Joel M. Smith
Lipids (Fatty Acids) in Organic Synthesis
Definitions
Focus of This Presentaion
Cultural References
Lipid (n.) – any of various substances that
are soluble in nonpolar organic solvents (as
chloro-form and ether), that are usually
insoluble in water, that with proteins and
carbohydrates constitute the principal
structural components of living cells, and that
include
fats,
waxes,
phosphatides,
cerebrosides, and related and derived
compounds.
(Merriam-Webster)
"Tyler sold his
soap to
department
stores at $20
a bar. Lord
knows what
they charged.
It was
beautiful."
Lipids – A loosely defined term for
substances of biological origin that are
soluble in nonpolar solvents. They consist of
saponifiable lipids, such as glycerides (fats
and oils) and phospholipids, as well as
nonsaponifiable lipids, principally steroids.
(IUPAC Gold Book)
"I love the smell
of...[hexadecanoic
acid and
napthenic acid]...
in the morning."
(Apocalypse Now)
Etymology
Derived from the French lipide which, in turn,
is derived from the Greek lipos meaning "fat,"
or "grease."
"I want my baby
back baby back
baby back baby
back baby back...
ribs. I want my
baby back baby
back baby back
baby back baby
back... ribs."
(Austin Powers 2)
Classes of Lipids and Characteristics
Fatty acids – characterized by having a hydrophilic, polar end, and a nonpolar hydrocarbon
chain.
Glycerolipids – characterized by a glycerol unit
acylacted by three fatty acid sidechains.
Glycerophospholipids – Similar to Glycerolipids
in structure, however, an acyl chain is often substituted with a polar head group like a phosphate
(common in cell membranes).
OH
vitamin A
OH
Sphingolipids – comprised of a serine backbone
conjoined to a fatty acyl side chain.
HO
Sterol lipids – (poly)cyclic, mostly hydrocarbon
molecules reponsible for much cell-sginaling and
membrane structure.
12
NH 2
sphingosine
Prenol lipids – molecules of repeating 5-carbon
units (isoprene) and include terpenes.
H
H
Saccharolipids – compounds with a sugar backbone with appended acyl fatty acids.
Polyketides – molecules with repeating acetyl and
propionyl subunits, and are often cyclic.
HO
Baran Group Meeting
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H
Cholesterol
lauric acid
O
OH
– Main focus is on fatty acids and derivatives (nomenclature, biosynthesis, sources, etc.)
– Functionalization and synthesis of simple fatty acids.
– Synthesis of natural products derived from long-chain lipids.
– Arachidonic Acid and derivatives
– CP molecules
– Chlorosulfolpids
– Endiandric Acids and Kingianins
– Prostaglandins
– Ladderanes
Items not covered
Steroids (See GM 2013)
Terpenes (Burns GM 2004, Maimone GM
2005, Michaudel GM 2013, Seiple GM 2007),
Sphingolipids, glyceroolipids, glycerophospholipids
Saccharolipids, Polyketides.
Supramolecular chemistry (micelles, lipisomes, etc.)
Nomenclature of fatty acids
omega
1
6
O
OH
8
5
alpha
Common nomenclature – Arachidonic acid
IUPAC nomenclature – (5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid
Δx nomenclature – cis, cis, cis, cis-Δ5,Δ8,Δ11,Δ14 icosatetraenoic acid
omega – x classification – omega-6
lipid numbers nomenclature – 20:4ω6
Sources of Fatty Acids (g/100g)
Fun Fatty Facts:
– linoleic acid is an essSource
Saturated
Polyunsaturated
Cholesterol
ential fatty acid and
Lard
40.8
9.6
93 mg
must be consumed.
– Omega-3 fatty acids
Duck Fat
33.2
12.9
100 mg
(α-linoleic acid) must
be consumed.
Butter
54
2.6
230 mg
– Most trans facts are
not found in nature,
Coconut Oil
85.2
1.7
and are artifacts of
hydrogenation.
Palm Oil
45.3
8.3
– lauric acid (C12H 24O2)
is converted to sodium
Soybean Oil
14.5
56.5
laureth sulfate, which
is used in everyday
cleaning items.
Olive Oil
14.0
11.2
– Items like Margarin
and Crisco are derived
Corn Oil
12.7
24.7
from hydrogenation of
unsaturated oils. This
Canola Oil
5.3
24.8
process is called "hardHemp Oil
10
75
ening" because they
are higher boiling and
Source: Food Standards Agency (1991). "Fats and Oils".
resistant to oxidation.
McCance & Widdowson's the Composition of Foods.
1
Dijkstra, Hamilton, and Hamm.
Fatty Acid Biosynthesis (via FAS I and II): "Fatty Acid Biosynthesis." Trans Fatty Acids.
O
Oxford: Blackwell Pub., 2008.
O 2C
O
O
O
O
NADPH + H
ACP
SCoA
SACP
SACP
NADP
HS ACP
CO2
as above
O
O
NADPH + H
– H 2O
Synthetic Manipulation of Arachidonic acid: Corey, Tetrahedron Lett. 1982, 23, 2351.
Corey, J. Am. Chem. Soc., 1980, 102 , 1435.
O
HO 2C
1. KI 3, KHCO 3
1. Et 3N, MeOH
O
THF/H2O, 0 °C
2. MsCl, Et 3N
2. DBU, PhH
3
OH O
(73%, 2 steps)
3
CO2Me
O
SACP
SACP
SACP
Tf2O, PMP,
NADP
– Fatty acid synthase II is mainly in
prokaryotic organisms. Capable
O
+ H 2O
of performing anaerobic oxidation
via not performing 2nd reduction
SACP
OH
13
13
– FAS I is common to all life.
HS ACP
palmitic acid
Capable of making medium chain
fatty acids in addition to palmitic
acid.
Chemistry on Fatty Acids and Derivatives:
Hosmane, Organometallics, 2012, 31, 2589.
O
[Ir(coe) 2Cl]2 (2.5 mol%)
dppf, pinBH
MeO 2C
6
5
Bpin
CH2Cl2, [THTdP][DBS]
(47% yield)
6
5
CO/MeOH
> 95% selectivity
MeO 2C
Meier,Eur. J. Lipid Sci. Technol. 2013, 115 , 76.
Pd(OAc) 2 (10 mol%)
1,4-BQ (2 equiv)
CO Me
2
6
MeO 2C
– For a review, see:
Mecking, ACS Catal.
2015, 5, 5951.
5 – For hydroformylation, see: Westfechtel,
Eur. J. Lipid Sci. 2005,
107 , 213.
MeO 2C
1:1 AcOH/DMSO, 50 °C
(81%, 18/1 E/Z)
O
tBu
F 3C
N
Cl
CF3
hv, Cs2CO3, 55 °C
(48% yield)
6
3
3
MeO 2C
MeO 2C
aq. KBr,
AcOH
+
HO
3
Br
OH
Br
2: 1
THF
(95%)
3
O
3
MeO 2C
MeO 2C
1. Tf2O, pyr., CH2Cl2
2. HMPT, CH2Cl2
O
OH Br
3
(85% yield)
O
3
Corey, J. Am. Chem. Soc. 1982, 104 , 1750.
MeO 2C
Alexanian and Vanderwal,
J. Am. Chem. Soc. 2016, 138 , 696.
Cl
MeO 2C
3
MeO 2C
CO2Me
5
(>98%)
3. KHSO 4, CH2Cl2
Me 2S
(63% yield)
AcO
3
Corey, J. Am. Chem. Soc. 1979, 101 , 1585; Corey, J. Am. Chem. Soc. 1980, 102 , 1433.
H
O
HO 2C
O
1. (imid)2CO, CH2Cl2
4. CH2N 2
O
2. H 2O 2, Li(imid)
VO(acac)2, TBHP,
PhH;
5
3. H 2O 2, Et 2O
–110 °C
(41% yield)
CO2Me
OOH
CH2Cl2,–78 °C;
Et 3N, hexane
(33% yield)
MeO 2C
Cole-Hamilton, Inorg. Chem. Commun. 2005, 8, 878.
MeO 2C
(dtbpx)Pd(OTf)2 (1 mol%)
6
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Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
+ regioisomers
Br
OH
3
+ regioisomer
MeO 2C
CrO3,
H 2SO4
acetone,
–20 °C
(82%)
Br
O
+ regioisomer
3
1. TsNHNH2
AcOH,
CH2Cl2, HQ
2. LiOH,
DME/H 2O
HO 2C
3
(52% yield)
2
Chlorosulfolipids (a neglected natural product family, until recently)
Cl OSO 3
Cl Cl
OSO 3
C6H13
Cl Cl Cl
Cl OSO 3 Cl
danicalipin A
OSO 3 Cl
Cl
Cl
Me
palmityl
Cl
OSO 3 Cl
7
OH
Cl
OH
Cl
Cl Cl Cl
X = OH, mytilipin B
X = H, mytilipin C
Stereoselective Chlorination: Vanderwal, J. Am. Chem. Soc. 2008, 130 , 12514.
OX
Et 4NCl 3
Bu
CH2Cl2, temp.
Cl
Cl
Cl
Ph
+
X
temp
H
Me
TBS
CO2Me
Boc
Ac
Piv
Cl3CCO
F 3CCO
dr (A/B)
–78
–78
–78
–78
–78
–78
–90
–90
–90
Cl
Cl
OTBS
Ph
Cl
70%, 10.9:1 dr
TCAO
Cl OMe
C6H13
Cl
2. OsO 4, NMO
(47%, 2 steps)
Cl
OTBS
7
KHMDS
THF, –78 °C to 0 °C
Cl
O
C6H13
Cl Cl
Cl
7
(63%, 2.5:1 Z/E)
Cl
7
Cl
Cl
tBu
Bu
CO2Et
Me
Cl
77%, 8.6:1 dr
TCAO
Cl
Cl
Et 4NCl 3
CH2Cl2
OTBS –78 °C to 0 °C
(97%, 8:1 dr)
OH
C6H13
Cl
Cl
Cl
Cl
OTBS
7
malhamensilipin A
Me
OTBS
TMSCl
O
Cl
OTBS
6
OH
Me
Cl
BF 3 Et 2O
Et 4NCl
OTBS (48% from E/Z misture)
Cl
OTBS
6
(43%, 9.8:1 dr)
CHO
Cl
5 steps
mCPBA
Me
OH
Cl
Me
CH2Cl2
(95%, 1:1 dr)
2. A, nBuLi
THF, –78 °C
(62%, 2 steps)
O
Me
Cl
OH
OSO 3 Cl
Cl
* * *
Cl Cl Cl
Does not match isolation 1H spectrum
Me
(major
isomer)
Cl
Cl
Cl
1. Swern
mechanism?
O
OTBS
6
A
Me
CH2Cl2, EtOAc
1. OsO 4, NMO
2. DABCO, Tf2O
3. CSA, MeOH
(50%, 3 steps)
Cl
PPh 3Br
Cl
Cl
Cl
Cl
1. DIBAL-H (72%)
2. TBSCl (87%)
Cl
Bu
3
Cl
CO2Me steps
C6H13
OH
Cl Cl
Ph 3P
ONs
Carriera's Approach to the Chlorosulfolipids: Carreira, Nature, 2009, 457, 573.
OH
C6H13
CO2Et
Cl
Cl
Cl
2 steps
Cl
OMe
1. Et 4NCl 3
Cl
Bu
OBn Cl
Cl 78%, >20:1 dr
67%, 4.6:1 dr
Total Synthesis of Danicalipin A: Vanderwal, J. Am. Chem. Soc. 2009, 131 , 7570.
CO2Me
OH
C6H13
B
TCAO
Cl
OTBS
as
above
OH
C 8H17
CH2Cl2, –78 °C
(83%, >10:1 dr)
ONs
Cl
TCAO
1:1
2:1
2:1
5:1
5:1
5:1
7.7:1
6.5:1
7.0:1
Cl
Et 4NCl 3
CO2Et
Cl
Ph
A Cl
7
Cl
OH
OX
Bu
Cl
Malhamensilipin A: Vanderwal, J. Am. Chem. Soc. 2010, 132 , 2542.
OH
Cl
Cl
Cl
Cl
2 steps
danicalipin A
X
OH
C6H13
OTBS 2. Bu 3SnH,
BEt 3, O 2
(30%, 2 steps)
Cl
O
Cl
Ph
Cl
C 8H17 OH
malhamensilipin A
OX
Cl
Cl
Cl
Cl
1. ICl, 1.8:1 dr
C6H13
mytilipin A
OSO 3
Cl
OH
Cl
Cl
Cl
Cl
Cl
C 8H17
Cl
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Joel M. Smith
O
steps
OH
(E)-mityllipin A
Cl
change stereochem!
3
Me
Vanderwal's approach to mytillipin A: Vanderwal, Angew. Chem. Int. Ed. 2013, 52, 10052.
Cl
OH Cl2, Et 4NCl
CH2Cl2, 0 °C
(89%)
OH 1. DMP
Cl
5
2 steps
2. CrCl2, CHCl3
(79%, 93:7 E/Z)
Cl
OH
Cl
mytilipin A
Cl
Cl
5
TBSO
BnO
(72% yield)
Cl
N
Cl
O
Me
Me
O
Cl
O
2. Et 4NCl 3
CH2Cl2, 0 °C
(45%, 2 steps)
Cl
5
Cl
O
O
C15H 31OC
TBSO
BnO
Cl
Cl
O
OH
Me
Me
Me
Cl
O
Cl
OH
Me
O
Cl
Cl
Cl
Cl
O 3SO
PhMe, –78 °C to rt
(67%, Z/E = 3:1)
O
O
Cl
Me
Me
NaHMDS,
Fragment A
Cl
Cl
1. Ph 3PCl 2
TBSO
CH2Cl2, 0 °C
Cl
O
Cl Cl Cl
N N
Cl Cl Cl
O
Me
O O O
Ph
S
N
4 steps
OH
Cl
DCE, CH2Cl2
Cl (32% yield, > 20:1 Z/E)
BF 3 Et 2O, Et 4NCl
OH
Fragment B
98:2 dr
30 mol% Grubbs
cycloadamantyl catalyst
5
Cl
Cl Cl Cl
BnO
TBSO
Cl
Br
;
NaOH,
Et 4NCl, H 2O
(52%, 2 steps)
O
O
AlEt2
2.
Me
Me
O
Cl
1. Mg, THF, then DMF
Br
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Joel M. Smith
Cl Cl Cl
O
O
M
Mee
Carraira's approach to mytilipin B: Carreira, Angew. Chem. Int. Ed. 2011, 50, 7940.
Cl
OTBS
Me
OH OH
Cl OH
Cl
6 steps
TBSO
Cl
8
steps
O
Me
O
Cl
Cl
3 PPh 3
Cl
O
CO2Et
OBn
OH
Cl Cl Cl Cl
O
Cl
KHMDS
OAc
Assigned Structure of mytilipin B (spectra did not match original data)
THF, –78 °C
1. Et 4NCl 3,
TBSO
Enantioselective Halogenation: Burns, J. Am. Chem. Soc. 2016, ASAP
(55% yield)
CH2Cl2
TBSO
TBSO
Cl
–78 °C (71%)
R 1 Cl
R1
tBu
O
TBSO
Cl
tBuOCl, TiCl(OiPr)3
BnO
O
HO
Cl
2. K 2CO3
R2
OH
OBn
OH
R2
OH
10-30 mol% (R,S)-L
MeOH
Cl
Cl
R
N
O 3. DMP
Cl
R
3
hexanes,
–20
°C
3
Cl
Ph
tBu
Fragment A
OAc
OH
Cl
1. RedAl
Ph
Cl
2. V(O)(acac)2, TBHP
BnOCH 2CCH
OHC
Me
OH
deschloro3 OTBS
3 OTBS
danicalipin A
Cl Cl
Me
OH
3. DMP
Cl Cl
mytilipin A
(–)-N-Methylephedrine
Cl
4
4. ZrCl4
Zn(OTf)2, Et 3N, PhMe, rt OBn
64% yield, 80% ee
Cl
5. NaBH 4
(70%, 92% ee)
86% yield, 83% ee
1. DIBAL-H
Me Me
Cl
Cl
2. Ti(OiPr)4, tBuO2H,
Cl
OH OH
O
O
malhamensilipin A
(+)-diethyl L-tartrate Me
OH
Cl
4 steps
Ph
OH
6
CH2Cl2, -20 °C
OH
3 OTBS
Cl
Ph
Cl
BnO
Cl Cl Cl
64% yield, 81% ee
BnO
Cl Cl Cl
CO2Me 3. TiCl(OiPr)3, PhH
61% yield, 90% ee 61% yield, 90% ee
(33%, 3 steps)
4
Biosynthesis of the Prostiglandins: Marnett and Rouzer, Chem. Rev. 2003, 103 , 2239.
Enantioselective Synthesis of danacalipin A: Burns, J. Am. Chem. Soc. 2016, ASAP
Cy
B(MIDA) 1. ICl, 2,6-lut.
(74%)
O
2. 1,2-diol, NaOH
Cl
(85%)
B(pin)
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Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
Cy
B
O
Cy
1. LiCHCl 2,
ZnCl2
Cl
O
B
Tyr
TBSO
Cy
I
7
Cl Cl
tBuLi
MgBr 2 Et 2O HO C
2
(24%)
O
Cl
O
O
H
H
4
O
4
O
COX
O
HO 2C
i. nBuLi, TFAA
Cl
OH
Cl
C6H13
Cl
Cl
OD
ii.
Me
(75%)
Cl
Cl
OTBS
7
Cl
CD 3OD
Cl
Cl
CHO
4
arachidonic acid
BR 2* TBSO
7
Cl
OTBS
2. Bu 3SnH
C6H13
BEt 3, air
Cl Cl
3. ClSO3H
(21% overall)
For other approaches to the chlorosulfolipids, see:
T. Yoshimitsu et al. J. Org. Chem.2009 74,696.
T. Yoshimitsu et al. J. Org. Chem. 2010, 75, 5425.
T. Yoshimitsu et al. Org. Lett. 2011, 13 , 908.
F. Matsuda et al. Org.Lett. 2011, 13 , 904.
CO2H
O O
CO2H
Cl
O
1. MeN 4(Cl2Br)
Cl
4 O O
O
4
O
Tyr OH
Cl
O
O
(–)-danacalipin A
without deuteration,
furan formation
predominated.
yield doubled for
dihalogenation
step with exchange
O
4
peroxidase
O OH
CO2H
O
4
OH
CO2H
O
cyclooxygenase and peroxidase are
apart of the same enzyme
all other
prostiglandins
PGH 2
Letter of prostiglandin refers to the structure of the 5-membered ring:
O
O
O
OH
O
OH
OH
Prostiglandins
R1
R1
R1
R1
R1
R1
R1
Fun Facts about Prostiglandins:
O
HO
HO
HO
– Derived from lipids (see biosynthesis) and responsible for steroid-like cell signaling in animals.
R2
R2
R2
R2
R2
R2
R2
– They are produced throughout the body and can produce similar or opposite effects depending
Fα
Fβ
A
B
D
E
C
on the tissue they are secreted. This is dependent on the cell receptors in the particular tissue.
– Two main derivatives: Prostacyclins: Mainly responsible for preventing blood clots; involved in
Prostiglandin arabic numerals refers to degree of sidechain unsaturation.
inflammation and regulation of smooth muscle contraction.
First
total
Synthesis of Prostiglandins: Corey, J. Am. Chem. Soc. 1969, 91, 5675.
Thromboxanes: Facilitate platelet aggregation (thrombosis) and blood-clots.
Cl
– Aspirin is an effective inhibitor of prostiglandin synthesis by acylating COX (cyclooxygenase),
1. KOH,
MeO
which is the enzyme involved in the biosynthesis of prostiglandins.
H 2O, DMSO MeO
CN
– Every parent prostiglandin has 20 carbons and one five-membered ring.
Cl
OMe
2. mCPBA
Cu(BF4)2, 0 °C
O
CH2Cl2
CN
CO2H
CO2H
CO2H
(76%, 3 steps)
CO2H
O
O
HO
O
O
1.
NaOH
O
O
O
name? O
I
2. KI 3
PGI 2
O
PGE2
1.
Ac
O
steps
2
NaHCO 3
(vasodilator)
and
HO
H 2O
OH
OH
2.
Bu
SnH
3
PGF 2α
HO
HO
HO
(72%,
AcO
PGF 2α
AIBN, PhH
OH
PGE2
OMe
2
steps)
route
used
for
OMe
Thromboxin
A2
(99%, 2 steps)
(labor induction)
(labor induction)
HO
therapeutic investigation
(thrombosis)
5
More recent approaches to the Corey Lactone: Rokach, Tetrahedron Lett. 1993, 34, 8245.
Me
S
5
Bu 3SnH, AIBN
O H
Me
steps
O
PhH, 80 °C, 1h
O
CO
Me
2
O
O
O
Me
(38%)
O Me
OH OH
HO
O
O
O
O
Clive, J. Org. Chem. 1999, 64, 2776.
Bu 3SnH,
AIBN
OBn
PhMe
(79%)
OCSOPh
MOMO
H
(tBu) 2SiO
MOMO
OPiv
O Si(tBu)
2
OPIv
mech?
TBAF
(88%)
OH
2 steps
OBn
MOMO
MOMO
HO
O
O
PMBO
PMBO
OH
CO2H
OBn
2. 10% HCl
(53% 2 steps)
O
AcOK
Ac2O, rt;
H 2O 2, AcOH
aq. NaS 2O 6
O
O
+
SePh
3 days
O
MeO
O
Marko´, Tetrahedron Lett.
2005, 46, 3895.
MeO
PhSe
MeO 2C
OMe
TMS3SiH
AIBN
PhH, reflux
O
CO2Me
OMe
O
O
OAc
OH
OBn
Sih synthesis of prostiglandin PGE 1: (a) Sih, Chem. Commun. 1972, 240–241. (b) Sih, J.
Am. Chem. Soc. 1972, 94, 3643. (c) Sih, Ann. N. Y. Acad. Sci. 1971, 180 , 64.
CO2Et
6
CO Et H 2O 2, NaOCl
6 2
O
HO
1. Li
HO
O
4:1
(undesired recycled)
O
CO Et
6 2
C 5H11
CO Et
6 2
OEE
CuI, PBu 3
2. AcOH, H 2O, THF
3. baker's yeast
(28%, 3 steps)
OH
CO Et
6 2
CO Et
6 2
+
DHP
acid
THPO
Other "conjugate addtion"-type approaches: Noyori, Tetrahedron Lett. 1982, 23, 4057
and 5563.
I
C 5H11
MO
O
CO2Me
OHC
OTBS
C 5H11
BF 3 Et 2O
tBuLi, CuI, PBu 3
O
Et
THF,
–78
°C,
1h
2O, –78 °C
TBSO
TBSO
OTBS
(83% yield)
*
OBn
+ epimer
OMe
O
O
O
2 steps
Gibbs, Synlett 1997, 657.
HO
O
2 steps
OBn
OBn
CO2Me
O
Rosini, Org. Lett. 2000, 2, 4145.
O
PhH-THF
0 °C–rt
(57%, 95% ee)
O
CO2H
3 steps
O
HO
OBn
15 Kbar
CO2Me
45 °C
OLi
(90%)
then heat
(93%)
OH
C 5H11
TBSO
TBSO
Ph
LiHN
O
CH2Cl2
40 °C
(50%)
OBPS 3
steps
1. RuCl 3, NaIO 4
Me
THF, rt
("100%")
Rh 2(OAc)2
N2
TBSO
OH
Li Br
OH
Ikeda,Synthesis 1998, 973.
O
CO2Me
OPIv
OPiv
HO
HO
OH
3: 1
OBn
O
O
Baran Group Meeting
4/09/16
Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
PGE 2
methyl
ester
CO2Me
Ph
C 5H11
K
Noyori, J. Org. Chem. 1989, 54,
1785.
I
C 5H11
O
OTBS
TBSO
nBuLi, Me 2Zn,
THF, –78 °C, 1h
, DMAP
Cl
O
HO MeO 2C
C 5H11
2. Bu 3SnH, DTBP
(70%, 2 steps)
TBSO
OTBS
MO
I
C 5H11
OTBS
SiO2, CH2Cl2, rt
(78% overall)
S
1.
2 steps
TBSO
O
O
MeO 2C
O
TBSO
OTBS
CO2Me
5 equiv
HMPA
Et 2O, –78 °C to –40 °C
(71% yield)
K
6
Feringa asymmetric conjugate addition: (a) Feringa, JACS 2001, 123 , 5841. (b) Feringa,
J. Org. Chem. 2002, 67, 7244. (b) For transposition: Grieco, J. Am. Chem. Soc. 1980, 102 , 7587.
Ph
CO2Me
Ph
Zn
TMS
HO
2
5
O
O
Cu(OTf)2 (3 mol%), L*
O
Zn(BH )
Aggarwal's organocatalystic approach: Aggarwal, Nature, 2012, 489, 278.
MeO
PhMe, –40 °C, 18 h, then
OHC
SiMe3
AcO
O
O
5
OMe
Pd(CH 3CN),Cl2 (5 mol%)
O
O
THF, 3 h
O
2. Ac2O
3
5 CO2Me
AcO
Ph
O
O
O
3
6 CO2Me
TMSO
CO Me
6 2
C 5H11
2 steps
Ph
O
P N
O
HO PGE 1 OH
methyl ester
Ph
Ph
Ph
L*
Wulff's creative approach: Wulff, J. Am. Chem. Soc. 1990, 112 , 5660.
I
O(NBu 4)
tBuLi
AcBr
(OC)5Cr
OPMB
AcO
C 5H11
TBSO
OPMB
2 steps
C 5H11
CP Molecules
EnzSOC
O
C 5H11
OH
HO
PGF 2α (over 2 g prepared)
O
O SEnz
O
O
O
O
O
O
O
O
R
O
O
O SEnz
O
O
O
O
–40 °C (38%)
–H2O
O
R
O
O
O
O
O
R
O SEnz
O SEnz
OPMB
O
O
O
PGE 2 methyl ester
and C15 epimer
First natural product synthesis using a Fischer Carbene as an intermediate!
–CO2
[O]
SEnz
O
O SEnz
O
C 5H11
CO2H
O
SEnz
SEnz
TBSO
Bu 2O, 190 °C
(85%)
O
R
OPMB
O
R
R
C 5H11
OTBS
C 5H11
(57%,
2 steps)
HO
Biosynthesis:
O
O
succinic
acid
(OC)5Cr
OAc
HO
NaBH 4
(60%, 2 steps)
1. HCl, THF
2. KOtBu, THF
Ph 3P
CO2H
TBSO
O
C 5H11
OMe
O
TBSO
OAc
CH2Cl2
–40 °C
C 5H11 Et O, –78 °C;
2
then Cr(CO)6;
OPMB
then TBAF
(14%, 98% ee)
O 3, then
vinyl Zn reagents not
compatible with this
approach
Ph
OAc
MeOH
amberlyst 15
MgSO 4
OHC
OMe
O
3
5 CO2Me
Ph
Ph
OHC
OMe
O
TMSCl, Et 3N
OAc
O
then
Bn 2NH 2TFA
OTBS
TMS
Ph
1. TBAF
C 5H11
Li 2(CN)Cu
OH
HO
CHO
(69%)
OH
O
(S)-proline;
OHC
2-thiophenyl
3 Et O, –30 °C
2
CO2Me (38%,
2 steps)
3
Ph
H 2O, 75 °C
O
4 2
O
Baran Group Meeting
4/09/16
Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
HO
HO
O
Spencer, J. Am. Chem. Soc. 2000, 122 , 420.
7
Fukuyama's approach: Fukuyama, J. Am. Chem. Soc. 2000, 122 , 7825.
Shair's approach: Shair, J. Am. Chem. Soc. 2000, 122 , 7424.
O
Bu 2BOTf, Et 3N, DCM
O
O
Bn
N
C 8H15
O
MeO 2C
CO2Me
O
CO2allyl
S
O
O
EtS
O
0 °C, (80%)
O
O
OHC
EtS
O
Baran Group Meeting
4/09/16
Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
Bn
C 8H15
Et 2O, 0 °C R 2N
O
O
O
O
O
MeO 2C
C 5H 9
CO2Me C 8H15
1. ZnCl2 - Et 2O
pyr, CH2Cl2, 1h
MOMO
5
Me
tBuLi
O
5
C 5H 9
OMOM
–78 °C; MgBr 2, rt
CO2Me
OPMB
OPMB
Endiandric acids: Nicolaou, J. Am. Chem. Soc., 1982,
5555 and 5557.
MOMO
O
O
O
C 5H 9
Lindlar's cat.
CH2Cl2, MeOH
quinoline
HO
O
OH
C 8H15
PMBO
HO
OH
HO
disrotatory 6π
OH
3 steps
Ph
Ph
110 °C
H
H
PhMe
OTBS (quant.)
H
HO
OTBS
HO
H
MeO 2C
endiandric acids
A and B
OTBS
110 °C
TBSO
OTBS
OHC
PO(OEt) 2
LDA
THF
(75% yield >20:1 E/Z)
endiandric
acid C
PhMe
(92%)
OH
conrotatory 8π
(45 – 55%)
1. I 2, K 2CO3
CHCl3
2. TBSCl
3. Zn, AcOH
(79 – 80%)
Ph
H
H
O
Br
name?
name?
M
e
Me
BrMgO
5
5
OPMB
R
MOMO
C 8H15
OO
O
CO2Me
R
BrMgO
C 8H15
Nicolaou's approach: Nicolaou, Angew. Chem. 1999, 111 , 1774 and 1781; ACIE. 2002, 41,
2678; J. Am. Chem. Soc., 2002, 124 , 2190; J. Am. Chem. Soc., 2002, 124 , 2183.
1. TPSO
I
CyN
PMBO
1. LDA, Et 2O
nBuLi
–20
°C;
OHC
OHC
C 8H15 THF, –78 °C (92%)
C9H17CHO
2. pyr-SO 3, Et 3N
O O (60%)
DMSO/CH 2Cl2
OO
2. KH, PMBCl
(76%)
(78%)
OTPS
O
O
OTPS
PMBO
RO
Me 2AlCl
CH2Cl2
–10 °C
(90%)
3 steps
Me
(53%, 2 steps)
C 8H15
R = PMB
O
DMF, 65 °C
(80% yield)
CO2Me
EtS
Me
5
Pd 2(dba)3, Ph 3P
I
EtS
MeO 2C CO2Me
MeO 2C CO2Me
Danishefsky's approach: Danishefsky, ACIE. 1998, 37, 1880 and 1877; ACIE. 1999, 38, 1485
and 3197; ACIE, 2000, 39, 4509.
O
TBS
CHO TBS
O
1. LDA, THF, –78 °C
O
H
2. TBSOTf
steps
TBS
H
RO
+
O
O
3. Pd(OAc) 2(PPh3)2
I
Et 3N, THF, 4d
(62%, 3 steps)
HO H
H
OTBS
O (CH2)6OBn
O
O
SnMe3
O
N
O
allylthioglycolate
LHMDS
C 5H 9
O
C 5H 9
2. SO3-pyr, DMSO,
DIPEA (75%)
C 5H 9
O
MeO 2C
MeO 2C
PO(OEt) 2
NaH, THF
OTBS
(80%)
8
Total Synthesis of The Unusual Pentacycloanammoxic Acid
Total Synthesis of Kingianins A, D, and F
Initial Racemic Approach:
For Initial Synthesis, see: Sherburn, Angew. Chem. Int. Ed. 2013, 52, 4221.
For divergence to endiandric acids, see: Sherburn, Chem. Sci. 2015, 6, 3886.
OH
TBSO
O
N
OTBS
O
O
O
OTBS
O
1: 1
O
O
(80% yield, 2 steps)
2 steps
MeHNOC
H
H
1. TPAP, NMO
H 2O, MeCN, rt
2. A, CH2Cl2, 0 *C
O
H
EtHNOC
O
1. A, CH2Cl2, 0 °C
2. TPAP, NMO
H 2O, MeCN, rt
3. EtNH 2, HOBt,
EDC, 40 °C
3. EtNH 2, HOBt,
EDC, 40 °C
(17% yield, 3 steps)
N2
O
O
H
kingianin A O
10 : 3
MeHNOC
H
H
O
H
CONHEt
kingianin D
3
O
O
kingianin F
Br
N
A
3. Swern
(91% yield, 2 steps)
Second Generation/Asymmetric Approach:
Corey, J. Am. Chem. Soc., 2006,128, 3118.
O
hν
H
CHO
O
+
H
H
CO2Me
CONHEt
O
CONHEt
1. hν, MeOH, Et 3N
23 °C (72% yield)
2. DIBAL-H, PhMe, –78 °C
2. NH 2NH 2, CuSO4, O 2
EtOH-H 2O, 23 °C (88% yield)
3. CH2N 2, Et 2O, 0 °C (95% yield)
(37%, 3 steps)
O
(80% yield)
1. LDA, (Br,Ph3P(CH 2)6CO2H
THF, –78 °C to 23 °C (67% yield)
O
Br
2. Zn, AcOH, 95 °C
21% yield, 3 steps
OH
Br
1. H 2, PtO 2, NaNO 2
EtOH/THF, 23 °C
2. hν, MeCN, 50 °C then
AcOH-H2O, 23 °C (6% yield)
H
OH
CbzN
O
H
H
Cbz
N
PhH, 60 °C
(95% yield)
Br
1. HC(OMe) 3, p-TSA
MeOH, 40 °C (91% yield)
1. PhMe, 100 °C
2. TBAF, THF, rt
NCbz
(76% yield)
Rieke Zn
EtOH/THF, 0 °C
H
CbzN
O 2. H 2, Pd-C, EtOH, 23 °C
then O 2, 23 °C
TMS
(3 steps from
3-butyn-1-ol)
O
Br
Cbz
1. hν, cyclopentenone
N
MeCN, 23 °C
CbzN
(40% bsm)
N
CuCl, dry air
DMF, 60 °C
(40%)
(84%, decagram scale)
O
H
O
TMS
ClZn
H
CH2Cl2, –15 °C
2. PdCl 2(dppf),
THF, 66 °C
O
Corey, J. Am. Chem. Soc., 2004,126, 15664.
Br 2
TMS
1. PBr 3, Et 2O (96%)
O
Baran Group Meeting
4/09/15
Lipids (Fatty Acids) in Organic Synthesis
Joel M. Smith
O
7 steps
+
MeCN, –15 °C
(78% yield)
hν, MeCN, rt
(50%)
SiPhMe2
O
O
3 steps
8 steps
O
CHO
Su GM, Cation-Radical
Cycloadditions
CO2Me
Me 2PhSi
9