Enantioselective modular synthesis of 2,4-disubstituted cyclopentenones by iridium-catalyzed allylic alkylation

Article abstract of DOI:10.1002/anie.200503945

Classy combo: Together, the asymmetric indium-catalyzed allylic alkylation and ruthenium-catalyzed ring-closing metathesis lead to an efficient synthesis of chiral cyclopentenones (see scheme). One example is the synthesis of the antitumor agent TEI-9826

Full text of DOI:10.1002/anie.200503945

Communications
Synthetic Methods
DOI: 10.1002/anie.200503945
Enantioselective Modular Synthesis of
2,4-Disubstituted Cyclopentenones by Iridium-
Catalyzed Allylic Alkylation**
Mathias Schelwies, Pierre Dübon, and
Günter Helmchen*
Cyclopentenones are important structural motifs of natural
products and pharmaceuticals.[1] Their stereoselective syn-
thesis remains a challenge because of the numerous possible
substitution patterns.[2] Here we report a new enantioselective
method for the synthesis of 2,4-disubstituted cyclopentenones
and its application in the synthesis of some interesting targets.
Cyclopentenones are also of interest as intermediates,
because of their suitability for reactions at position 3 with
nucleophiles and at position 5 with electrophiles; thus,
numerous
further
functionalizations
are
possible
(Scheme 1).[3]
Scheme 1.
The new method is based on the following concept
(Scheme 2): a) Iridium-catalyzed allylic alkylation using the
enolate of amide 1, a new prenucleophile, leads to a new
chirality center having an adjacent vinyl group with high
enantioselectivity.[4] b) The Weinreb-type[5] amide group
allows facile conversion of the alkylation product into an
enone. c) Finally, the enone can be cyclized by Ru-catalyzed
ring-closing metathesis (RCM).[6] The combination of metal-
catalyzed allylic alkylation and ring-closing metathesis is
already known as a method for the construction of cyclic
compounds;[4f,7] however, it has not yet found broad applica-
tion in organic synthesis.
Over the last few years iridium-catalyzed allylic alkylation
À
has evolved into a reliable method for enantioselective C C
bond formation.[4] The phosphorus amidite ligands, intro-
duced by Alexakis and Feringa,[4g,8] have proved to be
[*] M. Schelwies, P. Dübon, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut der Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-544-205
E-mail: g.helmchen@oci.uni-heidelberg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623), the Degussa Stiftung, and the Studienstiftung des
deutschen Volkes. We thank Sandra Dreisigacker for her assistance,
Dr. K. Ditrich (BASF AG) for enantiomerically pure 1-arylethyl-
amines, and Dr. G. Egri (Reuter Chemischer Apparatebau KG) for a
sample of (S)-binol.
2466
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 2466 –2469

Angewandte
Chemie
Table 1: Iridium-catalyzed allylic alkylation of carbonates 2a–c according
toScheme 3 (cf. Experimental Section).
Entry
Substr.
L*
t[a] [h] Yield
3+4 [%][b]
3/4[c]
ee (3) [%][d]
(abs. config.)
1
2a
2a
L1
L2
L1
L2
L1
L2
1
0.5
3
2
18
5.5
89
>98:2
>98:2
94:6
94:6
83:17
84:16
96 (R)
98 (R)
95 (R)
95 (R)
96 (R)
99 (R)
2[e]
3[e]
4
88
83
76
89
62
2b[f]
2b[f]
2c[f]
2c[f]
5
6[e]
[a] Reaction time. [b] Yield of the isolated mixture of the regioisomeric
products 3 and 4. [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by HPLC on a chiral column (Daicel Chiralcel AD-H, 250”
4.6 mm, 5 mm with guard cartridge AD-H, 10”4 mm, 5 mm,
0.5 mLminÀ1). In all cases the branched compounds 3 were obtained
as 1:1 mixtures of diastereoisomers; therefore, in each case the
chromatograms displayed four peaks. All given absolute configurations
refer to the starred chirality center in Scheme 3. Compounds 4 were
racemic. Chromatographic conditions and results (n-hexane/isopropyl
alcohol 95:5, 208C, 210 nm): tR[(S)-3a]=28 min/37 min, tR[(R)-3a]=
33 min/47 min, tR[4a]=39 min/42 min; (n-hexane/isopropyl alcohol
99:1, 208C, 210 nm): tR[(R)-3b]=36 min/43 min, tR[(S)-3b]=41 min/
47 min, tR[4b]=58 min/64 min; (n-hexane/isopropyl alcohol 99:1, 208C,
Scheme 2. Retrosynthetic concept.
particularly well suited for these reactions. Catalysts prepared
by reaction of [{Ir(cod)Cl}2] (cod = cyclooctadiene) with L1
or L2 and base (Scheme 3) induce very high activity and
220 nm):
tR[(R)-3c]=26 min/28 min,
tR[(S)-3c]=27 min/32 min,
tR[4c]=31 min/32 min. [e] Reaction was conducted with 0.02 equiv of
the Iridium catalyst. [f] The substrate contained 2–3% of the cis
diastereoisomer.
disubstituted cyclopentenones in overall yields of > 50%
(Scheme 4, Table 2). Saponification/decarboxylation gave the
amides 5, and in the next step, reaction with Grignard
reagents, the enones 6 were obtained with various substitu-
ents in position 2. Subsequent ring-closing metathesis using
Grubbsꢀ second-generation catalyst[11] afforded cyclopente-
nones 7–11 (Table 2); side products formed from regioisom-
ers 4 could be separated off easily. The enantiomeric excesses
of compounds 3 and those of the corresponding cyclopente-
nones were identical to within the accuracy of measurement;
in other words, the ring-closing metathesis proceeds without
Scheme 3. Allylic substitution using a malonic amide of the Weinreb-
type derived from dimethyl malonate.
selectivity (see Experimental Section). In these reactions,
iridacycles are formed by C H activation.[4d,9] We applied this
À
method to study allylic alkylations with the enolate of
compound 1 as a new nucleophile (Scheme 3). Absolute
configurations of the products were assigned in analogy to the
results of previously investigated substitutions with malonates
and amides as nucleophiles. To date, the steric course of all
substitutions yielding a product with known absolute config-
uration was found to be independent of the nucleophile.[10]
The results displayed in Table 1 demonstrate that the
alkylations were fast as well as highly regio- and enantiose-
lective. The enolate of 1 shows reactivity and selectivity
similar to that of enolates of malonic esters, which are the
standard nucleophiles employed in allylic alkylations. Prod-
ucts 3 were formed as 1:1 mixtures of diastereoisomers, which
were neither separated nor characterized because of facile
equilibration through enolization of the malonic amide part
of the molecule. Enantiomeric excesses were found to be in
the range of 95–99% ee and regioselectivities, in the range of
3/4 = 83:17 to 98:2.
The mixtures of the substitution products 3 and 4 could be
smoothly converted in three steps into the corresponding 2,4-
Scheme 4. Synthesis of chiral cyclopentenones.
Angew. Chem. Int. Ed. 2006, 45, 2466 –2469
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2467

Communications
Table 2: Synthesis of cyclopentenones according to Scheme 4.
subsequent aldol condensation was carried out according to a
procedure described by Kobayashi et al.[2d] and yielded the
desired prostaglandin analogue TEI-9826 with 95% ee
(Scheme 5).
Entry Substr. R1
R2
Yield [%][a] Product
ee [%][b]
Finally, we want to direct attention to the chiral 2-
substituted cyclopentenones listed in Table 2. In prostaglan-
din and carbonucleoside chemistry these compounds are of
interest as intermediates for the synthesis of analogues.[15]
1
2
3
(R)-3a Ph
(R)-3a Ph
(R)-3b Me
H
66
97
Ph 55
96
95
Experimental Section
General procedure for the iridium-catalyzed allylic alkylation: A
solution of the nucleophile was prepared by the dropwise addition of
malonic amide 1 (1.3 mmol) to a suspension of NaH (1.3 mmol) in
anhydrous THF (4.0 mL) (solution A).
Me 44[c]
Under an argon atmosphere, a solution of [{Ir(cod)Cl}2] (13.4mg,
0.02 mmol) and L1 or L2 (0.04mmol) in anhydrous THF (1.0 mL,
content of water < 50 mgmLÀ1, Karl Fischer titration) was treated
with tetrahydrothiophene (18 mL, 0.20 mmol) and 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD, 11.1 mg, 0.08 mmol), and the mixture was
stirred for 2 h. Then substrate 2 (1.0 mmol), CuI (38 mg, 0.20 mmol),
and solution A were added, and the mixture was stirred for the time
given in Table 1; conversion was monitored by thin-layer chromatog-
raphy. After complete conversion had been reached, Et2O (5 mL) and
saturated NH4Cl solution (5 mL) were added, and the aqueous phase
was extracted with Et2O (2 ” 20 mL). The combined organic phases
were washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was analyzed with respect
to the ratio 3/4 by 1H NMR spectroscopy and then subjected to flash
column chromatography (silica, petroleum ether/ethyl acetate).
Physical data of selected compounds: 10: [a]2D4 = À129 (c = 0.50,
CHCl3) (96% ee); 1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3J =
6.5 Hz, 3H, CH3), 1.19–1.44 (m, 13H, CH2(n-octyl)), 1.45–1.68 (m, 1H,
4
5
(R)-3c n-Octyl
H
56
96
(R)-3c n-Octyl Me 56
n.d.
[a] Starting from 3 + 4. [b] Determined by HPLC on a chiral column; in
each case synthesis of both enantiomers. [c] Volatile substance.
racemization. With respect to R2, there is the limitation that
with sterically demanding substituents, such as Si(CH3)3, the
ring closure by metathesis is currently not possible.
Of the examples presented in Table 2, compounds 9 and
10 deserve special comment. Enone 9 has been identified as a
volatile flavor component of dried fish.[12] A synthesis of the
nonracemic compound has not yet been described to the best
of our knowledge.
2
CH2(n-octyl)), 1.99 (dd, J5a,5b = 18.8, 3J5a,4 = 2.1 Hz, 1H, 5-Ha), 2.52 (dd,
3
2J5b,5a = 18.8, J5b,4 = 6.3 Hz, 1H, 5-Hb), 2.86–2.96 (m, 1H, 4-H), 6.13
(dd, 3J2,3 = 5.7, J = 2.0 Hz, 1H, CH ), 7.63 ppm (dd 3J3,2 = 5.6, J =
=
2.4Hz, 1H, CH ); 13C NMR (75 MHz, CDCl3): d = 14.22 (q, CH3),
=
22.78, 27.75, 29.36, 29.58, 29.73, 31.97, 34.89 (7 t, CH2(n-octyl)), 41.20 (t,
C-5), 41.63 (d, C-4), 133.68, 168.82 (2 d, C-2, C-3), 210.23 ppm (s, C-1).
TEI-9826: [a]2D0 = À121 (c = 0.58, CHCl3) (95% ee); 1H NMR
3
(500 MHz, CDCl3): d = 0.87 (t, J20,19 = 7.1 Hz, 3H, 20-H), 1.18–1.33
Compound 10 (entry 4in Table 2) is a particularly
interesting target in the area of synthesis of biologically
active compounds as it offers a fast access to the prostaglandin
analogue TEI-9826, a 5-alkylidene-4-alkyl-2-cyclopentenone
that displays high anticancer activity against cisplatin-resist-
ant tumors (Scheme 5).[13] Enone 10 has already been
synthesized as a racemate and as an enantiomerically pure
compound starting from (S)-but-3-yn-2-ol (> 98% ee), which
was obtained by resolution.[14] In our synthesis, the mixture of
the regioisomers 3c/4c, which was obtained by allylic
alkylation (Table 1, entry 3), was transformed directly into
cyclopentenone 10 (cf. Scheme 4). This was obtained in 56%
overall yield with an enantiomeric purity of 96% ee. The
(m, 12H, CH2), 1.34–1.42 (m, 2H, CH2), 1.45–1.55 (m, 3H, CH2),
1.58–1.68 (m, 2H, CH2), 1.75–1.85 (m, 1H, CH2), 2.18–2.32 (m, 4H, 2-
H, 6-H), 3.46 (m, 1H, 12-H), 3.66 (s, 3H, OCH3), 6.32 (dd, 3J10,11 = 6.0,
3
4J10,12 = 2.0 Hz, 1H, 10-H), 6.51 (t, J7,6 = 7.8 Hz, 1H, 7-H), 7.53 ppm
(dd, 3J11,10 = 6.0, 3J11,12 = 2.0 Hz, 1H, 11-H); 13C NMR (125 MHz,
CDCl3): 14.22 (q, C-20), 22.77, 24.86, 26.01, 28.48, 29.04, 29.05, 29.36,
29.58, 29.91, 31.97, 32.61, 34.04 (12 t, C-2, C-3, C-4, C-5, C-6, C-13, C-
14, C-15, C-16, C-17, C-18, C-19), 43.46 (d, C-12), 51.63 (q, OCH3),
134.92 (d, C-10), 135.33 (d, C-7), 138.25 (s, C-8), 162.12 (d, C-11),
174.17, 197.11 ppm (2s, C-1, C-9).
Received: November 7, 2005
Published online: March 9, 2006
Keywords: allylic substitution · cyclopentenones ·
.
enantioselectivity · iridium · ring-closing metathesis
[1] a) S. M. Roberts, M. G. Santoro, E. S. Sickle, J. Chem. Soc.
Perkin Trans. 1 2002, 1735 – 1742; b) M. Iqbal, P. Evans, A.
Lledó, X. Verdaguer, M. A. Pericàs, A. Riera, C. Loeffler, A. K.
Sinha, M. J. Mueller, ChemBioChem 2005, 6, 276 – 280; c) A.
Rossi, P. Kapahi, G. Natoli, T. Takahashi, Y. Chen, M. Karin,
M. G. Santoro, Nature 2000, 403, 103 – 108.
Scheme 5. Synthesis of TEI-9826 from (À)-(S)-10. LDA=lithium diiso-
propylamide, Ms=methanesulfonyl.
2468 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 2466 –2469

Angewandte
Chemie
[2] a) Review: S. E. Gibson, S. E. Lewis, N. Mainolfi, J. Organomet.
Chem. 2004, 689, 3873 – 3890; b) K. Tanaka, G. C. Fu, J. Am.
Chem. Soc. 2002, 124, 10296 – 10297; c) X. Shi, D. J. Gorin, F. D.
Toste, J. Am. Chem. Soc. 2005, 127, 5802 – 5803; d) Y. Kobayashi,
M. G. Murugesh, M. Nakano, E. Takahisa, S. B. Usmani, T.
Ainai, J. Org. Chem. 2002, 67, 7110 – 7123; e) C. Schultz-
Fademrecht, M. A. Tius, S. Grimme, B. Wibbeling, D. Hoppe,
Angew. Chem. 2002, 114, 1610 – 1612; Angew. Chem. Int. Ed.
2002, 41, 1532 – 1534; f) C. P. Davie, R. L. Danheiser, Angew.
Chem. 2005, 117, 6017 – 6020; Angew. Chem. Int. Ed. 2005, 44,
5867 – 5870.
[3] a) H. Grebe, A. Lange, H. Riechers, K. Kieslich, W. Viergutz, P.
Washausen, E. Winterfeldt, J. Chem. Soc. Perkin Trans. 1 1991,
2651 – 2655; b) M. Suzuki, Y. Morita, H. Koyano, M. Koga, R.
Noyori, Tetrahedron 1990, 46, 4809 – 4822.
[4] a) B. Bartels, G. Helmchen, Chem. Commun. 1999, 741 – 742;
b) B. Bartels, C. Garcia-Yebra, F. Rominger, G. Helmchen, Eur.
J. Inorg. Chem. 2002, 2569 – 2586; c) B. Bartels, C. Garcia-Yebra,
G. Helmchen, Eur. J. Org. Chem. 2003, 1097 – 1103; d) G.
Lipowsky, N. Miller, G. Helmchen, Angew. Chem. 2004, 116,
4695 – 4698; Angew. Chem. Int. Ed. 2004, 43, 4595 – 4597; e) A.
Alexakis, D. Polet, Org. Lett. 2004, 6, 3529 – 3532; f) S. Streiff, C.
Welter, M. Schelwies, G. Lipowsky, N. Miller, G. Helmchen,
Chem. Commun. 2005, 2957 – 2959; g) D. Polet, A. Alexakis,
Org. Lett. 2005, 7, 1621 – 1624.
[5] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 – 3818.
[6] For the construction of cyclopentenones from enones by RCM
see: a) A. K. Chatterjee, J. P. Morgan, M. Scholl, R. H. Grubbs,
J. Am. Chem. Soc. 2000, 122, 3783 – 3784; b) A. Wrobleski, K.
Sahasrabudhe, J. Aubꢁ, J. Am. Chem. Soc. 2004, 126, 5475 – 5481;
c) F. A. Davis, Y. Wu, Org. Lett. 2004, 6, 1269 – 1272; d) C. L.
Chandler, A. J. Phillips, Org. Lett. 2005, 7, 3493 – 3495.
[7] a) Pd: B. M. Trost, C. Jiang, Org. Lett. 2003, 5, 1563 – 1565;
b) Rh: P. A. Evans, L. J. Kennedy, Tetrahedron Lett. 2001, 42,
7015 – 7018; c) Cu: K. Tissot-Croset, D. Polet, A. Alexakis,
Angew. Chem. 2004, 116, 2480 – 2482; Angew. Chem. Int. Ed.
2004, 43, 2426 – 2428.
[8] a) B. L. Feringa, Acc. Chem. Res. 2000, 33, 346 – 353; b) K.
Tissot-Croset, D. Polet, S. Gille, C. Hawner, A. Alexakis,
Synthesis 2004, 2586 – 2590.
[9] C. A. Kiener, C. Shu, C. Incarvito, J. F. Hartwig, J. Am. Chem.
Soc. 2003, 125, 14272 – 14273.
[10] R. Weihofen, A. Dahnz, O. Tverskoy, G. Helmchen, Chem.
Commun. 2005, 3541 – 3543.
[11] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
[12] I. Yajima, M. Nakamura, H. Sakakibara, J. Ide, T. Yanai, K.
Hayashi, Agric. Biol. Chem. 1983, 47, 1755 – 1760.
[13] S. Fukushima, Y. Takeuchi, S. Kishimoto, S. Yamashita, K.
Uetsuki, S. Shirakawa, M. Suzuki, K. Furuta, R. Noyori, H.
Sasaki, Y. Kikuchi, T. Kita, T. Yamori, J. Sawada, M. Kojima, A.
Hazato, S. Kurozumi, M. Fukushima, Anti-Cancer Drugs 2001,
12, 221 – 234.
[14] a) Racemate: M. Iqbal, P. Evans, Tetrahedron Lett. 2003, 44,
5741 – 5745; b) Compound with > 98% ee: R. Weaving, E.
Roulland, C. Monneret, J.-C. Florent, Tetrahedron Lett. 2003,
44, 2579 – 2581.
[15] Y. Che, J. B. Gloer, D. T. Wicklow, J. Nat. Prod. 2002, 65, 399 –
402.
Angew. Chem. Int. Ed. 2006, 45, 2466 –2469
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2469