The intermolecular Pauson-Khand reaction of sugar-derived azaenynes: A case of total diastereoselectivity

Article abstract of DOI:10.1080/07328300600732733

Sugar azaenynes 1a and 1b, easily available from D-glucal and D-galactal, respectively, react with norbornene and norbornadiene under Pauson-Khand conditions to give the intermolecular adducts as major or exclusive product. In all cases only one diastereo

Full text of DOI:10.1080/07328300600732733

Journal of Carbohydrate Chemistry, 25:197–202, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600732733
The Intermolecular Pauson-
Khand Reaction of Sugar-
Derived Azaenynes: A Case
of Total Diastereoselectivity
Pilar Areces and Esther Carrasco
´
´
Departamento de Quımica Organica, Universidad de Extremadura, Facultad de
Ciencias, Badajoz, Spain
´
Joaquın Plumet
´
´
´
Departamento de Quımica Organica, Universidad Complutense, Facultad de Quımica,
Madrid, Spain
Sugar azaenynes 1a and 1b, easily available from D-glucal and D-galactal, respectively,
react with norbornene and norbornadiene under Pauson-Khand conditions to give the
intermolecular adducts as major or exclusive product. In all cases only one diastereomer
was obtained in convenient yield. This reaction constitutes an unprecedented case of
totally diastereoselective intermolecular Pauson-Khand reaction using a sugar moiety
as chiral auxiliary.
Keywords Intermolecular Pauson-Khand reaction, Cyclopentenones, Carbohydrates
Received November 10, 2005; accepted January 27, 2006.
´
´
Address correspondence to Pilar Areces, Departamento de Quımica Organica, Universi-
dad de Extremadura, Facultad de Ciencias, 06071 Badajoz, Spain. E-mail: pareces@
´
´
´
unex.es; and to Joaquın Plumet, Departamento de Quımica Organica, Universidad
´
Complutense, Facultad de Quımica, 28040 Madrid, Spain. E-mail: plumety@quim.ucm.es
197

P. Areces et al.
198
The Pauson-Khand (P-K) reaction, a cobalt carbonylative co-cyclization of an
alkene and an alkyne, is the most popular organometallic-mediated reaction
for the synthesis of cyclopentenones.[1] In the last few years, many efforts
were devoted to the development of the enantioselective version of this
reaction and, for the intermolecular process.[2] several methodologies in
which a chiral inductor is covalently bonded to one of both partners have
been developed.[3] Regarding the use of carbohydrates as a source of chirality,
these compounds have been considered as chiral substrates in the intramolecu-
lar P-K reactions.[4] Recently we have reported the intramolecular P-K reaction
of sugar azaenines 1a and 1b, derived from D-glucal and D-galactal, respect-
ively, obtaining the expected cycloadducts 2 and 3 with poor[5] to moderate[6]
diastereoselectivity (Sch. 1).
To the best of our knowledge, sugar derivatives have never been used as
chiral auxiliaries in the intermolecular Pauson-Khand reactions. In this
context we thought that compounds 1a and 1b may be interesting alkyne
partners for the intermolecular Pauson-Khand reactions, assuming that the
intermolecular reaction should be conveniently faster than the intramolecular
process. Taking into account that the concurrence between intermolecular and
intramolecular Pauson-Khand reactions have never been considered in sub-
strates capable to undergo the intramolecular process, we have selected the
reactive bicyclic alkenes norbornene 4 and norbornadiene 5 as olefinic counter-
parts. Norbornene and norbornadiene are very often used in the intermolecular
Pauson-Khand reaction because of their high reactivity. In particular, these
compounds are excellent reagents for testing the asymmetric version of the
reaction. See literature quoted in reference 2, p. 3028. For the use of oxa-
and azanorbornene derivatives in Pauson-Khand reaction, see ref.[7]
Compounds 1a and 1b reacted with norbornene and norbornadiene to give
the intermolecular exo cycloadducts 6 and 7, respectively (Table 1), as major
1
(entry 1) or only (entries 2–4) reaction products. On the other hand, H and
13C NMR spectra of the reaction mixtures showed that each individual
Scheme 1.

Intermolecular Pauson-Khand Reaction
199
Table 1: The intermolecular Pauson-Khand reaction of sugar azaenines
1a and 1b with norbornene (4) and norbornadiene (5).
Starting
materials
Isolated
yield
Entry
Cycloadduct
1
2
3
4
1a and 4
1a and 5
1b and 4
1b and 5
6a
7a
6b
7b
67%a
62%b
80%b
72%b
aTwenty percent of a mixture of intramolecular cycloadducts 2 and 3 was isolated.
bOnly traces of intramolecular cycloadducts 2 and 3 were observed in the crude
reaction mixture.
cyclopentenone was diastereomerically pure with only one set of peaks present
in each case. Flash chromatography of the crude reaction mixture through a
small column (silica gel, 3 cm high; hexane-ethyl acetate 3 : 1 ! ethyl
acetate) followed by HPLC analysis and purification (Zorbax Rx-SIL column,
isocratic normal phase separation, hexane-ethyl acetate 50 : 50) allowed us to
isolate compounds 6 and 7 in moderate to good isolated yields and diastereo-
meric purity .95%. General procedure for compounds 6a, 6b, 7a, and 7b. A
0.16 M solution of azaenine precursor (1a or 1b) in freshly distilled CH2Cl2
was treated with Co2(CO)8 (1.1 equiv.) under a CO atmosphere. After 45 min
of stirring, the corresponding alkene (4 or 5) was added, and the mixture
was stirred 10 min more. Then, NMO (6 equiv.) was added portionwise over a
15-min period, and the reaction mixture was cooled to 08C before each
addition and allowed to reach rt before a new one. The mixture was stirred
for 45 min at rt; diluted with CH2Cl2; washed successively wtih 2 N HCl, a satu-
rated solution of NaHCO3, and water; dried (MgSO4); and concentrated in
vacuo. The residue was first eluted through a short column (3 cm long) of
SiO2 (hexane/ethyl acetate 3 : 1 ! ethyl acetate) to remove metal impurities,
and the elution was concentrated; flash chromatography (hexane/ethyl
acetate 3 : 1 ! 1 : 1) or HPLC analysis (semipreparative system, Zorbax
Rx-SIL column, isocratic normal phase separation, hexane/ethyl acetate
50 : 50) of the residue gave the cyclopentenone (6 or 7).

P. Areces et al.
200
Compound 6a: 1H NMR (400 MHz, CDCl3) d 7.67 (d, 2H, J3 ,2 ¼ 8.2 Hz, H-3000,
000 000
H-5000), 7.30 (d, 2H, J5 ,6 ¼ 8.2 Hz, H-2000, H-6000), 7.35 (s, H-3), 5.52–5.56 (m, 2H,
000 000
H-20, H-30), 5.38 (m, H-40), 5.12 (m, H-5), 4.20–4.00 (m, 2H, H-60a, H-60b), 3.95–
3.60 (m, 4H, 2H-10, 2H-100), 2.59 (br s, H-3a), 2.43 (s, 3H, CH3-Ar), 2.34 (m, H-7),
2.14 (m, 2H, H-7a, H-4), 2.06 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.04 (s, 3H, OAc),
1.70–1.50 (m, 2H, H-5), 1.35–1.20 (m, 2H, H-6), 0.97–0.80 (m, 2H, H-8); 13C
NMR (100 MHz, CDCl3) d 209.5 (C-1), 170.4, 169.9, 169.3 (3O-CO-CH3), 162.6
(C-3), 144.4 (C-2), 143.5 (C-1000), 136.5 (C-4000), 130.0 (C-20), 129.6 (C-3000 and
C-5000), 128.0 (C-30), 127.1 (C-2000, C-6000), 71.2 (C-40, C-50), 61.5 (C-60), 54.0
(C-7a), 49.8, 49.7 (C-10), 48.3 (C-3a), 41.9 (C-100), 38.8 (C-7) 37.7 (C-4), 31.1
(C-8), 28.9 (C-5), 28.2 (C-6), 21.4 (C-7000), 20.7, 20.5 (3O-CO-CH3). HRMS calcd
for C30H37NO9S þ H: 588.2267. Found: 588.2267.
Compound 6b: 1H NMR (400 MHz, CDCl3) d 7.66 (d, 2H, J3 ,2 ¼ 8.2 Hz, H-3000,
000 000
H-5000), 7.35 (m, H-3), 7.30 (d, 2H, J5 ,6 ¼ 8.2 Hz, H-2000, H-6000, 5.59–5.53 (m, 2H,
000 000
H-20, H-30), 5.39 (m, H-40), 5.13 (m, H-50), 4.27 (dd, J5 ,6a ¼ 4.0 Hz,
0
0
J6b ,6a ¼ 12.0 Hz, H-60a), 3.98–3.93 (m, H-60b), 3.90–3.73 (m, 4H, 2H-10,
2H-100), 2.59 (br s, H-3a), 2.43 8 (s, 3H, CH3-Ar), 2.35 (br s, H-7), 2.17–2.14
(m, 2H, H-7a, H-4), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.04 (s, 3H, OAc),
1.67–1.57 (m, 2H, H-5), 1.31–1.25 (m, 2H, H-6), 0.93–0.90 (m, 2H, H-8); 13C
NMR (100 MHz, CDCl3) d 209.7 (C-1), 170.4, 170.0, 169.5 (3O-CO-CH3), 162.8
(C-3), 144.5 (C-2), 143.5 (C-1000), 136.6 (C-4000), 130.0 (C-3000, C-5000), 128.2 (C-30),
127.1 (C-2000, C-6000), 71.1, 71.0 (C-40, C-50), 61.9 (C-60), 54.1 (C-7a), 49.7 (C-10),
48.4 (C-3a), 41.8 (C-10), 38.9 (C-7), 37.8 (C-4), 31.2 (C-8), 29.0, 28.3 (C-5, C-6),
21.4 (C-7000), 20.8, 20.7, 20.6 (3O-CO-CH3); HRMS calcd for C30H37NO9S þ H:
588.2267. Found 588.2269.
0
0
Compound 7a: 1H NMR (400 MHz, CDCl3) d 7.67 (d, 2H, J3 ,2 ¼ 8.2 Hz, H-3000,
000 000
H-5000), 7.43 (br s, H-3), 7.31 (d, 2H, J5 ,6 ¼ 8.2 Hz, H-2000, H-6000), 6.29 (dd,
000 000
J4,5 ¼ 3.0 Hz, J5,6 ¼ 5.5 Hz, H-5), 6.19 (dd, J6,7 ¼ 2.9 Hz, J6,5 ¼ 5.5 Hz, H-6)
5.64–5.52 (m, 2H, H-20, H-30), 5.38 (m, H-40), 5.12 (m, H-50), 4.18–4.06 (m, 2H,
H-60a, H-60b), 3.93–3.73 (m, 4H, 2 H-10, 2 H-100), 2.90 (br s, H-7), 2.73 (br s,
H-3a), 2.68 (br s, H-4), 2.43 (s, 3H, CH3-Ar), 2.26 (d, J7a,7 ¼ 5.0 Hz, H-7a),
2.06 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.37 (d, J8a,8b ¼ 9.1 Hz,
H-8b), 1.12 (d, J8a,8b ¼ 9.1 Hz, H-8a); 13C NMR (100 MHz, CDCl3) d 208.4
(C-1), 170.0, 169.4 (3O-CO-CH3), 162.7 (C-3), 145.7 (C-2), 143.6 (C-1000), 138.5
(C-5), 137.0 (C-6), 136.6 (C-4000), 130.2 (C-20), 129.8, (C-3000, C-5000), 128.2 (C-30),
127.2 (C-2000, C-6000), 71.4, (C-40, C-50), 61.6 (C-60), 52.9 (C-7a), 50.1 (C-10), 48.0
(C-3a), 43.6 (C-7), 42.8 (C-4), 42.0 (C-100), 41.3 (C-8), 21.5 (C-7000), 20.8, 20.7
(3O-CO-CH3); HRMS calcd for C30H35NO9S þ H: 586.2110. Found: 586.2111.
Compound 7b: 1H NMR (400 MHz, CDCl3) d 7.67 (d, 2H, J2 ,3
000 000
¼
J5 ,6 ¼ 8.4 Hz, H-3000, H-5000), 7.42 (br s, H-3), 7.31 (d, 2H, J5 ,6 ¼ 8.4 Hz,
000 000
000 000

Intermolecular Pauson-Khand Reaction
201
H-2000, H-6000), 6.24 (dd, J4,5 ¼ 3.2 Hz, J5,6 ¼ 5.2 Hz, H-5), 6.19 (dd, J6,7 ¼ 2.8 Hz,
J6,5 ¼ 5.2 Hz, H-6), 5.57 (m, 2H, H-20, H-30), 5.39 (m, H-40), 5.13 (m, H-50), 4.27
(dd, J5 ,6 ¼ 4.4 Hz, J6 a,6 b ¼ 12.0 Hz, H-60a), 3.99-3.73 (m, H-60b), 3.88–3.72
(m, 4H, 2H-10, 2H-100), 2.87 (br s, H-7), 2.73 (br s, H-3a), 2.68 (br s, H-4), 2.43
(s, 3H, CH3-Ar), 2.26 (m, H-7a), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.04
(s, 3H, OAc), 1.37 (d, J8a,8b ¼ 9.6 Hz, H-8a), 1.12 (d, J8a,8b ¼ 9.6 Hz, H-8a);
13C NMR (100 MHz, CDCl3) d 209.0 (C-1), 171.0, 170.6, 170.1 (3O-CO-CH3),
163.4 (C-3), 146.2 (C-2), 142.2 (C-1000), 139.1 (C-5), 137.6 (C-6), 137.2 (C-4000),
130.6 (C-20), 130.4, 130.5 (C-3000, C-5000), 128.9 (C-30), 127.8 (C-2000, C-6000), 71.7,
71.6 (C-40, C-50), 62.6 (C-60), 53.5 (C-7a), 50.6 (C-10), 48.6 (C-3a), 44.2 (C-7),
43.4 (C-4), 42.6 (C-100), 41.9 (C-8), 22.1 (C-7000), 21.4, 21.3 (3O-CO-CH3);
HRMS calcd for C30H35NO9S þ H: 586.2110. Found: 586.2113.
0
0
0
0
The assignment of the relative configuration at the new formed stereocen-
ters in diastereomerically pure compounds 6 and 7 is being carried out and will
be reported in due course. On the other hand, the exo stereochemistry of the
cycloaddition was deduced from the lack of coupling between the endo hydro-
gens and the bridgehead protons in the norbornane framework.[8]
In summary, in this paper we have showed that the concurrence between
inter- and intramolecular Pauson-Khand reactions in substrates such as 1a
and 1b capable to give both types of reactions was clearly shifted toward the
intermolecular process using reactive bicyclic alkenes such as 4 or 5. Interest-
ingly, only one diastereomer was obtained in these reactions, showing an unpre-
cedent diastereoselective control, which must be exerted by the sugar side chain.
Synthetic applications of this process are now under research in our laboratory.
ACKNOWLEDGEMENTS
´
This work was supported by Ministerio de Educacion y Ciencia, Spain (Grant
BQU2003-04967-C02-01), and Gobierno de Extremadura, Spain (Grant
2PR02A016). One of us (E.C.) acknowledges a fellowship from the MEC, Spain.
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