1,3-dipolar cycloadditions of carbonyl ylides to aldimines: Scope, limitations and asymmetric cycloadditions

Article abstract of DOI:10.1002/adsc.200600324

The development of a diastereoselective 1,3-dipolar cycloaddition of carbonyl ylides and imines for the synthesis of α-hydroxy-β-amino esters is described. The methodology is successfully applied to chiral α-methylbenzylimines affording enantiomerically p

Full text of DOI:10.1002/adsc.200600324

FULL PAPERS
DOI: 10.1002/adsc.200600324
1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:
Scope, Limitations and Asymmetric Cycloadditions
Staffan Torssella and Peter Somfaia,*
a
KTH Chemical Science and Engineering, Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
Fax : (+46)-8-791-2333; e-mail: somfai@kth.se
Received: July 3, 2006; Accepted: September 5, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The development of a diastereoselective catalysts for the development of a catalytic enantio-
1,3-dipolar cycloaddition of carbonyl ylides and selective 1,3-dipolar cycloaddition is also described,
imines for the synthesis of a-hydroxy-b-amino esters affording syn-b-amino alcohols in modest enantio-
is described. The methodology is successfully applied meric purity (e.r. up to 82:18).
to chiral a-methylbenzylimines affording enantio-
merically pure syn-b-amino alcohols, which is exem- Keywords: amino alcohols; asymmetric 1,3-dipolar
plified with a short asymmetric synthesis of the pacli- cycloadditions; carbenoids; carbonyl ylides; imines;
taxel side-chain. The use of chiral Rh(II) carboxylate multicomponent reactions
Introduction
genic centers in a single step. This approach has been
realized by addition of glycine-derived enolates to al-
The b-amino alcohol and the a-hydroxy-b-amino acid dehydes[1b,8] or by addition of a-alkoxy enolates to al-
moieties are found in a vast array of biologically im- dimines in a Mannich-type reaction.[1a,9]
portant compounds and as a result these structural
In recent years multi-component 1,3-dipolar cyclo-
subunits are frequently used as building blocks in nat- additions involving ylides derived from transiently
ural product synthesis.[1] Moreover, the b-amino alco- formed carbenoid intermediates have received consid-
hol functionality also serves as a chiral ligand and erable attention since this constitutes a powerful tool
auxiliary, which has a broad application in asymmetric for constructing five-membered heterocycles.[10] Sur-
synthesis and catalysis.[2] Consequently, considerable prisingly, to our knowledge very few examples of cy-
efforts have been made to develop asymmetric routes cloadditions involving carbonyl ylides and imines
to enantiopure b-amino alcohols.[3] The amino alcohol have previously been reported.[11] With this in mind, it
functionality is most commonly introduced on a pre- was envisioned that 1,3-dipolar cycloadditions of sta-
existing carbon skeleton, which can be accomplished bilized carbonyl ylides (A) to imines (B) would be an
by Sharpless aminohydroxylation[4] or by the opening efficient entry to functionalized oxazolidines (C,
of epoxides[3,5,6] and aziridines[3,6,7] with appropriate Scheme 1). The carbonyl ylide A, in turn, should be
nucleophiles. More effectively, the amino alcohol available from diazo ester D and aldehyde E. Hydrol-
moiety can be constructed by concomitant formation ysis of the N,O-acetal C would ultimately yield the
of a new carbon-carbon bond and two vicinal stereo- desired b-amino alcohol F. The realization of this
Scheme 1. Synthetic strategy.
Adv. Synth. Catal. 2006, 348, 2421 – 2430
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Staffan Torssell and Peter Somfai
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three-component strategy for the synthesis of syn-a- hyde (2a) and Rh2ACHTREU(NG OAc)4 in CH2Cl2 (Scheme 2). Ad-
hydroxy-b-amino esters and its application to the dition of ethyl diazoacetate (EDA, 3) over 1 h at
asymmetric synthesis of the C-13 paclitaxel side-chain room temperature afforded the desired cycloadduct 4,
was recently reported from our laboratory.[12] Herein which upon hydrolysis yielded b-amino alcohol 5a
we report our full investigation of this asymmetric (syn:anti 93:7) in 82% yield (syn) (Table 1, entry 1).
three-component approach for the synthesis of syn-a- The relative stereochemistry of 5a was verified by
hydroxy-b-amino esters using both chiral imines and conversion into the corresponding oxazolidinone fol-
1
chiral Rh(II) catalysts.
lowed by H NMR analysis of the relevant coupling
constants.[13]
Mechanistically, the reaction is likely to proceed
through a chemoselective insertion of the electrophil-
ic Rh-metallocarbene into the lone pair of benzal-
Results and Discussion
The reaction was initially explored using commercial- dehyde forming either a metal-free[10a,14a] (6a) or a
ly available benzylidene-benzylamine (1a), benzalde- metal-associated ylide[14] (6b), which then undergoes a
1,3-dipolar cycloaddition with the aldimine yielding
trans-substituted oxazolidine 4a.
It was then of interest to optimize the key compo-
nents of the reaction. First the choice of metal cata-
lyst used for the diazo decomposition was examined.
Rh
gave the desired product albeit with diminished yield
and diastereoselectivity (Table 1, entry 2). Cu(OTf)2,
2ACHTRE(UGN pfb)4, used in a variety of carbenoid reactions,
ACHTREUNG
commonly used as a suitable catalyst for the decom-
position of 3, only led to recovery of 1a (entry 3), the
reason probably being coordination of the metal to
the basic imine nitrogen with concomitant inhibition
of the carbenoid formation.[10c,d,15] In order to investi-
gate if a Lewis acid activation of the imine would in-
Scheme 2. 1,3-Dipolar cycloaddition.
Table 1. Optimization of 1,3-dipolar cycloaddition.
Entry
1 (Ar)
2 (Ar’)
Cat.
dr[b] syn:anti
Yield[c] 5 (%)
1
2
3
a (Bn)
a (Bn)
a (Bn)
a (Bn)
a (Bn)
b (Ph)
c (4-MeO-C6H4)
d (Ts)
a (Bn)
a (Ph)
a (Ph)
a (Ph)
a (Ph)
a (Ph)
a (Ph)
a (Ph)
a (Ph)
Rh
Rh
CuACHTREUNG
Rh
Rh
Rh
Rh
Rh
Rh
Rh
2A
2A(pfb)4
(OTf)2
2A(OAc)4
2A(OAc)4
2A(OAc)4
2A(OAc)4
2A(OAc)4
2A(OAc)4
2A(OAc)4
93:7
a (82)
a (13)
a (0)[d]
a (67)
a (70)
b (0)[g]
c (0)[d]
d (19)[i]
a (67)
a (47)
88:12
N.A.
67:33
64:36
N.A.
N.A.
n.d.
4[e]
5[f]
6
7
8[h]
9
b (4-MeO-C6H4)
c (4-NO2-C6H4)
80:20
85:15
10
a (Bn)
[a]
The reaction was carried out with imine 1 (1.0equiv.), benzaldehyde (1.5 equivs.), Rh catalyst (2.0mol%) or Cu ACHTRE(UGN OTf)2 (5
mol%) and powdered 4 Š MS in CH2Cl2 (Rh catalyst) or THF (Cu catalyst) at room temperature with addition of ethyl
diazoacetate (1.5 equivs.) over 1 h.
Determined by H NMR spectroscopic analysis of the crude reaction mixture, syn- and anti-diastereomers separable with
[b]
1
flash chromatography.
Isolated yield (syn and anti).
Only starting material.
[c]
[d]
[e]
[f]
Cu
ACHTREUNG
Yb
ACHTREUNG
[g]
[h]
[i]
Complicated mixture of by-products.
Performed at 458C.
Ratio 5d:7=40:60.
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1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines
FULL PAPERS
Table 2. 1,3-Dipolar cycloaddition to benzylimines.[a]
fluence the reaction outcome, Cu
ACHTRE(UGN OTf)2 and Yb-
ACHTREUNG(OTf)3 were added to the reaction mixture (entries 4
and 5). In both cases the desired product was ob-
tained in good yield but with moderate diastereose-
lectivity. This change in reaction outcome indicated
that a complexation between the Lewis acid and
imine had indeed occurred. Next, a variety of differ-
ent N-substituted imines was screened, which proved
to have a large impact on the reaction outcome.
When using imine 1b, derived from aniline, a complex
reaction mixture was obtained with no trace of the
desired product (entry 6), while attempts with 1c only
gave recovered starting material (entry 7). Hetero-
atom substituents, for example, oxime ethers, hydra-
zones and N-trialkylsilylimines, only lead to the for-
mation of the corresponding 1,3-dioxolane 7 via a 1,3-
dipolar cycloaddition in which the aldehyde also
served as a dipolarophile [Eq. (1)].[10a,b] Apart from
Entry 1 (R)
dr[b] (syn:anti) Yield[c] syn-5 (%)
1
a (Ph)
e (4-NO2-C6H4) 91:9
f (4-Cl-C6H4)
g (4-F-C6H4)
93:7
a (82)
e (61)
f (75)
g (78)
h (77)
i (87)
j (78)
k (83)
l (75)
m (64)
2[d]
3
98:2
97:3
4
5
h (3-MeO-C6H4) 98:2
i (4-Me-C6H4) 97:3
j (4-MeO-C6H4) 94:6
k (2-naphthyl)
l (2-furyl)
6
7[d]
8
98:2
92:8
81:17
9[d,e]
10[d,e] m (CO2Et)
[a]
The reaction was carried out with imine 1 (1.0equiv.),
benzaldehyde (1.5 equivs.), Rh2A(OAc)4 (2.0mol%) and
CTHREUNG
powdered 4 Š MS in CH2Cl2 at room temperature with
addition of ethyl diazoacetate (1.5 equivs.) over 1 h.
Determined by 1H NMR spectroscopic analysis of the
crude reaction mixture, syn- and anti-diastereomers sepa-
rable with flash chromatography.
Isolated yield.
10h addition time.
08C.
[b]
[c]
[d]
[e]
N-benzyl-substituted imines, only N-sulfonylimine 1d
lead to the formation of the desired product, although and excellent diastereoselectivity irrespective of the
only as the minor product along with substantial steric or electronic properties of the aryl substituent
amounts of dioxolane 7 (entry 8). Exchanging benzal- (entries 1–8).[16] The furfural-derived imine 1l afforded
dehyde (2a) for other aromatic aldehydes (4-MeO- the corresponding product 5l in high yield and diaste-
C6H4 and 4-NO2-C6H4) did not improve the reaction reoselectivity (entry 9), which is of interest since the
outcome and thus the remaining experiments were furan moiety can be readily derivatized into several
performed with 2a (entries 9 and 10).
Interestingly, when 4-nitrobenzaldehyde was used glyoxalate imine 1m gave the syn-b-hydroxyaspartate
as the aldehyde component significant amounts of di- 5m, a potent blocker of the glutamate transporters[19]
useful functional groups.[17,18] The reaction of ethyl
,
oxolane 7 were formed [Eq. (2)]. In this case the elec- in high yield and good diastereoselectivity (entry 10).
It should be noted that imines derived from aliphatic
aldehydes did not react under these reaction condi-
tions.
The observed syn-diastereoselectivity can be ex-
plained by invoking an envelope-type transition state
where the thermodynamically most stable S-shaped
ylide[14a] reacts with the imine in an endo-selective cy-
cloaddition favoring the formation of trans-oxazoli-
dine 4 (Scheme 3). The endo-transition state is fa-
vored over the exo-transition state due to the steric
interaction between the ester functionality on the
tron-deficient 4-nitrobenzaldehyde also served as a di- ylide and the benzylidene substituent on the imine.
polarophile. This side product was not detected in the
case of benzaldehyde or 4-methoxybenzaldehyde.
During the last couple of years it has been recog-
nized that the diazoacetate structure has a large
With optimized reaction conditions at hand, the impact on the reaction outcome.[20] The most pro-
performance of other N-benzyl-substituted aldimines nounced effect was found for diazoacetates function-
was investigated and the results are summarized in alized with electron-donating groups, for example,
Table 2. In all cases, the reaction proceeded cleanly to vinyl and aryl. It has been shown independently by
provide the desired syn-b-amino alcohol in high yield the groups of Davies[21] and Doyle[22] that Rh-cata-
Adv. Synth. Catal. 2006, 348, 2421 – 2430
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Staffan Torssell and Peter Somfai
FULL PAPERS
Scheme 4. 1,3-Dipolar cycloaddition using pantolactone
diazo ester. Reagents and conditions: a) 1) Rh
2ACHTREU(NG OAc)4 (2
mol%), 4 Š MS, CH2Cl2, 08C; 2) p-TSA, MeOH/H2O
(95:5), room temperature (82%, dr 60:40); b) Ti
EtOH, PhMe, 1108C (60%, er 60:40).
ACHTREU(GN O-i-Pr)4,
Scheme 3. Proposed stereochemical model for the 1,3-dipo-
lar cycloaddition.
syn-b-amino alcohols and ultimately apply it to the
synthesis of biologically active natural products. Ini-
lyzed decomposition of donor/acceptor diazoacetates tial attempts with (ꢀ)-8-phenylmenthyl diazoace-
in the presence of aldehydes leads to the formation of tate[23] as the carbene source together with 1a and 2
epoxides and dihydrofurans through intramolecular gave none of the desired product. The chiral diazo-
ring closure of the transient carbonyl ylide. This is in acetate 13, derived from (R)-pantolactone,[24] has
contrast to the behavior of EDA, which forms 1,3-di- been reported to give good results when used in
oxolanes through 1,3-dipolar cycloadditions. The reac- asymmetric cyclopropanations[25] and aziridinations.[26]
tion between donor/acceptor diazoacetates 8 and 9 Unfortunately, when tested under the standard reac-
with imine 1a and aldehyde 2a gave, unfortunately, no tion conditions only a modest asymmetric induction
traces of the desired products [Eq. (3)and Eq. (4)]; in- was obtained (Scheme 4). The desired amino alcohol
14 was isolated in high yield as a 60:40 mixture of two
diastereomers (absolute configuration was not deter-
mined).[27] In order to determine the relative stereo-
chemistry of the product, the mixture was subjected
to a TiACHTRE(UNG O-i-Pr)4-catalyzed transesterification proto-
col,[28] which gave the known amino alcohol syn-5a as
single diastereomer indicating that the relative stereo-
chemistry of 14 was syn. The enantiomeric ratio of
syn-5a (er 60:40) was in good agreement with the dia-
stereomeric ratio of 14 (dr 60:40).
Chiral imines
Since the use of chiral diazo esters only met with lim-
ited success we became interested in investigating
chiral imines, a strategy that has been successfully ap-
stead epoxide 10 (from 8) and a mixture of epoxide plied in other cycloaddition reactions.[29] Consequent-
11 and dihydrofuran 12 (from 9) were isolated in ly, chiral imine 15a, derived from (+)-a-methylbenzyl-
comparable yields and selectivities as previously re- amine, was reacted under standard conditions, which
ported.
led to the formation of amino alcohol 16a in high
yield and diastereoselectivity (8.2:1:1:0) (Table 3,
entry 1). The major diastereomer was readily separat-
ed from the two minor diastereomers using flash
chromatography. The relative stereochemistry of the
major product was determined to be syn by conver-
Asymmetric 1,3-Dipolar Cycloadditions
Chiral diazo esters
sion into the corresponding oxazolidinone followed
1
It was also of interest to develop an asymmetric pro- by H NMR analysis of the relevant coupling con-
tocol for the synthesis of enantiomerically enriched stants.[30]
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1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines
FULL PAPERS
Table 3. Optimization of 1,3-dipolar cycloaddition using
Table 4. 1,3-Dipolar cycloaddition to (+)-a-methylbenzyl
chiral imines[a]
imines[a]
Entry 15 (XC)
Lewis
acid
dr[b]
Yield[c] 16
(%)
Entry
15 (R)
dr[b]
Yield[c] 16 (%)
1
2
a (Ph)
8.2:1:1:0
5.4:1:1:0
7.1:1:1:0
8.3:1:1:0
4.5:1:1:0
8.4:1:1:0
1.8:1.6:1:0
9.3:1.8:1:0
a (77)
e (86)
f (87)
ent-f (82)
g (71)
h (62)
i (67)
1
2
a
none
none
8.2:1:1:0
n.d.
a (77)
e (4-MeO-C6H4)
f (3-MeO-C6H4)
ent-f (3-MeO-C6H4)
g (4-F-C6H4)
h (4-Br-C6H4)
i (2-furyl)
3
4[d]
5
b
b (traces)
6
3
4
5
c
none
none
n.d.
n.d.
7 (n.d.)
7 (n.d.)
7[e]
8[e]
j (CO2Et)
j (58)
[a]
d
d
d
The reaction was carried out with imine 15 (1.0equiv.),
benzaldehyde (1.5 equivs.), Rh2A(OAc)4 (2.0mol%) and
powdered 4 Š MS in CH2Cl2 at 08C with addition of
ethyl diazoacetate (1.5 equivs.) over 10h.
Determined by 1H NMR spectroscopic analysis of the
crude reaction mixture.
Isolated yield (all isomers), major isomer separable from
minor isomers with flash chromatography.
Reaction performed using 2.0g of ( ꢀ)-imine.
Reaction performed at ꢀ108C.
CTHREUNG
Yb
(OTf)3 3.6:3:1.7:1 d (75)[d]
ACHTREUNG
[b]
[c]
6
Zn
ACHTREUNG
[a]
The reaction was carried out with imine 15 (1.0equiv.),
benzaldehyde (1.5 equivs.), Rh2A(OAc)4 (2.0mol%) and
powdered 4 Š MS in CH2Cl2 at 08C with addition of
ethyl diazoacetate (1.5 equivs.) over 10h.
Determined by 1H NMR spectroscopic analysis of the
crude reaction mixture.
[d]
[e]
CTHREUNG
[b]
ditions gave the corresponding cycloaddition products
in low selectivity (entry 7).
The utility of the present methodology was exem-
plified with a short asymmetric synthesis of the pacli-
taxel side-chain 18, which has previously been shown
[c]
[d]
Isolated yield (all isomers).
Isomers not separable with flash chromatography.
Several other commonly used chiral imines were to be an important pharmacophore for the anti-tumor
also screened in order to improve the results, but this activity of the diterpene.[31] Compound 16a, readily
met with no success (Table 3). When chiral imine 15d, isolated from the two minor isomers, was subjected to
derived from phenylalanine, was employed only diox- catalytic hydrogenolysis followed by benzoylation to
olane 7 could be detected with no trace of the desired give amide 17 (77% yield, 2 steps, Scheme 5). Finally,
product. Interestingly, when a Lewis acid was added hydrolysis of 17 using LiOH yielded the paclitaxel
to the reaction mixture, amino alcohol 16d was isolat- side chain 18 as a white solid in 4 steps and 53%
ed as the sole product in high yield although as an in- overall yield. Analytical data of 18 were in all aspects
separable mixture of all four possible diastereomers identical to those previously reported.[4,18,32] This also
(entries 5 and 6).
The performance of other imines derived from (+)-
a-methylbenzylamine is summarized in Table 4. For
all aromatic substrates the reaction proceeded cleanly
to give the desired syn-product in high yield and dia-
stereoselectivity (entries 1–6), and in all cases the
major isomer was separable from the mixture of the
two minor isomers using flash chromatography. It
should be noted that the reaction also proceeded
cleanly when conducted on a multigram-scale (2–4 g
of imine ent-15f, entry 4). Furthermore, chiral imine
15j, derived from ethyl glyoxalate, gave the product
in good yield and diastereoselectivity (entry 8). How-
Scheme 5. Asymmetric synthesis of paclitaxel side-chain. Re-
agents and conditions: a) 1) H2, Pd(OH)2, EtOH, 3M HCl,
room temperature; 2) PhCOCl, NaHCO3, EtOAc, 08C
(77% over steps); b) LiOH·H2O, THF:MeOH:H2O
2
ever, reaction of 2-furylimine 15i under standard con- (10:5:4), room temperature (89%).
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Staffan Torssell and Peter Somfai
FULL PAPERS
proved the absolute stereochemistry of 16a, obtained Chiral Rh(II) Catalysts
from (R)-imine 15a, to be (2R, 3S).
Since it was noted that Lewis acids could have an In order to determine if the cycloaddition proceeds
impact on the outcome of these cycloadditions reac- via the metal-free 6a (Scheme 2) or the metal-associ-
tions using both achiral and chiral imines in combina- ated ylide 6b several Rh(II) catalysts having different
tion with chiral Lewis acids were examined. Disap- ligands were screened. If 6b is an intermediate it can
pointingly, only low asymmetric inductions were ob- be expected that different catalysts would give differ-
tained in these experiments (<6% ee).[33]
ent stereochemical outcomes. Also, by employing
chiral Rh(II) catalysts provides the opportunity to in-
vestigate the catalytic enantioselective 1,3-dipolar cy-
cloaddition.
When exchanging Rh
yield and diastereoselectivity decreased (Table 1, en-
tries 1 and 2). Employing Rh2A(S-DOSP)4 (19,
2ACHTRENUG(OAc)4 for Rh2ACHTREU(GN pfb)4 both
CTHREUNG
Figure 1) under standard reaction conditions gave
amino alcohol 5a in good yield (62%) with excellent
diastereoselectivity (syn:anti 94:6) and modest enan-
tioselectivity (er 62:38) (Table 5, entry 1). Catalyst 19
has been reported to give best results in non-polar hy-
drocarbon solvents and when the reaction was per-
formed in hexane the enantiomeric ratio was in-
creased (82:18) albeit with decreased yield (17%,
entry 2).[34] The same trend was observed when Et2O
was used as solvent (entry 3). Unfortunately, both the
Hashimoto catalyst[14b] [Rh
(S-BPTV)4, 20] and the
second generation Davies catalyst[35] [Rh
CTHREUNG
21], which have been reported to give excellent asym-
metric induction in CH2Cl2, failed to give any im-
proved results (entries 4 and 5).
Although it has been suggested that carbonyl ylides
derived from EDA and benzaldehyde under Rh(II)
catalysis involves the metal-free species 6a, the pres-
ent results clearly support involvement of metal-asso-
ciated ylide 6b.[14a] This is also the first example of an
enantioselective intermolecular 1,3-dipolar cycloaddi-
Figure 1. Chiral Rh(II) catalysts.
Table 5. 1,3-Dipolar cycloadditions using chiral Rh(II) catalysts[a]
Entry
Catalyst
Solvent
Conditions[b] [8C/h]
dr[c] (syn:anti)
er[d] (syn)
Yield[e] syn-5a (%)
1
2
3
4
5
19
19
19
20
21
CH2Cl2
Hexane
Et2O
CH2Cl2
CH2Cl2
r.t./1
r.t./1
r.t./1
0/10
94:6
62:38
82:18
81:19
52:48
62
17
14
71:29
78:22
90:10
n.d.
56
r.t./10n.d.
<5[f]
[a]
The reaction was carried out with imine 1a (1.0equiv.), benzaldehyde (1.5 equivs.), chiral Rh(II) catalyst (2.0mol%) and
powdered 4 Š MS in CH2Cl2 with addition of ethyl diazoacetate (1.5 equivs.).
Reaction temperature and addition time.
Determined by H NMR spectroscopic analysis of the crude reaction mixture.
Determined by chiral HPLC (Chiracel OD-column).
Isolated yield.
[b]
[c]
[d]
[e]
[f]
1
7 is the major product.
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1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines
FULL PAPERS
3.94 (d, J=4.6 Hz, 1H), 3.87 (m, 2H), 3.53 (d, J=13.0Hz,
1H), 3.38 (d, J=13.0Hz, 1H), (s, 3H), 0.77 (s, 3H). Minor
isomer: 1H NMR (500 MHz, CDCl3): d=7.29–7.07 (m,
10H), 5.23 (s, 1H), 4.31 (d, J=4.2 Hz, 1H), 4.01 (d, J=
4.2 Hz, 1H), 3.87 (m, 2H), 3.59 (d, J=12.8 Hz, 1H), 3.49 (d,
J=12.8 Hz, 1H), 1.05 (s, 3H), 0.86 (s, 3H). 13C NMR
(125 MHz, CDCl3) d=172.3, 172.2, 171.9, 171.6, 139.6, 139.5,
139.3, 138.8, 128.7, 128.6, 128.33, 128.31, 128.28, 128.1, 128.0,
127.9, 127.84, 127.80, 127.03, 126.97, 76.23, 76.17, 76.1, 76.0,
75.9, 75.6, 74.8, 74.2, 64.2, 64.1, 51.3, 50.9, 40.2, 40.1, 22.85,
22.83, 22.6, 19.6, 19.5; IR (film): nmax =3448 (br), 2966, 1786,
1757, 1111 cmꢀ1; HR-MS (FAB+): m/z=384.1810, calcd.
for C22H26NO5 (M+H): 384.1811.
tion of carbonyl ylides to imines catalyzed by Rh(II)
carboxylates.
Conclusions
We have developed a three-component approach for
the synthesis of syn-a-hydroxy-b-amino esters based
on a Rh(II)-catalyzed 1,3-dipolar cycloaddition of car-
bonyl ylides to imines. By using chiral a-methylbenzyl-
imines as dipolarophiles an asymmetric version of the
cycloaddition was realized yielding enantiomerically
pure syn-a-hydroxy-b-amino esters, and this was ap-
plied in a short asymmetric synthesis of the paclitaxel
side-chain. Furthermore, the use of chiral Rh(II) car-
boxylates affords the b-amino alcohols in modest
enantioselectivity (er up to 82:18), which indicates
that the reaction proceeds via a metal-associated car-
bonyl ylide.
AHCTRE(UNG 2R,3S)-Ethyl 3-(Benzylamino)-2-hydroxy-3-
phenylpropanoate (5a)
To a solution of 14 (32.0 mg, 0.083 mmol, 60:40 mixture of
diastereomers) and dry EtOH (97 mL, 1.67 mmol) in PhMe
(2 mL) was added TiACHTRE(UNG O-i-Pr)4 (7.5 mL, 0.025 mmol) under
N2. The reaction mixture was heated to reflux over night
and quenched with 1M HCl (1 mL). Extrelutꢁ work-up fol-
lowed by flash chromatography (heptane:EtOAc, 4:1) of the
residue gave 5 (15.0mg, 60%) as a white solid ( er 60:40,
Experimental Section
Chiracel
OD
column,
15%
isopropanol-hexanes,
0.5 mLminꢀ1; tR(minor) =11.2 min, tR(major) =15.6 min); mp 76–
For general experimental procedure, analytical data for
compounds 5a, e–m and NMR spectra for all new com-
pounds, see Supporting Information.
1
778C; H NMR (400 MHz, CDCl3): d=7.38–7.23 (m, 10H),
4.23 (d, J=4.0Hz, 1H), 4.21–4.11 (m, 2H), 3.95 (d, J=
4.0Hz, 1H), 3.76 (d,
JAB =13.3 Hz, 1H), 3.50(d, JAB =
13.3 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=173.5, 140.0, 139.6, 128.5, 128.3, 128.2, 127.8,
127.0, 74.9, 63.6, 61.7, 50.7,14.0; IR (film): nmax =3467 (br),
2981, 1734, 1100 cmꢀ1; HR-MS (FAB+): m/z=300.1601,
calcd for C18H22NO3 (M+H): 300.1600.
General Procedure for 1,3-Dipolar Cycloaddition of
Carbonyl Ylides to Imines
To a solution of imine (0.256 mmol), benzaldehyde (39.0 mL,
0.384 mmol), Rh2ACHTREUNG(OAc)4 (2.3 mg, 5.12 mmol) and powdered
4 Š MS (250mg) in CH 2Cl2 (3 mL) was added diazoester
(0.384 mmol) in CH2Cl2 (1 mL) over 1 or 10h at indicated
temperature. The reaction mixture was stirred for an addi-
tional hour, filtered through a plug (pipette) of basic alumi-
na (activity grade I), eluted with CH2Cl2 (4–5 mL) and con-
centrated. The residue was dissolved in MeOH:H2O (4 mL,
95:5) and p-toluenesulfonic acid (0.340 mL, 0.512 mmol,
1.5M in MeOH) was added. The resultant mixture was stir-
red at room temperature for 2 h. The solvents were removed
under reduced pressure and the residue was dissolved in
CH2Cl2 and washed with saturated NaHCO3 solution. The
aqueous phase was extracted twice with CH2Cl2 and the
combined organic extracts were dried (MgSO4) and concen-
trated under vacuum. Flash chromatography of the residue
gave the pure amino alcohol.
AHCTRE(UNG 2R,3S)-Ethyl 3-[(S)-1-Phenylethylamino]-2-hydroxy-
3-phenylpropanoate (16a)
The general procedure was followed using 15a (53.6 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
08C; dr 8:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc 5:1)
of the residue gave 16a (49.0mg, 61%) as a white solid and
an inseparable mixture of two minor diastereomers
(12.6 mg, 16%) as a clear oil. Major isomer: mp 84–868C;
1
[a]2D0: 11.3 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3): d=
7.32–7.12 (m, 10H), 4.23–4.15 (dq, J=10.7, 7.2 Hz, 1H), 4.11
(d, J=3.2 Hz, 1H), 4.07–3.99 (dq, J=10.7, 7.2 Hz, 1H), 3.66
(d, J=3.2 Hz, 1H), 3.46 (q, J=6.6 Hz, 1H), 1.22 (d, J=
6.6 Hz, 3H), 1.10(t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=173.5, 145.1, 140.1, 128.4, 128.2, 127.7, 127.5,
126.9, 74.9, 61.8, 61.5, 54.4, 25.2, 13.9; IR (film): nmax =3421
(br), 2975, 1730, 1451, 1104 cmꢀ1; HR-MS (FAB+): m/z=
314.1754, calcd. for C19H24NO3 (M+H): 314.1756.
ACHTREUNG(2R*,3S*)-(R)-Tetrahydro-4,4-dimethyl-2-oxofuran-3-
yl 3-(Benzylamino)-2-hydroxy-3-phenylpropanoate
(14)
The general procedure was followed using 1a (53.6 mg,
0.256 mmol). Addition of diazoester 13 (76.1 mg,
0.384 mmol) over 10 h at 08C; dr 60:40, 1H NMR spectro-
scopic analysis on the crude product. Flash chromatography
(heptane:EtOAc, 2:1) of the residue gave 14 (81.0mg, 82%,
inseparable mixture of two diastereomers) as a pale yellow
oil. Major isomer: 1H NMR (500 MHz, CDCl3): d=7.29–
7.07 (m, 10H), 5.27 (s, 1H), 4.33 (d, J=4.6 Hz, 1H) ppm
AHCTRE(UNG 2R,3S)-Ethyl 3-[(R)-1-Phenylethylamino]-2-hydroxy-
3-(4-methoxyphenyl)propanoate (16e)
The general procedure was followed using 15e (61.3 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
08C; dr 5.4:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc,
6:1!2:1) of the residue gave 16e (51.1 mg, 58%) as a pale
Adv. Synth. Catal. 2006, 348, 2421 – 2430
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2427

Staffan Torssell and Peter Somfai
FULL PAPERS
yellow oil and an inseparable mixture of two minor diaste-
reomers (24.3 mg, 28%) as a pale yellow oil. Major isomer:
25.2, 13.9; IR (film) nmax =3496 (br), 2980, 1736, 1221,
1107 cmꢀ1
;
HR-MS (FAB+): m/z=332.1664, calcd. for
1
[a]2D0: 103.1 (c 1.1, CHCl3); H NMR (500 MHz, CDCl3): d=
C19H23FNO3 (M+H) 332.1662.
7.32 (m, 7H), 6.98 (m, 2H), 4.30(qd, J=10.7, 7.2 Hz, 1H),
4.20(d, J=3.4 Hz, 1H), 4.15 (qd, J=10.7, 7.2 Hz, 1H), 3.90
(s, 3H), 3.73 (d, J=3.4 Hz, 1H), 3.57 (q, J=6.6 Hz, 1H),
1.34 (d, J=6.6 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=173.5, 159.0, 145.2, 132.0, 128.7,
128.2, 126.92, 126.87, 113.8, 75.0, 61.7, 60.8, 55.2, 54.3, 25.1,
AHCTRE(UNG 2R,3S)-Ethyl 3-[(R)-1-phenylethylamino]-3-(4-
bromophenyl)-2-hydroxypropanoate (16h)
The general procedure was followed using 15h (73.8 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
08C; dr 8.4:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc,
6:1!4:1) of the residue gave 16h (51.1 mg, 51%) as a clear
oil and an inseparable mixture of two minor diastereomers
(11.0mg, 11%) as a clear oil. Major isomer: [ a]2D0: 334.7 (c
13.9; IR (film): nmax =3487 (br), 2962, 1732, 1248, 1109 cmꢀ1
;
HR-MS (FAB+): m/z=344.1875, calcd. for C20H26NO4
(M+H): 344.1862.
ACHTREUNG(2R,3S)-Ethyl 3-[(R)-1-Phenylethylamino]-2-hydroxy-
3-(3-methoxyphenyl)propanoate (16f)
1
1.3, CHCl3); H NMR (500 MHz, CDCl3): d=7.51 (m, 2H),
7.28 (m, 3H), 7.18 (m, 4H), 4.28 (qd, J=10.7, 7.2 Hz, 1H),
4.14 (d, J=3.2 Hz, 1H), 4.13 (qd, J=10.7, 7.2 Hz, 1H), 3.70
(d, J=3.2 Hz, 1H), 3.48 (q, J=6.6 Hz, 1H), 1.29 (d, J=
6.6 Hz, 3H), 1.20(t, J=7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=173.3, 144.8, 139.1, 131.5, 129.5, 128.2, 127.0,
The general procedure was followed using 15f (61.3 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
08C; dr 7.1:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc
6:1!2:1) of the residue gave 16f (59.3 mg, 67%) as a clear
oil and an inseparable mixture of two minor diastereomers
(17.4 mg, 20%) as a clear oil. Major isomer: [a]2D0: 110.8 (c
126.9, 121.4, 74.6, 62.0, 60.8, 54.4, 25.1, 13.9; IR (film): nmax
=
3487 (br), 2977, 1736, 1252, 1215, 1107 cmꢀ1
;
HR-MS
(FAB+): m/z=392.0876, calcd. for C19H23BrNO3 (M+H)
392.0861.
1
1.2, CHCl3); H NMR (500 MHz, CDCl3): d=7.30(m, 4H),
7.22 (m, 2H), 6.88 (m, 3H), 4.27 (qd, J=10.7, 7.2 Hz, 1H),
4.19 (d, J=3.2 Hz, 1H), 4.11 (qd, J=10.7, 7.2 Hz, 1H), 3.84
(s, 3H), 3.71 (d, J=3.2 Hz, 1H), 3.56 (q, J=6.6 Hz, 1H),
1.30(d, J=6.6 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=173.5, 159.8, 145.2, 141.8, 129.4,
128.2, 127.0, 126.9, 120.0, 113.4, 112.7, 74.9, 61.8, 61.4, 55.2,
54.4, 25.2, 13.9; IR (film): nmax =3473 (br), 2978, 1736, 1254,
AHCTRE(UNG 2R,3R)-Ethyl 3-[(R)-1-Phenylethylamino]-3-(furan-
2-yl)-2-hydroxypropanoate (16i)
The general procedure was followed using 15i (102.0 mg,
0.512 mmol). Addition of ethyl diazoacetate over 10 h at
ꢀ108C; dr 1.8:1.6:1:0, 1H NMR spectroscopic analysis on
the crude product. Flash chromatography (heptane:EtOAc,
6:1!4:1) of the residue gave 16i (43.6 mg, 28%) as a clear
oil and an inseparable mixture of two minor diastereomers
(60.9 mg, 39%) as a clear oil. Major isomer: [a]2D0: 127.2 (c
1107 cmꢀ1
C20H26NO4 (M+H). 344.1862.
; HR-MS (FAB+): m/z=344.1860, calcd. for
ACHTREUNG(2S,3R)-Ethyl 3-[(S)-1-Phenylethylamino]-2-hydroxy-
3-(3-methoxyphenyl)propanoate (ent-16f)
1
1.2, CHCl3); H NMR (500 MHz, CDCl3): d=7.42 (dd, J=
1.7, 0.7 Hz, 1H), 7.27 (m, 5H), 6.36 (dd, J=3.2, 1.8 Hz, 1H),
6.21 (d, J=3.1 Hz, 1H), 4.29 (d, J=3.1 Hz, 1H), 4.24 (qd,
J=10.6, 7.1 Hz, 1H), 4.05 (qd, J=10.7, 7.2 Hz, 1H), 3.81 (d,
J=3.1 Hz, 1H), 3.65 (q, J=6.6 Hz, 1H), 1.28 (d, J=6.6 Hz,
3H), 1.15 (t, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=173.0, 153.9, 144.9, 142.1, 128.2, 127.1, 127.0, 110.1, 107.6,
73.3, 61.9, 55.6, 55.0, 25.1, 13.9; IR (film): nmax =3483 (br),
2978, 1738, 1105 cmꢀ1; HR-MS (FAB+): m/z=304.1560,
calcd. for C17H22NO4 (M+H): 304.1549.
The general procedure was followed using ent-15f (2.0g,
8.36 mmol). Addition of ethyl diazoacetate over 10h at
08C; dr 8.3:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc,
6:1!2:1) of the residue gave ent-16f (1.840g, 64%) as a
pale yellow oil and an inseparable mixture of two minor dia-
stereomers (0.506 g, 18%) as a pale yellow oil. Major
isomer: [a]2D0: ꢀ109.2 (c 1.3, CHCl3).
A
ACHTRE(UNG 2R,3R)-Diethyl 2-[(R)-1-Phenylethylamino]-3-
hydroxysuccinate (16j)
fluorophenyl)-2-hydroxypropanoate (16g)
The general procedure was followed using 15g (58.2 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
08C; dr 4.5:1:1:0, 1H NMR spectroscopic analysis on the
crude product. Flash chromatography (heptane:EtOAc,
6:1!4:1) of the residue gave 16g (41.0mg, 48%) as a clear
oil and an inseparable mixture of two minor diastereomers
(19.6 mg, 23%) as a clear oil. Major isomer: [a]2D0: 93.5 (c
The general procedure was followed using 15j (52.5 mg,
0.256 mmol). Addition of ethyl diazoacetate over 10 h at
ꢀ108C; dr 9.3:1.8:1:0, 1H NMR spectroscopic analysis on
the crude product. Flash chromatography (heptane:EtOAc,
6:1!4:1) of the residue gave 16j (39.0mg, 49%) as a clear
oil and an inseparable mixture of two minor diastereomers
(7.1 mg, 9%) as a clear oil. Major isomer: [a]2D0: 74.0( c 1.0,
1
1
2.0, CHCl3); H NMR (500 MHz, CDCl3): d=7.29 (m, 5H),
CHCl3); H NMR (500 MHz, CDCl3): d=7.28 (m, 5H), 4.45
7.19 (m, 2H), 7.07 (m, 2H), 4.27 (qd, J=10.7, 7.1 Hz, 1H),
4.14 (d, J=3.3 Hz, 1H), 4.12 (qd, J=10.7, 7.1 Hz, 1H), 3.71
(d, J=3.3 Hz, 1H), 3.48 (q, J=6.6 Hz, 1H), 1.29 (d, J=
6.6 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=173.4, 163.2, 161.3, 144.9, 135.8, 135.7, 129.32,
129.26, 128.3, 127.0, 126.9, 115.3, 115.2, 74.8, 61.9, 60.7, 54.3,
(dd, J=4.4, 2.0Hz, 1H), 4.28 (m, 3H), 3.97 (qd, J=10.6,
7.2 Hz, 1H), 3.78 (q, J=6.5 Hz, 1H), 3.44 (d, J=2.1 Hz,
1H), 3.22 (d, J=5.2 Hz, 1H), 2.26 (br s, 1H), 1.36 (d, J=
6.5 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=172.4, 172.3, 144.9, 128.2,
127.1, 72.2, 62.1, 61.3, 60.8, 56.6, 25.1, 14.2, 13.8; IR (film):
2428
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2421 – 2430

1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines
nmax =3483 (br), 2980, 1741, 1223, 1105 cmꢀ1
FULL PAPERS
;
HR-MS
Wang, Y. Zhu, Z. Chen, A. Mi, W. Hu, M. P. Doyle,
Org. Lett. 2003, 5, 3923–3926.
(FAB+): m/z=310.1648, calcd. for C16H24NO5 (M+H):
310.1654.
[11] a) A. Padwa, L. Precedo, M. A. Semones, J. Org.
Chem. 1999, 64, 4079–4088; b) H. Suga, Y. Ebiura, K.
Fukushima, A. Kakehi, T. Baba, J. Org. Chem. 2005,
70, 10782–10791.
[12] S. Torssell, M. Kienle, P. Somfai, Angew. Chem. Int. Ed.
Acknowledgements
2005, 44, 3096–3099.
[13] The J4,5 =5.1 Hz coupling constant is consistent with
4,5-trans relative stereochemistry, see: C. H. Heath-
cock, T. A. Blumenkopf, K. M. Smith, J. Org. Chem.
1989, 54, 1548–1562.
This work was supported financially by AstraZeneca Sçder-
tälje, the Swedish Research Council and the Knut and Alice
Wallenberg Foundation. Prof. Huw M. L. Davies is gratefully
acknowledged for generously donating a sample of the
[14] For discussions about metal-associated ylides, see:
a) M. P. Doyle, D. C. Forbes, M. N. Protopopova, S. A.
Stanley, M. M. Vasbinder, K. R. Xavier, J. Org. Chem.
1997, 62, 7210–7215; b) S. Kitagaki, M. Anada, O. Ka-
taoka, K. Matsuno, C. Umeda, N. Watanabe, S.-I. Ha-
shimoto, J. Am. Chem. Soc. 1999, 121, 1417–1418;
c) D. M. Hodgson, A. H. Labande, F. Y. T. M. Pierard,
M. . Expósito-Castro, J. Org. Chem. 2003, 68, 6153–
6159.
Rh2ACHTREUNG(S-biTISP)2 catalyst.
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Adv. Synth. Catal. 2006, 348, 2421 – 2430
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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Staffan Torssell and Peter Somfai
FULL PAPERS
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2430
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Adv. Synth. Catal. 2006, 348, 2421 – 2430