Highly stereoselective 1,4-conjugate addition of organocopper reagents to methyl α-D-glucopyranoside derivatives tethering an unsaturated ester moiety at C-4 or C-6

Article abstract of DOI:10.1021/ol9909942

(formula presented) The 1,4-conjugate additions of a variety of organocopper reagents to some 4-O-crotonyl derivatives of methyl α-D-glucopyranoside proceeded with a high level of diastereochemical induction to provide the adducts carrying a β-substituted

Full text of DOI:10.1021/ol9909942

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1447-1450
Highly Stereoselective 1,4-Conjugate
Addition of Organocopper Reagents to
Methyl r-D-Glucopyranoside Derivatives
Tethering an Unsaturated Ester Moiety
at C-4 or C-61
Kiichiro Totani,† Takayuki Nagatsuka,† Ken-ichi Takao,† Shigeru Ohba,‡ and
,†
Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan, and Department of Chemistry, Keio UniVersity,
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
Received August 31, 1999
ABSTRACT
The 1,4-conjugate additions of a variety of organocopper reagents to some 4-O-crotonyl derivatives of methyl r-D-glucopyranoside proceeded
with a high level of diastereochemical induction to provide the adducts carrying a â-substituted butanoic ester at C-4. The 1,4-conjugate
addition to a 6-O-crotonyl derivative afforded the adduct with reverse configuration at the â-carbon to that obtained from the 4-O-crotonyl
derivatives.
The development of chiral auxiliaries based on readily
available natural products is an ongoing subject in the field
of asymmetric synthesis for obtaining useful levels of
stereoinduction.2 It has been widely recognized that a number
of carbohydrate-based templates existing in pentofuranose
or hexopyranose form can serve as good chiral auxiliaries
since they provide a stereochemically biased environment.3,4
We have investigated the utility of hexopyranose derivatives
with the expectation that they are synthetically useful chiral
auxiliaries in stereoseletive carbon-carbon-bond forming
reactions. In this paper, we provide recent results on the 1,4-
conjugate additions5 of a variety of organocopper reagents
to the 4-O- or 6-O-crotonyl derivatives of methyl R-D-
glucopyranoside.6
(4) For recent relevant reports on this subject, see: Ko, K.-Y.; Park,
J.-Y. Tetrahedron Lett. 1997, 38, 407-410. Follmann, M.; Kunz, H. Synlett
1998, 989-990. Weymann, M.; Schultz-Kukula, M.; Kunz, H. Tetrahedron
Lett. 1998, 39, 7835-7838.
(5) For leading reviews on asymmetric 1,4-conjugate addition, see:
Rossiter, B. E.; Swingle, N. M. Chem ReV. 1992, 92, 771-806. Noyori, R.
Asymmetric Catalysts in Organic Synthesis; John Wiley and Sons: New
York, 1994; pp 207-212. Alexakis, A. In Organocopper Reagents, a
Practical Approach; Taylor, R. J. K., Ed.; Oxford University Press: Oxford,
U.K., 1994; pp 159-183. Feringa, B. L.; de Vries, A. H. M. In AdVances
in Catalytic Processes; Doyle, M. P., Ed.; JAI Press Inc: Greenwich, CT,
1995; Vol. 1, pp 151-192.
† Department of Applied Chemistry.
‡ Department of Chemistry.
(1) This paper is dedicated with respect and admiration to Professor
Kenneth L. Rinehart on the occasion of his 70th birthday.
(2) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995. Ager, D. J.; Prakash, I.; Schaad, D. R.
Aldrichimica Acta 1997, 30, 3-12.
(3) Cintas, P. Tetrahedron 1991, 47, 6079-6111. Kunz, H.; Ru¨ck, K.
Angew. Chem., Int. Ed. Engl. 1993, 32, 336-358. Kunz, H. Pure Appl.
Chem. 1995, 67, 1627-1635. Hultin, P. G.; Earle, M. A.; Sudharshan, M.
Tetrahedron 1997, 53, 14823-14870.
10.1021/ol9909942 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/30/1999

The substrates we designed were methyl 2,3-di-O-
protected 6-iodo- (1a-1c), 6-deoxy- (2a-2c), and 2,3,6-tri-
O-protected (3a, 3b) R-D-glucopyranosides (Scheme 1).
yields, and with exceptionally high diastereoselectivity in
specified cases. The results are summarized in Table 1.10
Table 1
Scheme 1
a Isolated yields; yields in parentheses are for the recovered starting
material. b Determined by HPLC (TOSOH TSK-GEL SILICA-60, EtOAc/
hexane ) 1:30 for 4bR and 5bR, EtOAc/hexane ) 1:20 for 4aR and 5aR).
c Determined by 1H NMR. d The stereochemistry of each diastereomer was
not determined. e Determined by 13C NMR.
These substrates were prepared from known 2,3-di-O-
protected7 or 2,3,6-tri-O-protected derivatives8 of methyl R-D-
glucopyranoside.9
First, we investigated the conjugate addition of a vinyl
group to the 4-O-crotonyl derivatives 1a-1c, 2a-2c, 3a,
and 3b (Scheme 2). The carbon nucleophile was prepared
The 6-iodo derivatives 1a and 1b afforded the adducts 4aR
and 4bR, respectively, both virtually as a single diastere-
omer.11 In addition, the adduct 4bR was isolated as crystals
suitable for single-crystal analysis12 to unambiguously de-
termine the stereochemical assignment of the newly intro-
duced stereogenic carbon as depicted in Scheme 2. Further-
more, the stereochemistry of 4aR was confirmed to be that
assigned by chemical correlation to the stereochemistry of
4bR. In the case of 1c, an inseparable mixture of two isomers
4cR and 4cS was obtained with virtually no stereoselectivity.
The 6-deoxy derivatives 2a and 2b provided almost exclu-
sively 5aR and 5bR, respectively.13 Stereochemical assign-
ment of the newly introduced stereogenic center in 5aR or
5bR was conducted by chemical transformation and com-
parison with derivatives prepared from the adducts 4aR or
4bR. Consequently, the 1,4-additions to 1a, 1b, 2a, and 2b,
in all cases, provided the respective R-isomer with complete
stereoinduction. The same stereochemical outcome was
observed when the 6-O-protected substrates 3a and 3b were
subjected to 1,4-addition under the same reaction conditions
as those used for 1 and 2. The levels of diastereoselection
were lower in the 1,4-additions to 3a and 3b (dr ) 88:12 or
Scheme 2
by mixing vinylmagnesium bromide (10 molar equiv to the
substrate) and cuprous bromide-dimethyl sulfide complex
(5 molar equiv). In every case, the additions took place
rapidly to provide the respective 1,4-adducts in good to high
(6) Some of the results described herein have been presented at the 19th
International Carbohydrate Symposium (University of California, San Diego,
August 9-14, 1998) and at the 36th National Organic Chemistry Sympo-
sium (University of WisconsinsMadison, June 13-17, 1999).
(7) Compounds 1a, 1b, 1c, 2a, 2b, and 2c were prepared in the
conventional manner from methyl 2,3-di-O-benzyl-R-D-glucopyranoside (for
1a and 2a) (Yoshimoto, K.; Itatani, Y.; Shibata, K.; Tsuda, Y. Chem. Pharm.
Bull. 1980, 28, 208-219); from methyl 2,3-di-O-pivaloyl-R-D-glucopyra-
noside (for 1b and 2b) (Tomic-Kulenovic, S.; Keglevic, D. Carbohydr. Res.
1980, 85, 302-306); from methyl 2,3-di-O-acetyl-R-D-glucopyranoside (for
1c) (Whistler, R. L.; Kazenjac, S. J. J. Am. Chem. Soc. 1954, 76, 3044-
3045); and from methyl 6-deoxy-2,3-di-O-methyl-R-D-glucopyranoside (for
2c) (Shono, T.; Matsumura, Y.; Hamaguchi, H.; Naitoh, S. J. Org. Chem.
1983, 48, 5126-5128).
(8) Compound 3a was prepared from methyl 2,3,6-tri-O-benzyl-R-D-
glucopyranoside: Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93,
C10-C11. Compound 3b was prepared from the above methyl 2,3-di-O-
benzyl-R-D-glucopyranoside.
(9) The substrates were prepared as follows: for 1a-1c, transformation
of the 6-OH to an iodo group via the respective tosylate and then
esterification of the 4-OH with crotonic anhydride; for 2a-2c, hydride attack
or hydrogenolysis of the 6-O-tosyl or the 6-iodo derivatives followed by
esterification of the 4-OH; and for 3a and 3b, regioselective protection of
the 6-OH and then esterification of the 4-OH.
(10) All of the purified new compounds were fully characterized by 1H
and 13C NMR, IR, and either HRMS or combustion analysis.
(11) We selected the 6-iodo derivatives 1a and 1b, with the expectation
that a tandem intramolecular carbon-carbon bond formation could occur
through the enolate, which would be generated as a result of the 1,4-addition.
The enolate could then attack the C-6 carbon with removal of the iodo
group. This would have entailed the introduction of a second and consecutive
stereogenic center. However, the second carbon-carbon bond formation
did not occur in case of either 1a or 1b.
(12) X-ray Crystallographic Data for 4bR. Crystal data for 4bR
(crystals were grown from a methanol solution): C23H37IO8; Mr ) 3568.45;
monoclinic P21; a ) 14.982(6) Å, b ) 6.147(4) Å, c ) 15.473(8) Å; V )
1421.7(14) Å3; Z ) 2; Dx ) 1.328 mg m-3; Mo KR radiation λ ) 0.710 73
Å; 3070 independent reflections, R ) 0.052, wR ) 0.052, S ) 1.403, 2445
reflections, 288 parameters.
(13) We also examined the conjugate addition to 2a using a catalytic
amount of CuBr‚Me2S (0.1 molar equiv to 2a) and a reduced amount (4.0
molar equiv) of vinylmagnesium bromide. In this case, 5aR was isolated
in 72% yield as virtually a single diastereomer (d.r. >99:1) (19% of 2a
was recovered). However, the amount of Grignard reagent was critical for
the progression of the reaction. Thus, the use of 1.0 or 2.0 molar equiv of
the reagent resulted in the recovery of 2a in 93% or 91% yield, respectively.
1448
Org. Lett., Vol. 1, No. 9, 1999

86:14) than in the 1,4-additions to 1a, 1b, 2a, or 2b, although
the 1,4-additions to 3a and 3b proceeded smoothly at -78
°C.
Table 3
We also examined the use of various organocopper
reagents on the diastereoselectivity, exemplified by the
addition to 2a using three types of ethylcopper reagents, i.e.,
magnesium diethylcuprate, ethylcopper boron trifluoride
complex, or lithium diethylcuprate (Scheme 3, Table 2). The
a Isolated yields; yields in parentheses are for the recovered starting
material. b Determined by HPLC (TOSOH TSK-GEL SILICA-60, EtOAc/
1
hexane)1:12). c Determined by H NMR.
9R isomers.14 These results imply that the reaction of each
cuprate occurred from the same direction on all of the
substrates irrespective of the bulkiness of the â-substituent.
Next, we investigated conjugate addition to 6-O-crotony-
lated glucopyranoside derivative 10 (Scheme 5).15 As shown
Scheme 3
Scheme 5
first and second reagents provided predominantly the adduct
7S. These results are similar to the cases shown in Table 1.
However, the last reagent (the so-called Gilman-type cuprate)
preferentially provided 7R. This product incorporated a
reverse stereochemistry to that observed in the two cases
described above. From these results, we concluded that it is
essential to use the organocopper reagents prepared from the
corresponding Grignard reagent to realize the observed high
level of diastereoselective 1,4-addition.
in Table 4, remarkable diastereoselection was observed in
the 1,4-addition of vinyl and ethyl groups to 6-O-crotonylated
derivative 10 of methyl R-D-glucopyranoside. Quite interest-
ingly, the stereochemistry of the newly introduced stereo-
genic carbon in the predominant products 11S (R ) vinyl
or Et)16 was opposite of that in the predominant products
obtained from the 4-O-crotonyl derivatives 1a, 1b, 2a, and
2b. The precise mechanism that is responsible for the
stereochemical preference may remain uncertain until we
have accumulated sufficient experimental results. However,
it is apparent that the pivaloyloxy group at C-4 is necessary
because the C-6 crotonyl derivative bearing a benzyloxy
group at C-4 led to a lower level of diastereoselectivity (at
most 1.7 to 1) for the addition of a vinyl group.
Table 2
a Isolated yields; yields in parentheses are for the recovered starting
1
material. b Determined by H NMR.
To confirm the generality of the reaction, we examined
the conjugate addition to cinnamoyl ester derivative 8
(Scheme 4, Table 3). Two organocopper reagents prepared
from the corresponding Grignard reagent each attacked the
same face (si-face) of the â-carbon, preferentially providing
Table 4
Scheme 4
a Isolated yields; yields in parentheses are for the recovered starting
1
material. b Determined by H NMR.
Finally, removal of the carbohydrate moiety is readily
accomplished as shown for the adduct 5aR (Scheme 6).
(14) The stereochemistry of the introduced stereogenic center in the major
adduct 9R was determined by comparing the optical rotation of the acid,
which was obtained by cleavage of the carbohydrate auxiliary, to that of
known 3-vinyl-(or methyl-)3-phenylpropanoic acid.
Org. Lett., Vol. 1, No. 9, 1999
1449

be used to synthesize a variety of â-alkylated butanoic acid
derivatives in an efficient manner. Although the precise
transition states in the conjugate additions presented in this
study could not be elucidated, further utilization of the
substrates such as 2a and 2b in other types of carbon-carbon
bond-forming reactions is expected. Furthermore, we are
currently investigating the feasibility of using other hexopy-
ranosides as effective chiral auxiliaries.
Scheme 6
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research (No.10073038) from
the Ministry of Education, Science, Sports and Culture,
Japan, and in part by the Sasakawa Scientific Research Grant
from the Japan Science Society (K. Totani, 11-120).
Alkaline hydrolysis followed by extractive workup of the
reaction solution with chloroform afforded methyl 6-deoxy-
2,3-di-O-benzyl-R-D-glucopyranoside 13 (94%) in spectro-
scopically pure form. The aqueous layer was acidified, and
extraction with chloroform provided (-)-3-methyl-4-pen-
tenoic acid 12 (96%).17
Supporting Information Available: Detailed experi-
mental procedure for the synthesis of 5aR and its hydrolysis
to obtain 12, characterization of the products, and ORTEP
plot for 4bR. This material available free of charge via the
Internet at http://pubs.acs.org.
In summary, our novel asymmetric 1,4-conjugate addition
approach based on the carbohydrate auxiliary concept can
(15) Compound 10 was prepared from methyl 2,3-di-O-benzyl-R-D-
glucopyranoside7 by preferential crotonylation of 6-OH followed by
pivaloylation of 4-OH.
(16) The stereochemical assignment of 11S (R ) vinyl or Et) was
confirmed by comparison with the known optical sign of the butanoic acid,
which was obtained by removal of the carbohydrate auxiliary.
OL9909942
(17) Compound 12: [R]30.0 -17.4 (c 0.58, CHCl3); lit. [R]24 -17.42
(c 2.06, CHCl3) [Uematsu, T.; Umemura, T.; Mori, K. Agric. Biol. Chem.
1983, 47, 597-601.].
D
D
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Org. Lett., Vol. 1, No. 9, 1999