Asymmetric Sulfur Ylide Mediated Aziridination: Application in the Synthesis of the Side Chain of Taxol

Article abstract of DOI:10.1021/ol035554w

(Formula presented). Sulfur ylide methodology has been used to construct the Taxol side chain with a high degree of enantioselectivity via a trans-aziridine followed by stereospecific rearrangement of the trans-benzoylaziridine into a trans-oxazoline.

Full text of DOI:10.1021/ol035554w

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3987-3990
Asymmetric Sulfur Ylide Mediated
Aziridination: Application in the
Synthesis of the Side Chain of Taxol
Varinder K. Aggarwal* and Jean-Luc Vasse
School of Chemistry, Cantock’s Close, UniVersity of Bristol, Bristol BS8 1TS, UK
V.aggarwal@bristol.ac.uk
Received August 18, 2003
ABSTRACT
Sulfur ylide methodology has been used to construct the Taxol side chain with a high degree of enantioselectivity via a trans-aziridine followed
by stereospecific rearrangement of the trans-benzoylaziridine into a trans-oxazoline.
Aziridines are versatile synthetic intermediates1 in the
synthesis of R-amino alcohols.2 trans-Aziridines, for ex-
ample, can be converted into either syn- or anti-R-amino
alcohols quite simply (Scheme 1): direct ring opening with
hydrazone salts, a process mediated by sulfur ylides (Scheme
2).4 Key features of this process included (i) high conver-
Scheme 2. Catalytic Asymmetric Aziridination of Imines
Using Tosylhydrazone Salts
Scheme 1. Application of trans-Aziridines in the Synthesis of
syn- or anti-R-Amino Alcohols
gency, (ii) high enantioselectivity, (iii) use of sulfide in sub-
stoichiometric amounts (20 mol %), (iv) sulfide quantitatively
reisolated, (v) ready availability of both enantiomers of
sulfide 1 in four steps, and (vi) efficient and user-friendly
process.
(1) Reviews on applications and synthesis: (a) McCoull, W.; Davis, F.
A. Synthesis 2000, 1347. (b) Atkinson, R. S. Tetrahedron 1999, 55, 1519.
(c) Jacobsen, E. N. In ComprehensiVe Asymmetric Catalysis II; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 607. (d)
Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV. 1997, 97, 2341. (e)
Osborn, H. M. I.; Sweeney, J. B. Tetrahedron: Asymmetry 1997, 8, 1693.
(f) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
an oxygen nucleophile furnishes the anti isomer, whereas
stereospecific rearrangement of acylaziridines followed by
hydrolysis gives the syn isomer.3
We recently described a powerful method for the asym-
metric synthesis of trans-aziridines from imines and tosyl
10.1021/ol035554w CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/24/2003

So far, the vast majority of asymmetric sulfur ylide studies
have been directed at exploring the methodology5 rather than
exploiting their use in synthesis.6 In this paper, we describe
the first application of the asymmetric sulfur ylide mediated
aziridination methodology in synthesis and, in particular, to
the synthesis of the side chain of Taxol, a syn-R-amino
alcohol.
Scheme 3. Retrosynthetic Analysis of the Taxol Side Chain
Taxol (paclitaxel) is used in the treatment of various forms
of cancer.7 It can be isolated from the bark of Taxus
breVifolia but is more economically prepared by semisyn-
thesis through the coupling of the commercially synthesized
side chain 2 with 10-deactylbaccatin, which itself is isolated
from the tree’s leaves. Thus, synthetic routes for the side
chain of Taxol are important and indeed have attracted much
attention.8 A number of strategies have been used to prepare
this intermediate but none have involved aziridine intermedi-
ates. Epoxide intermediates have been utilized, but cis
stereochemistry is required to access the syn-R-amino
alcohol.9 On the basid of the above discussion, it was clear
to us that trans-aziridines could be employed to prepare the
syn-R-amino alcohol required for the Taxol side chain
(Scheme 3).
cleanly to give aziridines only.4 Both pathways a and c were
therefore investigated in the synthesis of the Taxol side chain
2.
We initially explored pathway a. The N-benzoylimine 4
was prepared cleanly using Katritzky’s benzotriazole method11
(this was found to be cleaner than the method employing
the N-trimethylsilylimine and reaction with benzoyl chlo-
ride12), but reaction of this substrate with the 3-furyl
tosylhydrazone salt lead to a complex mixture of products
(Scheme 4). This was disappointing as the 3-furyl tosyl-
Key to the success of the strategy was to ensure that during
rearrangement of the trans-aziridine 3 to the trans-oxazoline,
cleavage of the C-N bond occurred adjacent to the R group
rather than the Ph group. Thus, R had to be a group more
capable of stabilizing a transient positive charge than a
phenyl group and had to be readily converted into an acid.
These requirements led us to propose the 3-furyl moiety as
the R group. The disconnection of the benzoyl aziridine leads
to two possible direct coupling partners (paths a/b). However,
it was known that reactions of sulfur ylides with acyl imines
furnish a mixture of aziridines and (the required) oxazo-
lines.10 This mixture could be utilized in path a but not in
path b as the oxazoline would have the incorrect regiochem-
istry. However, a change of activating groups on nitrogen
(path c) provides another solution to the problem. For
example, it was known that phenyl-stabilized sulfur ylide
reacts with N-sulfonylimines (EWG ) sulfonyl group)
Scheme 4. Path a: Attempted Catalytic Aziridination of
Benzoyl Imine
(2) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(3) (a) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574 (and
references therein). (b) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett.
2000, 2, 4087.
(4) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433.
hydrazone salt had been successfully employed in catalytic
asymmetric epoxidation with benzaldehyde13 and N-benzoyl-
imines had successfully been employed in catalytic asym-
metric aziridination with benzaldehyde tosylhydrazone salt.10
We therefore investigated the stoichiometric variant6 of our
ylide reaction and positive results ensued.
The 3-furyl sulfonium 5 salt was prepared by alkylation
of sulfide 1 with the corresponding 3-furylmethyl bromide
(Scheme 5).14 The salt 5 was then deprotonated at low
(5) Aggarwal, V. K. In ComprehensiVe Asymmetric Catalysis II; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 679.
For recent references on the sulfur ylide route to aziridines, see: (a) Saito,
T.; Akiba, D.; Sakairi, M. Tetrahedron Lett. 2001, 42, 5451. (b) Aggarwal,
V. K.; Ferrara, M.; O’Brien, C. J.; Thompson, A.; Jones, R. V. H.;
Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001, 1635. (c) Yang, X.-F.;
Zhang, M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2002, 67, 8097.
(6) Application of the asymmetric epoxidation process in the synthesis
of CDP 840 was recently described: Aggarwal, V. K.; Bae, I.; Lee, H.-Y.;
Richardson, J.; Williams, D. T. Angew. Chem., Int. Ed. 2003, 42, 3274.
(7) For reviews, see: (a) Kingston, D. G. I. Chem. Commun. 2001, 867.
(b) Kingston, D. G. I. J. Nat. Prod. 2000, 63, 726. (c) Nicolaou, K. C.;
Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15.
(8) The most direct route is attributed to Sharpless: Li, G.; Chang, H.-
T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451.
(9) (a) Jacobsen, E. N. Deng, L.; Furukawa, Y.; Martinez, L. E.
Tetrahedron Lett. 1994, 50, 4323. (b) Denis, J.-N.; Greene, A. E.; Serra,
A. A.; Luche, M.-J. J. Org. Chem. 1986, 51, 46.
(11) Katritzky, A. R.; Fan, W.-Q.; Black, M.; Pernak, J. J. Org. Chem.
1992, 57, 547.
(12) Kupfer, R.; Meier, S.; Wu¨rthwein, E.-U. Synthesis 1984, 688.
(13) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Patel, M.; Richardson, J.; Stenson, R. A.; Studley, J.; Vasse,
J.-L.; Winn, C. J. Am. Chem. Soc. 2003, 125, 10926.
(14) Aggarwal, V. K.; Thompson, A.;. Jones, R. V. H. Tetrahedron Lett.
1994, 8659. This method was more successful than reaction of the sulfide
with 3-furylmethanol and HBF4 (see ref 6).
(10) Aggarwal, V. K.; Alonso, E. Unpublished results.
3988
Org. Lett., Vol. 5, No. 21, 2003

Scheme 5. Stoichiometric Sulfur Ylide Route to Taxol Side
Scheme 6. Catalytic Sulfur Ylide Route to Taxol Side Chain.
Chain.
in 74% yield over two steps. Finally, hydrolysis of the acetate
gave the Taxol side chain 2 in six steps and 16% overall
yield. This material was identical by NMR spectroscopy9b
and optical rotation20 to that reported in the literature.
Our second strategy, path c, was also explored. We decided
to employ the N-trimethylsilylethylsulfonyl (SES) imine as
we had previously found that N-sulfonylimines were more
stable than N-carbonylimines to the catalytic aziridination
conditions10 and that this group could be readily removed.
Thus, the N-SES imine 10 was prepared4 and reacted with
the tosylhydrazone salt derived from benzaldehyde in the
presence of a phase transfer catalyst (PTC), Rh2(OAc)4 and
catalytic quantities of chiral sulfide 1 (Scheme 6).4 After
optimization of the reaction conditions, aziridine 11 was
obtained in 57% yield as an 8:1 trans/cis diastereoisomeric
ratio. The trans isomer was obtained with an enantiomeric
excess of 98%. The inseparable mixture of aziridines 11 was
then deprotected using a mixture of CsF and tetrabutylam-
monium triphenyldifluorosilicate (TBAT)21 in a DMF/THF
mixture at 40 °C providing the N-H aziridines in 91% which
could be easily separated by column chromatography to
afford 12 in diastereoisomeric pure form (74%). The trans-
aziridine was then quantitatively converted into benzoyl
aziridine and subsequent treatment with BF3‚Et2O resulted
in regioselective ring-expansion/isomerization22 furnishing
the trans-oxazoline 8 in 81% yield over two steps with
complete retention of stereochemical integrity. The same final
steps as shown in Scheme 5 furnished the Taxol side chain
in a total of seven steps and 20% overall yield.
temperature with NaHMDS in THF6 and the N-benzoylimine
4 added giving a 2:1:0.2 mixture of trans-aziridine 6/cis-
aziridine 7/trans-oxazoline 8. During purification by column
chromatography, the trans-aziridine 6 was converted into
trans-oxazoline 8 while the cis-aziridine 7 was largely
untouched.15 The two isolated compounds 7 and 8 had
enantiomeric excesses of 94% and 97%, respectively. We
believe that the small reduction in enantioselectivity for the
trans-oxazoline 8 originates from partial isomerization of the
cis-aziridine 7 into ent-trans-oxazoline 8.16
We attempted oxidative cleavage of the furyl group on
substrate 8 as the corresponding acid had previously been
coupled with 10-deactylbaccatin and the oxazoline subse-
quently cleaved to give Taxol.17 However, all attempts at
this oxidation led to a complex mixture of products. We
believed that the oxazoline moiety was interfering with the
oxidative cleavage and so this group had to be modified.
Thus, hydrolysis of the oxazoline 8 with dilute HCl followed
by treatment with acetic anhydride led to the amide ester 9.
Oxidation of the furyl group using Sharpless’ conditions18
was now no longer problematic, furnishing the carboxylic
acid, which was esterified with trimethylsilyldiazomethane19
Our key sulfur ylide reactions in both routes gave
aziridines/oxazolines with very high enantioselectivity. We
believe this is because (Figure 1) (i) a single diastereomeric
(15) Silica gel has been reported to effect rearrangement of unsaturated
acyl aziridines into oxazolines: Lindstro¨m, U. M.; Somfai, P. J. Am. Chem.
Soc. 1997, 119, 8385.
(16) Treatment of the pure cis-aziridine with acetic acid resulted in a
3/1 mixture of trans/cis oxazoline, whereas pure trans-aziridine gave trans-
oxazoline only. This showed that rearrangement of the cis-aziridine is not
stereospecific.
(17) Cabri, W.; Curini, M.; Marcotullio, M. C.; Rosati, O. Tetrahedron
Lett. 1996, 37, 4785-4786.
(18) (a) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936. (b) Boger, D. L.; Lee, R. J.; Bournaud, P.-Y.;
Meier, P. J. Org. Chem. 2000, 65, 6770-6772.
(19) Murakami, N.; Tamura, S.; Wang, W.; Takagi, T.; Kobayashi, M.
Tetrahedron 2001, 57, 4323-4336.
(20) Hamamoto, H.; Mamedov, V. A.; Kitamoto, M.; Hayashi, N.;
Tsuboi, S. Tetrahedron: Asymmetry 2000, 11, 4485-4497.
(21) The use of CsF or TBAT on their own were much less effective
than the combination.
(22) Papa, C.; Tomasini, C. Eur. J. Org. Chem. 2000, 1569.
Org. Lett., Vol. 5, No. 21, 2003
3989

multiple purposes: it activates the imine toward nucleophilic
attack by the ylide, promotes rearrangement of the intermedi-
ate aziridine to the oxazoline, and is required in the final
product. The second route utilizes our catalytic asymmetric
aziridination process of N-sulfonylimines. Although our
syntheses do not compete with the shortest synthesis of the
Taxol side chain,8 they are nevertheless efficient and highly
enantioselective and demonstrate the application of asym-
metric sulfur ylide technology in the synthesis of syn-â-amino
alcohols, a common motif in natural products.
Figure 1. Origin of high enantioselectivity in ylide reactions with
imines.
Acknowledgment. We thank EPSRC for support of this
work.
sulfonium ylide is formed, (ii) high levels of control in ylide
conformation result from steric interactions of the aryl group
with the methylene bridge, (iii) high levels of control in face
selectivity of the ylide result from the bulky camphor moiety
blocking one face, and (iv) betaine formation is nonreversible
(proven by crossover experiments23).
Supporting Information Available: Experimental pro-
cedures, characterization data, and methods for determination
of enantioselectivities. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have described two routes to the syn-
R-amino alcohol found in the side chain of Taxol. The first
route involved a stoichiometric sulfur ylide mediated reaction
with an N-benzoylimine which furnished the required ox-
azoline directly. In this route, the benzoyl group serves
OL035554W
(23) Aggarwal, V. K.; Charmant, J. P. H.; Ciampi, C.; Hornby, J. M.;
O’Brien, C. J.; Hynd, G.; Parsons, R. J. Chem. Soc., Perkin Trans. 1 2001,
3159.
3990
Org. Lett., Vol. 5, No. 21, 2003