1,3-Dipolar cycloadditions of carbonyl ylides to aldimines: A three-component approach to syn-α-hydroxy-β-amino esters

Article abstract of DOI:10.1002/anie.200500296

(Chemical Equation Presented) A highly diastereoselective Rh ^II-catalyzed 1,3-dipolar cycloaddition leads to the formation of syn-β-amino alcohols and syn-α-hydroxy-β-amino acids in high yields (see scheme; p-TSA = poro-toluenesulfonic acid, Bn = benzyl). This three-component approach to the addition of metal-associated carbonyl ylides to aldimines was applied to a short enantioselective synthesis of the C13 side chain of taxol.

Full text of DOI:10.1002/anie.200500296

Communications
Synthetic Methods
1
,3-Dipolar Cycloadditions of Carbonyl Ylides to
Aldimines: A Three-Component Approach to
syn-a-Hydroxy-b-amino Esters**
Staffan Torssell, Marcel Kienle, and Peter Somfai*
The b-amino alcohol and a-hydroxy-b-amino acid moieties
are found in a large variety of biologically important
[
1]
compounds and natural products as well as in a growing
number of ligands and chiral auxiliaries for asymmetric
[
2]
synthesis. Existing synthetic routes towards enantiopure vic-
amino alcohols have traditionally relied on derivatization of
the chiral pool of amino acids for the most part; however,
[
3]
there is an inherent limitation of accessible targets. Consid-
erable efforts have been made in developing asymmetric
routes to b-amino alcohols to circumvent these drawbacks;
these can be divided into two strategically different
[
4]
approaches. Most commonly, the amino alcohol function-
ality is introduced into a pre-existing carbon skeleton, and this
[
5]
can be accomplished by Sharpless aminohydroxylation or by
[
4,6,7]
[4,7,8]
ring opening of epoxides
or aziridines
with appro-
priate nucleophiles. More effectively, the amino alcohol
moiety can be constructed by concomitant formation of a
new carbon–carbon bond and two vicinal stereogenic centers
in a single step. This approach has been realized by addition of
glycine-derived enolates to aldehydes to yield anti-b-amino
[
1b,9]
alcohols
or by addition of a-alkoxy enolates to aldimines
[
1a,10]
in a Mannich-type reaction.
Although several methods
are currently available for the stereo- and enantioselective
formation of vic-amino alcohols, there is clearly a demand for
simple and efficient entries to this interesting class of
substance.
It was envisioned that vic-amino alcohols A could be
obtained by hydrolysis of the corresponding oxazolidines B,
and that these heterocycles could be prepared from the 1,3-
dipolar cycloaddition of a carbonyl ylide C to an imine D
[
11]
(Scheme 1).
The carbonyl ylide C, in turn, could be
prepared from insertion of the carbene derived from E into
aldehyde F. Herein, we report the realization of this strategy
by detailing the first example of such a three-component
protocol for the synthesis of syn-a-hydroxy-b-amino esters
and its application to the asymmetric synthesis of the C13
taxol side chain.
[*] S. Torssell, M. Kienle, Prof. P. Somfai
Organic Chemistry
KTH Chemistry, Royal Institute of Technology
10044 Stockholm (Sweden)
Fax: (+46)8791-2333
E-mail: somfai@kth.se
[
**] This work was supported financially by AstraZeneca Sꢀdertꢁlje, the
Swedish Research Council, and the Knut and Alice Wallenberg
Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3
096
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DOI: 10.1002/anie.200500296
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Angewandte
Chemie
[
a]
Table 1: 1,3-Dipolar cycloaddition of carbonyl ylides to aldimines.
[
b]
Entry
1
1 (R/Ar)
d.r. (syn/anti)
Yield of
syn-5 [%]
[
c]
a (Ph/Bn)
a (Ph/Bn)
b (Ph/Ph)
c (Ph/4-MeOC H )
93:7
N.A.
N.A.
N.A.
91:9
98:2
97:3
98:2
97:3
94:6
98:2
92:8
83:17
a (82)
Scheme 1. Retrosynthetic analysis of the a-hydroxy-b-amino ester syn-
thesis.
[
d]
[e]
2
3
4
5
6
7
8
9
1
1
1
1
a (0)
[
f]
b (0)
[
e]
c (0)
6
4
[
g]
d (4-NO C H /Bn)
d (61)
e (75)
f (78)
g (77)
h (87)
i (78)
j (83)
k (75)
l (64)
2
6
4
e (4-ClC H /Bn)
Initially, a mixture of benzylidenebenzylamine (1a),
benzaldehyde (2), and Rh (OAc) in CH Cl was stirred at
6
4
f (4-FC H /Bn)
6
4
2
4
2
2
g (4-MeOC H /Bn)
h (4-MeC H /Bn)
i (4-MeOC H /Bn)
6 4
j (2-naphthyl/Bn)
k (2-furyl/Bn)
6
4
room temperature (Scheme 2). Addition of ethyl diazoace-
6
4
[
g]
0
1
2
3
[
[
g,h]
g,h]
l (CO Et/Bn)
2
[a] The reaction was carried out with imine 1 (1.0 equiv), benzaldehyde
(
1.5 equiv), Rh (OAc) (2.0 mol%), and powdered 4-ꢂ molecular sieves
2
4
in CH Cl at RT with addition of ethyl diazoacetate (1.5 equiv) over 1 h.
2
2
Hydrolysis was performed with p-TSA (2 equiv) in MeOH/H O (95:5).
2
[
b] Determined by NMR spectroscopic analysis of the crude product; syn
and anti diastereoisomers were separated with flash chromatography.
c] Yield of isolated product. [d] Cu(OTf)2 (5 mol%) in THF. [e] Only
imine and hydrolyzed imine. [f] Complex mixture of by-products.
g] Addition time=10 h. [h] 08C. N.A.=not available.
[
[
Scheme 2. 1,3-Dipolar cycloaddition to benzylidenebenzylamine.
p-TSA=para-toluenesulfonic acid, Bn=benzyl.
containing electron-withdrawing (entries 5–8) or electron-
donating substituents (entries 9–11) in the meta or para -
positions gave comparable yields and diastereoselectivities
irrespective of the steric or electronic properties of the aryl
substituent. The furfural-derived imine 1k afforded the
corresponding product 5k in high yield and diastereoselec-
tivity (entry 12), which is of interest as the furan moiety can
be readily derivatized into several useful functional groups.
The reaction of ethyl glyoxalate imine (1l) gave syn-b-
hydroxyaspartate (5l), a potent blocker of glutamate trans-
tate (EDA; 3) over 1 h at room temperature afforded the
desired cycloadduct 4, which yielded vic-amino alcohol 5a
(
syn/anti 93:7) in 82% yield (syn; Table 1, entry 1) on
[
12]
hydrolysis. The relative stereochemistry of 5a was verified
by its conversion into the corresponding oxazolidinone by
1
H NMR spectroscopic analysis of the relevant coupling
[
13]
constants.
With the reaction conditions established, it was of interest
to optimize the key components of the reaction. First, the
[
16]
porters,
in high yield and good diastereoselectivity
choice of metal catalyst was examined. Cu(OTf) is known to
(entry 13), thus indicating that the reaction is not only
restricted to aromatic imines and the scope of the trans-
formation can be widened.
2
be a suitable catalyst for the decomposition of 3, but
unfortunately this only led to recovery of 1a (entry 2),
probably because of coordination of the metal to the basic
imine nitrogen atom with concomitant inhibition of the
The mechanism of the reaction proceeds through a
chemoselective insertion of the metallocarbene into benzal-
[
11c,d,14]
[11a,17a]
carbenoid formation.
Next, the substituent on the imine
dehyde to form either a metal-free
6a or a metal-
[
17]
was varied to investigate if this would influence the reaction
outcome. When using imine 1b, which was derived from
aniline and 2, a complex reaction mixture was obtained with
no trace of the desired product (entry 3), whereas attempts
with 1c gave only recovered starting material (entry 4).
Aldehyde 2 could be exchanged for other aromatic aldehydes,
but this did not improve the reaction outcome so the
remaining experiments were performed with 2. The perform-
ances of other aldimines under the optimized reaction
conditions are summarized in Table 1. In all cases, the
reaction proceeded cleanly to provide the desired syn-a-
hydroxy-b-amino ester in high yield and excellent diastereo-
associated ylide 6b, both of which can then undergo a 1,3-
dipolar cycloaddition with the aldimine yielding the trans-
substituted oxazolidine 4, which can then be hydrolyzed to the
corresponding syn-a-hydroxy-b-amino ester 5 (Scheme 2). To
ascertain if ylide 6 is metal-associated, the generation of the
ylide and its subsequent reaction with imine 1a was per-
formed with [Rh (hfb) ] (hfb = heptafluorobutyrate) and
2
4
[Rh {(S)-dosp} ] ((S)-dosp = (S)-N-dodecylbenzenesulfonyl
2
4
prolinate), respectively. When [Rh (hfb) ] was used, 5a was
2
4
obtained in only 13% yield with lower diastereoselectivity
(syn/anti = 88:12 compared to entry 1, Table 1), whereas with
[Rh {(S)-dosp} ] 5a was obtained in 62% yield with excellent
2
4
[
15]
selectivity.
Several benzylidenebenzylamine derivatives
diastereoselectivity (syn/anti = 94:6) and modest enantiose-
Angew. Chem. Int. Ed. 2005, 44, 3096 –3099
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Communications
lectivity (24% ee). These preliminary results support the
[
1] a) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998,
20, 431 – 432; b) J. Kobayashi, M. Nakamura, Y. Mori, Y.
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references therein.
formation of a metal-associated ylide in this case. It is
interesting to note that no products derived from the
formation of azomethine ylides, by combination of 1 with 3,
1
9
[
11c,d]
was observed in these reactions.
It was also of interest to develop an asymmetric protocol
for the synthesis of enantiomerically enriched syn-a-hydroxy-
b-amino esters and to apply it to the synthesis of the taxol C13
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Chem. Int. Ed. Engl. 1991, 30, 1531 – 1546.
[
5,18]
side chain 9 (Scheme 3),
which is known to be important
[
[
4] S. C. Bergmeier, Tetrahedron 2000, 56, 2561 – 2576.
5] G. Li, H.-T. Chang, K. B. Sharpless, Angew. Chem. 1996, 108,
4
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[
[
[
[
1
8
6
8
298; c) T. Ooi, M. Taniguchi, M. Kameda, K. Maruoka,
Angew. Chem. 2002, 114, 4724 – 4726; Angew. Chem. Int. Ed.
002, 41, 4542 – 4544.
2
Scheme 3. Asymmetric synthesis of the C13 side chain of taxol.
[10] Mannich-type reaction: a) B. List, P. Pojarliev, W. T. Biller, H. J.
Martin, J. Am. Chem. Soc. 2002, 124, 827 – 833; b) A. Cꢀrdova,
W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J. Am.
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Am. Chem. Soc. 2003, 125, 338 – 339; d) S. Matsunaga, N.
Kumagai, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2003,
Reagents and conditions: a) 1) Rh (OAc) (2 mol%), 4-ꢂ molecular
2
4
sieves, CH Cl , 08C; 2) p-TSA, MeOH/H O (95:5), RT (77%, 2 steps,
2
2
2
d.r. 8:1:1); b) 1) H , [Pd(OH) ], EtOH, 3m HCl, RT; 2) PhCOCl,
2
2
NaHCO , EtOAc, 08C (77% over 2 steps); c) LiOH·H O, THF/MeOH/
3
2
H O (10:5:4), RT (89%).
2
125, 4712 – 4713.
[
11] For three-component reactions using diazo compounds for
carbonyl ylides, see: a) C.-D. Lu, Z.-Y. Chen, H. Liu, W.-H.
Hu, A.-Q. Mi, Org. Lett. 2004, 6, 3071 – 3074; b) A. E. Russell, J.
Brekan, L. Gronenberg, M. P. Doyle, J. Org. Chem. 2004, 69,
[
18]
for the antitumor activity of taxol. Initial attempts with (À)-
[
19]
8
-phenylmenthyl diazoacetate as the carbene source with
5
269 – 5274; for azomethine ylides, see: c) K. B. Hansen, N. S.
1
a and 2 gave none of the desired product. Gratifyingly,
Finney, E. N. Jacobsen, Angew. Chem. 1995, 107, 750 – 752;
Angew. Chem. Int. Ed. Engl. 1995, 34, 676 – 678; d) C. V.
Galliford, M. A. Beenen, S. T. Nguyen, K. A. Scheidt, Org.
Lett. 2003, 5, 3487 – 3490; e) M. Yan, N. Jacobsen, W. Hu, L. S.
Gronenberg, M. P. Doyle, J. T. Colyer, D. Bykowski, Angew.
Chem. 2004, 116, 6881 – 6884; Angew. Chem. Int. Ed. 2004, 43,
however, reaction of the enantiomerically pure imine 1m,
derived from (+)-a-methylbenzylamine, with 2 and 3 gave the
desired syn-amino alcohol 7 in good yield (77%) and
selectivity (syn/syn/anti = 8:1:1) after hydrolysis (Scheme 3).
Compound 7 was readily isolated from the two minor isomers
by flash chromatography, and subsequent catalytic hydro-
genolysis of this compound followed by benzoylation under
Schotten–Baumann conditions afforded amide 8 (77% yield,
two steps). Finally, hydrolysis of 8 using LiOH yielded the
taxol side chain 9 as a white solid in five steps and an overall
yield of 42%. Analytical data of 9 were in good agreement
6
713 – 6716; for oxonium ylides, see: f) C.-D. Lu, H. Liu, Z.-Y.
Chen, W.-H. Hu, A.-Q. Mi, Org. Lett. 2005, 7, 83 – 86; for
ammonium ylides, see: g) Y. Wang, Y. Zhu, Z. Chen, A. Mi, W.
Hu, M. P. Doyle, Org. Lett. 2003, 5, 3923 – 3926.
[
[
12] Addition of powdered activated 4-ꢁ molecular sieves gave
higher yields and more reproducible results, see: C.-D. Lu, Z.-Y.
Chen, H. Liu, W.-H. Hu, A.-Q. Mi, M. P. Doyle, J. Org. Chem.
2004, 69, 4856 – 4859.
13] The J(4,5) = 5.1 Hz coupling constant is consistent with 4,5-trans
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kopf, K. M. Smith, J. Org. Chem. 1989, 54, 1548 – 1562.
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15] The syn and anti diastereoisomers where readily separated by
flash chromatography for all substrates.
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Yumoto, T. Nakajima, Bioorg. Med. Chem. Lett. 2000, 10, 2407 –
2410.
[
5,18]
with previously reported data.
In conclusion, we have developed an efficient protocol for
the synthesis of syn-b-amino alcohols and syn-a-hydroxy-b-
amino acid derivatives based on a highly diastereoselective
three-component coupling of imines, benzaldehyde, and
EDA. The methodology was applied to a short enantioselec-
tive synthesis of the C13 side chain of taxol.
[
[
[
Received: January 26, 2005
Published online: April 12, 2005
[
17] 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. Kataoka, K. Matsuno, C. Umeda,
N. Watanabe, S.-I. Hashimoto, J. Am. Chem. Soc. 1999, 121,
1417 – 1418; c) D. M. Hodgson, A. H. Labande, F. Y. T. M.
Keywords: amino alcohols · carbenoids · cycloaddition ·
.
multicomponent reactions · ylides
3
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Angewandte
Chemie
Pierard, M. ꢂ. Expꢀsito Castro, J. Org. Chem. 2003, 68, 6153 –
159.
6
[
18] For the shortest synthesis of the C13 side chain of taxol, see
Ref. [5] a) L. Deng, E. N. Jacobsen, J. Org. Chem. 1992, 57,
4320 – 4323; b) D.-M. Gou, Y.-C. Liu, C.-S. Chen, J. Org. Chem.
1993, 58, 1287 – 1289; c) V. K. Aggarwal, J.-L. Vasse, Org. Lett.
2003, 5, 3987 – 3990.
[
19] For the synthesis of (À)-8-phenylmenthyl diazoacetate, see:
A. V. Bedekar, E. B. Koroleva, P. G. Andersson, J. Org. Chem.
1997, 62, 2518 – 2526.
Angew. Chem. Int. Ed. 2005, 44, 3096 –3099
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