Reversing the reactivity of carbonyl functions with phosphonium salts: Enantioselective total synthesis of (+)-centrolobine

Article abstract of DOI:10.1002/anie.201106046

Step saver: Carbonyl groups with lower reactivities can be transformed in the presence of more reactive ones by treatment with PPh₃ (or PEt₃) and TMSOTf prior to the reaction (see scheme; TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl). This methodology can be applied to reduction and alkylation reactions, and enabled the short asymmetric total synthesis of (+)-centrolobine with the highest overall yield reported to date.

Full text of DOI:10.1002/anie.201106046

Communications
DOI: 10.1002/anie.201106046
Carbonyl Reactivity
Reversing the Reactivity of Carbonyl Functions with Phosphonium
Salts: Enantioselective Total Synthesis of (+)-Centrolobine**
Hiromichi Fujioka,* Kenzo Yahata, Ozora Kubo, Yoshinari Sawama, Tomohito Hamada, and
Tomohiro Maegawa
The control of chemoselective transformations irrespective of
the individual reactivity of functional groups still remains a
largely unanswered challenge. Carbonyl groups, such as
aldehydes and ketones, are without doubt the most important
functional groups in organic chemistry and their reactions are
well known. The order of the reactivity of carbonyl groups
toward nucleophiles is generally aldehyde > ketone > ester.
Therefore, it is easy to react an aldehyde in the presence of
ketones and esters. In contrast, it is difficult to react a ketone
prior to an aldehyde. Therefore, protective groups have to be
employed for such transformations, which thus become
intrusive three-step operations that involve the protection
of the aldehyde, transformation of the ketone, and depro-
tection of the aldehyde. The reversal of the reactivity of
functional groups is a challenging theme in chemistry and
there are few reports on such transformations.[1,4b] Luche and
Gemal reported pioneering and representative work, in which
a ketone was selectively reduced in the presence of an
aliphatic aldehyde.[1a] The conversion of the aldehyde into an
acetal, the subsequent reduction of the ketone with NaBH4,
and the deacetalization were carried out in one pot by using
the CeCl3–MeOH–NaBH4 system. However, this reaction
was limited to reductions and is difficult to apply to other
reactions. Other methods, such as the use of metal amides,[1b–g]
a bulky Lewis acid,[1i] and a copper catalyst with a bulky
phosphine ligand,[1j] were reported. However, these methods
have drawbacks, such as lower generality, the need to prepare
special reagents, and strict control of stoichiometry because of
the use of highly reactive reagents. Therefore, more practical
and facile methods for the selective transformation of
carbonyl groups are required.
aldehyde prior to the addition of the nucleophile (Scheme 1).
The asymmetric transformation of a less-reactive carbonyl
group in the presence of a more-reactive carbonyl group was
also accomplished, and was applied to the short asymmetric
total synthesis of (+)-centrolobine.
Scheme 1. Reversal of the reactivity of ketone and aldehyde. Tf=tri-
fluoromethanesulfonyl, TMS=trimethylsilyl.
We previously developed the unprecedented chemoselec-
tive deprotection of acetals in the presence of ketals with
TESOTf–2,4,6-collidine.[2] This is the only method reported to
date with which the reactivity of acetals and ketals can be
switched. The key aspect of the reaction is the selective
formation of collidinium salt intermediates from acetals by
distinguishing their steric environment using TESOTf. In
addition, the reactivity of the salt could be changed by
changing the structure of the base. We have also recently
reported the reactivity of O,P acetals, which were generated
from O,O acetals and various phosphines and have a similar
reactivity to pyridinium salts.[3] We then presumed that if the
salt of an aldehyde in a keto aldehyde could be formed
selectively and would be less reactive than the ketone, the
selective transformation of the ketone should be possible
(Scheme 2).[4]
We investigated several Lewis acid/pyridine and Lewis
acid/phosphine combinations and reducing reagents. As a
result, the selective transformation of a ketone to an alcohol
in the presence of an aldehyde was achieved by the
combination of PPh3–silyltriflate and BH3·THF (Table 1).
When TMSOTf was used, the aldehyde was recovered from
the phosphonium salt by hydrolysis with a weak base
(aqueous NaHCO3; Table 1, entry 1). On the other hand,
Herein we report the convenient and versatile selective
one-pot transformation of less-reactive carbonyl groups in the
presence of aldehydes (or ketones) by using the combination
of PPh3 (or PEt3) and TMSOTf to selectively mask the
[*] Prof. Dr. H. Fujioka, K. Yahata, O. Kubo, Y. Sawama, T. Hamada,
Dr. T. Maegawa
Graduate School of Pharmaceutical Sciences
Osaka University
1-6, Yamada-oka, Suita, Osaka, 565-0871 (Japan)
E-mail: fujioka@phs.osaka-u.ac.jp
[**] This work was financially supported by the Hoansha Foundation,
the Uehara Memorial Foundation, Takeda Science Foundation, and
a Grant-in-Aid for scientific research from the Ministry of Education,
Culture, Sports, Sciences, and Technology of Japan. K.Y. is grateful
for financial support from the Japan Society for the Promotion of
Science Research Fellowship for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106046.
Scheme 2. Strategy for the reversal of the reactivity.
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Angew. Chem. Int. Ed. 2011, 50, 12232 –12235

Table 1: Optimization of the reaction conditions.[a]
Table 2: Selective one-pot transformation of carbonyl groups in the
presence of aldehydes.[a]
Entry Lewis acid (equiv) Equiv PPh3 Equiv BH3·THF Yield [%][b]
Entry Substrate
Reagent
(equiv)
Product
Yield
[%][b]
1
TMSOTf (2.0)
TESOTf (2.0)
TBSOTf (2.0)
BF3·Et2O (2.0)
TMSOTf (1.2)
TMSOTf (1.2)
–
3.0
3.0
3.0
3.0
1.2
1.2
–
4.0
4.0
4.0
4.0
1.5
1.5
1.2
90
86
94
trace
88
96
0
2[c]
3[c]
4
5[d]
6[d,e]
7[f]
BH3·THF
(1.5)
PhMgBr
(3.0)
EtMgCl
(1.5)
allylMgBr 2d R=allyl
(1.5)
BH3·THF
(1.5)
1
2
2a R=H
2b R=Ph
96
93
[a] Reaction conditions: 1a was treated with PPh3 and Lewis acid in
CH2Cl2 (0.1m) at 08C for 1 h. Then, BH3·THF was added at 08C. After the
reaction was completed, the mixture was treated with sat. NaHCO3
(unless stated otherwise). [b] Yield of isolated product 2a. [c] TBAF
(3.0 equiv) was used for the work-up. [d] PPh3 and TMSOTf were added
at RT. [e] Reduction was performed at ꢀ408C. [f] Reaction was
performed in the absence of Lewis acid and PPh3. TBAF=tetra-n-
butylammonium fluoride, TBS=tert-butyldimethylsilyl, TES=triethyl-
silyl, THF=tetrahydrofuran.
1a
3
2c R=Et
87
75
4
5
6
1b
1c
2e
87
89
BH3·THF
2 f
(1.5)
when other silyltriflates, such as TESOTf and TBSOTf, were
used, treatment with TBAF was necessary to recover the
aldehyde (Table 1, entries 2 and 3). The use of BF3·Et2O was
not effective in this reaction (Table 1, entry 4). Reducing the
amount of PPh3 and TMSOTf did not lead to a significantly
lower yield, however, the reduction at ꢀ408C gave the best
results (Table 1, entries 5 and 6). The nonselective reduction
proceeded in the absence of the silyltriflate and PPh3, and diol
and aldehyde-reduced keto alcohol were obtained in 20%
and 74% yield, respectively (Table 1, entry 7).
We explored the generality of the reaction by using
various keto aldehydes under the optimized conditions
(Table 2). Our method could be applied to both the reduction
of ketones and their alkylation with various Grignard
reagents. Aliphatic aldehydes were effectively masked
in situ, and the selective transformation of aliphatic, aromatic,
and cyclic ketones proceeded selectively (Table 2, entries 1–
7). The selective transformation of the 5-oxoaldehyde deriv-
ative 1c gave lactols 2 f and 2g in good yields (Table 2,
entries 6 and 7), thus providing an efficient route for the
construction of lactol derivatives in one pot. The aromatic
aldehydes were also protected without difficulty (Table 2,
entries 8–13).[5] The easily enolizable ketone 1e could be
converted into the corresponding alcohol 2j in good yield
(Table 2, entry 10). A bulky ketone 1 f was selectively reduced
with 2 equivalents of reductant (Table 2, entry 11). The
selective reduction as well as the selective alkylation of an
ester in the presence of an aldehyde were also successful;
when DIBAL-H and the Grignard reagent were used, the
benzyl alcohols 2l and 2m were obtained in 80% and 76%
yields, respectively (Table 2, entries 12 and 13).
(3.0)
7
8
9
2g
2h
93
96
BH3·THF
(1.5)
1d
PhMgBr
(3.0)
2i
85
87
74
80
76
BH3·THF
(1.5)
10[c] 1e
11[d] 1 f
12[e]
2j
BH3·THF
(2.0)
2k
2l
DIBAL-H
(2.2)
1g
EtMgCl
(3.0)
13
2m
[a] Reaction conditions: Substrate 1 was treated with PPh3 (1.2 equiv) and
TMSOTf (1.2 equiv) in CH2Cl2 (0.1m) at RT for 1 h. Then, the reagent was
added at the given temperature. After the reaction was completed, the
mixture was treated with aq sat. NaHCO3/MeOH at 408C for 2 h. [b] Yield
of isolated product 2. [c] Reduction was performed at ꢀ408C!ꢀ208C.
[d] Reduction was performed with BH3·THF (2.0 equiv) at ꢀ408C!RT.
[e] DIBAL-H (2.2 equiv) was used as a reductant at 08C. DIBAL-H=diiso-
butylaluminium hydride.
pretreatment with PEt3–TMSOTf, the keto esters were
selectively reduced with DIBAL-H to give the keto alcohols
in high yields (Table 3, entries 1–3). The selective alkylation
of the ester group of keto esters was also successful and left
the ketone intact (Table 3, entries 4–7). In addition, MOM
and TBS groups were able to endure the reaction conditions
to give the desired products in high yields (Table 3, entries 6
and 7).
To demonstrate the synthetic utility of this methodology,
we carried out the total synthesis of centrolobine, which is
isolated from the heartwood of Centrolobium robustum and
exhibits anti-inflammatory and antibacterial as well as anti-
It is notable that this method can also be applied to the
selective transformation of ketones by changing PPh3 to PEt3.
The ketone did not react with PPh3–TMSOTf even when an
excess of reagents was used, because of the low nucleophi-
licity of PPh3. Therefore, we attempted to employ PEt3
instead of PPh3, because the former has a high reactivity
and is commercially available. As we anticipated, after
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Communications
Table 3: Selective one-pot transformation of esters in the presence of
ketones.[a]
Entry Substrate
Reagent
(equiv)
Product
Yield
[%][b]
1
2
3a
3b
DIBAL-H (3.0) 4a
DIBAL-H (3.0) 4b
82
93
Scheme 3. Asymmetric synthesis of (+)-centrolobine. a) O3, CH2Cl2,
ꢀ788C; PPh3, 99%; b) PPh3, TMSOTf, CH2Cl2, RT; (S)-CBS (30 mol%),
BH3·THF, ꢀ408C, then aq sat. NaHCO3/MeOH, 408C, 81%; c) 8,
LiOMe, MeOH, 08C!RT, 99%; d) LiBH4, Et2O, 08C; Et3SiH, TFA,
08C!RT, 96%; e) CuI, NaOMe, DMF, 1008C, 99%. DMF=N,N-
dimethylformamide, TFA=trifluoroacetic acid.
3
4
3c
3d
DIBAL-H (3.0) 4c
PhMgBr (4.0) 4d
76
76
5
3b
MeMgBr (3.0) 4e
83
aldehydes by using the commercially available reagents PPh3
and TMSOTf. A variety of reagents can be used in this
reaction, such as BH3, DIBAL-H, the CBS catalyst, and
Grignard reagents. In addition, the selective transformation
of esters in the presence of ketones was achieved by replacing
PPh3 with PEt3. Furthermore, we accomplished the asym-
metric synthesis of (+)-centrolobine in five steps with the
highest reported overall yield. Further investigations of the
applicability of other reagents and the reversal of the
selectivity of other functional groups are currently under way.
6
7
3e R=MOM
3 f R=TBS
EtMgCl (3.0)
EtMgCl (3.0)
4 f R=MOM
4g R=TBS
80
74
[a] Reaction conditions: Substrate 3 was treated with PEt3 (1.2 equiv) and
TMSOTf (1.2 equiv) in CH2Cl2 (0.4m) at RT for 1 h. Then, the reagent was
added at the given temperature. After the reaction was completed, the
mixture was treated with aq sat. NaHCO3/MeOH at 408C for 2 h.
[b] Yield of isolated product 4. MOM=methoxymethyl.
leishmanial activities.[6] Although the asymmetric synthesis of Experimental Section
General procedure for the selective reduction of a ketone in the
centrolobine has been reported by several groups, these
routes consist of multiple steps and/or have low yields.[7]
Centrolobine has a chiral tetrahydropyranyl (THP) ring
skeleton that can be constructed by the ketone-selective
asymmetric reduction of 5-oxoaldehyde (see Table 2, entry 6).
The ozonolysis of commercially available cyclopentene 5
quantitatively afforded the key intermediate keto aldehyde 6
(Scheme 3). As we expected, the asymmetric reduction of the
ketone efficiently proceeded with the Corey–Bakshi–Shibata
(CBS) reagent[8] to give lactol 7 with high selectivity
(97.4:2.6)[9] without reducing the aldehyde. To the best of
our knowledge, this result is the first reported asymmetric
transformation of a ketone in the presence of an aldehyde.
The Horner–Wadsworth–Emmons (HWE) reaction of 7
using phosphonate 8 was followed by the decarbonylation of 9
and furnished the desired 2,6-cis-THP 10 with a phenethyl
group. Finally, an Ullmann coupling with CuI–NaOMe
completed the synthesis. The spectral data of the synthetic
(+)-centrolobine were identical in all respects to those
reported for the natural product. This enantioselective syn-
thesis was accomplished in five steps from commercially
available cyclopentene 5, and with an overall yield of 75%,
which is the highest total yield reported for the asymmetric
synthesis of centrolobine.
presence of an aldehyde: TMSOTf (0.238 mmol) was added dropwise
to a solution of keto aldehyde (0.200 mmol) and PPh3 (0.240 mmol) in
CH2Cl2 (2.0 mL) at RT. The reaction mixture was stirred for 1 h at RT,
then cooled to ꢀ408C, and BH3·THF (0.302 mmol) was added slowly
by syringe. Stirring at ꢀ408C was continued until the starting material
was consumed (TLC analysis was conducted after quenching a small
amount of the reaction mixture with a drop of TBAF (1.0m in THF)).
A saturated aqueous solution of NaHCO3 (2.0 mL) and MeOH
(1.0 mL) were added to the solution, and the resulting mixture was
stirred for 2 h at 408C. The mixture was cooled to RT and extracted
several times with EtOAc (total amount 50 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated under reduced
pressure to give a residue. Purification was accomplished by flash
column chromatography to afford the desired product (see the
Supporting Information for details).
Received: August 26, 2011
Published online: November 3, 2011
Keywords: alkylations · carbonyl reactivity · natural products ·
.
phosphonium salts · reductions
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