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 O X 5-(C-enolendo)-exo-tet
-O -O

*
C-Nuc out of plane O-Nuc in plane

O 5-(O-enolexo)-exo-tet

Based on ideal angle of trajectory for maximal orbital overlap

180

X-

X-

107

XC

60

Y trig: 107 Burgi-Dunitz

tet: 180 Walden Inversion

dig: acute angle 60 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

Baran Group Meeting

Breaking the Rules: "Anti-Baldwin" Cyclizations

Baldwin's Enolate Rules: ENOLEXOEXO-TET

Sarah Wengryniuk

Baldwin's Original Rules: Apply to Nuc -, Rad, Elec + X X

TET

Y 3-exo-tet Favored Y X 3-endo-tet ????

Y 4-exo-tet Favored Y X 4-endo-tet ????

Y 5-exo-tet Favored Y X

X Y 6-exo-tet Favored Y X 6-endo-tet Disfavored

-O

O Y

All 3-7 membered ring closures are favored!!! Same applies to (enolexo)-exo-trig ALDOLS. ENOLENDOEXO-TET O Y

5-endo-tet Disfavored

-O

X TRIG

3-exo-trig Favored Y X 3-endo-trig Disfavored

Y 4-exo-trig Favored Y X 4-endo-trig Disfavored

3-5 membered ring closures are disfavored 6-7 membered ring closures are favored Same rules apply to (enolendo)-exo-trig ALDOLS X Y 5-exo-trig Favored 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 n5, cyclization occurs preferentially in the exo mode. A B (Y)n X A B (Y)n X exo-mode Favored A B 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 4-exo-dig Disfavored X Y 5-exo-dig Favored X Y 6-exo-dig Favored R R vs. Favored Disfavored R

X Y 3-endo-dig Favored

X Y 4-endo-dig Favored

X Y 5-endo-dig Favored

X Y 6-endo-dig Favored

3. Homolytic cleavage is favored when bond concerned lies close to plane of adjacent semi-occupied, filled non-bonding, or -orbital

Baran Group Meeting

Breaking the Rules: "Anti-Baldwin" Cyclizations

Sarah Wengryniuk

Common Transformations that Break the Rules: Cyclic Acetal Formation: 5-endo-trig via oxonium O HO H+
Perkins, J.M.; JOC, 1981, 46, 2196.

"Tet"-Cyclizations: Overriding exo- to get endo-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 -trig endo exo O O XOH vs. Xexo-preferred Xendo-desired OH HO O OAc O 1. PPh 3, imid., I 2 2. PPh 3, imid., I 2 O OH O O OH O O OH O O SePh 4-exo-tet kinetic PhSe Phytuberin
Suarez, E.; JOC, 2003, 68, 4422.

HO OH

5-endotrig

Favorskii Rearrangement: 3-enolendo? O Cl NaOH O Cl 3-(enolendo)exo-tet O HO

3 n y

4 n y

5 n y

6 y y

7 -y HO

Common Transformations that Make you Question the Rules: -Baldwin says his rules extend to "nucleophilic, electrophilic, and homolytic" processes but is this true? Wagner Meerwein vs [1,2]-Wittig RAR

4-endo-tet: Synthesis of Phytotuberin OH HO MsOH, CH2Cl2 AcO 0 C, 1h, 53% Ac-transfer, OAc 4-endo-tet

topologically equiv to 3-endo-tet

O but cationic...

CO2Me

O OH

3. N -(PSPTH) OH

H R' R C O R R

Li

R R C O R

via 3-endo-tet

R R C O R

R R C OH R
homolytic, intermol. recomb.

OH

anionic so can't be concerted

R C O + R R

OAc

5-endo-tet thermo

Baran Group Meeting

Breaking the Rules: "Anti-Baldwin" Cyclizations

Sarah Wengryniuk

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) Cyclic Sulfates
Enantiopure Tetrahydrofurans

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 60 100 100 40 0 0

R OBn O S O O O

R2

Pachastrissamine

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.

HO

Br

Br H

Me

HO

N3 TrO O O S O O C13H 27

1. H 2O,CH3CN, 74% 5-endo-tet 2. H 2, Pd/C, 93%

H 2N

OH

Nicolaou, K.C.; JCS Chem. Commun., 1985, 1359. Nicolaou, K.C.; JACS, 1989, 5330.

C13H 27 O Pachastrissamine
Kim, S.; OL, 2007, 9, 429.

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.

O O O O O O HO

HO OH H O H

OH

1-Benzoxepines

OH CO2Et O O S O O 1. K 2CO 3, acetone, 2. 20% H 2SO 4 THF, rt, OT O R 67%

Panda, G.; Eur. JOC, 2009, 204.

OH

OH R

CO2Et OH

THF of Amphidinolides X and Y

Vatele, J-M.; Synlett, 2007, 6, 983

THP Unit of Amphidinol 3

Oishi, T.; JOC, 2009, 74 , 8810.

7-endo over 6-exo

CSA, DCM O HO 75%

R 6-endo 0 CH2CH2CO2Me E -CH=CHCO2Me 22 82 60 92 CH=CH2 Z-CH=CHCl E-CH=CHCl

5-exo 100 78 18 40 8

Nicolaou, K.C.; JACS, 1989, 111 , 5335.

Baran Group Meeting

Propargyl Oxiranes

Breaking the Rules: "Anti-Baldwin" Cyclizations

Methoxy-Methyl Ethers: Use Lanthanide Metal HO O R MeO MeO M O DCM, 2d H Me OH H Me 68-96% yield; 82:18 90:10 endo:exo No metal: Exclusive exo-cyclization O La(OTf) 3 (2.2 equiv.),

Sarah Wengryniuk
OH MeO H Me O

Cobalt Complexed Propargyl Epoxides: 6-endo-tet

O HO R

Co2(CO) 8 Co

O HO

BF 3 OEt2 65-98% cis:trans (>91:9)

68-96% OH

R R= H, TMS, alkyl, ester, aryl

Hanaoka, M.; TL , 1994, 35, 2179. w/o Co: Hanaoka, M.; TL , 1994, 35, 2183.

Murai, A.; TL, 1995, 36, 8063.

Sulfones: Disfavor exo-pathway via e--withdrawing H H n-BuLi, DMPU OTBS OR OTBDPS p-TsOH, 55 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 OH

Reagent Control: Selection of Activator

Exclusive reagent control: Approach to Oxasqualenoids

CSA O or TfOH OH

TIPSOTf 5 equiv. O

OR

H HO H exo-major

up to 7:1 endo
Morimoto, Y.; ACIE, 2006, 45, 810. Se: Noto R.; Tet. , 2001, 57, 1819. S: Noto, R.; J. Het. Chem., 2001, 765.

Mori, Y.; JACS, 1996, 118 , 8158. Other ex: Mori, Y.; Chem. Eur. J.; 1997, 3, 849. Mori, Y.; TL , 1995, 40, 8019.

6-endo Cyclizations onto Activated Alkenes "-Onium Ions"

Iodonium Ions: 4-exo then RAR

Epoxysilanes: 1. DIBAL; I 2 Me 3Si HO O 2. Me 3Si C C Me n-BuLi, TMEDA; CuI, DMAP Me 3Si OH BF 3 OEt2 H HO

HO HO SiMe 3

HTIB (2.0 equiv.) I 2 (0.2 equiv.) MeOH, rt 64% Initial 4-exo then RAR

I OAc O O

HOMe O

OMe

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.
Mech on regio: Schumann; TL , 1995, 36, 8771.

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 HO R

CO2Me N Ns

NBS (1.0 equiv.) CSA (0.1 equiv.) THF, 0 C

O Ph Br

CO2Me N Ns

>20:1 dr >20:1 endo:exo in most cases

Moitessier, N.; JOC, 2013, 78 , 872.

Baran Group Meeting

Random Other Methods

Breaking the Rules: "Anti-Baldwin" Cyclizations

Sarah Wengryniuk

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 [CoIII(salen)] Complex: Regio- and Kinetic Res. O 1 mol% cat. O OH ( )n TBME ( )n OH tBu 95% ee, 46% W(CO)5
Gasparrini, F.; OL, 2005, 7 , 4895.

"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
107

required trajectory not possible

Co O O OAc tBu tBu

H N

H N

tBu

4-endo-trig: Examples using heteroatom nucleophiles XO Ph Ph R1 OH R2 N N Br + R1 R 2 Br R R R COYH Y= O, N X-= PF 6 or SbF6

-

oxetanes 48-78% yield azetidinones 43-45% yield

Jacobsen, E. N.; ACIE, 1999, 38, 2012.

Ph Br

Y O

Catalytic Antibody Catalysis HO + Ab O Kinetic Res. and excl. 6-endo

oxetanones 23-85% yield

O HO

No Ab

HO

Rousseau, G.; TL , 2001, 42, 2477. Rousseau, G.l JOC, 1999, 64, 81.

R Racemic
-O

Racemic 5-exo only

5-endo-trig Alabugin suggests aromatic character to 5-endo t.s.: lone pair, -bond, -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.

Antibodies produced by immunization of mice with compound to mimic t.s.:

N+ R

Lerner, R.; Science, 1993, 259, 490.

Baran Group Meeting

Unsaturated Sulfones:

Breaking the Rules: "Anti-Baldwin" Cyclizations

Sarah Wengryniuk

Nucleophilic Cyclizations: EWGs at 4-position SO2R RO 2S O R R EtO 2C EtO 2C SO2R KH CO2Et 65% R CO2Et R SO2R

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

KH cat. THF, 10 min 81-88%

HO R R OH CO2Me R

OH R R

I 2, NaHCO 3 63%

HO R O R

HO O NMe 3+
Knight, D.; Eur. JOC; 2004, 1973.

Knochel, P.; TL , 1985, 26, 4455.

Tandem Intermol-Michael then 5-endo-trig to pyrrolidines

SO2Ph

RNH 2

SO2Ph SO2Ph RHN

SO2Ph 5-endo 2. base N R

Padwa, A.; JOC, 1990, 55, 4801.

Mercuronium-mediated 5-endo: (+)-Castanospermine and analogues

NHBn O OH
OBn

SO2Ph

1. Hg(OAc) 2, NaBH 4 O 2. NaH, BnBr 66%

NBn H OBn

O
OBn

HO

N OH OH

Total Synthesis of ()-Lepadiformine

O SO2Ph HO N OBn SES R N

()-Lepadiformine
Craig, D.; ACIE, 2007, 46, 2631.

H HO

PhO 2S SESHN R

n-BuLi (2 eq.) BnOCH 2CHO, then PhCOCl

Dhavale, D.; JOC, 2006, 71 , 4667.

Iminium and Oxonium Cyclizations:

Ring-expansion/Iminium 5-endo to ()-Spirotryptostatin B

R + N H O

R N

MgI 2, THF 75 C

R N

5-(enolexo)endo-trig

Nitro-group

NO 2 Ar O2N

O2N Ar RNH 2 85-98% Ar N H

NHR Ar

1. PPTS 2. DDQ ~50%, 2 steps

O2N Ar N H Ar

TIPS R N HN O

N H O

TIPS

Tavani, C.; Eur. JOC, 2000, 903.

N N O H
()-Spirotryptostatin B
Carreira, E.; JACS, 2005, 127 , 11505.

-CF3 group: Fluorinated hetereocycles

CF 3 R HY R Base 57-96%

F 2C Y

R or R

F 3C Y

R R

F 2C or

R R

N H

TIPS

Y= O ,NTs, S Y= C(CO 2Et 2 ), C(CN) 2

Ichikawa, J.; Chem. Asian J., 2008, 3, 393.

Baran Group Meeting

O R N MeO MeO O HN O H H

Breaking the Rules: "Anti-Baldwin" Cyclizations

H N MeO N MeO O H

Sarah Wengryniuk

Pictet-Spengler to 2,5-Diketopiperazines: "MUPS" Sequence

TFAA, 1:1 TFA/DCM 60%

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.
Diastereoselective C-2 Alkenylation of Indoles via 5-endo "Fujiwara-Moritani"

R Pd(OAc) 2, Lig., O2 N O R NMe R mesitylene, t-BuCO2H, 120 C 47-99% conv.

R R N O R
Oestreich, M.; ACIE, 2012, 51, 1265.

Orru, R.; Chem. Commun., 2010, 46, 7706.

O-nucleophile onto Iminium: ()-Quinocarcin

H N

SEt NCbz AgBF4 H N O OTIPS O

CHO

CO2H H N OMe O

Unexpected result in synthesis of Teleocidin B NCbz Pd(OAc) 2, dppe, 2.5h 94%

Zhu, J.; JACS, 2008, 130 , 7148.

TfO

N H

CO2Et

N H

CO2Et

5-(enolendo)-exo/endo-trig
Onto an oxonium: THFs from 1,3-Dioxolan-4-ones
Tanner, D.; Synlett, 2006, 18 , 3140.

O R O

R1 R2

iBu 3Al 55-91%

Bu 3AlO R O R2 R1

HO R1 R O R2

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 Br 1. Bu 3SnH, AIBN 2. HCl 67% overall CO2Et O Without subtituents or with gem-dimethyl, no cyclization was observed. CO2Et
Jung, M.E.; TL , 1992, 33, 6719.

Petasis, N.; JACS, 1995, 117 , 6394.

5-(enolendo)-exo-trig in Co-mediated O-->C Rearrangement

Ph Et 2AlCl (3.0 equiv.) 47-57%

OPh Co(CO) 3 R O

O Ph

Co2(CO) 6 R

(OC) 3Co

Other approaches: Substituent effects still important O O Titan. (10mol%) SmI2 OH Mn (2 equiv.) H CO2Et

OH CO2NMe

R
Harrity, J.; JOC, 2005, 70 , 10046.

Proctor, D. Synlett, 2012, 23, 6.

CO2Et

CONMe2
Ganauser, A.; JACS, 2008, 130 , 1788.

Baran Group Meeting

O OTMS CHO O

Breaking the Rules: "Anti-Baldwin" Cyclizations

OH O H MeO O HO O H CO2H

Sarah Wengryniuk
H SPh R N O N no rxn CO2Me

4-exo-trig-rad: Synthesis of strained ring of Solanoeclepin SmI2 76% OH 5-endo-trig-rad:

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. First "successful" example: Similar substrates don't work
O

Carbamoylmethyl Radicals: By far most common approach

OTMS

SPh SPh N O

Bu 3SnH, AIBN 59%

Ishibashi, H.; TL , 1991, 32, 1725.

Nishikawa, T.; Chem. Lett., 2012, 41, 287.

Carbamoylmethyl Radicals: Hydrazone Derivative

Ph N

Ph N Ph

Me Br O

Bu 3SnH, AIBN 92%

Ph HN

Ph N Ph

Me O
Krause, J.; TL, 1993, 34, 797.

CN CO2Et (PhCO 2)2 Cy,

CN CO2Et 30%

CN CO2Et

same cond. No dp

Carbamoylmethyl Radicals: Attempt at stereoselectivity

Br O N Bn O O

Ph Bu 3SnH, AIBN 26% 71% de O N Bn O OR*

Julia, M.; Bull. Soc. Chim. Fr., 1965, 1550.

Aided by radical stabilizing group: leads to high yields

O Br

Bu 3SnH, AIBN 97%

Parsons, A.F.; TL , 1997, 38, 491.

1,4-Pentadienyl-3-sulfonamides: Cascade sequences

O
Reddy, K.M.; TL , 1993, 34, 2665.

I N Ms OMe OMe

Bu 3SnH, AIBN 5-exo-trig N Ms

H 30% 5-endotrig N H Ms

Aided by radical stabilizing group: Reverse regioselectivity of SmI2

O Me OMe OMe SmI2, THF HMPT 66%

HO Me R R Si H O

Murphy, J.; OL, 2001, 3, 3405.

Silicon Radical: Prostaglandin Synthesis

Bats, W.J.; ACIE, 1995, 34, 2383.

Carbamoylmethyl Radicals: By far most common approach

SPh SPh N O

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, , -unsaturated carbonyl

SePh

Bu 3SnH, OBn AIBN 5-exo-dig 1,5-H trans.

R R Si O

OBn

5-endotrig 75% H

R O Si

R OBn

CO2Me

CO2Me

H CO2 Me

Clive, D.; JOC, 1999, 64, 2776.

Baran Group Meeting Breaking the Rules: "Anti-Baldwin" Cyclizations

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 Baldwin says: -dig endo exo Nuc, Elec, Rad 3 y n 4 y n 5 y y 6 y y

Sarah Wengryniuk

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.

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. Hope for development of a 3-exo-dig radical method? vs. Significant drop in endothermicity suggets that a properly designed system Ph may be able to shift equilibrium. E r 2.4 kcal/mol

"Favored" Trajectory for Digonal Closure XBaldwin Acute angle of attack 60 60 XObtuse angle of attack 120

X
120

based on X-ray studies and preference for endo- closure theoretical calculations, avoidance of *-nodal plane, analogous to Burgi-Dunitz angle

E r 8.2 kcal/mol Anionic 3-exo-dig

Revised

120

X
120

Carbon Nucleophile: Vinylidene Cyclopropanes from E--deficient Alkenes OTBS CO2Me

n

The obtuse trajectory should translate into stereoelectronic preference for exo-cyclization as opposed to endo! Stereoelectronic Differences in Nucleophilic vs Electrophilic Cylization Nucleophilic LUMO NuNuLUMO Electrophilic HOMO E+ + Nuc: Secondary orbital interaction is destabilizing Elec: Secondary orbital interaction is stabilzing

O TBAF I THF, rt 62-95% X

n

O CO2Me I X
n

CO2Me

H H

R X= C, O

R= i-Pr, H,

Endo

Johnson, J.; JACS, 2008, 130 , 9180.

Exo

Oxygen Nucelophile: Vinyl Oxiranes OH HCl, EtOH N N N H H O N N N N N H OH HCl, EtOH N N H H O N N H

Endo/Exo

Three Modes of Cyclization to Consider E+ E+

Nu

Electrophilic Closure

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)

Bonus: 4-exo-dig (10% conv.)

Baran Group Meeting

Br R2
+

Breaking the Rules: "Anti-Baldwin" Cyclizations

4-exo (Disfav.) vs. 5-endo (Fav.):
Me Br R2 Me NAc

Sarah Wengryniuk

Nitrogen Nucleophile: Vinyl aziridines via electrohalogenation of propargyl amides

R2

Me 2eMe NHAc NaBr/H 2O 76%

Me Me NHAc

-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 1. Bu 3SnH, AIBN O Si Br Bu 3SnH HO H Si Bicyclo[3.1.1]Heptanes MeLi H O Si 4-exodig 5-exo-dig 2. 1,6-H transfer O Si 6-endotrig O Si

Torii et. al.; J. Org. Chem., 1992, 57, 5023.

4-endo-dig??? Despite being "Favorable" by Baldwins rules, these types of nucleophilic cyclizations remain unknown. This is not surprising based on activation barrier: vs. Ea E r Cationic 7.8 -4.5 27.0 -13.0 ~20 kcal/mol higher barrier to activation for 4-endo, which overrides the fact that it is ~7kcal/mol more exothermic than 3-exo

Alabugin, I. et. al.; JACS, 2011, 133 , 12608. Hanack, M.; JACS, 1974, 96, 6686. Hanack, M.; JOC, 1983, 48, 5260. Wilson, J.W.; JACS, 1969, 91, 3238.

3-exo-dig vs. 4-endo-dig 1 carbocation: Controlled by substitution on alkyne: Example of NPEC R Nf R ROH, H 2O R 3-exo : 4-endo H Me Ph An 0:100 1:99 31:17 57:43 R -OR ROH, H 2O Br

Malacria, M.; JACS, 1997, 119 , 5037.

Carbamoyl Radicals via photolysis of carbamotelluroates O Bu N TeAr h PhCH 3 110 C R R Bu N O 4-exodig ArTe R O N Bu exclusive 4exo. only trace 5endo when R=Et

3-exo : 4-endo 0:100 1:89 -------54:4

Kambe, N.; TL , 2009, 50, 3628.

2/3 carbocations: Similar behavior to 1 or lack of cyclization X CF 3CO2H O OH CHO2H OCOH O +

O Bu N YPh Pd(PPh 3)4 (5 mol%) toluene, 59-88% yield R Y= S, Se PhY

O N

Bu **Not Radical but related transformation. 4-exo via Pd

Kambe, N.; JACS, 2005, 127 , 9706.

Baran Group Meeting

Breaking the Rules: "Anti-Baldwin" Cyclizations

Double Synchronous 5-endo-radical cyclization

Sarah Wengryniuk

5-endo-dig: Examples employing O, S, Si, C 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!
O and S require flash vaccum pyrolysis

Other Examples of Proposed 5-endo-dig radicals: O Ar 4 equiv. LiNaph 52% Ar O Ar OH Ar 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.

Li

O Ar

Double synchronous 5-endo-dig

YMe PPh 3 O Y FVP, 850 C PPh3PO, Me

Y 5-endo-dig

6-endo-trig aromat.

Y= O, 36% Y= S, 28% Ar OH

Aitken, R. A.; Synlett, 1995, 53. Aitken, R. A.; JCS PT1, 1994, 2455.

Other "O" example: Barton, T.; JOC, 1985, 50, 158.

Si-Centered Radical: Intramolecular radical hydrosilylation

1. MeO Si O OMe

N N
OtBu

BuOt

Si O

Si

PhLi OH

SiR 3

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

Studder, A.; Chem. Commun.; 2002, 1592.

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

R OMe tBuLi

R R OMe

R 88% R

RO RO

Me h TsBr Me

RO RO

Me

5-endodig Br Ts

RO RO

Me Br

Bailey, W.F.; JACS, 1995, 60, 754.

Achieving 4-exo is still not easy: Stabilizing negative charge

Me

R= H, 5 or 6-mem ring
Alabugin, I.; JACS, 2008, 130 , 10984.

Ts 51-72% yield Almost exclus. Z-exoolefin

Me

Y 1. n-BuLi or t -BuLi 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.

Baran Group Meeting

O EWG Cs2CO 3 82% H O

Breaking the Rules: "Anti-Baldwin" Cyclizations

Use of an external electrophile O

Sarah Wengryniuk

Stabilization of the negative charge: 5-endo-dig onto ynone

EWG

Au: Endo-selective Conia-ene without need for substrate-mediated polarization

O CO2Me [Au(PPh 3)]OTf R DCM

CO2Me R R= H, Me, Ph 74-94% yield H

Toste, D.; ACIE, 2004, 43, 5330.

H O

Grein, F.; TL , 1986, 27, 5455.

Destabilization via electron-donating group

W(CO)5: The use of silyl-enol ether as nucleophile

PhO 2S

OEt

1. n-BuLi 2. MeI

SO2Ph OEt 96% yield

OTBS W(CO)5(THF) H 2O, THF 72%

Zn or Cu (or I 2): Oxygen nucleophile

note: Could proceed via attack on allene intermediate

Iwasawa, N.; OL, 2002, 4, 4463.

Stallman, J.B.; JACS, 1993, 115, 7023.

H R O

Producing an aromatic product: Pyrroles via 5-endo-dig then [3,3]

Ph

CO2Ph

BnNH 2, MeO 2C Ph DCE 74% Bn NH

CO2Ph

PhOCO [3,3] MeO 2C

Ph

O HN O N

ZnCl2/DCM or

CO2Me

CO2Me

CO2Me

HN MeO 2C

Garcia-Tellado, F.; ChemEur. J., 2009, 15 , 838.

N CuI/Et 3N/MeCN 60-99% O N

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.

Producing an aromatic product: Carbon Nucleophile

Cu(II), Pd, Ag or Hg: Nitrogen Nucleophile

X CF 3

RLi (4 equiv.) 40-60%

X R

X Ph

HO

Me CO2Et NHTs

Cu(OAc)2 Et 2O:pyridine 88% Ph

HO Me CO2Et N Ts

R= nBu, Pr, Ph; X=O, S, N

Strained Products: 5-endo favored

Johnson, F.; JOC, 1986, 51, 5040. For related N-nuc: Knochel, P.; ACIE, 2000, 39, 2488.

Cu, Pd, Hg: Knight, D.W.; Synlett, 2004, 1 , 119.

Ar Ag(OTf) Ph H2 Ar N CO2Me Pd/C Ar N H CO2Me

Ph Br nBuLi Ph vs. not seen HN CO2Me Boc

MeCN 54-80%

Rujes, P.J.T.; JOC, 2005, 70 , 1791.

Baran Group Meeting

Breaking the Rules: "Anti-Baldwin" Cyclizations

Modified Baldwin's Rules: X Y 6-exo-tet Favored Y X 6-endo-tet Disfavored

Sarah Wengryniuk

Baldwin's Original Rules: Apply to Nuc -, Rad, Elec + X X

TET

Y 3-exo-tet Favored Y X 3-endo-tet ????

Y 4-exo-tet Favored Y X 4-endo-tet ????

Y 5-exo-tet Favored Y X

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 TRIGONAL Anionic endo exo Radical endo exo Cationic endo exo DIGONAL 3 X F 3 X F 3 X F 4 F 4 X F 4 X F 5 F 5 F 5 F 6 F F 6 F F 6 F F 3 X --4 --5 F 6 F

5-endo-tet Disfavored

X TRIG

3-exo-trig Favored Y X 3-endo-trig Disfavored

Y 4-exo-trig Favored Y X 4-endo-trig Disfavored

Y 5-exo-trig Favored Y X

Y X 6-exo-trig Favored Y X 6-endo-trig Favored

5-endo-trig Disfavored

X DIG Y 3-exo-dig Disfavored

X Y 4-exo-dig Disfavored

X Y 5-exo-dig Favored

X Y 6-exo-dig Favored

Anionic endo exo Radical endo exo Cationic endo exo

3 X (F ) 3 X (F ) 3 X (F )

4 X (F ) 4 X (F ) 4 (F )

5 (F ) F 5 (F ) F 5 (F ) F

6 (F ) F 6 F F 6 F F

X Y 3-endo-dig Favored

X Y 4-endo-dig Favored

X Y 5-endo-dig Favored

X Y 6-endo-dig Favored