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Y. Ishihara Teruaki Mukaiyama - 向山 光昭 Baran Lab Group Meeting
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
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 ...632Bull. Chem. Soc. Jpn ...165
Chemistry Letters, founded in 1972 by Mukaiyama.
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 $5,000, a medallion, and a certificate. The recipient shall deliver an award lecture at the Seminar on Synthetic Organic Chemistry. - A nomination form can be downloaded from http://wwwsoc.nii.ac.jp/ssocj/ - Selection: The award committee selects two award recipients, one from the non- Japanese nominees and the other from the Japanese nominees.
An excerpt from Mukaiyama's publication list, published in Heterocycles 2000, 52, 13-66.
Notable chemists originating from the Mukaiyama Group:Isao Kuwajima, formerly at Tokyo Institute of Technology; Eiichi Nakamura, University of Tokyo; Koichi Narasaka, University of Tokyo; Shuu Kobayashi, University of Tokyo; Masahiro Murakami, Kyoto University; Yujiro Hayashi, Tokyo University of Science; Kenso Soai, Tokyo University of Science; the late professor Oyo Mitsunobu, formerly at Aoyama Gakuin University.
1
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Harnessing the ability of phosphorus (III) to reduce...
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.
Synthesis of phosphoric esters as an application of oxidation-reduction condensation:Mukaiyama's early years: An organophosphorus chemist
PhNCO + EtNO2NH
O
NH
PhPh +
NO
N
Me Me
cat. R3NO
P(OEt)3
NO
N
Me Me
J. Am. Chem. Soc. 1960, 82, 5339; J. Org. Chem. 1962, 27, 3651.
RNCO + P(OEt)3 RNC + O=P(OEt)3
Ph Ph
O O P(OEt)3O O
P
EtO
OEt
OEt
Ph Ph
Ph
C
Ph
O Ph PhP(OEt)3
!
Side product: Diphenylketene dimer
J. Org. Chem. 1964, 29, 2243.
(RCO2)2Hg + R'3P (RCO)2O + Hg + R'3P=O Hg is a good [O] for this reaction!
2 RCO2H + Ar2Hg + R'3P
J. Org. Chem. 1963, 28, 2024.
(RCO)2O + Hg + 2 ArH + R'3P=O
-H2O 2[H] [O]
2 RCO2H + PhCO-CH=CH-COPh + R'3P
J. Org. Chem. 1964, 29, 1385.
(RCO)2O + PhCO-CH2CH2-COPh + R'3P=O
-H2O 2[H] [O]
Variations in the type of oxidant used:
N
NO
PhO
Ph
Variations in the type of products made: Esters, thioesters, amides, thioethers, pyrophosphates... also useful in peptide and nucleotide chemistry.
Amide coupling using PySSPy: Tetrahedron Lett. 1970, 22, 1901. Precedes Corey-Nicolaou macrolac-tonization (JACS 1974).
N S S N
BnOH + R3P + EtO2C-N=N-CO2Et BnO-PR3 + EtO2C-N-NH-CO2Et
O=PR3 + EtO2C-NBn-NH-CO2Et
ROH + (EtO)2P-OAllyl + EtO2C-N=N-CO2Et RO-P(OEt)2 + EtO2C-NAllyl-NH-CO2Et
O
Desired product for MukaiyamaO. Mitsunobu, M. Yamada and T. Mukaiyama, Bull. Chem. Soc. Jpn 1967, 40, 935.
Six months later... the Mitsunobu reaction:
R1OH + R3P + EtO2C-N=N-CO2Et + R2CO2H
R1O-PR3 + EtO2C-NH-NH-CO2Et + R2CO2
O=PR3 + EtO2C-NBn-NH-CO2Et + R2CO2R1
O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn 1967, 40, 2380.
Mitsunobu later expanded the scope of this reaction to include other nucleophiles.
Oxidation-Reduction Condensation: an Extension to the Mitsunobu Reaction (2003)
Ph2POR1R2CO2H
OO
Me
Me
Reductant present within
substrate; adamantanols and
tert-butyl alcohol, among other
3º R1OH, work well;
stereospecific inversion for 1º
or 2º; 70-100% inversion for 3º;
mild and neutral reaction, even
works for chloroacetic acid.
R2CO2R1
DMBQ
DMBQ
R1 = 1º or 2º, 85-96%; 3º, 72-82%
Chem. Lett. 2003, 32, 300; Bull. Chem. Soc. Jpn 2003, 76, 1645.
Ph2POR1 ArOHArOR1
DMBQ
R1 = 1º or 2º, 78-92%; 3º, 62%
Even 2,6-disubstituted phenols give 70% yield
Ph2POR1 R2OHR2OR1 not formed!
DMBQ
Ph2POR1 R2OHR2OR1
Fluoranil
Ether formations:
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
unpublished results
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Mukaiyama's Named Reagent: N-Methyl-2-Chloropyridinium Iodide
N
Me
X
I
X = Cl or Br in original reference: Chem. Lett. 1975, 1045.
R1CO2H
base N
Me
O
R2OH
base
O
R1 R1CO2R2 +N
Me
O
fast slow
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).
NN
N
N
Z
Me
Cl
R1
XR4
R3
R2
X
RFSO3
Y Y
R = Me or Et; X = F or Cl; Y = BF4 or FSO3; Z = O or S
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
R1 N
O
S
S
R1 N
O
R3
R2
R1 N
O O
R1 SR2
O
Carboxylic acid derivatives formed:
R1 F
O
Chem. Lett. 1977, 1443.
Chem. Lett. 1975, 1163.
Chem. Lett. 1976, 711.
Chem. Lett. 1976, 711.
Chem. Lett. 1976, 303.
Without overlooking the macrolactonization...
O
Me
OH
MeMe
MeOH
HO
OHO
O
Me
OH
MeMe
MeO
HO
O
J. Am. Chem. Soc. 2003, 125, 5393; Angew. Chem. Int. Ed. 2002, 41, 1787.
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).
Types of onium salts used:
HO OH
On
O
On
Chem. Lett. 1976, 49: "their procedure requires rather ele-vated Tº; lactonized in better yields than those obtained by previous methods".
Various hydroxyl activations:
R1 R2
OH
R1
R3
R2 R1 R2
R3
1. Pyridinium salt, Et3N
2. R3MgBr+
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.
R2
OH1. Pyridinium salt, Et3N
2. R3MgBr, cat. CuI
R1
•
H
R2R1
R3
Chem. Lett. 1978, 785.
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.
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.
SPh
OH
R3R4
R1R2
Pyridinium salt, Et3N
then LiI
R2
R1
R4
R3
R1 or R2 can also be SPh,
generating vinyl sulfides:
Chem. Lett. 1978, 413.
Various dehydrations and dethiohydrations:
R1
N
R2
OH HN
O
R2
R1
RCO-NH2
RNH-CHO
R3
O
R1
R2
R3
R2
OH
R1OH
Pyr. salt, Et3N
then H2O
Pyr. salt
Et3N
Chem. Lett. 1976, 1397.
Chem. Lett. 1977, 179.
RNHCS2- Et3NH+
C NR
R N C
R-N=C=O
R-N=C=S
R1-N=C=N-R2R1NHC(=S)NHR2
R1NHC(=S)OMe
Chem. Lett. 1977, 573.
Chem. Lett. 1977, 575.
Chem. Lett. 1977, 1345.
unpublished
Chem. Lett. 1977, 697.
3
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Mukaiyama's Claim to Fame: The Mukaiyama Aldol Reaction
R1
O
H
OSiMe3
Y R1 Y
O
R1 Y
OOH
R2
OH
R2
R2+and/or
Lewis acid or Lewis base
then aq. workup
...vs. the Evans aldol reaction:
NO
O O
Y
R1 can be H;
Y = H, alkyl, Ar, OR, SR
Me
Me
Y = alkyl, Ar, OR, SR, Cl, Br but not H
iPr2NEt
Bu2BOTf NO
O OBBu2
Y
Me
Me
then [O] workup
R2 H
O
NO
O O
Me
Me
R2
Y
OH
"Evans syn aldol"
Enol silane geometry rarely affects the syn/anti geometry of the product
But Evans ! boron enolate! Rather, Evans = use of chiral oxazolidinone for aldol.
History behind boron-mediated aldols:
OBR2
Men-PnMVK + BBu3
Brown et al., JACS 1967, 89, 5708 & 5709; for other preparations of vinyloxyboranes, see: Hooz et al., JACS 1968, 90, 5936; Tufariello et al., JACS 1967, 89, 6804; Koster et al., Angew. Chem. 1968, 80, 756.
But no one used boron enolates in aldol reactions!
Mukaiyama's fortuitous discovery:
Me2CO H2C=C=Oh"
Bu2B-SBu expected product: H2C=C(SBu)2
Me SBu
OH
Me
O
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.
H2C=C=O + Bu2B-SBu
OBBu2
SBu
Me2CO
Instead:
Me SBu
O
Me
O
Bu2B
R1
O
Me
The "current" method to generate boron enolates:
iPr2NEt
Bu2BOTf
R1
OBBu2R2CHO
R1
O
R2
OHChem. Lett. 1976, 559; 1977, 153.
A switch to silyl enol ethers: Use of TiCl4 as Lewis acid
R1
O
Me base
Me3SiCl
R1
OSiMe3R2CHO
R1
O
R2
OH Chem. Lett. 1973,1011; J. Am. Chem. Soc. 1974, 96, 7503.TiCl4
Reactivity as electrophile: RCHO (#78°C) > RCOR' (0°C) >> RCO2R'Chem. Lett. 1975, 741; Bull. Chem. Soc. Jpn 1976, 49, 2284.
Expanding substrate scope:
OSiMe3
R5
R4
R3
R1 OR
OR
R2
+TiCl4
R1 R5
OR
R2
O
R3 R4
Chem. Lett. 1974,15.
R1OMe
R2
OMeBr
OSiMe3
R4
R3
+TiCl4
R1
Br OH
R2 OMe
R4
O
PhMe, reflux
O
R2 R3
R1 R4
OSiMe3
OR5
R4
R3
R1 R2
O
+TiCl4
R1 OR5
OH
R2
O
R3 R4
Chem. Lett. 1975, 989; 1976, 769.
Mechanism of the Mukaiyama aldol reaction:
R1
O
H R1 H
OMX3 O
R3
R2
SiMe3
XX3M
X
silyl enol ether
#Me3SiXR1 R3
OO
R2
X3M
aq. workupR1 R3
OOH
R2
R1
O
H
MX3
R1O
H
X3M
R1
O
H
MX3
R1O
H
X3M
R2 H
R3Me3SiO
R2 H
R3Me3SiO
H R2
OSiMe3R3
H R2
OSiMe3R3
TS for Z-enol silanes:
R1
O
H
MX3
R1O
H
X3M
R1
O
H
MX3
R1O
H
X3M
R2 H
OSiMe3R3
R2 H
OSiMe3R3
H R2
R3Me3SiO
H R2
R3Me3SiO
TS for E-enol silanes:
Z-A Z-B
Z-C Z-D
E-A E-B
E-C E-D
R1 R3
OOH
R2
R1 R3
OOH
R2
anti
syn
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!
Chem. Lett. 1975, 527.
4
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Lewis acid-catalyzed Mukaiyama aldol reactions:
R1 R3
OO
R2
X3M
needs to transmetallate
R1 R3
OO
R2
SiMe3
+ MX4
Me3Si-X
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.
Chem. Lett. 1989, 297; J. Am. Chem. Soc. 1991, 113, 4247.
R
O
H
OSiMe3
SEt R SEt
OOH
Me
+
Sn(OTf)2, Bu2Sn(OAc)2, chiral diamine
CH2Cl2, !78 °C
Z enolates work well; E enolates are mismatched; H instead of Me works very well.
Me
70-96%; 100% de, >98% ee
Chiral diamine, eg.
NMe NHNaph
But the above chiral Lewis acid reagents are stoichio-metric! 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.
Enantioselective diol formation:
R
O
H
OSiMe3
SEt R SEt
OOH
OBn
+
Sn(OTf)2, Bu2Sn(OAc)2, chiral diamine
CH2Cl2, !78 °COBn
72-88%; >96% de, >95% ee
Chem. Lett. 1990, 1019; Replacing Bn by TBS results in the syn product (Chem. Lett. 1991, 1901.)
Proposed TS for -OBn:
Lewis base-catalyzed Mukaiyama aldol reactions:
Titanium tetrachloride reactions (See review in Angew. Chem. Int. Ed. 1977, 16, 817-826):
OSiMe3
OMe Ph OMe
OO
PhCHO +
LiNR2
Solvent
Me
Me
Me Me
Me3Si-NR2
Ph OMe
OO
Me Me
Li SiMe3
turnover
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).
Characteristics: Strong Lewis acid, strong oxophile and dehydrater; may act as an electrophile for C!C " bonds.
TiCl4eg.
(91%)
Ph OH
EtSH, TiCl4
CH2Cl2Ph SEt + Ph SEt
SEt
R1
O
unpublished
R2
R3
R1
SR
R3
RSH, TiCl4
Bull. Chem. Soc. Jpn 1972, 45, 3723; Chem. Lett. 1973, 479.
H2O, TiCl4
Et3NR1
O
R2
R3
Vinyl chlorides work as well.
Aldol-like reactions:
OSiMe3 Ph OMe
OMe
+
TiCl4,
Ti(OiPr)4
Ph O
OiPr
(80%)
Chem. Lett. 1975, 319.
OO
Me
Me
Trioxane, TiCl4
73%, dr 17:3 O
O
MeAc
(Mechanism and stereoselectivity?)Chem. Lett. 1974, 381 and 1181.
Ph
OSiMe3O O
+TiCl4, Ti(OiPr)4
then HSCH2CH2SH
Reactions on #,$-unsaturated ketones work as well. Chem. Lett. 1974, 1223; Bull. Chem. Soc. Jpn 1976, 49, 779.
cyclohexanol + benzene cyclohexylbenzene
Ph
S SO
Titanium tetrachloride reduced in situ:
-TiCl4/LiAlH4:
S S
R2R1
H H
R2R1
ArCl ArH
Chem. Lett. 1973, 291.
MeO OMe
MePh
MePh
OMe
MeO
MePh
RCH(OMe)2 RCH2OMe
unpublished
-TiCl4/Zn:
2
PhCHO PhCH-CHPh
OH OH
+ PhCH=CHPh
room T°, THF: 98% 1%reflux, dioxane: 0% 98%
Chem. Lett. 1973, 1041; precedes TiCl3-based McMurry coupling (JACS 1974, 96, 4708).
N
O
N
OTfSn
R1
R2
R3
H
OSiMe3
EtS
Bn
O
R
H
5
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Miscellaneous reactions
(98%)O O
Cl
Cl
PhBrMg+
TiCl4
O Ph
Mixed ether formation from acetals: mixed acetals work best (Chem. Lett. 1975, 305).
Named reaction (??): "Mukaiyama Oxidation"; 2° alcohols to ketones work equally well. (Chem. Lett. 2001, 846; Tetrahedron 2003, 59, 6739.)K2CO3, 4Å MS, CH2Cl2,
0 °C, 30 min (86-100%)
NCS or NBS (1.1 eq)
O O
S NHtBu
Ph
Ph
S NtBu
Cl
LDA, then
(93%)
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.
R OH R H
O
Some more Grignard chemistry:
PipCO-N=N-COPip (89-96%)
R OH R H
OPrMgBr or tBuOMgBr
Pip = N-substituted piperidine
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:
Sugar chemistry:
O O
ORO
OH
MeMe
N
Me
F
OTs O O
ORO
F
MeMeEt3N
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.
OBnO
BnO
OBn
FOBn O
HO
BnO
BnOBnO
OMe
+SnCl2, AgClO4
4Å MS84%
dr = 84:16
OBnO
BnO
OBn
OBnO
O
BnO
BnOBnO
OMe
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.
Protic acid-catalyzed activation:
OBnOBnO
BnO
FOBn O
HO
BnO
BnOBnO
OMe
+cat. HX
5Å MSSolvent
OBnOBnO
BnO
OBnO O
BnO
BnOBnO
OMe
Tf2NH, PhCF3: 99%, !/" = 9:91 HSbF6, PhCF3: 100%, !/" =12:88HB(C6H5)4, PhCF3: 99%, !/" = 7:93
TfOH, Et2O: 98%, !/" = 88:12 HClO4, Et2O: 98%, !/" = 92:8C4F9SO3H, Et2O: 99%, !/" = 88:12
Chem. Lett. 2001, 426; Bull. Chem. Soc. Jpn 2002, 75, 291.
Chiral "-substituted carboxylic acid formation:
Chem. Lett. 1977, 1165; Bull. Chem. Soc. Jpn 1978, 51, 3368.
R1CHO +
N
O
Me
OPh
MeO
TiCl4
Pyr.>76%
>17:3 drN
O
Me
OPh
MeO
R1
R2MgBr
>75%N
O
Me
OPh
MeO
R1
prepared from ephedrine hydrochloride in 3 steps
R2
O
OH
R1
R2
H3O+
Chiral !-hydroxyaldehyde formation:
NH
PhHN
N
NPh
Ph
PhCOCHO +
O
PhH
Dean-Stark N
NPh
Ph
OHsingle
diastereomerR
H1. RMgX
2. NH4Cl
CHO
Ph
OHR
N NPh
H Ph
OMg
R
XCram-
chelate TSOverall yield: 67-82%; optical purity > 94%.Chem. Lett. 1978, 1253; 1979, 705.
H3O+
6
E-alkene
S
Me
Me Me
COPhO
Me Ph
MeO2C CO2MeDMAD
DMSO: 88% 0%
Me
PhOC CO2Me
MeO2C
SMe+
Tet. Lett. 1970, 29, 2565.PhH: 27% 70%
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Total Synthesis Targets - Application of Synthetic Methodology
N
NN
N
NH2
O
HO
HHHH
O
PO O
OH
P
O
O
OP
O
O
O
MeMe
NH
O
OH
O
NH
HS
Coenzyme A - Coupling with [O]-[H] condensationChem. Lett. 1972, 595.
Me Me
Me
Me Me
OH
Vitamin A - Ti coupling of acetals with silyl enol ethersChem. Lett. 1975, 1201.
O
MeOH
N
O
nBu
dl-Variotin - Ti coupling of acetals with silyl enol ethers, and amide formation using Mukaiyama reagentChem. Lett. 1977, 467; Bull. Chem. Soc. Jpn 1978, 51, 2077.
NH
O
NMe
O
NHMe
Indolmycin - Methyl group introduction via a chiral oxazepine appendageChem. Lett. 1980, 163.
NH
Me
O
N
O
OMe
Ph
Me
O
O
Me
nC9H19
OHMalyngolide - Quaternary stereocenter synthesis via asymmetric !-hydroxyaldehyde synthesisChem. Lett. 1980, 1223.
OH
nC9H19
NPh
N
Integerrimine (Chem. Lett. 1982, 57 and 455):
O
Me 1) Me2CuLi; CO2
2) CH2N2 (80%)
O
Me
CO2Me
Me
1) MCPBA (76%)
2) LDA; MeCHOO
O
Me
OH
Me
CO2Me
Me
1) (60%)
2) LiOH (100%)
N
Me
FTsOO
O
Me
Me
CO2H
Me
1) (98%)N
Me
ClI
2) LiOH, H2O2 (71%)
Me
CO2HCO2CH2CH2TMS
OH
Me
Me
HOCH2CH2TMS
MeOH
Me
Me
N
OOO
O
integerrimine
F1! Antigen (Chem. Lett. 2001, 840; Bull. Chem. Soc. Jpn 2003, 76, 1829):
OBnO
BnO
OBn
FO(4-Me)Bz
OBnO
SEtN(4,5-Cl2)Phth
HOBnO
A
B
O
OH
N3
BnOC
BnO
OCO2H
NHCbz
A + B + cat. H+ + MS 5Å, then C + NIS
OBnO
BnO
OBn
O(4-Me)Bz
OBnO
Cl2Phth-N
OBnO
O
O
N3
BnO
BnO
OCO2H
NHCbz
One-Pot Sequential Stereoselective Glycosylation(89%)
via one more Mukaiyama condensation
7
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.
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
Total Synthesis of Taxol® (Proc. Jpn. Acad. 1997, 73B, 95; Chem. Eur. J. 1999, 5, 121.)
OAcO
MeOH
OAcOH
BzO
Me
Me
HO
O
O
NH
O
Ph
Ph Me
OH
910
12
13
78
14
12 11
5
6
43
15 16, 17
1819
20
OBnO
TBSO
Me
Me
PMBO OBn
Me OTBS
OBn
OTBS
MeMeBnO
OPMBO
60 steps, ~0.02 % overall yield
CO2Me
MeMe
HO
1. Swern [O] (89%)2. HC(OMe)3 (93%)
3. LiAlH4 (90%)4. Swern [O] (85%)
CHO
MeMe
MeO
OMe
OTBS
OMeBnO
, Sn(OTf)2
NMe
N
, Bu2Sn(OAc)2
MeMe
MeO
OMe
CO2Me
OBn
OH
(68%, 4:1 dr; although the alcohol stereocenter is erased after step 31)
6. PMB Prot. (95%)7. LiAlH4 (86%)
8. TBSCl (93%)9. AcOH (87%)
OHC
MeMe OBn
PMBO
OTBS
OMeBnO
TBSOMgBr2
(77%, 87% brsm, 71:16 dr)
MeMe OBn
PMBOHO
MeO2C
BnO11. TBSOTf12. DIBAL13. Swern [O] (94%)
14. MeMgBr (99%)15. Swern [O] (97%)OTBS
MeMe OBn
PMBOTBSO
BnO
OTBS
Me
O
Primarily an aldol-based strategy!
Me
16. LHMDS, TMSCl 17. NBS 18. LHMDS, MeI
19. 1N HCl (83%)20. Swern [O] (95%)
MeMe
CHO
OBn
PMBOTBSO
BnO
O
Me
Br 21. SmI2 (70%)22. Ac2O (87%)
23. DBU (91%)
OBnO
TBSO
Me
Me
PMBO OBn
Me
Br
TESO
tBuLi, CuCN
(92%, 99% brsm)
OBnO
TBSO
Me
Me
PMBO OBn
Me
OTES
25. 0.5 N HCl (97%)26. TPAP-NMO (92%)
27. NaOMe (98%, 23:2 dr)(Minor enantiomer can be
epimerized)
OBnO
TBSO
Me
Me
PMBO OBn
OHMe
H
28. AlH3 (94%)29. Me2C(OMe)2
30. DDQ, H2O (97%)31. PDC (90%, 94% brsm)
OBnO
TBSO
Me
Me
OBn
OMe
HO
MeMe
32. H2C=CH(CH2)2Li
33. TBAF (96%)
OBnO
HO
Me
Me
OH OBn
OMe
H
34. cHxMeSiCl2 (99%)
35. MeLi (96%)
OBnO
HO
Me
Me
O OBn
OMe
H
36. TPAP-NMO (80%)
37. PdCl2, DMF-H2O (98%)
SiMe2cHx
OBnO
O
Me
Me
O OBn
OMe
H
38. TiCl2, LiAlH4
(43-71%)
39. Na-NH3 40. TBAF (100%)
OHO
HO
Me
Me
OH OH
OMe
H
OSiMe2cHx
MeMe Me
Me
MeMe
Me
HO
MeMe
MeMe
MeO
OMe
CO2Me
OBn
OH
8
Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting
OHO
MeO
H
HO
Me
Me
HO
Me
HOHO
MeMe
Formation of the D-Ring Oxetane: End-Game
41. (Cl3CO)2CO42. Ac2O (84%)43. 3N HCl
44. TESCl (83%)45. TPAP-NMO (76%)
OAcO
MeOTES
H
O
Me
Me
O
Me
HOHO
46. (Imid)2C=S47. P(OEt)3 (53%)48. PCC (78%)
49. K-Selectride (87%)50. TESOTf (98%)
O
OAcO
MeOTES
H
O
Me
Me
O
O
Me
TESO 51. CuBr, PhCO3tBu
OAcO
MeOTES
H
O
Me
Me
O
O
Me
TESO
52. CuBr (58%)
Br
53. OsO4 (92%, 96% brsm)
54. DBU (42%, 81% brsm)55. Ac2O (91%)
OAcO
MeOTES
H
O
Me
Me
O
O
Me
TESO
O
AcO
56. PhLi (94%)
57. HF-py (96%)
OAcO
MeOH
OAcOH
BzO
Me
Me
HO
HO
Me
baccatin III
58. TESCl (87%, 92% brsm)59. Side Chain Acid, [(2-Py)O]2CS, DMAP (88%, 95% brsm)
O
BzN
Ph
PMP
O
OH
Side Chain Acid
60. TFA (94%)
TAXOL!!!
Words of Wisdom...
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
[...] 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.)
