y. ishihara erythronolide and erythromycin baran lab gm ... · y. ishihara erythronolide and...
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Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
1
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
12
3
56
89
10
1213
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
3
5612
6-deoxyerythronolide B
cytochrome P450 (C6
hydroxylase) OH
erythronolide B
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
3
5612 OH
erythronolide A
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612
mycarose glycosyl
transferase OH
erythromycin D(JACS 1977, 99, 1620)
O
NMe2
MeHO
OMe
OH
MeOH
desosamine glycosyl
transferaseO
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612
O-methyl transferase OH
erythromycin B(JACS 1957, 79, 6070)
O
NMe2
MeHO
OMe
OMe
MeOH
[O] at C12[O] at C6 and C12
HO
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612 OH
erythromycin C(JACS 1957, 79, 6074)
O
NMe2
MeHO
OMe
OH
MeOH
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612
O-methyl transferase OH
erythromycin A(JACS 1957, 79, 6062)
O
NMe2
MeHO
OMe
OMe
MeOH
HOHO
mycarose glycosyl
transferase
desosamine glycosyl
transferase
[O] at C12 [O] at C12Absolute configuration of erythromycin A was first established via X-ray analysis in Tetrahedron Lett. 1965, 6, 679.
propionyl CoA
methylmalonyl CoA (6 equiv.), polyketide synthase, β-ketoacyl reductase, β-ketoacyl dehydratase
enzyme-bound 6-deoxy-erythronolide seco acid (linear heptaketide)
cyclization upon cleavage from polyketide synthase
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
3
5612 OH
erythromycin E(Tet. 1975, 31, 1985)
O
NMe2
MeHO
OMe
OMe
MeOH
HO
O
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
3
5612 OH
erythromycin F(J. Antibiot. 1982, 35, 426)
O
NMe2
MeHO
OMe
OMe
MeOH
HO
OH
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
3
5612 OH
erythromycin G(J. Antibiot. 2003, 56, 280)
O
NMe2
MeHO
OMe
OMe
MeOHOH
O
O
O
Me
OH
OH
MeOH
Me
Me
Me
3
5612 O
erythronolide H
Me
HO
O
OMe
MeO
O
Me
Me Me
OHMe
Et
HO
erythronolide I(Org. Lett. 2009, 11, 1353)
23
5
6
9
1213
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
2
12
89
10
13
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612 OH
O
NMe2
MeHO
OMe
OMe
MeOH
HO
Currently used as an antiobiotic agent; especially useful for patients with penicillin allergies.Isolation first reported in U.S. Patent 2,653,899 by R. L. Bunch and J. M. McGuire (Eli Lilly), filed in 1952 and approved in 1953; originally called "erythromycin".Quotes from the 1953 patent: "[...] the empirical formula of erythromycin [is] C38-9H69-71NO13." "We claim: 1. A method of producing an antibiotic agent which comprises cultivating under aerobic conditions an erythromycin-producing strain of Streptomyces erythreus in a culture medium containing assimilable sources of carbohydrate, nitrogen and inorganic salts until substantial antibiotic activity is produced by said organism in said culture medium. [...]"Structure first reported in 1957 without stereochemical assignments; X-ray analysis established the absolute configuration at each stereocenter in 1965.Quote from R. B. Woodward: "Erythromycin, with all our advantages, looks at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers." (In Perspectives in Organic Chemistry, Todd, A., Ed., Interscience Publishers: New York 1956, p.155.)Quote from J. Mulzer's review entitled "Erythromycin Synthesis - A Never-Ending Story?": "The synthesis of [...] erythromycin A and B [...] is probably the most extensive single project in the history of synthetic organic chemistry. This phenomenon is not rational as [they] are accessible in large quantities from fermentation [...]. It is the complexity of the molecule's structure, the plethora of stereocenters and functional groups and the magic of the medium ring that has fascinated about 15 large research groups worldwide for more than a decade." (Angew. Chem. Int. Ed. 1991, 30, 1452-1454)Cost of erythromycin A is 2.80 $/g, so just buy it for medchem/chembio purposes...This molecule caught the attention of... - "Giants": Woodward, Stork, Corey, Danishefsky; - "Aldol Giants": Masamune, Evans, Paterson; - "European Giants": R. W. Hoffmann, Mulzer, and recently Carreira.
erythromycin A:
-
-
-
-
erythromycin A
[...]
-
-
-
Our modern "retrosynthetic reflex" effectuates the following disconnections:
1
13
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
MeOHHO
erythromycin A
erythronolide A
macrolactonization1
13
OH
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
MeOHHO
seco acid of erythronolide A
HO
smaller aldol precursors
Commonly used macrolactonization methods:1. Corey-Nicolaou macrolactonization (PyS-SPy + PPh3 on the hydroxyacid, then heat; J. Am. Chem. Soc. 1974, 96, 5614);2. Masamune thiol ester activation (TlStBu on the acyl chloride to generate a thioester, then Hg(OCOCF3)2 or CuOTf to lactonize; J. Am. Chem. Soc. 1975, 97, 3515);3. Mukaiyama onium salt method (N-methyl-2-chloropyridinium iodide and Et3N on the hydroxyacid; Chem. Lett. 1976, 49);4. Mitsunobu alcohol activation (DEAD + PPh3 on the hydroxyacid; Tetrahedron Lett. 1976, 17, 2455);5. Yamaguchi mixed anhydride lactonization (2,4,6-trichlorobenzoyl chloride + DMAP on the hydroxyacid; Bull. Chem. Soc. Jpn 1979, 52, 1989);6. Keck-Steglich activation (DCC + DMAP + DMAP•HCl on the hydroxyacid; Angew. Chem. Int. Ed. 1978, 17, 522 and J. Org. Chem. 1985, 50, 2394);7. Shiina benzoic anhydride lactonization (various benzoic anhydrides + Lewis acid or base; Nature Protocols, 2007, 2, 2312).
Examples of asymmetric control in the synthesis of stereotriads found in polyketides (for an excellent review on this topic, see: R. W. Hoffmann, Angew. Chem. Int. Ed. 1987, 26, 489-503):
OH
Me Me
* * *1. Propionate enolate additions onto α-methylaldehydes (i.e. aldol);2. Propionate enolate additions onto α-methylesters, followed by carbonyl reduction;3. Acetate enolate additions onto α-methylaldehydes followed by α-methylation;4. Propenyl or butenyl group additions onto α-methylaldehydes, followed by hydrogenation or hydroboration;5. Danishefsky's diene (methylated version) Diels-Alder onto α-methylaldehydes followed by hydrolysis and ozonolysis; 6. Crotyl-metal and pentenyl-metal additions onto α-methylalde- hydes followed by ozonolysis;7. Epoxidation of an allylic alcohol bearing a methyl group at the allylic position, followed by methylcuprate addition;8. Hydroboration-oxidation or hydrosilylation-oxidation of the alkene motif shown on the right.
Me Me
-
eg.
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
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E. J. Corey (Harvard; 1978, 1979):
2
810
13
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
3
5612 OH
erythronolide A (R=OH)erythronolide B (R=H)
R
First total syntheses of erythronolide B (JACS 1978, 100, 4618 and 4620) and erythronolide A (JACS 1979, 101, 7131), synthesized in (longest linear) 31 steps (ca. 0.8% overall, yields of the last epimerization-deprotection steps are not reported).
OHMe Me
Me
56
1
43
2
OMe Me
Me
OMe Me
MeO
OH
OMe Me
MeO
O
Br
OMe Me
MeO
OHO
(resolution at this stage)
OMe Me
Me
O
98
7
56
1
43
2
O
O
OHMe Me
MeHO O
O
O
MeMeOBz
OBzOMe O
SPyMe
56
14
32
98
798
7
56
14 3 2
O
MeMeOBz
OBzOMe O
Me
98
7
56
14 3 2
EtMe
BrMg
Me
OTBS
131211
10
EtMe Me
OTBS
131211
10 12
89
13
OH
OH
O
Me
Me
O
O
Et
Me
Me
Me
Me
3
5612 OH
erythronolide BHO
(The erythronolide A synthesis simply uses a coupling partner with a protected hydroxyl group at C12)
-
-
-
-
89
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me6
6-deoxyerythronolide B
S. Masamune (MIT; 1981):First total synthesis of 6-deoxyerythronolide B (JACS 1981, 103, 1568), synthesized in (longest linear) 22 steps (<7 % overall; missing yields for the last few steps).4 students worked on it.41 % yield for the macrolactonization, effectuated with Masamune's own t-butylthioester method, using CuOTf.Key feature: Aldol, aldol, aldol... a synthetic mimic of a polyketide synthase.Textbook-style retrosynthesis!Excellent demonstration of his own methodology.
-
-
-
- macrolactonization
89
CHO
MeO
OMe
Me
56
R2BOOTBS
c-Hx
8
OMe
Me
O
O
Me
3then 4-step redox
Me
4
12
89
O
O
Me
Me
O
OMe
Me
3S
tBu
13
OTESEt
MeO12
11
(Coupling partner prepared from EtCHO in 70-85% yield and in >100:1 dr)
LHMDS, thenMe
10
12
89
10
13
OTES
OH
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612
tBuS
6-deoxyery-thronolide B
9
1) (COCl)22) Et2CuLi
(88%, 17:1 dr)
(71%, 14:1 dr)(85%, 40:1 dr)
R2BO
OTBSc-Hx
Me
34
12
MeMe
MeMe
MeMe
-
-
Key features: Cyclic stereocontrol (i.e. not a single aldol!); convergency amenable to the synthesis of both erythronolides A and B.Hard to retrosynthetically disconnect!"Classics-worthy" synthesis!
11 students worked on it, including K. C. Nicolaou.50% yield for the macrolactonization, effectuated with a modified Corey-Nicolaou procedure (substituted imidazoles instead of pyridines).
5 steps
2 steps
8 steps
2 steps6 steps
7 steps
aldol
aldol
-
-
NaOMeAllyl-Br
1) BH3; H2O2
2) CrO3
Br2
KOH
(2 steps from chiral pool)
7
then 2-step [O]
8
OMe
Me
O
OH
Me
34
9
MeO
OH1
2
5 steps, then
12
89
10
13
OTES
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me
3
5612
tBuSMe
Me
NaBH4
including [O]
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
4
R. B. Woodward (Harvard; posthumous, 1981):First and only total synthesis of erythromycin A (JACS 1981, 103, 3210, 3213 and 3215), synthesized in (longest linear) 52 steps (0.0089% overall, of which the last 10 steps, required for the glycosidations, yielded 1.54%).48 students worked on it, including R. M. Williams.70% yield for the macrolactonization, effectuated with a Corey-Nicolaou macrolactonization.Key features: Aldols using asymmetric induction via dithiadecalins; interestingly convergent; first detailed study on the structural requirements of the erythronolide seco acid macrolactonization.The end of the "Woodwardian era"...
erythronolide A analog, and then 10 more steps to erythromycin A
-
-
-
G. Stork (Columbia; 1987):First total synthesis of 9S-dihydroerythronolide A (JACS 1987, 109, 1564 and 1565), synthesized in (longest linear) 30 steps (1.3 % overall).Only one student: S. D. Rychnovsky64 % yield for the macrolactonization, effectuated with a Keck-Steglich macrolactonization.Key features: Aldols performed via butenolides; convergent synthesis.
-
-
-
12
89
O
O
PivO
Me
Me
O
O
Et
MeO
Me
Me
Me
3
56
9S-dihydroerythronolide A
10
13
O
O
O
Me
Me
O
O
Et
MeOH
Me
Me
Me12 OH
O
NMe2
MeHO
OMe
OMe
MeOH
HO
erythromycin A
MeMe
12
89
10
OMOM
OAc
O
Me
Me
O
OH
Et
MeO
Me
Me
Me
3
56 OO
tBuS
MeMe
Me
Me(33%
overall) 12
13
OH
NH
O
Me
Me
O
O
Et
MeO
Me
Me
Me
3
5612 OHHO
PySMes
O
10 steps
S
MeO OMe
SHCH2OMs
BnOOMeMeO
+1) NaH2) AcOH
3) D-proline(asym. aldol, 70%, 1:1 dr, 36% ee; then recrystallize)
S SH
OH
OH
(6 steps to make; racemic)
(5 steps to make; racemic)
BnO
S SH
MOMOO
OBnOMeO
OMe
S SH
OO
OBnOMeO
OMe
Me Me Me
MOMOO
O OMeO
OMe
8 67 5 3
4
1213 11 9
10
7
MesLi
and then 7 steps to
manipulate C7 and C9
S SH
BnSO
OBnOMeO
OMe
8 67 5 3
4Me Me Me
MOMOO
O AcOMeO
OMe
1213 11 9
10
5 steps
Ra-Ni, aldol with EtCOStBu,
etc...
12
10
13
O
OH
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
3
12 OHHO
9S-dihydro-erythronolide A
7
-Butenolide strategy in polypropionate synthesis(JACS 1987, 109, 1564):
O OOiPr
OiPr
Me OH
OiPr O
Me OH
OiPr
O
Me OH
OiPr
O OiPr
O OiPr
Me OH Me OH2 steps 4 steps
3 steps 1 step
iPr CO2H
OH
Me
OH
iPr CO2H
OH
Me
OH
iPr CO2H
OH
Me
OH
iPr CO2H
OH
Me
OH
MeH
7 steps
O Me
12
PivO
Me
O
OMe
Me
3
56
MeMe
OOH
89
O
MgBr
OMe
Et
MeO
MeMe
H
O Me+ 73%
single isomer
O OPiv
Me
6 steps
O
O
OBn
MeOEt
MeO Me
13 steps
910
11
8
1 235
4
Grignard addition
macrolactonization
6 steps
(2 steps)
(3 steps)
(4R)-ethyl 4-hydroxy-2-hexynoate9 steps
11
11
-
-
butenolide carbonyl attack
(All discon-nections shown here are aldols)
3 steps;racemic
3 steps;racemic
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
5
I. Paterson (Cambridge; 1988):Total synthesis of 9S-dihydroerythronolide A (TL 1988, 29, 1461 and 1989, 30, 7463), synthesized in (longest linear) 22 steps (3.4% overall).2 students worked on it.91-96% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key features: Excellent use of "modern" (Evans herein) aldol technology; convergent; macrolactonization performed on a conformationally favorable system bearing two olefins, precluding the use of acetonides.
-
-
S. J. Danishefsky (Yale; 1990):Relay synthesis of 6-deoxyerythronolide B (JOC 1990, 55, 1636), synthesized in (longest linear) 35 steps (ca. 0.014 % overall, yields of the last two steps are not reported). A total synthesis from the procedures described herein would result in racemic 6-deoxyerythronolide B.Only one student worked on it.17 % yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key feature: "Formal double aldol" using a Lewis-acid catalyzed diene aldehyde condensation (LACDAC) strategy.Great application of his own methodology.
-
-
-2
10
13
O
OH
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me12 OHHO
9S-dihydro-erythronolide A
4 steps
7
2
10
13
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me
3
12
6-deoxyerythronolide B
7
HWE olefination
aldol
aldol
12
Xc
PhS
O
OHMe
Me10
OHMe
PhS
Me
734
5
5
O Xc11
98
PhS
O(racemic)
+
ON
O
iPrO
Me
Bu2BOTf, iPr2NEt(70%, 10g scale, 1:1 dr; both isomers needed)
10
CO2Me
OHMe
SPh
Me 98
1) NaOMe2) TBSOTf3) NCS4) ZnBr2, enolate of 3-pentanone
Me
OEt1312
10
CHO
OHMeMe 9
8
Me
OHEt13
1) [O]
2) [H]3) [H]
12
10
13
OH
OTBS
PhS
Me
O
OTBS
Et
Me
Me
Me
Me 5
3 steps to generate phosphonate; then add aldehyde fragment C7-C13
6 steps
O
OTBS
O
Me
O
OTBS
Et
Me
Me
Me
Me
98
3
O
OTBS
O
Me
OTMS
OTBS
Et
Me
Me
Me
Me
-
Me9S-dihydro-
erythronolide A
1) OsO4-NMO, 1h
2) Zn(BH4)23) OsO4-NMO, 5d
"LACDAC"
Me
Me
OTMS
OMe
HCHO, ZnCl2heat
(69%)O
OMe
Me
3 steps
O
OHMe
Me
4 steps
OMe
1 2 34
5 2PG-O
O
OBnMe
Me
31
54
"diene" "diene"(40%)
2PG-O
O
OBnMe
Me
31
4
OMeMe
H 56 7 8
2
O
PG-O
Me
Me
OBn
OBnMe
Me
3
7
PG = TBDPS
1
456
89
-
6 steps"diene"(76%)
2
10
OBn
PG-O
Me
Me
OBn
OBn
Me
Me
Me
Me
31
7
then 6 stepsO
4 steps
OBn
PG-O
Me
Me
OBn
OBn
Me
Me
Me
MeOH
OBn
Et
4 steps
O
O
Me
Me
O
O
Me
Me
Me
MeOH
O
Et
5 steps
HO
Me
Me
MeMe
6-deoxyery-thronolide B
-
-
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
6
J. Mulzer (Institut für Organische Chemie; 1991):Total synthesis of erythronolide B (JACS 1991, 113, 910), synthesized in (longest linear) 25 steps (<2.4% overall, yields of first few steps unclear).4 students worked on it.>85% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key features: Great use of a simple starting material from the chiral pool, glyceraldehyde; convergent; macrolactonization performed on a conformationally favorable system bearing an olefin.
-
-
R. W. Hoffmann (Universität Hans-Meerwein-Strasse; 1993):Total synthesis of 9S-dihydroerythronolide A (ACIEE 1993, 32, 101), synthesized in a total of 23 steps (6.6% overall).2 students worked on it.>77% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key feature: Completely linear synthesis, but this synthesis is one of the shortest in total number of steps.Excellent application of his own crotylation methodology.
-
-
-2
10
13
O
O
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me12 OH
7
carbonyl addition
-
9S-dihydro-erythronolide A
-
1) crotyl-boronate 1) TNT, HCl
erythronolide B
O O
MeMe
CHO
2HO OH
Me
Me
1 3
45
2BnO OTBS
Me
Me
1 3
45
OH
Me6
2BnO O
Me
Me
1 3
45
O
MeO6
MeMe
98 710
Et
MeOH
Me
Me
2O
Me
Me3
45
O
MeOH6
MeMe
O
O
2
13
O
OH
O
Me
Me
OH
OH
Et
MeOH
Me
Me
Me12 OHHO
9S-dihydro-erythronolide A
7
aldol
aldol
5
aldol
macrolactonization
Et
MeOH
1312
11
Et
MeO
11
3 steps
O-PG
PG-O Me
BO
Oc-Hx
c-Hx
Me"crotylboronate" Et
MeOH
11
O-PG
PG-O
MeMe10
9
1) PMBCl2) O3; Ph3P3) ent-crotylboronate
Et
Me
OPMB
11
O-PG
PG-O
MeMe10
9
Me
OH
87
Et
MeO
O-PG
PG-O
MeMeO
87 Me
OH
MeOC6H4
4 steps
HWE
1) Sharpless AE2) TPAP-NMO3) crotylboronate4) LAH5) PMBCl6) OsO4-NMO
PG = cyclic acetal using cyclopentanone
Et
MeO
O-PG
PG-O
MeMeO
87 Me
OPMB
MeOC6H4
OHMe
O
56
2) DDQ3) OsO4-NMO-NaIO4
Et
MeO
O-PG
PG-O
MeMeO
87 Me
O
MeOC6H4
OHMe
O
56
MeC6H4OMeO
HO2) Yamaguchi3) HCl
9S-dihydro-erythronolide A
--
HOMe Me
OH
139
12 11 10HO
Me Me
OH
15
2 3 4
3) Acid 4) Base5) Me2CuLi
1) Crotylation2) Tosylation
3) Acid 4) Base5) Me2CuLi
1) Crotylation2) Tosylation
4 steps 3 steps
98 710
13
OH
MeOH
Me
12
10
13
OHEt
MeOBn
Me
12
10
13
OHEt
MeOBn
Me
12Me
SPh
5 steps 5 steps
9710
OHEt
MeOBn
Me
12
Me
SPh
2
BnOO
Me
Me3
5
O
MeOH6
MeMe
BuLi
BF3
(82%)
6 steps3 steps
crotyladdition
crotyladdition
9 9
Y. Ishihara Erythronolide and Erythromycin Baran Lab GM 2009-08-15
7
D. A. Evans (Harvard; 1997):Total synthesis of 6-deoxyerythronolide B (TL 1997, 38, 53), synthesized in (longest linear) 18 steps from β-ketoimide, add 2 steps to make the SM (4.3% overall).Only one student worked on it; 86% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key feature: Evans aldol and its majesty. Convergency is also a plus.
-
K. A. Woerpel (UC Irvine; 2003):Total synthesis of 9S-dihydroerythronolide A (JACS 2003, 125, 101), synthesized in (longest linear) 28 steps (5.6% overall).Only one student worked on it.>80% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key feature: Great application of his own "allylsilane [3+2]" methodology. Convergency is also a plus.
--
-
-
NO
O O
Me
O
MeBn
NO
O O
Me
O
MeBn
OH
Me
2 3 41 56
7
NO
O O
Me
O
MeBn
OH
Et10 11 129 13
TiCl4,iPr2NEt
OMe
Sn(OTf)2,Et3N
O
Et
4 steps
6 steps
Xc
O O
MeMe
O
Me
2 3 41 56
7
O
OTMS OPMB
MeMe
OTBS
Et10 11 129 13Me
8
Me Me
Et
MeO
OH
MeMeO
87 Me
O
MeOC6H4
Me
O
56
MeMeO
HO
1) BF3•OEt2(83%)
2) Zn(BH4)23) DDQ4) NaH, CS2, MeI5) Bu3SnH, AIBN6) LiOOH7) TBAF
Me23
1312
1) Yamaguchi2) Pd(OH)2
3) PCC4) HCl
6-deoxyery-thronolide B
-
-
MeSiMe2Ph
MeOAc
MeO COOR*SnCl4,
O CO2EtMeMe
MeOAcPhMe2Si
R* = S-pantolactone
>78%,>98% ee
7 steps
O MeMe
MeOPivBnO
I 7 steps
Me
OH
Me
OH
BnO Me
OTBS
3 steps 4 steps
Et OMe
OPMB
BnO Me
OTBS12 11 1013
9
Me
O
Me
O
BnO Me
OTBS
Me
O
XcAr
9 steps
9S-dihydro-erythronolide A
Total synthesis of erythronolide A (ACIEE 2005, 44, 4036), synthesized with the best total thus far of 21 steps (1.5%).2 students worked on it; 78% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization.Key feature: Great application of his own "Mg-mediated nitrile oxide [3+2]" methodology for polyketide synthesis.
---
E. M. Carreira (ETH Zürich; 2005):
TBSO N
Me
OH tBuOCl; then iPrOH, EtMgBr,
Me OH
Methen
TBSO N
Me
O
Me OH
Me2 3 41 5 62 31
9 stepsTBSO O
Me
O
Me TESO
2 3 41 5 6Ph
Me Me
NOH
7 8 9
TBSO O
Me
O
Me TESO
2 3 41 5 6Ph
Me Me
N
7 8 9
(86%, dr >19:1)
Me
OHMe
O
10 11 12
repeatstep 1
6 stepsHO2CO
Me
O
Me TESO
Ph
Me Me
N
MeHOMe
O OH
Et4 stepserythro-
nolide A
Macrolactonization: 1) Since 1990, all syntheses utilized the Yamaguchi macrolactonization method; 2) A 6-membered cyclic acetal over the hydroxyl groups at C3 and C5 are necessary to induce (in part) the correct conformation for the lactonization, unless there are olefins within the seco acid that rigidify the conformation; 3) Woodward has contributed greatly toward examining different conformations of the macrolactonization step.Asymmetric stereocontrol: Development of aldol, dithiadecalin, butenolide, "LACDAC", crotylations and other methods such as [3+2] strategies, many of which were developed for the sake of conquering the erythronolide/erythromycin family.Other notable formal or total syntheses: Deslongchamps (CanJChem, 1985, 63, 2818), Kinoshita (TL 1986, 27, 1815), Kochetkov (TL 1987, 28, 3835 and 3839), Nakata (BCSJ 1989, 62, 2618), Chamberlin (JACS 1989, 111, 6247), Martin (JACS 1989, 111, 7634), Yonemitsu (JOC 1990, 55, 7), Vogel (HCA 2002, 85, 417), Crimmins (OL 2006, 8, 2191), Martin (Tet 2007, 63, 5709), and, as a note added after this presentation, White (NatChem 2009 AOP, DOI: 10.1038/NCHEM.351).