Total synthesis of (-)-centrolobine: β-C-glycoside formation via a tandem Grignard addition and stereoselective hemi-ketal reduction

Article abstract of DOI:10.1016/j.tetlet.2005.01.156

It has been demonstrated that an aryl-β-C-glycoside can be efficiently constructed via a sequence consisting of Brown asymmetric allylation, ring-closing metathesis, hydrogenation, nucleophilic addition, and stereoselective Et₃SiH reduction. Th

Full text of DOI:10.1016/j.tetlet.2005.01.156

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2021–2024
Total synthesis of (À)-centrolobine: b-C-glycoside
formation via a tandem Grignard addition and stereoselective
hemi-ketal reduction
Michael P. Jennings* and Ryan T. Clemens
Department of Chemistry, 500 Campus Drive, The University of Alabama, Tuscaloosa, AL 35487-0336, USA
Received 6 November 2004; revised 27 January 2005; accepted 27 January 2005
Abstract—It has been demonstrated that an aryl-b-C-glycoside can be efficiently constructed via a sequence consisting of Brown
asymmetric allylation, ring-closing metathesis, hydrogenation, nucleophilic addition, and stereoselective Et3SiH reduction. The anti-
biotic natural product (À)-centrolobine was synthesized in this manner utilizing only five steps with an overall 53% yield.
Ó 2005 Elsevier Ltd. All rights reserved.
R'
O
R'
Over the past two decades, the construction of a- and b-
C-glycosides has become increasingly important in the
synthesis of biologically active natural products. Along
this line, there has been substantial growth in new syn-
thetic methodology within this area. Such building
blocks have been synthesized by using several methodol-
ogies including the hetero-atom Diels–Alder reaction,1
Petasis–Ferrier rearrangement,2 intermolecular silyl-
modified Sakurai and Prins cyclizations,3 exo-Pd-
mediated allylic etherification,4 radical cyclization,5
and intramolecular Michael addition with oxygen
nucleophiles.6
H-
R'
HO
O
a) R'MgX
O
O
b) BF3.OEt2
Et3SiH
O
O
+
O
R
R
R
R
R
R
H-
R'
O
R'
HO
O
a) R'MgX
b) BF3.OEt2
Et3SiH
+
O
R
R
R'
H-
Scheme 1.
Et3SiH should proceed in a very stereoselective manner
to provide the dehydro-b-C-glycoside.
With this in mind, we were interested in expanding
Kishiꢀs strategy for the synthesis of b-C-glycosides.7
To the best of our knowledge, there are no reports of
a nucleophilic addition/reduction sequence to an a,b-
unsaturated lactone as shown in Scheme 1. We envi-
sioned utilizing such a methodology for the synthesis
of dehydro-b-C-glycosides. In turn, these compounds
could readily serve as advanced intermediates for the
synthesis of a variety of natural products. As reported
for the synthesis of dehydro-a-C-glycosides8 and shown
in Scheme 1, it was reasoned that the reduction of the in
situ generated a,b-unsaturated oxonium cation with
(À)-Centrolobine (1) is a naturally occurring antibiotic,
isolated from the heartwood of Centrolobium robustum
and from the stem of Brosimum potabile, both indige-
nous to tropical South America.9 Solladie and co-work-
ers were the first to disclose the asymmetric total
synthesis and thus determined the absolute configura-
tion of (À)-centrolobine.10 Three other total syntheses
of 1 have independently since been reported.11 The rela-
tively simple structure of (À)-centrolobine makes it an
ideal target for testing synthetic methodologies of b-C-
glycosides.
As shown in Scheme 2, our initial approach to the syn-
thesis of 1 was based on a stereoselective reduction of a
cyclic a,b-unsaturated oxonium cation mediated by the
treatment of an appropriate hemi-ketal with Lewis acid.
Keywords: C-Glycoside; Centrolobine; Ring-closing metathesis; One-
pot reaction; Tetrahydropyran.
*
Corresponding author. Tel.: +1 205 348 0351; fax: +1 205 348
9104; e-mail: jenningm@bama.ua.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.156

2022
M. P. Jennings, R. T. Clemens / Tetrahedron Letters 46 (2005) 2021–2024
O
O
O
O
MeO
MeO
a) 4-MeOPhMgBr
BF3.OEt2, Et3SiH
O
2
1
BnO
OH
OBn
MeO
OBn
3
8
O
b) H2/Pd-C
OH
O
O
MeO
MeO
OH
OH
1
BnO
O
BnO
4
3
+
MeO
OBn
9
Scheme 2. Retrosynthetic analysis of 1.
HO
10
In turn, the hemi-ketal was envisaged to be derived from
a nucleophilic addition of the 4-methoxyphenyl Grig-
nard reagent to the corresponding lactone 3. With the
dehydro-b-C-glycoside in hand, a global hydrogenation
was reserved for the concomitant removal of both the
unsaturation and the benzyl protecting group resident
in 2 to provide the natural product 1.
Scheme 4. Attempted synthesis of 1: Reagents and conditions: 4-
MeOPhMgBr (1.0 equiv), THF, À78 °C, 1.5 h, then Et3SiH
(10.0 equiv), BF3ÆOEt2 (5.0 equiv), CH3CN, À30 °C, 45 min, then
0 °C to rt, 1 h, 24%; (b) Pd/C (1.0% mol), EtOH, rt, 10 h, 10%.
to optimize the nucleophilic addition to 3 with the 4-
methoxyphenyl Grignard reagent, but these efforts were
unsuccessful beyond a 30% yield. We are currently
investigating this addition/reduction sequence with a
variety of other nucleophilic coupling partners.
The synthesis of 1 was initiated with the previously re-
ported benzyl protected aldehyde 5 as shown in Scheme
3. Thus, allylation of 511a with allyl magnesium bromide
furnished the homoallylic alcohol 4 in 84% yield. Ester-
ification of 4 with acryloyl chloride and subsequent ring-
closing olefin metathesis (0.017 M) with 5 mol% of
Grubbsꢀ second-generation catalyst (7) proceeded
smoothly and provided lactenone 3 in a 75% yield over
two steps.12
In the short term, we were interested in completing the
targeted natural product and treatment of 8 with the
standard catalytic hydrogenation protocol (Pd/C,
1 atm of H2, EtOH, 2 h) readily removed the olefin dou-
ble bond, but did not cleave the benzyl-protecting
group. Further hydrogenation of the Bn protected inter-
mediate 9, for additional 10 h surprisingly afforded only
10% of the desired final natural product 1, coupled with
the ring cleaved compound 10 in 82% yield.13 The pro-
posed mechanism leading to the formation of 10 is delin-
eated in Scheme 5.
The attempted transformation of lactenone 3 into cen-
trolobine over two steps is highlighted in Scheme 4.
With this in mind, nucleophilic addition of 4-methoxy-
phenylmagnesium bromide to lactenone 3 followed by
Lewis acid promoted a,b-unsaturated oxonium forma-
tion and subsequent stereoselective Et3SiH reduction
furnished the cis-2,6-disubstituted dehydro-pyran inter-
mediate 8 in 24% yield. Initially, we were pleased by
the stereoselective nature of the addition/reduction se-
quence. It was deemed that the unsaturation resident
in 3 hindered the nucleophilic addition to the carbonyl
moiety and thus lowered the overall yield for the two-
step process. Unfortunately, several attempts were made
It seems likely that the catalytic hydrogenation of a benz-
yl (or derivative thereof) protecting group with Pd/C
occurs via an oxidative insertion of the Pd0 into the benz-
ylic carbon–oxygen bond. Specifically in our case, this
required a peculiar ring expansion from the pyran ring
O
O
OH
9
HO
MeO
H
MgBr
Pd0
a)
MeO
BnO
BnO
10
5
4
O
b)
Cl
N
N
O
O
Pd
O
Cl
Pd
H
HO
O
O
11
MeO
Ru
Cl
MeO
Ph
13
7
PCy
c)
3
H
H
BnO
BnO
3
6
Pd
O
Scheme 3. Synthesis of the a,b-unsaturated lactone 3: Reagents and
conditions: (a) allylMgBr (2.0 equiv), Et2O, À78 °C, 1 h, 84%; (b)
acryloyl chloride (5.0 equiv), Et3N (10 equiv), DMAP (5% mol),
CH2Cl2, 0 °C, 6 h, 86%; (c) catalyst 7 (5% mol), CH2Cl2, reflux, 5 h,
87%.
H
H
MeO
12
Scheme 5. Proposed Pd catalyzed ring-expansion/cleavage of 9.

M. P. Jennings, R. T. Clemens / Tetrahedron Letters 46 (2005) 2021–2024
2023
to a seven-membered PdII palladacycle 11. An ensuing
O
coordination-insertion of H2 with the PdII complex 11
allows for the creation of 12 and resulting protonation
of the Pd–O bond set the stage for reductive elimination
of 13 to provide the observed ring-cleaved product. It is
worth noting that an alternative mechanism can be envi-
sioned via a sigma bond metathesis between H2 and the
corresponding palladacycle to afford the alcohol prod-
uct 13 directly from intermediate 11. In either case,
reductive elimination of the PdII–hydride complex 13
would allow for the regeneration of the Pd0 catalyst
and the observed product 9.
a) 4-MeOPhMgBr
BF3 OEt2, Et3SiH
O
HO
10
MeO
OH
TESO
15
Scheme 7. Lewis acid promoted pyran ring cleavage: Reagents and
conditions: 4MeOPhMgBr (1.0 equiv) THF, À78 °C, 2.5 h; then
Et3SiH (10.0 equiv), BF3ÆOEt2 (5.0 equiv), CH3CN, À40 °C warm to
0 °C, 4 h, 90%.
OH
5 steps
O
Schemes 3 and 6
In an attempt to obtain more desirable results we aban-
doned the initial strategy and devised a new route incor-
porating the removal of the olefin to give the
corresponding saturated lactone (Scheme 6). Thus,
simultaneous reduction of the double bond and debenz-
ylation by means of Pd/C catalyzed hydrogenation fur-
nished lactone 14 with an 84% yield over two steps
from 3.
MeO
OH
BnO
4
1
94% ee
Scheme 8. Asymmetric total synthesis of 1.
oxonium reduction step to 0 °C after the addition of
the corresponding Grignard reagent to 15 provided the
ring cleaved product 10 in very good yields. As shown
in Scheme 7, this one-pot, six step sequence consisting
of nucleophilic addition, oxonium cation formation,
stereoselective reduction, desilylation of the phenolic
TES group, Lewis acid promoted cleavage of the pyran
ring, and final hydride reduction of the presumed carbo-
cation intermediate proceeded in an overall 90% yield.15
Subsequent protection of the corresponding free hydro-
xyl moiety as a TES ether provided lactone 15 and set
the stage for the ensuing addition/reduction sequence
in anticipation of stereoselectively obtaining 1. With this
in mind, addition of 4-methoxyphenylmagnesium bro-
mide to 15 furnished the lactol, which was immediately
reduced via the oxonium cation with Et3SiH in the pres-
ence of BF3ÆOEt2 to furnish (+/À)-centrolobine with
combined 96% yield for the one-pot, four step sequence
consisting of nucleophilic addition, oxonium cation for-
mation, stereoselective reduction, and final desilylation
of the phenolic TES group.14 The relative configuration
of (+/À)-centrolobine was confirmed by NOE enhance-
ments as shown in Scheme 6.
With all of this information in hand, the asymmetric
synthesis of (À)-centrolobine was conducted with the
chiral benzyl protected homoallylic alcohol 4. Thus,
intermediate 4 was prepared via an asymmetric allyl-
ation with Brownꢀs Ipc2B allyl reagent16 of the corre-
sponding protected aldehyde 6 in 75% yield with an ee
of 94% as shown in Scheme 8. The completion of the
enantioselective synthesis of (À)-centrolobine from 4
utilized the identical strategy as delineated in both
Schemes 3 and 6. Thus, 1 was obtained in a 53% overall
yield from the chiral homoallylic alcohol 4.
Similar to that of the overreduction of intermediate 9
with H2 and Pd/C, it was observed that warming the
O
O
In conclusion, we have demonstrated that an aryl-b-C-
glycoside can be efficiently constructed via a sequence
consisting of Brown asymmetric allylation, ring-closing
metathesis, hydrogenation, nucleophilic addition, and
stereoselective Et3SiH reduction. The antibiotic natural
product (À)-centrolobine was synthesized in this manner
utilizing only five steps with an overall 53% yield. Fur-
ther investigation into a nucleophilic addition/stereo-
selective reduction protocol of an a,b-unsaturated
lactone for the synthesis of dehydro-b-C-glycosides will
be reported in due course.
O
O
a) H2/Pd-C
BnO
MeO
HO
3
14
b) TESCl,
imid.
MgBr
O
O
c)
MeO
BF3.OEt2, Et3SiH
TESO
O
OH
1
15
nOe enhancement
H
H
Acknowledgements
O
MeO
This work was supported by the University of Alabama.
OH
References and notes
Scheme 6. Synthesis of (+/À)-centrolobine: Reagents and conditions:
(a) Pd/C (3% mol), EtOH, rt, 40 h, 84%; (b) TESCl (12 equiv),
imidazole (5 equiv), DMF, rt, 87%; (c) 4MeOPhMgBr (1.0 equiv)
THF, À78 °C, 2.5 h; then Et3SiH (10.0 equiv), CH3CN, À40 °C, 96%.
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