Carbohydrate to carbocycle conversions via intramolecular propargylation with Et2Zn/Pd(0)/Yb(OTf)3

Article abstract of DOI:10.1055/s-2001-14597

Abstract: Carbohydrate-derived propargylic esters react with Et2Zn and catalytic Pd(0), in the presence of a Lewis acid, to generate nucleophilic allenyl metal species capable of intramolecular addition to a tethered carbonyl group. This results in the fo

Full text of DOI:10.1055/s-2001-14597

872
LETTER
Carbohydrate to Carbocycle Conversions via Intramolecular Propargylation
with Et2Zn/Pd(0)/Yb(OTf)3
José M. Aurrecoechea,* Mónica Arrate, Beatriz López
Departamento de Química Orgánica II, Facultad de Ciencias, Universidad del País Vasco, Apartado 644, 48080 Bilbao, Spain
Fax 34-94 464 8500; E-mail: qopaufem@lg.ehu.es
Received 4 April 2001
for conversion of carbohydrates into carbocycles would
Abstract: Carbohydrate-derived propargylic esters react with
be significantly expanded with the use of substrates 5 de-
Et2Zn and catalytic Pd(0), in the presence of a Lewis acid, to gener-
rived from carbohydrates. In this manner, a more diverse
ate nucleophilic allenyl metal species capable of intramolecular ad-
dition to a tethered carbonyl group. This results in the formation of
array of enantiomerically pure cyclopentanes 4, with R2
enantiomerically pure functionalized cyclopentanes with high stere- H, would become readily available.
oselectivity and in preparatively useful yields. A high preference is
In related work, the transmetalation of analogous allenyl-
observed for a trans relationship between the alkynyl and OH
Pd(II) complexes 6 with Et2Zn or InI has been utilized to
groups in the cyclopentane products, implying that the cyclization
generate the corresponding organometallic species 7 or 8,
respectively, capable of intermolecular addition to a car-
bonyl derivative to yield homopropargyl alcohols 10 with
excellent stereocontrol (Scheme 2).4 The intramolecular
application of these processes to effect carbohydrate-to-
carbocycle conversions of the type 1, 5 4 through inter-
mediates 3 (MLn = ZnX, InIX), would be also a valuable
addition to the synthetic chemist repertoire. This paper re-
ports our preliminary results in this area.
proceeds through open transition states.
Key words: carbohydrates, carbocycles, cyclizations, palladium,
zinc
The stereoselective synthesis of densely functionalized
carbocycles from carbohydrate starting materials is a top-
ic of current interest.1 We have recently reported that
treatment of modified carbohydrates 1 with the one-elec-
tron reducing agent SmI2 and a catalytic amount of Pd(0)
brings about the formation of homopropargyl cyclopen-
tanols 4 (Scheme 1).2 These transformations are thought
to proceed through the intermediacy of Pd(II)-complexes
2 resulting from Pd(0)-promoted carbohydrate ring-open-
ing. Intermediates 2 are then reduced in situ with two
equivalents of SmI2, presumably generating the cyclizing
carbanionic species 3 and regenerating the Pd(0) catalyst.
Access to intermediates analogous to 2 and 3 can also be
gained, under similar treatment with SmI2/Pd(0),3 from
non-carbohydrate open-chain propargylic esters 5 with a
tethered carbonyl group. These two methods for prepara-
tion of carbocycles 4 are complementary in that the con-
version 5 4 is only effective for ketone substrates (R2
H)3 whereas substrates 1 (R2 = H) function as aldehyde
equivalents.2 Therefore, the scope of this general strategy
Scheme 2
Scheme 1
Synlett 2001, No. 6, 872–874 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Carbohydrate to Carbocycle Conversions
873
Appropriate model substrates for this study were prepared Yb(OTf)3 has been found to be the most effective Lewis
from commercial 2,3,4,6-tetra-O-benzylglucopyranose acid to promote these reactions. ZnCl2, TiCl4 and TMSCl
(11) in three steps as outlined in Scheme 3. Key to this gave inferior results and TMSOTf led only to degradation.
straightforward synthesis was the chemoselective As for the Pd(0) catalyst, Pd(PPh3)4, Pd(OAc)2•4PBu3 and
benzoylation5 of propargylic alcohols 12. Oxidation of the Pd2(dba)3•4PBu3 were all found to give good yields of 16.
remaining secondary hydroxyl group in benzoates 13 af- Pd2(dba)3•4PPh3 and Pd(OAc)2•4PPh3 gave inferior re-
8
forded the corresponding ketones 14.
sults while PdCl2(dppf)2 and Pd(OAc)2•PPh3 were inef-
fective. Both THF and benzene are useful solvents for
these reactions. CH2Cl2 has also been effective but its gen-
eralized use was not explored. For practical purposes, the
combination of Yb(OTf)3 as Lewis acid with a
Pd(OAc)2•4PBu3 catalyst and benzene as solvent gave the
best results in terms of combined yields and diastereose-
lectivities.9 Under these conditions, one diastereoisomer
was obtained as a single or very major product in prepar-
atively useful yields (Scheme 4).
Interestingly, the stereochemical course of these reactions
departs from that reported for the corresponding intermo-
lecular additions of allenylzinc reagents to aldehydes.8 In
the latter cases the formation of a configurationally stable
key allenylzinc intermediate 7 takes place with net inver-
sion of configuration from precursor propargylic mesy-
lates. Carbonyl addition then proceeds through a chelated
Scheme 3 a) H-C C-MgBr; b) BnO(CH)2)2-C C-Li; c) BzCl, Pyr.; cyclic transition state 9 (Scheme 2).8 A similar arrange-
d) PCC, NaOAc; e) Sml2, t-BuOH
ment, i.e 17, in our cyclizations would lead to a product
with a cis relationship between the alkynyl and OH
groups. However, the major diastereoisomer formed dis-
Treatment of 14a with either SmI2/Pd(0) or Et2Zn/Pd(0),
played instead a trans relationship between those groups
led to substantial degradation whereupon methyl ketone
implying that open transition states 18 are probably in-
15a and benzyl alcohol were isolated in low yields. Ke-
volved in the formation of 16. One reasonable explanation
tones 15 were independently prepared in high yield by
for this behavior is that coordination of the carbonyl group
treatment of 14 with SmI2/t-BuOH6 and their reactivity
to the strong Lewis acid Yb(OTf)310 is the stereocontrol-
with both SmI2/Pd(0) and Et2Zn/Pd(0) was tested.
ling factor11,12 in our reactions.
The reactions of methyl ketones 15 with SmI2/Pd(0) re-
sulted again in degradation, with benzyl alcohol being the
only identified product. On the other hand, the same sub-
ZnX
strates produced cyclopentanes 16 when treated with
Et2Zn/Pd(0) in the presence of an external Lewis acid
•
ZnX
•
Me
O
(Scheme 4). In the absence of this no reaction was ob-
served at room temperature and higher temperatures led to
O
Me
L.A.
the degradation of 15. The stereochemistry of cyclopen-
17
18
tanes 16 was unambiguously determined with the aid of
1H NMR NOE experiments.7
In conclusion, propargylic esters with a tethered carbonyl
group are prepared in few steps from carbohydrate precur-
sors. These esters react with Et2Zn and catalytic Pd(0) in
the presence of a Lewis acid to generate nucleophilic alle-
nyl metal species that undergo intramolecular carbonyl
addition to afford enantiomerically pure, densely func-
tionalized cyclopentanes with high diastereoselectivity.
Acknowledgement
Scheme 4
Financial support by the Universidad del País Vasco (170.310-
EB001/99) and Ministerio de Ciencia
y Tecnología (DGI
BQU2000-01354) is gratefully acknowledged. We also thank the
Ministerio de Educación y Cultura for a Fellowship to M. A.
A number of reaction conditions have been tested by
changing solvent, Pd catalyst and Lewis acid. So far,
Synlett 2001, No. 6, 872–874 ISSN 0936-5214 © Thieme Stuttgart · New York

874
J. M. Aurrecoechea et al.
LETTER
gel to afford cyclopentanes 16. Data for 16a: [ ]D20 -32.0° (c
0.01, CHCl3); 1H NMR (CDCl3, 250 MHz) 1.38 (s, 3H), 2.31
(d, J = 2.4 Hz, 1H), 2.98-3.03 (m, 1H), 3.05 (s, 1H), 3.55 (d,
J = 2.2 Hz, 1H), 3.91-3.95 (m, 2H), 4.51 (s, 2H), 4.56 (d,
J = 11.6 Hz, 1H), 4.63 (d, J = 11.8 Hz, 1H), 4.69 (d, J = 11.6
References and Notes
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(2) Aurrecoechea, J. M.; Lopez, B.; Arrate, M. J. Org. Chem.
2000, 65, 6493.
(3) Aurrecoechea, J. M.; Fañanás, R.; Arrate, M.; Gorgojo, J. M.;
Aurrekoetxea, N. J. Org. Chem. 1999, 64, 1893.
(4) For a review, see: Marshall, J. A. Chem. Rev. 2000, 100, 3163.
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(6) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 53, 1135.
(7) Under appropriate conditions all four isomers of 16 could be
obtained and were readily separated by liquid
Hz, 1H), 4.83 (d, J = 11.8 Hz, 1H), 7.30-7.38 (m, 15H); 13
C
NMR (CDCl3, 62.9 MHz) 22.3, 45.5, 71.9, 72.1, 73.0, 77.1,
82.4, 85.6, 86.5, 86.6, 127.7, 127.9, 128.0, 128.3, 128.4,
128.5, 137.3, 137.7, 137.8; IR (neat) 3680-3400, 3360, 2215
cm-1; HRMS calcd for C29H30O2 442.2144, found 442.2158.
Data for 16b: [ ]D20+21.9° (c 0.03, CHCl3); 1H NMR (CDCl3,
250 MHz) 1.36 (s, 3H), 2.57 (td, J = 7.2, 2.4 Hz, 2H), 2.98
(m, 1H), 3.02 (s, 1H), 3.55 (d, J = 2.9 Hz, 1H), 3.62 (t, J = 7.1
Hz, 2H), 3.76-3.96 (m, 2H), 4.52-4.59 (m, 5H), 4.63 (d,
J = 11.9 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.83 (d, J = 11.9
Hz, 1H), 7.28-7.36 (m, 20H); 13C NMR (CDCl3, 62.9 MHz)
20.3, 22.5, 45.7, 68.6, 71.7, 71.9, 72.0, 72.8, 77.5, 79.2, 81.5,
85.6, 86.5, 86.7, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0,
128.2, 128.3, 128.4, 137.4, 137.8, 137.9, 138.0; IR (neat)
3600-3300, 3000-2850 cm-1; HRMS calcd for C38H40O5
576.2876, found 576.2851.
(10) Kobayashi, S. Synlett 1994, 689.
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(12) It is important to note that substrates 15 were obtained and
used as approximately 3:1 diastereomeric mixtures at the
propargylic position. Therefore, from the results presented in
Scheme 4, the conclussion could be drawn that the major
product 16 originates in the major diastereoisomer of 15 and
that this one has an (S) configuration at the propargylic center.
The implicit assumption is that, under the reaction conditions,
little stereochemical scrambling takes place at the allenyl
metal moiety of species 2 and 3.13,14
chromatography. This facilitated the stereochemical
assignments, as useful comparisons could be made between
the observed NOE's of the individual isomers.
(8) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
(9) Experimental procedure: To a solution of Pd(OAc)2•4PBu3
(0.05 mmol) and 15 (1.0 mmol) in dry THF (10 mL) under Ar
were successively added Yb(OTf)3 (744 mg, 1.2 mmol) and
Et2Zn (1.0 M in hexanes, 3.0 mL, 3.0 mmol). The mixture was
stirred at r.t. (15a) or 50 °C (bath temperature, 15b) until
consumption of the substrate (TLC). The mixture was diluted
with EtOAc (40 mL) and washed successively with 1 M HCl
(20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The
crude product was purified by liquid chromatography on silica
(13) Marshall, J. A.; Chobanian, H. R. J. Org. Chem. 2000, 65,
8357.
(14) Poisson, J. F.; Chemla, F.; Normant, J. F. Synlett 2001, 305.
Article Identifier:
1437-2096,E;2001,0,06,0872,0874,ftx,en;D08301ST.pdf
Synlett 2001, No. 6, 872–874 ISSN 0936-5214 © Thieme Stuttgart · New York