Baran Group Meeting Breaking the Rules: "Anti-Baldwin" Cyclizations
Baldwins Rules of Ring Closure
Sir Jack Baldwin
- 1938: Born in London
- 1964: Awarded Ph.D. from Imperial College
under Professor Sir Derek Barton. Studied
structure elucidation of byssochalmic acid
using chemical methods.
- 1965: Assistant lecturer at Imperial College
- 1967: Moved to UPenn
- 1970: Moved to MIT
- 1972: Moved to King's College
- 1972: Back to MIT
- 1976: Published "Baldwin's Rules" and two related articles
- 1977: Published Rules on Enolates
- 1978: Moved to Oxford. Elected as Fellow of Royal Society and appointed
as Waynflete Professor of Chemistry at Oxford.
- 1982: Published Rules on Aldols
- 1997: Awarded a Knighthood for his contributions to organic chemistry
- Other areas of Investigation:
- Biomimetic syntheses of sponge alkaloids and fungal metabolites.
- Development of synthetic methods
- Chem. and bio studies on biosynthesis of b-lactam antibiotics
- More than 600 papers. See "Sir Jack Baldwin" GM (Georgiades, 2006)
Seminal Papers:
Tetrahedral Sys: Eschenmoser, A.; Helv. Chim. Acta, 1970, 53, 2059.
Radicals: Beckwith, A. L. J.; JACS, 1974, 96, 1613.
Burgi-Dunitz: Burgi, H.B., Dunitz, J.D.; Tet. 1974, 30, 1563.
Rules: Baldwin, J.; J.C.S. Chem. Comm., 1976, 734.
5-endo-trig: Baldwin, J.; J.C.S. Chem. Comm. 1976, 736.
Vector Analysis: Baldwin, J.; J.C.S. Chem. Comm. 1976, 738.
Enolates: Baldwin, J.; J.C.S. Chem. Comm., 1977, 233.
Radical Rules: Beckwith, A. L. J.; J.C.S. Chem. Comm., 1980, 482.
Aldols: Baldwin, J.; TL, 1982, 38, 2939.
- According to CRC, over 90% of natural products contain a carbo- or
hetereocycle
- Seminal paper in 1976: Cited 2,160 times. (plus an extra 685 for papers
immediately following.)
- Most cited paper in history of RSC Chemical Communications.
- Baldwin published formal rules but compliation of many people's work
- Beckwith published rules specific to radical cyclizations
Sarah Wengryniuk
Terminology
#- refers to number of carbons in the forming ring (≥3)
Endo/Exo- refers to position of breaking bond relative to forming ring
Endo bond is inside the newly formed ring
Exo bond is outside of the newly formed ring
ex. 5-exo-tet
Tet/Trig/Dig- Hybridization at the ring closure point. -X
Y
Tet- sp3; Trig- sp2; Dig- sp
For enolate reactions:
Same terms as above, plus designator for position of enolate.
Enol-endo: Enolate is inside of the newly forming ring.
Enol-exo: Enolate is outside of the newly forming ring.
C vs. O: Whether cyclization occurs via C or O centered nucleophile.
Br
Br
σ*
O
X 5-(C-enolendo)-exo-tet
-O
C-Nuc out of plane
O-Nuc in plane
-O
O
5-(O-enolexo)-exo-tet
Based on ideal angle of trajectory for maximal orbital overlap
180 º
X-
Y
tet: 180 º
Walden Inversion
X-
X-
107 º
Y
trig: 107 º
Burgi-Dunitz
60 º
C
Y
dig: acute angle 60 º
Wegner and Baughman
"Caveats" to the Rules:
- Atoms involved must be in the first row
- Larger atomic radii and longer bond lengths allow for more flexibility with
second row elements and below
- Do not apply to concerted electrocyclic processes.
- Rules imply inversions at the reacting centers and therefore do not apply
to processes where inversion is not required.
- "I thank Professor R.B. Woodward for pointing this out to me." -JEB
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Baldwin's Original Rules: Apply to Nuc -, Rad•, Elec +
X
TET
Y
3-exo-tet
Favored
X
Y
4-exo-tet
Favored
X
X
3-endo-tet
????
TRIG
Y
5-exo-tet
Favored
Y
Y
X
X
Y
3-exo-trig
Favored
3-endo-trig
Disfavored
X
4-endo-tet
????
5-endo-tet
Disfavored
Baldwin's Enolate Rules:
X
Y
6-exo-tet
Favored
ENOLEXOEXO-TET
O
-O
Y
All 3-7 membered ring closures are favored!!!
Same applies to (enolexo)-exo-trig ALDOLS.
Y
X
6-endo-tet
Disfavored
ENOLENDOEXO-TET
O
-O
Y
3-5 membered ring closures are disfavored
6-7 membered ring closures are favored
Same rules apply to (enolendo)-exo-trig ALDOLS
X
Y
4-exo-trig
Favored
X
Y
5-exo-trig
Favored
Y
Y
X
Y
Sarah Wengryniuk
X
4-endo-trig
Disfavored
Y
X
5-endo-trig
Disfavored
Y
X
6-exo-trig
Favored
Y
X
6-endo-trig
Favored
Beckwith's Radical Rules:
1. Intramolecular addition under kinetic control when n≤5, cyclization occurs
preferentially in the exo mode.
A B
(Y)n
X
A B
A B
(Y)n
X
exo-mode
Favored
vs. (Y)n
X
endo-mode
Disfavored
Thermodynamic preference
for secondary radical
overridden by kinetic pref.
based on required orbital
alignment for cyclization.
2. Substituents disfavor cyclization at substituted position.
X
DIG
Y
3-exo-dig
Disfavored
X
Y
3-endo-dig
Favored
X
Y
4-exo-dig
Disfavored
X
Y
4-endo-dig
Favored
X
Y
5-exo-dig
Favored
X
Y
5-endo-dig
Favored
X Y
6-exo-dig
Favored
X Y
6-endo-dig
Favored
R
R
R
vs.
Favored
Disfavored
3. Homolytic cleavage is favored when bond concerned lies close to plane of
adjacent semi-occupied, filled non-bonding, or π-orbital
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
"Tet"-Cyclizations: Overriding exo- to get endo-
Common Transformations that Break the Rules:
Cyclic Acetal Formation: 5-endo-trig via oxonium
O
O
HO
HO
5-endotrig
OH
O
-Since all exo-tets are favored this section with discuss how to override that
selectivity to get endo-selectivity.
-Examples of anionic openings (Cationic and Radical not common)
-This section could also be called: "Regiochemical control in epoxide opening"
-Seminal work by Nicolaou during brevotoxin synthesis
Baldwin says:
Nuc, Elec, Rad
O
H+
Perkins, J.M.; JOC, 1981, 46, 2196.
-trig
endo
exo
Favorskii Rearrangement: 3-enolendo?
O
O
Cl
NaOH
O
3-(enolendo)exo-tet
Cl
Sarah Wengryniuk
HO
3
n
y
5
n
y
4
n
y
7
-y
6
y
y
O
HO
OH
O
vs.
Xexo-preferred
XCommon Transformations that Make you Question the Rules:
-Baldwin says his rules extend to "nucleophilic, electrophilic, and homolytic"
processes but is this true?
4-endo-tet: Synthesis of Phytotuberin
OH
HO
MsOH, CH2Cl2
Wagner Meerwein vs [1,2]-Wittig RAR
O
Li
anionic so can't be
concerted
R
R C O
R
HO
O
via
3-endo-tet
X
R
R C O
R
R C O + R
R
CO2Me
OAc
but cationic...
1. PPh 3, imid., I 2
2. PPh 3, imid., I 2
O
H
R'
R C O R
R
OH
0 ºC, 1h, 53%
Ac-transfer,
OAc 4-endo-tet
AcO
topologically
equiv to 3-endo-tet
Xendo-desired
R
R C OH
R
homolytic,
intermol. recomb.
O
3. N-(PSPTH)
O
OH
OH
OH
OH
O
O
O
O
O
OH
SePh
4-exo-tet kinetic
PhSe
O
OH
OAc
Phytuberin
5-endo-tet thermo
Suarez, E.; JOC, 2003, 68, 4422.
Baran Group Meeting
Breaking the Rules: "Anti-Baldwin" Cyclizations
5,6,7-endo-tet over 4,5,6-exo-tet
General comments:
-Exo- mode is always preferred (even in 6-endo case)
-However, control of regiochemistry in these systems is very well understood.
-Few basic strategies are employed, section catagorized by approach:
- Cyclic sulfates (Sharpless)
- Substituent effects (started with Nicolaou vinyl oxiranes)
- Use of "-onium" ions (iodo-, bromo-, seleno-)
- Use of select activating agents (LA, antibodies)
Nicolaou and Brevetoxin: Endo-control via Substituent Effects
Vinyl oxiranes
HO
vs. HO
O
O
H
R
O
R HO
R
5-exo
R
6-endo
0
CH2CH2CO2Me
100
E-CH=CHCO2Me
CH=CH2
CH=CBr2
Cyclic Sulfates
Enantiopure Tetrahydrofurans
R2
R
OBn O
O
S
O
O
Pachastrissamine
40
0
0
HO
1. H 2O,CH3CN, 74%
5-endo-tet
N3
TrO
60
100
100
A,B,C Rings of Brevetoxin B
enantiopure diols to
enantiopure, substituted Br
Br
CSA
2. 4 days
tetrahydrofurans
R
R2 O
Me
(0.1 equiv.)
HO
5-endo 82%
O
93%
Sharpless, B.K.; Acta Chim Scanda, 1993, 47, 307.
O
H
H
1. Hydrog.
C13H 27
O
O
S
O
O
Sarah Wengryniuk
2. H 2, Pd/C, 93%
H 2N
HO
R
Me
H
O
H
HO
OH
O
O
O
O
O
O
OH
CO2Et
O
O S O
O
1. K 2CO 3,
acetone, Δ
2. 20% H 2SO 4
THF, rt, OT
O
THF of Amphidinolides X and Y
CO2Et
Vatele, J-M.; Synlett, 2007, 6, 983
OH
R
67%
CSA,
DCM
O
HO
75%
H
H
H
O
H
OH
THP Unit of Amphidinol 3
Oishi, T.; JOC, 2009, 74, 8810.
R
6-endo
0
CH2CH2CO2Me
7-endo over 6-exo
Panda, G.; Eur. JOC, 2009, 204.
OH
HO
1-Benzoxepines
OH
O
Similar strategy used in approaches to numerous natural products
5-endo over 4-exo
OH
Analogous reaction with epoxide gave only trace product under various cond.
Kim, S.; OL, 2007, 9, 429.
Br
H
Nicolaou, K.C.; JCS Chem. Commun., 1985, 1359.
Nicolaou, K.C.; JACS, 1989, 5330.
OH
C13H 27
O
Pachastrissamine
Br
O
5-exo
100
E-CH=CHCO2Me
22
78
CH=CH2
Z-CH=CHCl
E-CH=CHCl
82
60
92
18
40
8
Nicolaou, K.C.; JACS, 1989, 111 , 5335.
Baran Group Meeting
Breaking the Rules: "Anti-Baldwin" Cyclizations
Propargyl Oxiranes
Methoxy-Methyl Ethers: Use Lanthanide Metal
Cobalt Complexed Propargyl Epoxides: 6-endo-tet
Co2(CO) 8
O
Co
HO
R
HO
BF 3•OEt2
O
R
R= H, TMS, alkyl, ester, aryl
O
R
Hanaoka, M.; TL, 1994, 35, 2179.
w/o Co: Hanaoka, M.; TL, 1994, 35, 2183.
Sulfones: Disfavor exo-pathway via e--withdrawing
H
H
n-BuLi, DMPU
OTBS
OR
OTBDPS p-TsOH, 55 º
O
OTBDPS
80%
OTf
O SO2Ph
O
O
SO
Ph
2
H
H
90%
H
H
H
H
H
O
O
O
OTBDPS
OR
O
H
O
iterative oxiranyl anion
addition 6-endo-tet
O
H
H
O
H
H
HO
O
2. Me 3Si C C Me
n-BuLi, TMEDA; CuI, DMAP Me 3Si
OH
BF 3•OEt2
H
OH
MeO
H
Me
OH
O
Murai, A.; TL, 1995, 36, 8063.
Reagent Control: Selection of Activator
Exclusive reagent control: Approach to Oxasqualenoids
CSA
O
H
HO H
exo-major
or
TfOH
OR
TIPSOTf
O
5 equiv.
OH
O
up to 7:1 endo
Morimoto, Y.; ACIE, 2006, 45, 810.
6-endo Cyclizations onto Activated Alkenes
"-Onium Ions"
HO
SiMe 3
Mech on regio: Schumann; TL, 1995, 36, 8771.
HTIB
(2.0 equiv.)
I 2 (0.2 equiv.)
I
OAc
HOMe
O
O
OMe
O
MeOH, rt
64%
HO
80%
iterative, as
O
H
SiMe 3 >95% ee
>95% dr
above
SiMe 3
>95% endo
H
H
H
HO
O
Ladder THP Synthesis: THP triad in 18 steps
Mori and Nicolaou: 10-13 steps per unit
Me
O
O
H
H
H
Jamison, T.; OL, 2003, 5, 2339.
Se: Noto R.; Tet., 2001, 57, 1819.
S: Noto, R.; J. Het. Chem., 2001, 765.
Iodonium Ions: 4-exo then RAR
HO
1. DIBAL; I 2
Me 3Si
MeO
M O
DCM,
2d
H Me OH
H Me
68-96% yield; 82:18 – 90:10 endo:exo
No metal: Exclusive exo-cyclization
68-96%
OH
Mori, Y.; JACS, 1996, 118 , 8158.
Other ex: Mori, Y.; Chem. Eur. J.; 1997, 3, 849.
Mori, Y.; TL, 1995, 40, 8019.
Epoxysilanes:
La(OTf) 3
(2.2 equiv.),
MeO
O
65-98%
cis:trans (>91:9)
HO
Sarah Wengryniuk
Initial 4-exo then RAR
Giannis, A.; JOC, 2011, 76, 1499.
Another ex of 5-endo with I 2: Elliott, M. C.; OL, 2007, 9, 3635.
Bromonium Ion: 7-endo by desymm. of bromonium give oxazepanes
Me
CO2Me
HO
N Ns
R
NBS (1.0 equiv.)
CSA (0.1 equiv.)
THF, 0 ºC
O
Ph
CO2Me
N Ns
>20:1 dr
>20:1 endo:exo
in most cases
Br
Moitessier, N.; JOC, 2013, 78, 872.
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Random Other Methods
Sarah Wengryniuk
"Trig" Cyclizations
-Many examples of overcoming Baldwin's rules here
-Primarily rely on heteroatoms (O, N, S...)
-Nucleophilic, electrophilic and radical methods
-Primary focus will be on 5-endo-trig
-Will be broken down by method of activation
W(CO)5
Fischer Carbene: Example of a carbon nucleophile: Tetrahydronapthols
H 3CO
OH
O R
O R
Ph
Li
R2
W(CO)5
OCH3
3-endo-trig: As you might imagine,
Li
52-83% yield
no examples in the literature
dr >98:2
R1 OCH3
R
W(CO)5
6-endo only
107 º
Y
required trajectory
not possible
Gasparrini, F.; OL, 2005, 7, 4895.
[CoIII(salen)] Complex: Regio- and Kinetic Res.
O
1 mol% cat.
O
OH
( )n
TBME
( )n OH tBu
H
N
H
N
Co
O O
OAc
tBu tBu
95% ee, 46%
tBu
Jacobsen, E. N.; ACIE, 1999, 38, 2012.
Catalytic Antibody Catalysis
HO
+ Ab
O
R
Kinetic Res.
and excl. 6-endo
Antibodies produced by
immunization of mice with
compound to mimic t.s.:
R
R
O
HO
No Ab
HO
R
R
Racemic
-O
N+
R
4-endo-trig: Examples using heteroatom nucleophiles
XO
Ph
Ph
R1
OH
R2
N
N
Br +
R1 R 2
Br
O
Racemic
5-exo only
Lerner, R.; Science, 1993,
259, 490.
R
-
COYH
Y= O, N
X-= PF 6 or SbF6
-
azetidinones
43-45% yield
Y
Ph
O
Br
oxetanes
48-78% yield
oxetanones
23-85% yield
Rousseau, G.; TL, 2001, 42, 2477.
Rousseau, G.l JOC, 1999, 64, 81.
5-endo-trig
Alabugin suggests aromatic character to 5-endo t.s.: lone pair, π-bond, σ-bond
"Anionic 5-endo closures are "aborted" sigmatropic shifts"
Think of 5-endo closures are competition between pericyclic and ring closure:
[2,3]
X
X
X Nu X Nu 5-endo
Wittig
Nu
Nu
Y
Y
Y
Y Y= EWG
Stabilize (-) at X
EWGs at the Y-position promote 5endo cyclizations by further lowering
energy of "intermediate".
Alabugin, I.; JACS, 2012, 134 , 10584.
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Nucleophilic Cyclizations: EWGs at 4-position
Unsaturated Sulfones:
SO2R
KH cat.
THF, 10 min
81-88%
OH
R R
SO2R
RO 2S
SO2R
KH
CO2Et 65% R
CO2Et
R
EtO 2C
EtO 2C
O
R R
Activating Alkene: "-Onium Cyclizations
-Put them here because these the authors called 5-endo-trig, but similar
approach to -onium ions in 5-endo-tet section
More iodoniums: Total synthesis of (–)-Muscarine
HO
R
R
Knochel, P.; TL, 1985, 26, 4455.
Sarah Wengryniuk
I 2, NaHCO 3
OH
CO2Me
R
63%
HO
R
HO
R
O
O
NMe 3+
Tandem Intermol-Michael then 5-endo-trig to pyrrolidines
SO2Ph
SO2Ph
SO2Ph
RNH 2
Mercuronium-mediated 5-endo: (+)-Castanospermine and analogues
5-endo
SO2Ph
NHBn
N
R
2. base
SO2Ph
Knight, D.; Eur. JOC; 2004, 1973.
RHN
O
Padwa, A.; JOC, 1990, 55, 4801.
OBn
OH
O
Total Synthesis of (±)-Lepadiformine
SESHN
HO
R
Ar
O2N
O2N
NHR
RNH 2
85-98%
R
R
N
HY
R
Base
57-96%
OH
OH
Ar
Ar
N
H
O2N
1. PPTS
2. DDQ
~50%,
2 steps
Ar
+
N
H
N
H
F 2C
F 3C
F 2C
or
R
O
TIPS
Ar
N
H
R
or
Y= O ,NTs, S
Y= C(CO 2Et 2 ), C(CN) 2
R
Y
R
R
Ichikawa, J.; Chem. Asian J., 2008, 3, 393.
O
TIPS
O
O
N
O
N
N
H
R
5-(enolexo)endo-trig
N
HN
R
Y
R
MgI 2, THF
75 ºC
-CF3 group: Fluorinated hetereocycles
R
O
Ring-expansion/Iminium 5-endo to (–)-Spirotryptostatin B
Tavani, C.; Eur. JOC, 2000, 903.
CF 3
H
HO
O
Iminium and Oxonium Cyclizations:
N
Craig, D.; ACIE, 2007, 46, 2631.
Ar
N
HO
Dhavale, D.; JOC, 2006, 71, 4667.
(±)-Lepadiformine
NO 2
OBn
O
OBn
SO2Ph
N
OBn SES R
Nitro-group
2. NaH, BnBr
66%
O
n-BuLi (2 eq.)
BnOCH 2CHO,
then PhCOCl
PhO 2S
NBn
H
1. Hg(OAc) 2,
NaBH 4
N
H
O
TIPS
(–)-Spirotryptostatin B
Carreira, E.; JACS, 2005, 127 , 11505.
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Pictet-Spengler to 2,5-Diketopiperazines: "MUPS" Sequence
O
H
R
N
O
MeO
HN
MeO
N
MeO
60%
H
Diastereoselective C-2 Alkenylation of Indoles via 5-endo "Fujiwara-Moritani"
H
N
MeO
O
5-endo Heck Reactions
IHR typically proceed via exo-pathway
- For 5-endo requires harsh reaction conditions and/or specially designed
substrates and yields are typically low.
H
O
TFAA,
1:1 TFA/DCM
R
O
N
O-nucleophile onto Iminium: (–)-Quinocarcin
H
AgBF4
NCbz
N
O
H
H
N
N
R
O
CO2H
CHO
R
Pd(OAc) 2, Lig., O2
Orru, R.; Chem. Commun., 2010, 46, 7706.
SEt
Sarah Wengryniuk
R
mesitylene,
t-BuCO2H, 120 ºC
47-99% conv.
N
O
R
R
Oestreich, M.; ACIE, 2012, 51, 1265.
Unexpected result in synthesis of Teleocidin B
OTIPS
NCbz
OMe
O
NMe
O
TfO
Zhu, J.; JACS, 2008, 130 , 7148.
N
H
CO2Et
Pd(OAc) 2,
dppe, 2.5h
N
H
94%
CO2Et
5-(enolendo)-exo/endo-trig
Tanner, D.; Synlett, 2006, 18 , 3140.
Onto an oxonium: THFs from 1,3-Dioxolan-4-ones
O
R
O
R1
iBu 3Al
R2
55-91%
HO
Bu 3AlO
R
R1
R1
O
R
R2
R2
O
Radicals: Focus on 4-exo vs 5-endo
- Despite being a favored process, not many examples of 4-exo in literature
- Examples of 5-endo radicals are scare, often involve heteroatoms.
4-exo-trig-rad: Employing the gem-dialkoxy effect
EtO OEt
Petasis, N.; JACS, 1995, 117 , 6394.
Br
5-(enolendo)-exo-trig in Co-mediated O-->C Rearrangement
Ph
OO
Et 2AlCl
(3.0 equiv.)
Co2(CO) 6
R
CO2Et
Ph
47-57%
(OC) 3Co
O
Without subtituents or with
gem-dimethyl, no cyclization
was observed.
67% overall
O
Ph
1. Bu 3SnH, AIBN
2. HCl
Co(CO) 3
R
CO2Et
Jung, M.E.; TL, 1992, 33, 6719.
Other approaches: Substituent effects still important
O
O
Titan. (10mol%)
SmI2
OH
Mn (2 equiv.)
OH
CO2NMe
R
Harrity, J.; JOC, 2005, 70, 10046.
CO2Et
H
CO2Et
Proctor, D. Synlett, 2012, 23, 6.
CONMe2
Ganauser, A.; JACS, 2008, 130 , 1788.
Baran Group Meeting
Breaking the Rules: "Anti-Baldwin" Cyclizations
Carbamoylmethyl Radicals: By far most common approach
4-exo-trig-rad: Synthesis of strained ring of Solanoeclepin
O
SmI2
OTMS
CHO
O
OH
O
H
CO2H
SPh
SPh
O
OTMS
76%
H
MeO
OH
O HO
N
O
Nishikawa, T.; Chem. Lett., 2012, 41, 287.
59%
O
H
Cy, Δ
Ph
N
same cond.
No dp
30%
Ph
Me
Br
N
Ph
O
O
O
N
Bn
O
O
Aided by radical stabilizing group: Reverse regioselectivity of SmI2
SmI2, THF
HMPT
HO
Me
OMe
OMe
Bats, W.J.; ACIE, 1995, 34, 2383.
Carbamoylmethyl Radicals: By far most common approach
N
O
N
Ph
O
Krause, J.; TL, 1993, 34, 797.
O
O
N
Bn
OR*
O
I
Bu 3SnH,
AIBN
N
Ms
5-exo-trig
H
30%
5-endotrig
N
Ms
N
H
Ms
Murphy, J.; OL, 2001, 3, 3405.
OMe
66%
SPh
SPh
Me
Bu 3SnH,
AIBN
26%
71% de
Reddy, K.M.; TL, 1993, 34, 2665.
OMe
HN
92%
Ph
1,4-Pentadienyl-3-sulfonamides: Cascade sequences
O
Me
Ph
Parsons, A.F.; TL, 1997, 38, 491.
97%
O
Bu 3SnH,
AIBN
Ph
Br
O
Bu 3SnH,
AIBN
Br
N no rxn
CO2Me
O
Carbamoylmethyl Radicals: Attempt at stereoselectivity
Julia, M.; Bull. Soc. Chim. Fr., 1965, 1550.
Aided by radical stabilizing group: leads to high yields
N
Carbamoylmethyl Radicals: Hydrazone Derivative
First "successful" example: Similar substrates don't work
CN
CO2Et
R
Ishibashi, H.; TL, 1991, 32, 1725.
Review: Ishibashi, H.; Synthesis, 2002, 6, 695. Lots of things that don't work.
5-endo-trig rad, disfavored?: Gimisis, T.; JACS, 2002, 124 , 10765.
CN
CO2Et
SPh
H
Bu 3SnH,
AIBN
5-endo-trig-rad:
CN
CO2Et (PhCO 2)2
Sarah Wengryniuk
General Notes
-Must have carbonyl incorporated into 5-mem ring
-Initiators: Bu 3SnH/AIBN; Ni/AcOH, CuCl/bipyridine
-X: Cl, Br, I, SPh, Se
-Alkene: Isolated, benzylic, α,β-unsaturated carbonyl
Silicon Radical: Prostaglandin Synthesis
R
R Si H
O
SePh
Bu 3SnH,
OBn AIBN
5-exo-dig
1,5-H trans.
CO2Me
R
R Si
O
OBn
75%
CO2Me
R OBn
R
5-endotrig
O
H
Si
H
CO2
Me
Clive, D.; JOC, 1999, 64, 2776.
Baran Group Meeting Breaking the Rules: "Anti-Baldwin" Cyclizations
This section will cover: 3-exo vs. 4-endo (rad, anionic, cationic)
4-exo vs. 5-endo (rad, anionic, cationic)
Not covered: 5-exo vs 6-endo. Both favored. See review for details.
Alkyne Cyclizations: "Dig"
-Recent theoretical and mechanistic work in field by Igor Alabugin from FSU
-Review: Alabugin, I.; Chem. Rev. 2011, 111, 6513
-Alkyne cyclizations display most deviation from Baldwin's Rules
-Alabugin proposes modified set of "rules" for alkyne cyclizations
Nuc, Elec, Rad
Baldwin says:
-dig
endo
exo
3
y
n
5
y
y
4
y
n
"Favored" Trajectory for Digonal Closure
XBaldwin
Acute angle of attack
60º
60 º
Revised
X-
Obtuse angle of attack
120 º
120º
3-exo vs. 4-endo: By Baldwin's Rules, 4-endo should be favored.
Radical
No examples of either 3-exo and 4-endo radical cyclizations in literature.
Theoretical studies reveal that both processes are endothermic and as such
they are not likely to be practically viable.
6
y
y
Hope for development of a 3-exo-dig radical method?
vs.
X
120º
X
120º
based on X-ray
studies and preference
for endo- closure
theoretical calculations,
avoidance of π*-nodal
plane, analogous to
Burgi-Dunitz angle
The obtuse trajectory should translate into stereoelectronic preference for
exo-cyclization as opposed to endo!
Nu-
LUMO
-
Exo
Endo
Electrophilic
HOMO
E+
+
Endo/Exo
Three Modes of Cyclization to Consider
E+
E+
Electrophilic
Closure
Nuc: Secondary
orbital interaction is
destabilizing
Elec: Secondary
orbital interaction is
stabilzing
Significant drop in endothermicity
suggets that a properly designed system
Ph
may be able to shift equilibrium.
ΔE r 2.4 kcal/mol
ΔE r 8.2 kcal/mol
Anionic
3-exo-dig
Carbon Nucleophile: Vinylidene Cyclopropanes from E--deficient Alkenes
X
OTBS
CO2Me
O
TBAF
n
Stereoelectronic Differences in Nucleophilic vs Electrophilic Cylization
Nucleophilic
LUMO
Nu-
Sarah Wengryniuk
R
X= C, O
I
X
THF, rt
62-95%
O
CO2Me
CO2Me
H
X
n
n
I
R
H
R
H
R= i-Pr, H,
Johnson, J.; JACS, 2008, 130 , 9180.
Oxygen Nucelophile: Vinyl Oxiranes
OH
H
N
N
N
N
N
N
N
N
H
H
Nu
E+
Berg, C.; Eur. J. Org. Chem. 2005, 4988.
E+-Promoted
Nu-Promoted
Electrophilic Closure (NPEC) Nucleophilic Closure (EPNC)
H
OH
O
HCl,
EtOH
Nu
H
H
HCl,
EtOH
N
N
N
N
H
O
N
N
N
N
H
Bonus: 4-exo-dig (10% conv.)
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Nitrogen Nucleophile: Vinyl aziridines via electrohalogenation of propargyl amides
Me
–2eMe
NHAc NaBr/H 2O
76%
R2
Br
+
R2
Me
Me
NHAc
Me
Me
Br
NAc
R2
Sarah Wengryniuk
4-exo (Disfav.) vs. 5-endo (Fav.):
-Clear thermodynamic preference for 5-endo (much more exothermic)
-Kinetic preference can often favor 4-exo closure so selectivity is balance
of two factors.
Radical
4-exo-dig: Only two examples in literature
Torii et. al.; J. Org. Chem., 1992, 57, 5023.
4-endo-dig???
1. Bu 3SnH,
AIBN
Despite being "Favorable" by Baldwins rules, these types of nucleophilic
cyclizations remain unknown.
This is not surprising based on activation barrier:
vs.
Ea
7.8
27.0
ΔE r
-4.5
-13.0
HO
H Si
3-exo-dig vs. 4-endo-dig
1º carbocation: Controlled by substitution on alkyne: Example of NPEC
R
Δ
Δ
Nf
ROH, H 2O
R 3-exo : 4-endo
H
Me
Ph
An
ROH, H 2O
R
-OR
0:100
1:99
31:17
57:43
Br
H
N
O
TeAr
hυ
Bu
4-exodig
N
PhCH 3
110 ºC
0:100
1:89
-------54:4
R
N
N
R
O
YPh
R
Y= S, Se
Bu
N
Pd(PPh 3)4 (5 mol%)
toluene, Δ
59-88% yield
Bu exclusive 4exo.
only trace 5endo when
R=Et
Kambe, N.; TL, 2009, 50, 3628.
O
Bu
O
ArTe
R
O
+
Malacria, M.; JACS, 1997, 119 , 5037.
O
3-exo : 4-endo
OCOH
O
Si
Carbamoyl Radicals via photolysis of carbamotelluroates
O
CHO2H
4-exodig
MeLi
Bicyclo[3.1.1]Heptanes
Bu
2º/3º carbocations: Similar behavior to 1º or lack of cyclization
X
CF 3CO2H
OH
O
Si
Bu 3SnH
Hanack, M.; JACS, 1974, 96, 6686.
Hanack, M.; JOC, 1983, 48, 5260.
Wilson, J.W.; JACS, 1969, 91, 3238.
R
O
Si
Br
Alabugin, I. et. al.; JACS, 2011, 133 , 12608.
Cationic
5-exo-dig
2. 1,6-H
transfer
O
Si
~20 kcal/mol higher barrier
to activation for 4-endo, which
overrides the fact that it is
~7kcal/mol more exothermic
than 3-exo
6-endotrig
PhY
R
**Not Radical
but related
transformation.
4-exo via Pd
Kambe, N.; JACS, 2005, 127 , 9706.
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Sarah Wengryniuk
5-endo-dig: Examples employing O, S, Si, C radicals
Other Examples of Proposed 5-endo-dig radicals:
Is a favored process by Baldwin's Rules, but examples are scarce! Went
40 years without example of carbon radical 5-endo-dig cyclization!
Double Synchronous 5-endo-radical cyclization
O
Li
O and S require flash vaccum pyrolysis
Ar
YMe
Y
Ar
Ar OH
Y
Y
6-endo-trig
Y= O, 36%
Y= S, 28%
aromat.
Aitken, R. A.; Synlett, 1995, 53.
Aitken, R. A.; JCS PT1, 1994, 2455.
Ar
Other "O" example: Barton, T.; JOC, 1985, 50, 158.
Si-Centered Radical: Intramolecular radical hydrosilylation
1.
MeO
OMe
N N
BuOt
Ar
O
–PPh3PO, –Me
O
OtBu
O
Si
Si
Si
PhLi OH
Double
synchronous
5-endo-dig
Ar
52%
5-endo-dig
FVP, 850 ºC
PPh 3
O
4 equiv.
LiNaph
SiR 3
O
O
Studder, A.; Chem. Commun.; 2002, 1592.
O Li
Computational studies support this proposed mechanism.
If only one ketone present, dimerization
rather than radical cyclization occurs.
Yamaguchi, S.; OL, 2009, 11, 3076.
OH
Anionic:
-4-exo-dig is disfavored by Baldwin's Rules but is possible!
-5-endo is not easy to facilitate either; diff. btw 4-exo/5-endo is very small
-Can facilitate 5-endo:
- Stab/Destab of resulting negative charge
- 4-exo product disfavored by ring strain
- Aromatic Stability of products
- Use of an external electrophile
4-exo-dig
Achieving 4-exo is still not easy: Use of Propargylic leaving group
C-Centered Radical: Igor contributes a reaction!
-40 years since Baldwin's Rules and no 5-endo-dig radical from carbon
-DFT calculations predicted that while plausible, 5-endo-dig is a slow process
-Bias system with strain effects and prediction that vinyl radical should cyclize fastest
-Use of AIBN/Bu3SnH led to complex product mixtures
RO
Me
RO
hυ
RO
TsBr
RO
Me
R= H, 5 or 6-mem ring
Alabugin, I.; JACS, 2008, 130 , 10984.
Me
Me
Ts
5-endodig
RO
Br
RO
Me Br
R
R
OMe tBuLi
R
R R
OMe
I
88%
R
Bailey, W.F.; JACS, 1995, 60, 754.
Achieving 4-exo is still not easy: Stabilizing negative charge
Y 1. n-BuLi or
t-BuLi
Me
Ts
51-72% yield
Almost exclus. Z-exoolefin
I
2. MeOH or
TMSCl
X
Y
Y= -CBMes2, -CO2tBu2, Ph, TMS
X= H, TMS
48-95% yield
Bailey, W.F.; TL, 1990, 31, 627.
Cooke, M.; JOC, 1994, 59, 2930.
Bailey, W.F.; JACS, 1993, 115, 3080. Cooke, M.; JOC, 1993, 58, 6833.
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baran Group Meeting
Use of an external electrophile
Stabilization of the negative charge: 5-endo-dig onto ynone
O
O
EWG
Au: Endo-selective Conia-ene without need for substrate-mediated polarization
EWG
Cs2CO 3
O
H O
OEt
H
O
OTBS
96% yield
W(CO)5(THF)
Stallman, J.B.; JACS, 1993, 115, 7023.
H 2O, THF
72%
OEt
2. MeI
Toste, D.; ACIE, 2004, 43, 5330.
W(CO)5: The use of silyl-enol ether as nucleophile
SO2Ph
1. n-BuLi
R= H, Me, Ph
74-94% yield
DCM
R
Grein, F.; TL, 1986, 27, 5455.
Destabilization via electron-donating group
PhO 2S
[Au(PPh 3)]OTf
CO2Me
O
CO2Me
R
O
82%
H
Sarah Wengryniuk
H
note: Could proceed via
attack on allene intermediate
Iwasawa, N.; OL, 2002, 4, 4463.
H
Producing an aromatic product: Pyrroles via 5-endo-dig then [3,3]
Ph
CO2Ph
BnNH 2, MeO 2C Ph
DCE
74%
CO2Me
Bn
CO2Me
PhOCO
CO2Ph
[3,3]
Ph
MeO 2C
HN
MeO 2C
NH
CO2Me
Zn or Cu (or I 2): Oxygen nucleophile
O
R
HN
O
RLi
(4 equiv.)
X
CF 3
N
X
HO
Me
CO2Et
R
R
R= nBu, Pr, Ph; X=O, S, N
Ph
Cu(OAc)2
Et 2O:pyridine
HO Me
88%
N
Ts
NHTs
Cu, Pd, Hg: Knight, D.W.; Synlett, 2004, 1 , 119.
Ar
Strained Products: 5-endo favored
Ag(OTf)
Ph
Ph
Br
CO2Et
Ph
Johnson, F.; JOC, 1986, 51, 5040.
For related N-nuc: Knochel, P.; ACIE, 2000, 39, 2488.
nBuLi
Cu: Robins, M.J.; J.M.C., 2006, 49, 391.
Zn: Dembinski, R.; JOC, 2008, 73, 5881.
For I 2: Knight, D.W.; TL,2001, 42, 5945.
Cu(II), Pd, Ag or Hg: Nitrogen Nucleophile
X
40-60%
O
N
CuI/Et 3N/MeCN
60-99%
O
N
Garcia-Tellado, F.; Chem–Eur. J., 2009, 15 , 838.
Producing an aromatic product: Carbon Nucleophile
R
ZnCl2/DCM
or
Ph
vs.
not seen
HN
CO2Me
Boc
MeCN
54-80%
H2
Ar
N
CO2Me Pd/C
Ar
N
H
CO2Me
Rujes, P.J.T.; JOC, 2005, 70, 1791.
Baran Group Meeting
Breaking the Rules: "Anti-Baldwin" Cyclizations
Baldwin's Original Rules: Apply to Nuc -, Rad•, Elec +
X
TET
Y
3-exo-tet
Favored
X
Y
4-exo-tet
Favored
X
X
3-endo-tet
????
TRIG
Y
5-exo-tet
Favored
Y
Y
X
X
Y
3-exo-trig
Favored
3-endo-trig
Disfavored
X
4-endo-tet
????
X
Y
4-exo-trig
Favored
5-endo-tet
Disfavored
X
Y
5-exo-trig
Favored
Y
Y
X
Y
X
4-endo-trig
Disfavored
Y
X
5-endo-trig
Disfavored
Modified Baldwin's Rules:
X
Y
6-exo-tet
Favored
X = No examples in literature still
√ = Possible, sparse examples
√√ = Many methods available
F = Favored by Baldwin's Rules
TETRAHEDRAL: Cationic and Radical are as per Baldwin
Anionic
endo
exo
Y
X
6-endo-tet
Disfavored
Sarah Wengryniuk
3
X
---
4
5
6
√
---
√√
F
√√
F
TRIGONAL
Y
X
6-exo-trig
Favored
Y
X
6-endo-trig
Favored
4
5
6
F
√
F
√√
F
F
F
Radical
endo
3
X
4
X
5
exo
F
F
√
F
6
F
Cationic
endo
exo
3
X
4
5
6
X
F
√
F
F
F
Anionic
endo
exo
3
X
F
F
DIGONAL
X
DIG
Y
3-exo-dig
Disfavored
X
Y
3-endo-dig
Favored
X
Y
4-exo-dig
Disfavored
X
Y
4-endo-dig
Favored
X
Y
5-exo-dig
Favored
X
Y
5-endo-dig
Favored
X Y
6-exo-dig
Favored
X Y
6-endo-dig
Favored
5
6
√ (F)
F
√ (F)
F
Anionic
endo
exo
3
X (F)
√
4
X (F)
√
Radical
endo
exo
3
4
5
6
X (F)
√
X (F)
√
√ (F)
F
F
F
Cationic
endo
exo
3
X (F)
√
4
5
6
√ (F)
√
√ (F)
F
F
F