Diastereoselective Addition Reactions of Furyl Sulfonylimine Using Chiral Boronates as Auxiliary: Application to the Enantioselective Synthesis of 2,3-Disubstituted Furyl Sulfonylamides

Article abstract of DOI:10.1021/jo030385e

The addition reactions of various nucleophiles to a furyl sulfonylimine bearing a chiral boronate at the C-3 position furnished chromatographically separable diastereomers. The R diastereoselection was found to be more favorable. Further transformation of C-B bonds to C-C bonds was achieved by using standard Suzuki coupling conditions to give optically active 2,3-disubstituted furyl sulfonylamides.

Full text of DOI:10.1021/jo030385e

Dia ster eoselective Ad d ition Rea ction s of
F u r yl Su lfon ylim in e Usin g Ch ir a l
Bor on a tes a s Au xilia r y: Ap p lica tion to th e
En a n tioselective Syn th esis of
2,3-Disu bstitu ted F u r yl Su lfon yla m id es†
Ho-Kee Yim and Henry N. C. Wong*
Department of Chemistry, Institute of Chinese Medicine, and
Central Laboratory of the Institute of Molecular Technology
for Drug Discovery and Synthesis,‡
The Chinese University of Hong Kong. Shatin,
New Territories, Hong Kong SAR, China
hncwong@cuhk.edu.hk
Received December 23, 2003
Abstr a ct: The addition reactions of various nucleophiles
to a furyl sulfonylimine bearing a chiral boronate at the C-3
position furnished chromatographically separable diaster-
eomers. The R diastereoselection was found to be more
favorable. Further transformation of C-B bonds to C-C
bonds was achieved by using standard Suzuki coupling
conditions to give optically active 2,3-disubstituted furyl
sulfonylamides.
F IGURE 1. Oxidative rearrangement of furylamine and
structure of diol 2.
furylamines possess only C-2 substituents. 2,3-Disubsti-
tuted furylamines, on the other hand, have attracted
much less attention.
1,6-Dihydro-2H-pyridin-3-one (1) is a useful intermedi-
ate for the synthesis of bioactive natural products.1 It
contains several functionalities that allow its conversion
to many potential precursors or valuable natural prod-
ucts (Figure 1).2 Although there are many possible ways
to synthesize derivatives of 1, the easiest and simplest
method is based on the aza-Achmatowicz reaction, an
oxidative rearrangement of furylamines.3
Although various methods have been developed for the
synthesis of optically active furylamines,4 the nucleophilic
addition to imino group has not been too actively inves-
tigated as compared to those for carbonyl compounds, the
major difference being the poor electrophilicity of the
imino group. Generally, this difficulty could be overcome
by activation of the imino group through the introduction
of an electron-withdrawing substituent. Despite the high
yield and high enantioselectivity, all the synthesized
The boronic ester of (2R,3R)-1,4-dimethoxy-1,1,4,4-
tetraphenyl-2,3-butanediol (2)5 has been used as an
efficient chiral auxiliary in asymmetric synthesis.6 More-
over, in our earlier work, we have successfully employed
a similar strategy to synthesize various optically active
2,3-disubstituted furyl alcohols from furyl aldehyde 3
with high diastereoselectivities.7 In connection with our
interest in the realization of highly functionalized dihy-
dropyridone 1, we herewith wish to report our employ-
ment of boronic ester as chiral auxiliary for the synthesis
of optically pure 2,3-disubstituted furylamines.
Employing our own experience on the regiospecific
synthesis of substituted furans,8 furyl sulfonylimine 7
was designed as our initial target molecule, which in turn
was synthesized from commercially available 3-bromo-
furan (4) via the regiospecific route as shown in Scheme
1.
In earlier work, we disclosed that for the addition
reactions to furyl aldehyde 3, the Re-face attack of
nucleophiles to the carbonyl group of 3 was found to be
more favorable.7a This result was consistent with infor-
mation being obtained from both X-ray crystallography
(solid state) and AM1 calculations (solution state).9 From
the X-ray crystallographic analysis of 7, it can be clearly
† Dedicated to Professor Sunney I. Chan on the occasion of his
retirement.
‡ An area of Excellence of the University Grants Committee (Hong
Kong).
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Yang, C. F.;
Liao, L. X.; Xu, Y. M.; Zhang, H. X.; Xia, P.; Zhou, W. S. Tetrahedron:
Asymmetry 1999, 10, 2311. (c) Michael, J . P. Nat. Prod. Rep. 1997, 14,
619. (d) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 11, 135.
(2) (a) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401. (b)
Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetrahedron
2002, 58, 9621. (c) Zhang, H. X.; Xia, P.; Zhou, W. S. Tetrahedron 2003,
59, 2015.
(3) (a) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett 1998, 105. (b) Achmatowicz, O., J r.;
Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Tetra-
hedron 1971, 27, 1973.
(4) (a) Bushey, M. L.; Haukaas, M. H.; O’Doherty, G. A. J . Org.
Chem. 1999, 64, 2984. (b) Zhou, W. S.; Lu, Z. H.; Wang, Z. M.
Tetrahedron 1993, 49, 2641. (c) Kobayashi, S.; Ishitani, H.; Ueno, M.
J . Am. Chem. Soc. 1998, 120, 431. (d) Willoughby, C. A.; Buchwald, S.
L. J . Am. Chem. Soc. 1994, 116, 8952. (e) Koriyama, Y.; Nozawa, A.;
Hayakawa, R.; Shimizu, M. Tetrahedron 2002, 58, 9621.
(5) Nakayama, K.; Rainer, J . D. Tetrahedron 1990, 46, 4165.
(6) (a) Luithle, J . E. A.; Pietruszka, J . J . Org. Chem. 2000, 65, 9194.
(b) Luithle, J . E. A.; Pietruszka, J . Eur. J . Org. Chem. 2000, 2557. (c)
Luithle, J . E. A.; Pietruszka, J . J . Org. Chem. 1999, 64, 8287. (d)
Luithle, J . E. A.; Pietruszka, J .; Witt, A. J . Chem. Soc., Chem.
Commun. 1998, 2651.
(7) (a) Chan, K. F.; Wong, H. N. C. Org. Lett. 2001, 3, 3991. (b) Chan,
K. F.; Wong, H. N. C. Eur. J . Org. Chem. 2003, 82.
(8) Wong, M. K.; Leung, C. Y.; Wong, H. N. C. Tetrahedron 1997,
53, 3497.
10.1021/jo030385e CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/13/2004
2892
J . Org. Chem. 2004, 69, 2892-2895

F IGURE 2. X-ray crystal structure of 7. The black arrows show the predicted more favorable Re-face attack.
TABLE 1. Ad d ition Rea ction s of Va r iou s Nu cleop h iles
SCHEME 1. Syn th esis of F u r yl Su lfon ylim in e 7
to 7a
seen that furyl sulfonylimine 7 (Figure 2) retains a
geometry similar to that of furyl aldehyde 3 with furan
and borolane rings arranging on the same side. In this
way, the Si-face of the imino group of furyl sulfonylimine
7 is blocked by the bulky substituents, and as a result
the less hindered Re-face attack of nucleophiles to the
imino group is therefore expected. Moreover, the huge
geometric differentiation and conformational difference
between the resulting diastereomers should also allow a
successful separation of both diastereomers by common
flash column chromatography.
The addition reactions of various nucleophiles to 7
afforded diastereomers 8a -d and 9a -d in good yields
and good diastereoselectivities (Table 1). As anticipated,
all these diastereomers could be efficiently separated by
flash column chromatography and the newly created
chiral centers were confirmed directly or indirectly by
X-ray crystallographic analyses.10 It was found that
the R diastereomers 8a -d were more polar than S
diastereomers 9a -d .
conditions
(solvent,
T (°C)
yieldb dec
entry
nucleophile
n-BuLi
n-BuLi
n-BuLi
products (%)
(%)
1
2
3
4
5
6
7
THF, -78 8a 9a
DME, -60 8a 9a
PhMe, -78 8a 9a
THF, -78 8b 9b
THF, -40 8c 9c
DME, -30 8c 9c
THF/Et2O 8c 9c
1:4
THF/Et2O 8c 9c
1:8
DCM, -40 8c 9c
PhH, -40
45 33 (R)
58 33 (R)
64 33 (R)
35 33 (R)
94 20 (R)
81 83 (R)
88 80 (R)
t-BuLi
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
8
9
Me3SiCH2MgCl
Me3SiCH2MgCl
85 86 (R)
82 25 (R)
78 56 (R)
90 25 (R)
75 74 (R)
80 78 (R)
10 Me3SiCH2MgCl
8c 9c
11 CH2dC(SiMe3)MgBr THF, -40 8d 9d
12 CH2dC(SiMe3)MgBr DME, -30 8d 9d
13 CH2dC(SiMe3)MgBr THF/Et2O 8d 9d
1:4
14 CH2dC(SiMe3)MgBr THF/Et2O 8d 9d
1:8
76 80 (R)
a
The difficulty of performing an addition reaction to
imines is a result of the poor electrophilicity of imines,
which proved to be rather inert to alkyl Grignard
reagents.11 Fortunately, encouraging results were ob-
tained by employing Me3SiCH2MgCl and CH2dC(SiMe3)-
MgBr as nucleophiles. As shown in Table 1, the addition
reactions to 7 with Me3SiCH2MgCl furnished furyl sul-
All reactions were carried out by adding nucleophiles (4 equiv)
to furyl sulfonylimine 7. Total isolated yield of 8 and 9. c Deter-
b
mined by 1H NMR analysis of crude mixture. The major diaste-
reomer is indicated in the parentheses.
fonylamides 8c and 9c in high yields (Table 1, entries
5-10). It is surprising that the choice of solvent greatly
affects the diastereoselectivity of the addition reaction.
When THF was employed, low diastereoselectivity was
observed (Table 1, entry 5). However, when the less Lewis
basic DME was employed as solvent, the diastereoselec-
tivity was tremendously increased to over 80% (Table 1,
entry 6). It should be mentioned that Et2O was not
employed as solvent because of the poor solubility of the
starting material. Surprisingly, however, when a mixture
(9) Courtesy of Prof. Yundong Wu, The Hong Kong University of
Science and Technology.
(10) See the Supporting Information.
(11) (a) Yamaguchi, M. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 325.
(b) Volmann, R. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; p 355. (c) Stork, G.;
Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178.
J . Org. Chem, Vol. 69, No. 8, 2004 2893

F IGURE 3. Proposed transition states for the addition reaction of metal enolates to 7.
TABLE 2. Ad d ition Rea ction of En ola tes 10 a n d 11 to 7a
TABLE 3. Su zu k i Cou p lin g Rea ction s of 8 a n d 9
starting conditiona
R
product yield (%)
8b
8c
8d
9b
9c
9d
A
B
B
A
B
B
t-Bu
Me3SiCH2
CH2dC(SiMe3)MgBr
t-Bu
Me3SiCH2
12a
12b
12c
13a
13b
13c
62
88
82
64
90
82
conditions
(solvent,
T (°C)
yieldb
(%)
dec
(%)
entry enolate
metalb
Li
Na
products
CH2dC(SiMe3)MgBr
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10d
11a
11b
11c
11d
11d
THF, -78 8e
THF, -78 8e
9e
9e
9e
9e
9e
9f
9f
9f
9f
9f
76
54
92
95
96
68
56
88
85
88
46 (R)
20 (R)
83 (R)
92 (R)
94 (R)
36 (R)
38 (R)
86 (R)
96 (R)
99 (R)
a
A ) Ba(OH)2, PhMe/MeOH (1:1), reflux, 2 h. B ) 2 M K3PO4,
Ti(OiPr)3 THF, -78 8e
DME/H2O (4:1), reflux, 2 h.
Et2Al
Et2Al
Li
THF, -78 8e
DME, -78 8e
THF, -78 8f
THF, -78 8f
increases its reactivity. This combined effect, neverthe-
less, would at the same time decrease its diastereoselec-
tivity toward the imino group.
Na
Ti(OiPr)3 DME, -78 8f
Et2Al
Et2Al
THF, -78 8f
DME, -78 8f
Asymmetric Mannich-type reactions are known to
provide useful routes for the synthesis of optically active
â-amino ketones or esters, which are versatile chiral
building blocks in the preparation of many nitrogen-
containing biologically important compounds.13 Encour-
aging results were obtained from the addition reactions
of metal enolates 10 to 7. As shown in Table 2, the
addition products 8e and 9e were obtained in good yield
and excellent diastereoselectivity. Aluminum and tita-
nium enolates (Table 2, entries 3-5) gave significantly
better results than lithium and sodium enolates (Table
2, entries 1-2).
When the reaction was carried out in DME, the best
result was observed with 96% isolated yield and with 94%
de (Table 2, entry 5). More bulky enolates 11 were also
examined for the addition reactions to 7 (Table 2, entries
6-10), and similar results were also observed. The
diastereoselectivity could be predicted by employing a
chelation-control model. In the case of aluminum and
titanium enolates, a six-membered chairlike transition
10
a
All reactions were carried out by adding enolates (4 equiv) to
b
furyl sulfonylimine 7. For transmetalation, metal halides such
as Et2AlCl and Ti(OiPr)3 were added to the lithium enolates at
-78 °C, and the resulting enolate was stirred for 30 min. c Total
isolated yield of 8 and 9. Determined by 1H NMR analysis of
d
crude mixture. The major diastereomer is indicated in the
parentheses.
of THF and Et2O in a ratio of 1:4 was employed as
solvent, the diastereoselectivity was greatly increased to
80% (Table 1, entry 7). Further increasing the solvent
ratio of THF and Et2O to 1:8 gave the best result with
85% yield and 86% de. Similar results were observed
when CH2dC(SiMe3)MgBr was used instead as the
nucleophile (Table 1, entries 11-14). This phenomenon
can be briefly explained in terms of the Grignard re-
agent’s reactivity.12 A more strongly Lewis basic solvents
such as THF would increase the number of monomeric,
solvated species of the Grignard reagent, as well as
leading to enhanced polarity of the C-Mg bond, thereby
(13) (a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 893.
(b) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
VCH: Weinheim, 1997.
(12) Wakefield, B. J . Organomagnesium Methods in Organic Syn-
thesis; Academic Press: London, 1995; Chapter 1.
2894 J . Org. Chem., Vol. 69, No. 8, 2004

F IGURE 4. Suzuki coupling reaction of 14.
state I and/or a seven-membered counterpart II may
likely be involved (Figure 3). It should be mentioned that
in the transition state II, the chelation between the
metals with the oxygen of sulfonyl group and the oxygen
of furan ring might be involved. Moreover, the transition
states I and II are both responsible for the formation of
R-diastereomers because the Si-face of the imine group
is sterically hindered by the bulky group of the boronic
ester so that the enolates approach from a less sterically
congested Re-face, forming the C-C bond with high
diastereoselectivity.
The Suzuki coupling reactions of chiral furyl sulfonyl-
amides 8 and 9 with organic halides provide an efficient
method to realize optically pure 2,3-disubstituted furyl
sulfonylamides. It is not surprising that all Suzuki
coupling reactions between the furyl sulfonylamides and
iodobenzene proceeded smoothly to furnish furyl sulfo-
nylamides 12, 13 (Table 3), and 15 (Figure 4) in high
yields. In addition, the optically pure 2,3-disubstituted
furyl sulfonylamides could serve as important precursors
for dihydropyridone 1. Thus, treatment of furyl sulfony-
lamide 13b and 16 with m-chloroperbenzoic acid in CH2-
Cl2 at room temperature furnished dihydropyridone 1a
in 94% yield and 1b in 83% yield, respectively (Figure
5).
F IGURE 5. Oxidative rearrangement of 13b and 16.
achieved by employing palladium-catalyzed Suzuki cou-
pling with various halides to furnish optically active 2,3-
disubstituted furyl sulfonylamides. Oxidative rearrange-
ment of these optically active 2,3-disubstituted furyl
sulfonylamides afforded highly functionalized dihydro-
pyridone 1, which is a useful building block for natural
product synthesis.
Ack n ow led gm en t. The work described in this paper
was supported by a grant from the Research Grants
Council of the Hong Kong SAR, China (Project No.
CUHK 4178/97P), a Direct Grant (A/C No. 2060186)
administered by the Chinese University of Hong Kong,
and the Areas of Excellence scheme established under
the University Grants Committee of the Hong Kong
SAR, China (Project No. AoE/P-10/01).
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedures and characterization of all new compounds
and ORTEP drawings of compounds 7, 8a , and 9c,e,f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have described the addition reactions
of 7 with different nucleophiles such as Grignard re-
agents and alkyllithiums. The transformation of the
carbon-boron bond of chiral furyl sulfonylamides was
J O030385E
J . Org. Chem, Vol. 69, No. 8, 2004 2895