CHEMICAL SYNTHESIS FATTY ACIDS

can be isolated from natural sources or purchased commercially at purity of 70-95% chemical synthesis becomes necessary when FA are

o not readily isolated from natural sources due to lack of rich sources (i.e. myristoleic acid) o not known to occur naturally such as the many stereoisomers of octadecenoic acid o required in an isotopycally labeled form (2H, 3H, 13C, 14C) for the study of reaction

mechanism and biochemical processes some acids can be made by chain extension of readily available starting acids Unsaturated FA

o Acetylenic reaction - based on the ability of the acetylene (ethyne) to be alkylated once or twice and the ability of the triple bond to be partially reduced stereospecific olefinic (double-bonded) compounds

can produce polyenes ex. reaction between propargyl bromides and ethynyl compounds as

organometallic derivatives – mainly sodium, lithium and magnesium – in the presence of cuprous salt:

Silver ion chromatography is used to remove over-reduced and/or trans-olefinic

isomers to purify the polyenes o Wittig reaction - an alkyl halide and its phosphonium salt reacts with a base to produce

ylid that is subsequently condensed with an aldehyde

product may be a mixture of cis- or trans-isomers Cis is favored at low temperature, high dilution and absence of Li+, while sodium

bistrimethyl-silylamide is recommended as the base Incorporation of isotopic hydrogen or carbon

o Deuterium incorporated by exchange or reduction (hydrogenation) Hydrogen on carbon atom adjacent to an aldehyde or ketone function is replaced

by deuterium from 2H2O with mildly acidic or basic catalyst which promotes enolization

Carboxylic acids need more vigorous conditions

Complex FA – Prostaglandins

o first main contributions in this field are those from Corey in 1869 o uses bicycloheptane precursur (Corey’s lactone), one of the most successful building

blocks which is also used for the industrial production of PG analogs o commercially available lactone can be converted into the dialdehyde and in the classical

approach side chains introduced by Wittig and Wittig-Horner reactions. o His synthesis of PGF2 and PGE are shown in the following figure:

POLYKETIDES Aims of organic synthesis of PK

o to develop new synthetic routes to polyketide aromatic systems (i.e. benzenes, naphthalenes, anthracenes)

o to carry out mechanistic studies on the chemical factors that govern the inherent preference for one cyclisation mode over another and the role of enzymes in controlling ring formation in vivo

Simple PK o developed by Tom Harris in the 1970s o involves condensation of poly-anions of polyketones with acylating agents o ex. condensation of acetate with the acetoacetate anion resulting in polyketone

Complex PK

o common technique in formulating the total synthesis of polyketides is through retrosynthesis

the product (the polyketide itself) is methodologically broken down in order to obtain an idea on what starting material and processes to use and follow

o examples: o Pteridic acids A and B - spiroacetal-containing polyketides, isolated by Igarashi et al. from

a fermentation broth of Streptomyces hygroscopicus TP-A0451 Preliminary biological testing indicated potent plant growth promoter properties,

inducing the formation of adventitious roots in kidney beans at exceptionally low concentrations

(Z)-enone (7) was thought to function as a suitable acyclic precursor Produced from coupling of the C1-C11 aldehyde (8) with the C12-C16 vinyl

bromide (9)

C1-C11 aldehyde (8)

began with a boron-mediated anti aldol reaction to rapidly establish the required C6-C10 stereopentad.

formation of the (E)-enolate of the Roche ester derived ethyl ketone ((S)-10) upon treatment with c-Hex2BCl/Et3N

followed by addition of the a-chiral aldehyde ((R)-(11)) anti-anti aldol adduct (12) was generated in 87% yield with excellent

selectivity (>99:1 dr) installation of the remaining C7 stereocentre achieved using an Evans-

Saksena hydroxyl-directed reduction

treatment of (12) with Me4NBH(OAc)3 in MeCN/AcOH (3:1) provided the corresponding 1,3-anti diol (13) in 87% yield and 95:5 dr

convertion into the acetonide (14) by (MeO)2CMe2 in the presence of catalytic acid (PPTS)

hydrogenolysis of the PMB ether (H2, Pd(OH)2) Oxidation of the resulting alcohol (15) using Dess-Martin periodinane

(DMP) (15) led smoothly to the corresponding aldehyde (16) elaboration of the diene side chain of the pteridic acids was undertaken

via a Hornere-Wadsworthe-Emmons olefination high degree of selectivity for the desired (E,E)-diene (17) (>95:5) was

achieved using triethyl- 4-phosphonocrotonate with LiHMDS as base Finally, TBAF-mediated cleavage of the TBS ether, followed by Dess-

Martin oxidation of the resulting alcohol (18) to give the aldehyde (8) (79%, 3 steps)

C12-C16 vinyl bromide coupling partner (9)

preparation of the ketone (19) via a second antiselective boron aldol reaction

Weinreb amide (20) derived from ethyl (S)-lactate was treated with n-PrMgCl followed by benzoylation to give the propyl ketone ((S)-21)

enolization of (21) with c-Hex2BCl/Me2Net followed by addition of acetaldehyde at -85C, generated the desired anti

adduct (22) (90:10 dr) TBS ether formation to give the b-siloxy ketone (19) one-pot NaBH4 reduction/ester solvolysis cleavage of the resulting glycol with NaIO4 to generate aldehyde (23) in

92% overall yield treatment of (23) with CBr4 and PPh3 converted the aldehyde into the

corresponding vinyl dibromide (24) (18) the less hindered bromide of which was selectively reduced

(Pd(PPh3)4, Bu3SnH)19 to provide the necessary (Z)-alkenyl bromide (9)

Coupling Reaction of 9 and 8

generation of the corresponding (Z)-alkenyl lithium species, via treatment of the bromide (9) with tert-butyl lithium in Et2O at -78C followed by addition of the aldehyde (8)

generated two epimeric alcohol adducts subjected directly to Dess-Martin oxidation to give the (Z)-enone (7) in 53% overall yield

end product required suitable acid treatment to cleave the TBS ether and acetonide groups, thereby inducing spiroacetalization of the resulting triol with the C11 ketone

saponification of the esters to produce the corresponding acids separate treatment of the epimeric ethyl esters with KOH in EtOH

generated pteridic acids A (25/5, 76%) and B (26/6, 73%).

o Graphislactone A - identified as reduction product of the fungal metabolite botrallin in

1968 first isolated as a natural product from the lichen Graphis scripta var. pulverulenta an antioxidant and a scavenger of free radicals as well as a moderate inhibitor of

AChE Retrosynthesis of the target compound suggested a Suzuki coupling as key step

for the construction of the central biaryl bond Boronate (4) prepared according to a published procedure starting with

commercially available acetal-protected phloroglucinic acid (2) or, with one more step necessary, from phloroglucinic acid (1) other component, aryl bromide (12) required for a Suzuki coupling was

prepared essentially according to a known protocol starting with

commercially available orsellinic acid (6), which can be easily prepared in two steps from orcinol (5) with 65% yield

methyl ester (7) obtained with methyl iodide and potassium carbonate

(91%) chlorination with freshly distilled sulfuryl chloride afforded chlorinated

methyl orsellinate (8) in 95% yield, while the dichlorinated substrate (9) was obtained in traces

separation simply achieved by recrystallization selective methylation of the 4-hydroxyl group with subsequent

saponification (10) and decarboxylation using 2,2-bipyridyl in the presence of CuO2 at elevated temperature (160C) furnished the known compound (11) with 58% yield

aryl bromide (12) suitable for a Suzuki coupling was obtained by bromination with N-bromosuccinimide

Suzuki coupling of aryl bromide (12) and boronate (4) with concomitant

lactonization was achieved with a protocol, which previously proved itself suitable for the synthesis of similar compounds, thus yielding the natural product graphislactone G in 72%

reaction occurred with complete chemoselectivity, no Suzuki coupling of the chloro function was observed.