◆ Development of Efficient and Practical Ti-Claisen Condensation and the Related Aldol Reaction
Ti(Zr)-Claisen condensations, Ti-direct aldol additions, related catalytic Claisen condensation have been applied for efficient and
practical syntheses of useful fine chemicals and biologically active natural products. These protocols are new avenues for the
synthesis of a variety of carbonyl compounds.
1.
Prologue
O
TiCl2(OTf) 2
In 1989, the first Lewis acid-mediated Claisen condensation (Ti-Claisen
condensation) utilizing TiCl2(OTf)2 – Et3N was disclosed. This method included
only self- but also crossed Claisen condensations, the latter of which, however,
resulted in moderate selectivity. After long period, in 1997, we exploited a novel
highly practical method utilizing TiCl4 – Bu3N, which exhibited sufficient
reactivity and avoided readily unavailable TiCl2(OTf)2.
We restarted a
full-dressed investigation of the present useful, convenient, and cost-effective
Ti-Claisen condensation and related aldol type reactions.
2 R
R
CO2Me
Et3N
51 - 80%
not
R
O
TiCl2(OTf) 2
1
R
CO2Me
Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917-1924.
Yosida, Y.; Hayashi, R.; Sumihara, H.; Tanabe, Y. Tetrahedron Lett.
1997, 38, 8727-8730.
Yoshida, Y.; Matsumoto, N.; Hamasaki,, R.; Tanabe, Y. Ibid. 1999, 40, 4227-4230.
2. Fundamental Profile of
CO2Me
+
2
R
CO2
OMe
O
R1
Et3N
CO2
R2
OMe
2
R2
CO2R2
/ CH2Cl2 or toluene, 0 - 5 oC, 1 h
R2
CO2
R2
cross
57 - 83 %
TiCl4 - Bu3N
+
OMe
and
self
cross : self 8 : 2 ~ 9 : 1
O
1
CO2R2
R
R1
Ti-Claisen Condensations and Related Ti-Aldol (Type) Reactions
The C-C bond formations utilizing carbonyl nucleophiles and electrophiles have provided a number of
useful methodologies in organic syntheses due to their broad utility, representatively, the aldol addition,
ZrCl
4
O
O
2
O
the Munnich type reaction, and the Claisen condensation. Threse methods are classified into two
R
OMe
i-Pr2NEt
1
1
R
CO
R'
2
2
R
CO2Me
R
CO2R' categories: (i) carbonyl substrates are converted to their metal enolates by treatment with strong bases (e.g.
2
OMe
TiCl4 - Bu3N R
2
2
1
LDA, MHDMS, etc), followed by the addition of carbonyl acceptors, and (ii) carbonyl substrates are
1
R2
1
R
R R R
O
converted to enol silyl ethers or ketene silyl acetals, which react with carbonyl acceptors promoted by
O
O
OH
Lewis acids or other catalysts.
O
R3
R4
4
4 OH
1
3
4
R
R
R
CO2R'
1
R
R
Ti-mediated aldol additions, originally called Mukaiyama – Narasaka aldol reaction, and Ti-direct aldol
R2
R
CO2R'
1
3
3
R
R
TiCl4 - Bu3N
R
2
addition, originally exploited by Evans’ group, are regarded as an important milestone for Lewis
2
R
2
1
R
TiCl4 - Bu3N
R R
cat. TMSCl (0.05 equiv)
syn
acid-mediated addition reactions.
The present protocol of Ti-mediated reactions (Ti-Claisen condensation and related Ti-direct aldol type additions) demonstrates that the reactivity of C-C bond formation rivals or surpasses numerous
such reactions so far reported. The salient features are as follows.
① High reaction velocities, powerful reactivities, high yields, high stereoselectivities.
② Direct use of carbonyl compounds has advantages due to higher atom-economical
③ Avoidance of preparation of enol silyl ethers and ketene silyl acetals; atom economical and cost-effective.
④ Toleration against basic labile functionalities (halogens, tosyloxy, ketone, hydroxyl, etc.).
⑤ Use of readily available and low toxic metal reagents (e.g. TiCl4, ZrCl4), practical amines (Et3N and Bu3N) and solvents (toluene and CH2Cl2), under practical reaction conditions (-40 – +50 ◦C).
⑥ Development of highly selective Ti-crossed Claisen condensation between simple esters and acid chlorides.
⑦ Extension to inaccessible Lewis acid-mediated direct Munnich reaction and asymmetric Ti-Claisen condensation.
⑧ ZrCl4-mediated powerful Claisen condensation between -disubstituted esters to obtain inaccessible -dialkylated -keto esters.
O
Mukaiyama, T. Organic Reactions; Wiley: New York, 1982; Vol. 28, p. 203.
3. Practical Synthesis of (Z)-Civetone Utilizing Ti-Dieckmann Condensation
i) microbial
oxidation
An efficient, practical, and stereocontrolled synthesis of (Z)-civetone, a representative musk perfume,
has been performed utilizing a Ti-Dieckmann (intramolecular Ti-Claisen) condensation of dimethyl
(Z)-9-octadecenedioate as the key step. This cyclization reaction has some advantages compared with
the traditional basic Dieckmann condensation: higher concentration, lower reaction temperature, shorter
reaction time, use of environmentally benign (low toxicity and safe) reagents (TiCl4 and Et3N or Bu3N).
◆ Ti-Dieckmann condensation：0-5 ℃, 100-300 mM, 1 h.
CO2Me
CO2Me
Z-oleic acid
+
ii) MeOH, H
O
TiCl4 - Et3N
i) OHii) H+
CO2Me
0 - 5 oC, 1 h
100 - 300 mM
O
54%
95%
Z-Civetone
◆ McMurry coupling（TiCl3 - Zn/Cu）：80 ℃, 5 mM, 50 h．
This protocol is a promising candidate for the industrial production of (Z)-civetone and provides a novel
methodology for large carbon ring construction.
Y. Tanabe, A. Makita, S. Funakoshi, R. Hamasaki, T. Kawakusu, Adv. Synth. Catal., 344,
507-510 (2002).
4. A Short Synthesis of Civetone Utilizing Ti-Claisen Condensation and Olefin Metathesis
cat.
CO2Me
1
O
TiCl4 - Bu3N
CO2Me
/ Toluene
o
0 - 5 C, 1 h
93%
Grubbs' reagent
TiCl4 - Bu3N
PCy3
Ph
Ru
Cl
PCy3
(Grubbs' reagent)
/ Toluene
o
110 C, 2 h
-CO2, -MeCl
Civetone
CO2Me
2
Cl
/ Toluene
o
0 - 5 C, 1 h
/ Toluene
o
110 C, 8 h
48%
E:Z = ca. 3:1
O
CO2Me
-
+
i) OH ii) H
Civetone
95%
84%
E:Z = ca. 3:1
stepwise
one-pot
E:Z = ca. 3:1
Ti-Claisen condensation of methyl 9-decenoate successfully afforded the
ketoester in higher yield and much milder reaction conditions, compared
with traditional basic Claisen condensation.
Subsequent ring-closing
metathesis using the Grubbs’ reagent to afford the desired 17-membered
ketoester (E/Z = ca. 3:1).
Final conventional hydrolysis and
decarboxylation gave the desired civetone. The overall isolated yield is
74%, which is considerably high compared with hitherto reported syntheses.
As a further notable extension, we acheived a one-pot reaction sequence:
methyl 9-decenoate was straightforwardly transformed into civetone in a
one-pot manner in 48% yield. This highly efficient method is regarded as
simplest synthesis of civetone
R. Hamasaki, S. Funakoshi, T. Misaki, and Y. Tanabe, Tetrahedron,
56, 7423-7425 (2000).
5. Practical and Short Synthesis of (R)-Muscone Utilizing Ti-Aldol Addition or Claisen Condensation
O
O
O
1
TiCl4 - iPr2NEt
Ti(OR) 4
HO
o
0 C - rt
o
35 C, 3 h
50-100 mM
46%
(CH2)8CO2Me
2
CO2H
(R)-citronellic acid
TiCl4 - Bu 3N - imidazole
Crossed Ti-Caisen Condensation
The powerful Ti-aldol addition was successfully applied to a formal synthesis of (R)-muscone.
The key intramolecular Ti-aldol addition of dimethylketone produced the cyclic aldol adduct
O
O
with a higher concentration (50-100 mM) than conventional cyclization reactions.
H2
Moreover, stereoselective dehydration of the aldol adduct afforded E-rich -unsaturated
enone (E/Z = ca. 9:1), which was converted to (R)-muscone by the Noyori’s Ru-BINAP
cat. (S)-Ru-BINAP
88%
asymmetric hydrogenation with ca. 99% enantioselectivity. The present method is regarded as
(R)-Muscone
E : Z = 91 : 9
one of the simplest and most practical synthesis of (R)-muscone.
Ti-crossed Claisen condensation between methyl 10-undecenate and (R)-citroneric acid
O
PCy3
CO2Me
afforded -keto ester, which was converted to the ketone by hydrolysis-decarboxylation.
Cl
cat.
Ru Ph
Second generation ring-crosing metathesis of the ketone, followed by catalytic hydrogenation,
Cl
PCy3
(R)-Muscone afforded (R)-muscone in 53% overall yield. The present method is the shortest and the highest
yield method among ever reported.
53%
Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T. Itoh, M. Yamamoto, K.
Mitarai, and Y. Nishii, Ttrahedron (Symposium), 58, 8269-8280 (2002).
T. Misaki, R. Nagase, K. Matsumoto, Y. Tanabe, J. Am. Chem. Soc., 127, 2854-2855 (2005).
6. Efficient Synthesis of cis-Jasmone Lactone Analog Utilizing Ti-Aldol Addition
O
OAc
PhO 2C
PhO 2C
TiCl4 - Bu3N
O
O
i) HO - ii) H +
Although lactone analog of cis-jasmone, a jasmine natural perfume, was expected as a
promising synthetic perfume, there is no report to synthesize it. Powerful Ti-aldol addition
realized the synthesis of cis-jasmone lactone analog. Perfume evaluation revealed that it showed
a characteristic odor.
O
AcO
80%
OH
80%
cis-Jasmone
Y. Tanabe, N. Matsumoto, S. Funakoshi, and N. Manta, Synlett, 1959-1961 (2001).
cis-Jasmone
Lactone Analog
7. Efficient One-step Synthesis of Trialkylsubstituted 2(5H)-Furanones Utilizing Direct Ti-crossed Aldol Condensation
O
R2
MeO
MeO
O
O
1
OH O
R
3
R
TiCl4 - Bu3N
MeO
MeO
1
R
H
+
3
2
O
R
R
O
O
OMe
2
3
O
OMe
O
1
R
2(5H)-Furanones (α,β-butenolides) comprise an important heterocycle incorporated in
natural products and serve as useful synthetic building blocks for lactones and furans.
TiCl4–Bu3N-mediated condensation of ketones with α,α-dimethoxyketones afforded
trialkylsubstituted 2(5H)-furanones in a one-pot manner, wherein aldol addition and
furanone formation occurred sequentially. Its application to straightforward synthesis of
(R)-mintlactone and (R)-menthofuran, two representative natural mint perfumes, was
demonstrated.
R
R
33-77%
52%
TiCl4 - Bu3N
(R)-Mintlactone
Y. Tanabe and N. Ohno, J. Org. Chem., 53, 1560-1563 (1988);
Y. Tanabe, K. Mitarai, T. Higashi, T. Misaki, Y. Nishii, Chem. Commun., 2542-2543 (2002).
8. Practical Short Synthesis of 1β-Methylcarbapenem Utilizing a New Dehydration Type Ti-Dieckmann Condensation
TBSO
S
N
X
H H
+
O
OAc
TBSO
TiCl4 / sec-Bu2NH
TBSO
H H
NH
O
(X = O or S)
TBSO
O
TBSO
NH O
COSR
X
S
N
O
CO2
75 ~ 82%
O
N
CO2
H H
O
H H
TiCl4 / sec-Bu2NH
O
N
The discovery of methylcarbapenems such as meropenem and biapenem, which
have potent and broad antibacterial activity as well as enhanced metabolic and chemical
stability, has prompted many synthetic organic chemists to develop efficient methods for
the stereoselective synthesis of the key carbapenem skeleton. 
An efficient, practical, and stereocontrolled synthesis of methylcarbapenems has
been performed utilizing a novel dehydration type of Ti-Dieckmann (intramolecular
Ti-Claisen) condensation. The present reaction has the advantage of direct incorporation
of the thiol moiety into the target methylcarbapenem, compared with the traditional
basic Dieckmann condensation.
H H
H H
Base（Known）
2 Intramolecular
Dieckamann condensation
97 : 3 ~ 99 : 1
OH
O
1
1 Intermolecular
aldol reaction
COOH
1 Methylcarbapenem
SR
N
N
Y. Tanabe, N. Manta, R. Nagase, T. Misaki, Y. Nishii, M. Sunagawa, A. Sasaki,
Adv. Synth. Catal., 345, 967-970 (2003).
SR
A. Iida, H. Okazaki, T. Misaki, M. Sunagawa, A. Sasaki, Y. Tanabe,
J. Org. Chem., in press.
CO2
CONMe2
R=
N
Meropenem
Alloc
R
9. Ti-Crossed Claisen Condensation between Carboxylic Esters and Acid Chlorides or Acids:
Highly Selective and General Method for the Preparation of Various -Keto Esters
The Claisen condensation is recognized as a fundamental and useful C-C bond
imidazole , TiCl 4  Bu3N
forming synthetic reaction to obtain -keto esters. The major problem of the
O
1
R COX
X = Cl
Claisen condensation lies in the difficulty in controlling the direction of the
R2
O
1
2
R
3 steps, 46%
1.0 eq.
2
R
3
reaction: the reaction of a mixture of two different esters, each of which
R
CO2R
3
cis
Jasmone
and
+
CO2R
cross
possesses -hydrogens, generally affords all four products.
2
3
O
R CO2R
self
i)
NaH,
CCl
COCl
3
X = OH
Ti-crossed-Claisen condensation between a 1 : 1 mixture of carboxylic esters
25 examples 48 95% yield
1.0 eq.
cross : self = 91 : 9 ~ 99 : 1
and acid chlorides promoted by TiCl4-Bu3N-N-methylimidazole proceeded
ii) imidazole, TiCl4  Bu3N
successfully to give various -keto esters in good yields with excellent
4
R
4 steps, 53%
selectivities (19 examples, 48 ~ 95% yield; cross / self selectivity = 96 / 4 ~
Ti-Crossed Claisen Condensation
(R)Muscone
imidazole = N NMe
99 / 1).
The present method was extended to the condensation between a 1 : 1 mixture
of carboxylic acids and carboxylic esters (6 examples, 70 ~ 92% yield; cross / self selectivity = 91 / 9 ~ 99 / 1). To demonstrate the utility of the present two Ti-crossed-Claisen condensations, we
performed a couple of efficient short-step syntheses of two natural, representative, and useful perfumes, cis-jasmone and (R)-muscone. In conclusion, the present method is a new avenue for the synthesis of
a variety of -keto esters, which will be useful achiral and chiral synthons.
O
T. Misaki, R. Nagase, K. Matsumoto, Y. Tanabe, J. Am. Chem. Soc., 127, 2854-2855 (2005).
10. NaOH-catalyzed Crossed Claisen Condensation between Ketene Silyl Acetals (KSA) and Methyl Esters
The present work is a new version of our contined study on the crossed-Claisen condensation. The reaction of ketene silyl acetals with methyl esters proceeded smoothly promoted by NaOH catalyst
(0.05 equiv). Claisen condensation of -dialkylated esters is very difficult, because retro-Claisen condensation of -dialkylated -ketoesters usually predominates. The present mild, catalytic,
practical and efficient method afforded a variety of -ketoesters using -mono and -dialkylated
KSA-Crossed Claisen Condensation
KSAs.
O
TMS
O
O O
cat. NaOH (5 mol%)
OTMS
Surprisingly, the crossed-Claisen condensation using -dialkylated KSAs, which looked like less
2
1
1
R
4
R
R
4 +
4
OR
+
OR
reactive nucleophiles than -monoalkylated KSAs, proceeded smoothly and the yields were good to
3 OR
1
3
2
2
R
R
CO2Me
3
/
DMF,
rt
R
R
R
R
excellent in every case examined. In addition, several functionalities, such as an acetal, an epoxide, a
KSA
-dialkylated -ketoester
tert-butyl ester, a cyclopropane, and an indole, and a benzyloxy, tolerated the reaction conditions.
Further functionalization utilizing not only the Mukaiyama aldol reaction but also the Ti-aldol
34 examples 57 - 99% yield
reactions demonstrates the usefulness of the present method.
Ti-Aldol Reactions of Crossed Claisen Adducts
Judging from the fact that the Claisen condensation of-dialkylated esters is very difficult, the
TiCl4
OTMS
1
R
CO2Me
present method provide a new avenue for the preparation of inaccessible ketoesters..
o
R1
or
O
+
CO2Me
2
/ CH2Cl2, -45  -50 C, 1 h
OH O
CO2Me
2
R CHO
R
TiCl4 - Bu3N
/ CH2Cl2, 0 - 5 oC, 2 h
R1
6 examples 67 - 83% yield
A. Iida, K. Takai, T. Okabayashi, T. Misaki, Y. Tanabe,
Chem. Commun., 3171-3173 (2005).
11.
Isolation of Intermediary anti-Aldol Adducts of the Horner-Wadsworth-Emmons (HWE) Reaction Utilizing Direct Ti-aldol Addition and
Successive Brønsted Acid-Promoted Stereoselective Elimination leading to (Z)--Unsaturated Esters
O
O
(EtO) 2P
CO 2Et
+
R2
O
TiCl4 -Et3N
H
R1
EtO
OH
2
R
R P(O)(OEt) 2
anti - adduct
1
OTBS
O
EtO
OH
R
P(O)(OEt) 2
Ph
N
Ph (TBS-BEZA)
EtO 2C
cat. PyH . TfO +
R
(Z)--unsaturated ester
The Horner-Wadsworth-Emmons (HWE) reaction is well recognized as a highly useful tool for the preparation of -unsaturated
esters under basic media. Although a number of methods have been explored, there remains a demand for a more efficient method.
These reactions generally give (E)--unsaturated esters; in contrast, Still’s and Ando’s groups independently explored practical
methods for preparing less accessible (Z)-isomers, which have been widely used in organic syntheses. Nagao and Sano’s group
reported the finding that Sn(OTf)2 – N-ethylpiperidine reagent promoted the HWE-type reaction, which is the first example of a Lewis
acid-mediated method. These HWE reactions proceed through the two steps; (i) the aldol addition and (ii) the stereoselective
elimination of phosphono moiety via oxaphospoxetane intermediate.
We disclose here the first reliable method for isolation of intermediary anti-selective aldol adducts of the HWE reaction
utilizing TiCl4 – Et3N reagent, and subsequent TBS-BEZA / PyH+·OTf- (Chem. Commun. 2001, 2478）-promoted stereoselective
elimination to give (Z)--unsaturated esters.
As might be expected, these adducts were too unstable for column chromatographic purification (SiO 2, neutral alumina, and Florisil®). To overcome this
problem, we adopted a neutral silyl derivatization method using N,O-bis(trimethylsilyl)acetamide (BSA) – pyridinium triflate (PyH+·OTf-), and the corresponding TMS ethers were easily isolated.
products were stable enough for purification using conventional SiO 2-column chromatography.
These
To the best of our knowledge, this is the first concrete example of the isolation of intermediary aldol adducts
of the HWE reaction.
M. Katayama, R. Nagase, K. Mitarai, T. Misaki, Y. Tanabe, Synlett, 129-131 (2006).
◆ Rationalization of Greenchemical Versatile Reactions (Esterification・Amide formation・Sulfonylation・Silylation)
Esterification, sulfonylation, amide formation, and silylations are well recognized as frequently used reactions for organic syntheses.
natural products, however, require the further rationalization of these reactions, which is an endless development of the software.
Recent syntheses of fine chemicals and complex
We describe herein our recent studies in this area.
Review: Y. Tanabe, T. Misaki, A. Iida, Y. Nishii, J. Synth. Org. Chem. Jpn., 62, 1248-1259 (2004)．
1. Esterification and Transesterification Using Ammonium Triflate Catalyst (DPAT and PFPAT)
We introduced two efficient ammonium triflate catalysts (DPAT and PFPAT) for the esterification between 1 : 1 mixture of carboxylic acids and alcohols.
catalytic esterification for fine and bulk chemicals syntheses.
The present method is a new avenue for the
This was introduced in the Highlight of Angew. Chem. Int. Ed. [J. Otera, 40, 2044 (2001)] and released by the Nippon Keizai news paper
[ 2001/9/21].
◆ Carboxylic acid s (or Esters) : Alcohol s = 1 (1) : 1 (1.5).
cat. Ph2N+H2•OTf - (DPAT; 0.01 - 0.1 equiv )
NH3•OTf
or
RCO2H
+
+
◆ Use of toluene or hydrocarbon type solvent.
(PFPAT; 0.01 equiv)
R'OH
◆ Dean-Stark apparatus is not necessary.
RCO2R'
DPAT
RCO2R"
F5
◆ DPAT and PFPAT catalysts are moisture insensitive solids and easy to handle.
-
or
PFPAT
R'OH
cat. TMSCl (0.1 - 1.0 equiv)
a
12 examples; 78 -96%
RCO2R'
9 examples; 79 -97%
◆ Transesterification was also performed using TMSCl co-catalyst.
◆ PPFPAT showed higher reactivity and water-resistant property. Separation of PFPAT is very easy due to the low
boiling point of the 2,3,4,5,6-F5-PhNH2 part.
K. Wakasugi, T. Misaki, K. Yamada, Y. Tanabe, Tetrahedron Lett., 41, 5249-5252 (2000).
Y. Tanabe, T. Misaki, A. Iida, Y. Nishii, J. Synth. Org. Chem. Jpn., 62, 1248-1259 (2004).
2. Esterification and Amide Formation Using a Novel Condensation Agent, N,N-Dimethylsulfamoyl Chloride (Me2NSO2Cl) / Me2NR
From the standpoint of elaborated complex natural product synthesis and process chemistry, mild and effective esterification or amide formation between 1 : 1 mixture of carboxylic acids and alcohols or
amines is one of the most frequently used unit reactions due to its broad utility.
inexpensive, and atom-economical agents.
Although several efficient methods have been exploited, there still remains a strong need for simpler, more convenient,
We developed a novel efficient condensation agent for esterification and amide formation, Me2NSO2Cl together with sterically unhindered N,N-dimethylamines
(Me2NR: R = Me, Bu).
◆ Carboxylic acids : Alcohols (or Amines) = 1 : 1 (1).
R2OH
1
Me2NSO2Cl
R CO2H
Me2NR (R = Me, Bu)
1
R CO2SO2NMe2
+
Me2N+RH.Cl-
3 4
or R R NH
1
2
R CO2R
◆ High reactivity and yield under mild conditions.
15 examples; 71 - 96%
cat. DMAP
1
◆ Me2NSO2Cl and Me2NR condensation reagents are relatively inexpensive, structurally simple, and
3 4
or R CONR R
8 examples;
a 92 - 97%
atom-economical.
◆ Characteristic chemoselectivity : Me2NSO2Cl forms mix anhydride selectively with carboxylic acid,
that is, experimental procedure is simple and convenient.
◆ No -isomerization using the substrate, unsaturated carboxylic acids
CON
HO
Coumaperine
◆ Successful application to the synthesis of a naturally occurring chemopreventive dieneamide compound,
Coumaperine, which was isolated from Piper nigrum L.
K. Wakasugi, A. Nakamura, and Y. Tanabe, Tetrahedron Lett., 42, 7427-7430 (2001).
K. Wakasugi, A. Nakamura, A. Iida, Y. Nishii, N. Nakatani, S. Fukushima, Y. Tanabe, Tetrahedron, 59, 5337-5345 (2003).
3.
Efficient Esterification, Thioesterification, and Amide formation utilizing p-Toluenesulfonyl Chloride（TsCl）/ N-Methylimidazole
From the standpoint of elaborate complex natural product synthesis and process chemistry, direct esterification, thioesterificaton, and amide formation between 1 : 1 mixture of carboxylic acids and
alcohols, thiols, and amines, respectively, are well recognized as important unit reactions for a wide range of organic syntheses. In view of process chemistry, there remains a strong need for simpler, more
reactive, convenient, and inexpensive agents. The mixed anhydride method, composed of different acids, is a rational process: Use of sulfonic acid as a counter acid moiety is a promising candidate for an
efficient esterification due to its simplicity, ready availability and low cost of the reagents.
We introduce an easily accessible reagent, TsCl / N-methylimidazole. The present method is now applied to the process chemistry for the synthesis of pharmaceuticals. It was picked up as the
Highlight of Organic Process Research & Development [ 8, 138-145 (2004)].
◆ Carboxylic acids : Alcohols (Thiols, Amines) = 1 : (1, 1).
RCO2Ts
TsCl
◆ Mild and high reactivity.
N Me
N Me
N
N Me
a
RCO2R1
R1OH
+
RCO2H
N
N
or R2SH
HCl
RCON
or R R NH
+
N Me
OTs-
economical (reagent cost : about 1/10 of Me2NSO2Cl method).
19 examples; 82 - 96%
3 4
TsCl and N-methylimidazole reagents are much available and
◆ N-Boc amino acids were smoothly esterified without racemization.
◆ No necessity for using DMAP.
or
2
RCOSR
11 examples; 87 - 94%
or
RCONR3R4
◆ The labile 1-methylcarbapenem key intermediate and a pyrethroid insecticide, prallethrin,
were successfully prepared.
◆ The existence of the reactive acylammonium intermediate was rationally supported by 1H
7 examples; 90 - 95%
NMR monitoring study.
K. Wakasugi, A. Iida, T. Misaki, Y. Nishii, Y. Tanabe, Adv. Synth. Catal., 345, 1209-1214 (2003).
4. Green Chemical Sulfonylation of Alcohols Utilizing Sterically Uncrowded Tertiary Amine Catalysts
The p-toluenesulfonylation (tosylation) and methanesulfonylation (mesylation) of alcohols are well recognized as fundamental processes in various fields of organic syntheses.
Traditional tosylation
using TsCl/Py (Ts = p-toluenesulfony, Py = pyridine) reagent is less reactive and requires over ca. 10 equiv of pyridine and careful conditions to prevent undesirable side substitution from ROTs to RCl.
The present four pyridine-free methods (Methods A-D) are a useful alternative to sulfonylation to resolve these problems.
This protocol has been utilized for the syntheses of complex natural products and fine chemicals both on laboratory and industrial scales; for example, vinblastine [Fukuyama, Tokuyama, JACS, 124,
2137 (2002)], fluoresence amino acid derivatives [Nau, JACS, 124, 556 (2002)], and flumioxadine herbicid (Sumitomo Chemical group).
◆ Sterically uncrowded tertiary amines are used as key base, which form reactive sulfoniumammonium
Ts(Ms)Cl, amine
ROTs(Ms)
ROH
intermediate with sulfonyl chlorides.
◆ Higher reactivity compared with conventional TsCl / Py method.
/ Toluene (MeCN, CH2Cl2, H2O)
a
.
Method A: Et3N / cat. Me3N HCl
+
TsN Me2R'•Cl-
Method B: K2CO3 / cat. Et3N / cat. Me3N.HCl
Method C: Me2N(CH2)nNMe2
plausible reaction species
Method D: cat. BnNMe2 / H2O (pH~10)
◆ Operationally simple.
◆ Circumvention of undesirable conversion from ROTs(OMs) into RCl.
Applicable to allylic sulfonates.
◆ The existence of the reactive sulfoniumammonium intermediate was rationally supported by 1H NMR
monitoring study.
Y. Tanabe, H. Yamamoto, Y. Yoshida, T. Miyawaki, and N. Utsumi, Bull. Chem. Soc. Jpn., 68, 297-300 (1995).
Y. Yoshida, Y. Sakakura, N. Aso, S. Okada, and Y. Tanabe, Tetrahedron, 55, 2183-2192 (1999).
Y. Yoshida, K. Shimonishi, Y. Sakakura, S. Okada, N. Aso, and Y. Tanabe, Synthesis, 1633-1636 (1999).
J. Morita, H. Nakatsuji, T. Misaki, Y. Tanabe, Green Chem. 7, 711-715 (2005). Selected as a Hot Article.
5. Mild, Effective, Powerful Method for the Silylation of Alcohols Using Silazanes Promoted by Catalytic TBAF
The silylation of alcohols is indispensable for organic syntheses as the most reliable protective method.
Despite the well-established method, there still remains a strong need for improved efficiency.
In view of the restrictions involved during elaborate syntheses of complex compounds, the development of mild and efficient silylation methods has become increasingly important for: (i) smooth silylation
against sterically crowded and functionalized alcohols under mild conditions, (ii) introduction of bulky silyl groups into unreactive alcohols, and (ii) mild alternatives to some bulky-sized silyl triflates, one
of the most powerful agents, because the preparation of silyl triflates sometimes requires tedious procedures.
We introduce TBAF catalyzed silylations methods: The presence of catalytic amounts (0.02 eq.) of TBAF significantly promoted silylation of alcohols
SiN
ROH
using a variety of available silazane (R3Si-N), hydrosilane (R3Si-H), and disilane [(R3Si)2] under mild conditions. TBAF is well known as an
ROSi
+
HN
representative “desilylation” agent.
cat. TBAF (0.02 equiv)
intermediate.
In clear contrast, catalytic use exhibits an efficient “silyl transfer” agent through the hyper valent silicate
The choice of silazanes allows an alternative method for both the powerful silylation of various kinds of alcohols and the highly
regioselective silylation of primary alcohols.
Recently, a mild, efficient, and very powerful method for the silylation of alcohols using anilinosilane (PhNHSi, Si = TMS, TES, TBS) with catalytic
Si
SiH
or
2
ROH
ROSi
+
TBAF has been exploited. Despite the mildness, the reactivity of the present method is considered to rival the most powerful method using SiOTfs /
H2
2,6-lutidine.
cat. TBAF (0.02 equiv)
Y. Tanabe, M. Murakami, K. Kitaichi,, Y. Yoshida, Tetrahedron Lett., 35, 8409-8412 (1994).
Y. Tanabe, H. Okumura, A. Maeda, M. Murakami, Tetrahedron Lett., 35, 8413-8414 (1994).
A. Iida, A. Horii, T. Misaki, Y. Tanabe, Synthesis, 2677-2682 (2005.
6. Si-BEZA (O-Silylbenzamide）/ Catalytic PyH+●OTf- : Mild and Powerful Agent for the Silylation of Alcohols
A highly efficient method for the silylation using a novel agent, Si-BEZA (silylbenzamide), together with a pyridinium triflate catalyst was developed. A variety of silyl groups can be introduced into
sterically crowded alcohols under mild conditions.
SiCl
Si-BEZA
ROH
PhCONHPh
ROSi
cat. PyH+.OTf-
◆ Si-BEZA (O-Silylbenzamide) is a most powerful silylation reagent among hitherto reported agents.
OSi
Ph
NaH
N
◆ Preparation and handling of both Si-BEZA and PyH+•OTf- are quite easy.
Ph
◆ Si-BEZAs [TMS, TES, TBS, TIPS (i-Pr3Si-), and TBDPS (t-BuPh2Si-)] are available, considerably
Si-BEZA
a
moisture-insensitive, and easily prepared and purified.
(Si = TMS, TBS, TES, TIPS,TBDPS)
◆ Without PyH+•OTf- catalyst, the reaction did not proceed.
Fig. 2
100
90
90
80
70
■: Si-BEZA method
60
▲: Si-OTf method
50
40
OH
30
OTIPS
80
70
■: Si-BEZA method
60
▲: Si-OTf method
40
30
20
10
10
0
0
0
2
4
6
8
time / h
10
12
14
◆ Two parallel experiments for silylation using TIPS-BEZA with linalool and o-cresol demonstrate that the ability is
considered to rival or surpass the most powerful method using SiOTfs / 2,6-lutidine under standard conditions (Fig.
50
20
0
That is, Si-BEZAs themselves adequately stable and
PyH+•OTf- acts as a useful trigger.
/ %
100
GC conv.
GC conv. / %
Fig. 1
20
OH
OTIPS
Me
Me
40
60
80
time / min
100
1 and 2).
◆ Careful NMR experiments (1H,
120
a
13
C,
29
Si,
15
N) of TBS-BEZA revealed that the structure was not an N-TBDMS
amide but a O-TBDMS imidate.
T. Misaki, M. Kurihara, and Y. Tanabe, Chem. Commun., 2478-2479 (2001).
7. Silazanes / Catalytic bases: Mild, Powerful and Chemoselective Agents for the preparation of Enol Silyl Ethers from Ketones and Aldehydes
Enol silyl ethers are widely employed as reactive precursors for carbonyl compounds in a wide range of organic syntheses. Conventional preparations of enol silyl ethers use chlorosilanes with amine
(e.g., Et3N) and amide (e.g., LDA) agents. Despite these two well-established methods, there still remains a need for an alternative method with improved efficiency, that is, for an elaborate and practical
scale synthesis from a recent recognized standpoint of green chemistry. We developed an efficient method for the preparation of enol silyl ethers using novel agents, silazanes together with NaH or DBU
catalyst, wherein TMS and TBDMS groups were smoothly and chemoselectively introduced into ketones and aldehydes under mild conditions.
◆ The present method is the first example using catalytic bases.
cat. DBU
cat. NaH
SiN
◆ Mild conditions (rt - 60 oC).
SiN
(0.05
equiv)
O
(0.05 equiv)
O
OSi
OSi
1
◆ Among
the
commercially
available
N-(TMS)amines
screened,
1
R1
R
1
2
R
R
2
R
o
H
o
R
rt ~ 60 C
H
rt ~ 60 C
N-methyl-N-(TMS)acetamide gave the best result.
/ cyclohexane or DMF
/ cyclohexane or DMF
◆ Unreactive ’-disubstituted and -chloro ketones, and labile -unsaturated
16 examples; 72 - 96%
9 examples; 86 - 96%
Si = TMS or TBDMS
ketones could be converted.
◆ NaH catalyst is used for ketones, where as DBU catalyst is used for aldehydes.
O
◆ Both enol TMS- and TBDMS-ethers were obtained.
NTMS
◆ On the regiochemistry, thermodynamic controlled products were generally obtained.
a
O
Me
Pen
◆ Powerful silylation reactivity compared with the conventional methods.
Hex CHO +
O
cat. DBU
(TMSCl / Et3N or TMSI / (TMS)2NH).
NTMS
( 0.05 equiv )
cat. NaH H2
Me
O
O
OTMS
2
2
O
◆ For aldehydes, N-(TMS)amines and N-methyl-N-(TMS)acetamide gave the best
1
1
R
R
1
R2
R
R
Hex
+
R
Pen
OTMS
results using DBU catalyst.
O
(100% recovery)
(100%)
NHMe O
◆ A notable aspect of the present protocol is the highly chemoselective conversion of
Naldehydes against ketones
Me
Y. Tanabe, T. Misaki, M. Kurihara, A. Iida, Chem. Commun., 1628-1629 (2002).
In close connection: A. Iida, K. Takai, T. Okabayashi, T. Misaki, Y. Tanabe, Chem. Commun., 3171-3173 (2005).
TiCl4 - complex
TiCl4 - AcOEt ;
11examples, 94 - 99% yield
ROH
TiCl4 - CH3NO2 ;
11 examples, 85 - 99% yield
/ CH2Cl2 or C6H5Cl
TBSO
HO
HH
TiCl4 - CH3NO2
1
O
SR
N
HH
1
N
o
/ CH2Cl2, -78 C, 14 h
2
CO2R
O
SR
2
CO2R
6 examples ; 60 - 91% yield
100
●
80
●
●
60
●
●
▲
▲
■
20
▲
3
OTBS
4
100
■
80
▲
40
0●
0
0
●
▲
GC conv. / %
ROTBS
Efficient method for the deprotection of TBS-ethers using TiCl4 – Lewis base complexes: Application to the synthesis of
1-methylcarbapenem
GC conv. / %
８.
■
■
■
6
TiCl4 - additive
(1.2 eq.)
12
15
time / min
◆
■
◆
■
■
■
◆
●
▲
■
▲
●
●
■
60
▲
●
40
▲
20
9
/ C6H5Cl
◆
●
▲
0 ■
▲
0
▲
●
10
20
30
40
50
60
time / min
TiCl4 - CH3NO2 (2.4 eq.)
ROTBS
OH
ROH
/ CH2Cl2, -18 oC
4
o
05 C
O
■
◆
TBSO O
O
OTBS
●
■
TiCl4 - AcOEt complex
TiCl4
▲ TiCl4 - CH3NO2 complex
▲
TBSO O
●
OTBS
5
We developed an efficient, practical, and chemoselective method for the deprotection of
TBDMS ethers using economical and available TiCl4 - Lewis base (AcOEt or CH3NO2)
complexes.
◆ The present TiCl4 complexes smoothly promote the desilylation and circumvent
undesirable side-reaction from ROTBS to RCl.
◆ The reaction velocity using these complexes was considerably greater than that
using TiCl4 alone
◆ Selective desilylations between aliphatic and aromatic TBDMS ethers, and between
TBDMS and TBDPS ethers were successfully performed.
◆ Desilylation of TBDMS-aldol, acyloin, and -lactam analogs proceeded smoothly
due to anchimeric assistance by the neighboring carbonyl groups.
◆ The present method was successfully applied to the practical synthesis of
1-methylcarbapenems (The deprotection of TBS-1b-methylcarabapenem is an
critical issue among the carabapenem synthesis.
A. Iida, H. Okazaki, T. Misaki, M. Sunagawa, A. Sasaki, Y. Tanabe,
J. Org. Chem., in press
Development of Synthetic Study on the Utilization of gem-Dihalo (or Halo) cyclopropnes:
Cationic Approach, Radical Approach, Anionic Approach, Stereostructure-Activity Relationship
◆
R3
R
R2
R1=H, Alkyl
R3
HO R
R
Y
Acid
OH
Ph-(p-R) Lewis acid
Ph-(p-R)
Me
X
Y
2
R
X X
3
X
Cl
R2
Y
R1=Aryl
Me
Bioorg. Med. Chem., 9, 33 (2001).
Tetrahedron Lett., 41, 5937 (2000)
Biosci. Biotech. Biochem., 59, 1355 (1995)
R
1
R2
R1
2
R1
MeM gBr
OH
R
(-)-1R ,2S ,3S
J. Chem. Soc., Perkin Trans. 1, 1243 (1996)
R
X
Tetrahedron Lett., 31, 6883 (1990)
J. Chem. Soc., Perkin Trans. 1, 2157 (1996)
O
O
R1
1
Y
cat. Fe(DBM) 3
Cl Cl
R2
Me
Me
Y
( R1=
R1
Y)
Z
R1
Z
AlCl3
COCl
R
X
X X
OH
Y
2
R
R2
R1
MeM gBr
cat. Co(dppe) 2Cl
Cl Cl
X (X)
2
R2
Cl
Synlett, 67 (1998)
2
Y
( R1= Me, H )
AlCl3
R
OH
1
Tetrahedron Lett., 36, 8803 (1995)
J. Chem. Soc., Perkin Trans. 1, 477 (1997)
Br
X = Cl or Br
Y
OH
Br
2 Bu3SnH
cat. AIBN
OH
OH
Chem. Lett. 30 (2002)
Y
R
Y
Z
COCl
Z
O
1
Bu3SnH
AlCl3
X X
X
Synthesis, 388 (1996)
R
1
cat. AIBN
X X
X
Chem. Lett., 1757 (1994)
OH
R
Ar12
Ar
Me
Cl Cl
Ar 1
Ar 2
Me
Reagent
MCl4: A>B (M=Ti or Sn)
A:B=3:1~99:1
TBDMSOTf: A<B
A:B=1:4~1:99
Me
Ar
+
2
R
Ar
1
R
Cl
Cl
A
B
O
R
R
Br
Y
R
Br
Bu3SnH
2
OMe
O
cat. AIBN
OMe
O
O
O
MeO
OMe
O
O
OMe
Justicidin B
Retrojusticidin B
Dehydrodesoxypodophyllotoxin
Z
R2
Cl
Cl
O
O
O
cat. AIBN
R
O
O
OMe
R2
Bu3SnH
Y
1
Tetrahedron Lett., 37, 1837 (1996)
O
O
Z
1
Y
O
OMe
O
Br
1
MeO
OMe
(S)
Me
R
Cl
Cl
*
OH
OMe
Cl
TiCl4
aromatize
Me
R
Me
(M)
R
5'-Methoxyretrochionensin
anti-HIV activity
Tetrahedron Lett., 38, 7195 (1997), J. Org. Chem., 70, 2667-2678 (2005).
99 %ee
Central Chirality
Chirality Exchamge
J. Am. Chem. Soc., 126, 5358 (2004)
99 %ee
Axial Chirality
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
S. Seko, Y. Tanabe, G. Suzukamo, "A Novel Synthesis of - and -Halo-naphthalenes via Regioselective Ring Cleavage of Aryl(gem-Dihalocyclopropyl)methanols and Its Application to Total
Synthesis of Lignan Lactones, Justicidin E and Taiwanin C," Tetrahedron Lett., 31, 6883-6886 (1990).
Y. Tanabe, Y. Nishii, K. Wakimura, "A Novel and Regioselective Radical Cyclization of gem-Dihalocyclopropyl Substituted Alkenes and Alkynes Using Tributyltin Hydride and Catalytic AIBN,"
Chem. Lett., 1757-1760 (1994).
Y. Nishii, H. Matsumura, Y. Muroya, T. Tsuchiya, Y. Tanabe, "Novel Synthetic Pyrethroid Containing a Halocyclopropane Structure," Biosci. Biotech. Biochem., 59, 1355-1357 (1995).
Y. Nishii, Y. Tanabe, "Sequential and Regioselective Friedel-Crafts Reactions of gem-Dihalocyclopropanecarbonyl Chlorides with Benzenes for the Synthesis of 4-Aryl-1-naphthol Derivatives,"
Tetrahedron Lett., 36, 8803-8806 (1995).
Y. Tanabe, K. Wakimura, Y. Nishii, Y. Muroya, "Synthesis of 2,5-Diaryl-3-halofurans via Regioselective Ring Cleavage of 3-Aryl-2,2-dihalocyclopropyl Aryl Ketones," Synthesis, 388-392 (1996).
Y. Tanabe, K. Wakimura, Y. Nishii, "Sequential and Highly Stereospecific Intermolecular Radical Additions of 2,3-cis-Disubstituted 1,1-Dibromo- and 1-Bromocyclopropanes with Electron-Deficient
Olefins," Tetrahedron Lett., 37, 1837-1840 (1996).
Y. Nishii, K. Wakimura, T. Tsuchiya, S. Nakamura, Y. Tanabe, "Synthesis and Stereostructure-Activity Relationship of a Synthetic Pyrethroid, 2-Chloro-1-methyl-3- phenylcyclopropylmethyl
3-Phenoxybenzyl Ether," J. Chem. Soc., Perkin Trans. 1, 1243-1249 (1996).
Y. Tanabe, S. Seko, Y. Nishii, T. Yoshida, N. Utsumi, G. Suzukamo, "Novel Method for the Synthesis of - and -Halonaphthalenes via Regioselective Benzannulation of
Aryl(gem-dihalocyclopropyl)methanols. Application to Total Synthesis of Lignan Lactones, Justicidin E and Taiwanin C," J. Chem. Soc., Perkin Trans. 1, 2157-2166 (1996).
Y. Nishii, Y. Tanabe, "Sequential and Regioselective Friedel-Crafts Reactions of gem-Dihalocyclopropanecarbonyl Chlorides with Benzenes for the Synthesis of 4-Aryl-1-naphthol Derivatives," J.
Chem. Soc., Perkin Trans. 1, 477-486 (1997).
Y. Nishii, T. Yoshida, and Y. Tanabe, "Regiocontrolled Benzannulation of Diaryl(gem-dichlorocyclopropyl)methanols for the Synthesis of "Unsymmetrically" Substituted 4-Arylnaphthalenes,"
Tetrahedron Lett., 38, 7195-7198 (1997).
Y. Nishii, K. Wakasugi, and Y. Tanabe, "Dimethylation and Hydrodechlorination of gem-Dichlorocyclopropanes with Grignard Reagents Promoted by Fe(III) or Co(II) Catalyst," Synlett, 67-69
(1998).
K. Wakasugi, Y. Nishii, and Y. Tanabe, "Cyclopropane-shift Type Reactions of Diaryl(chlorocyclopropyl)methanols Promoted by Lewis Acids," Tetrahedron Lett., 41, 5937-5942 (2000).
Y. Nishii, N. Maruyama, K. Wakasugi, and Y. Tanabe, "Synthesis and Stereostructure-activity Relationship of Three Asymmetric Center Pyrethroids [2]: 2-Methyl-3-phenylcyclopropylmethyl
3-Phenoxybenzyl Ether and Cyanohydrin Ester," Bioorg. Med. Chem., 9, 33-39 (2001).
Y. Nishii, A. Fujiwara, K. Wakasugi, K. Yanagi, M. Miki, and Y. Tanabe, “Stereoselective Bifurcating-type Radical Cyclization of gem-Dibromocyclopropanes for the Synthesis of Uniquely Fused
5-3-5-Type Tricyclic Compounds,” Chem. Lett., 30-31 (2002).
Y. Nishii, K. Wakasugi, K. Koga, Y. Tanabe, "Chirality Exchange from sp3 Central Chirality to Axial Chirality: Benzannulation of Optically Active Diaryl-2,2-dichrolocyclopropylmethanols to
Axially Chiral -Arylnaphthalenes," J. Am. Chem. Soc., 126, 5358-5359 (2004).
Y. Nishii, T. Yoshida, H. Asano, K. Wakasugi, J. Morita, Y. Aso, E. Yoshida, J. Motoyoshiya, H. Aoyama, Y. Tanabe, “Regiocontrolled Benzannulation of Diaryl(gem-dichlorocyclopropyl)methanols
for the Synthesis of Unsymmetrically Substituted -Arylnaphthalenes: Application to Total Synthesis of Natural Lignan Lactones,” J. Org. Chem., 70, 2667-2678 (2005).