Teruaki Mukaiyama - 向山 光昭
Y. Ishihara
Prof. Teruaki Mukaiyama
Bibliography:
- Jan 5 1927: Born in Nagano, Japan
- 1948: B.Sc., Tokyo Institute of Technology
- 1953: Assistant Professor, Gakushuin University
- 1957: Ph.D., University of Tokyo
- 1958: Assistant Professor, Tokyo Institute of Technology
- 1963: Full Professor, Tokyo Institute of Technology
- 1973: Full Professor, University of Tokyo
- 1987: Completed his term at the University of Tokyo;
move to Tokyo University of Science (formerly
Science University of Tokyo)
- 1991: President of the Research Institute, Tokyo
University of Science
- 1992: Distinguished Professor, Tokyo University of
Science
- 2002: Move to Kitasato University
Baran Lab Group Meeting
An excerpt from Mukaiyama's publication list, published in Heterocycles 2000, 52, 13-66.
Notable chemists originating from the Mukaiyama Group:
Isao Kuwajima, formerly at Tokyo Institute of Technology; Eiichi Nakamura,
University of Tokyo; Koichi Narasaka, University of Tokyo; Shuu Kobayashi,
University of Tokyo; Masahiro Murakami, Kyoto University; Yujiro Hayashi, Tokyo
University of Science; Kenso Soai, Tokyo University of Science; the late professor
Oyo Mitsunobu, formerly at Aoyama Gakuin University.
Mukaiyama Award:
- Administered by the Society of Synthetic Organic Chemistry, Japan (SSOCJ).
- The award was established in 2005 by SSOCJ to celebrate the 77th birthday of
Professor Teruaki Mukaiyama, who received the Order of Culture in 1977 from
Japanese government for his outstanding contributions to synthetic organic
chemistry and to commemorate his election in 2004 to the National Academy of
Science, USA, as a foreign associate.
- The award shall be granted to an individual of 45 years old or younger without
regard to nationality for their outstanding contributions to synthetic organic
chemistry.
- Nature: The award consists of $5,000, a medallion, and a certificate. The recipient
shall deliver an award lecture at the Seminar on Synthetic Organic Chemistry.
- A nomination form can be downloaded from http://wwwsoc.nii.ac.jp/ssocj/
- Selection: The award committee selects two award recipients, one from the nonJapanese nominees and the other from the Japanese nominees.
Publications: Close to 1000 to date.
- Science
...1 (Perspective)
- Angewandte CIEE
...5 (4 Reviews)
- JACS
...22
- JOC
...22
- Tetrahedron Lett.
...26
- Tetrahedron
...11
- Tetrahedron: Asym. ...1
- Minor/inaccessible papers/abstracts <100
Chemistry Letters
...632
Bull. Chem. Soc. Jpn ...165
Chemistry Letters, founded
in 1972 by Mukaiyama.
1
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Mukaiyama's early years: An organophosphorus chemist
O
Ph
PhNCO + EtNO2
cat. R3N
N
H
Synthesis of phosphoric esters as an application of oxidation-reduction condensation:
Me
Me
Me
Me
BnOH + R3P + EtO2C-N=N-CO2Et
Ph +
N
H
N
O
N O
N
N
P(OEt)3
O
O
Ph
RNC + O=P(OEt)3
OEt
EtO
OEt
P
O
O
P(OEt)3
Ph
!
Ph
P(OEt)3
C
O
Ph
(RCO2)2Hg + R'3P
Ph
Desired product for Mukaiyama
R1OH + R3P + EtO2C-N=N-CO2Et + R2CO2H
Side product: Diphenylketene dimer
J. Org. Chem. 1964, 29, 2243.
[O]
2[H]
-H2O
(RCO)2O + Hg + 2 ArH + R'3P=O
[O]
(RCO)2O + PhCO-CH2CH2-COPh + R'3P=O
J. Org. Chem. 1963, 28, 2024.
J. Org. Chem. 1964, 29, 1385.
Variations in the type of products made: Esters, thioesters, amides, thioethers,
pyrophosphates... also useful in peptide and nucleotide chemistry.
Ph
O
unpublished results
Oxidation-Reduction Condensation: an Extension to the Mitsunobu Reaction (2003)
Reductant present within
R2CO2R1 substrate; adamantanols and
DMBQ
tert-butyl alcohol, among other
1
1
R = 1º or 2º, 85-96%; 3º, 72-82% 3º R OH, work well;
stereospecific inversion for 1º
or 2º; 70-100% inversion for 3º;
ArOH
1
Ph2POR
ArOR1
mild and neutral reaction, even
DMBQ
works for chloroacetic acid.
Ph2POR1
N
S
S
N
Amide coupling using
PySSPy: Tetrahedron
Lett. 1970, 22, 1901.
Precedes CoreyNicolaou macrolactonization (JACS 1974).
Me
R2CO2H
R1 = 1º or 2º, 78-92%; 3º, 62%
Even 2,6-disubstituted phenols give 70% yield
O
O
Me
DMBQ
Chem. Lett. 2003, 32, 300; Bull.
Chem. Soc. Jpn 2003, 76, 1645.
Ether formations:
Ph2POR1
Variations in the type of oxidant used:
N
EtO2C-NH-NH-CO2Et +
O. Mitsunobu and M.
Yamada, Bull. Chem.
Soc. Jpn 1967, 40, 2380.
Mitsunobu later expanded the scope of this reaction to include other nucleophiles.
2 RCO2H + PhCO-CH=CH-COPh + R'3P
2[H]
3+
R2CO2
O=PR3 + EtO2C-NBn-NH-CO2Et + R2CO2R1
Hg is a good [O] for this reaction!
(RCO)2O + Hg + R'3P=O
2 RCO2H + Ar2Hg + R'3P
N
O. Mitsunobu, M. Yamada and T. Mukaiyama,
Bull. Chem. Soc. Jpn 1967, 40, 935.
R1O-PR
Oxidation-Reduction Condensation (Review in Angew. Chem. Int. Ed. 1976, 15, 94-103):
Employs an oxidant that removes 2 H from a reaction, and a reductant that removes 1 O
from the same reaction, such that a net loss of water is observed. Essentially, a
dehydrating agent, that takes place under neutral conditions.
Ph
O
RO-P(OEt)2 + EtO2C-NAllyl-NH-CO2Et
Six months later... the Mitsunobu reaction:
Ph
Harnessing the ability of phosphorus (III) to reduce...
O
ROH + (EtO)2P-OAllyl + EtO2C-N=N-CO2Et
Ph
Ph
-H2O
BnO-PR3 + EtO2C-N-NH-CO2Et
O=PR3 + EtO2C-NBn-NH-CO2Et
O
J. Am. Chem. Soc. 1960, 82, 5339;
J. Org. Chem. 1962, 27, 3651.
RNCO + P(OEt)3
Baran Lab Group Meeting
Ph2POR1
R2OH
R2OR1 not formed!
DMBQ
R2OH
Fluoranil
R2OR1
Very low yields with DDQ or
chloroanil; chiral center at R1
gets inverted; coupling of 3º-3º
ROH are not possible but 2º- 3º
ROH couplings work.
Chem. Lett. 2003, 32, 984.
2
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Various hydroxyl activations:
Mukaiyama's Named Reagent: N-Methyl-2-Chloropyridinium Iodide
R1CO2H
N
X
Me
N
base
fast
I
OH
O
R2OH
R1
O
R1CO2R2
base
slow
Me
+
N
O
N
R
N
Y
R4
Cl
Me
R = Me or Et; X = F or Cl;
Y = BF4 or FSO3; Z = O or S
R1
FSO3
R1
O
N
R2
R1
O
O
R1
N
N
S
R3
Chem. Lett.
1975, 1163.
R1
Y
O
SR2
R1
OH
n
R3
R2
+
R1
R2
Pyridinium salt, Et3N
then LiI
R3
H
•
R1
R2
R2
R4
R1
R3
Chem. Lett. 1978, 785.
R1 or R2 can also be SPh,
generating vinyl sulfides:
Chem. Lett. 1978, 413.
Various functional groups generated from ROH + onium salt:
- Inverted ROH (acyclic only) from Cl3CCO2H, followed by saponification, Mukaiyama's
version of a Mitsunobu inversion: Chem. Lett. 1976, 893;
- RCl from LiCl (acyclic), R3NH+Cl- or R4N+Cl- (cyclic): Chem. Lett. 1976, 619; 1977, 383;
- RBr or RI from LIBr and NaI, respectively (acyclic only): Chem. Lett. 1976, 619;
- RSH (acyclic and cyclic) from Me2NC(=S)SNa, followed by LiAlH4: Chem. Lett. 1977,
437;
- RNH2 (acyclic and cyclic) from LiN3 + HMPA, followed by LiAlH4 or H2/Pd reduction:
Chem. Lett. 1977, 635;
- ROPO2OR' (acyclic) from R'OPO2H; exception to the rule - a benzoxazole is used,
and not an onium salt (the onium is prepared in situ): Chem. Lett. 1978, 349.
- RO-(Nucl.Base), i.e. nucleosides, from nucleic acid bases: Chem. Lett. 1978, 605.
If R has a stereocenter at the carbon bearing the hydroxyl group (i.e. 2º; 3º are
not tolerated), it will be inverted, unless R is a sugar, in which anomeric effects
and neighboring group participation dominate.
F
Various dehydrations and dethiohydrations:
Chem. Lett.
1976, 711.
Chem. Lett.
1977, 1443.
Chem. Lett.
1976, 711.
Chem. Lett.
1976, 303.
N
Without overlooking the macrolactonization...
HO
2. R3MgBr, cat. CuI
OH
X
O
R1
1. Pyridinium salt, Et3N
R4
R3
R2
R1
= Me, Et or Ph; R2 = H, Me or
Ph; R3 = H or Me; R4 = H or Me;
X = F, Cl or Br; Y = I, BF4 or TsO
S
2. R3MgBr
SPh
R1
Carboxylic acid derivatives formed:
O
N
OH
R2
R2
N
R2
R1
These findings opened a whole new area of study for redox-neutral dehydration
reactions: The utilization of onium salts of aza-arenes (Review in Angew. Chem. Int.
Ed. 1979, 18, 707-721).
R3
Types of onium salts used:
X
R1
R3
1. Pyridinium salt, Et3N
The course of the reaction (SN2 vs. SN2') depends on the nature of the R groups,
and in almost all cases, one isomer predominates. Chem. Lett. 1977, 1257; 1978, 689.
Me
X = Cl or Br in original reference: Chem. Lett. 1975, 1045.
It turns out that the nature of the alkyl group on pyridine, the X group and the
counterion all affect the yields of the coupling reactions in subtle fashion.
When R1 and R2 are 3º, the yields are dismal with the original Mukaiyama reagent,
but using 2-bromo-N-ethylpyridinium tetrafluoroborate with R1 = R2 = tBu resulted
in a 54% yield (Bull. Chem. Soc. Jpn 1977, 50, 1863).
Z
Baran Lab Group Meeting
O
n
O
O
Chem. Lett. 1976, 49: "their
procedure requires rather elevated Tº; lactonized in better
yields than those obtained by
previous methods".
Me
HO
OH
O
HO
Me
O
R1
Me
J. Am. Chem. Soc. 2003, 125, 5393;
Angew. Chem. Int. Ed. 2002, 41, 1787.
R2
R1
H
N
then H2O
R2
RNHCS2- Et3NH+
R1NHC(=S)NHR2
O
Chem. Lett. 1976, 1397.
R2
OH
O
Me
Pyr. salt, Et3N
Me
HO
OH
O
Me
Me
O
OH
R1
Me
OH
R1NHC(=S)OMe
O
OH Pyr. salt
R3
Et3N
R1
R2
Chem. Lett. 1977, 179.
R3
RCO-NH2
RNH-CHO
R-N=C=S
Chem. Lett. 1977, 573.
R1-N=C=N-R2
Chem. Lett. 1977, 575.
R-N=C=O
Chem. Lett. 1977, 1345.
R C N
unpublished
R N C
Chem. Lett. 1977, 697.
3
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Mukaiyama's Claim to Fame: The Mukaiyama Aldol Reaction
O
R1
OSiMe3
H
+ R2
OH
Lewis acid or
Lewis base
Y
R1 can be H;
Y = H, alkyl, Ar, OR, SR
A switch to silyl enol ethers: Use of TiCl4 as Lewis acid
O
R1
then aq.
workup
OH
Y
and/or
O
R1
O
Y
R2
O
N
Bu2BOTf
O
Y
N
iPr NEt
2
Me
Me
Me
O
OBBu2
O
R2
H
O
O
then [O]
workup
R1
R2
"Evans syn aldol"
History behind boron-mediated aldols:
OBR2 Brown et al., JACS 1967, 89, 5708 & 5709; for other
preparations of vinyloxyboranes, see: Hooz et al.,
MVK + BBu3
n-Pn
JACS 1968, 90, 5936; Tufariello et al., JACS 1967,
Me 89, 6804; Koster et al., Angew. Chem. 1968, 80, 756.
R5
R2
+
R3
h"
H2C=C=O
Instead:
expected product:
H2C=C(SBu)2
Me
Me
Bull. Chem. Soc. Jpn 1971, 44, 3215; mechanism corrected in J. Am.
Chem. Soc. 1973, 95, 967 and Bull. Chem. Soc. Jpn 1973, 46, 1807.
OBBu2
H2C=C=O + Bu2B-SBu
Me2CO
SBu
Me
Me
The "current" method to generate boron enolates:
O
OBBu2
O
Bu2BOTf
R2CHO
R1
Me
iPr NEt
2
R1
R1
R1
X3M
H
O
R2
Z-A
O
H
R1
Z-C
Chem. Lett. 1976,
559; 1977, 153.
MX3
X
O
R1
R2
R3
Chem. Lett. 1975, 527.
O
Chem. Lett. 1975, 989; 1976,
769.
OR5
R2
R3 R4
SiMe3
R3
H
R2
H
R3
R3
R2
R1
MX3
H
Me3SiO
OH
O
X
silyl enol
ether
R1
SBu
OR5 TiCl
4
R2
O
#Me3SiX
TS for Z-enol silanes:
SBu
Bu2
B
O
O
PhMe,
reflux
R4
Mechanism of the Mukaiyama aldol reaction:
O
Me2CO
OH
O
R1
R2 OMe O
R4
Mukaiyama's fortuitous discovery:
O
OH
R1
TiCl4
Chem. Lett. 1974,15.
R4
OSiMe3
R2
R5
R2
R3 R4
Br
OSiMe3
O
R1
O
R4
+
But no one used boron enolates in aldol reactions!
OH
R1
TiCl4
R3
OMe
OMe
R1
But Evans ! boron enolate! Rather, Evans = use of chiral oxazolidinone for aldol.
Bu2B-SBu
R2
OR
R4
Br
Me
Y = alkyl, Ar, OR, SR, Cl, Br but not H
OSiMe3
3
+ R
OR
R2
Y
Me
Me
R1
TiCl4
Chem. Lett. 1973,1011;
J. Am. Chem. Soc.
1974, 96, 7503.
Expanding substrate scope:
OH
N
OH
Reactivity as electrophile: RCHO (#78°C) > RCOR' (0°C) >> RCO2R'
Chem. Lett. 1975, 741; Bull. Chem. Soc. Jpn 1976, 49, 2284.
OR
O
O
R2CHO
R1
base
Me
R2
Enol silane geometry rarely affects
the syn/anti geometry of the product
O
Y
OSiMe3
Me3SiCl
R1
...vs. the Evans aldol reaction:
O
Baran Lab Group Meeting
X3M
Me3SiO
R3
MX3
R2
H
H
X3M
OSiMe3
OH
H
O
O
R3
Z-D
OSiMe3
OH
R3
aq. workup
O
R1
R3
R2
R2
R3
R1
E-A
O
R1
H
R3
R2
syn
O
R1
Me3SiO
MX3
R2
R1
R3
E-B
H
X3M
H
O
MX3
R3
E-C
X3M
OSiMe3
H
H
R2
H
H
R3
anti
OH
O
R2
R2
R2
R1
O
R1
Z-B
H
O
R1
TS for E-enol silanes:
H
R1
X3
M
H
OSiMe3
R2
R1
O
R3
Me3SiO
E-D
The most favorable conformations: A and D. If R2 = large and R3 = small, D is favored; if
R2 = small and R3 = large, A is favored. Conclusion: Z/E of the enol silane rarely matters!
4
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Lewis acid-catalyzed Mukaiyama aldol reactions:
X3
M
SiMe3
O
O
O
O
Me3Si-X
R1
R3
R2
needs to
transmetallate
R1
Titanium tetrachloride reactions (See review in Angew. Chem. Int. Ed. 1977, 16, 817-826):
R3
+ MX4
R2
First catalysis: Trityl salts
(Chem. Lett. 1985, 447,
1535 and 1871); in situ
Me3Si+: SnCl2, Me3SiCl
(Chem. Lett. 1987, 463).
Typically 1-10 mol%.
Chiral Lewis acids: The true strength of the Mukaiyama aldol reaction.
Sn(OTf)2,
Chiral diamine, eg.
O
OSiMe3 Bu2Sn(OAc)2,
OH
O
chiral diamine
+
R
H
SEt
R
SEt
CH2Cl2, !78 °C
N
Me
Me
Me
NHNaph
Z enolates work well; E
70-96%;
enolates are mismatched; H
100% de,
Chem. Lett. 1989, 297; J. Am.
instead of Me works very well.
>98% ee
Chem. Soc. 1991, 113, 4247.
Enantioselective diol formation:
O
OSiMe3
+
R
H
SEt
OBn
CH2Cl2, !78 °C
Chem. Lett. 1990, 1019; Replacing
Bn by TBS results in the syn
product (Chem. Lett. 1991, 1901.)
Characteristics: Strong Lewis acid, strong oxophile and dehydrater; may act as an
electrophile for C!C " bonds.
eg.
OH
O
N
N
R
OBn
72-88%;
>96% de,
>95% ee
R1
EtS
O
O
Ph
OH
O
R1
Et3N
R2
H
OSiMe3
Me
OSiMe3
R
But the above chiral Lewis acid reagents are stoichiometric! The chiral diamines are "promoters"...
Simple solution: Replace CH2Cl2 for CH3CH2CN (Sn-Si exchange is faster; Chem.
Lett. 1990, 1455), and add the two substrates slowly into the catalyst mix to prevent
undesired Me3SiOTf-promoted, racemic aldol formation.
Lewis base-catalyzed Mukaiyama aldol reactions:
Li
SiMe3
OSiMe3
O
O
O
O
LiNR2
Me
Si-NR
3
2
Me
PhCHO +
OMe Solvent Ph
OMe
Ph
OMe
turnover
Me Me
Me Me
Me
LiNPh2 was initially used over LDA, but Li 2-pyrrolidone was optimal; THF did not allow
turnover but DMF did; a milder version using LiOAc as a base in DMF/H2O systems
allowed the compatibility of hydroxyl and carboxyl functionalities in the substrate
(Chem. Lett. 2002, 182 and 858; 2003, 462 and 696).
R2
+
Ph
OMe
Ac
73%,
dr 17:3
O
+
Ph
TiCl4,
Ti(OiPr)4
OMe
Trioxane,
TiCl4
O
O
R3
R1
Vinyl chlorides work as well.
OSiMe3
Bull. Chem. Soc.
Jpn 1972, 45,
3723; Chem.
Lett. 1973, 479.
Ph
(80%)
O
Chem. Lett. 1975, 319.
O
(Mechanism and stereoselectivity?)
Chem. Lett. 1974, 381 and 1181.
O
TiCl4, Ti(OiPr)4
O
SEt
OiPr
Me
O
Ph
O
H2O,
TiCl4
R3
R1
+
SEt
SR
Aldol-like reactions:
Me
Ph
CH2Cl2
RSH,
TiCl4
R3
OTf
H
unpublished
SEt
R3
Bn
cyclohexylbenzene
(91%)
EtSH, TiCl4
R2
Sn
SEt
TiCl4
cyclohexanol + benzene
Proposed TS for -OBn:
Sn(OTf)2,
Bu2Sn(OAc)2,
chiral diamine
Baran Lab Group Meeting
then HSCH2CH2SH
S
S
Ph
Reactions on #,$-unsaturated ketones work as well. Chem.
Lett. 1974, 1223; Bull. Chem. Soc. Jpn 1976, 49, 779.
Titanium tetrachloride reduced in situ:
-TiCl4/LiAlH4:
S
ArCl
S
R1
R2
ArH
H
R1
H
R2
Chem. Lett. 1973, 291.
-TiCl4/Zn: PhCHO
RCH(OMe)2
Me
Ph
OMe
2
MeO
RCH2OMe
Me
Me
Ph
Ph
MeO
OMe
unpublished
PhCH-CHPh + PhCH=CHPh
OH OH
room T°, THF:
98%
1%
reflux, dioxane:
0%
98%
Chem. Lett. 1973, 1041;
precedes TiCl3-based
McMurry coupling
(JACS 1974, 96, 4708).
5
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Miscellaneous reactions
Chiral !-hydroxyaldehyde formation:
Sugar chemistry:
RO
RO
O
O
Me
OH
N
F
O
Me
OTs
Me
Et3N
O
O
Me
F
O
Me
OBn
BnO
Chem. Lett. 1983, 935;
anomers are separable and
the ! can be converted to the
" form using BF3; at the time,
this reaction could only be
done using anhydrous HF;
reaction discovered from
analogy of RCO2H to RCOF.
F
OBn
+ HO
O
BnO
BnO
BnO OMe
SnCl2, AgClO4
4Å MS
84%
dr = 84:16
N
Mg O
X
O
BnO
BnO
Protic acid-catalyzed activation:
O
OBn
F
cat. HX
+ HO
5Å MS
O
BnO
Solvent
BnO
BnO OMe
TfOH, Et2O: 98%, !/" = 88:12
HClO4, Et2O: 98%, !/" = 92:8
C4F9SO3H, Et2O: 99%, !/" = 88:12
BnO
BnO
BnO
PipCO-N=N-COPip
R
(89-96%)
Pip = N-substituted piperidine
O
LDA, then
Ph
O
BnO OMe
S
Tf2NH, PhCF3: 99%, !/" = 9:91
HSbF6, PhCF3: 100%, !/" =12:88
HB(C6H5)4, PhCF3: 99%, !/" = 7:93
O
Ph
TiCl4
R1CHO +
O
N
Me
Pyr.
>76%
>17:3 dr
Me
prepared from ephedrine
hydrochloride in 3 steps
R1
O
O
N
Me
E-alkene
O
Chem. Lett. 2000, 1250; if DBU is used instead of
LDA, 2° amines to imines, (Chem. Lett. 2001, 390)
and N,N-disubstituted hydroxylamines to nitrones
(ARKIVOC 2001, 10, 58) can be formed.
NtBu
Cl
(93%)
Ph
S NHtBu
NCS or NBS (1.1 eq)
Chiral "-substituted carboxylic acid formation:
O
O
Ph
Me
DEAD does not give as high yields
(Yoneda et al., JACS 1966, 88, 2328).
Named reaction (??): "Mukaiyama
Oxidation"; 2° alcohols to ketones
work equally well (Bull. Chem. Soc.
Jpn 1977, 50, 2773).
Some sulfur chemistry:
O
BnO
BnO
BnO
H
R
OH
Cl
O
Chem. Lett. 2001, 426; Bull. Chem. Soc. Jpn 2002, 75, 291.
O
O
Ph
H3O+
Mixed ether formation from acetals: mixed acetals work best (Chem. Lett. 1975, 305).
Cl
TiCl4
+ BrMg
Ph
(98%)
O
O
O
Ph
Chem. Lett. 1981, 431. Yields and stereoselectivities are typically better than
Cl or Br analogs due to the C-F bond strength at the anomeric position: C#F
552 kJ/mol; C#Cl 397 kJ/mol; C#Br 280 kJ/mol.
BnO
BnO
BnO
NPh
R
OH
O
Overall yield: 67-82%; optical purity > 94%.
Chem. Lett. 1978, 1253; 1979, 705.
OH
BnO OMe
Ph
CHO
Cramchelate TS
R
O
H
NPh
PrMgBr or tBuOMgBr
BnO
N
1. RMgX
NPh 2. NH Cl
4
PhH
single Ph
PhHN diastereomer
Some more Grignard chemistry:
O
BnO
N
H
H Ph
R
N
Dean-Stark
PhCOCHO +
OBn
BnO
O
BnO
Baran Lab Group Meeting
R2MgBr
>75%
R1
R2
O
H3O+
Chem. Lett. 1977, 1165; Bull. Chem. Soc. Jpn 1978, 51, 3368.
R1
R2
O
Ph
N
Me
R
OH
O
R
K2CO3, 4Å MS, CH2Cl2,
0 °C, 30 min (86-100%)
Me
Me
DMAD
H
MeO2C
Named reaction (??): "Mukaiyama
Oxidation"; 2° alcohols to ketones
work equally well. (Chem. Lett. 2001,
846; Tetrahedron 2003, 59, 6739.)
CO2Me
S
Me
O
Me
OH
MeO2C
+
COPh
Tet. Lett. 1970, 29, 2565.
Me
DMSO:
PhH:
O
88%
27%
Me
SMe
Ph
PhOC
CO2Me
0%
70%
6
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Total Synthesis Targets - Application of Synthetic Methodology
Integerrimine (Chem. Lett. 1982, 57 and 455):
NH2
N
O
HS
O Me
N
H
O
Me
O
N
H
P
O
O
O
OH
O
Me
Me
1) Me2CuLi; CO2
1) MCPBA (76%)
O
O
Coenzyme A - Coupling with [O]-[H] condensation
Chem. Lett. 1972, 595.
N
Me
H
H
O
H
Me
P
O
N
1) TsO
O
F
1)
(60%)
Me
Me
N
Me
O
Me
Ph
NHMe
N
O
N
H
N
H
Me
CO2H
A
B
O
Me
O
OH
nC H
9 19
OH
nC
N
9H19
N
Ph
Malyngolide - Quaternary
stereocenter synthesis via
asymmetric !-hydroxyaldehyde
synthesis
Chem. Lett. 1980, 1223.
O
Me
CO2CH2CH2TMS
O
O
via one more
Mukaiyama
condensation
Me
O
N
integerrimine
F1! Antigen (Chem. Lett. 2001, 840; Bull. Chem. Soc. Jpn 2003, 76, 1829):
BnO
Me
Indolmycin - Methyl group introduction via a chiral oxazepine appendage
Chem. Lett. 1980, 163.
OH
OH
BnO
O
Me
Me
Me
O
2) LiOH, H2O2 (71%)
Me
dl-Variotin - Ti coupling of acetals
with silyl enol ethers, and amide
formation using Mukaiyama reagent
Chem. Lett. 1977, 467; Bull. Chem.
Soc. Jpn 1978, 51, 2077.
O
(98%)
HOCH2CH2TMS
Me
O
Me
Cl
Me
N
OH
N
O
CO2H
O
OH
I
Me
OH
nBu
Vitamin A - Ti coupling of acetals
with silyl enol ethers
Chem. Lett. 1975, 1201.
CO2Me
Me
H
Me
Me
O
Me
2) LiOH (100%)
Me
Me
O
H
Me
O
CO2Me 2) LDA; MeCHO
2) CH2N2 (80%)
O
OH
O
N
N
P
Baran Lab Group Meeting
BnO
HO
BnO
BnO
C
BnO
OBn
A + B + cat. H+ + MS 5Å, then C + NIS
O
F
O(4-Me)Bz
One-Pot Sequential
Stereoselective
Glycosylation
(89%)
O
SEt
N(4,5-Cl2)Phth
BnO
OH
O
NHCbz
N3 O
BnO
CO2H
OBn
BnO
O
O
O
BnO
BnO
O(4-Me)Bz
Cl2Phth-N
O
BnO
N3 O
O
NHCbz
CO2H
Reduction of the azide, removal of the phthaloyl group, acetylation of two
N atoms and removal of all protection groups lead to the F1! antigen.
7
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Baran Lab Group Meeting
Total Synthesis of Taxol® (Proc. Jpn. Acad. 1997, 73B, 95; Chem. Eur. J. 1999, 5, 121.)
AcO
18
O
Ph
Ph
N
H
Me
O
12 11
O
OH
10 9
O
19 OH
Me
Me
13
15
14 1
HO
8
16, 17
Me 3
2
BzO
7
O
TBSO
6
5
4
H
AcO
BnO
Me
19. 1N HCl (83%)
20. Swern [O] (95%)
Me
Me
PMBO
O
20
BnO
16. LHMDS, TMSCl
17. NBS
18. LHMDS, MeI
OBn
BnO Me
Me OBn
MeO
CO2Me
Me
HO
1. Swern [O] (89%)
2. HC(OMe)3 (93%)
Me
OTBS
O
OMe OH
CO2Me 3. LiAlH4 (90%)
4. Swern [O] (85%)
Me
MeO
t
BuLi, CuCN
(92%, 99% brsm)
, Sn(OTf)2
O
TBSO
OMe
Me
PMBO
N
, Bu2Sn(OAc)2
MeO
6. PMB Prot. (95%)
7. LiAlH4 (86%)
CO2Me
8. TBSCl (93%)
9. AcOH (87%)
OMe OH
Me
Me OBn
BnO Me
HO PMBO
OMe
OHC
PMBO TBSO
MgBr2
(77%, 87% brsm,
71:16 dr)
H
OBn
HO
Me
Me
BnO
28. AlH3 (94%)
29. Me2C(OMe)2
O
TBSO
30. DDQ, H2O (97%)
31. PDC (90%, 94%
brsm)
Me
O
Me
32. H2C=CH(CH2)2Li
33. TBAF (96%)
Me
Me
H
OBn
O
Me
Me
O
O
Me
BnO
34. cHxMeSiCl2
(99%)
HO
35. MeLi (96%)
Me
36. TPAP-NMO (80%)
Me
H
OH OBn
O
H
OBn
37. PdCl2, DMF-H2O
(98%)
SiMe2cHx
Me
Me OBn
MeO2C
BnO
OTBS
(68%, 4:1 dr; although
the alcohol stereocenter
is erased after step 31)
OBn
Me
Me
O
O
Me
BnO
Me OBn
OH
Me
Me
CHO
N
Me
Me
27. NaOMe (98%, 23:2 dr)
(Minor enantiomer can be
epimerized)
Me
BnO
OMe
OTBS
OBn
25. 0.5 N HCl (97%)
26. TPAP-NMO (92%)
Me
Me
PMBO
Me
OTES
TBSO
OTBS OPMB
BnO
Me
O
Me
PMBO
Me
Me OBn
Me
21. SmI2 (70%) TBSO
22. Ac2O (87%)
CHO
Me
23. DBU (91%)
O TBSO PMBO
BnO
Br
O
Me OBn
Me
TESO
60 steps, ~0.02 % overall yield
Me
Br BnO Me
11. TBSOTf
12. DIBAL
13. Swern [O] (94%)
14. MeMgBr (99%)
OTBS 15. Swern [O] (97%)
BnO Me
BnO
Me OBn
O
O
Me
O TBSO PMBO
OTBS
Me
O
Me
38. TiCl2, LiAlH4
(43-71%)
Me
Me
O
Primarily an aldol-based strategy!
O
H
OBn
Me
Me
O
O
Me
HO
HO
HO
39. Na-NH3
Me
40. TBAF (100%)
Me
Me
H
OH OH
SiMe2cHx
8
Teruaki Mukaiyama - !"#
$%
Y. Ishihara
Formation of the D-Ring Oxetane: End-Game
Words of Wisdom...
Me
Me
HO
O
AcO
O
HO HO
HO HO
41. (Cl3CO)2CO
Me
42. Ac2O (84%) Me
Me
Me
43. 3N HCl
Me
44. TESCl (83%)
45. TPAP-NMO
H
(76%)
HO
O
HO
O
OTES
Me
Me
Me
H
O
O
Me
46. (Imid)2C=S
47. P(OEt)3 (53%)
48. PCC (78%)
AcO
O
OTES
Me
Me
TESO
51. CuBr, PhCO3tBu
Me
49. K-Selectride (87%)
50. TESOTf (98%)
O
H
52. CuBr (58%)
O
O
Me
AcO
O
OTES
Me
Me
53. OsO4 (92%,
96% brsm)
Me
TESO
Me
O
H
O
AcO
Br 54. DBU (42%,
81% brsm)
55. Ac2O (91%)
AcO
O
OH
Me
O
O
H
AcO
O
58. TESCl (87%, 92% brsm)
59. Side Chain Acid, [(2-Py)O]2CS,
DMAP (88%, 95% brsm)
Me
HO
Me
57. HF-py (96%)
HO
BzN
Me
O
56. PhLi (94%)
Ph
O
OTES
Me
Me
TESO
O
Me
BzO
60. TFA (94%)
H
AcO
O
baccatin III
O
OH
O
PMP Side Chain Acid
Baran Lab Group Meeting
TAXOL!!!
[...] The development of novel synthetic methodologies is now an essential part of synthetic organic
chemistry. The most fruitful approach to this problem, I believe, is 'to let something come from
nothing', i.e. we must discover new possibilities in a field previously neglected, and create innovative
concepts in synthetic organic chemistry. It is absolutely essential to carry out one's research on one's
own ideas, unaffected by the current fashion. I have tried to explore new methodologies in this way,
keeping in mind the words 'no imitation' that Professor Toshio Hoshino said to me at the start of my
research career.
An active and original programme is vital to the execution of basic research. Only the research
work that has been fostered with one's own hands, thus spreading its roots deep and never being
washed away, will survive forever. Fashionable works may soon be forgotten, as quickly as floating
weeds. Needless to say, an unpretentious, enduring, and systematic attack on problems is required if
you want to obtain fruitful results in basic research. [...]
I have submitted all my articles to Chemistry Letters since the first publication in 1972, because I
think that the results of one's chemistry should be published in journals of one's country. [...]
I have tried to change my topics about every four years. I admit that a deep and thorough study on
a single topic is very important for a researcher; however, I think it is more significant to change topics
at various times, especially in the fields of explorationof new methodologies. Perhaps it is related to
my own nature - I do not like to stick to a particular matter for too long. New ideas come to me, one
after another, and I encourage myself to build new hypotheses and initiate new active research
programmes, purposely putting the pressure on myself.
In the first year, I learn various things about the new problem itself. In the second year, I begin to
get some possibilities and then in the third year I have some more results. The fourth year is harvest
time, and at the same time I plan what to do next. Thus, I have always pursued new research
programmes. There may be many things still left undone when I take the move on to the next
programme, and if any treasures remain they will be left to the hands of many other able chemists. [...]
(From the review of his life's works in Challenges in Synthetic Chemistry, Clarendon
Press, Oxford, 1990, 225 pages.)
In basic science it is critical to find the first approach (“seeds-oriented” work), but it is equally
important to optimize the approach and to develop new systems (“needs oriented”). In either case,
ample time and energy need be invested before a chemist can garner anything useful. Once the
fundamental target is reached, however, the whole process appears so easy that anyone else could
have done it, like the episode of “Columbus! egg”. However, to win through to the result, a researcher
must go through unrewarding months and years of making hypotheses and repeating experiments,
and this is exactly what makes a chemist. The most important thing here is “not to imitate others”. If
someone has already been involved with the topic, dare not to stick to the same topic, but find
something of your own. This is our code, which should never be forgotten.
Experience and the accumulation of experiences play a very important role in pursuing research
work. If a mature hypothesis does not lead you to a satisfactory result, just try once more from the
beginning and continue to do the experiments. You will then eventually find an interesting clue, unless
you give up half way. Chemistry is still more or less unpredictable. Wisdom learned not from books or
what others said but from one's own experience—which I call “chemical wisdom”—will become a
motivating force for associating problems with questions that give you a different idea. Those who
have accumulated a lot of such “chemical wisdom” should be able to formulate a seminal hypothesis
by the association of small clues. By overcoming difficulties without compromise, hard and steady
work done (especially at the time of one's youth) will give you love for your work and will furnish you
with “chemical wisdom”, and consequently will lead you to successful later development.
The fun of chemistry is in its unexpectedness. There are times when you come to face-to-face with
an unexpected phenomenon while carrying out experiments. You simply have to be sufficiently aware
and open to accept the seemingly unbelievable. There are still many more valuable ideas remaining to
be discovered. The question is how to find them and how to develop them into new possibilities.
(From the review of his life's works in Angew. Chem. Int. Ed. 2004, 43, 5590-5614.)
9