Y.

Ishihara Teruaki Mukaiyama - 向山 

光昭 Baran Lab Group Meeting

Bibliography: An excerpt from Mukaiyama's publication list, published in Heterocycles 2000, 52, 13-66.
- 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
Prof. Teruaki Mukaiyama - 2002: Move to Kitasato University

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 non-
Japanese nominees and the other from the Japanese nominees.

Publications: Close to 1000 to date.

- Science ...1 (Perspective)
- Angewandte CIEE ...5 (4 Reviews) Chemistry Letters ...632
- JACS ...22 Bull. Chem. Soc. Jpn ...165
- JOC ...22
- Tetrahedron Lett. ...26 Chemistry Letters, founded
- Tetrahedron ...11 in 1972 by Mukaiyama.
- Tetrahedron: Asym. ...1
- Minor/inaccessible papers/abstracts <100

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Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting
Mukaiyama's early years: An organophosphorus chemist Synthesis of phosphoric esters as an application of oxidation-reduction condensation:
O Me Me Me Me
PhNCO + EtNO2 Ph Ph + BnOH + R3P + EtO2C-N=N-CO2Et BnO-PR3 + EtO2C-N-NH-CO2Et
cat. R3N N N
H H N N O N N O=PR3 + EtO2C-NBn-NH-CO2Et
O O
J. Am. Chem. Soc. 1960, 82, 5339; O
J. Org. Chem. 1962, 27, 3651. ROH + (EtO)2P-OAllyl + EtO2C-N=N-CO2Et RO-P(OEt)2 + EtO2C-NAllyl-NH-CO2Et
P(OEt)3
RNCO + P(OEt)3 RNC + O=P(OEt)3 O. Mitsunobu, M. Yamada and T. Mukaiyama,
Bull. Chem. Soc. Jpn 1967, 40, 935. Desired product for Mukaiyama
OEt
EtO OEt
O O Ph Six months later... the Mitsunobu reaction:
P(OEt)3 P P(OEt)3
O O C O Ph Ph R1OH + R3P + EtO2C-N=N-CO2Et + R2CO2H
!
Ph Ph Ph O. Mitsunobu and M.
Yamada, Bull. Chem.
Ph Ph R1O-PR 3+ EtO2C-NH-NH-CO2Et + R2CO2
Side product: Diphenylketene dimer Soc. Jpn 1967, 40, 2380.
O=PR3 + EtO2C-NBn-NH-CO2Et + R2CO2R1
J. Org. Chem. 1964, 29, 2243.
Mitsunobu later expanded the scope of this reaction to include other nucleophiles.
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 Oxidation-Reduction Condensation: an Extension to the Mitsunobu Reaction (2003)
from the same reaction, such that a net loss of water is observed. Essentially, a
dehydrating agent, that takes place under neutral conditions. R2CO2H Reductant present within Me
Ph2POR1 R2CO2R1 substrate; adamantanols and
(RCO2)2Hg + R'3P (RCO)2O + Hg + R'3P=O Hg is a good [O] for this reaction! DMBQ tert-butyl alcohol, among other
1
O O
R = 1º or 2º, 85-96%; 3º, 72-82% 3º R OH, work well;
1
stereospecific inversion for 1º
2 RCO2H + Ar2Hg + R'3P 2 RCO2H + PhCO-CH=CH-COPh + R'3P Me
ArOH or 2º; 70-100% inversion for 3º;
1
-H2O 2[H] [O] -H2O 2[H] [O] Ph2POR ArOR1 mild and neutral reaction, even DMBQ
DMBQ works for chloroacetic acid.
(RCO)2O + Hg + 2 ArH + R'3P=O (RCO)2O + PhCO-CH2CH2-COPh + R'3P=O
R1 = 1º or 2º, 78-92%; 3º, 62% Chem. Lett. 2003, 32, 300; Bull.
J. Org. Chem. 1963, 28, 2024. J. Org. Chem. 1964, 29, 1385. Even 2,6-disubstituted phenols give 70% yield Chem. Soc. Jpn 2003, 76, 1645.

Variations in the type of products made: Esters, thioesters, amides, thioethers, Ether formations:
pyrophosphates... also useful in peptide and nucleotide chemistry.
R2OH Very low yields with DDQ or
Ph2POR1 R2OR1 not formed!
Variations in the type of oxidant used: Amide coupling using DMBQ chloroanil; chiral center at R1
N Ph PySSPy: Tetrahedron gets inverted; coupling of 3º-3º
O Lett. 1970, 22, 1901. R2OH ROH are not possible but 2º- 3º
Precedes Corey- Ph2POR1 R2OR1 ROH couplings work.
O Nicolaou macrolac- Fluoranil
Ph N N S S N Chem. Lett. 2003, 32, 984.
tonization (JACS 1974).
unpublished results

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Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting
Mukaiyama's Named Reagent: N-Methyl-2-Chloropyridinium Iodide Various hydroxyl activations:
OH R3 R3
O 1. Pyridinium salt, Et3N
R1CO2H R2OH +
R1CO2R2 + R1 R2 2. R3MgBr R1 R2 R1 R2
N X base N O R1 base N O
Me I fast Me slow Me 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.
X = Cl or Br in original reference: Chem. Lett. 1975, 1045.
OH R3 H
It turns out that the nature of the alkyl group on pyridine, the X group and the R1 1. Pyridinium salt, Et3N
counterion all affect the yields of the coupling reactions in subtle fashion. •
R2 2. R3MgBr, cat. CuI
When R1 and R2 are 3º, the yields are dismal with the original Mukaiyama reagent, R1 R2 Chem. Lett. 1978, 785.
but using 2-bromo-N-ethylpyridinium tetrafluoroborate with R1 = R2 = tBu resulted SPh
in a 54% yield (Bull. Chem. Soc. Jpn 1977, 50, 1863). R4 Pyridinium salt, Et3N R2 R4 R1 or R2 can also be SPh,
R2 R3
These findings opened a whole new area of study for redox-neutral dehydration R1 generating vinyl sulfides:
then LiI
reactions: The utilization of onium salts of aza-arenes (Review in Angew. Chem. Int. OH R1 R3 Chem. Lett. 1978, 413.
Ed. 1979, 18, 707-721).
Types of onium salts used: R3 Various functional groups generated from ROH + onium salt:
- Inverted ROH (acyclic only) from Cl3CCO2H, followed by saponification, Mukaiyama's
Z R2
N version of a Mitsunobu inversion: Chem. Lett. 1976, 893;
X - RCl from LiCl (acyclic), R3NH+Cl- or R4N+Cl- (cyclic): Chem. Lett. 1976, 619; 1977, 383;
N N Cl R4 N X - 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,
R Y Me R1 Y 437;
FSO3
R = Me or Et; X = F or Cl; R1 = Me, Et or Ph; R2 = H, Me or - RNH2 (acyclic and cyclic) from LiN3 + HMPA, followed by LiAlH4 or H2/Pd reduction:
Y = BF4 or FSO3; Z = O or S Ph; R3 = H or Me; R4 = H or Me; Chem. Lett. 1977, 635;
X = F, Cl or Br; Y = I, BF4 or TsO - ROPO2OR' (acyclic) from R'OPO2H; exception to the rule - a benzoxazole is used,
Carboxylic acid derivatives formed: 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.
O O O O S O O
If R has a stereocenter at the carbon bearing the hydroxyl group (i.e. 2º; 3º are
R2 not tolerated), it will be inverted, unless R is a sugar, in which anomeric effects
R1 N R1 N R1 N R1 SR2 R1 F and neighboring group participation dominate.
S
R3
Various dehydrations and dethiohydrations:
Chem. Lett. Chem. Lett. Chem. Lett. Chem. Lett. Chem. Lett.
1975, 1163. 1976, 711. 1977, 1443. 1976, 711. 1976, 303. OH H
N Pyr. salt, Et3N N R2 RNHCS2- Et3NH+ R-N=C=S
R1 Chem. Lett. 1977, 573.
Without overlooking the macrolactonization... then H2O
R1 R2 O R1NHC(=S)NHR2 R1-N=C=N-R2
HO OH O HO O
OH O Me O Me Chem. Lett. 1976, 1397. Chem. Lett. 1977, 575.
Me Me R1NHC(=S)OMe R-N=C=O
n n O HO HO
OH OH R2 O
O Chem. Lett. 1977, 1345.
O O
Chem. Lett. 1976, 49: "their R1 OH Pyr. salt R1 RCO-NH2 R C N
procedure requires rather ele- Me Me Me Me R3 R3 unpublished
vated Tº; lactonized in better Et3N
OH R2 RNH-CHO R N C
yields than those obtained by J. Am. Chem. Soc. 2003, 125, 5393;
previous methods". Angew. Chem. Int. Ed. 2002, 41, 1787. Chem. Lett. 1977, 179. Chem. Lett. 1977, 697.

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Y. Ishihara Teruaki Mukaiyama - !"#
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Mukaiyama's Claim to Fame: The Mukaiyama Aldol Reaction A switch to silyl enol ethers: Use of TiCl4 as Lewis acid
O OSiMe3 Lewis acid or OH O OH O O OSiMe3 O OH Chem. Lett. 1973,1011;
Me3SiCl R2CHO
+ R2 Lewis base J. Am. Chem. Soc.
R1 H Y R1 Y and/or R1 Y R1 Me base R1 TiCl4 R1 R2 1974, 96, 7503.
then aq.
workup R2 R2 Reactivity as electrophile: RCHO (#78°C) > RCOR' (0°C) >> RCO2R'
R1 can be H;
Y = H, alkyl, Ar, OR, SR Enol silane geometry rarely affects Chem. Lett. 1975, 741; Bull. Chem. Soc. Jpn 1976, 49, 2284.
the syn/anti geometry of the product
Expanding substrate scope:
...vs. the Evans aldol reaction: OR OSiMe3 OR O
O O O OBBu2 O O O OH 3
+ R
R1 OR R5 TiCl4 R1 R5 Chem. Lett. 1974,15.
Y Bu2BOTf Y R2 H R2 R2
O N O N O N R2 R4 R3 R4
iPr NEt
2 then [O] Y Br R3
workup OMe Br OH O
Me Me Me OMe R4 R1 R4
Me Me Me R1 + R4
TiCl4 R1 PhMe,
Y = alkyl, Ar, OR, SR, Cl, Br but not H "Evans syn aldol" R2 OSiMe3 reflux
R2 OMe O R2 R3
But Evans ! boron enolate! Rather, Evans = use of chiral oxazolidinone for aldol. O OSiMe3 OH O Chem. Lett. 1975, 527.

History behind boron-mediated aldols: + R3 Chem. Lett. 1975, 989; 1976,

R1 R2 OR5 TiCl R1 OR5 769.
OBR2 Brown et al., JACS 1967, 89, 5708 & 5709; for other 4 R2
preparations of vinyloxyboranes, see: Hooz et al., R4 R3 R4
MVK + BBu3 n-Pn JACS 1968, 90, 5936; Tufariello et al., JACS 1967,
Me 89, 6804; Koster et al., Angew. Chem. 1968, 80, 756. Mechanism of the Mukaiyama aldol reaction:
X3
But no one used boron enolates in aldol reactions! SiMe3 M
MX3 X O O O OH O
O O
X3M X
Mukaiyama's fortuitous discovery: R3 R1 R3 R1 R3
OH O R1 H silyl enol R1 H #Me3SiX aq. workup
Bu2B-SBu expected product: Instead: ether R2 R2 R2
Me2CO H2C=C=O
h" H2C=C(SBu)2
Me SBu TS for Z-enol silanes: TS for E-enol silanes:
Me MX3
MX3
Bull. Chem. Soc. Jpn 1971, 44, 3215; mechanism corrected in J. Am. O H OH O O H
R2 H R2 H R2 H R2 H
Chem. Soc. 1973, 95, 967 and Bull. Chem. Soc. Jpn 1973, 46, 1807. X3M X3M
R1 H O R1 R1 R3 R1 H O R1
Bu2
OBBu2 B Me3SiO R3 Me3SiO R3 R2 R3 OSiMe3 R3 OSiMe3
Me2CO O O Z-A Z-B anti E-A E-B
H2C=C=O + Bu2B-SBu MX3 MX3
O H O H
SBu H R2 H R2 OH O H R2 H R2
Me SBu
Me X3M X3M
R1 H O R1 R1 R3 R1 H O R1
The "current" method to generate boron enolates: R3 OSiMe3 R3 OSiMe3 R2 Me3SiO R3 Me3SiO R3
O OBBu2 O OH Z-C Z-D syn E-C E-D
Bu2BOTf R2CHO Chem. Lett. 1976,
559; 1977, 153. The most favorable conformations: A and D. If R2 = large and R3 = small, D is favored; if
iPr NEt
R1 Me 2 R1 R1 R2 R2 = small and R3 = large, A is favored. Conclusion: Z/E of the enol silane rarely matters!

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Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting
Lewis acid-catalyzed Mukaiyama aldol reactions: Titanium tetrachloride reactions (See review in Angew. Chem. Int. Ed. 1977, 16, 817-826):
X3 Characteristics: Strong Lewis acid, strong oxophile and dehydrater; may act as an
First catalysis: Trityl salts
M SiMe3 electrophile for C!C " bonds.
O O O O (Chem. Lett. 1985, 447,
Me3Si-X 1535 and 1871); in situ eg. TiCl4
+ MX4 Me3Si+: SnCl2, Me3SiCl cyclohexanol + benzene cyclohexylbenzene unpublished
R1 R3 needs to R1 R3
(Chem. Lett. 1987, 463). (91%)
R2 transmetallate R2 SEt
Typically 1-10 mol%.
EtSH, TiCl4
Chiral Lewis acids: The true strength of the Mukaiyama aldol reaction. Ph OH Ph SEt + Ph SEt
CH2Cl2
Sn(OTf)2,
O OSiMe3 Bu2Sn(OAc)2, OH O Chiral diamine, eg.
O RSH, SR H2O, O
+ chiral diamine TiCl4 TiCl4 Bull. Chem. Soc.
R3 R3 R3 Jpn 1972, 45,
R H SEt R SEt R1 R1 R1
CH2Cl2, !78 °C N Et3N 3723; Chem.
Me Me Me NHNaph R2 R2 Lett. 1973, 479.
Z enolates work well; E 70-96%; Vinyl chlorides work as well.
enolates are mismatched; H 100% de, Chem. Lett. 1989, 297; J. Am.
instead of Me works very well. >98% ee Chem. Soc. 1991, 113, 4247. Aldol-like reactions: TiCl4,
OMe OiPr
Enantioselective diol formation: Ti(OiPr)4
Proposed TS for -OBn: +
Sn(OTf)2, OSiMe3 Ph OMe (80%) Ph O
O OSiMe3 OH O R2
Bu2Sn(OAc)2, N R3 Me Ac Me Chem. Lett. 1975, 319.
+ chiral diamine N Trioxane,
R H SEt R SEt Sn TiCl4
CH2Cl2, !78 °C OTf (Mechanism and stereoselectivity?)
R1 Bn Chem. Lett. 1974, 381 and 1181.
OBn OBn O Me O 73%, O
O H O dr 17:3 O
Chem. Lett. 1990, 1019; Replacing 72-88%; EtS
Bn by TBS results in the syn >96% de, H
>95% ee R OSiMe3 O
product (Chem. Lett. 1991, 1901.) O O TiCl4, Ti(OiPr)4 S S
OSiMe3 +
But the above chiral Lewis acid reagents are stoichio- Ph then HSCH2CH2SH Ph
metric! The chiral diamines are "promoters"...
Reactions on #,$-unsaturated ketones work as well. Chem.
Simple solution: Replace CH2Cl2 for CH3CH2CN (Sn-Si exchange is faster; Chem.
Lett. 1974, 1223; Bull. Chem. Soc. Jpn 1976, 49, 779.
Lett. 1990, 1455), and add the two substrates slowly into the catalyst mix to prevent
undesired Me3SiOTf-promoted, racemic aldol formation. Titanium tetrachloride reduced in situ:
Lewis base-catalyzed Mukaiyama aldol reactions: -TiCl4/LiAlH4: ArCl ArH RCH(OMe)2 RCH2OMe
Li SiMe3 Me Me Me
OSiMe3 O O O O Ph Ph Ph
S S H H 2 OMe
LiNR2 Me Si-NR
Me 3 2
R1 R2 R1 R2 MeO OMe
PhCHO + OMe Solvent Ph OMe Ph OMe MeO
turnover Chem. Lett. 1973, 291. unpublished
Me Me Me Me Me

LiNPh2 was initially used over LDA, but Li 2-pyrrolidone was optimal; THF did not allow -TiCl4/Zn: PhCHO PhCH-CHPh + PhCH=CHPh Chem. Lett. 1973, 1041;
turnover but DMF did; a milder version using LiOAc as a base in DMF/H2O systems OH OH precedes TiCl3-based
allowed the compatibility of hydroxyl and carboxyl functionalities in the substrate room T°, THF: 98% 1% McMurry coupling
(Chem. Lett. 2002, 182 and 858; 2003, 462 and 696). reflux, dioxane: 0% 98% (JACS 1974, 96, 4708).

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Y. Ishihara Teruaki Mukaiyama - !"#
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Miscellaneous reactions Chiral !-hydroxyaldehyde formation:
Sugar chemistry: Chem. Lett. 1983, 935;
anomers are separable and N 1. RMgX N
Dean-Stark
RO RO the ! can be converted to the PhCOCHO + NPh 2. NH Cl H NPh
O O N PhH 4
OH N F F " form using BF3; at the time, H
H Ph single Ph Ph R
this reaction could only be PhHN diastereomer
O O Me OTs O O done using anhydrous HF; O OH
R H3O+
reaction discovered from N NPh CHO
Me Me Et3N Me Me
analogy of RCO2H to RCOF. Mg O Overall yield: 67-82%; optical purity > 94%.
Cram- Ph R
OBn OBn X chelate TS Chem. Lett. 1978, 1253; 1979, 705.
OH
BnO BnO
O SnCl2, AgClO4 O Some more Grignard chemistry:
+ HO O DEAD does not give as high yields
BnO F BnO PrMgBr or tBuOMgBr
4Å MS (Yoneda et al., JACS 1966, 88, 2328).
OBn BnO O BnO
84% O PipCO-N=N-COPip Named reaction (??): "Mukaiyama
BnO R OH R H Oxidation"; 2° alcohols to ketones
BnO OMe dr = 84:16 BnO O (89-96%)
BnO work equally well (Bull. Chem. Soc.
Pip = N-substituted piperidine Jpn 1977, 50, 2773).
BnO OMe
Chem. Lett. 1981, 431. Yields and stereoselectivities are typically better than Mixed ether formation from acetals: mixed acetals work best (Chem. Lett. 1975, 305).
Cl or Br analogs due to the C-F bond strength at the anomeric position: C#F Cl
552 kJ/mol; C#Cl 397 kJ/mol; C#Br 280 kJ/mol. TiCl4
+ BrMg
Protic acid-catalyzed activation: Ph
O O (98%) O Ph
BnO BnO
BnO O cat. HX BnO O Cl
BnO F + HO BnO Some sulfur chemistry:
O
OBn BnO O 5Å MS BnO O
Solvent BnO LDA, then
BnO BnO O Ph O
BnO OMe BnO OMe
S NtBu Chem. Lett. 2000, 1250; if DBU is used instead of
LDA, 2° amines to imines, (Chem. Lett. 2001, 390)
TfOH, Et2O: 98%, !/" = 88:12 Tf2NH, PhCF3: 99%, !/" = 9:91 Cl and N,N-disubstituted hydroxylamines to nitrones
HClO4, Et2O: 98%, !/" = 92:8 HSbF6, PhCF3: 100%, !/" =12:88 (ARKIVOC 2001, 10, 58) can be formed.
C4F9SO3H, Et2O: 99%, !/" = 88:12 HB(C6H5)4, PhCF3: 99%, !/" = 7:93 (93%)

Chem. Lett. 2001, 426; Bull. Chem. Soc. Jpn 2002, 75, 291. Ph
S NHtBu
Chiral "-substituted carboxylic acid formation: O Named reaction (??): "Mukaiyama
NCS or NBS (1.1 eq) Oxidation"; 2° alcohols to ketones
O O O work equally well. (Chem. Lett. 2001,
O Ph O Ph O Ph R OH K2CO3, 4Å MS, CH2Cl2, R H
R1 R1 846; Tetrahedron 2003, 59, 6739.)
TiCl4 R2MgBr 0 °C, 30 min (86-100%)
R1CHO +
Pyr. >75% R2 MeO2C CO2Me MeO2C
N Me >76% N Me N Me Me Me
O O O DMAD
>17:3 dr S Me
Me Me Me +
H3O+ Me COPh SMe
prepared from ephedrine E-alkene R1 O Me Ph
O PhOC CO2Me
hydrochloride in 3 steps
Chem. Lett. 1977, 1165; Bull. Chem. Soc. Jpn 1978, 51, 3368. R2 OH Tet. Lett. 1970, 29, 2565. DMSO: 88% 0%
PhH: 27% 70%

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Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting

Total Synthesis Targets - Application of Synthetic Methodology Integerrimine (Chem. Lett. 1982, 57 and 455):
NH2 O O OH O

N 1) Me2CuLi; CO2 Me 1) MCPBA (76%)

N Me Me O
2) CH2N2 (80%) CO2Me 2) LDA; MeCHO
O O Me Me O O CO2Me
N N
HS O P O P O Me Me
N N Me
H H O O O
OH H H
H H O I
O H N Cl
1) (98%)
1) TsO N F (60%)
O P O Me O Me
Coenzyme A - Coupling with [O]-[H] condensation Me
Chem. Lett. 1972, 595. HOCH2CH2TMS
OH CO2H
2) LiOH (100%) Me 2) LiOH, H2O2 (71%)
O Me
Me Me Me Me O
Me
nBu
Me
OH N Me OH
OH Me Me O Me
OH
Me
dl-Variotin - Ti coupling of acetals O O O
Me
Vitamin A - Ti coupling of acetals with silyl enol ethers, and amide CO2H
with silyl enol ethers CO2CH2CH2TMS via one more
formation using Mukaiyama reagent Mukaiyama
Chem. Lett. 1975, 1201. Chem. Lett. 1977, 467; Bull. Chem. condensation
Soc. Jpn 1978, 51, 2077. N integerrimine

O O
F1! Antigen (Chem. Lett. 2001, 840; Bull. Chem. Soc. Jpn 2003, 76, 1829):
O Ph
Me N Me OBn
BnO A + B + cat. H+ + MS 5Å, then C + NIS
O NHMe A O
N Me BnO F One-Pot Sequential
O O(4-Me)Bz Stereoselective
Me
N N Glycosylation
H H BnO (89%)
B HO O
Indolmycin - Methyl group introduction via a chiral oxazepine appendage BnO SEt OBn
Chem. Lett. 1980, 163. BnO
N(4,5-Cl2)Phth BnO
O O
BnO O
OH BnO O
O
BnO O(4-Me)Bz BnO
Me Malyngolide - Quaternary
C O Cl2Phth-N O
O OH OH N stereocenter synthesis via BnO BnO
asymmetric !-hydroxyaldehyde NHCbz NHCbz
synthesis N3 O N3 O
N CO2H CO2H
nC H Ph Chem. Lett. 1980, 1223.
nC
9H19
9 19
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.

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Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting

Total Synthesis of Taxol® (Proc. Jpn. Acad. 1997, 73B, 95; Chem. Eur. J. 1999, 5, 121.) BnO O
16. LHMDS, TMSCl Br BnO Me
18 AcO O BnO O 17. NBS Me OBn 21. SmI2 (70%) TBSO Me
19 OH
O Ph O Me 18. LHMDS, MeI 22. Ac2O (87%)
Me
12 11 10 9 TBSO Me Me CHO
23. DBU (91%) Me
Me 8
7
6 19. 1N HCl (83%)
Ph N O 13 15 16, 17 20. Swern [O] (95%) O TBSO PMBO Me
H Me 3 5 Me
14 1 4
OH 2 PMBO OBn
H O Me
HO AcO PMBO OBn TESO
BzO 20
BnO O OTES
Br
60 steps, ~0.02 % overall yield TBSO 25. 0.5 N HCl (97%)
Me 26. TPAP-NMO (92%)
Me Me OBn BnO Me Me OBn Me
t
BuLi, CuCN 27. NaOMe (98%, 23:2 dr)
MeO Me OTBS Me (Minor enantiomer can be
CO2Me (92%, 99% brsm)
PMBO OBn epimerized)
OMe OH O OTBS OPMB Me
Me
BnO O OH BnO O O
OMe Me Me
BnO TBSO 28. AlH3 (94%) TBSO
1. Swern [O] (89%) , Sn(OTf)2
Me Me Me Me 29. Me2C(OMe)2 32. H2C=CH(CH2)2Li
2. HC(OMe)3 (93%) OTBS
HO MeO Me 30. DDQ, H2O (97%) Me 33. TBAF (96%)
CO2Me 3. LiAlH4 (90%) CHO
4. Swern [O] (85%) Me 31. PDC (90%, 94% Me
OMe H H
brsm) O
N PMBO OBn OBn

N , Bu2Sn(OAc)2
Me Me Me
Me Me
BnO O O BnO O O
OMe Me Me
BnO HO 34. cHxMeSiCl2 HO
Me Me OBn 6. PMB Prot. (95%) Me Me OBn 36. TPAP-NMO (80%)
(99%)
MeO 7. LiAlH4 (86%) OTBS
CO2Me OHC Me 35. MeLi (96%) Me 37. PdCl2, DMF-H2O
8. TBSCl (93%) MgBr2
Me H Me H (98%)
OMe OH 9. AcOH (87%) PMBO TBSO (77%, 87% brsm,
71:16 dr) OH OBn O OBn
(68%, 4:1 dr; although
the alcohol stereocenter SiMe2cHx
is erased after step 31) Me Me
Me Me
11. TBSOTf BnO O O HO O O
BnO Me Me OBn 12. DIBAL BnO Me Me OBn Me Me
13. Swern [O] (94%) Me O 38. TiCl2, LiAlH4 HO
MeO2C (43-71%) HO
14. MeMgBr (99%) Me
HO PMBO OTBS 15. Swern [O] (97%) O TBSO PMBO OTBS Me 39. Na-NH3 Me
Me 40. TBAF (100%) Me
H H
O OBn OH OH
Primarily an aldol-based strategy!
SiMe2cHx
O

8
Y. Ishihara Teruaki Mukaiyama - !"#
$% Baran Lab Group Meeting
Formation of the D-Ring Oxetane: End-Game Words of Wisdom...
Me [...] The development of novel synthetic methodologies is now an essential part of synthetic organic
Me chemistry. The most fruitful approach to this problem, I believe, is 'to let something come from
HO O AcO O
HO HO O HO HO OTES nothing', i.e. we must discover new possibilities in a field previously neglected, and create innovative
Me 41. (Cl3CO)2CO Me concepts in synthetic organic chemistry. It is absolutely essential to carry out one's research on one's
Me 42. Ac2O (84%) Me own ideas, unaffected by the current fashion. I have tried to explore new methodologies in this way,
Me 43. 3N HCl Me keeping in mind the words 'no imitation' that Professor Toshio Hoshino said to me at the start of my
Me 44. TESCl (83%) Me research career.
45. TPAP-NMO An active and original programme is vital to the execution of basic research. Only the research
H H work that has been fostered with one's own hands, thus spreading its roots deep and never being
HO (76%) O washed away, will survive forever. Fashionable works may soon be forgotten, as quickly as floating
HO O weeds. Needless to say, an unpretentious, enduring, and systematic attack on problems is required if
O 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
AcO O think that the results of one's chemistry should be published in journals of one's country. [...]
Me OTES I have tried to change my topics about every four years. I admit that a deep and thorough study on
46. (Imid)2C=S Me a single topic is very important for a researcher; however, I think it is more significant to change topics
47. P(OEt)3 (53%) Me at various times, especially in the fields of explorationof new methodologies. Perhaps it is related to
48. PCC (78%) TESO 51. CuBr, PhCO3tBu my own nature - I do not like to stick to a particular matter for too long. New ideas come to me, one
Me after another, and I encourage myself to build new hypotheses and initiate new active research
49. K-Selectride (87%) 52. CuBr (58%) programmes, purposely putting the pressure on myself.
50. TESOTf (98%) H In the first year, I learn various things about the new problem itself. In the second year, I begin to
O
O 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
O programmes. There may be many things still left undone when I take the move on to the next
AcO O AcO O programme, and if any treasures remain they will be left to the hands of many other able chemists. [...]
Me OTES Me OTES
Me Me (From the review of his life's works in Challenges in Synthetic Chemistry, Clarendon
53. OsO4 (92%, Press, Oxford, 1990, 225 pages.)
Me Me
TESO 96% brsm) TESO
Me Me In basic science it is critical to find the first approach (“seeds-oriented” work), but it is equally
Br 54. DBU (42%, important to optimize the approach and to develop new systems (“needs oriented”). In either case,
H 81% brsm) H O ample time and energy need be invested before a chemist can garner anything useful. Once the
O O AcO
O 55. Ac2O (91%) O 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
O O 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
AcO O someone has already been involved with the topic, dare not to stick to the same topic, but find
Me OH something of your own. This is our code, which should never be forgotten.
Me 58. TESCl (87%, 92% brsm)
59. Side Chain Acid, [(2-Py)O]2CS, Experience and the accumulation of experiences play a very important role in pursuing research
Me work. If a mature hypothesis does not lead you to a satisfactory result, just try once more from the
56. PhLi (94%) DMAP (88%, 95% brsm) beginning and continue to do the experiments. You will then eventually find an interesting clue, unless
HO
57. HF-py (96%) Me 60. TFA (94%) 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
H O motivating force for associating problems with questions that give you a different idea. Those who
HO AcO
BzO 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
Ph baccatin III work done (especially at the time of one's youth) will give you love for your work and will furnish you
O 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
BzN OH
TAXOL!!! an unexpected phenomenon while carrying out experiments. You simply have to be sufficiently aware
O 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.
PMP Side Chain Acid
(From the review of his life's works in Angew. Chem. Int. Ed. 2004, 43, 5590-5614.)