Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
THE YEAR 1978
Science:
- First 'test-tube' baby is born in England
- Insulin is produced by transgenic bacteria via recombiant
DNA
- Nobel prize in Chemsitry goes to Peter D. Mitchell for work on
chemiosmotic theory and engery transfer in the cell
World:
- the first recorded ascent of Mt. Everest without the aid of
oxygen
- First ever transatlantic balloon flight (Double Eagle II)
- Famous Camp David Accords are signed by Israeli and
Egyptian governments
David Peters
Total Syntheses In This Year Not Covered:
Seychellene (Jung, 5207)
Giberellic Acid (Corey, 8034)
N-methylmaysenine (Corey, 2916)
Cytochalasin B (Greenlee, 7775)
Vernolepin (Schlessinger, 1938)
Vindoline (Kutney, 4220)
Epidregamine (Kutney, 938)
Meroquinine (Uskokovik, 571)
Quinine/Quinidine (Uskokovik, 576)
Pentalenolactone (Danishefsky, 6536)
Prostoglandins I 1, I 3, F1 α (Johnson, 7690)
Para-/Pseudozoanthoxanthin (Buchi, 4208)
Dendrobine (Roush, 3599)
Brefeldin A (Green, 4858)
Longifolene (Oppolzer, 2583)
Pumiliotoxin (Overman, 5179)
Cherylline (Evans, 1548)
Eriolanin, (Grieco, 1616)
Estradiol (Kemetani, 6218)
Biotin (Marquette, 1558)
Lycopodine (Heathcock, 8036)
Nanoamycin A (Li, 6263)
Anthopleurine (Rapoport, 4865)
Some Publications Not Covered:
American Culture:
- the movie Grease is released
- the comic strip Garfield is released in newspapers
- "Night Fever" and "Staying Alive" by the Bee Gees are still
topping the charts
- New York Yankees win the World Series
- Dallas Cowboys win the Super Bowl
- Simon Says becomes the most popular toy in America
Volume: 100
Issues: 26
Articles: 1931
Top Cited Article: 890 citings
"Strong metal-support interactions. Group 8 noble metals supported on titanium
dioxide," JACS 1978, 170.)
"Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated
ketones," Luche, JACS 1978, 2226. (677 citings)
"Olefin homologation with titanium methylene compounds," Tebbe, JACS
1978, 3611. (511 citings)
"A general, selective, and facile method for ketone synthesis from acid
chlorides and organotincompounds catalyzed by palladium," Stille, JACS
1978, 3636. (390 citings)
"Selective carbon-carbon bond formation via transition metal catalysis. 9.
Double metal catalysis in the cross coupling reaction and its application to the
stereo- and regioselective synthesis of trisubstituted olefins," Negishi, JACS
1978 ,2254. (196 citings)
"Selected ion fragmentation with a tandem quadrapole mass spectrometer,"
Yost, JACS 1978, 2274. (120 citings)
"Allylic alkylation: preparation of π-allylpaladium complexes from olefins,"
Trost, JACS 1978, 3407. (91 citations)
Least Cited Paper: 0 citings
"An experimental determination of the geometry and electron affinity of
methyl radical, Ellison" , JACS 1978, 2556. (78 citings)
"Unusual reactivity of trifluoroacetyl peptide chloromethyl ketones with
pancreatic elastase," Dimicoli, JACS 1978, 1005.
"Mechanisms of gas-phase and liquid-phase ozonolysis," Goddard, JACS
1978, 7180. (64 citings)
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
Ph
O
Nocardicins A and D
Koppel (Eli Lilly), JACS 1978, 3933-3935.
N
Ph
O
NH 2
HO
SH
S
Cl
Ph
2. C6H 5COCl,
H
propylene oxide HO 2C
H
H
N
H
H
Cl
H 2N
O
1. KOtBu; BnBr
2. HCl
3. NaHCO 3
BocHN
O
HO 2C
OBn
CO2H
+ Ph
H 2N
CO2Bn
N
H
O
HN
H
S
H
H
CO2Bn
1. (PhCO 2)2
2
34% from 1
BocHN
H
N
H
HO 2C
2. HCl
OBn
N
H
O
DCC
S
90%
H
H
O
H 2N
TFA, anisole
O
OH
O
CO2H
S
Cl
H
HN
H
O
CO2Bn
NH
CO2Bn
1 45-55%
NaH
N
O
HO 2C
OBn
O
H 2N
H
O
CO2H
NH
HO
Nocardicin A
OH
O H
Nocardicin D
Ph
1. NaHCO 3
OBn 2. Pd/C, H 2
1. Bu 3SnH, AIBN H N •pTsOH
2
2. pTsOH/H2O
H
N
OBn
O
BnO C H
O
Ph
OBn
O
BnO 2C H
O
85%
O
H
N
OH N,O-bis(TMS)acetamide,
ClCO2Et
H
N
OH
PCl 4 (3 eq)
O
H
X
N
O
BnO 2C H
"excellent
yields"
OBn
N
Y
3:1 A:B
A: X = CO2Bn; Y = H
B: X = H; Y = CO2Bn
O
N
H
N
Ph
1. acetone,
reflux (3 d)
Hg(OAc) 2 (4 eq)
H 2O/THF
S
H
- Nocardicins isolated from Nocardia uniformis
O
(J. Antibiot. 1977)
- bacteriocidal - inhibits cell wall synthesis
OH
- Strong Gram-negative activity compared to other
N O
β-lactams
H
S
N
CH 3
- resistant to narrow spectrum β-lactamases
N
- Currently 1 approved monobactam: Aztreonam H 2N
O
N
(Azactam or Cayston)
SO 3H
O
- important in treating cystic fibrosis patients
Aztreonam
(P. aeruginosa)
O
David Peters
OH
N H
N
O
HO 2C
H
NH 2OH•HCl
pH = 7
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
Phytuberol and Phytuberin
Masamune, JACS, 1978, 7751.
- sesquiterpene isolated from a number of species of Solanum
(includes potatoes, tomatoes, and tobaco)
- involved in resistance to pathogenic fungi
- implications in arms race against blight and other plant diseases
1. LDA
2. MoO 5•Pyr•HMPA Si'O
3. TBDMSCl, imidazole
O
O
O
Si'O
Li-Selectride
then
HO
LAH
1. AcOH
2. MnO 2
separated
1. MoO 5•Pyr•HMPA
2. mCPBA
HO
3. LAH
proposed
biosynthetic step
DIBAL
OH
O
O
R = H, Phytuberol
OR R = Ac, Phytuberin
established C7
stereochemistry
H
O
OH
Et
5 steps
Ar
OH
Et
97%
10:1
1/2. Repeat
3. Ac2O, pyr.
Pb(OAc) 4
pyr.
OH
1. VO(acac)2,
tBuOOH
2. AcOH
Ar
OH
N HN
H
OH
OH
OHC
O
1. CrO 3/H2SO 4
2. LAH,
Ar
OH
O
1. LAH
2. PCC
3. Grignard
reagent
MeO
2:1
OH
(+)-β-rutanol
O
Lasalocid
Kishi, JACS, 1978, 2933.
- Isolated from fungus - Streptomyces lasaliensis
- polyether antibiotic with weak activity - highly studied before1978
- active ingrediet in feed additive Bovatec
-no clinical relevance due to toxicity and activity
EtO 2C
(+)-α-cyperone
1. VO(acac)2, tBuOOH
2. Mesylation
Si'O
3. Birch reduction
(−)-carvone
David Peters
H
O
Et OAc
O
H
MeO
O
Et H
O
8 steps
1. MsCl, pyr.
Et
Et 2. AgCO , H O,
3 reductions,
3
2
acetone
2 oxidations,
O
O
Et H
H
1 epoxidation, O
OH
1 protection,
1:1
1 C-C bond
chromatographed
cleavage
& recycled
OH
Et
Et
O
H
O
Et H
O
Me
HO
CHO
Me
CO2H
OH
Et
Me Et
HO
Me
deprotection
1. LDA, then ZnCl2,
then CO2Bn Me
H
OH O
Lasalocid A
O
Et H
O
Me
40:10:7:3
OMOM
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
Erythronolide B
Corey, JACS 1978, 4618-4620.
Corey, JACS 1978, 4620-4622.
1.MsSO2Cl,
pyr.
2. Me 2CuLi
- Erythromycin B isolated from Streptomyces erythreus in 1949
(Eli Lilly)
- 16 membered macrolide; most famous
- Inhibits protien synthesis at the ribosome; bacteriostatic
- take it how you like! - IV, IM, orally, topically, eye drops
- mostly active against Gram-positive bacteria (respritory tract, muccous
membrane, and skin infections)
- resistance arises via ribosomal mutation, eflux, and xenobiotic modification
- currently 12 erythromycin-based antibiotics on the market
- respritory tract, muccous membrane, and skin infections
OH
O
Me
Me
Me
O
Me
1. Br 2/KBr, H 2O O
2. Bu 3SnH,
AIBN (1 mol%) Me
BzO
Me
OBz
H
Me
Me
Al-Hg
THF/H2O
O
O
Me
Me 1. Br 2/KBr, H 2O Me
2. KOH (aq), THF
O
CO2H
H
Me
HO
Me
O
H
Me
1. tBuLi
2. MgBr 2
Me
1. [ZrCp 2HCl]
2. I 2, CCl4
Me
OTBDMS
Me
Me
3
OTBDMS
I
BrMg
BzO
Me
1.CH 3CO 3H
(±)-2
2. 2,2'-dipyridyldisulfide, BzO
Me
PPh 3
3. 3
1. Raney Ni
2. BzCl, pyr.
Me
O
O
Me
O
OH OH
OH
Me
OTBDMS
Me
Me
Me
Me
Me
Me
O
O
Me
Me
1. ZnBH4
2. HOAc, H 2O/THF
O
OO
Me
Me
O
Me
1. 2-methoxypropene,
HO
1. THF/H2O2/LiOH
HBr
O
2. Amberlite
2. KOH, DME/H 2O Me
3. CH2N 2
OH OMe 3. KOH/H 2O/MeOH
HO
OH
OH
OH
Me
Me
Me
BzO Me
Me
O
OH
BzO
CO2H
O
Me
O
Me
Me 1. TBDMSCl
2. LDA, MeI
OH
OTBDMS
Me
OBz
OBz
H
H
Me
Me
Me 1. LiOH (aq.)
2. CrO 3/H 2SO 4
BzO
O
O
BzO
O
Me
Me
CO2H
O
O
(±)-2 Me
Me
1.TEA,ClCO 2Et
OH
H 2O2/H2O
2. NaBH 4
O H
NaWO 4
3. POCl 4, and
Me
Me
OH (recry. of
2-methoxypropene
OH
H
CO2H
S,R
4. LiCCH•en
chiral salt)
5. Amberlite
Me 1. LDA
Me
2. MeI, HMPA
Me
O
Me
1. Br
2. B 2H 6 /THF
3. CrO 3/H2SO 4 Me
Me
David Peters
4-tBu-N-iPr-2O
O
mercaptoimidazole
Me
toluene, r.t.-reflux Me
HO
OH
10
Me
Me 9
Me
Me
OH
O
HO
1. MnO 2 (C 9)
2. H 2O2, H 2O, then OH- (olefin) HO
3. H 2, Pd/C, MeOH (C10 )
Me
4. K 2CO 3 (cat.), MeOH (epi. C10 ) HO
5. THF/HCl (deprot.)
Me
O
Me
HO
O
Me
Et
Me
10
9
Et
Me
(±)-Erythronolide B
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
Prostaglandin F 2α
Stork, JACS 1978, 8272-8273.
HO CN
H
HO
H
H
O
O
O
1. NaBH 4, H +
OHOH 2. Acetone
O O
OH
OH
OH
O
OH
CHO
OH
H
OH
OH
CH2OH
D-glucose
(commercial)
1. CH(OMe)2NMe 2
2. Ac2O
O
1. LiCuBu 2
2. H 2SO 4 (aq), O
THF
3. protection
EEO
O
O
O
1. K 2CO 3
2. TsCl, pyr.
3. protection
O
LiHMDS
EEO
Bu
Bu
EEO
COOH
HO
Ibogamine
Trost, JACS, 1978, 3930.
O
O
O
H
H
R
EEO
EEO
O
O
OEE
O
O
H
O
OTs
O
OTBDPS
THF/HMPA
HO
HO
CO2Me
O
Br
R
EEO
Bu
O
HO
O
H O
O
O
OH
O
H
HO
OAc
O
O
O
O
O
H+
CN
TsO
OH
O
OAc
1. CO2CH 3Cl, pyr.
O
2. CuSO4, MeOH/H 2O, Δ
3. Acetone, H 2SO 4 (cat.)
O
O
HO
OH
Prostaglandin F 2α
HO
O
CO2Me
CH 3C(OMe) 3,
OH 1. NaBH 4,
then HOAc
2. Ac2O, pyr.
1. Protection
2. KHMDS
R
- large class of fatty acid derived molecules; found in every human tissue
- discovered in 1935 by Ulf von Euler
- act as autocrine effectors for a diverse range of functions
- Letter designates ring structure; number indicates degree of unsaturation
- most are synthesized from one precursor - arachidonic acid
- inhibition of synthesis lead to discovery of aspirin
- medicinal uses are as wide as the functions of natural prostaglandins
- this synthesis done at the height of prostaglandin research
David Peters
1. DIBALH
2. HCN
3. AcOH/THF
4. TsCl, pyr.
Bu
R=
R
OHC
+
- iboga alkaloids from Taberanthe iboga
- most have psychoactive properties
- synthetically related compound: vinblastine
- ibogaine: (5-OMe) is Schedule 1 in the U.S.
NH 2
O
O
O
BF 3•OEt2
PhCH 3
H OCH3
(S)
Ph
R
COH
NH
1.
O
R
NH
2. NaBH 4,
MeOH
80:20
(3R,4S,6R)
N
H
1. [(CH 3CN)2PdCl 2],
AgBF4; r.t.
D N
2. NaBD 4,
CH 3CN, 70°C
N
MeOD
N
H
H
H
H H
80:20
+: −
- done first with R=CH 3 to yield racemic ibogamine
ibogamine
- 17% from diene, "without yield optimization"
- most natural igobamine is (−); propose using (R) auxiliary
- deuteration suggest Pd is in association with indole at initiation of cyclization
[Pd(PPh 3)4] (cat.)
N
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
(±)−thienamycin
Johnston, D.B.R. (Merck), JACS 1978, 313-315.
OCO2PNB
- first isolated carbapenem; from Streptomyces
cattleya (J. Antibiot. 1979, 1, 1-12.)
- unstable in water (pH > 8); derivitization needed
- imipenem closest related derivative and first to get
use
- 4 carbapenems approved in U.S.
- resistant to most β-lactamases
- does not bind PBP-2a (no MRSA activity)
- A class of reserved antibiotics. Some resistance
scares (New Delhi, Greece)
SO2Cl
O C N
+
O
O
1. ether, −20°C
2. K 2HPO 4, Na 2SO 4,
H 2O
42%
O
OAc
N
MeO OMe
,
BF 3•OEt2
77%
O
H
9
N
NH
HN
OH
1. iPr 2NH, MeSO 2
2. H 2, Pd/C
23%
4:1
CO2H
imipenem
1. H 2, Pd/C
2. NaOMe,
MeOH
95%
OH
N
O
H
OCO2PNB
1. LDA, MeCHO
2. nBuLi, PNBO 2CCl
O
75%
O
2:3 R:S (9)
N
1. CrO 3, pyr., Br 2, Et 2O/THF; OCO2PNB
then Et 3N 0°C
Celite
2. BF 3•OEt2,
87%
O
NH
NH OH HS N OPNB
H
O
46%
1. H 2O/HOAc
2. recrys.
O
82%
1:1 R:S (8)
OCO2PNB
8
O
O
S
O
OPNB
1. PNBO
OCO2PNB
O
toluene, reflux
S
2. SOCl2, pyr.
3. P(nBu) 3, K 2HPO 4,
N
CO2PNB
DMF/H 2O
O
CO
26%
2PNB
H
S
S
N
O
OCO2PNB
HN CO2PNB
1. AgF, pyr. (8R isol.)
2. collidine, LiI, Δ
O
O
CO2PNB
32%
PNBO 2C
N
OH
Br
David Peters
1. Br 2/Et2O/THF
2. TEA
NH
58%
OCO2PNB
NH
OCO2PNB
NH
N
O
S
CO2H
(±)−thienamycin
HN CO2PNB
S
N
H
CO2PNB
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
David Peters
"A new photochemical transformation of 6-azido-1,3-dimethyluracil to 6"Electroorganic Chemistry. Reductive cyclization of Nonconjugated Olefinic
alkylamino-5-amino-1,3-dimethyluracils and its application to one-step synthesis Ketones to Cyclic Tertiary Alcohols," Shono, JACS, 1978, 545-550.
of lumazines and fervenulins," Senda, JACS 1978, 7661-7664.
O
R' OH
Carbon Electr.
O
O
(Et 4NOTf)
R
CH2R
H 3C
NH 2
R'
H 3C
N
MeOH/dioxane
N
HNR'R''
H
27-83%
75-98%
hυ
O
N
NR'R''
O
N
N3
MeOH
O
H 3C OH
O
CH 3
OH CH 3
CH 3
OH
H 3C
ee2
e69%
61%
36-24%
O
O
N
N
O
H
O
R'HN
H 3C
N
R
R
O
OEt
R
N
H 3C
O
H 2N
N
N
Ar
R
2
R
and
R'
substituents
show
little
affect
on
ring
formation
2
hυ
hυ
- regio- and stereoselective; only 5 and 6 membered rings oserved
O
N
N
O
N
N
R
55-81%
70-75%
H
- substitution at the proximal olefinic carbon precludes cyclization
CH
CH 3 R'
3
- done in diaphragm split cell as well; some 1,2-reduction of carbonyl
O
O
O
O
2
H 2N
OEt
H 3C
hυ
59%
O
N
H
N
O
H 2N
2
N
N
CH 3 H
R
H 3C
hυ
55-81%
O
N
H
N
N
N
N
CH 3
R
N
"An unusual New Allene Cyclization Reaction. Synthesis of Dihydrofuran3(2H)-ones," Magnus, JACS 1978, 7746-7747.
tBuOK or KH,
•
dicyclohexyl-18O
n-BuLi
crown-6
HO
•
•
OMe
THF, -72°C
tBuOH or
Li
OMe
90-80%
H
OMe
THF (reflux)
74%
O
OMe
H
O
O
O
O
H
O
73%
42%
H
H
H
Me
47%
N
R2
R2
R1 = Me, Et, iPr, Ar
R2
R1
O
R1
(CH 2)n
R1
n = 1−8
O
R4
R3
65−>98%
A
R1
O
R4
R2 R3
(CH 2)n
R1
n = 1−8
R1
O
R1
O
O
H
O
O
R1
O
O
"Novel cyclopentenone synthesis via the iron carbonyl aided coupling between
α,α'-dibromo ketones and enamines," Noyori, JACS 1978, 1799.
O
R1
R1
O
O
silica or
O
R1
Br Br [Fe 2(CO) 9]
3% NaOH R1
R1
R1
N
R4 +
benzene
57%
O
L nFeO
+
N
L nFeO
L nFeO
Y
H
- Fe(CO) 5, Zn-Cu couple give low yields, no reaction NaI
- Trans isomer predominant, except in fused rings
- No reductant = no reaction; in furan yields [3+4]
Y
A
Baran Group Meeting
10/31/2015
JACS Year in Review: 1978
"Nickel-catalyzed addition of Grignard reagents to silylacetylenes. Synthesis
of tetrasubstituted alkenes," Snider, JACS, 1978, 4624.
1 Ni(acac) 2 : 1 (CH 3)3Al C H
SiMe 3
6 13
(10 mol%), CH 3MgBr
+
SiMe 3
THF
H 3C
R
A
C6H13
Quench
H 2O
R
Yield
H
80%
CHO
CO2
I2
CH2OH
CO2H
66%
61%
4:1
I
71%
9:1
C6H13
R
H 3C
SiMe 3
"A New synthetic method for medium- and large-membered lactones by
intramolecular alkylation of -haloalkyl phentylthioacetates," Tsuji, JACS, 1978,
O
7425.
O
B
O
A: B
9:1
I
O
nBu O
72%
CO2H
nBu
51%
NaIO 4
toluene
O
OH
CH 3
H 3C
51%
Cl
3 steps
54%
O
O
9-decanolide
Phoracantha synonyma
NO 2
1. (Me 3Si)2NK
2. Raney Ni
O
O
I
SPh
O
O
Lactonization:
75% (unsat.)
51% (sat.)
recifeiolide
Cephalosporium recifei
Steric steering with supported palladium catalysts, Trost, JACS, 1978, 7779.
CO2CH 3
CO2CH 3
H 3C
CO2H
H 3C nBu
1 or 2
Et 2NH
OAc THF
< 6%
- RCu•BF 3 prepared from alkyl lithium reagent, CuI, and BF 3•OEt; overall
one pot
- yields generally decrease with substitution; β,β-disub. enoic acids
-1,4-addition to enoate ester conjugated diene, and 1,6-addition to enoic acid
conjugated diene
O
SPh
O
(Me 3Si)2NK
THF, 65°C
9:1
"RCu•BF 3. 3. Conjugate addition to previously unreactive substituted enoate
esters and enoic acids," Yamamoto, JACS, 1978, 3240.
O
O
R 4Cu•BF 3
R1
R1
Y
R4
R1 -R3 = H, alkyl, and/or aryl
Y = H, CH 3 OR, OH
R3
R2
R3
R2
R4
CO2Et
Raney Ni
EtOH (reflux)
O
SPh
- reaction time/conditions sensitive due to isomerization of A→B
- crude vinyl organometallic also coupled with allyl and vinyl halides
- EtMgBr only yields trisubstituted alkenes
nBu
David Peters
1
2
+
NEt 2
Pd
(Ph 3P)4Pd
Pd on posph. silica
OAc
Pd
L
NEt 2
Yield A : B
85% 67:33
72% 100:0
+ Et 2NH
L
CO2CH 3
NEt 2
- (Ph 3P) 4Pd treatment of
posphenylated silica and
polystyrene: active & air stable
- comparable results with PS
and with opposite
stereochemistry
- nucleophile precluded from
face Pd initially binds
- flow reactor developed