Total synthesis

Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. While total synthesis aims for complete construction from simple starting materials, modifying or partially synthesizing these compounds is known as semisynthesis.

Natural product synthesis serves as a critical tool across various scientific fields. In organic chemistry, it tests new synthetic methods, validating and advancing innovative approaches. In medicinal chemistry, natural product synthesis is essential for creating bioactive compounds, driving progress in drug discovery and therapeutic development. Similarly, in chemical biology, it provides research tools for studying biological systems and processes. Additionally, synthesis aids natural product research by helping confirm and elucidate the structures of newly isolated compounds.

The field of natural product synthesis has progressed remarkably since the early 19th century, with improvements in synthetic techniques, analytical methods, and an evolving understanding of chemical reactivity.

Scope and definitions

There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): terpenes, alkaloids, and polyethers. Total synthesis targets are sometimes referred to by their organismal origin such as plant, marine, and fungal. It is not uncommon for natural product targets to feature multiple structural components of several natural product classes.

Aims

Although untrue from an historical perspective (see the history of the steroid, cortisone), total synthesis in the modern age has largely been an academic endeavor (in terms of manpower applied to problems). Industrial chemical needs often differ from academic focuses. Typically, commercial entities may pick up particular avenues of total synthesis efforts and expend considerable resources on particular natural product targets, especially if semi-synthesis can be applied to complex, natural product-derived drugs. Even so, for decades there has been a continuing discussion regarding the value of total synthesis as an academic enterprise. While there are some outliers, the general opinions are that total synthesis has changed in recent decades, will continue to change, and will remain an integral part of chemical research. Within these changes, there has been increasing focus on improving the practicality and marketability of total synthesis methods. The Phil S. Baran group at Scripps, a notable pioneer of practical synthesis have endeavored to create scalable and high efficiency syntheses that would have more immediate uses outside of academia.

History

thumb|right|300px|[[Vitamin B12 total synthesis|Vitamin B12 total synthesis: Retrosynthetic analysis of the Woodward–Eschenmoser total synthesis that was reported in two variants by these groups in 1972. The work involved more than 100 PhD trainees and postdoctoral fellows from 19 different countries. The retrosynthesis presents the disassembly of the target vitamin in a manner that makes chemical sense for its eventual forward construction. The target, Vitamin B12 (I), is envisioned being prepared by the simple addition of its tail, which had earlier been shown to be feasible. The needed precursor, cobyric acid (II), then becomes the target and constitutes the "corrin core" of the vitamin, and its preparation was envisaged to be possible via two pieces, a "western" part composed of the A and D rings (III) and an "eastern" part composed of the B and C rings (IV). The restrosynthetic analysis then envisions the starting materials required to make these two complex parts, the yet complex molecules V–VIII.]]

Friedrich Wöhler discovered that an organic substance, urea, could be produced from inorganic starting materials in 1828. That was an important conceptual milestone in chemistry by being the first example of a synthesis of a substance that had been known only as a byproduct of living processes.

Another gifted chemist is Elias James Corey, who won the Nobel Prize in Chemistry in 1990 for lifetime achievement in total synthesis and for the development of retrosynthetic analysis.

List of notable total syntheses

Quinine total synthesis Synthesized by Robert Burns Woodward in 1951, this was a significant achievement in steroid synthesis.
Cortisone: Another notable steroid synthesis by Robert Burns Woodward in 1951.
Lysergic acid: Synthesized by Robert Burns Woodward in 1954, this was an important precursor to LSD.
Reserpine: Completed by Robert Burns Woodward in 1956, this synthesis was notable for its complexity and the molecule's importance as an antihypertensive drug.
Chlorophyll: Synthesized by Robert Burns Woodward in 1960, this achievement was significant due to chlorophyll's crucial role in photosynthesis.
Colchicine: Another notable synthesis by Robert Burns Woodward, completed in 1963.
Prostaglandin F2α: Synthesized by E.J. Corey in 1969, this was an important achievement in the synthesis of prostaglandins.
Vitamin B12 total synthesis Completed by Robert Burns Woodward and his team in 1972, this synthesis is considered one of the most complex ever achieved, involving over 100 steps.
Paclitaxel (Taxol) total synthesis: First synthesized by Robert A. Holton in 1994, and later by K. C. Nicolaou in 1995, this anticancer drug's synthesis was a major breakthrough in medicinal chemistry.
Brefeldin A: Synthesized by S. Raghavan in 2017, this complex macrolide has potential as an anticancer agent.
Ryanodine: Synthesized by Sarah E. Reisman in 2017, this complex diterpenoid has important biological activity.

References

</references>

External links

The Organic Synthesis Archive
Total Synthesis Highlights
Total Synthesis News
Total syntheses schemes with reaction and reagent indices
Group Meeting Problems in Organic Chemistry