CHIẾN LƯỢC TỔNG HỢP HỮU CƠ

Retrosynthesis
Chương 1: Đại cương về các chiến lược trong tổng
hợp hữu cơ
Chapter 1: The basic for Retrosynthetic Analysis
1.1. Các quá trình tổng hợp nhiều giai đoạn ( Multistep
Chemical Synthesis)

The chemical synthesis of carbon-containing molecules, which are called

carbogens (from the Greek word genus for family), has been a major field of
scientific endeavor for over a century.*

Nonetheless, the subject is still far from fully developed. For example, of the
almost infinite number and variety of carbogenic structures which are capable
of discrete existence, only a minute fraction have actually been prepared and
studied. In addition, for the last century there has been a continuing and
dramatic growth in the power of the science of constructing complex molecules
which shows no signs of decreasing.

The ability of chemists to synthesize compounds which were beyond reach in a

preceding 10-20 year period is dramatically documented by the chemical
literature of the last century.
1.1. Các quá trình tổng hợp nhiều giai đoạn ( Multistep
Chemical Synthesis) (t.t.)

Efficient synthesis requires multistep construction processes which utilize at

each stage chemical reactions that lead specifically to a single structure. The
development of carbogenic chemistry has been strongly influenced by the need
to effect such multistep syntheses successfully and, at the same time, it has
been stimulated and sustained by advances in the field of synthesis.

Carbon chemistry is an information-rich field because of the multitude of

known types of reactions as well as the number and diversity of possible
compounds. This richness provides the chemical methodology which makes
possible the broad access to synthetic carbogens which characterizes today’s
chemistry.

The synthesis of carbogens now includes the use of reactions and reagents
involving more than sixty of the chemical elements, even though only a
dozen or so elements are commonly contained in commercially or biologically
significant molecules.
1.2. Tính phức tạp của phân tử sản phẩm ( Molecular
Complexity)

Molecular size, element and functional-group content, cyclic connectivity,

stereocenter content, chemical reactivity, and structural instability all
contribute to molecular complexity in the synthetic sense. In addition, other
factors may be involved in determining the difficulty of a problem. For instance,
the density of that complexity and the novelty of the complicating elements
relative to previous synthetic experience or practice are important.

The successful synthesis of a complex molecule depends upon the analysis of

the problem to develop a feasible scheme of synthesis, generally consisting of
a pathway of synthetic intermediates connected by possible reactions for the
required interconversions. Although both inductivelassociative and logic-
guided thought processes are involved in such analyses, the latter becomes
more critical as the difficulty of a synthetic problem increases.
1.2. Tính phức tạp của phân tử sản phẩm ( Molecular
Complexity) (t.t.)

Logic can be seen to play a larger role in the more sophisticated modern
syntheses than in earlier (and generally simpler) preparative sequences. As
molecular complexity increases, it is necessary to examine many more possible
synthetic sequences in order to find a potentially workable process, and not
surprisingly, the resulting sequences are generally longer.

After a synthetic plan is selected the chemist must choose the chemical
reagents and reactions for the individual steps and then execute, analyze and
optimize the appropriate experiments..

.
1.2. Tính phức tạp của phân tử sản phẩm ( Molecular
Complexity) (t.t.)

For complex molecules even much-used standard reactions and reagents may
fail, and new processes or options may have to be found. Also, it generally
takes much time and effort to find appropriate reaction conditions. The time,
effort, and expense required to reduce a synthetic plan to practice are generally
greater than are needed for the conception of the plan

Molecular complexity can be used as an indicator of the frontiers of synthesis,

since it often causes failures which expose gaps in existing methodology. The
realization of such limitations can stimulate the discovery of new chemistry and
new ways of thinking about synthesis
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis)
During the last quarter of the 19th century many noteworthy syntheses were
developed, almost all of which involved benzenoid compounds. The
carbochemical industry was launched on the basis of these advances and the
availability of many aromatic compounds from industrial coal tar. Very little
planning was needed in these relatively simple syntheses. Useful synthetic
compounds often emerged from exploratory studies of the chemistry of
aromatic compounds.

The starting point for a synthesis was generally the most closely related
aromatic hydrocarbon and the synthesis could be formulated by selecting the
reactions required for attachment or modification of substituent groups.
Associative thinking or thinking by analogy was sufficient

The same can be said about most syntheses in the first quarter of the 20th
century with the exception of a minor proportion which clearly depended on a
more subtle way of thinking about and planning a synthesis. Among the best
examples of such syntheses are those of α-terpineol (W. H. Perkin, 1904),
camphor (G. Komppa, 1903; W. H. Perkin, 1904), and tropinone (R. Robinson,
1917).
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)

During the next quarter century this trend continued with the achievement of
such landmark syntheses as the estrogenic steroid equilenin (W. Bachmann,
1939),protoporphrin IX (hemin) (H. Fischer, 1929),2,4 pyridoxine (K. Folkers,
1939),and quinine (R. B. Woodward, W. von E. Doering, 1944) . In contrast to
the 19th century syntheses, which were based on the availability of starting
materials that contained a major portion of the final atomic framework, these
20th century syntheses depended on the knowledge of reactions suitable for
forming polycyclic molecules and on detailed planning to find a way to apply
these methods.
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
In the post-World War II years, synthesis attained a different level of
sophistication partly as a result of the confluence of five stimuli:
(1) the formulation of detailed electronic mechanisms for the fundamental
organic reactions,
(2) the introduction of conformational analysis of organic structures and
transition states based on stereochemical principles, (
(3) the development of spectroscopic and other physical methods for structural
analysis,
(4) the use of chromatographic methods of analysis and
separation
(5) the discovery and application of new selective chemical reagents.

As a result, the period 1945 to 1960 encompassed the synthesis of such

complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward,
R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork,
1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin
V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll
(R. Woodward, 1960)
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
The 1959 ‘s was an exhilarating period for chemical synthesis-so much so that
for the first time the idea could be entertained that no stable carbogen was
beyond the possibility of synthesis at some time in the not far distant future.
Woodward’s account of the state of “organic” synthesis in a volume dedicated
to Robert Robinson on the occasion of his 70th birthday indicates the spirit of
the times.9 Long multistep syntheses of 20 or more steps could be undertaken
with confidence despite the Damocles sword of synthesis-only one step need
fail for the entire project to meet sudden death.

It was easier to think about and to evaluate each step in a projected synthesis,
since so much had been learned with regard to reactive intermediates, reaction
mechanisms, steric and electronic effects on reactivity, and stereoelectronic
and conformational effects in determining products.
1.3 Các suy nghĩ định hướng cho quá trình tổng hợp (
Thinking about synthesis) (t.t.)
It was possible to experiment on a milligram scale and to separate and identify
reaction products. It was simpler to ascertain the cause of difficulty in a failed
experiment and to implement corrections. It was easier to find appropriate
selective reagents or reaction conditions. Each triumph of synthesis
encouraged more ambitious undertakings and, in turn, more elaborate planning
of syntheses.

However, throughout this period each synthetic problem was approached as a

special case with an individualized analysis. The chemist’s thinking was
dominated by the problem under consideration. Much of the thought was either
unguided or subconsciously directed. Through the 1950’s and in most schools
even into the 1970’s synthesis was taught by the presentation of a series of
illustrative (and generally unrelated) cases of actual syntheses.

Chemists who learned synthesis by this “case” method approached each

problem in an ad hoc way. The intuitive search for clues to the solution of the
problem at hand was not guided by effective and consciously applied general
problem-solving techniques
1.4. Phân tích chiến lược tổng hợp hữu cơ ( Retrosynthesis
analysis)
Reactions were classified according to the types of substrates that underwent
the chemical change (for example “aromatic substitution,” “carbonyl addition,”
“halide displacement,” “ester condensation”). Chemistry was taught and learned
as transformations characteristic of a structural class (e.g. phenol, aldehyde) or
structural subunit type (e.g. nitro, hydroxyl, α,β-enonel).

The natural focus was on chemical change in the direction of chemical

reactions, i.e. reactants ® products. Most syntheses were developed, as
mentioned in the preceding section, by selecting a suitable starting material
(often by trial and error) and searching for a set of reactions which in the end
transformed that material to the desired product (synthetic target or simply
TGT).
1.4. Phân tích chiến lược tổng hợp hữu cơ ( Retrosynthesis
analysis)
By the mid 1960’s a different and more systematic approach was developed which
depends on the perception of structural features in reaction products (as
contrasted with starting materials) and the manipulation of structures in the
reverse-synthetic sense. This method is now known as retrosynthetic or
antithetic analysis. Its merits and power were clearly evident from three types of
experience.
First, the systematic use of the general problem-solving procedures of
retrosynthetic analysis both simplified and accelerated the derivation of
synthetic pathways for any new synthetic target.

Second, the teaching of synthetic planning could be made much more logical
and effective be its use.

Finally, the ideas of retrosynthetic analysis were adapted to an interactive

program for computer-assisted synthetic analysis which demonstrated
objectively the validity of the underlying logic.Indeed, it was by the use of
retrosynthetic analysis in each of these ways that the approach was further
refined and developed to the present level.
1.4. Phân tích chiến lược tổng hợp hữu cơ ( Retrosynthesis
analysis)

Retrosynthetic (or antithetic) analysis is a problem-solving technique for

transforming the structure of a synthetic target (TGT) molecule to a sequence of
progressively simpler structures along a pathway which ultimately leads to
simple or commercially available starting materials for a chemical synthesis.

The transformation of a molecule to a synthetic precursor is accomplished by

the application of a transform, the exact reverse of a synthetic reaction, to a
target structure. Each structure derived antithetically from a TGT then itself
becomes a TGT for further analysis.
1.4. Phân tích chiến lược tổng hợp hữu cơ ( Retrosynthesis
analysis)

Repetition of this process eventually produces a tree of intermediates having

chemical structures as nodes and pathways from bottom to top corresponding
to possible synthetic routes to the TGT. Such trees, called EXTGT trees since
they grow out from the TGT, can be quite complex since a high degree of
branching is possible at each node and since the vertical pathways can include
many steps.

This central fact implies the necessity for control or guidance in the generation
of EXTGT trees so as to avoid explosive branching and the proliferation of
useless pathways. Strategies for control and guidance in retrosynthetic analysis
are of the utmost importance,
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
In order for a transform to operate on a target structure to generate a synthetic
predecessor, the enabling structural subunit or retron8 for that transform must
be present in the target. The basic retron for the Diels-Alder transform, for
instance, is a six-membered ring containing a π-bond, and it is this
substructural unit which represents the minimal keying element for transform
function in any molecule. It is customary to use a double arrow (=>) for the
retrosynthetic direction in drawing transforms and to use the same name for the
transform as is appropriate to the reaction. Thus the carbo-Diels-Alder
transform (tf.) is written as follows:
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
The Diels-Alder reaction is one of the most powerful and useful processes for the
synthesis of carbogens not only because it results in the formation of a pair of bonds and
a six-membered ring, but also since it is capable of generating selectively one or more
stereocenters, and additional substituents and functionality. The corresponding
transform commands a lofty position in the hierarchy of all transforms arranged
according to simplifying power.

The Diels-Alder reaction is also noteworthy because of its broad scope and the
existence of several important and quite distinct variants. The retrons for these variants
are more elaborate versions, i.e. supra retrons, of the basic retron (6- membered ring
containing a π-bond), as illustrated by the examples shown in Chart 1, with exceptions
such as (c) which is a composite of addition and elimination processes.
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)

Given structure 1 as a target and the recognition that it contains the retron for
the Diels-Alder transform, the application of that transform to 1 to generate
synthetic precursor 2 is straightforward. The problem of synthesis of 1 is then
reduced retrosynthetically to the simpler task of constructing 2, assuming the
transform 1 => 2 can be validated by critical analysis of the feasibility of the
synthetic reaction. It is possible, but not quite as easy, to find such
retrosynthetic pathways when only an incomplete or partial retron is present.
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
For instance, although structures such as 3 and 4 contain a 6-membered A ring
lacking a π-bond, the basic Diels-Alder retron is easily established by using
well-known transforms to form 1. A 6-membered ring lacking a π-bond, such as
the A ring of 3 or 4, can be regarded as a partial retron for the Diels-Alder
transform. In general, partial retrons can serve as useful keying elements for
simplifying transforms such as the Diels-Alder.
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
For instance, although structures such as 3 and 4 contain a 6-membered A ring
lacking a π-bond, the basic Diels-Alder retron is easily established by using
well-known transforms to form 1. A 6-membered ring lacking a π-bond, such as
the A ring of 3 or 4, can be regarded as a partial retron for the Diels-Alder
transform. In general, partial retrons can serve as useful keying elements for
simplifying transforms such as the Diels-Alder.
1.5. Chuyển hóa và các phân tử cơ bản ( Transforms and
retrons)
1.6. Các loại chuyển hóa ( Types of transforms)

There are many thousands of transform which are potentially useful in

retrosynthetic analysis just as there are very many known and useful chemical
reactions. It is important to characterize this universe of transforms in ways
which will facilitate their use in synthetic problem solving.

One feature of major significance is the overall effect of transform application

on molecular complexity. The most crucial transforms in this respect are those
which belong to the class of structurally simplifying transforms.

They effect molecular simplification (in the retrosynthetic direction) by

disconnecting molecular skeleton (chains (CH) or rings (RG)), and/or by
removing or disconnecting functional groups (FG), and/or by removing ® or
disconnecting (D) stereocenters (ST). The effect of applying such transforms
can be symbolized as CH-D, RG-D, FG-R, FG-D, ST-R, or ST-D, used alone or
in combination.
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
1.5. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)

Transforms may also be distinguished according to retron type, i.e. according to

the critical structural features which signal or actuate their application. In
general, retrons are composed of the following types of structural elements,
singly or in combination (usually pairs or triplets): hydrogen, functional group,
chain, appendage, ring, stereocenter.

A specific interconnecting path or ring size will be involved for transforms

requiring a unique positional relationship between retron elements. For other
transforms the retron may contain a variable path length or ring of variable size.

The classification of transforms according to retron type serves to organize

them in a way which facilitates their application. For instance, when confronted
with a TGT structure containing one or more 6- membered carbocyclic units, it
is clearly helpful to have available the set of all 6-ring-disconnective transforms
including the Diels-Alder, Robinson annulation, aldol, Dieckmann, cation-π
cyclization, and internal SN2 transforms.
1.6. Các loại chuyển hóa ( Types of transforms)

The reduction of stereochemical complexity can frequently be effected by

stereoselective transforms which are not disconnective of skeletal bonds.
Whenever such transforms also result in the replacement of functional groups
by hydrogen they are even more simplifying.

Transforms which remove FG’s in the retrosynthetic direction without removal

of stereocenters constitute another structurally simplifying group. Chart 3
presents a sampling of FG- and/or stereocenter-removing transforms most of
which are not disconnective of skeleton.
1.6. Các loại chuyển hóa ( Types of transforms)

There are many transforms which bring about essentially no change in

molecular complexity, but which can be useful because they modify a TGT to
allow the subsequent application of simplifying transforms. A frequent
application of such transforms is to generate the retron for some other
transform which can then operate to simplify structure.

There are a wide variety of such non-simplifying transforms which can be

summarized in terms of the structural change which they effect as follows:

1. molecular skeleton: connect or rearrange

2. functional groups: interchange or transpose
3. stereocenters: invert or transfer
1.6. Các loại chuyển hóa ( Types of transforms)

Functional group interchange transforms (FGI) frequently are employed to allow

simplifying skeletal disconnections. The examples 9 => 10 and 11 => 12+13, in
which the initial FGI transform plays a critical role, typify such processes.
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)

The transposition of a functional group, for example carbonyl, C=C or C≡C,

similarly may set the stage for a highly effective simplification, as the
retrosynthetic conversion of 14 to 15 + 16 shows.
1.6. Các loại chuyển hóa ( Types of transforms)

Rearrangement of skeleton, which normally does not simplify structure, can

also facilitate molecular disconnection, as is illustrated by examples 17 => 18 +
19 and 20 => 21.
1.6. Các loại chuyển hóa ( Types of transforms)
The last category of transforms in the hierarchy of retrosynthetic simplifying power are
those which increase complexity, whether by the addition of rings, functional groups
(FGA) or stereocenters.

The corresponding synthetic reactions generally involve the removal of groups which no
longer are needed for the synthesis such as groups used to provide stereocontrol or
positional (regio-) control, groups used to provide activation, deactivation or protection,
and groups used as temporary bridges.

The retrosynthetic addition of functional groups may also serve to generate the retron for
the operation of a simplifying transform. An example is the application of hydrolysis and
decarboxylation transforms to 22 to set up the Dieckmann retron in 23.
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
1.6. Các loại chuyển hóa ( Types of transforms)
The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or
diastereoselective processes) obviously requires the addition of such units
retrosynthetically, as illustrated by the antithetic conversion 34 =>35.
1.6. Cách Chọn chuyển hóa ( Selecting transforms)

Fundamental to the wise choice of transforms is the

awareness of the position of each transform on the
hierarchical scale of importance with regard to
simplifying power and the emphasis on applying those
transforms which produce the greatest molecular
simplification.
1.8. Các kế hoạch để phân tích chiến lược tổng hợp ( Types
of stratergies for retrosynthesis analysis)

In brief these strategies may be summarized as follows.

1. Transform-based strategies-long range search or look-ahead to

apply a powerfully simplifying transform (or a tactical combination
of simplifying transforms to a TGT with certain appropriate keying
features. The retron required for application of a powerful
transform may not be present in a complex TGT and a number of
antithetic steps (subgoals) may be needed to establish it.

2. Structure-goal strategies directed at the structure of a potential

intermediate or potential starting material. Such a goal greatly
narrows a retrosynthetic search and allows the application of
bidirectional search techniques.
1.8. Các kế hoạch để phân tích chiến lược tổng hợp ( Types
of stratergies for retrosynthesis analysis)

3. Topological strategies:the identification of one or more

individual bond disconnections or correlated bond-pair
disconnections as strategic. Topological strategies may also lead
to the recognition of a key substructure for disassembly or to the
use of rearrangement transforms.
1.8. Các kế hoạch để phân tích chiến lược tổng hợp ( Types
of stratergies for retrosynthesis analysis)

4. Stereochemical strategies general strategies which remove

stereocenters and stereorelationships under stereocontrol.

Such stereocontrol can arise from transformmechanism control or

substrate-structure control. In the case of the form the retron for a
particular transform contains critical stereochemical information
absolute or relative) on one or more stereocenters.

Stereochemical strategies may also dictate the retention of certain

stereocenter(s) during retrosynthetic processing or the joining of
atoms in three-dimensional proximity.
1.8. Các kế hoạch để phân tích chiến lược tổng hợp ( Types
of stratergies for retrosynthesis analysis)

5. Functional group-based strategies. The retrosynthetic reduction

of molecular complexity involving functional groups (FG’s) as
keying structural submits takes various forms.

Single FG’s or pairs of FG’s (and the interconnecting at path) can

(as retrons) key directly the disconnection of a TGT skeleton to
form simpler molecules or signal the application of transforms
which replace function groups by hydrogen.

Functional group interchange (FGI) is a commonly usentactic for

generating from a TGT retrons which allow the application of
simplifying transforms. FG’s may key transforms which
stereoselectively remove stereocenters, break topologically
strategic bonds or join proximate atoms to form rings.
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