{(S)-4-Cl-nttl}4]
[Rh2{(S)-4-Br-nttl}4]
H
Ph
7
H
Ph
7
H
Ph
7
[Rh2{(S)-4-NO2-nttl}4] 10a, 60 66
H
4-BrC6H4
4-MeC6H4
C3H7
Ph
7
[Rh2{(S)-4-Br-nttl}4]
[Rh2{(S)-4-Br-nttl}4]
[Rh2{(S)-4-Br-nttl}4]
[Rh2{(S)-nttl}4]
10b, 65 90
10c, 62 87
10d, 56 98
11a, 90 43
11d, 70 72
11a, 76 92
11d, 65 87
H
7
H
[Rh2{(S)-ptpa}4] toluene 14a, 86 88 95
[Rh2{(S)-dosp}4] toluene 14a, 84 81 98.5
7
H
9b
9b
9b
9b
4-Br
4-Cl
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
toluene 14b, 70 92 nd
toluene 14e, 77 94 nd
C3H7
Ph
[Rh2{(S)-nttl}4]
[Rh2{(S)-4-Br-nttl}4]
[Rh2{(S)-4-Br-nttl}4]
4-MeO [Rh2{(S)-nttl}4]
2-Br [Rh2{(S)-nttl}4]
2-Me [Rh2{(S)-nttl}4]
toluene 14f, 80
89 nd
C3H7
6g
6h
toluene 14g, 71 11 nd
toluene 14h, 84 91 nd
a Conditions: In CH2Cl2 (5.0 mL), 7 (10 mmol), PhI=O (1.4 equiv),
MgO (2.3 equiv), molecular sieves (250 mg), olefin (10 equiv), and
catalyst (5 mol%), at r.t.
a Conditions: 6 (8.7 mmol), 13 (0.6 mmol) in the appropriate solvent
(5.0 mL), and catalyst (2 mol%), 0 °C. nd = not detected.
b In CH2Cl2 (10 mL), 9 (10 mmol), PhI(OAc)2 (1.4 equiv), Al2O3 (2.3
equiv molecular sieves (250 mg), and catalyst (5 mol%), 30 °C.
b In neat styrene (6a).
c At –78 °C.
d ent-14a.
enantioselectivity at –78 °C in toluene (Table 2). The ab-
solute configuration of 14a was determined to be 1R,2S by
X-ray crystallography. Lower selectivities were observed,
when the TIPS group was replaced by the sterically less
demanding TBDMS.
Surprisingly, when 2-bromostyrene (6g) was cyclopro-
panated with 13 and [Rh2{(S)-nttl}4] as catalyst, the re-
sulting cyclopropane 14g had an ee of only 11%. In
contrast, the 2-methyl derivative 6h reacted normally with
N2
Ph
OMe
Ph
+
Ph
2b
O
O
COOMe
O
COOMe
[Rh2{(S)-nttl}4]
68%
O
trans-12
racemic
cis-12
16% ee
6a
[Rh2{L*}4]
Ph
N2
X
COOMe
X
COOMe
O
COOMe
OTIPS
OTIPS
13
(trans)-17
6a,b,e–h
14a,b,e–h
OTIPS
OTIPS
MeOOC
–
MeOOC
–
Ph
O
a X = H
b X = 4-Br
e X = 4-Cl
f X = 4-MeO
g X = 2-Br
h X = 2-Me
Br+
Br+
HO
COOMe
18
15
16
Scheme 2
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

1692
P. Müller et al.
SPECIAL TOPIC
91% ee. The 4-bromo substituted styrene 6b, in turn, re- Table 3 Intramolecular Cyclopropanation of Allyl 2-Diazo-3-silyl-
oxybut-3-enoates 19a–c in Toluenea
acted with an enantioselectivity of 92%, while the selec-
tivity of the 4-chloro and the 4-methoxy derivatives were
Precursor R
Catalyst
Product, ee
found in the same range with 94% and 89%, respectively.
These observations may be rationalized by formation of a
(achiral) intermediate bromonium ylide 15, which trans-
fers the carbene moiety intramolecularly to the ortho-dou-
ble bond without intervention of the chiral catalyst. In
contrast, the high enantioselectivity of the cyclopropane
14b derived from 4-bromostyrene suggests the interven-
tion of the catalyst in the transfer of the carbene moiety of
the (hypothetical) ylide 16.
yield (%) (%)
19a
H
[Rh2{(S)-nttl}4]
[Rh2{(S)-pttl}4]
[Rh2{(S)-pttl}4]b
[Rh2{(S)-nttl}4]
[Rh2{(S)-pttl}4]
[Rh2{(S)-pttl}4]b
20a, 81
20a, 75
20a, 50
20b, 77
20b, 93
20b, 66
22, 77
47c
50c
70c
73d
77d
89d
67e
60e
68e
19a
H
19a
H
19b
Ph
Ph
Ph
19b
Treatment of 14a with TBAF afforded the methyl ketone
trans-17 (61%), while its ozonolysis led to the half-ester
18 (16%). Thus, the two-step procedure allows the ste-
reospecific introduction of a cyclopropane carrying two
different carbonyl substituent with high enantioselectivi-
ty.
19b
19c
(E)-CH=CHMe [Rh2{(S)-nttl}4]
(E)-CH=CHMe [Rh2{(S)-pttl}4]
(E)-CH=CHMe [Rh2{(S)-pttl}4]b
19c
22, 81
19c
22, 71
a At 0 °C.
b At –78 °C.
Intramolecular Cyclopropanation of Allyl 2-Diazo-3- c 1R,5S.
d 1S,5R,6S.
e 3aR,6R.
silyloxybut-3-enoates 1915
The intramolecular cyclopropanation of (silyloxyvinyl)
diazoacetates, i.e. allyl 2-diazo-3-silyloxybut-3-enoates
19 was somewhat less successful. The diazo precursors
19a–c were synthesized by conventional procedures and
subjected to diazo decomposition with a limited selection
of catalysts (Scheme 3 and Table 3). The cyclopropana-
tion product of 19c underwent Cope rearrangement under
the reaction conditions to afford 22. The enantioselectivi-
ties of all these reactions were below those achieved with
styrene. [Rh2{(S)-nttl}4] and [Rh2{(S)-pttl}4] provided the
best selectivities, although even at –78 °C the highest ee
was only 89%. Surprisingly, Davies’ [Rh2{(S)-dosp}4]
catalyst was less suitable for these transformations, al-
though it has been found to be the catalyst of choice in
other intramolecular cyclopropanations of allyl diazoace-
tates.16
The absolute configurations of 20a and 22, were deter-
mined by degradation with O3 to afford 21 and 23, respec-
tively, of known absolute configuration. The absolute
configuration of 20b, in turn, was tentatively assigned on
OTIPS
OMe
OMe
O
O
R = H
O
O
H
H
(1R,5S)-21
(1R,5S)-20a
O
OTIPS
OTIPS
R
OTIPS
O
R = Ph
[Rh2{L*}4]
O
O
R
N2
R
Ph
S
S
Ph
S
O
O
H
H
19a R = H
19b R = Ph
19c R = (E)-CH=CHMe
(1R,2S)-24
(1S,5R,6S)-20b
OMe
Me
H
O
TIPSO
Me
H
O
O
H
[Rh2{L*}4]
O
O
O
TIPSO
R = (E)-CH=CHMe
MeO
H
(1S,5R,6S)-20c
(R)-23
(3aR,6R)-22
Scheme 3
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cyclopropanations
1693
the grounds of its CD in comparison to that of 24. The re- tivity and yield. Treatment of the cyclopropane 27 with
sults indicate an inversion of the sense of absolute config- TBAF affords the formal cycloadduct 26.13
uration between 20a as opposed to that of 20b and 20c.
Precedents for such inversions upon change of substitu-
The cyclopropanation of 2,3-dihydrofuran (25) with 13 in
the presence of [Rh2{(S)-nttl}4] afforded 27 as a single di-
astereoisomer (Scheme 4). The enantiomers of 27 were
not separable; however, upon treatment with TBAF the si-
ents have been reported, however, for other intramolecu-
lar cyclopropanations of diazoacetates.16,17
lyloxy group of 27 was cleaved off, and the resulting ke-
tone 28 underwent spontaneous ring-opening to 29 and
recyclization to afford 26, on which the enantioselectivity
could be determined by GC. In general, 27 was not isolat-
ed, and the yields reported in Table 4 refer to the two-step
sequence. The yield for transformation of isolated 27 to 26
was in the order of 80%. Other catalysts were examined,
but led to lower selectivities, except [Rh2{(S)-pttl}4]. The
analogous reaction of 3,4-dihydro-2H-pyran (30) yielded
the corresponding adduct 31 in 79% yield and 95% ee in
the presence of [Rh2{(S)-pttl}4], as determined on 34 after
treatment with TBAF (Scheme 4, Table 4). In view of
these satisfactory results, no extensive screening with oth-
er catalysts was carried out. A secondary product 32 re-
sulting from direct cycloaddition of 13 to 30 was also
isolated in ca. 10% yield, but the enantioselectivity of the
secondary process was not investigated.
A Formal Cycloaddition of 2,3-Dihydrofuran (25) via
Cyclopropanation with Methyl (Silyloxyvinyl)diazo-
acetate (13)18
Diazo compounds, when exposed to transition-metal cat-
alysts react with olefins usually via cyclopropanation.
However, some oxocarbenes, when exposed to polar or
polarizable olefins, undergo dipolar cycloadditions. For
example, methyl diazoacetoacetate (2b), in the presence
of [Rh2{(S)-nttl}4] reacts with 2,3-dihydrofuran (25) to af-
ford the cycloadduct 26 in 30% yield and 33% ee
(Scheme 4). The result is as unsatisfactory as the cyclo-
propanation of styrene with 2b mentioned above. Howev-
er, if 2b is replaced by the vinyl diazoacetate 13, the
cyclopropane 27 may be obtained with high enantioselec-
MeOOC
25
MeOOC
O
N2
[Rh2{(S)-nttl}4]
O
O
O
26 30%, 33% ee
2b
OTIPS
O
MeOOC
MeOOC
MeOOC
O
25
TBAF
N2
[Rh2{(S)-nttl}4]
OTIPS
O
O
¨
27 90% ee
28
COOMe
MeOOC
–O
O
O
O+
26 80%
28
OTIPS
MeOOC
MeOOC
MeOOC
30
[Rh2{(S)-pttl}4]
N2
O
OTIPS
+
O
O
OTIPS
O
13
31 79%
32 11%
TBAF
O
O2N
OTIPS
MeOOC
O
O
O2N
O
O
34 92%, 95% ee
33
Scheme 4
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

1694
P. Müller et al.
SPECIAL TOPIC
Table 4 Cyclopropanation–Rearrangement of 2,3-Dihydrofuran
(25) and 3,4-Dihydro-2H-pyran (30) with 13a
The racemic cyclopropane 31 was reduced with LiAlH4 to
afford the corresponding alcohol, which was derivatized
with 3,5-dinitrobenzoyl chloride to afford 33. The struc-
ture of 33 was unambiguously confirmed by X-ray struc-
ture analysis. Unfortunately, no suitable crystals could be
obtained from enantiopure derivatives from any com-
pound in this series, and the absolute configuration of the
products could not be established.
Olefin Catalyst
Solvent
Product, ee
yield (%) (%)
33
(%)
25
25
25
25
25
25
25
25
25
25
25
30
30
30
[Rh2{(S)-nttl}4]
25
26, 44
26, 63
26, 58
26, 77
84
76
86
82
90
64
85
60
59
40
44
82b
95b
53b
–
–
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-nttl}4]
[Rh2{(S)-ptpa}4]
[Rh2{(S)-pttl}4]
[Rh2{(S)-tbsp}4]
[Rh2{(S)-dosp}4]
[Rh2{(S)-bnp}4]
CH2Cl2
pentane
PhF
–
–
Cycloadditions with Dioxocarbenes
toluene3 26, 68
–
If the transition-metal-catalyzed diazo decomposition of
diazo esters carrying a second carbonyl substituent is car-
ried out in the presence of polar olefins, products of for-
mal [2+3] dipolar cycloadditions may be formed. This is
typically the case with ethyl diazoacetoacetate (2d)19 and
2-diazodimedone (3)20 but also with ethyl diazopyruvate
(4).21 There is evidence that some of these cycloadditions
are concerted; however, the occurrence of two-step addi-
tions involving intermediate cyclopropanes or dipolar
species may not be definitely ruled out.
toluene
toluene
toluene
toluene
toluene
26, 75
26, 95
26, 59
26, 50
26, 35
26, 43
31, 78
31, 79
31, 68
–
–
–
–
–
[Rh2{(S)-mepy}4] toluene
–
[Rh2{(S)-nttl}4]
[Rh2{(S)-pttl}4]
[Rh2{(S)-dosp}4]
toluene
toluene
toluene
7
11
Cycloaddition of 2-Diazo-5,5-dimethylcyclohexane-
1,3-dione (3a) to 2,3-Dihydrofuran (25)
not
detected
2-Diazodimedone (3a) undergoes cycloaddition to 2,3-di-
hydrofuran (25) upon diazo decomposition to afford the
a Conditions: At 0 °C, 13 (0.3 mmol) was reacted with 25 or 30 (10–
adduct 36 (Scheme 5). Contrary to previous claims in the 15 equiv), respectively, in the appropriate solvent (3.0 mL), and cata-
literature,22 these cycloadditions are not enantioselective
lyst (3 %).
b Determined based on 32 by GC.
when catalyzed by Rh(II).23 In light of our observations
Our expectations were only partially satisfied.25 Under
with diazo acetoacetate presented above, we tried to cir-
optimized conditions the Ru-catalyzed cycloaddition of 2-
diazodimedone (3a) to 25 in the presence of the pybox
ligand 35 (10 mol%) produced the adduct 36 in only 40%
yield although with 56% ee. With 5 mol% of catalyst, the
yield was 22% (in CH2Cl2). The yield increased to 70%
when the reaction time was increased to 72 hours, and to
76% when the reaction was carried out at 45 °C with
5 mol% of catalyst. In this latter case, the ee decreased
slightly to 52%. A large selection of Ru catalysts was
screened, but the enantioselectivity of the reaction could
not be improved. In the hope of speeding up the reaction,
the diazo precursor 3a was replaced by the corresponding
phenyliodonium ylide 3c. However, the results with ylide
cumvent the problem by preparing the silyl enol deriva-
tive 37 of diazodimedone; however, we were unable to
isolate the desired product. Subsequently, we turned our
attention to Ru catalysts. Recently, Mezzetti has reported
highly diastereo- and enantioselective cyclopropanations
of styrene with Ru catalysts. These cyclopropanations
have exceptionally high (negative) r-values of –2.3.24 By
extending the reasoning of Davies mentioned above, we
hypothesized that the Ru-catalyzed cycloadditions might
exhibit higher enantioselectivities than the Rh-catalyzed
reactions.
O
O
N
N
N
O
O
X
35
O
+
[Ru(p-cymene)Cl2]2, 10 mol%
O
O
O
25
O
X
36
N2
3a X = N2
3c X = IPh
X = N2 25 °C, 16 h, 40%, 56% ee
X = IPh 20 °C, 72 h, 45%, 17% ee
37
OTIPS
Scheme 5
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Cyclopropanations
1695
3c under similar reaction conditions were even more dis- temperature was lowered to 0 °C. Other pybox ligands
appointing. The reaction proceeded even more sluggishly were examined, but afforded lower enantioselectivities. In
than that of 3a and the enantioselectivity decreased to addition, the cycloaddition to other olefins, such as ethyl
17%. This suggests that the postulated metallocarbene in- vinyl ether, tert-butyl vinyl ether and dihydropyran pro-
termediate was not formed between 3c and the Ru cata- ceeded with lower yields and enantioselectivities.
lyst. The residual enantioselectivity which was observed
in the adduct 36 may be ascribed to a loose association be-
tween the catalyst and the ylide 1c or to a complex of un-
known structure derived from 1b.
The presence of a second carbonyl substituent of a diazo
carbonyl precursor results in a more electron-deficient
carbene which exhibits intrinsically lower selectivities in
carbene transfer reactions. Nevertheless, high selectivities
in such reactions have been achieved. With dimethyl ma-
lonate and Meldrum’s acid as precursor, optimization of
the carboxylate ligand of the Rh(II) carboxylate catalyst
led to substantial enhancement of selectivity. In the case
of diazo acetoacetate, the problem was solved by its trans-
formation to the silyl enol ether, which is a synthetic
equivalent. Encouraging results were obtained for dipolar
cycloadditions of diazopyruvates to dihydrofuran by the
use of chiral Ru catalysts, although further optimization is
necessary.
Cycloaddition of Ethyl Diazopyruvate (38) to 2,3-Dihy-
drofuran (25)25
The diazo decomposition of ethyl diazopyruvate (38) in
the presence Rh(II) carboxylate catalysts afforded good
yields of adduct 39, but the reactions were not enantiose-
lective (Scheme 6, Table 5). With Ru–pybox catalysts,
the cycloadditions of 38 contrary to those of 3a proceeded
conveniently at room temperature, although the Ru-cata-
lyzed reactions afforded lower yields of 39 than the
Rh(II)-catalyzed ones.
The catalysts were prepared according to published procedures:
[Rh2{(S)-nttl}4];8
[Rh2{(S)-dosp}4];26
[Rh2{(S)-pttl}4];29
[RuCl2(35)].31
[Rh2{(R)-ntv}4];14
[Rh2{(S)-tbsp}4];27
[Rh2{(S)-mepy}4];30
[Rh2{(S)-4-X-nttl}4];12b
[Rh2{(S)-ptpa}4];28
[Rh2{(S)-bnp}4];22a
N2
[Ru(p-cymene)Cl2]2
O
H
O
+
O
O
EtO
O
EtO
O
One-Pot Cyclopropanation of Olefins with Dimethyl Malonate;
General Procedure
O
O
38
25
39
N
N
N
Dimethyl malonate (7; 1.32 g. 0.01 mol, 1 equiv) was added to a
mixture of iodosylbenzene (1.4 equiv), olefin 6 (10 equiv), MgO
(2.3 equiv), rhodium(II) catalyst (5 mol%) and molecular sieves 4 Å
(250 mg) in CH2Cl2 (10 mL). The mixture was stirred under argon
for 24 h. Samples (100 mL) were taken after several time intervals.
The samples were filtered using a syringe filter holder (0.2 mm pore
size) and the organic layer was diluted with CH2Cl2 (100 mL) and
analyzed by GC. The reaction progress was monitored qualitatively
by TLC using heptane–EtOAc (5:1) as eluent. An aliquot of the su-
pernatant was used for GC analysis. When maximum conversion
was reached, the reaction was terminated by filtration through
Celite. The Celite pad was washed with CH2Cl2 (2 ×). Evaporation
of the combined filtrates under reduced pressure followed by chro-
matography on silica gel with heptane–EtOAc (5:1) as eluent af-
forded the desired cyclopropane derivatives 10.
35
Scheme 6
Table 5 Cycloaddition of Ethyl Diazopyruvate (38) and 2,3-Dihy-
drofuran (25)a
Catalystb
Solvent
toluene
toluene
toluene
neat
Yield of 39 (%)
ee (%)
–
[Rh2(OAc)4]
[Rh2{(S)-tbsp}4]
[Rh2{(R)-ntv}4]
[RuCl2(35)]
[RuCl2(35)]
[RuCl2(35)]c
[RuCl2(35)]
[RuCl2(35)]
[RuCl2(35)]
85
70
80
65
65
68
55
20
50
0
12
62
68
74
56
66
58
Cyclopropanation of Styrene with Methyl (Triisopropylsilyl-
oxyvinyl)diazoacetate (13); (1R,2S)-1-[Tri(isopropyl)silyloxy-
vinyl]-2-phenylcyclopropanecarboxylate (14a)
toluene
toluene
CH2Cl2
hexane
PhCF3
The catalyst [Rh2{(S)-nttl}4] (11.6 mg, 0.008 mmol) was activated
by heating in vacuo, and dissolved in toluene (3.0 mL). After addi-
tion of styrene (6a; 730 mg, 7.0 mmol) the mixture was cooled to
0 °C, and 13 (208 mg, 0.70 mmol) in toluene (2.0 mL) was added
dropwise. After the addition, stirring was continued for 1 h. The sol-
vent was evaporated and the residue was purified by flash chroma-
tography (SiO2, Et2O–pentane, 5:95) to afford 14a (194 mg, 77%)
as a colorless solid. For data, see ref. 7.
a Conditions: catalyst (10 mol%) and 30-fold excess of 25 over 38 at
25 °C.
b Threefold excess of 35 over [Ru(p-cymene)Cl2]2.
Intramolecular Cyclopropanation of Allyl 2-Diazo-3-silyloxy-
but-3-enoate (19a); (1R,5S)-1-[1-Tri(isopropyl)silyloxyvinyl]-3-
oxabicyclo[3.2.0]hexan-2-one (20a); Typical Procedure
c At 0 °C.
[Rh2{(S)-nttl}4] (13.9 mg, 0.01 mmol) was activated by heating in
vacuo, dissolved in toluene and cooled to 0 °C. The diazoacetate
19a (152.4 mg, 0.47 mmol) in toluene (1.0 mL) was added drop-
wise. After stirring for 1 h, the solvent was evaporated and the res-
At 25 °C, the highest enantioselectivity of 68% was ob-
tained with [Ru(p-cymene)Cl2]2 in conjunction with
ligand 35 in toluene, and this improved to 74% when the
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York

1696
P. Müller et al.
SPECIAL TOPIC
(9) (a) Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327.
idue was purified by flash chromatography (SiO2, Et2O–pentane
15:85) to afford 20a as a colorless oil in 81% yield. For data, see ref.
15.
(b) Espino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001,
40, 598.
(10) Dauban, P.; Sanière, T.; Tarrade, A.; Dodd, R. H. J. Am.
Chem. Soc. 2001, 123, 7707.
(11) (a) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327.
(b) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69,
1262.
Cyclopropanation–Rearrangement of 2,3-Dihydrofuran (25)
with Methyl (Triisopropylsilyloxyvinyl)diazoacetate (13);
Methyl cis-2-Methyl-3a,4,5,6a-tetrahydrofuro[2,3-b]furan-3-
carboxylate (26)
The catalyst (1.0 mol%) was activated by heating in vacuo and dis-
solved in toluene (2.0 mL). 2,3-Dihydrofuran (25, 10 equiv) was
added and the mixture was cooled to 0 °C. The diazoacetate 13
(0.30 mmol) in toluene (1.5 mL) was added dropwise with stirring.
After the addition, stirring was continued for 1 h. The solvent was
evaporated and the residue was dissolved in Et2O (5.0 mL). After
cooling to –78 °C, TBAF (0.5 mL, 1 M in THF, 0.5 mmol) was add-
ed. After 1 h, the reaction was quenched by addition of 5% aq
NH4Cl (1.0 mL). The mixture was diluted with H2O (4.0 mL), the
aqueous layer was extracted with Et2O (3 × 10 mL) and the com-
bined organic layers were dried (MgSO4) and filtered. The solvent
was evaporated and the residue was purified by flash chromatogra-
phy to afford 26 (77%) as a colorless oil. For data, see ref. 18.
(12) (a) Müller, P.; Ghanem, A. Synlett 2003, 1830. (b) Müller,
P.; Ghanem, A. Org. Lett. 2004, 6, 4347.
(13) Davies, H. M. L.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.;
Churchill, D. G. J. Org. Chem. 1998, 63, 2641.
(14) Müller, P.; Allenbach, Y.; Ferri, M.; Bernardinelli, G. H.;
Flack, H. F. Org. Lett. 2004, 6, 1725.
(15) Müller, P.; Allenbach, Y. F.; Grass, S. Tetrahedron:
Asymmetry 2005, 16, 2007.
(16) (a) Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1999, 64,
8501. (b) Davies, H. M. L.; Doan, B. D. Tetrahedron Lett.
1996, 37, 3967.
(17) Fok, M. E.; Li, C.; Marino, J. P.; Overman, L. E. J. Am.
Chem. Soc. 1999, 121, 5467.
(18) Müller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.;
Grass, S. Synlett 2005, 1397.
(19) Alonso, M.-E.; Morales, A.; Chitty, A. W. J. Org. Chem.
1982, 47, 3747.
Cycloaddition of Ethyl 2-Diazopyruvate (38) to 2,3-Dihydrofu-
ran (25); Ethyl 4,5-Dihydro-3aH-furo[2,3-b]furan-2-carboxy-
late (39)
(S,S)-2,6-Bis(4-isopropyl-2-oxazolin-2-yl)pyridine (86 mg, 0.294
mmol) was added to a solution of [RuCl2(p-cymene)]2 (58 mg,
0.095 mmol) in CH2Cl2. The dark-red mixture was stirred at r.t. for
1 h under argon. The solvent was removed under reduced pressure.
2,3-Dihydrofuran (25; 1.4 mL) and a solution of ethyl diazopyru-
vate (38; 100 mg, 0.95 mmol) in toluene (3.0 mL) was added. The
resulting suspension was stirred until complete consumption of
starting material (TLC). The mixture was concentrated, and the res-
idue was purified by column chromatography on silica gel using
EtOAc–pentane (60:40) as eluent to afford 39 as pale-yellow solid.
(20) (a) Pirrung, M. C.; Zhang, J.; Lackey, K.; Sternbach, D. D.;
Brown, F. J. Org. Chem. 1985, 60, 2112. (b) Pirrung, M.
C.; Zhang, J.; McPhail, A. T. J. Org. Chem. 1991, 56, 6269.
(c) Pirrung, M. C.; Lee, Y. R. Tetrahedron Lett. 1994, 35,
6231. (d) Pirrung, M. C.; Lee, Y. R. J. Am. Chem. Soc. 1995,
117, 4814. (e) Pirrung, M. C.; Blume, F. J. Org. Chem.
1999, 64, 3642. (f) Pirrung, M. C.; Kalliappan, K. P. Org.
Lett. 2000, 3, 353.
(21) (a) Alonso, M.-E.; Jano, P.; Hernandez, M. I.; Greenberg, R.
S.; Wenkert, E. J. Org. Chem. 1983, 48, 3047. (b) Wenkert,
E.; Alonso, M.-E.; Buckwalter, E. L.; Sanchez, E. L. J. Am.
Chem. Soc. 1983, 105, 2021. (c) Alonso, M.-E.; Hernandez,
M. I.; Gomez, M.; Jano, P.; Pekerar, S. Tetrahedron 1985,
41, 2347.
(22) (a) Pirrung, M. C.; Zhang, J. Tetrahedron Lett. 1992, 33,
5987. (b) Ishitani, H.; Achiwa, K. Heterocycles 1997, 46,
153.
(23) (a) Müller, P.; Allenbach, Y. F.; Bernardinelli, G. Helv.
Chim. Acta 2003, 86, 3164. (b) Müller, P.; Allenbach, Y. F.;
Ferri, M.; Bernardinelli, G. Arkivoc 2003, (vii), 80;
www.arkat-usa.org.
(24) Bachmann, S.; Mezzetti, A. Helv. Chim. Acta 2001, 84,
3963.
(25) (a) Müller, P.; Chappellet, S. Synlett 2004, 2573.
(b) Müller, P.; Chappellet, S. Helv. Chim. Acta 2005, 88,
1010.
(26) Davies, H. L. M.; Bruzinski, P. R.; Lake, D. H.; Kong, N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897.
(27) Roos, G. H. P.; McKervey, A. E. Synth. Commun. 1992, 22,
1751.
(28) Hashimoto, S.-I.; Watanabe, N.; Ikegami, S. Tetrahedron
Lett. 1993, 34, 5173.
Acknowledgment
This work was supported by the Swiss National Science Foundation
(projects No. 20-52581.97 and 2027-048156). The support and
sponsorship conceded by COST Action D24 (‘Sustainable Chemi-
cal Processes: Stereoselective Transition Metal-Catalysed Reac-
tions’) are kindly acknowledged.
References
(1) (a) Pfaltz, A. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
Berlin, 1999, Vol. 3, 513–538. (b) Doyle, M. P. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,
1993.
(2) Doyle, M. P.; McKervey, M. A. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds. From
Cyclopropanes to Ylides; Wiley: New York, 1998.
(3) (a) Davies, H. M. L. Aldrichimica Acta 1997, 30, 107.
(b) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001,
57, 1.
(4) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(5) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
(6) Müller, P. Acc. Chem. Res. 2004, 37, 243.
(7) Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.
(8) Müller, P.; Allenbach, Y.; Robert, E. Tetrahedron:
Asymmetry 2003, 14, 779.
(29) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.;
Hashimoto, S. Synlett 1996, 85.
(30) Doyle, M. P.; Winchester, W. N.; Protopopova, M. N.;
Kazala, A. P.; Westrum, L. J. Org. Synth. 1995, 73, 13.
(31) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, K.;
Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1253.
Synthesis 2006, No. 10, 1689–1696 © Thieme Stuttgart · New York