Total synthesis of (+/-)-FR66979.

Full text of DOI:10.1002/anie.200290017

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unambiguously confirmed by observation of NOE interactions
between 7-H and 9-H.
[16] In addition to 22, formation of a side product, which was tentatively
assigned as hydroxylamine hemiacetal diastereomer 22’, was ob-
served. This mixture was subjected to the next acetonide formation
without separation.
tral data were completely identical with those reported in
literature.[1b]
In conclusion, we have completed a highly efficient total
synthesis of FR900482 (1). The present synthesis features a
facile formation of N-hydroxybenzazocine by intramolecular
reductive hydroxylamination and an ensuing facile construc-
tion of the hydroxylamine hemiacetal. The synthetic strategy
described above should be applicable to the synthesis of
analogues of FR900482 as well as of other benzazocine
derivatives. Application of this approach to the synthesis of
mitomycin C is currently under investigation in our laborato-
ries.
[17] The ratio of 22/22’ was almost the same as that of 23 and a side
product, which was tentatively assigned as 23’. Furthermore, depro-
tection of the acetonide of 23 and 23’ under acidic conditions (HCl
(1n) in THF, room temperature) gave only 22 and 22’, respectively.
These observations would indicate that neither epimerization of C7
nor interconversion of the hemiacetal diastereomers via the eight-
membered ring ketone occurred during the acetonide formation.
Received: August 6, 2002 [Z19901]
[1] a) M. Iwami, S. Kiyoto, H. Terano, M. Kohsaka, H. Aoki, H. Imanaka,
J. Antibiot. 1987, 40, 589; b) S. Kiyoto, T. Shibata, M. Yamashita, T.
Komori, M. Okuhara, H. Terano, M. Kohsaka, H. Aoki, H. Imanaka,
J. Antibiot. 1987, 40, 594; c) I. Uchida, S. Takase, H. Kayakiri, S.
Kiyoto, M. Hashimoto, J. Am. Chem. Soc. 1987, 109, 4108.
[2] K. Shimomura, O. Hirai, T. Mizota, S. Matsumoto, J. Mori, F.
Shibayama, H. Kikuchi, J. Antibiot. 1987, 40, 600.
[3] a) R. M. Williams, S. R. Rajski, S. B. Rollins, Chem. Biol. 1997, 4, 127;
b) M. M. Paz, P. B. Hopkins, J. Am. Chem. Soc. 1997, 119, 5999;
c) R. M. Williams, S. B. Rollins, S. R. Rajski, J. Am. Chem. Soc. 1998,
120, 2192.
[18] T. Fukuyama, A. A. Laird, L. M. Hotchkiss, Tetrahedron Lett. 1985,
26, 6291.
[19] The aldehyde was protected as the dimethyl acetal to prevent
reduction during hydrogenolysis of the phenolic benzyl ether.
[4] For representative examples, see: a) N. Yasuda, R. M. Williams,
Tetrahedron Lett. 1989, 30, 3397; b) R. J. Jones, H. Rapoport, J. Org.
Chem. 1990, 55, 1144; c) S. J. Miller, S. H. Kim, Z. R. Chen, R. H.
Grubbs, J. Am. Chem. Soc. 1995, 117, 2108; d) H. J. Lim, G. A.
Sulikowski, Tetrahedron Lett. 1996, 37, 5243; e) S. Mithani, D. M.
Drew, E. H. Rydberg, N. J. Taylor, S. Mooibroek, G. I. Dmitrienko, J.
Am. Chem. Soc. 1997, 119, 1159.
[5] a) T. Fukuyama, L. Xu, S. Goto, J. Am. Chem. Soc. 1992, 114, 383;
b) J. M. Schkeryantz, S. J. Danishefsky, J. Am. Chem. Soc. 1995, 117,
4722.
Total Synthesis of (ꢀ )-FR66979**
Richard Ducray and Marco A. Ciufolini*
In the late 1980s, scientists at the Fujisawa Co. (Japan)
unveiled a new class of antitumor agents with general
structure 1 (Scheme 1).[1] These substances, denoted FR-
66979 (1a) and FR-900482 (1b), are structurally related to the
mitomycins (see mitomycin C (2)).[2] Indeed, the two families
of anticancer agents possess comparable bioactivity[3] and are
believed to act by a similar mechanism, yet FR-type
compounds are less toxic than mitomycins, probably as a
result of the absence of a quinoid nucleus.[4] Derivatives of 1b
are currently undergoing clinical trials.[5]
[6] a) T. Katoh, E. Itoh, T. Yoshino, S. Terashima, Tetrahedron 1997, 53,
10229; b) T. Yoshino, Y. Nagata, E. Itoh, M. Hashimoto, T. Katoh, S.
Terashima, Tetrahedron 1997, 53, 10239; c) T. Katoh, Y. Nagata, T.
Yoshino, S. Nakatani, S. Terashima, Tetrahedron 1997, 53, 10253.
[7] I. M. Fellows, D. E. Kaelin, Jr., S. F. Martin, J. Am. Chem. Soc. 2000,
122, 10781.
[8] After submission of this manuscript, we learned that two groups have
independently completed enantioselective total syntheses; see the
previous communication: a) T. C. Jude, R. M. Williams, Angew. Chem.
2002, 114, 4877; Angew. Chem. Int. Ed. 2002, 41, 4683; and the
following communication: b) R. Ducray, M. A. Ciufolini, Angew.
Chem. 2002, 114, 4882; Angew. Chem. Int. Ed. 2002, 41, 4688.
[9] For an approach utilizing intramolecular [3þ2] cycloaddition of nitrile
oxide, see: M. Kambe, E. Arai, M. Suzuki, H. Tokuyama, T.
Fukuyama, Org. Lett. 2001, 3, 2575.
The biomedical potential and unusual architecture of
compounds 1 have stimulated substantial interest at a
[10] G. Pandey, M. Kapur, Tetrahedron Lett. 2000, 41, 8821. Alternatively,
we prepared 9 by a modified procedure: 2,3-di-O-isopropylidene-l-
threitol, NaH, TBSCl, THF; cat. TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy, free radical), PhI(OAc)2, CH2Cl2; dimethyl-1-diazo-2-
oxopropylphosphonate, K2CO3, MeOH (S. M¸ller, B. Liepold, G. J.
Roth, H. J. Bestmann, Synlett 1996, 521).
[11] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16,
4467.
[12] The coupling reaction under typical conditions ([PdCl2(PPh3)2] and
CuI in Et3N) gave a considerable amount of the homocoupling by-
product of the acetylene.
[13] T. Nakata, Y. Tani, M. Hatozaki, T. Oishi, Chem. Pharm. Bull. 1984,
32, 1411.
[14] J. Hartung, S. H¸nig, R. Kneuer, M. Schwarz, H. Wenner, Synthesis
1997, 1433.
[15] Ketone 21 could be isolated when the reaction was quenched with
NH4Cl (1n) instead of HCl (1n), and its diastereomeric ratio was
estimated by means of 1H NMR spectroscopy. The structure of 21 was
[*] Prof. Dr. M. A. Ciufolini, R. Ducray
Laboratoire de Synthõse et Mÿthodologie Organiques
CNRS UMR 5078
Universitÿ Claude Bernard Lyon 1
and
…cÙle Supÿrieure de Chimie, Physique, Electronique de Lyon
43, Bd. du 11 Novembre 1918, 69622 Villeurbanne cedex (France)
Fax : (þ 33)4-7243-2963
E-mail: ciufi@cpe.fr
[**] We thank the MENRT (doctoral fellowship to R.D.), the CNRS, and
the Rÿgion RhÙne-Alpes for support of our research. We are grateful
to Ms. Laurence Rousset and Dr. Denis Bouchu for the mass spectral
data, to Dr. Bernard Fenet for the NMR spectroscopic data. Finally,
we thank the Fujisawa Co. for a gift of natural FR-66979. M.A.C. is the
recipient of a Merck & Co. Academic Development Award.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4688
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0044-8249/02/4124-4688 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 24

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Scheme 1. Structure of FR66979 (1a), FR900482 (1b), and mitomycin C
(2).
chemical level. In that respect, the fragile nature of these
molecules and their problematic structural features have
inspired the development of much innovative synthetic
chemistry.[6,7] Our own involvement in this area[8] has recently
produced a new method for benzazocene assembly through an
unusual fragmentation of a silylated aziridine[9] orchestrated
by a preliminary homo-Brook[10] transposition (Scheme 2).
We describe herein a total synthesis of (ꢀ )-FR-66979 (1a),
which showcases this new reaction as a key step.
Scheme 3. Reagents and conditions: a) THF, À788C; b) toluene, 1008C,
80% over two steps; c) hn, THF, 77%; d) nBu4NOH, DMF, À208C, 49%.
DMF ¼ N,N-dimethylformamide.
the best of our knowledge, only approaches that rely on olefin
metathesis[7k] appear to be competitive with our aziridine
fragmentation methodology for the creation of such medium-
ring N-heterocycles.
Straightforward operations patterned after reported syn-
theses of 1b[6a] advanced 8 to 11, oxidation of which to ketone
12 was best carried out with TPAP NMO.[15] Release of the
hydroxylamine O-acetyl group precipitated transannular
cyclization to 13, which upon hydrogenolytic cleavage of all
benzyl groups furnished 14. The progress of the debenzylation
step was carefully monitored to minimize formation of by-
product 15 (Scheme 4). The latter is an interesting intermedi-
ate in its own right,[6h] but, of course, it is not useful for the
pursuit of the total synthesis. The relative configuration of 13
and 14 was assigned as shown in Scheme 4 on the basis of an
observed NOE interaction between the indicated protons
(2D-NOESY).
Tetraol 14 was elaborated to (ꢀ )-1a by a modification of
known procedures,[6a,h] as detailed in Scheme 5. Selective
acetonide formation led to 16, which underwent regioselec-
tive azidolysis of the oxirane, followed by selective acetylation
of primary and phenolic OH groups, to give 17. Mesylation of
the hindered, electronically deactivated secondary alcohol
and exchange of the acetonide with a cyclic carbonate
provided 18.[16] Finally, sequential Staudinger-type aziridine
formation and ammonolysis of both cyclic carbonate and
acetate units in 19 produced the target (ꢀ )-1a, which was
spectrally and chromatographically identical to authentic
material.
Scheme 2. Presumed mechanism for the homo-Brook aziridine fragmen-
tation.
Aldehyde (ꢀ )-3[11] reacted with the organometallic species
arising through the interaction of lithiated allyltrimethylsilane
and [Ti(iPrO)4],[12] and represented simply in Scheme 3 as 4,
to furnish adduct 5 as a diastereomerically homogeneous
1
product (by H NMR spectroscopy). The relative configura-
tion of this intermediate[13] suggests that the addition process
occurred with essentially complete Cram Felkin selectivity
(see 5, descriptor ™C-F∫) within the manifold of a Zimmer-
man Traxler-type cyclic transition state (descriptor ™Z-T∫).
The simultaneous presence of an activated double bond (the
allylsilane) and of a 1,3-dipole (the azido group) in 5
engendered a smooth intramolecular cycloaddition upon
heating in toluene. Triazoline 6 thus emerged as a single
1
diastereomer (by H NMR spectroscopy). Brief photolysis of
6
[14] provided aziridine 7,[13] which underwent a homo-Brook-
triggered fragmentation to form benzazocenol 8. This crucial
eight-membered N-heterocycle was thus assembled in just
four steps in a fully diastereocontrolled manner from readily
available 3.
Substances of the type 8 are known intermediates for the
synthesis of FR900482 and of mitomycinoids,[6] except that
their construction normally requires considerably longer
sequences; hence, the interest of the new methodology. To
In summary, the homo-Brook-mediated aziridine fragmen-
tation avenue to medium-sized N-heterocycles can be used to
prepare molecules of at least moderate complexity (e.g. 1a).
The applicability of the new method to the construction of
other mitomycinoids, as well as further simplifications of the
Angew. Chem. Int. Ed. 2002, 41, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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4689

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[4] a) T. Fukuyama, S. Goto, Tetrahedron Lett. 1989, 30, 6491; b) R. M.
Williams, S. R. Rajski, Tetrahedron Lett. 1992, 33, 2929; c) R. M.
Williams, S. R. Rajski, Tetrahedron Lett. 1993, 34, 7023; d) H. Huang,
S. R. Rajski, R. M. Williams, P. B. Hopkins, Tetrahedron Lett. 1994, 35,
9669; e) J. Woo, S. T. Sigurdsson, P. B. Hopkins, J. Am. Chem. Soc.
1993, 115, 1199; f) H. Huang, T. K. Pratum, P. B. Hopkins, J. Am.
Chem. Soc. 1994, 116, 2703; g) M. M. Paz, P. B. Hopkins, Tetrahedron
Lett. 1997, 38, 343; h) M. M. Paz, P. B. Hopkins, J. Am. Chem. Soc.
1997, 119, 5999; i) R. M. Williams, S. R. Rajski, Chem. Biol. 1997, 4,
127; j) L. Beckerbauer, J. J. Tepe, R. A. Eastman, P. Mixter, R. M.
Williams, R. Reeves, Chem. Biol. 2002, 9, 427; k) L. Beckerbauer, J.
Tepe, J. Cullison, R. Reeves, R. M. Williams, Chem. Biol. 2000, 7, 805;
l) R. M. Williams, S. R. Rajski, J. Am. Chem. Soc. 1998, 120, 2192;
m) T. C. Judd, R. M. Williams, Org. Lett. 2002, 4, 3711.
[5] a) K. Shimomura, T. Manda, S. Mukumoto, K. Masuda, T. Nakamura,
T. Mizota, S. Matsumoto, F. Nishigaki, T. Oku, J. Mori, F. Shibayama,
Cancer Res. 1988, 48, 1166; b) T. Nakamura, K. Masuda, S. Matsu-
moto, T. Oku, T. Manda, J. Mori, K. Shimomura, Jpn. J. Pharmacol.
1989, 49, 317; c) K. Masuda, T. Nakamura, T. Mizota, J. Mori, K.
Shimomura, Cancer Res. 1988, 48, 5172; d) K. Masuda, T. Nakamura,
K. Shimomura, J. Antibiot. 1988, 41, 1497; e) Y. Naoe, M. Inami, S.
Matsumoto, F. Nishigaki, S. Tsujimoto, I. Kawamura, K. Miyayasu, T.
Manda, K. Shimomura, Cancer Chemother. Pharmacol. 1998, 42, 31;
f) Y. Naoe, M. Inami, I. Kawamura, F. Nishigaki, S. Tsujimoto, S.
Matsumoto, T. Manda, K. Shimomura, Jpn. J. Cancer Res. 1998, 89,
666; g) Y. Naoe, M. Inami, S. Takagaki, S. Matsumoto, I. Kawamura, F.
Nishigaki, S. Tsujimoto, T. Manda, K. Shimomura, Jpn. J. Cancer Res.
1998, 89, 1047; h) Y. Naoe, M. Inami, S. Matsumoto, S. Takagaki, T.
Fujiwara, S. Yamazaki, I. Kawamura, F. Nishigaki, S. Tsujimoto, T.
Manda, K. Shimomura, Jpn. J. Cancer Res. 1998, 89, 1306; i) Y. Naoe,
I. Kawamura, M. Inami, S. Matsumoto, F. Nishigaki, S. Tsujimoto, T.
Manda, K. Shimomura, Jpn. J. Cancer Res. 1998, 89, 1318; j) M. Inami,
I. Kawamura, S. Tsujimoto, F. Nishigaki, S. Matsumoto, Y. Naoe, Y.
Sasakawa, M. Matsuo, T. Manda, T. Goto, Cancer Lett. 2002, 181, 39;
k) M. Tomasz, R. Lipman, D. Chowdary, J. Pawlak, G. Verdine, K.
Nakanishi, Science 1987, 235, 1204; l) M. Tomasz, Chem. Biol. 1995, 2,
575, and references therein.
Scheme 4. Reagents and conditions: a) MCPBA, CH2Cl2, 08C; b) neat
Ac2O, room temperature, 87% over two steps; c) MCPBA, CH2Cl2,
NaHCO3, room temperature, 70%; d) cat. TPAP, NMO, CH2Cl2, molecular
sieves (4 ä), room temperature, 83%; e) N2H4¥H2O, MeOH, CH2Cl2,
100%; f) H2 (1 atm), Pd/C, EtOAc, 97% crude. MCPBA ¼ m-chloroper-
oxybenzoic acid, TPAP ¼ tetrapropylammonium perruthenate, NMO ¼
4-methylmorpholine N-oxide.
[6] For total syntheses of 1b, see: a) T. Fukuyama, L. Xu, S. Goto, J. Am.
Chem. Soc. 1992, 114, 383; b) J. M. Schkeryantz, S. J. Danishefsky, J.
Am. Chem. Soc. 1995, 117, 4722; c) T. Katoh, E. Itoh, T. Yoshino, S.
Terashima, Tetrahedron 1997, 53, 10229; d) T. Yoshino, Y. Nagata, E.
Itoh, M. Hashimoto, T. Katoh, S. Terashima, Tetrahedron 1997, 53,
10239; e) T. Katoh, Y. Nagata, T. Yoshino, S. Nakatani, S. Terashima,
Tetrahedron 1997, 53, 10253; see also two previous communications:
f) T. C. Judd, R. M. Williams, Angew. Chem. 2002, 114, 4877; Angew.
Chem. Int. Ed. 2002, 41, 4683; g) M. Suzuki, M. Kambe, H. Tokuyama,
T. Fukuyama, Angew. Chem. 2002, 114, 4882; Angew. Chem. Int. Ed.
2002, 41, 4688. We are grateful to Profs. Robert M. Williams and Tohru
Fukuyama for informing us of their independent syntheses of FR-
900482 and FR-66979 prior to submission of our work, and for
agreeing to have our three papers appear consecutively in this issue of
Angewandte Chemie.
[7] For synthetic studies, see: a) N. Yasuda, R. M. Williams, Tetrahedron
Lett. 1989, 30, 3397; b) R. J. Jones, H. Rapoport, J. Org. Chem. 1990,
55, 1144; c) S. J. Miller, S. H. Kim, Z. R. Chen, R. H. Grubbs, J. Am.
Chem. Soc. 1995, 117, 2108; d) T. Katoh, E. Itoh, T. Yoshino, S.
Terashima, Tetrahedron Lett. 1996, 37, 3471; e) T. Yoshino, Y. Nagata,
E. Itoh, M. Hashimoto, T. Katoh, S. Terashima, Tetrahedron Lett.
1996, 37, 3475; f) T. Katoh, T. Yoshino, Y. Nagata, S. Nakatani, S.
Terashima, Tetrahedron Lett. 1996, 37, 3479; g) H. J. Lim, G. A.
Sulikowski, Tetrahedron Lett. 1996, 37, 5243; h) F. E. Ziegler, M.
Belema, J. Org. Chem. 1997, 62, 1083; i) S. Mithani, D. M. Drew, E. H.
Rydberg, N. J. Taylor, S. Mooibroek, G. I. Dmitrienko, J. Am. Chem.
Soc. 1997, 119, 1159; j) W. Zhang, C. Wang, L. S. Jimenez, Synth.
Commun. 2000, 30, 351; k) I. M. Fellows, D. E. Kaelin, Jr., S. F.
Martin, J. Am. Chem. Soc. 2000, 122, 10781; l) M. Kambe, E. Arai, M.
Suzuki, H. Tokuyama, T. Fukuyama, Org. Lett. 2001, 3, 2575.
Scheme 5. Reagents and conditions: a) 2-Methoxypropene, PPTS, DMF,
room temperature, 83%; b) LiN3, DMF, 1008C, 67%; c) Ac2O, K2CO3,
THF, room temperature, 81%; d) MsCl, Et3N, CH2Cl2, room temperature,
71%; e) TFA, CH2Cl2, room temperature; f) COCl2, CH2Cl2, Et3N, 0 8C,
28%; g) Ph3P, iPr2NEt, aqueous THF (90%), 608C, 78%; h) NH3, MeOH,
room temperature, 40%. PPTS ¼ pyridinium p-toluenesulfonate, Ms ¼
methanesulfonyl, TFA ¼ trifluoroacetic acid.
synthetic pathway, are currently under study and will be
reported in due course.
Received: September 18, 2002 [Z50186]
[1] a) I. Uchida, S. Takase, H. Kayakiri, S. Kiyoto, M. Hashimoto, T. Tada,
S. Koda, Y. Morimoto, J. Am. Chem. Soc. 1987, 109, 4108; b) H.
Terano, S. Takase, J. Hosoda, M. Kohsaka, J. Antibiot. 1989, 42, 145.
[2] For a review, see: W. T. Bradner, Cancer Treat. Rev. 2001, 27, 35.
[3] K. Shimomura, O. Hirai, T. Mizota, S. Matsumoto, J. Mori, F.
Shibayama, H. Kikuchi, J. Antibiot. 1987, 40, 600.
[8] cf. a) M. A. Ciufolini, M. Chen.
, D. P. Lovett, M. V. Deaton,
Tetrahedron Lett. 1997, 38, 4355; b) M. A. Ciufolini, M. V. Deaton, S.
Zhu, M. Chen, Tetrahedron 1997, 53, 16299.
[9] R. Ducray, N. Cramer, M. A. Ciufolini, Tetrahedron Lett. 2001, 42,
9175.
4690
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4124-4690 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 24

COMMUNICATIONS
[10] a) P. F. Hudrlik, A. M. Hudrlik, A. K. Kulkarni, J. Am.
Chem. Soc. 1982, 104, 6809; b) P. F. Hudrlik, P. E. Holmes,
A. M. Hudrlik, Tetrahedron Lett. 1988, 29, 6395.
PPh2
PPh2
[11] Prepared from the corresponding, known 2-(2-nitroaryl)-
propanediol (see compound 24 in reference [7k]), readily
available in > 10-g batches, by: a) H2, Raney Ni; b) HONO/
NaN3; c) BnBr, NaH (facile monobenzylation); d) IBX,
H
HN
N
O
HN
N
O
O
X
O
X
P
O
O
O
O
O
DMSO, 53% overall yield; Bn
iodoxylbenzoic acid, DMSO ¼ dimethyl sulfoxide.
¼
benzyl, IBX
¼
o-
n
H
H
CH3
PPh2
PPh2
[12] M. T. Reetz, R. Steinbach, J. Westermann, R. Peter, B.
Wenderoth, Chem. Ber. 1985, 118, 1441.
2
1
[13] The relative configuration of this intermediate was inferred
from the X-ray crystal structure of compound 7.
[14] This photolysis reaction occurred most efficiently when a
Sylvania 250-W suntanning lamp was used as the light
source (water-cooled pyrex reactor). A standard Hanovia
lamp produced less satisfactory results.
a: X, X=H, H
b: X, X=OH, OH
c: X, X=O(CH3)2CO
[15] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639.
[16] The relative configuration of the bridged system of this
substance was not determined.
Polymer-Supported C2-Symmetric
Ligands for Palladium-Catalyzed
baseline, the reaction was performed in normal solution phase
with the simple ligands 1a and 1b. Table 1, entries 1 and 2,
reveals the effectiveness of this class of ligands. It is somewhat
surprising that a small dip in enantiomeric excess (ee) occurs
on introducing electronegative oxygen atoms into the remote
bridge (91 to 87% ee). The supported ligand 2 was effective in
performing the reaction but there was a more significant drop
in enantiomeric excess (Table 1, entry 3) although it was still
reasonable. Simply decanting the reaction mixture from the
solid support and washing the beads with fresh THF prepared
the beads for the next cycle. No additional palladium was
loaded after the initial charge. The yield dipped in the second
cycle but subsequently stabilized at 60 ꢀ 5%. Thus, the
supported catalyst was quite robust remaining highly active
even after seven cycles (Table 1, entries 3 9). The enantio-
meric excess also remained quite constant through most of the
cycles at 70 ꢀ 1%. In earlier experiments with normal solution
ligands, addition of triethylamine led to a significant enhance-
Asymmetric Allylic Alkylation Reactions**
Barry M. Trost,* Zhengying Pan, Jorge Zambrano,
and Christof Kujat
Development of immobilized ligands/catalysts for asym-
metric synthesis is a rapidly growing field.[1] Because of
palladium©s broad applications in organic synthesis,[2] many
types of supported ligands have been reported for allylic,[3]
alkylation,[4] amination, and cross-coupling reactions.[5] How-
ever, there are surprisingly few successful polymer-bound
ligands for palladium-catalyzed asymmetric allylic alkyla-
tions.[6,7] In the late 1970s, we demonstrated the use of
polymer-bound phosphane ligands in Pd-catalyzed transfor-
mations.[8] We here report a competent, easily prepared,
recyclable chiral ligand for asymmetric allylic alkylation
(AAA) reactions.
Initially, we examined the supported ligand 2, which was
derived from the rigid bicyclic templates 1[9] to minimize any
perturbation of the chiral pocket. The supported ligand 2
formed readily by reacting the diol 1b with ArgoGel-CHO
catalyzed by p-toluenesulfonic acid (TsOH) in dichlorome-
thane. Cyclization of the bisurethane 3a to the oxazolidin-2-
one 4a[10,11] was examined as the test reaction [Eq. (1)]. As a
Table 1. First-generation bicyclic ligands.[a]
Entry
Ligand
Run
Yield
of 4a [%]
ee[b]
[%]
[d]
[d]
1[c]
2[c]
3
4
5
6
7
8
1a
1c
2
2
2
2
2
2
69
79
81
74
70
63
63
60
66
78
91
87
73
71
70
71
69
70
69
68
1
2
3
4
5
6
[*] Prof. B. M. Trost, Z. Pan, J. Zambrano, C. Kujat
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (þ 1)650-725-0259
9
10
2
2
7
[d]
E-mail: bmtrost@stanford.edu
[a] All reactions were performed with 10 mol% [{h3-C3H5PdCl}2] and
25 mol% ligand in THF at room temperature; the vessel was shaken for
mixing unless otherwise indicated. [b] Determined by chiral HPLC in an
AD chiralpak column. [c] Performed with 2.5 mol% [{h3-C3H5PdCl}2],
7.5 mol% ligand in THF at room temperature with normal magnetic
stirring for mixing. [d] Not applicable. [e] Triethylamine added.
[**] We thank the National Science Foundation and the National Institute
of Health, General Medical Sciences (GM13598), for their generous
support of our programs. We thank Argonaut Technologies for a
generous gift of ArgoGel resins.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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