Recent Progress in Macrocyclizations A B

Reviews:
Recent Progress in Macrocyclizations
by Essa Hu
Evans Group Seminar
December 3, 1999
Direct ring closure:
Weber, E.; Vogtle, F. Topics in Current Chemistry; Springer-Verlag: Germany, 1992; vol. 161, pp109-176
Large ring syntheses:
Roxburgh, C. Tetrahedron 1995, 51, 9767-9822
Macrolide syntheses:
Paterson, I.; Norcross, R. D. Chem. Rev. 1995, 95, 2041-2114
Macrocyclic musks syntheses:
Williams, A. S. Synthesis 1999, 10, 1707-1723
Photochemical macrocyclizations:
Griesbeck, A. G.; Henz, A.; Hirt, J. Synthesis 1996, 1261-1276
Ester activation and peptide coupling:
Katz, J. Evans Group Seminar Dec. 1998
A B

Field of Macrocyclizations:
Defining the Scope of This Presentation*
I. Ring size: "Macrocycle" = medium rings (8-11), large rings (12+)*, supramolecules
II. Types of rings:
- natural products*
- polymers (polyethers, polyamines, etc.)
- polydentate molecules
- others
III. Approaches to ring construction:
- direct ring closure*
- ring enlargement/expansion
- ring contraction
- tandem macrocyclization-transannulation
IV. Medium of cyclization:
- homogeneous organic solvent*
- heterogeneous
- enzymatic
- solid phase
- zeolite

Ring Strain
Strain = observed heat of formation (or combustion) - calculated heat of formation (or combustion)
==> Large rings have low ring strain.
Eliel, S. T.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons: US, 1994, pg677

Kinectics of cyclizing ω−bromoacids Br(CH 2) nCO 2H :
Ease of Cyclization
Rate of Cyclization Entropy (∆S)
==> Synthesis of large rings still a synthetic challenge
To cyclize: both end terminus need to overcome their high conformational entropy
Competing routes: dimerization or oligomerization
Eliel, S. T.; Wilen, S. H. Stereochemistry of Organic Compounds pg680
Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 96, 99, 100

Other Cyclization Series
Kinetics of ring formation, comparison with related cyclization series:
EM = K intra/K inter
==> Similar ring formation kinetics for other cyclization series.
Illuminati, G. J. Am. Chem. Soc. 1997, 99, 6308-6312
Galli, C.; Mandolini, L. J. Org. Chem. 1981, 46, 3127-3128

Thorpe-Ingold Effect
==> An isolated gem dialkyl substitution has little influence on the cyclization of large rings.
Galli, C.; Illuminati, G.; Mandolini, L. J. Org. Chem. 1979, 44, 1258-1261

Promoting Intramolecular Cyclization
Ways to favor Intramolecular over Intermolecular reaction pathways:
I. High dilution effect:
=> goal: minimize the concentration of reacting species
- very low reaction concentration
- high reaction temperature
- slow addition of substrate
- heterogeneous reactions: use of a low solubility component or phase transfer catalyst
- high pressure conditions (increases viscosity of reaction medium)
- catalyst on polymer support
II. Lowering the substrate entropy via conformational control:
=> goal: bring the two reacting ends to close proximity
- rigid group principle: use of functional groups and/or protecting groups
- template-directing effect
Weber, E.; Vogtle, F. Topics in Current Chemistry; Springer-Verlag: Germany, 1992; vol. 161, pp1-36

Macrocyclization I : via carbonyl formation
O
X
Y
Lactonization & Lactamization
Industrial approaches
Activated ester methods
Corey Method
Mukaiyama Method
Keck's modified procedure
Masamune Method
Mixed anhydride methods
Yamaguchi Method
BOP-Cl
Mitsunobu Method
Ketene trapping method
β-lactam opening
Photocyclization
O
Ketone Formation
Free-radical cyclization
Stork-Takahashi Method
Z

"Story" synthesis
for synthesis of Exaltolide, most widely produced macrocyclic musk lactone, 200 tons 1996
O
H 2O 2
H +
Industrial approaches: thermal decomposition
O
OOH
O OOH
O
CuSO 4
O
O
O O
O ∆
O
Story, P. J. Am. Chem. Soc. 1968, 90, 817; J. Org. Chem. 1970, 35, 3059
Story, P. US Patent 3925421 1973, Research Corp.; Chem. Abstr. 1976, 84, 73673
Story, P. US Patent 3776926 1968, Research Corp.; Chem. Abstr. 1972, 77, 61273
+
O
O

OH
OH
O
O
OH
OH
∆
-H 2O
polymerization
HO
Industrial approaches 2: distillation
OH
K 2CO 3
Carothers, W. H. US Patent 2020298 1935, DuPont de Nemours & Co.; Chem. Abstr. 1939, 33, 7816
Carothers, W. H. J. Am. Chem. Soc. 1936, 58, 654
Collaud, C. US Patent 2417151 1941, Givaudan-Delawanna Inc.; Chem. Abstr. 1941, 35, 3649
Collaud, C. Helv. Chim. Acta 1943, 26, 849 and 1155
Kohler, G. EP Patent 739889 1996, Huls A.G.; Chem. Abstr. 1996, 125, 329885
OH
O
O
H
] n
OH
] n
depolymerization
catalyst, vacuum
distillation
catalyst examples: Bu 2SnO, MgCl 2, Zn(OAc) 22H 2O, Ti(OBu) 4, PbO, (MeO) 3Al
OH
O
O
OH
OH
vaccum
distillation
HO
+
OH
(recycled)
O
O
OH
O
O

Yamamoto's Method
Yamamoto: "To our knowledge, this is the most selective monomeric lactonization method available..."
ring size
7
8
9
10
11
12
13
14
15
16
17
HO(CH 2) nCO 2H
Sc(OTf) 3
(mol%)
20
20
20
20
20
10
10
10
10
10
10
Sc(OTf) 3 (10-20 mol%)
(p-NO 2C 6H 4CO) 2O (2 eq.)
CH 3CN : THF = 168 : 10
< 0.005M , reflux
addn
time (hr)
15
15
15
15
15
15
6
15
15
9
9
reaction
time (hr)
5
5
5
5
5
0
0
5
5
0
0
lactone + diolide
yield (%)
lactone
>99
71
52
87
77
78
91
94
99
99
92
yield (%)
diolide

Lactonization Comparisons
Yamamoto, H. J. Org. Chem. 1996, 61, 4560-4567

HO
HO
O
+
N S S N
Ph 3P
original paper: Corey, E. J. J. Am. Chem. Soc. 1974, 96, 5614
2-thiopyridyl chloroformate/ triethylamine: Corey, E. J. Tetrahedron Lett. 1979, 2875
AgClO 4 or AgBF 4 additive: Gerlach, H. Helv. Chim. Acta 1974, 57, 2661
alternative disulfides: Corey, E. J. Tetrahedron Lett. 1976, 3409
Me
Me
Me
OH
Me
OH
HOOC
Me
Me
Me
OH
O
O
Me
Me
t Bu
Corey Method
N
N
iPr iPr
S S
N
N
N H
O
Ph 3P, toluene; ∆; (50%)
S
t Bu
O
Me
Me
Me
O
O
O
OH
Me
O
Me
+
Me
HN
Me
OH
O
O
to Erythronolide B
S
Me
Me
Corey, E. J. J. Am. Chem. Soc. 1978, 100, 4620

HO
HO
O
+
Me
N Cl Et3N I
N O
Me
original paper: Mukaiyama, T. Chem. Lett. 1976, 49
2-chloro-3-methoxymethyl-1-methylpyridinium iodide: Mukaiyama, T. Chem. Lett. 1977, 763
2-chloro-6-methyl-1,3-diphenylpyridinium tetrafluoroborate: Mukaiyama, T. Chem. Lett. 1978, 885
6-phenyl-2-pyridyl esters: Mukaiyama, T. Chem. Lett. 1977, 441
Me
O
O
Me Me
Me
S
O
NH
OMOM
NH 2
O
OMe
OH
Mukaiyama Method
O
HO
MuKaiyama Salt
toluene-THF, Et 3N
(61%)
Me
O
O
Me Me
Me
O
S
O
O
NH
MOMO
O
+
NH
to (+)-Thiazinotrienomycin E
N
Me
OMe
Smith, A. B., III Organic Lett. 1999, 1, 1491-1494
O

TBSO
Keck's Method
Keck's modified Steglich esterification
DCC: Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522-524
DCC, DMAP, DMAP-HCl : Keck, G. E. J. Org. Chem. 1985, 50, 2394
Me
DEIPSO
Me
H
Me
O
HO
H OH
H
H
H
O
H
Me
Me
OTES
OPMB
to Cytovaricin
O
Me
OTES
Evans, D. A. J. Am. Chem. Soc. 1990, 112, 7001-7031
O
O
OTES
Me
O
Si( t Bu) 2
H H
MeO
O
Me
OTES
H
H
Mukaiyama's method did not work
Keck's method: (92%)
DCC, DMAP, DMAP-HCl, CHCl 3, 61°C
TBSO
Me
DEIPSO
Me
Me
H
O
H
H O
H
H
H
OPMB
O
Me
O
Me
OTES
Me
O
O
Me
OTES O
OTES
Si(
H H
MeO
O
Me
OTES
H
H
t Bu) 2

HO
HO
O
Cl
HO
O
Or
EtO
EtO
Masamune Method
O
P
O
HO
O
TlS t Bu
t BuS
original paper: Masamune, S. J. Am. Chem. Soc. 1975, 97, 3512
copper(I) triflate - benzene complex additive: Huang, J.; Meinwald, J. J. Am. Chem. Soc. 1981, 103, 861
benzenethiol ester: Masamune, S. J. Am. Chem. Soc. 1977, 99, 6756
PhSCO OH
MeO
O
OSEM
Me
O
O
Me
O
H OMOM
to synthesis of Chlorothricolide
Na 2HPO 4, AgOTf,
benzene, ∆; (75%)
- Corey's method did not work
- mixed phosphate anhydride
did not work
HO
O
O
O
MeO
O
Hg(TFA) 2
OSEM
Me
O
O
Me
O
H OMOM
O
O
Ireland, R. J. Org. Chem. 1986, 51, 635

Me
Yamaguchi's Method
2,4,6-trichlorobenzoyl chloride: Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993
modified DMAP concentration and reaction temperature:
Yonemitsu, O. J. Org. Chem. 1990, 55, 7-9;Tetrahedron 1990, 46, 4613-4628
problem with olefin isomerization:
Keck, Mukaiyama, and Corey methods all afforded unfavorable ratios
only 'promising' lead, Yamaguchi's original procedures (1:1)
TBSO
Et
to Rutamycin B
HO O
H
Me
O
Me
H OH Me
H O
H
Me Me
H
O
TBSO
OTBS
Me
O
Me
OTBS
Me
Evans, D. A. J. Am. Chem. Soc. 1993, 115, 11446-11459
Me
TBSO
Cl 3C 6H 2COCl, DMAP,
Et 3N, PhH, 23°C
(86%, exclusively desired)
Me
H
O
H O
H O
H
Me
H
Et
O
O
TBSO
+
Me
Me
Me
O
Me
O Me
OTBS
Me
O
Me
OTBS
OTBS
Me

Et
OH
HO
Yamaguchi 2 : effect of temperature and addition time
O
Me
H
T
(°C)
25
70
110
110
OTIPS
OTES
SnBu 3
addn time
(hr)
0.5
0.5
10
1
1) 2,4,6-trichlorobenzoyl chloride
Hunig's base, THF, rt
2) DMAP, 0.007M in toluene
macrocycle
prod (%)
13
63
10
78
destannylated
monomer (%)
0
7
63
3
Et
O
O
Me
to (+)-Lepicidin A
dimer
(%)
33
10
1
3
H
OTIPS
OTES
SnBu 3
Evans, D. A. J. Am. Chem. Soc. 1993, 115, 4497-4513

Me
Me 2CH
OH
HO 2C
O O OTBS O O
Evans, D. A.; Connell, B. T. unpublished results
Yamaguchi 3: mild conditions
O
Me
O
Me
Me 2CH
Keck and Mukaiyama methods did not work
2,4,6-trichlorobenzoyl chloride,
Et 3N, THF; DMAP, benzene, rt, 2hr
(66%)
O
O
O O OTBS O O
to Roxaticin
O
Me
O

Me
Me
HO
Me
Me
OH
Me
O
Et OH
Me O
Me
Me
Me
MeO
O
PMP
Me
Me
O
COOH
2,4,6-trichlorobenzoyl chloride, Et 3N,
pyridine; DMAP, toluene, reflux, 5hr
(>85%, 14 membered isomer only)
CO 2H
Me OMe OH OH
an approach to Aplyronine A
Yamaguchi 4: regioselectivity
- Corey method did not work
25
Me Me
OTIPS
Me
Et
Me
HO
O
Me
Me
O
Me
O
Me
OH
O
Me
Me
to 9-Dihydroerythronolide B Derivatives
Mulzer, J. J. Am. Chem. Soc. 1991, 113, 910-923
(79%, only the larger macrocycle)
Paterson, I. Tetrahedron Lett. 1998, 39, 6041-6044

Me
O
OMe
Me
O TBSO
Ar
Me
Me
O
23
21
Me
OH
OH
O
OH
Paterson, I. Tetrahedron 1995, 51, 9467-9486
Yamaguchi 5: regiocontrol?
Yamaguchi procedure (in toluene)
Keck's procedure (in chloroform)
Keck's procedure (in toluene)
OMe
O
Me
Me
C 21 : C 23
82 : 18
05 : 95
40 : 60
O
OMe
Me
O TBSO
Ar
Me
Me
O
23
21
Me
yield (%)
92
94
73
O
to hemiswinholide A
OH
O
OMe
O
Me
+ C 23 isomer

OTBS
OTBS
H
Me
R
Me
H
Me
OTBS
9
O
Me
OTBS
Me
Me
Me OH O
HO2C O
Me
Me
Me
9S :
9R :
Yamaguchi 6: stereochemical effect
Yamaguchi
yield
60%
0%
Me
Me
R 1
Me
R 2
HO 2C
O
9R
O
Me
OH
Me
O
O
Me
O
Me
Me
R 1 = Me, R 2 = H :
R 1 = Me, R 2 = Me :
78%
0%
H
Me
Yamaguchi
yield
O
O
R 1
Paterson, I. J. Am. Chem. Soc. 1994, 116, 11287-11314
R 2
Me
H

Hydroxyl activation:
O
O
EtO N N OEt
O
O
Ph 3P
Ph 3P
O
O
EtO N N OEt
O
O
Mitsunobu Cyclization
PPh 3
O
+ HO
O
O
HO
EtO N H N H
original papers: Mitsunobu, O. Synthesis 1981, 1; Mitsunobu, O. Tetrahedron Lett. 1976, 2455
N, N-dimethylformamide dineopentylacetal: Vorbruggen, H. Angew. Chem. Int. Ed. Engl. 1977, 16, 876
O
+
O
OEt
EtO N N H
H
O
PPh 3
O
O
O
OEt

O
BMPN
O
HO2C Me
OH
OMe
HO 2C
S
H
O
BMPN
O
Me
OMe
S
HO 2C
H
OH
Me
Mitsunobu (cont'd)
PPh 3, DEAD, PhH, rt
(69%)
(31%)
HO 2C
O
BMPN
O
BMPN
O
O
OMe
O
Me
OMe
S
O
H
S
H
O
O
Me
Me
to (+)-Latrunculin B
to (+)-Latrunculin A
Smith, A. B., III J. Am. Chem. Soc. 1992, 114, 2995-3007

Generating β-keto lactone:
Me
Me
OH
Me
OH
Me
O
O O
Me
O
Intramolecular Ketene Trapping
Me
Me
Me
(10 -4 M) toluene, ∆, 4.5hr
(70%, only product)
Me
Me
O
O
OH
Me
O
Me
Me
O
Me
to (-)-Kromycin
Boeckman, R. K., Jr. J. Am. Chem. Soc. 1989, 111, 8286-8228

Transesterification of trichloroethyl ester:
Me
O
NHBoc
O
O
BocHN
O
O
O
Me
CO 2CH 2CCl 3
HO
O
Me
NHBoc
(10-20 eq. solid K 2CO 3)
solvent conc. (M) time (d) yield (%, 1: 2)
CH 2Cl 2 0.002 5 74 : 10
toluene 0.002 1 64 : 11
CH 3CN 0.002 1 38 : 62
THF 0.002 1 88 : 12
THF 0.005 2 69 : 07
THF 0.01 1 60 : 10
THF 0.1 1 24 : 26
Template-Directed Macrolactonization
Me
O
NHBoc
O
O
BocHN
O
O
O
Me
O
O
O
Me
NHBoc
+
NHBoc
(10-20eq. solid salt, 0.002 M, in THF)
salt time (d) yield (%, 1 : 2)
K 2CO 3 1 88 : 12
Li 2CO 3 4 0
Na 2CO 3 4 0
Cs 2CO 3 8 hr 52 : 20
KOAc 3 47 : 0
KI 3 hr 65 : 0
NaI 4 0
KBPh 4 3 0
Burke, S. J. Org. Chem. 1998, 63, 2715-2718
O
1 2
Me
O O

Various esters for cyclizations:
Me
O
NHBoc
O
O
BocHN
O
O
O
Me
CO 2R
HO
O
Me
NHBoc
R
CH2CCl3 methyl
allyl
benzyl
Template-Directed 2
Me
O
time (d)
1
2
5
5
NHBoc
O
O
BocHN
- Reaction conditions also do not promote intermolecular transesterification.
O
O
O
Me
O
O
O
Me
NHBoc
1
yield (%, 1:2:3)
88 : 12 : 0
18 : 50 : 20
39 : 28 : 17
37 : 16 : 17
+
NHBoc
NHBoc
O
Me
O O
O
OH
Me
OH
Burke, S. J. Org. Chem. 1998, 63, 2715-2718
2
O
3

Counterion effect and substituent effect:
O
O
O
O
O
O
CO 2CH 2CCl 3
HO
(10 eq. solid salt, 0.002 M, in THF)
salt time (hr) yield (%)
K2CO3 2 90
Na2CO3 36 73
Cs2CO3 1 93
KOAc 1 96
KI 2 81
NaI 10 min 90
LiI 18 10
KBPh4 24 0
O
Template-Directed 3
AcO - M +
(equiv)
O
O
O
conc
(M)
O
O
O
O
O
O
18-C-6
(equiv)
time
(hr)
yield
(%)
K (0.5) 0.002 0 1 100%
K (0.5) 0.002 1 24 97
K (0.05) 0.05 0 1 87
Bu 4N (0.5) 0.002 0 8 trace
Bu 4N (0.5) 0.002 1 18 trace
Burke, S. J. Org. Chem. 1998, 63, 2715-2718

Norrish Type I cleavage to dienyl ketene:
PhO 2S
O OAc
(CH 2) 10
via
Me
H OH
Photolactonization
hv (λ>340nm), CCl 4,
N-Methylimidazole, 30min
(69%, 2.5 : 1 isomers)
H
Me
O
OH
SO 2Ph OAc
H
Me
O
O
SO 2Ph
to aspicilin
OAc
Quinkert, G. Angew. Chem. Int. Ed. Engl. 1987, 26, 362
Quinkert, G. Tetrahedron Lett. 1991, 32, 7397

BocN
O
Me
Me
S
N
OH
β-Lactam Based Macrocyclization
O
Me
Me
O
Br
(0.002 M)
BocHN
conditions (equiv) temp (°C) yield (%)
NaHMDS (1.1), THF, 45min -40 37
LiHMDS (1.1), THF, 2.5hr -40 11
NaH (1.1), THF, 1hr -10 42
0.5-0.6 M KCN, DMF, 1-2hr 25 52-72
Et 4NCN (9.0), CH 2Cl 2, 4-9hr 25 59-68
O
Me
O
S
N
Me
O
Me
Me
O
Br
to (-)-Pateamine A
Romo, D.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237-12254

MeO
MeO
Me
OMe
Me
OTBS
Me
HO
OMe 2C
OMe
NH 2
Me
Me
BOP-Cl, Hunig's base
toluene, 85°C
(67%)
BOP-Cl = N, N' - bis(2-oxo-3-oxazolidinyl)phosphinic chloride
O
O O
O
N
P N O
Cl
Macrolactamization
MeO
MeO
Me
Me
OTBS
OMe
O
Me
OMe
OMe
NH
Me
Me
to (+)-Macbecin I
Evans, D. A. J. Org. Chem. 1992, 1067
Evans, D. A. J. Org. Chem. 1993, 471

Ph
Me
O
Me
Me
O HN
O
O O
Me
Intramolecular Aminolysis of Trichloroethyl Esters
Me
NH 2
O
O
CCl 3
Cl
OMe
catalyst, 20°C,
(0.02 M) toluene
catalyst equiv
Ph
Me
O
Me
Me
%conv
t=6hr
O HN
O
O N
H
Me Me
%conv
t=25hr
none -- 3.1 15
HOBt 0.5 -- 36
Imidazole 0.5 -- 22
iPr 2NEt 0.5 7.6 --
Pyridine 0.5 4.9 --
DMAP 0.5 4.8 --
2-Hydroxypyridine 0.5 42 >99
nBu 4N Benzoate 0.1 37 87
TFA 1.0 00 00
O
O
to Cryptophycin-51
Fray, A. H. Tetrahedron: Asymmetry 1998, 9, 2777-2781
Cl
OMe

TBSO
Me
O NH
Me
O
O
O
Me Cl
Stork-Takahashi Cyanohydrin Cyclization
Me
CN
OTMS
1) LiHMDS, THF, -78°C
2) AcOH, THF-H 2O, NaOH
(61%)
TBSO
Me
O NH
Me
O
O
Me
Takahashi, T. J. Org. Chem. 1986, 51, 3393
Takayanagi, H. Tetrahedron Lett. 1990, 31, 3317
Kende, A. S. J. Am. Chem. Soc. 1995, 117, 8258-8270
O
Me
O
to Lankacidin C

PhSe
O
O
Me
Me
O
Acyl Radical Cyclizations to Ketones
Me
O
Me
COSePh
Bu3SnH, AIBN/PhH
reflux, 1.5hr
O O
(40%, 1:1 dr) Me
Bu 3SnH
AIBN
(70%)
Me
Me
Me
approach to Lophotoxin
Pattenden, G. Synthesis 1992, 101-105
O
O
Boger, D. L. J. Am. Chem. Soc. 1990, 112, 4008-4011
O

Me
Me
O
H
Macrocyclization II: via C-C bond formation
OMOM
SnBu 3
C(Sp 3 ) - C(Sp 3 )
Metal mediated nucleophilic addition to carbonyl
Cr and Nozaki-Kishi
Alkenylboron / alkenylzinc
Ti Aldol
Sulfone coupling
Michael addition
Free-radical cyclization
C(Sp 2,3 ) - C(Sp 2,3 )
Stille coupling
Suzuki coupling
aryl-aryl coupling
BF 3•OEt 2, CH 2Cl 2
-78°C
(88%, 88:12 cis/trans)
Me
Me
OH OMOM
to Cembranolide
Marshall, J. A. J. Org. Chem. 1988, 53, 1616-1623

OHC
H
OHC
H
H
H
Intramolecular Nozaki-Kishi Reactions
Me
Me
O I
O
O I
O
CrCl 2, Ni(acac) 2
DMF
(61%, 4: 1 dr)
HO
HO
(70%, >10: 1 dr) O
H
H
H
H
O
to (+)-brefeldin C
Schreiber, S. L. J. Am. Chem. Soc. 1988, 110, 5198-5200
O
O
Me
Me
major isomer
major isomer

Me
O
O
O
CO 2CH 3
CHO
but these wouldn't cyclize...
Me
O
O
O
CO 2CH 3
CHO
Me
Me
Cr(II) Mediated Macrocyclization
SiMe 3
Br CrCl 2 (20equiv),
THF, rt, 4A mol sieves
(25%, single isomer)
via
Me
O
O
R
R
H
Me
H
O
O
L
Cr
L
CO 2CH 3
CHO
Me
Me
Me
O
Me
O
O
O
CO 2CH 3
OH
Me
to furanocembranolides
O
Paquette, L. A. J. Am. Chem. Soc. 1992, 114, 3926-3936
O
CO 2CH 3
CHO
Me
Br

Catalyst control:
O
O
O
Stereodirecting effects:
O
O
Me
O
Oppolzer, W. J. Am. Chem. Soc. 1993, 115, 1593-94
Oppolzer, W. Tetrahedron Lett. 1995, 36, 2607-2610
H
H
Alkenyl Zinc Macrocyclization
(c-hex) 2BH, hexane, rt;
Et 2Zn, 1 mol% (-)-DAIB;
(52%, 79% ee)
same
as above
O
Me
HO
O
matched case
(-)-DAIB
60%y, 82%de
to (+)-Aspicilin
O
HO
O
OR
R
O
(-)-DAIB =
Me
HO
O
Me Me
Me
OH
mismatched case
(+)-DAIB
40%y, 70%de
NMe 2

- Danishefsky: "...highly novel macroaldolization..."
- tried lithium enolates, cerium enolates, (c-hex) 2BCl, Sn(OTf) 2, Bu 3SnCl, ZnCl 2, ZrCp 2Cl 2,,, none worked
- TiCl 4, Et 3N, CH 2Cl 2, -78°C afforded 21%y, 1:2 desired/undesired isomer
O
HO
Me
O
H
Me
O
H
O
H
O
OCH 3
Me
OCH 3
OTIPS
Me
O Me CHO
MeO
Me
Titanium Aldol Macrocyclization
O
Me
to Rapamycin
TiCl 3(OiPr), CH 2Cl 2, -78°C;
Et 3N; (33%)
O
HO
Me
O
H
Me
O
H
O
H
O
OCH 3
Me
OCH 3
Me
O Me
OTIPS
MeO
Me
OH
1 : 2 , desired/undesired isomers
O
Me
Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 9345-9346

O
PhO 2S
Me
PhO 2S
Me
H
Me
H 3CO
O
Me
H
O
O
Me
O
H
O
Me
Me
O
Sulfone-Aldehyde Cyclization
sodium tert-amylate
benzene, rt, 10min;
(ca. 100%)
LHMDS (1.5x)
benzene, rt, 15min
(50%, 3:2:1 diastereomers)
sodium tert-amylate did not work
HO
PhO 2S
Me
Me
H 3CO
O
Me
O
O
to Tetronolide
Takeda, K. Yoshii, E. J. Org. Chem. 1986, 51, 4735
PhO 2S
Me
HO
Me
H
O
Me
Me
O
to Terpestacin
Takeda, K.; Yoshii, E. Synlett 1995, 249-250

O
EtO 2C CO 2Et
EtO 2C
EtO 2C
H
O
Intramolecular Michael Reaction
CO 2Et
O
EtO 2C
(25%, dimers only)
Cs 2CO 3, CH 3CN;
(90%, trans fused only)
H
O
EtO 2C
EtO 2C
O
EtO 2C CO 2Et
O
EtO 2C
CO 2Et
(48%, 1 : 0 : 4 cis:trans:dimers)
Deslongchamps, P. Bull. Soc. Chim. Fr. 1995, 132, 360-370 and 371-383
H
O
O
H

X
(CH 2) n
O
Z
I
X
(CH 2) n
O
Z
X
(CH 2) n
O
Z
+
X
(CH 2) n
1 2 3 4
endo product
(to muscone)
exo product
1a) n=1, X=CH2, Z=COOEt
1b) n=0, X=CH2, Z=CONEt2 1c) n=0, X=CH2,Z= O
1d) n=1, X=CH 2,Z=
Stereoselectivity of Free Radical Cyclization
1e) n=1, X=O, Z=COOEt
N
Product Ratio
endo, 3 exo, 4
>98 (15)
10 (14)
14:1 R/S (14)
13:1 R/S (15)
2.5 (16)
O

Two different Stille macrocyclizations to (-)-Macrolactin A:
X
TBSO
MeO
TBSO
MeO
OTBS
OMOM
Y O O
Pd2dba3, NMP
DIPEA, rt
Me
SnBu 3
O
Me
O
X = Bu 3Sn, Y = I
X = I, Y = Me 3Sn
I
Stille Macrocyclization
Ph 3As-Pd 2dba 3
DMF, 60°C
(58%, 1hr)
(42%, 7days)
(50%, 5hr)
TBSO
TBSO
OTBS
O
O
Me
Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095-13096
MeO
MeO
OMOM
O
O
Me
Pattenden, G. Tetrahedron Lett. 1996, 37, 3501-3504

Bu 3Sn
SnBu 3
Me
Me
Me
I
I
O
OMe
OH
O
H OH
OMe
Me
O
Me
to Rapamycin
Me
Nicolau, K. C. J. Am. Chem. Soc. 1993, 115, 4419-4420
H
O
N
O
O
O
Me
Stille Stitching
H
20 mol% Pd(CH 3CN) 2Cl 2, DIPEA,
DMF/THF (1:1) (0.003 M), 25°C, 24hr;
(28% product, 30% recovered SM,
30% intermediate iodostannane precursor)
OMe
OH
Me
Me
Me
O
OMe
OH
O
H OH
OMe
Me
O
Me
Me
H
O
N
O
O
O
Me
H
OMe
OH

Me
Me
9
Me
7
PMBO OH O
Me
O I
9.6 : 1 (C 7:C 9 regioisomer)
Cu(I) Promoted Stille Cyclodimerization
SnMe 3
S
CO 2Cu
(0.01 M) NMP,
rt, 15min
Me
(10 equiv)
Me
Me
PMBO OH O
O
Me
Me Me
OH
80% (88% based on C 7 regioisomer)
Me
OPMB
Me
Paterson, I. Organic Lett. 1999, 1, 19-22
Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748
O
to Elaiolide
but (0.2 M) NMP afforded 42% dimer and 47% trimers
O

Me
TBSO
Me
Et
O
H
O
H O
H O
H
Me
H
I
Me
Me
TBSO
B
O O
Me
O
Me Me
Me Me
White, J. D. Chem. Comm. 1998, 79-80
Suzuki Macrocyclization
OTBS
Me
O
Me
OTBS
Me
Pd(MeCN) 2Cl 2, AsPh 3,
Ag 2O, THF
(70%)
Me
TBSO
Me
H
O
H O
H O
H
Me
H
Et
O
Me
Me
TBSO
to Rutamycin B
Me
O
OTBS
Me
O
Me
OTBS
Me

MeHN
MeO
MeHN
O
O
7
O
HO
7
HO
H
N
N
H
NH BnO
OMe
O
MeO OMe
6
O
Cl
N
H
5
OMe
O
Cl
Cl
6
O
H
N
5
OMe
O
OCOPh
Cl
NHTFA
OSO2Me Br
4
OBn
NHTFA
Aryl-Aryl Cyclization
VOF 3, BF 3•OEt 2,
AgBF 4, TFA
Zn 0 °C
(70-90%)
VOF3, BF3•OEt2 AgBF4, TFA;
Zn
(72%)
MeHN
O
MeHN
MeO
HO
O
HO
O
O
N
H
NH
Cl
O
7 OMe
MeO OMe
7
NH
6
5
Cl
OMe
OMe
Cl
H
N
O
OH O
OSO2Me Br
4
NHTFA
Evans, D. A. JACS 1993, 115, 6426; JACS 1997, 119, 3417
6
H
N
OCOPh
5
Cl
O
NHTFA
OH

C-X Bond Formation
Bis-alkylation
Macrotransacetalization
Aryl-ether coupling
C=C Bond Formation
Wittig-like cyclization
Ring Closing Metathesis
HO
OH
Br
Macrocyclization III
via exo-Ring Formation
Intramolecular Diels Alder
[3+2]
Intramolecular cyclopropanation
(0.01 M) THF,
NaH, HMPA
(80%) O
HO
to Neocarzinostatin-Chromophore
analogues
Takahashi, T. J. Org. Chem. 1991, 56, 3465-3467

O
N
H
Me
N
N
H
O
+
X X
Solvent base yield (%)
DMF Cs2CO3 56%
THF Cs2CO3 0
ACN Cs2CO3 0
DMF K2CO3 40
DMF NaH 34
THF NaH 0
toluene KOH 16
H2O NaOH 6
Cyclizations via Bis-Alkylation
O
OTr
X M
OMs
I
OMs
I
OMs
OMs
Br
Cl
0.0083
0.0083
0.029
0.029
0.058
0.029
0.029
0.029
O
N
O
addn
time (h)
72
72
60
60
60
6
60
60
Me
N
N
O
yield
(%)
56
48
66
67
53
54
68
56
OTr
to
bisindoylmaleimides
Faul, M. M. J. Org. Chem. 1998, 63, 1961-1973

Me
H H
Me
O O O
H 15C 7
CHO
Me Me
O
Me
OH
O
O
OH
Me
CO 2Me
O
O
OBn
Macrotransacetalization
Amberlyst-15, rt,
4-A molecular sieves,
(0.004 M) CH 2Cl 2
(88%, single isomer)
thermodynamic control
H H
O O O
Me Me
H 15C 7
O
OH
O
O
Me
OH
CO 2Me
O
O
OBn
to Bryostatin analogues
Wender, P. A. J. Am. Chem. Soc. 1998, 120, 4534-4535
Still, W. C. J. Am. Chem.Soc. 1993, 115, 3804-3805

O
MeHN
O
HO
MeO 2C
HO
BnO
H H
H
N
NH
7
6
N
H
Cl
O
5
OH
Br
Cl
OBn
H
N
O
OH
4
Br
6 1) Tl(NO 3) 3, Py,
NHBoc
Evans, D. A. JACS 1989, 111, 8912; JACS 1997, 119, 3419
H
N
HO
O
O
NH
THF, MeOH
2) CrCl 2
(70% overall)
HO
MeO 2C
OAllyl
Cl
O
Cl
OH
F
5
Cl
O
H
N
OBn
OBn
O
4
N
H
O
DdmHN
O
S NAr Macrocyclization
2
NO 2
NMeBoc
CH 2CH(CH 3) 2
CsF, DMSO
87%
N
H
O
O
6
5
Cl
OBn
O
Cl
H
N
O
OAllyl
O
OH
4
Br
NHBoc
NO 2
O H
BnO
OBn
OBn
HO
6
Cl
4 2
O
H
N
H
NH
O
H
N
5
O
N
H
O
H
N
O
O
O
MeHN 7
DdmHN
atropdiastereoselection
7:1 as shown
OH
NH
NMeBoc
CH 2CH(CH 3) 2

Me
O
Me
Me
O
Me
OHC
Intramolecular Horner-Emmons Macrocyclization
P(O)(OEt) 2
OTBS O O O O O O
Me Me Me Me Me Me
to Roflamycoin
Me
Me
Me
O
Me Me
O
O
O
O
O
Me
Me
Me
LiCl, DBU, CH 3CN
(44-51%, single isomer)
OTBS O O O O O O
Me Me Me Me Me Me
O
Me Me
O
O
O
Me
Me
Rychnovsky, S. D. J. Am. Chem. Soc. 1997, 119, 2058-2059

Stereodivergence in an Intramolecular Horner-Emmons Macrocyclization
(EtO) 2
P
O
O
CHO
O
O
Me
O
Me
Me
Base (equiv) Solvent Temp(°C)
O
O
O
Me
O
Me
Me
+
O
O
O O
Me
1 2
Me
Me
yields (%)
1 2
K2CO3 (6) / 18-crown-6 (12) toluene 65 62 12
K2CO3 (6) / 18-crown-6 (12) toluene 80 mix mix
K2CO3 (6) / 18-crown-6 (12) THF 65 0 0
KHMDS (1.1) / 18-crown-6 (3) toluene 25 49 3
KHMDS (1.1) / 18-crown-6 (3) CH3CN 25 22 8
DBU (10) / LiCl (10) CH3CN 25

Me
S
N
Me
H
O O
Me
Me
OR
X
Y
Me
Me
Remote Effects in RCM
50 mol% Grubbs's catalyst
(0.001 M) C 6H 6, rt, 24hr
X Y R E/Z (yield%)
α-OH α-OTPS TBS 1 : 3 (86)
α-OTES α-OTPS TBS 1 : 5 (80)
α-OTBS =O TBS 1.7 : 1 (86)
α-OH =O H 1 : 2 (65)
β-OH α-OTPS TBS 1 : 9 (81)
β-OTBS =O TBS 1 : 2 (88)
Me
S
N
Me
H
O O
Me
Me
OR
X
Y
Me
Me
to Epothilone
congeners
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 2733-2734
RCM seminar: Hu, E. Evans Seminar, Feb 1999

Me
Me
Me
Me
Ph
Me
O
O
NCOPh
Me
Ph
Intramolecular Diels-Alder Reactions
O
O
100°C (55%, 52:48 endo/exo)
O
O
NCOPh
Me
∆
(58%, only prod)
Me
Me
Me
H
Me
O
O
NCOPh
Me
Ph
H
O
Me
+
O
O
O
Me
NCOPh
Ph
Me
H
O
O
NCOPh
Thomas, E. J. Acc. Chem. Res. 1991, 24, 229-235
Thomas, E. J. J. Chem. Soc. Perkin Trans. 1 1989, 489-397
Ph
to cytochalasan

via [3+2] exo-Ring Cyclization
O
O
N
O
O
Me
O2N O
Me
OTES
O
O
Me
OMe
3-ClPhNCO, iPr2NEt, PhH, 90°C; slow addn of
substrate over 20hr
(68%, only isoxazole isomer)
Me
O
O
Me
OTES
O
O
X p
O
Me
Me
Me
OPMB
CO 2Me
X p
O
Me
Me
Me
OPMB
to (+)-Miyakolide
Me
OMe
Evans, D. A. J. Am. Chem. Soc. 1999, 121, 6816-6826
CO 2Me

Catalyst ligand and product distribution:
Me
Me
Me Me O
Catalytic Intramolecular Cyclopropanation
O CHN 2
catalyst
Rh 2(pfb) 4
Rh 2(pfb) 4
Rh 2(tfa) 4
Rh 2(NHCOCF 3) 4
Rh 2(OAc) 4
Rh 2(oct) 4
Rh 2(cap) 4
CH 2Cl 2
Me
Me
temp (°C)
25
10
25
25
25
25
40
Me
Me
H
H
yield (%)
56
60
50
60
63
50
79
O
O
+
Me
O O
Me
Me
H Me
1 2
1 : 2 trans : 2 cis
0 : 51 : 49
0 : 48 : 52
0 : 77 : 23
0 : 75 : 25
0 : 86 : 14
0 : 84 : 16
100 : 0 : 0
Doyle, M. P. J. Am. Chem. Soc. 1995, 117, 7281-7282; J. Am. Chem. Soc. 1997, 119, 8826-8837