15.10.03 · orgchem / retrosynthesis

Total synthesis case study: landmark syntheses and the logic of route selection

stub3 tiersLean: nonepending prereqs

Anchor (Master): Nicolaou & Sorensen — Classics in Total Synthesis II (2003)

Intuition Beginner

A total synthesis builds a complex natural product from simple, commercially available starting materials. The word "total" means the chemist makes every bond in the target molecule — nothing is borrowed from a related natural product. Total synthesis is the ultimate test of retrosynthetic planning: the chemist must design a sequence of reactions that constructs the target's entire carbon skeleton, installs every functional group, and sets every stereocentre correctly.

The history of total synthesis begins with Robert Burns Woodward. In 1944, Woodward and William von Eggers Doering published a synthesis of quinine, an antimalarial alkaloid with 20 carbon atoms and four stereocentres. Although the route was not truly "total" in the modern sense — it relied on a naturally occurring fragment for one key intermediate — it demonstrated that complex natural products could be rationally constructed in the laboratory. Woodward went on to complete landmark syntheses of strychnine (1954), chlorophyll (1960), and vitamin B $_{12}$ (1973, with Albert Eschenmoser), earning the 1965 Nobel Prize.

E. J. Corey systematised the logic behind these achievements. Corey introduced the formal concept of retrosynthetic analysis: working backward from the target through deliberate bond disconnections until every fragment is a simple starting material. His 1989 monograph The Logic of Chemical Synthesis ^{[Corey and Cheng 1989]} codified the planning principles — transform-based strategy, topological strategy, and structure-goal strategy — that chemists still use today. Corey received the 1990 Nobel Prize for this contribution.

Total synthesis serves three purposes. First, it proves the structure of a natural product by constructing it from known materials and comparing the product with the isolated compound. Second, it provides access to analogues — modified versions of the natural product — for drug discovery. Third, it drives the development of new reactions and methodologies, because challenging targets expose gaps in the chemist's toolkit.

Visual Beginner

Think of a total synthesis as building a cathedral from individual bricks. The architect (retrosynthetic planner) draws blueprints showing how the finished structure can be broken down into walls, arches, and foundations. Each component is traced back to standard bricks (starting materials). The builders (synthetic chemists) then follow the blueprint forward, assembling the cathedral one piece at a time.

Each level of the tree represents one disconnection. The longest branch from root to leaf determines the longest linear sequence — the number of sequential steps any single molecule must pass through.

Worked example Beginner

Target: Woodward's strychnine synthesis (simplified overview).

Strychnine ( $C_{21} H_{22} N_{2} O_{2}$ ) is a complex alkaloid with seven rings and six stereocentres. When Woodward completed its synthesis in 1954, it was the most complex molecule ever made in the laboratory.

Step 1. Identify the most complex ring junction. Strychnine contains a tryptamine unit (an indole ring fused to a piperidine) attached to a second ring system. The indole is available as a starting material — 2-(3-indolyl)ethylamine.

Step 2. Disconnect the C-C bonds that form the piperidine ring. These bonds are made by electrophilic additions to the indole nucleus. The synthetic equivalents are a tryptamine and an appropriate electrophilic partner carrying the remaining carbon atoms.

Step 3. Disconnect the lactam (amide ring) bond. This bond is formed by condensation of an amine with a carboxylic acid. The synthetic equivalents are straightforward.

Step 4. Continue disconnecting until every fragment is a commercially available material. Woodward's route required approximately 28 steps from tryptamine, using a combination of electrophilic aromatic substitutions, Michael additions, and intramolecular cyclisations to construct the seven rings sequentially.

The key strategic insight was constructing the indole-containing rings first and building the remaining framework outward from that core — an example of the structure-goal strategy where a complex but available starting material anchors the plan.

Check your understanding Beginner

Exercise (easy, multiple choice).

What does "total synthesis" mean in organic chemistry?

A. Synthesising a molecule using every known reaction type B. Building a complex natural product entirely from simple, commercially available starting materials C. Completing a synthesis with 100% yield at every step D. A synthesis that uses only total (complete) reactions rather than partial ones

Hint

The word "total" refers to making the entire molecule from scratch, not borrowing fragments from related natural products.

Answer

B. Total synthesis constructs a complex natural product from simple, commercially available starting materials, forming every bond in the target molecule. The chemist does not rely on any naturally occurring intermediate — every atom is introduced through deliberate chemical reactions.

Formal definition Intermediate+

A total synthesis is a laboratory preparation of a natural product in which every carbon-carbon bond in the target molecule is formed by a deliberate chemical reaction, starting from simple, commercially available precursors. The plan is evaluated by four metrics:

Step count. The total number of synthetic operations, including protecting-group manipulations. Step count correlates with material throughput and operational complexity.
Longest linear sequence (LLS). The maximum number of sequential steps through which any single molecule passes. The overall yield scales approximately as $y^{LLS}$ where $y$ is the average per-step yield.
Overall yield. The fraction of starting material converted to purified target. For a linear plan of $n$ steps at per-step yield $y$ : $Y = y^{n}$ .
Selectivity profile. The number of stereocentres set with correct configuration, expressed as a fraction of the total stereocentres in the target.

Route selection criteria

Given a target, the retrosynthetic planner typically generates several candidate routes. Route selection weighs competing criteria:

Criterion	Description	How it is evaluated
Step economy	Minimise total steps	Count all bond-forming and protecting-group steps
Yield efficiency	Maximise overall yield	Compute $y^{LLS}$ from estimated per-step yields
Stereocontrol	Set all stereocentres correctly	Assess substrate-controlled versus reagent-controlled stereochemistry at each step
Convergence	Minimise LLS via branch points	Compare LLS across candidate topologies
Reliability	Prefer well-precedented reactions	Literature precedent for each transform on similar substrates
Scalability	Amenable to gram-scale preparation	Avoid air-sensitive intermediates, chromatographic purifications, and cryogenic conditions where possible

No route optimises all criteria simultaneously. The planner selects the route whose strengths best match the purpose of the synthesis — a methodology-driven synthesis may tolerate lower yield to test a novel reaction, while a process-chemistry route prioritises scalability and reliability.

Key disconnection strategies in total synthesis

Retrosynthetic analysis of complex targets applies three strategic approaches concurrently:

Transform-based strategy. Identify a high-yielding named reaction whose product motif appears in the target. The Diels-Alder transform is privileged because it forms two C-C bonds and up to four stereocentres in one step. Corey's prostaglandin synthesis (1969) used a Diels-Alder disconnection to construct the cyclopentane core ^{[Corey 1969]}.

Topological strategy. Analyse the carbon skeleton for bonds whose disconnection most reduces complexity. Ring-junction bonds in polycyclic systems, bonds at the branch points of highly branched skeletons, and bonds exploiting molecular symmetry are strategic. Woodward's strychnine synthesis disconnected at the indole-piperidine junction, reducing the seven-ring system to a simpler indole-based framework.

Structure-goal strategy. Start from a commercially available starting material structurally related to the target and work forward. This is effective when the target contains a recognisable substructure such as an amino acid, sugar, or terpene unit.

Counterexamples to common slips

Assuming the shortest route is always best. A 12-step route with unreliable reactions may give lower overall yield than a 15-step route using well-precedented chemistry. Reliability matters as much as step count.
Neglecting protecting-group overhead. A route that looks elegant in its bond-forming steps may require eight protecting-group operations, adding 16 steps (installation and removal) that consume material without advancing the synthesis.
Comparing routes by total step count instead of LLS. A convergent 20-step route with LLS = 8 generally outperforms a linear 15-step route with LLS = 15, because the exponential yield penalty depends on LLS, not total steps.

Key result Intermediate+

Case study: Corey's prostaglandin E $_{1}$ synthesis (1969)

Prostaglandin E $_{1}$ ( $P G E_{1}$ ) is a 20-carbon fatty acid derivative containing a functionalised cyclopentane ring with four stereocentres and three oxygenated substituents. Corey's synthesis is a landmark because it demonstrated the power of retrosynthetic planning applied to a biologically important target.

Retrosynthetic analysis. The cyclopentane ring is the strategic substructure. Corey recognised that the ring could be constructed by a Diels-Alder cycloaddition followed by functional-group manipulations. The key disconnection opens the cyclopentane to a cyclohexene precursor, which is the Diels-Alder product of a diene and a dienophile.

Forward synthesis (simplified).

Step 1. Diels-Alder reaction between cyclopentadiene and an appropriate dienophile gives a functionalised bicyclo[2.2.1]heptene system.

Step 2. Selective oxidative cleavage of the bridgehead double bond opens the six-membered ring to give a functionalised cyclopentane with the correct substitution pattern.

Step 3. Functional-group interconversions install the three oxygenated substituents (two hydroxyl groups and one ketone) with correct stereochemistry, controlled by the facial selectivity of the Diels-Alder step.

Step 4. Wittig reaction attaches the two alkyl side chains, completing the carbon skeleton.

Step 5. Deprotection and final oxidation state adjustments give prostaglandin E $_{1}$ .

Route evaluation. The synthesis uses approximately 15 steps from simple starting materials. The Diels-Alder step sets multiple stereocentres in a single operation, demonstrating the power of the transform-based strategy. The convergent topology — building the cyclopentane core and the side chains separately — reduces the LLS relative to a fully linear approach.

Comparing two routes to the same target

Consider a target molecule containing a functionalised six-membered ring with an exocyclic ketone and a side chain bearing a secondary alcohol. Two candidate routes:

Route A (Diels-Alder approach). Construct the ring by a Diels-Alder reaction between a substituted diene and an acrylate dienophile. The dienophile carries a protected alcohol. After the cycloaddition, the exocyclic ketone is installed by ozonolysis of the endocyclic double bond. The side chain is attached by a Wittig reaction. Total: 10 steps, LLS = 8. Diels-Alder sets two stereocentres with high endo selectivity.

Route B (Robinson annulation approach). Construct the ring by a Robinson annulation (Michael addition followed by intramolecular aldol condensation) from a cyclic ketone and methyl vinyl ketone. The exocyclic ketone is installed by conjugate addition. The side chain is attached by a Grignard reaction. Total: 8 steps, LLS = 8. The Robinson annulation sets one stereocentre, and the remaining stereochemistry must be controlled by substrate effects.

Comparison. Route A has two more steps but sets stereochemistry more reliably through the Diels-Alder step. Route B has fewer steps but requires more careful stereochemical control at the Grignard step. For a target where stereochemical fidelity is paramount (e.g., a pharmaceutical intermediate), Route A is preferred despite its length. For a target where the stereochemistry is less critical or can be resolved later, Route B's step economy wins.

The comparison illustrates the general principle: route selection is a multi-criteria optimisation, and the winning route depends on which criterion the planner prioritises.

Exercises Intermediate+

Exercise 3 (medium, short-answer).

In Corey's prostaglandin E $_{1}$ synthesis, the Diels-Alder reaction is the key strategic step. Explain why the Diels-Alder disconnection was chosen over a polar disconnection (e.g., aldol or Grignard) for constructing the cyclopentane ring.

Hint

The cyclopentane ring has multiple stereocentres and a specific substitution pattern. Consider which reaction sets stereochemistry most efficiently.

Answer

The cyclopentane ring in PGE $_{1}$ contains four stereocentres with specific relative configurations. The Diels-Alder reaction sets multiple stereocentres simultaneously through its concerted, stereospecific mechanism, with the endo transition state providing the correct relative stereochemistry. A polar disconnection (aldol or Grignard) would require separate steps for each stereocentre, increasing the step count and introducing opportunities for epimerisation at each stage. The Diels-Alder was chosen for its ability to establish the stereochemical framework in a single operation.

Exercise 5 (medium, short-answer).

Explain the concept of "step economy" as articulated by Baran, and how it differs from simply minimising the total number of steps.

Hint

Step economy considers the purpose of each step, not just the count. A step that forms a C-C bond with correct stereochemistry is more "economical" than two steps that achieve the same transformation indirectly.

Answer

Step economy, as articulated by Baran, measures the density of productive bond-forming events per step. It differs from minimising total steps because it weights steps by their synthetic impact. A 12-step synthesis where every step forms a C-C bond or sets a stereocentre has higher step economy than a 10-step synthesis where four steps are devoted to protecting-group manipulations. The concept encourages the planner to maximise the fraction of steps that directly advance the molecular construction, even if this means tolerating slightly more total steps when those steps are all productive.

Exercise 6 (hard, short-answer).

Woodward's strychnine synthesis (1954) required approximately 28 steps. A later synthesis by Overman (1993) required approximately 25 steps, and one by Shibasaki (2002) used about 20 steps. Explain why later syntheses of the same natural product tend to be shorter, and discuss whether this means the earlier syntheses were poorly designed.

Hint

Consider what changed between 1954 and 2002: the available reactions, the understanding of reactivity, and the purpose of the synthesis.

Answer

Later syntheses are shorter primarily because the toolkit of available reactions expanded dramatically between 1954 and 2002. Palladium-catalysed cross-coupling reactions (Suzuki, Stille, Heck — developed in the 1970s-1980s), asymmetric catalysis (developed in the 1980s-1990s), and olefin metathesis (Grubbs catalyst, developed in the 1990s) enable bond formations that were impossible or unreliable in Woodward's era. Each new methodology reduces the number of steps needed to accomplish a given structural transformation.

This does not mean the earlier syntheses were poorly designed. Woodward's strychnine synthesis was brilliantly planned given the reactions available in 1954. The purpose also differs: Woodward's synthesis proved that strychnine could be made in the laboratory at all, while later syntheses demonstrate methodology and improve efficiency. The later syntheses stand on the methodological foundations that earlier total synthesis campaigns helped create.

Exercise 7 (hard, short-answer).

Design a retrosynthetic analysis for the following target: a functionalised cyclohexene bearing a ketone at C-1, a protected alcohol at C-3, and a methyl group at C-4 with $(E)$ -geometry relative to the C-5/C-6 double bond. Propose two routes — one using a Diels-Alder disconnection and one using a Robinson annulation — and compare their strategic merits.

Hint

For the Diels-Alder route, identify a diene and dienophile that would give the cyclohexene with the correct substitution pattern. For the Robinson annulation, identify a Michael donor and acceptor. Compare stereochemical control and step economy.

Answer

Diels-Alder route. Disconnect the cyclohexene ring to a diene (e.g., 2-substituted butadiene carrying the C-3 alcohol precursor) and a dienophile (e.g., methyl acrylate or a ketone-bearing acrylate). The Diels-Alder sets the relative stereochemistry of C-3 and C-4 in a single step. The endo transition state places the electron-withdrawing group (which becomes the ketone) and the C-3 substituent in a cis relationship on the cyclohexene. The ketone at C-1 is installed by oxidation of the initial adduct. Merits: excellent stereochemical control, two bonds formed in one step. Drawbacks: regioselectivity may be an issue with unsymmetrical diene/dienophile pairs.

Robinson annulation route. Disconnect to a cyclic ketone (e.g., cyclopentanone) and methyl vinyl ketone. The Michael addition gives a 1,5-diketone, which cyclises via intramolecular aldol condensation to give the cyclohexenone. The C-3 alcohol is installed by reduction of the enone (Luche conditions for 1,2-selectivity, giving the allylic alcohol) and then protected. Merits: fewer steps for the ring construction, well-precedented chemistry. Drawbacks: stereochemical control at C-3 requires substrate-directed reduction, and the $(E)$ -geometry of the exocyclic double bond must be controlled separately.

The Diels-Alder route is preferred when the C-3/C-4 relative stereochemistry is critical. The Robinson route is preferred when step economy is the priority and the stereochemistry can be managed by selective reduction.

Landmark syntheses and the evolution of strategy Master

The history of total synthesis is a record of escalating ambition and methodological innovation. Each landmark synthesis pushed the boundary of what was considered synthetically possible and, in doing so, expanded the toolkit available to all chemists.

Woodward's strychnine (1954)

Strychnine ( $C_{21} H_{22} N_{2} O_{2}$ ) was the most complex natural product synthesised when Woodward completed it in 1954. The molecule contains seven rings (five- and six-membered), six stereocentres, and a dense pattern of nitrogen and oxygen substituents. Woodward's retrosynthetic analysis, though not formalised in Corey's later terminology, applied what would now be called a structure-goal strategy: starting from the commercially available 2-(3-indolyl)ethylamine (tryptamine), the plan built outward from the indole core through a sequence of electrophilic aromatic substitutions, Michael additions, and intramolecular cyclisations.

The key strategic insight was the recognition that the indole nitrogen could serve as an internal nucleophile for ring closure, converting a linear precursor into the polycyclic framework in a single step. Woodward exploited this recognition in a cascade of cyclisations that constructed three rings in rapid succession. The synthesis required approximately 28 steps and proceeded in low overall yield, but it established the principle that retrosynthetic reasoning could solve problems of arbitrary complexity.

Corey's prostaglandins (1969)

Corey's synthesis of prostaglandin E $_{1}$ and E $_{2}$ demonstrated the power of formal retrosynthetic analysis applied to a biologically important target. The prostaglandins are 20-carbon fatty acid derivatives with a functionalised cyclopentane ring. Corey's key strategic decision was to construct the cyclopentane ring from a Diels-Alder adduct rather than by polar cyclisation. The Diels-Alder disconnection produced a simple diene and dienophile as the ultimate starting materials, and the forward synthesis used the stereospecificity of the cycloaddition to set multiple stereocentres correctly.

Corey's synthesis also pioneered the concept of intermediate relay: rather than synthesising every intermediate from scratch, the synthesis was designed so that a key intermediate could be prepared in multi-gram quantities and then diverted to multiple prostaglandin targets. This convergent approach to a family of related natural products is now standard practice in process chemistry.

Kishi's palytoxin (1989, 1994)

Palytoxin ( $C_{129} H_{223} N_{3} O_{54}$ ) is one of the most complex non-protein natural products ever characterised. It contains 64 stereocentres, 8 double bonds with defined geometry, and multiple oxygenated functional groups. Kishi's total synthesis, completed in two parts (the C-1 to C-51 fragment in 1989, the C-52 to C-115 fragment in 1994), remains the longest total synthesis ever completed.

The retrosynthetic strategy was relentlessly convergent. Kishi divided the molecule into eight major fragments, each prepared independently and then coupled in a carefully sequenced series of cross-coupling and aldol reactions. The fragment coupling plan was designed so that the most stereochemically demanding unions occurred on smaller, more manageable fragments before the final assembly.

The synthesis demonstrated several methodological advances: improved methods for stereocontrolled aldol reactions using chiral boron enolates, the use of Nozaki-Hiyama-Kishi (NHK) coupling for C-C bond formation between large fragments, and a protecting-group strategy that employed over 20 different protecting groups from orthogonal classes. The protecting-group tax was nontrivial — approximately 40 of the 70+ total steps were devoted to protection and deprotection — but the scale of the molecule left no alternative.

Baran's protecting-group-free syntheses (2007-present)

Phil Baran challenged the prevailing assumption that complex natural products require extensive protecting-group strategies. Beginning with the synthesis of haouamine A in 2007 and continuing through a series of terpenoid and alkaloid syntheses, Baran demonstrated that careful reagent selection and exploitation of innate chemoselectivity can eliminate many or all protecting-group operations.

The philosophical principle is step economy: every step should advance the molecular construction. A protecting-group installation step does not advance the construction — it merely preserves existing functionality. By selecting reagents whose chemoselectivity matches the target's functional-group hierarchy, Baran's syntheses achieve higher overall yields in fewer steps than earlier routes that relied on protecting groups.

The approach has limitations. Targets with closely spaced, similarly reactive functional groups still require protecting groups. Baran's syntheses tend to succeed best on terpenoid targets, where the functional groups are dominated by alcohols and alkenes with well-separated reactivity. For alkaloid targets containing multiple nitrogen functional groups, protecting groups remain common.

Modern trends: C-H functionalisation and late-stage diversification

The most recent development in total synthesis strategy is the use of C-H functionalisation — the direct conversion of a C-H bond to a C-C, C-O, or C-N bond without pre-functionalisation of the carbon. C-H functionalisation bypasses the traditional sequence of functional-group installation, manipulation, and removal, reducing the step count and protecting-group overhead.

The Baran laboratory's synthesis of ingenol (2013) used a two-phase approach: a "cyclase phase" that constructs the carbon skeleton through C-H functionalisation and radical cyclisations, followed by a "late-stage oxidation phase" that installs oxygen functionality selectively. This two-phase strategy separates the skeletal construction from the oxidation-state installation, simplifying the retrosynthetic analysis and reducing the number of steps.

Late-stage diversification extends this principle: after completing the total synthesis, the final intermediate is subjected to a panel of selective reactions (C-H functionalisation, directed metallation, enzymatic oxidation) to produce a library of analogues. This approach combines the rigour of total synthesis with the efficiency of combinatorial chemistry, and has become the standard strategy in pharmaceutical synthesis of natural-product-derived drug candidates.

Connections Master

Retrosynthetic analysis 15.10.01. This unit applies the disconnection framework and synthon-tree search to the specific challenge of constructing complex natural products. Every landmark synthesis is a worked example of retrosynthetic principles in action.
Multi-step synthesis design 15.10.02 pending. Protecting-group strategies, convergent topology, and yield analysis are the operational tools that make total synthesis feasible. The protecting-group tax is most visible in large-scale total syntheses such as Kishi's palytoxin.
Carbonyl chemistry 15.07.01. The majority of bond-forming steps in landmark total syntheses are carbonyl addition reactions — aldol, Grignard, Michael, and Wittig. Corey's prostaglandin synthesis relies on a sequence of carbonyl manipulations to install the oxygenated substituents.
Palladium-catalysed cross-coupling 15.09.02 pending. Modern total syntheses from the 1990s onward make extensive use of Suzuki, Stille, and Heck reactions for fragment coupling. Kishi's palytoxin synthesis uses NHK coupling, a nickel/chromium-mediated variant.
Olefin metathesis 15.09.03 pending. Ring-closing metathesis (RCM) has become a standard tool for constructing medium and large rings in total synthesis, particularly for macrocyclic natural products such as epothilones and discodermolide.
Amino acids and protein chemistry 15.12.01. The solid-phase peptide synthesis paradigm applies linear multi-step synthesis principles at each amide bond, and the protecting-group strategies used in peptide synthesis (Fmoc/ $t$ -Bu orthogonal set) were developed in parallel with total synthesis methodology.

Historical and philosophical context Master

The concept of total synthesis predates the formalisation of retrosynthetic analysis. Friedrich Wohler's synthesis of urea from ammonium cyanate in 1828 is often cited as the first organic synthesis, though it was a simple rearrangement rather than a planned multi-step construction. The first deliberate total synthesis of a complex natural product is generally attributed to Woodward's quinine work (1944), though even this synthesis relied on a naturally derived intermediate and was completed as a formal synthesis (to a known intermediate) rather than a complete synthesis from simple starting materials.

Woodward's career (1917-1979) defined the field. His syntheses of strychnine (1954), reserpine (1956), chlorophyll (1960), cephalosporin C (1966), and vitamin B $_{12}$ (1973, with Eschenmoser) established total synthesis as a discipline. Woodward's approach was intuitive rather than systematic — he relied on deep knowledge of reaction mechanisms and an exceptional ability to visualise molecular geometry — but his successes demonstrated that complex targets could be rationally planned.

Corey's contribution was to systematise Woodward's intuition. The formalisation of retrosynthetic analysis in the 1960s, the development of LHASA as a computer-assisted planning tool, and the articulation of strategic principles (transform-based, topological, and structure-goal strategies) transformed total synthesis from an art into a methodological discipline. Corey's 1990 Nobel Prize citation specifically recognised "his development of the theory and methodology of organic synthesis."

The modern era of total synthesis has seen a shift in emphasis from proving structures to developing methodology and enabling drug discovery. Baran's protecting-group-free philosophy, the development of C-H functionalisation as a synthetic tool, and the advent of computer-assisted retrosynthetic planning have all contributed to a synthesis culture that values efficiency and innovation as much as sheer ambition. The total synthesis of palytoxin — a 64-stereocentre molecule that required over 70 steps — remains the high-water mark of synthetic ambition, while Baran's syntheses of complex terpenoids in under 15 steps represent the current frontier of synthetic efficiency.

Bibliography Master

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Intuition Beginner

Visual Beginner

Worked example Beginner

Check your understanding Beginner

Formal definition Intermediate+

Route selection criteria

Key disconnection strategies in total synthesis

Counterexamples to common slips

Key result Intermediate+

Case study: Corey's prostaglandin E1​ synthesis (1969)

Comparing two routes to the same target

Exercises Intermediate+

Landmark syntheses and the evolution of strategy Master

Woodward's strychnine (1954)

Corey's prostaglandins (1969)

Kishi's palytoxin (1989, 1994)

Baran's protecting-group-free syntheses (2007-present)

Modern trends: C-H functionalisation and late-stage diversification

Connections Master

Historical and philosophical context Master

Bibliography Master

Case study: Corey's prostaglandin E $_{1}$ synthesis (1969)