Organometallic Origins
Cyclometalation with Late Transition Metals
An E ar ly Ex am ple of C yc lom e ta la tion ( 40 y ea r s a go):
N ot only f or H e te roa tom s :
H
H
P h 2P
Ir I
Ph 3 P
!
C 6D 6
P Ph 3
Cl
P h 2P
Ph 3 P
L
O ne o f th e e a rl ie st
o b se rva tio n s o f m e tal m e di ate d C- H a cti va tio n
( di re cte d a n d
i n tr am o le cu la r)
Ir II I P Ph 3
H
Cl
B enne tt J AC S 1 9 69 6 98 3
L
- PP h3
Pt II
L
L
+ P Ph 3
P t IV
- C M e4
Pt II
L
"ta ilbiting".
L = P Ph 3
White s id es JA CS 19 8 19 4 8
M oder n A pplica tion of C y clom e ta lat ion: Sy nthe s is of P ince r Com ple x es (c a taly s ts for C -C bond for m a tion)
( OAc )
Pd
N
(OA c)
Pd
N
Pd (OA c)2
O
A cOH , rt
O
O
N
O
L
2 ) Ag BF 4
N
Ac OH , refl ux
C o mp le xa ti on is d e p en d en t on me ta l
s ou rc es a n d i s e mp ir ica l .
O
Pd
A hn OM 2 00 6 2 40 9
N
Cl
P (tBu )2
BF 4 -
S Ph
1) P d (Ph C N )2 Cl 2
N
O
K2 Pd C l4
Ir Cl 3 or [Ir( CO E)2 C l] 2
R
P d N CC H 3
S Ph
No C -H ac tiva tio n wi th ou t Ag BF 4
(for ms a mo re e le ctro p hi li c Pd sp e cie s)
L
H 2O , r efl ux
X
M
X
n
H C
R2
( )n
M
X = C, N, O , P ,
S , A s, Se
C oor dina ted M e tal
O
Me 3 P
Et 2 O, -5 0º C
Me 3 P
no O 2
N iI I
r t, 4 h
Me 3 P
C a rm ona JA CS 19 8 9 , 2 8 83
H illhouse JA C S 1 99 7 , 8 1 3 5
Slide by Mark Chen
ora nge cr y st alline
m e ta llac y c le
Ph
C H 2O
Ni O
s tab le d im er
2 4%
n+ 2
( )n = 0,
C
R2
M e talla c yc le
= 0, 1, 2
!
N iC l2 (P Me 3 )2
Je ns e n J OM C 2 0 02 4 4
Ev a ns D T 1 97 5 10 2 0
Cl
L ow va le n t me tal sp ec ie s ca n in se rt vi a fo rma l o x id ati ve ad d iti on .
Pr oduc ts fr om Me ta lla c yc le s D e co mp osition:
C lM g
H
P (tBu )2
B er gbr eit er JAC S 19 9 9 9 5 31
su lfo xi de s: E va ns OM 2 0 02 8 93
Ta ke H om e M e ss a ge on M et alla cy c le For m a tion:
1 ) C ycl om e ta l la tio n o cc u rs to fo rm fo u r, five o r si x-m em b er ed ri ng s.
2 ) Me ta l ca n be di re cte d b y C , N , O, P , S , As, Se (l ew i s b as ic fu n ctio n al ity)
3 ) Ge ne ra ll y, m eta ls m u st be in u ns atu ra te d, lo w va le n t s tate in or de r to
p e rfo rm o xi da tiv e a d di tio n (n - -> n+2 )
a ) P d c an in se rt vi a h e ter ol ytic C- H c le av ag e or hi gh l y tra ns ie nt P dI V )
b ) E le ctro p hi li c sp e ci es m a y b e n ec e ssa ry.
Ir
O
H
Ph
O
19 %
O
O2
v ia :
72 h , r t
39%
M e3 P
Ni O
1, 2
pr oduc ts of
initial
P h "- hydr ide
e lim ina tion
r edu ctiv e elim ina tion
prom ot ed by ox id ation
of m et al
Functionalization via Insertion
Heck Reactions via Aryl C-H Activation
N on- Dir e cte d:
O
O
O Me
O
OEt
0.4 % Ru C l3 * H2 O
6.1 atm CO , 1 8 0o C , Me O
2 a tm O 2
M ec ha nism :
H
! -cl ou d
[M]
[M ]
Ish ii J AC S 2 00 3 14 7 6.
" -h yd rid e
e li mi na ti on
[M ]X
In se rtio n
Ph
[M] X
R
R
1 0% Pd (O Ac) 2, 8 0 C
O 2 , py rid in e
1 % Pd (OA c)2 , 1 00 o C,
C O 2 R' P hC O 3 t Bu , 1 M AcOH
O
+
N a gas him a Te t. 19 8 4 2 6 99 .
+
O
1% Pd (O Ac) 2, 5 0o C , R
HC O 3 t Bu , 1 0 % BQ
.7 5 M A cOH :Ac 2O
O
+
C O2 R '
R = H , M e, C H O
N
H
4 0 -5 0%
N o O xid a tio n S tate C ha n ge
Me ch anis m :
86%
C O 2 Et
[M]
X
Y
Aro m ati c Su b .
[M]X
X
R a re Th i op h en e Exa m pl e
Wo rk s for fu ra n ...n o t i n do le .
Y= N
X
X
[M ]
El im in a ti o n
Y
[M ]X
H
Y = O, S, Se
Y
Slide by Jared Delcamp & Alex Brucks
5% P d( OAc) 2,1 0 % bp y
8 0o C ,Di o xa ne
M a TL 2 00 4 84 1 9.
In do le g av e 5 2 % .
N o Th i op h en e s.
S
EW G
N
H
7 5 -50 %
7% Pd (O Ac) 2, 2 % HP Mo 1 1 V1
C O 2 Et 7% Ac a c, O 2 6 % N a OA co
.3 3 M P ro pi on i c Ac id , 6 0 C
Is hii JOC 20 0 4 1 2 21 .
CO 2R '
E WG
Y
S
R
73 %
R in g S iz e
Fujiwa r a O L 1 99 9 20 9 7.
2
+ [M] + H X
3 0 -60 %
OA c
C O2 R '
R
NM e
o
S toltz J AC S 2 00 3 95 7 8 .
O
Ph
R
H OA c
Ele c troph ilic Ar om a tic S ubs titution:
R
69 %
1:3 :3 o :m:p
Ste ric
X
X
NM e
OEt
o
OE t 9 0 C , 1 a tm O 2
47%
1 :1:1 o:m :p
E le ctro n ic
D e p roto n ati on
H
A g os ti c
O
OE t
M ils te in JAC S 20 0 1 3 3 7.
7 % Pd (OA c)2 ,
H 4 PM o1 1 V1 O 4 0 ,
X A ro ma tic Su b.
-
Y
-
E li mi n ati on
Y
X
[M ]X
[M]X
Functionalization via Insertion
Heck Reactions via Directed C-H Activation
D ir ec ting Gr oups :
Me O
10 % Pd (O Ac) 2,
Me O
20 % e th y l n ico tin a te
BQ, .1 M tAm OH :Ac OH ( 4:1 )
2 N a OAc , 1 0 0 o C , 12 -1 6 hr
O
OM e
H
N
O
R1
OMe
Me O
+
1.1
O
5 % Pd (OA c)2
B Q, .67 M AcO H,
o
9 0 C, 1 2 h r
O
v a n Lee uwe n JA C S 2 00 2 15 8 6.
H
N
O
Pd
Di re ctio n fro m b oth
ox yg en a nd o le fin .
OH
+
R
H
N
R1
1 .1 O
O
R2
O
3 8 -91 %
C OOB u
H
N
5 % Pd (O Ac) 2, p -TSA
1.3 BQ, A cOH ,
R
0.7 7 M to lu e ne , r.t.
O
R = Br, I
OM e
2
OB u
5 2 -7 9%
St oltz AC IE E 2 00 4 61 4 4.
N Me 2
+
R2
Pr a sa d Ad v. S yn th. C ata l . 2 0 05 1 92 1 -1 92 4 .
5% P dC l 2, C u (OAc )2 ,
C OOB un .2 M TFE o l/Ac OH ( 4/1 ),
8 5 oC , 4 8 h r
C O2 H
NM e 2
C OOBu
n
R
Miiur a J OC 19 9 8 5 2 11 .
C OO Bu
C O2 H
1 0% Pd (O Ac) 2,
1 0% C u (OAc )2 ,
D MF, 1 00 o C
70 -8 6 %
h ig h ly pH d ep e nd a nt
Shi JA C S 2 00 7 76 6 6.
+
5 4- 67 %
R
~60 %
ox yp a lli d ati on to fo rm la cto ne s
i s a c om p eti tive p ath w ay
M ec ha nis m:
Y C oo rd in a tio n
+
N
C O 2 Me
10 % Pd C l2 , 2 Cu (OA c)2 ,
Me C N, 2 hr , 6 0 oC
N
C O 2 Me
N
H
Y
[M]X2 Ch e la tio n
H
9 9 % c on ve rs io n
o ve rco m es EAS at 3 po si tio n .
!-h yd ri d e
el im in a ti o n
Ph
R
Ph
[M]X
Ins er tio n
Y
[M ]X
H -X
Slide by Jared Delcamp & Alex Brucks
H
A go sti c
N
De p ro ton a ti o n
R ic c i Ch e m. C om mu n . 20 0 5 1 8 54 .
Y
D is so ci ati on
R
+ [M ] + HX
R
[M]X 2
Functionalization via Transmetalation
Directed C-H Activation by a Palladium(II) Catalyst
C- H c le av ag e
DG
DG
C H
Pd
P dI I
C
Tra ns me tal la tio n ,
re du cti ve el im .
DG
B a c kgr ound
C R
N
P d0
R -M
P h4 S n
R hC l (PP h 3) 3 5 % ,
1 20 o C , 4 0 h
N
H
Y u , J . A m. C h em . So c. 20 0 6, 1 2 8, 1 26 3 4.
Y u , J . A m. C h em . So c. 20 0 7, 1 2 9, 3 51 0 .
Ph
Oi, C h em . Co m mu n. 1 99 8 , 24 3 9.
58%
Th e C ha lle nge : C -H cle a va g e i s o fte n r el a ti ve ly slo w , wh i le tran sm e tal la tio n is fa st.
H o mo co u pl in g of the o rg an o me ta ll ic re a ge n t ma y o utc om p ete C -H fu n ctio n al iz ati on .
Th e S olu tion: C -H ac ti va tio n i s a cc el er ate d b y a teth e re d d ir ec ti n g g ro u p to a p p rox im a te Pd .
Tra n sm eta ll a ti o n i s sl ow e d b y u si n g a lk ylb o ro ni c a cid s o r b u lky ar ylb o ro ni c e ste rs.
A lk yla tion of s p 2 C -H bonds
A lk y la tion of s p 3 C -H bonds
Pd (OA c)2 1 0% ,
BQ 0 .5 eq u iv,
R
R B(O H) 2
N
N
Ag 2 O 1 e q u iv,
1 00 o C , 6 h
H
R
R
Et
C H 2C H 2 Ph
C yc lo pr op yl
C O2 H
H
M e B( OH) 2
Pd (OA c)2 10 % ,
BQ 0 .5e q , A g 2C O 3 1 eq ,
K2 H PO 4 1 .5 e q ,
10 0 oC , 3 h
B
O
B
Ag 2 O 1 e q ui v,
1 00 o C , 6 h
H
Yie ld
64
53
52
C O2 H
Me
OH
O
N
Ph
CO 2 H
Me
2 0%
R
N
Me
R
n -P r
C H 2 C H2 OH
C H 2 C O 2M e
H
P d (OAc )2 10 % ,
B Q 0 .5e q , A g 2C O 3 1 eq ,
O
Ph B
O
K 2 HP O 4 1.5 e q,
1 0 0 oC
Y ield
60
51
70
Ph
OH
O
3 8%
U nique m ec ha nis tic c ons ider a tion
Me
22 %
Pd (OA c)2 1 0 %,
BQ 0 .5 eq u iv,
75%
A c tiva tion of m e thy le ne C -H bonds st ill c ha lle nging
Slide by Andrew Young
N
Me
B
O
O
N
Pd
O
B
B
O
O
B
An in tra mo le cu la r
tran sm e ta l la tio n i s p ro po se d for
me thy lb o ro xin e on the b as is o f
me a su red KIE s a nd o bs er ve d
re ac ti vi ty of th e s toi ch io me tri c
pa ll a da cy cl e
Functionalization via Transmetalation
Ruthenium Arylation Reaction and Carbon as a Director
O
tBu
R u H 2 (C O)(P Ph 3 )3 2 m ol % ,
O
1 .0 M to lu e ne , re flu x, 1h
O
Ln R u
tBu
Ph B
2 equiv
H
O
M ec ha nis m
O
O
1 equi v
H
Ph
Ph
Ka ki u ch i, F. J. Am . C h e m. So c. 2 00 3 , 12 5 , 1 6 98 .
O
B a c kgr ound
O
O
R u H2 (C O) (PP h3 )3
R1
R2
Y
H
R1
R2
To lu e ne , re flu x
O
Ru
Ph
Y
Ph
M u ra i, S. N atu re , 19 9 3, 3 6 6, 5 29 .
D ia ry la tion C om pet es
H
O
R
Co n d itio n s
H
Ph
O
R
H(P h )
R
Me
i
Pr
t Bu
Monoa r yl
7
9i
95
Ru
H
O
O
O B
O
D ia ry l
60
76
0i
O
O
Ph B
O
O
One e qu i va le nt o f
su bs tr ate is sa cri fi ce d
to h yd ro ge n ati on
H
Ru
Ph
Ph
Bu t
C a rbon a s Dir e ct in g G roup:
Bu t
tB u
LP d( 0)
Br
Bu t
t
Bu
Br
t
Bu
+
(H O) 2B
P d2 (d b a) 3
K3 P O 4
li g an d
L
Pd
Bu t
B u ch wa l d, S. J . A m. C he m . S o c. 20 0 5, 1 27 , 4 68 5 .
t
Bu
t
tBu
H
Bu t
Ph
B ut
H
H
Pd Br
tB u
t
L
Pd
X
(H O)2 B
B ut
H
t
Bu
Slide by Andrew Young
Bu
Bu
-H Br
HX
Pd
B ut
t
Bu
L
L
Functionalization via Oxidation
Norbornene as a Catalytic Template
B as ic Tra ns for ma tion
H
Pd (OAc)2
K2 CO 3
DMF
I
R '-Y
R-X
Me ch anis m
H
R
I
R'
H
Pd L 2
P d II
O.A.
H
R
H
H
0
I
Inse r.
II
Pd
H
R '-Y: Boro nic Aci d, Alkyn e,Al kene
I
H
K 2C O3
-K I
Me thod S c ope
Fin al ste p: In tra mol ecu la r H eck
H
O
I
OE t
H
Pd (OAc)2
Cs 2C O3 , TFP
Me CN , R eflu x
H
OE t
R-X
O
Br
Me
H
P dI I
Me
R .E.
R
I
Pd I V
R
I
P dI I
Twice
90 % Yi eld
L a u te n s AC IE E. 20 0 0, 3 9 , 1 0 45 .
I
Me
Fin al ste p: In te rmol ecu la r H eck, ami na ti on
H
Pd (OAc)2
Br
O
Cs 2C O3 , TFP
D MF, 8 0o C
OtBu
O
Me
OtBu
N Cb z
O
Me
R
He ck
Ca te ll an i A C IE E, 1 99 7 , 36 , 11 9 .
Pd(OAc)2
K2 CO 3 , TFP
DMF, 8 0o C
O
O Me
Y
R
R
R
R
OM e O
H CO 2N a
H
Proto nol ysis
Ca te ll an i P ur e A pp . C he m . 2 0 05 , 42 , 1 24 3 . R
R
R
R
O
Al kyne Ad di ti on
Me
83 % Yi eld
C a tel la n i P ure Ap p . Ch e m. 2 00 5 , 42 , 12 4 3.
Slide by Sean Reed & Nicolaas Vermeulen
I
Tran smetal atio n
Ca te ll an i C h e m. C om m. 2 00 0 , 15 7 .
C a te l la ni Te t. L e tt. 2 00 4 , 45 , 69 0 3.
Fin al ste p: In te rmol ecu la r H eck, Mic hae l-typ e rea cti on
OH
Y
II
B( OH )2
N H Cb z
Br
Pd
68 % Yi eld
OtBu
H
R
R
N H C bz
Me
I
D ei nser ti on
R
Ca te ll an i J . O rg an o me t. C h e m. 2 00 4 , 6 8 9, 3 7 41 .
Functionalization via Oxidation
Oxidative C-H Activation, C-C Bond-forming Reactions
Me c han is m
B as ic Tra ns for ma tion
5 % Pd (OAc)2
X
Pd(OAc )2
X
[Ar2 I]BF 4
10 0° C
H
N
Ar
N
-HOAc
A cO
H
Pd
2
Pois oning Stu die s N ega tiv e !
50 0 eq u iv Hg -N ot a he te ro ge n eo u s, Pd (0 ) p roc e ss
25 m ol % ME HQ o r g a lvi n ox yl- N ot a fr ee ra d ica l p ro ce ss
Me thod S c ope
O
OM e
O
N
N
N
Ph
84 %
O
Ph
9 1%
Ph
Ph
4 9%
O
Bu t
O
tBu
C
B ut
N
PhOTf
or
PhI
O
O
tBu
[Ph 2I]BF 4
X
N
Ph
OH
N
N
O
Cl
2 P os si bl e P ath w a ys
Ph
5 1%
67 %
BF 4 -
Ph
5 8%
O.A.
N
N
X =H
N
72 %
O
X
N
Ph
8 5%
C F3
87
F
88
Cl
83
Me
84
OMe
81
Ac O
N
Ph
Pd
2
Ac O
+ Ph I
Pd
2
R .E.
C o nc er ted in se rti on ,
N o me ta l o xid a tio n
sta te c ha n ge
N
7 5%
Ph
Sa n for d J. A m. C he m. S oc . 2 0 0 5, 1 27 , 73 3 0 .
Slide by Sean Reed & Nicolaas Vermeulen
Functionalization via Oxidation
Highly Regioselective Arylation of sp3 C-H Bonds
B a s ic Tr an sfor m a tion
X
NH
Pd II, AgOAc
N
Y
ArI
H
X = C H2 , a roma tic li nke r
X
N
X
L Pd N
N
M ec ha nis m
N o Bn C -H bo nd s to a ll ow for re activi ty
NH
Y
O
Y
NH
Ar
Y = !-A ryla ti on = carb oxyli c aci d, carb onyl
Y = "-Aryla ti on = CH 2, ami ne
N
Pd (OAc)2
N
Pd N
Ac O
Y
O
H
R e pre s ent at iv e Re a c tions
Iso late d an d Ch ara cte rize d
(X-ra y)
O.A.
!-Aryl atio n
I
Br
N
O
NH
H
HN
6 5% Yi el d
N
I Pd IV N
Ar
So lven t l ig and omi te d
for cla rity of in te rmed ia te
O.A.
Pd II
N
R.E.
Br
I
N
Pd N
A cO
"-Aryl atio n
Br
O
NH
H
C -H
O
N
O
O
I
N
O
A cO Pd IV
N
Ar I
N
0 .1 mol % Pd(OAc) 2
Ag OAc
ne at, 1 30 oC , 1 6h
N
C-H
activa tion
5 m ol% Pd(OAc)2
AgOAc
n eat, 150 oC , 1 h
O
O
N
Ar
HN
Proto nol ysis
72% Yie ld
I
N
Br
O
HN
Ar
D a ug u li s J. Am . Ch e m. So c. 2 0 05 , 12 7 ,13 1 54 .
Slide by Sean Reed & Nicolaas Vermeulen
Streamlining Synthesis
Reductive Heck-type Insertions in Complex Molecule Synthesis
1 s t Ge ne ra tion, R h(I)/A chir a l Liga nd
N H2 H C l
H
N Bn
i . 1 0 mo l% [R h Cl (co e )2 ] 2
20 m ol % FcPC y 2
CHO
O
2 ste p s
[ RhCl (c oe )2 ]2
to l, 1 5 00 C , 2 h
O
Cl Rh
Rh Cl
O
i i. 1N H C l, 3 h
OM e
O
O
O
OM e
6 s tep s, 3 8 % o ve ra ll C O 2M e
yi el d fro m
OM e
65%
Me sc al in e An a lo gu e
HO
OH
O Me
E ll ma n e t al . Org . Le tt. 2 0 0 3, 5 , 1 3 01 -1 3 03 .
2 nd Ge ne ra tion, R h(I)/C hira l Au xilia ry
CO 2H
CH O
1 . ( R) -(-) -am i no in d an e ,
P h H, re flu x, 9 9%
2 . i . 10 m ol % [R h C l(c oe )2 ] 2
E
O
CHO CO M e
2
OM e
3 0 m ol % FcP Cy 2
O Me
OM e
O
HO
0 .1 M i n to l ue n e, 7 5 C , 20 h
OM e
CO 2H
OMe
OH
i i. H Cl , H2 O, 8 8%
O
7 3% e e
(5 6% , 9 9 % e e afte r
re cry sta ll iza tio n )
5 s te ps to t his inte r m edia te
PC y2
Fe
O
OH
O
0
OMe
4 s te p s
OH
OH
( +) -L ith os pe rm ic ac id
1 0 ste ps , 5 .9 %
o ve ra l l yi el d fr om
CHO
NH2
( R )-(-) -a mi no in d a ne
FcPC y 2
OMe
OM e
El lm an e t a l . J . A m. C he m . S o c. 20 0 5, 1 2 7, 1 34 9 6- 13 4 97 .
Slide by Marinus Bigi
Streamlining Synthesis
Reductive Heck-type Insertions in Complex Molecule Synthesis
A lte r nat iv e s to 2nd G ene r at ion A ppr oa ch:
N2
Me O
CH O
C O 2 Me
C O2 M e
O
+
O
0
to lu e ne , -6 0 C , 0.5 h
2 0 m ol % Ag OTf
2 0 mo l% (+)- Tol BIN AP
OP iv
1 mo l% R h (II)/C hi ra l li g an d
O
OM e
O
1 e q . K F, [1 8 ]cro w n -6
O
7 9 % , 1 3 :1 d r; 9 5% e e
O
HO
0
TH F, -80 C
7 5% , 8 4 % e e
Si
O
O
D av ie s e t a l . Or g. L e tt. 2 00 6 , 8, 3 43 7 -3 44 0 .
R od ri gu e z-G ar cia e t a l . C h em . Eu r. J. 2 00 6 , 1 2 , 87 6 2- 87 6 9.
3 r d Ge ner a tion, Rh( I)/Chir a l Liga nd
H
N
RN
i . 10 mo l% [R h Cl (co e )2 ] 2
H
2 0 m o l% L *
to lu e ne , 90 0 C , 2 1 h
N
i i. 10 % Ac OH /THF , 6 h
OM e
O
CH O
N
H
4 ste ps
N
OMe
6 1 %, 9 0 % e e
O
N
OM e
PKC In hi b ito r
Ph
L* =
O
P N
O
8 l in ea r s te p s, 3 .2 %
o v era l l yi el d fr om
Ph
Cl
Cl
E llm a n e t al . Org . L e tt. 2 0 06 , 8, 1 7 45 -1 7 47 .
Slide by Marinus Bigi
Streamlining Synthesis
Metal Carbenoid-Induced C-H Insertion
" -D ia zoa c et a te s :- Se l ec ti vi ty: te n de n cy fo r 5 -m em b er ed ri ng fo rm ati on o ve r b en zy li c
C -H ac ti va tio n
- Sy nth e tic U til ity: a sym me tri c sy nth e sis of # -b u ty ro la cto ne s
O
O
O
O
O
O
Me O
N2
O
O
6 7% yi e ld , 9 5 % ee
O
O
N
O
O
O
O
N2
O
o
CH 2 C l2 , 40 C
N2
O
OMe
Rh 2 (OA c)4
DCE
OMe
96 %
O
EtO
N2
O
OMe
D oy le J OC 1 9 96 , 61 , 9 14 6
O 2N
O 2N
O
O
N
N2
C O 2M e
R h 2 (S- PTTL )4
OM e
C H 2 C l2 , 23 o C
8 3 % , 8 2 % ee
C 6 H 4 p-C l
A r y ld ia zoa c et a te s :
pr e fer en tia l ly fo rm !-l a cto ne s
Ph
O
N2
O
Me
Me R
O
O
R h(II) ca ta lys t
o
C H2 C l2 , 4O C
H
D oy le J OC 2 0 01 , 66 , 8 11 2
Slide by Chris Taylor
Cl
Ph
Me
OMe
O
OMe
OMe
-re g io se l ec ti vi ty de p en d e nt u po n su bs ti tuti on a t n i tr og e n
! -la cta m s el ec tive w / t-B u ty l
#-la cta m s el e ctive w / p-N O 2 C 6 H 4 H as him ito TL 1 9 98 , 39 , 7 9
R2
H O 2C
O
R1
O
O
X
OTB S R 2
Cl
R1
X
R
R1
R2
(R )-( -)-b a clo fe n . H C l
R
N H2. HC l
O
N
OE t
(+) -Am ur en si n in e
Stoltz JAC S 2 0 0 6, 1 28 , 11 7 5 2
( -)-e n te r ol ac ton e
" -D ia z oac e toa c e ta m id es :
O
N
HO
6 2 % yie l d, 9 3% e e
O
OM e
O
OM e
N
Tota l Sy nthe s is of A m ur ens inine via C- H B ond Ins er tion
OH
R h2 (4 R -M PP IM )4
C H 2C l 2, 4 0 o C
H
8 6% yi e ld , 9 6 % de
" -D ia zok e t ones :
- e xtre me l y re ac tive g ivi n g l ow e na n tio se le cti vity c om p ar ed to
d ia zo a ce ta te s a nd di a zo ac eta mi d es
D oy le TL 19 9 6 , 3 7 , 1 3 71
( +)-is od e o xyp o do p hy ll oto xi n
O
R h2 (4 S -MA C IM )4
O
Me O
O
( -)h el e io trid a n e
Me
Me
M eO
R h2 (4 S -MP PIM )4
o
C H 2C l 2, 4 0 C
O
" -D ia zoa c et a m ide s :
- co m pe titi on be tw e en !- a n d #-l ac ta m f or ma tio n
Me R
H
69 % yi el d , 8 0 % d e
R2
I nte r m ole c ula r V a r ia nt :
a sy mm e tr ic a l do l, M ich a e l,
M a nn i ch r ea cti on s , a n d
C l ai se n R e a rra n ge m en t
NHR O
u si n g R h 2( S-D OS P)4
R1
R1
X
R
O
R2 N
X
R
N2
R1
OH
T BSO
R1
R1
O
X
R
D a vie s C h e m. R ev . 2 0 03 , 10 3 , 28 6 1
Streamlining Synthesis
C-H to C-C Bond Forming Reactions in Synthesis: The Other Stuff
B ac k to Ba s ics :
OM e
O
R1
O
O
C O2 M e
Me
H
O
R2
O
C O 2 Me
N
O
OM e B r
OH
H
H
OM e
M eO
A gO Tf, 4 Å M S
C H 2C l 2
5 7%
Frie de l- C ra fts a lk y lat io n
S ch re ib er JA C S 1 99 3
OM e
O Me
en ro u te to D y ne m ici n in A
un su cc es sfu l
H
N
B oc
n -Bu L i, -7 8 °C
O2 N
(-)- sp ar te i ne
th e n,
O2 N
OTIPS
A rH N
Be ak JA C S 2 0 01
H
TB S O
B oc
8 3% , >9 9:1 d r
97 :3 e r
F
Dir e cte d Li-p-a lly l
func tiona liza tion en ro u te to (-)-P a ro xeti n e
Me O
N ico l ao u AC IEE 20 0 6
O
HO
O
5 ste ps
M eO
M eO
H
O
H
M eO
H
O
( ±)- De gue lin
(>5 0% o ve ra ll y ie ld )
Sa me s OL 2 0 03
M eO
Slide by Dustin Covell
Pd C l2 ,
N a OA c
A cOH
75 %
N
Me O
O
AcO
NH
O
6- endo H y dr oar y la tion
( Form a l Alk y ne U m polung)
Pd H O
O
HO
N
O
SEM
e n r ou te to (+)- Dr ag m ac id in F
OMe
B (OH )2
N
Pd OM e
A g2 O, D MF
86 %
Cl
H
Pa lla dac y cle D ir e ct ed
C -H A ct iva tion
OMe
OM e
O
H
M eO
OM e
2 s tep s Me O
TB SO
HO
OM e
O
Me O
OM OM
C O 2 Me
O
Dir e cte d A r yl C -H
A c tiva tion
H
O
O
N
S EM
OM e
5 mo l% PtC l 2
to lu e n e, 5 5° C
9 1%
O
O
Li
S EM
N
OMe
OM e
OH
M eO
N H B oc
O
D ir ec te d Or tho- e n rou te to P la te n si my cin
M e ta la tion
P d (OAc )2
DM SO ,
t- Bu OH ,
A cOH , 6 0° C
7 4%
Sto ltz J A CS 20 0 4
O
M eO
OMO M
Le ts Ge t Tra ns ition Me ta l-r if ic:
TIPS O
F
OM OM
N H Boc
OMO M
N H B oc 1 .) n-B u Li , -78 ° C ,
TMS C l
2 .) n- Bu Li , -7 8° C ,
OM OM
M e OC (O)C N
H
1 .) Pd Cl 2 ,Na OA c
2 .) CO , M eO H
3 .) SiO 2
65%
e n ro ute to Te le o ci di n B -4
N
DG
M eS O 3 H
83 %
OM e
N
M eO
H
S a me s J AC S 20 0 2