VIII Fortuitous Symmetry Elements and Pattern Recognition

Many natural products, or sub-units within them, possess elements of symmetry; some are very
obvious, others less so. However if they can be recognised and exploited in a synthetic strategy,
they usually reduce the number of steps and greatly simplify the problem.

Examples:

O
O O
O
O O x2
OH OH
O
O
pyrenophorin

O O O O
O H H
HO OH x2
HO H
H H
O O
H H O

O HO OH x2
H H O
O O O H H

nonactin
O
S
O N
H H
N N N
N
O
NH S S HN ulithiacyclamide
O
N N N N
H H O
N
S
calycanthine O

Symmetry in molecules is often disguised. Dimerisation reactions are frequently observed in

biosynthetic pathways. Subsequent transformations however can make the two monomers
difficult to identify.
Consider a retrosynthesis for the following benzyl isoquinoline alkaloid:

HO HO

NMe NMe
HO HO
H H
HO HO still no symmetry
oxidative phenol elements
coupling
HO HO

no symmetry elements intramolecular

Mannich
HO NHMe
HO
HO
NMe
reductive HO
amination HO
HO O
HO
H
HO

The molecule looks as though it may be a dimer of a functionalised catechol but in its natural form
there are no obvious symmetry elements. Two strategic disconnections reveal a possible
synthetic approach starting from the catechol aldehyde.

HO O

H
HO

HO O H2NMe HO NHMe
heat
H NaCNBH3
HO HO

HO HO

NMe Fe(III) NMe

HO HO
HO HO

HO HO

This synthetic approach would be described as BIOMIMETIC in that Nature constructs this
molecule in a similar way, although obviously with different reagents and under milder conditions.
VIII.A Two-Directional Synthesis

Using two-directional synthesis, a molecule is constructed by starting from a central core and
moving outwards in two − rather than just one − directions. Two reactions are therefore
performed at a time installing two identical functional groups in each step. This strategy is
therefore only applicable to molecules possessing a relatively high degree of symmetry. Two-
directional syntheses generate symmetrical products; however at some point it is usually
necessary to break up the symmetry, most commonly by differentiating the chain termini. This
can be achieved in a number of interesting and creative ways depending on the type of symmetry
element present in the chain. We will see later how two-directional chain synthesis has been
applied with particular success to the preparation of the skipped (1, 3, (2n+1)) polyol motif found
in an important class of polyketide macrolide antibiotics.

For good reviews:

i) S. R. Magnuson, Tetrahedron, 1995, 51, 2167-2213.
ii) C. S. Poss, S. Schreiber, Acc. Chem. Res., 1994, 27, 9-17.

Two-Directional Approach to Acyclic Chain Preparation

Compare the linear and two-directional approaches.

A B

linear approach A B
3 2 1

A A A A B

1 1
two-directional approach A B (two-bond disconnection)

A B
form two bonds differentiate the
simultaneously termini

A number of approaches can be used to differentiate the chain termini. These are best illustrated
by example.
VIII.A.1 Achiral Chain (including meso compounds)

X X X X

A B
Z Z Z Z Z Z

enantiotopic chain termini

In this case the molecule is not chiral until the enantiotopic termini have been differentiated.

Schreiber's synthesis of (+)-KDO:

D-(−)-DIPT
OH OH
Ti(OiPr)4
BnO OBn BnO OBn
TBHP
O
meso compound
i) PhNCO
ii) BF3 ·OEt2
iii) NaOMe
iv) BnBr
v) O3

OH
HO OBn OBn
OH
H OBn
HO2C O
OH
OH O OBn
H
(+)-KDO

The key step involves a Sharpless Asymmetric Epoxidation, which is an excellent method for
desymmetrising this type of system:

• the reaction exhibits very high diastereo- and enantiofacial selectivity.

• minor stereoisomers are 'destroyed' in a kinetic resolution:
 OH OH
fast slow
BnO OBn BnO OBn
O O O
D-(−)-DIPT
Ti(OiPr)4
TBHP OH OH
slow fast
BnO OBn BnO OBn
O O O
OH
BnO OBn

meso compound OH OH
slow fast
BnO OBn BnO OBn
O O O

OH OH
slow slow
BnO OBn BnO OBn
O O O

VIII.A.2 C2-Symmetrical Chain

In this case the terminal groups are homotopic and therefore monofunctionalisation is sufficient to
differentiate the chain termini.

C2

X X X X

A B
Z Z Z Z

homotopic chain termini

One way in which this type of chain can be prepared, is by simultaneous homologation of a C2-
symmetrical starting material.
Example:

OBn i) OsO4 TBDMSO OBn OTBDMS

CO2Et CO2Et
EtO2C ii) TBDMSOTf EtO2C
OBn TBDMSO OBn OTBDMS
diastereoselectivity
of dihydroxylation >20:1

2.2 eq. DIBALH

H 2N OH
OH
HO
H O TBDMSO OBn OTBDMS
H 2N N O 2
O OH OH 7
EtO2C OH
N O 7 OH
1
TBDMSO OBn OTBDMS
OH OH
HO NH2
OH (-)-hikizimycin

N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc., 1992, 114, 2524-2536

Note the effect of carrying out the reaction twice: if the diastereoselectivity of dihydroxylation for
each olefin is 10:1, then the expected diastereoselectivity of the double reaction (assuming the
intermediates react at a similar rate and selectivity) is 100:20:1 as illustrated below.

OH OBn OH

1
k=1 OH OBn OH
OH OBn
slow
k=1 k = 10 OH OBn OH
OBn
OH OBn
20
OH OBn k=1
OBn OH OBn OH
fast
k = 10
OH OBn OH OBn OH
k = 10

OH OBn OH 100
Synthesis of (+)-Mycoticin A

C. S. Poss, S. D. Rychnovsky, S. L. Schreiber, J. Am. Chem. Soc., 1993, 115, 3360-3361

macrolactonisation Horner-Wadsworth-Emmons

O OH

O OH
mycoticin A
27 17

OH OH OH OH OH HO

two-bond disconnection provides a

fragment suitable for two-directional
chain synthesis

We will only consider the preparation of the symmetrical polyol fragment.

O O O
i) NaH
SO2 Ph MeO OMe
MeO then:
O O SO2 Ph
t
MeO O Bu
Zn(0)

MeO OMe i) RuCl 2[(R)-BINAP] O O

OH OH H2, 100 atm
MeO OMe
H
i) (EtO)2CHCH3 , H
ii) Li, NH3
iii) O 3

i) RuCl 2[(R)-BINAP]
MeO OMe H2, 100 atm MeO OMe

O O O O O O ii) (CH3 O)2C(CH3)2, H O O O O O O

Continuing...

MeO OMe i) DIBALH

O O O O O O OH O O O O OH
ii) MgBr

(CH3O)2C(CH3) 2, H

H H
i) O3, Me2S
O O
O O O O O O ii) K2CO3 , MeOH O O O O O O

i) NaBH4
ii) TBDMSCl

TBDMSO OH
O O O O O O

Make sure you can rationalise each step in this synthetic sequence.

Summary

Many molecules or sub-units within molecules possess elements of symmetry, which, if

recognised, can be very helpful in designing efficient synthetic sequences. We have
concentrated on one approach, two-directional synthesis. Clearly this strategy can only
be applied to a limited number of molecules; however, when suitable symmetry elements
are present, it provides a very efficient synthetic strategy.