Allylic substitution on the pyran ring

Article abstract of DOI:10.1016/j.tetlet.2009.03.018

Allylic substitution of pyrans 10 and 15 possessing the picolinoxy leaving group with several alkyl and aryl copper reagents derived from RMgBr and CuBr·Me₂S was studied. First, reaction of 10 with three copper reagents derived from EtMgBr (2 e

Full text of DOI:10.1016/j.tetlet.2009.03.018

Tetrahedron Letters 50 (2009) 3547–3549
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Allylic substitution on the pyran ring
*
Tomonori Hyodo, Yuji Katayama, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Allylic substitution of pyrans 10 and 15 possessing the picolinoxy leaving group with several alkyl and
aryl copper reagents derived from RMgBr and CuBrꢀMe2S was studied. First, reaction of 10 with three cop-
per reagents derived from EtMgBr (2 equiv) and different equivalents of CuBrꢀMe2S (2, 1, and 0.5 equiv,
respectively) was examined in THF at ꢁ20 °C for 1 h to afford anti SN20 product 16a in high yields in
all cases. Under these reaction conditions Me, i-Pr, Ph, o-MeC6H4, and o-MeOC6H4 were installed on
the pyran ring of 10 successfully. Similar results were also obtained with pyran 15.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 January 2009
Revised 2 March 2009
Accepted 5 March 2009
Available online 9 March 2009
Substituted pyrans are a class of biologically active com-
pounds,1 while such a structure has been used as a mimic of spe-
cific amino acids in peptides.2 To install substituent on the pyran
ring Claisen rearrangement,3 BF3-catalyzed allylation,4 Indium-
mediated reaction with carbonyl compounds,5 Pd-catalyzed [3+2]
cyclization,6 Pd-catalyzed allylic substitution with soft nucleo-
philes,7 allylic substitution with copper reagents as hard nucleo-
philes,8 etc.9 have been studied so far. Among these reactions we
were attracted by the last type because various types of alkyl
and aryl groups are installed in principle.10 This possibility, how-
ever, has limitedly been studied using pyrans possessing the acet-
oxy and pivaloxy (t-BuCO2) leaving groups and organocopper
reagents derived from RLi and CuX to afford anti SN20 products 2
in moderate to good yields8b,c (Fig. 1). In contrast, reaction of BTZ
ethers with copper reagents derived from Grignard reagents pro-
duces syn or anti SN20 products depending on the nature of R in
(R2Cu)MgBr: that is, syn products 3 from Me, n-Bu, i-Pr cuprates;
anti product 2 from the Ph cuprate.8d,e Interestingly, the corre-
sponding thio ethers afford syn SN20 products independent of the
R group in (R2Cu)MgBr.
R3
R3
" R3–Cu"
L
;
;
R1
O
OR2
R1
O
OR2
R1
O
OR2
syn SN2'
product (3)
1
anti SN2'
product (2)
and two stereoisomers of
SN2 products
previous results with
R1: CH2OR (R = Ac, Piv, Bz)
N
N
O
L: AcO, PivO,
,
S
S
S
(BTZ-O)
(BTZ-S)
present study with
R1: C5H11, CH2OTBS
CO2
N
L:
Recently, (2-Py)CO2 has been reported by us as a new leaving
group for allylic substitution with copper reagents as illustrated
in Scheme 1.11,12 Although the leaving group is quite stable for
purification by chromatography, MgBr2 formed in situ from
R3MgBr and CuBrꢀMe2S or added from outside activates this group
through chelation, thus attaining high anti SN20 selectivity even
with aryl and alkenyl coppers, which are less selective in the reac-
tion with allylic esters such as acetates and pivalates due to the
low reactivity.10 With these findings in mind, we studied the allylic
substitution shown in Figure 1 with a hope that the picolinates will
Figure 1. Allylic substitution of pyrans 1 and possible stereo- and regioisomers.
R3MgBr / CuBr·Me2S
or
N
R3Li / CuBr·Me2S
with MgBr2
R3
O
O
R2
R1
R2
R1
anti SN2' mode
5
4
* Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
Scheme 1. Allylic substitution using (2-Py)CO2 as a leaving group.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.018

3548
T. Hyodo et al. / Tetrahedron Letters 50 (2009) 3547–3549
moiety to form p-allyl Pd complexes.13 The picolinates were syn-
O
t-BuOOH
C5H11
thesized by the methods delineated in Schemes 2 and 3, respec-
O
tively. In brief, alcohol 6 (½a D24
ꢂ
+14.3 (c 0.61, CHCl3); lit. ½a D25
ꢂ
VO(acac)2 (cat.)
78%
C5H11
O
OH
OH
+13.8 (c 1.07, CHCl3)) was synthesized efficiently (45% yield) by
the kinetic resolution of the racemic alcohol under the asymmetric
epoxidation conditions according to the literature14 (t-BuOOH, L-
(+)-DIPT, Ti(OPr)4) and oxidatively converted to pyranone hemiac-
etal 7 as a 2:1 anomeric mixture. The anomeric hydroxyl group of 7
was protected as a Piv ester with 93% stereoselectively under the
conditions disclosed. The minor stereoisomer was separated easily
by chromatography. Reduction of the ketone 8 with NaBH4 in
MeOH at ꢁ78 °C was stereoselective and subsequent esterification
of the resulting alcohol 9 with (2-Py)CO2H and DCC produced pico-
linate 1015 in high yield. As for picolinate 15, asymmetric reduction
of ketone 11 with the Ru diamine catalyst developed by Noyori16
produced alcohol 12,17 which was 94% ee by chiral HPLC (chiral
AD-H). NBS oxidation of 12 afforded an anomeric mixture of the
pyranone (3:2 ratio). Subsequent Piv protection under the condi-
tions reported18 was quite slow (DMAP (cat.), Et3N, CH2Cl2,
ꢁ78 °C), whereas the conditions used above gave the Piv-protected
pyranone 13 and its diastereoisomer in a 75:25 ratio. Fortunately,
13 was purified easily by chromatography. Further transformation
was carried out successfully to afford picolinate 1515 in good yield.
According to the previous success for anti SN20 reaction with the
three types of reagents derived from RMgBr and CuBrꢀMe2S in the
ratios of 1, 2, and 4:1, three reagents derived from EtMgBr (2 equiv)
and CuBrꢀMe2S (2, 1, or 0.5 equiv) at 0 °C for 30 min in THF were
subjected to reaction with 10 at ꢁ20 °C for 1 h (Table 1, entries
1, 2, and 4). The product 16a (anti SN20 product) was obtained in
high yields, whereas the stereoisomer of 16a (syn SN20 product),
7
6
O
NaBH4
PivCl / DMAP
MeOH, –78 °C, 2 h
92%
C5H11
O
OPiv
THF, 0 °C, 1 h
71%
8
HO
(2-Py)CO2
C5H11
(2-Py)CO2H
DCC
C5H11
O
OPiv
O
OPiv
96%
9
10
Scheme 2. Synthesis of pyran 10.
TBSO
TBSO
TBSO
Noyori-Ru
1) NBS
O
O
i
-PrOH
~ 100%
2) PivCl / DMAP
57%
O
O
OH
11
12
RO
TBSO
NaBH4
O
OPiv
O
OPiv
14, R = H
15, R = (2-Py)CO2
66% from 13
(2-Py)CO2H
DCC
13
the regioisomer, and the product(s) that reacted at the
c
a and/or
Scheme 3. Synthesis of pyran 15.
position of the allylic pivalate moiety were not detected by 1H
NMR spectroscopy. For determination of the regio- and stereo-
chemistries of 16a, the product was transformed to the known
compound 19a19 as shown in Scheme 4 since the coupling con-
stants between the protons on the pyran ring were not decisive
for determination. In another experiment at ꢁ40 °C, a mixture of
16a and a small amount of alcohol 9 were produced (entry 3).
On the basis of these results, following reactions were conducted
at ꢁ20 °C for 1 h.20 The Me and i-Pr copper reagents of the 2:1 ratio
underwent smooth reaction to produce the desired anti SN20
expand the scope of the copper reagents. Herein, we present re-
sults of this study.
As typical examples we chose picolinates 10 and 15, in which
the anomeric hydroxyl group was protected as the pivaloxy group.
Although the pivaloxy group constitutes another allylic moiety, we
expected almost no allylic substitution at the allylic pivalate moi-
ety because of the higher reactivity of the picolinoxy leaving group
than the pivaloxy group and because of the low reactivity of this
Table 1
Allylic substitution of pyrans 10 and 15 with alkyl and aryl copper reagentsa
R3
R3MgBr / CuBr·Me2S
THF, 1 h
(2-Py)CO2
R1
R1
O
OPiv
O
OPiv
10, R1 = C5H11
16a– f, R1 = C5H11
17a– f, R1 = CH2OTBS
15, R1 = CH2OTBS
Entry
Substrate
Reagent
R3/Cu ratio
Temp (°C)
Major product
R3
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
10
10
10
10
10
10
10
10
10
10
15
15
15
15
15
EtCuꢀMgBr2
1:1
2:1
2:1
4:1
2:1
2:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
ꢁ20
ꢁ20
ꢁ40
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
16a
16a
16a
16a
16b
16c
16d
16d
16e
16f
17a
17b
17d
17e
17f
Et
Et
Et
Et
Me
i-Pr
Ph
Ph
o-MeC6H4
o-MeOC6H4
Et
Me
Ph
93
97
80
93
93
92
94
95
95
92
80
94
71
91
89
Et2CuMgBrꢀMgBr2
Et2CuMgBrꢀMgBr2
EtMgBr/CuBrꢀMe2S
Me2CuMgBrꢀMgBr2
i-Pr2CuMgBrꢀMgBr2
PhCuꢀMgBr2
Ph2CuMgBrꢀMgBr2
(o-MeC6H4)2CuMgBrꢀMgBr2
(o-MeOC6H4)2CuMgBrꢀMgBr2
Et2CuMgBrꢀMgBr2
Me2CuMgBrꢀMgBr2
Ph2CuMgBrꢀMgBr2
(o-MeC6H4)2CuMgBrꢀMgBr2
(o-MeOC6H4)2CuMgBrꢀMgBr2
o-MeC6H4
o-MeOC6H4
a
Reactions were carried out with the indicated reagent (2 equiv) at ꢁ20 °C for 1 h in THF.

T. Hyodo et al. / Tetrahedron Letters 50 (2009) 3547–3549
3549
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1) DIBAL
–78 °C
R3
R3
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2008, 10, 1719–1722.
O
OPiv
OH OH
C5H11
C5H11
2) NaBH4
MeOH
16a,d
18a,d
OH
R2
1) TBSCl, Imid.
DMF, –20 °C
2) O3, MeOH
then NaBH4
OTBS
19a, [α]D23 –12(
c
0.54, CHCl3)
1.42, CHCl3)
lit., [α]D26 –11.41 (
for ( )-enantiomer
19d, [α]D29 –18(
0.47, CHCl3)
lit., [α]D23 +14.6 (
1.03, CHCl3)
for ( )-enantiomer
c
S
c
c
R
Scheme 4. Transformation of 16a and 16d to the known compounds. R3 for 16, 18,
19: a, Et; d, Ph.
12. Kiyotsuka, Y.; Kobayashi, Y. Tetrahedron Lett. 2008, 49, 7256–7259.
13. (a) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
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2085–2091.
products 16b and 16c, respectively, in high yield (entries 5 and 6).
No isomers were detected as well. However, t-Bu2CuMgBrꢀMgBr2
afforded a complex mixture (no entry given). Next, the Ph reagents
of PhCuꢀMgBr2 and Ph2CuMgBrꢀMgBr2 were subjected to the reac-
tion to afford 16d in good yields (entries 7 and 8). The structure of
16d was confirmed by transformation to the known alcohol 19d21
as shown in Scheme 4. Reaction with sterically more hindered re-
agents given in entries 9 and 10 proceeded without a hitch to af-
ford 16e and 16f, respectively.
In a similar way, reaction of the other picolinate 15 with the Me,
Et, and Ph copper reagents at ꢁ20 °C in THF was examined under
the conditions established above to afford the corresponding prod-
ucts 17a,b,d regio- and stereoselectively in high yields: cf. 50–74%
yields for the BTZ ether 1.8e Further experimentation with o-
MeC6H4 and o-MeOC6H4 reagents furnished the products 17e and
17f efficiently.
15. Spectral data: Compound 10: ½a D23
ꢂ
+79 (c 0.65, CHCl3); 1H NMR (300 MHz,
CDCl3) d 0.85 (t, J = 6.5 Hz, 3H), 1.24 (s, 9H), 1.20–1.74 (m, 8H), 4.10 (dt, J = 9,
2 Hz, 1H), 5.54 (dq, J = 9, 1.5 Hz, 1H), 5.87 (ddd, J = 10, 3, 2 Hz, 1H), 6.12 (dt,
J = 10, 1 Hz, 1H), 6.33 (br s, 1H), 7.53 (ddd, J = 8, 5, 1 Hz, 1H), 7.89 (dt, J = 8, 2 Hz,
1H), 8.17 (dt, J = 8, 1 Hz, 1 H), 8.81 (dm, J = 5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 14.0 (ꢁ), 22.6 (+), 24.7 (+), 27.1 (ꢁ), 31.4 (+), 31.5 (+), 39.0 (+), 70.3 (ꢁ), 70.7
(ꢁ), 88.0 (ꢁ), 125.5 (ꢁ), 126.4 (ꢁ), 127.3 (ꢁ), 131.1 (ꢁ), 137.1 (ꢁ), 147.6 (+),
150.1 (ꢁ), 164.7 (+), 177.4 (+); HRMS (FAB) calcd for C21H30NO5 [(M+H)+]
376.2124, found 376.2128. Compound 15: ½a D25
ꢂ
+49 (c 1.20, CHCl3); 1H NMR
(300 MHz, CDCl3) d ꢁ0.02 (s, 6H), 0.83 (s, 9H), 1.22 (s, 9H), 3.79–3.85 (m, 2H),
4.21 (dt, J = 10, 4 Hz, 1H), 5.72 (dq, J = 10, 1.5 Hz, 1H), 5.87 (ddd, J = 10, 3, 2 Hz,
1H), 6.14 (d, J = 10 Hz, 1H), 6.36 (br s, 1H), 7.51 (ddd, J = 8, 4.5, 1 Hz, 1H), 7.87
(dt, J = 1.5, 8 Hz, 1H), 8.16 (dt, J = 8, 1 Hz, 1H), 8.79 (dm, J = 4.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d ꢁ5.4 (ꢁ), 5.3 (ꢁ), 18.4 (+), 25.9 (ꢁ), 27.1 (ꢁ), 39.0 (+),
62.7 (+), 66.5 (ꢁ), 71.7 (ꢁ), 88.1 (ꢁ), 125.1 (ꢁ), 126.4 (ꢁ), 127.2 (ꢁ), 130.5 (ꢁ),
137.1 (ꢁ), 147.7 (+), 150.1 (ꢁ), 164.5 (+), 177.3 (+).
16. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521–2522.
In summary, allylic substitution with the picolinoxy leaving
group was established to be an efficient method to install alkyl
and aryl groups on the pyran ring. The groups investigated were
Me, Et, i-Pr, Ph, o-MeC6H4, and o-MeOC6H4, and these results would
be a good guideline for designing substituted pyrans.
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Zhou, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 4339–4342; (c) Zhou, M.;
O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493.
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2983; (b) Harris, J. M.; Keränen, M. D.; Nguyen, H.; Young, V. G.; O’Doherty, G.
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Acknowledgments
20. Typical procedure: To an ice-cold suspension of CuBrꢀMe2S (252 mg, 1.23 mmol)
in THF (10 mL) was added EtMgBr (2.34 mL, 1.05 M in THF, 2.46 mmol)
dropwise. After 30 min of stirring, the resulting mixture was cooled to ꢁ20 °C,
and a solution of 10 (230 mg, 0.613 mmol) in THF (5 mL) was added to the
mixture dropwise. The resulting mixture was stirred at ꢁ20 °C for 1 h, and
diluted with hexane and saturated NH4Cl with vigorous stirring. The crude
product thus obtained was purified by chromatography on silica gel (hexane/
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
References and notes
EtOAc) to afford 16a (168 mg, 97%): ½ ꢂ
a 2D2 +86 (c 0.92, CHCl3); 1H NMR
(300 MHz, CDCl3) d 0.88 (t, J = 7 Hz, 3H), 0.99 (t, J = 7 Hz, 3H), 1.21 (s, 9H), 1.20–
1.62 (m, 10H), 1.89–1.98 (m, 1H), 4.25 (br s, 1H), 5.68 (d, J = 11 Hz, 1H), 5.76
(ddt, J = 11, 5, 2 Hz, 1H), 6.01 (s, 1H); 13C NMR (75 MHz, CDCl3) d 11.3 (ꢁ), 14.1
(ꢁ), 22.6 (+), 24.5 (+), 26.4 (+), 27.1 (ꢁ), 31.9 (+), 34.8 (+), 39.0 (+), 39.4 (ꢁ), 69.3
(ꢁ), 94.2 (ꢁ), 125.3 (ꢁ), 128.2 (ꢁ), 177.3 (+).
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