Remarkably high 1,5-diastereoselectivity in a nickel-catalyzed conjugate addition of Me2Zn and carbonyl compounds to 1,ω-dienynes with through-space coupling

Article abstract of DOI:10.1002/1521-3773(20020802)41:15<2784::AID-ANIE2784>3.0.CO;2-A

A four-component reaction: A nickel catalyst promotes the conjugate addition of Me₂Zn and a carbonyl compound to 1,ω-dienynes 1 at the terminal positions of the alkyne and the diene moieties, respectively; the through-space interactions of the

Full text of DOI:10.1002/1521-3773(20020802)41:15<2784::AID-ANIE2784>3.0.CO;2-A

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an indispensable strategy in synthetic chemistry.[1] Since the
pioneering work of Wilke and co-workers,[2] nickel complexes
H. Alper, Organometallics 1984, 3, 1767 1769; for enantiospecific
carbonylation, see: b) S. Calet, F. Urso, H. Alper, J. Am. Chem. Soc.
1989, 111, 931 934.
À
have been widely utilized as efficient catalysts for C C-bond
[15] For Pd-catalyzed aziridine carbonylations, see: a) H. Alper, N. Hamel,
Tetrahedron Lett. 1987, 28, 3237 3240; b) G. W. Spears, K. Nakanishi,
Y. Ohfune, Synlett 1991, 91 92; c) D. Tanner, P. Somfai, Bioorg. Med.
Chem. Lett. 1993, 3, 2415 2418.
[16] Compound 1 was first synthesized by Merola and co-workers, see:
a) J. S. Merola, K. S. Campo, R. A. Gentile, Inorg. Chem. 1989, 28,
2950 2954; b) J. S. Merola, K. S. Campo, R. A. Gentile, M. A.
Modrick, Inorg. Chim. Acta 1989, 165, 87 90.
formations.[3] Intramolecular variants such as the [4‡2] cyclo-
addition reaction of 1,w-dienynes [Eq. (1)],[4] cyclization of
1,w-bis(enones),[5] w-dienyl aldehydes,[6] and w-alkynyl
enones [Eq. (2)][7] are all useful methods for the synthesis of
rather complex cyclic molecules of physiological interest.[8]
[17] salph ˆ N,N'-bis(3,5-di-tert-butylsalicylidene)phenylenediamine. Cat-
alyst 2 is highly active for epoxide carbonylation (ref. [11]).
[18] Complexes screened for activity included Na[Co(CO)4], [Ph4P][Co-
(CO)4], [nBu4N][Co(CO)4], and [Cp2Co][Co(CO)4].
[19] During the screening phase, Na[Co(CO)4] (2 mol%, 16 h, 808C,
6900 kPa (1000 psi) CO, triglyme) reacted with propylene oxide to
give a mixture of products, yielding mostly acetone (6%) and poly(b-
hydroxybutyrate) (40%).
[20] M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science 1997,
277, 936 938.
[21] S. C. Casegreen, S. G. Davies, C. J. R. Hedgecock, Synlett 1991, 7 7 9
780.
Ni (cat.)
(1)
R
R
O
O
Ni (cat.)
R2' Zn
(2)
R'
R
R
[22] A. Griesbeck, D. Seebach, Helv. Chim. Acta 1987, 70, 1320 1325.
[23] a) D. S. Noyce, E. H. Banitt, J. Org. Chem. 1966, 31, 4043 4047; b) W.
Adam, J. Baeza, J. Liu, J. Am. Chem. Soc. 1972, 94, 2000 2006.
[24] Alper and co-workers have reported the retention of stereochemistry
in the carbonylation of 2,3-epoxybutanes (ref. [12d]), which is in
variance with our results. As the result of a typographical error
(personal communication, P. Dervan) in the literature upon which
these assignments were based (ref. [25]), we propose that the
[PPN][Co(CO)4]/BF3 ¥ OEt2 system in fact proceeds with inversion
of stereochemistry, as well.
[25] P. B. Dervan, C. R. Jones, J. Org. Chem. 1979, 44, 2116 2123.
[26] H. M. I. Osborn, J. Sweeney, Tetrahedron: Asymmetry 1997, 8, 1693
1715.
[27] D. Tanner, Angew. Chem. 1994, 106, 625 646; Angew. Chem. Int. Ed.
Engl. 1994, 33, 599 619.
We report herein the four-component reaction of dime-
thylzinc, carbonyl compounds (aldehydes, ketones), and
dienes and alkynes of 1,w-dienylalkynes 1 in the presence of
a catalytic amount of [Ni(acac)2] (acac ˆ acetylacetonato) at
room temperature to provide alkylidene cyclopentanes 2a,b
(X ˆ C(CO2Et)2) and their heterocyclic analogues 2c
e
(X ˆ O, NTs) in good yields and with excellent stereoselec-
tivity (Table 1). This four-component reaction may be re-
garded as an extended version of the reactions portrayed in
Equation (1) (a two-component coupling of a diene and an
alkyne) and in Equation (2) (a three-component coupling of
organozinc, alkyne, and enone).
The scope of the present reaction was examined with
various 1,w-dienynes 1a e (1.0 mmol) in the presence of a
catalytic amount of [Ni(acac)2] (0.1 mmol), an aldehyde or
ketone (2.0 mmol), and dimethylzinc (2.4 mmol) in dry THF
at room temperature under nitrogen. All the 1,w-dienynes
1a e were so reactive that almost all the reactions were
complete within 1 h at room temperature, irrespective of R1
and X of 1 and of the carbonyl compounds (Table 1). The
conjugate addition of [Me2Zn] and of the carbonyl compound
to 1,w-dienynes 1 occurs at the terminal positions of the
alkyne and the diene moieties, respectively; the through-
Remarkably High 1,5-Diastereoselectivity in a
Nickel-Catalyzed Conjugate Addition of
Me2Zn and Carbonyl Compounds to 1,w-
Dienynes with Through-Space Coupling**
Akihiro Ezoe, Masanari Kimura,* Takahiro Inoue,
Masahiko Mori, and Yoshinao Tamaru*
À
space interactions of the alkyne and diene groups ensure C C
coupling at the internal positions. Terminal alkyne 1a
provided 2a in moderate yield (Table 1, entry 1), whereas
internal alkynes 1b e general gave more satisfactory results
(Table 1, entries 2 11). Especially rewarding here is that the
1,w-dienynes tethered by a nitrogen (1c) or an oxygen (1d,e)
reacted with similar ease and furnished pyrrolidine and
tetrahydrofuran derivatives, respectively, in reasonable yields.
Bulky substituents around the carbonyl group either retard
the reaction (Table 1, entry 10) or cause a decrease in yield
(Table 1, entry 11). The reaction displayed a remarkably high
level of stereoselectivity (>97%, in most cases) between the
cycloalkane methine and the OH-bearing carbon centers as
well as excellent stereoselectivity (100%) with respect to the
exocyclic tri- and tetrasubstituted double bonds.[9]
Carbon carbon-bond formation is the most important and
fundamental process in organic synthesis. In particular, the
À
coupling reaction of unsaturated C C bonds mediated by low-
valent transition metals is a rapidly growing field and is now
[*] Dr. M. Kimura, Prof. Dr. Y. Tamaru, A. Ezoe, T. Inoue, M. Mori
Department of Applied Chemistry
Faculty of Engineering, Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
Fax : (‡81)95-847-9008
E-mail: masanari@net.nagasaki-u.ac.jp, tamaru@net.nagasaki-u.ac.jp
[**] We thank Y. Ohhama (NMR Facility) for technical assistance.
Financial support by the Ministry of Education, Culture, Sports,
Science, and Technology, Japanese Government, is gratefully ac-
knowledged.
The structures of 2 were tentatively assigned by analogy
with the structure of piperidine derivative 4, which was
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2002, 41, No. 15

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Table 1. Ni-catalyzed coupling reaction of 1,w-dienynes, carbonyl compounds,
Ts
H
and dimethylzinc.[a]
H
N
Ni0
TsN
R2
+
PhCHO
Ni
Ph
ZnMe2
Ni (cat.)
O
[Me2Zn]
R2CHO
Me
X
+
X
L
OH
Me
[Me2Zn]
3
R1
I
2
1
R1
Entry
1
Carbonyl
compound
t [h]
2
Yield Ratio[c]
[%][b]
Ts
H
N
H
4 + Ni0
Ni
Ph
O
Me
1
2
a
PhCHO
PhCHO
1
1
45
63
11:1
7:1
Me
ZnMe
II
Scheme 1. Plausible reaction mechanism for the Ni-catalyzed four-com-
ponent coupling reaction.
b
nickel(0) species. It is premature to discuss the origin of 1,5-
diastereoselectivity. This issue will be addressed in the near
future with the help of quantum mechanics and additional
experimental data. A scenario outlined in Scheme 1 also
agrees well with the stereoselective formation of (Z)-2a and
(Z)-2e, the structures of which were determined on the basis
of NOE experiments.
The conditions applied to the present reaction is essentially
the same as those developed in our laboratories[12] for a three-
component coupling reaction ([Me2Zn], 1,3-dienes, and
carbonyl compounds) in which [Me2Zn] and the carbonyl
compounds undergo conjugate addition to the 1,3-dienes in a
1,4-fashion and provide 3-hexenols; however, no such prod-
ucts were detected at all for all the reactions of 1 and 3
examined so far. This indicates that an alkyne is an excellent
reaction partner.
In conclusion, we have developed a nickel-catalyzed
conjugate addition reaction of [Me2Zn] and carbonyl com-
pounds to 1,w-dienynes 1 and 3, which afford cycloalkanes
and their heterocyclic analogues 2 and 4, respectively, in good
yields. The products 2 and 4 are characterized by the
stereodefined exocyclic tri- and tetrasubstituted double bonds
(100% purity) and also by the remarkably high 1,5-diaster-
eomeric purity (>97%, in most cases) with respect to C2 of
cycloalkane rings and C4 of trans-4-hydroxy-1-butenyl side
chains. Synthetic applications and further methodological
studies, including a fully intermolecular version of the present
four-component coupling reaction, that is, a coupling of four
independent reaction partners, are in progress.
3
4
5
6
c
PhCHO
PhCHO
PhCHO
1
67
71
61
89
> 30:1
> 30:1
7:1
d
e
b
0.5
1
PhCH2CH2CHO
PhCH2CH2CHO
tBuCHO
1
> 30:1
7
8
9
b
c
c
1
1
1
64
64
71
> 30:1
> 30:1
> 30:1
10
11
c
c
2
1
6712:1
33
[a] See Experimental Section for procedure. [b] Yield of isolated product. [c] The
ratio of diastereomers was determined on the basis of the 1H NMR spectra
(400 MHz).
obtained as a single diastereomer in almost quantitative yield
by reacting 3 and benzaldehyde under the standard conditions
[Eq. (3)]; to our delight, a crystalline solid was formed which
was suitable for X-ray crystallographic analysis.[10]
Experimental Section
2 f (Table 1, entry 6): Dihydrocinnamaldehyde (268 mg, 2.0 mmol) and
dimethylzinc (2.4 mL, 1m in hexane) were added successively to
a
homogeneous solution of [Ni(acac)2] (25.6 mg, 0.1 mmol) and 1b
(278 mg, 1.0 mmol) in dry THF (5 mL). The reaction mixture was stirred
at room temperature for 1 h under N2 and then quenched by the addition of
HCl (2m, 20 mL). The mixture was extracted twice with ethyl acetate. The
combined organic extract was washed with a saturated NaHCO3 solution
and a saturated NaCl solution and then dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography over silica gel
(hexane/ethyl acetate 12:1) to give 2 f (380 mg, 89%). Rf ˆ 0.56 (hexane/
ethyl acetate 2:1); IR (neat): nÄ ˆ 3480 (s), 2930 (s), 1732 (s), 1497 (m), 1252
(s), 1191 (s), 1062 (m), 972 (m), 700 (s) cmÀ1; 1H NMR (400 MHz, CDCl3,
TMS): d ˆ 1.23 (t, J ˆ 7.1 Hz, 3H), 1.24 (t,J ˆ 7.1 Hz, 3H), 1.58 (s, 3H), 1.66
(s, 3H), 1.76 (dt, J ˆ 6.2, 8.4 Hz, 2H), 2.06 (dt, J ˆ 13.7, 7.8 Hz, 1H), 2.11
(dd, J ˆ 5.1, 13.2 Hz, 1H), 2.22 (dtm, J ˆ 13.7, 5.5 Hz, 1H), 2.58 (dd,J ˆ 8.4,
13.2 Hz, 1H), 2.68 (dt, J ˆ 13.9, 8.4 Hz, 1H), 2.78 (br ddd, J ˆ 6.2, 8.4,
13.9 Hz, 1H), 2.83 (br d, J ˆ 15.3 Hz, 1H), 2.98 (br d, J ˆ 15.3 Hz, 1H), 3.35
Ph
Ni cat.
TsN
TsN
(3)
+
PhCHO
OH
[Me2Zn]
RT, 0.5 h
4 (96%)
3
A plausible reaction mechanism for the nickel(0)-catalyzed
coupling reaction is shown in Scheme 1.[11] Either a concerted
or a stepwise mechanism could be involved in the oxidative
cyclization of nickel(0) metal with aldehyde, alkyne, and diene
to give rise to intermediate I, which would then undergo
migration of a methyl group from zinc(ii) to nickel(ii) to afford
a methylvinylnickel(ii) intermediate II. The intermediate II
undergoes reductive elimination to provide 4 and an active
Angew. Chem. Int. Ed. 2002, 41, No. 15
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(br d, J ˆ 5.1 Hz, 1H), 3.60 (dddm, J ˆ 5.5, 7.8, 8.4 Hz, 1H), 4.16 (q,
J ˆ 7.1 Hz, 2H), 4.17 (q,J ˆ 7.1 z, 2H), 5.30 (br ddd, J ˆ 5.5, 7.8, 15.2 Hz,
1H), 5.39 (br dd, J ˆ 5.9, 15.2 Hz, 1H), 7.16 7.32 ppm (m, 5H);13C NMR
(100 MHz, CDCl3, TMS): d ˆ 14.1, 20.9, 30.7, 35.3, 38.4, 40.5, 40.8, 44.1,
59.4, 70.2, 125.7, 125.8, 128.5, 133.1, 136.3, 140.3, 172.3 ppm; elemental
analysis calcd for C26H36O5: C 72.87, H 8.47; found: C 72.94, H 8.29.
Total Synthesis of Polycephalin C and
Determination of the Absolute Configurations
at the 3'',4'' Ring Junction**
Deborah A. Longbottom, Angus J. Morrison,
Darren J. Dixon, and Steven V. Ley*
Received: March 15, 2002 [Z18903]
Tetramic acids (2,4-pyrrolidinediones) are an important
family of nitrogen-containing heterocycles, well known for
their potent antibiotic, antiviral, antifungal, and cytotoxic
activity.[1] Many tetramic acid natural products are highly
complex frameworks containing several stereogenic centers.
It is this complexity, together with the fact that these targets
have potential or known biological activity, which makes their
synthesis a worthwhile and challenging goal for the organic
chemist, particularly so when the natural product is in short
supply from the natural source.
[1] J. Tsuji, Transition Metal Reagents and Catalysts, Wiley, Chichester,
2000.
[2] a) G. Wilke, B. Bogdanovic, P. Hardt, P. Heimbach, W. Keim, M.
Krˆner, W. Oberkirch, K. Tanaka, D. Steinbr¸cke, E. Walter, H.
Zimmermann, Angew. Chem. 1966, 78, 157 172; Angew. Chem. Int.
Ed. Engl. 1966, 5, 151 164; b) R. Benn, N. B¸ssemeier, P. Holle, W.
Jolly, R. Mynott, I. Tkatchenko, G. Wilke, J. Organomet. Chem. 1985,
279, 63 86.
[3] a) K. Tamao, K. Kobayashi, Y. Ito, Synlett 1992, 539 546; b) E.
Oblinger, J. Montgomery, J. Am. Chem. Soc. 1997, 119, 9065 9066;
c) M. Kimura, A. Ezoe, K. Shibata, Y. Tamaru, J. Am. Chem. Soc.
1998, 120, 4033 4034; d) M. Kimura, H. Fujimatsu, A. Ezoe, K.
Shibata, M. Shimizu, S. Matsumoto, Y. Tamaru, Angew. Chem. 1999,
111, 410 413; Angew. Chem. Int. Ed. 1999, 38, 397 399; e) Y.
Tamaru, Organomet. Chem. 1999, 576, 215 231; f) J. Montgomery,
Acc. Chem. Res. 2000, 33, 467 473; g) S. Ikeda, Acc. Chem. Res. 2000,
33, 511 520; h) I. N. Houpis, J. Lee, Tetrahedron 2000, 56, 817 846.
[4] a) P. A. Wender, T. E. Jenkins, J. Am. Chem. Soc. 1989, 111, 6432
6434; b) P. A. Wender, T. E. Smith, J. Org. Chem. 1995, 60, 2962
2963; c) P. A. Wender, T. E. Smith, J. Org. Chem. 1996, 61, 824 825;
for rhodium-catalyzed reactions, see: d) L. McKinstry, T. Livinghouse,
Tetrahedron 1994, 50, 6145 6154; e) S-J. Paik, S. U. Son, Y. K. Chung,
Org. Lett. 1999, 1, 2045 2047; f) B. Wang, P. Cao, X. Zhang,
Tetrahedron Lett. 2000, 41, 8041 8044; for palladium-catalyzed
reactions, see: g) X. Xie, X, Lu, X. Tetrahedron Lett. 1999, 40,
8415 8418.
In 1998, Nowak and Steffan isolated polycephalin C (1) as a
new member of this group of natural products from Physarum
polycephalum.[2] Polycephalin C (1) is a bis(trienoyltetramic
acid), linked by an unusual asymmetric cyclohexene ring. The
O
HO
Me
N
H
O
OH
4''
3''
H
O
OH
[5] A. V. Savchenko, J. Montgomery, J. Org. Chem. 1996, 61, 1562 1563.
[6] a) Y. Sato, M. Takimoto, M. Mori, J. Am. Chem. Soc. 2000, 122, 1624
1634; b) K. Shibata, M. Kimura, M. Shimizu, Y. Tamaru, Org. Lett.
2001, 3, 2181 2183.
[7] a) J. Montgomery, E. Oblinger, A. V. Savchenko, J. Am. Chem. Soc.
1997, 119, 4911 4920; b) J. Seo, H. M. P. Chui, M. J. Heeg, J.
Montgomery, J. Am. Chem. Soc. 1999, 121, 476 477; c) S. K.
Chowdhury, K. K. D. Amarasinghe, M. J. Heeg, J. Montgomery, J.
Am. Chem. Soc. 2000, 122, 6775 6776.
[8] a) X.-Q. Tang, J. Montgomery, J. Am. Chem. Soc. 1999, 121, 6098
6099; b) M. V. Chevliakov, J. Montgomery, J. Am. Chem. Soc. 1999,
121, 11139 11143; c) J. Seo, H. Fain, J. B. Blanc, J. Montgomery, J.
Org. Chem. 1999, 64, 6060 6065.
[9] The two isomers of 2 are apparently as a result of the relative
configuration of the 1,5-stereogenic centers and not that of exocyclic
double bonds. For example, PCC oxidation of a 7:1 mixture of 2e
provided the corresponding ketone as a single isomer, which furnished
a 1:1 mixture of 2e upon reduction with NaBH4.
N
HO
Me
O
polycephalin C (1)
showing unknown 3",4" absolute stereochemistry
tetramic acid unit of each terminus is derived from (S)-N-
methyl serine and is linked by a fully conjugated all-E-triene
chain to the cyclohexene ring. This unusual tetramic acid is
thought to be one of several metabolites responsible for the
yellow color of the wild-type plasmodia of Physarum poly-
cepahlum.[2]
Although the structure elucidation had established that the
relative stereochemistry at the 3'',4'' ring junction of the
natural product was trans, the absolute configuration at these
positions had not been determined.[2] Therefore, intrigued by
both the novel structure of this unusual polyenoyltetramic
acid and the need to define the absolute stereochemistry at
[10] CCDC-178844 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ, UK;
fax: (‡44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[11] A similar reaction mechanism has been reported for a Ni-catalyzed
alkylative carbocyclization of alkynyl enones [e.g., Eq. (2)] and for a
Ni-catalyzed three-component coupling reaction of alkynes, alde-
hydes, and organozinc compounds: a) A. V. Savchenko, J. Montgom-
ery, J. Am. Chem. Soc. 1996, 118, 2099 2100; b) X. Q. Tang, J.
Montgomery, J. Org. Chem. 1999, 64, 9310 9313; c) K. K. D. Amar-
asinghe, S. K. Chowdhury, M. J. Heeg, J. Montgomery, Organometal-
lics 2001, 20, 370 372.
[*] Prof. Dr. S. V. Ley, Dr. D. A. Longbottom, Dr. A. J. Morrison,
Dr. D. J. Dixon
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (‡44)1223-336-442
E-mail: svl1000@cam.ac.uk
[**] We gratefully acknowledge financial support from the EPSRC (to
D.J.D. and D.A.L.), AstraZeneca (to A.J.M.), and the Novartis
Research Fellowship (to S.V.L.). The authors also thank Dr. B. Steffan
(Thetis - Institut f¸r biomolekulare Naturstoffforschung) for NMR
and CD spectra of natural polycephalin C.
[12] a) M. Kimura, S. Matsuo, K. Shibata, Y. Tamaru, Angew. Chem. 1999,
111, 3586 3589; Angew. Chem. Int. Ed. 1999, 38, 3386 3388; b) M.
Kimura, K. Shibata, K. Koudahashi, Y. Tamaru, Y. Tetrahedron Lett.
2000, 41, 6789 6793; c) K. Shibata, M. Kimura, K. Kojima, S. Tanaka,
Y. Tamaru, J. Organomet. Chem. 2001, 624, 348 353.
2786
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1433-7851/02/4115-2786 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 15