An intramolecular Pauson-Khand approach to the synthesis of chiral cyclopentadienes

Article abstract of DOI:10.1016/S0040-4039(01)02328-0

A procedure for the synthesis of chirally-substituted cyclopentadienes has been developed by employing the intramolecular Pauson-Khand reaction of chiral amides derived from 8-nonen-2-ynoic acid. Hydride-mediated reduction of the resulting cyclopentenone adducts followed by acid-catalysed dehydration leads to the formation of the corresponding cyclopentadienes in good overall yield.

Full text of DOI:10.1016/S0040-4039(01)02328-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1023–1026
An intramolecular Pauson–Khand approach to the synthesis of
chiral cyclopentadienes
Ramon Rios, Albert Moyano* and Miquel A. Perica`s*
Unitat de Recerca en S´ıntesi Asime`trica, Departament de Qu´ımica Orga`nica, Universitat de Barcelona, c/Mart´ı i Franque`s, 1-11,
08028 Barcelona, Spain
Received 4 December 2001; revised 5 December 2001; accepted 6 December 2001
Abstract—A procedure for the synthesis of chirally-substituted cyclopentadienes has been developed by employing the intramolec-
ular Pauson–Khand reaction of chiral amides derived from 8-nonen-2-ynoic acid. Hydride-mediated reduction of the resulting
cyclopentenone adducts followed by acid-catalysed dehydration leads to the formation of the corresponding cyclopentadienes in
good overall yield. © 2002 Elsevier Science Ltd. All rights reserved.
Although chirally-substituted cyclopentadienes are very
popular ligands both in organometallic chemistry and
in asymmetric catalysis,1 the preparation of these com-
pounds in enantiomerically pure form is not straight-
forward and is usually achieved either by resolution of
racemic mixtures or by multi-step syntheses from natu-
ral products.2 On the other hand, 2-cyclopentenones are
convenient starting materials for substituted cyclopen-
tadienes, and in the past few years the Pauson–Khand
reaction (a most efficient tool for the construction of a
cyclopentenone unit by the cobalt-mediated assembly
of an alkyne, an alkene, and carbon monoxide)3 has
been used in several instances for the synthesis of
substituted cyclopentadienes.4,5 Up to now, however, all
of the Pauson–Khand adducts used for this purpose
have been obtained in racemic form from achiral pre-
cursors. We disclose herein a short and convenient
approach to chirally-substituted, enantiopure cyclopen-
tadienes, that is based on the intramolecular Pauson–
Khand reaction of chiral amides derived from enynoic
acids.
In the course of our studies on the Pauson–Khand
reactivity of electron-deficient alkynes,6,7 we discovered
that under appropriate reaction conditions the cobalt-
mediated cyclisation of N-(8-nonen-2-ynoyl)oxazolidi-
nones 1 takes place with high yields (Scheme 1).7 How-
ever, the resulting Pauson–Khand adducts 2 did not
prove to be suitable for further elaboration into
cyclopentadiene derivatives, since all of our attempts at
effecting nucleophilic addition reactions at the
cyclopentenone carbonyl led either to the recovery of
starting materials (DIBAL, MeMgBr, PhLi, nBuLi) or
to complete degradation (NaBH4/CeCl3,8 lithium
aminoborohydrides9).
We decided therefore to reduce the functional group
complexity in our adducts, and we thought that the use
Scheme 1.
Keywords: cyclopentadienes; cyclopentenones; Pauson–Khand reactions.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02328-0

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R. Rios et al. / Tetrahedron Letters 43 (2002) 1023–1026
of chiral amides instead of N-acyloxazolidinones would
be a reasonable choice. To that effect, we prepared the
8-nonen-2-ynamides 3a and 3b, derived from (S)-2-
determined by HPLC) were obtained in satisfactory
yields, together with small amounts of the exocyclic
dienes 5a and 5b,13,14 that were easily separated from
the corresponding cyclopentenones by column
chromatography.
(methoxymethyl)pyrrolidine10
and
from
(S)-2-
phenylethylamine, respectively, by treatment of
8-nonen-2-ynoic acid7 with N-hydroxysuccinimide (1.2
equiv.), N,N%-dicyclohexylcarbodiimide (1.2 equiv.) and
the corresponding amine (1.0 equiv.) in dioxane at
room temperature.11 In this way, after chromatographic
purification 3a and 3b were isolated in 86 and 79%
yield, respectively. Optimal conditions for the Pauson–
Khand cyclisation of 3a and 3b (Scheme 2) consisted of
heating their dicobalt hexacarbonyl complexes (pre-
pared in situ by treatment of the enynes with a slight
excess of dicobalt octacarbonyl) in toluene in the pres-
ence of DMSO (10 equiv.).12 The expected cycloadducts
4a and 4b (both as a 1:1 diastereomer mixture, as
We were next pleased to find that, unlike their oxazo-
lidinone counterparts 2a,b, hydride-mediated carbonyl
reduction of the enones 4a and 4b took place unevent-
fully, giving rise to the allylic alcohols 6a and 6b in 80
and 76% yield, respectively (Scheme 3). It is worth
noting that while the best results for the reduction of 4a
were achieved by means of Luche’s reagent,8 these
reaction conditions, when applied to 4b, afforded 6b in
only 42% yield, together with some overreduction prod-
ucts; on the other hand, treatment of 4a with diisobutyl-
aluminum hydride (that proved to be a totally selective
Scheme 2.
Scheme 3.

R. Rios et al. / Tetrahedron Letters 43 (2002) 1023–1026
1025
reagent for the reduction of 4b) led to exclusive forma-
tion of the saturated ketone 8a. Finally, when both 6a
and 6b were submitted to acid-catalysed dehydration,
the rather unstable, chirally-substituted cyclopentadi-
enes 7a and 7b were obtained in good yields (73 and
79%, respectively).
6. (a) Fonquerna, S.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron 1995, 51, 4239–4254; (b) Fonquerna, S.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Am. Chem. Soc.
1997, 119, 10225–10226; (c) Balsells, J.; Moyano, A.;
Riera, A.; Perica`s, M. A. Org. Lett. 1999, 1, 1981–1984.
7. Fonquerna, S.; Rios, R.; Moyano, A.; Perica`s, M. A.;
Riera, A. Eur. J. Org. Chem. 1999, 3459–3478.
In summary, we have disclosed a short, high-yielding
route to chirally-substituted cyclopentadienes, that
takes place in only four steps from readily available
chiral amines.15,16 Ongoing work in our laboratories is
directed towards the preparation of enantiopure metal
complexes derived from these ligands.17
8. Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1974, 23,
4187–4189.
9. Fisher, G. B.; Harrison, J.; Fuller, J. C.; Goralski, C. T.;
Singaram, B. Tetrahedron Lett. 1992, 33, 4533–4536.
10. Enders, D.; Fey, H.; Kipphardt, H. Org. Synth. 1987, 65,
173–182.
11. Coppola, G. M.; Damon, R. E. Synth. Commun. 1993,
23, 2003–2010.
Acknowledgements
12. For the use of DMSO as a promoter of the Pauson–
Khand reaction, see: (a) Chung, Y. K.; Lee, B. Y.; Jeong,
N.; Hudecek, M.; Pauson, P. L. Organometallics 1993,
12, 220–223; (b) Stumpf, A.; Jeong, N.; Sunghee, H.
Synlett 1997, 205–207.
We are grateful to DGI/DGES (grants BQU2000-0648
and PB96-0376) for financial support. R.R. thanks the
Ministerio de Educacio´n y Cultura for a pre-doctoral
fellowship.
13. The (E) stereochemistry of compounds 5a and 5b was
ascertained by means of NOE experiments.
14. For previous reports on the formation of exocyclic 1,3-
dienes in Pauson–Khand cyclisations of enynes, see: (a)
Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetra-
hedron Lett. 1990, 31, 5289–5292; (b) Krafft, M. E.;
Wilson, A. M.; Dasse, O. A.; Bon˜aga, L. V. R.; Cheung,
Y. Y.; Fu, Z.; Shao, B.; Scott, I. Tetrahedron Lett. 1998,
39, 5911–5914; (c) Mukai, C.; Kim, J. S.; Sonobe, H.;
Hanaoka, M. J. Org. Chem. 1999, 64, 6822–6832; (d)
Pagenkopf, B. L.; Belanger, D.; O’Mahony, D. J. R.;
Livinghouse, T. Synthesis 2000, 1009–1019; (e) Jeong, N.;
Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122,
6771–6772.
References
1. (a) Coates, G. W.; Waymouth, R. M. In: Comprehensive
Organometallic Chemistry II; Abel, E. W.; Stone, F. G.
A.; Wilkinson, G.; Hegedus, L. S., Eds.; Pergamon Press:
Oxford, 1995; Vol. 12, Chapter 12, pp. 1193–1208; (b)
Applied Homogeneous Catalysis with Organometallic
Compounds; Cornils, B.; Herrmann, W. A., Eds.; VCH:
Weinheim, 1996; (c) Metallocenes; Togni, A.; Halterman,
R. L., Eds.; Wiley-VCH: New York, Weinheim, 1998; (d)
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer-Verlag: Berlin,
Heidelberg, New York, 1999 (3 Vols.).
15. All previously unknown compounds were completely
characterised and gave satisfactory spectral and/or ana-
lytical data. Selected data: (3a) 1H NMR (300 MHz,
CDCl3, TMS): l=5.9–5.7 (m, 1H), 5.1–4.9 (m, 2H), 4.25
(m, 1H), 3.75–3.4 (m, 4H), 3.36/3.34* (s, 3H), 2.35 (m,
2H), 2.2–1.8 (m, 6H), 1.7–1.5 (m, 4H) ppm; 13C NMR
(75 MHz, CDCl3, TMS): l=153.2/153.1* (Cq), 138.2
(CH), 114.8/114.7* (CH2), 91.3/91.1* (Cq), 75.2/75.1*
(Cq), 73.7/72.0* (CH2), 59.6 (CH3), 58.2/58.1* (CH), 48.8
(CH2), 45.5 (CH2), 33.00/32.98* (CH2), 27.91/27.87*
(CH2), 27.15/27.12* (CH2), 23.6/22.4 (CH2), 18.6 (CH2)
ppm; IR (NaCl): w=2242, 1744, 1626 cm−1; MS (CI,
NH3) m/e: 250 (M+1, 100%), 267 (M+18, 6%). HRMS
calcd for C15H24NO2: 250.1807. Found: 250.1811. (3b) 1H
NMR (300 MHz, CDCl3, TMS): l=7.4–7.2 (m, 5H),
6.2–6.1 (br, 1H), 5.9–5.7 (m, 1H), 5.2 (m, 1H), 5.1–4.9
(m, 2H), 2.27 (t, J=7.2 Hz, 2H), 2.1 (m, 4H), 1.6–1.4 (m,
5H) ppm; 13C NMR (75 MHz, CDCl3, TMS): l=152.6
(Cq), 138.2 (CH), 128.7 (CH), 127.5 (CH), 126.2 (CH),
125.7 (Cq), 114.8 (CH2), 87.2 (Cq), 75.9 (Cq), 49.1 (CH),
33.0 (CH2), 27.9 (CH2), 27.1 (CH2), 21.4 (CH2), 18.4
2. (a) Okuda, J. Top. Curr. Chem. 1991, 160, 97–145; (b)
Halterman, R. L. Chem. Rev. 1992, 92, 965–994.
3. Reviews on the Pauson–Khand reaction: (a) Schore, N.
E. Org. React. 1991, 40, 1–90; (b) Geis, O.; Schmalz, H.
G. Angew. Chem., Int. Ed. Engl. 1998, 37, 911–914; (c)
Buchwald, S. L.; Hicks, F. A. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto,
H., Eds.; Springer-Verlag: Berlin, Heidelberg, New York,
1999; Vol. II, pp. 491–510; (d) Brummond, K. M.; Kent,
J. L. Tetrahedron 2000, 56, 3263–3283; (e) Sugihara, T.;
Yamaguchi, M.; Nishizawa, M. Chem. Eur. J. 2001, 7,
1589–1595.
4. (a) Buchholz, H.; Reiser, O.; de Meijere, A. Synlett 1991,
20–23; (b) Lee, B. Y.; Moon, H.; Chung, Y. K.; Jeong,
N.; Carpenter, G. B. Organometallics 1993, 12, 3879–
3884; (c) Lee, B. Y.; Moon, H.; Chung, Y. K. J. Am.
Chem. Soc. 1994, 116, 2163–2164; (d) Halterman, R. L.;
Ramsey, T. R.; Paides, N. A.; Khan, M. A. J.
Organomet. Chem. 1995, 497, 43–53; (e) Kang, Y. K.;
Lee, H.-K.; Lee, S. S.; Chung, Y. K.; Carpenter, G.
Inorg. Chim. Acta 1997, 261, 37–44; (f) Halterman, R. L.;
Ramsey, T. R. J. Organomet. Chem. 1997, 530, 225–234;
(g) Grossman, R. B. Tetrahedron 1999, 55, 919–934.
5. For the application of Negishi’s zirconium-mediated
enyne cyclisation to the synthesis of achiral substituted
cyclopentadienes, see: Takahashi, T.; Xi, Z.; Kotora, M.;
Xi, Ch. Tetrahedron Lett. 1996, 37, 7521–7524.
(CH2) ppm; IR (NaCl): w=3260, 2242, 1628, 1537 cm−1
;
MS (CI, NH3) m/e: 256 (M+1, 60%), 273 (M+18, 100%).
HRMS calcd for C17H22NO: 256.1701. Found: 256.1696.
1
(4a) H NMR (300 MHz, CDCl3, TMS): l=4.3–4.2 (m,
1H), 3.9–3.1 (m, 7H), 3.0–2.8 (m, 1H), 2.7–2.5 (m, 2H),
2.3–2.1 (m, 2H), 2.0–1.7 (m, 7H), 1.6–1.3 (m, 2H), 1.3–1.1
(m, 1H) ppm; 13C NMR (75 MHz, CDCl3, TMS): l=
203.6/203.3* (Cq), 181.9/181.8* (Cq), 164.0/163.9* (Cq),

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R. Rios et al. / Tetrahedron Letters 43 (2002) 1023–1026
136.1/136.0* (Cq), 74.2/72.1* (CH2), 59.0 (CH3), 57.6/
(M+1, 100%); HRMS calcd for C16H24NO2: 262.1807.
Found: 262.1794. (7b) 1H NMR (300 MHz, CDCl3,
TMS): l=7.8 (m, 1H), 7.4–7.2 (m, 5H), 5.6 (s, 1H), 5.2
(m, 1H), 3.4–3.0 (m, 2H), 2.9 (m, 2H), 2.3 (m, 2H),
1.8–1.6 (m, 4H), 1.5 (d, J=6.9 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3, 25°C, TMS): l=169.7 (Cq), 155.7
(Cq), 149.3 (Cq), 134.1 (Cq), 132.4 (CH), 131.1 (CH),
130.8 (Cq), 130.3 (CH), 118.4 (CH), 52.5 (CH), 44.2
(CH2), 39.4 (CH2), 33.5 (CH2), 30.5 (CH2), 30.0 (CH2),
25.7 (CH3) ppm; IR (NaCl): w=2929, 1628, 1534, 1420,
1364, 1252, 1177, 1095, 978, 818 cm−1; MS (CI, CH4)
m/e: 268 (M+1, 100%). (Signals marked with an asterisk
correspond to a rotamer or to a diastereomer.)
57.5*/56.3*/56.2* (CH), 47.8/47.7* (CH2), 45.8/45.7*
(CH2), 42.0/41.9* (CH2), 40.8/40.7* (CH), 35.0/34.8*/
34.3* (CH2), 29.5/29.4* (CH2), 28.3/28.2* (CH2), 27.6/
27.5* (CH2), 26.6/26.4* (CH2), 25.0/24.0* (CH2) ppm; IR
(NaCl): w=1701, 1626 cm−1; MS (CI, CH4) m/e: 278
(M+1, 100%); HRMS calcd for C16H24NO3: 278.1756.
Found: 278.1758. (4b) 1H NMR (300 MHz, CDCl3,
TMS): l=8.90–8.80 (m, 1H), 7.40–7.20 (m, 5H), 5.30–
5.10 (m, 1H), 4.34 (d, J=12.6 Hz, 1H), 2.75–2.55 (m,
2H), 2.30–2.00 (m, 4H), 1.90–1.10 (m, 7H) ppm; 13C
NMR (75 MHz, CDCl3, TMS): l=207.7 (Cq), 194.4/
194.3* (Cq), 161.7 (Cq), 143.7 (Cq), 128.6 (CH), 127.6
(Cq), 127.0 (CH), 126.1/126.0* (CH), 48.1/48.0* (CH),
42.0 (CH2), 41.1 (CH), 35.4/35.3* (CH2), 30.1/30.0*
(CH2), 26.9/25.1* (CH2), 22.7 (CH2), 22.6 (CH3) ppm; IR
(NaCl): w=3303, 1690, 1618 cm−1; MS (CI, CH4) m/e:
284 (M+1, 100%), 301 (M+18, 96%); HRMS calcd for
C18H22NO2: 284.1651. Found: 284.1652. (7a) 1H NMR
(300 MHz, CDCl3, TMS): l=5.6 (s, 1H), 4.3 (m, 1H),
3.8–3.2 (m, 3H), 3.3 (s, 3H), 2.6–1.4 (m, 14H). ppm; 13C
NMR (75 MHz, CDCl3, TMS): l=167.8 (Cq), 154.5
(Cq), 150.5 (Cq), 123.2 (Cq), 118.4 (CH), 72.3 (CH2),
59.3 (CH3), 56.1 (CH), 48.1 (CH2), 43.1 (CH2), 31.8
(CH2), 27.8 (CH2), 26.9 (CH2), 24.6 (CH2), 24.4 (CH2),
22.1 (CH2) ppm; IR (NaCl): w=2929, 1616, 1420, 1339,
1252, 1198, 1115, 972, 748 cm−1; MS (CI, CH4) m/e: 262
16. It is worth noting that an alternative route to 7a,b based
on the Pauson–Khand cyclisation of 8-nonen-2-ynoic
acid or of its esters and on the introduction of the chiral
amine at a later stage would be thwarted by the low
yields obtained in the Pauson–Khand reaction (see Ref.
7).
17. In a preliminary series of experiments, we have found
that the reaction of 7a with Mn2(CO)10 in refluxing
toluene gives rise to the corresponding cyclopentadienyl–
manganese tricarbonyl complex (30% yield); on the other
hand, treatment of the potassium salt of 7a with CpZrCl3
in THF afforded the expected dichlorozirconocene com-
plex (30% yield).