Total Synthesis of Longithorone A

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Total Synthesis of Longithorone A

• Literature Meeting
• March 11th 2008
• Charette group
• Angelique Fortier

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Longithorone A

• Key Concepts
• Biomimetic synthesis
• Atropisomerism
• Enyne metathesis
• Organozinc reagents
• Transannular Diels-Alder reactions

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Longithorone A

• Marine natural product
• Found on island of Palau in 1994

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Desirable synthetic target?
Isolate of tunicate Aplydium longithorax sponge

• Its low cytotoxicity and
• lack of biological
• activity is over
• compensated by its
• attractive
• conglomeration
• of rings and its
• stereochemical
• complexity.

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Logistics

• 5x 6-, 10-, and 16 membered rings
• 2 types of chirality
• Stereogenic centers
• Atropisomerism
• 6 stereogenic centers
• 2 of which are quaternary

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Biomimetics - Structural Harmony

• Amalgamation of two smaller macrocyclic subunits
• These subunits are comprised of
• Farnesyl units conecting position 2 and 5 of
• Paraquinone moiety
• One aspect to beware of

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Atropisomerism

• Severely strained sequential 6-memered rings
• None can adopt the most stable chair conformation
• B-ring is cis fused to with C-ring, trans fused
  with A-ring, and has attachment point to D-ring
• Forces A- and B-rings in distorted boat
  conformation
• Forces C- and D-rings in mutated half-chairs
• Spacial constraints give rise to an element of
  chirality known as atropisomerism

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Longithorone A

• First isolated in 1994
• by Professor
• F. J. Schmitz
• and co-workers at the
• University of Oklahoma

J. Am. Chem. Soc. 1994, 116, 12125-12126
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Schmitz biogenetic retrosynthetic analysis
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Schmitz biogenetic retrosynthetic analysis
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Longithorone A

• First chemically
• synthesized in 2002
• by Professor
• Matthew Shair
• and two of his graduate
• students at Harvard
• University

J. Am. Chem. Soc. 2002, 124, 773-775
PNAS 2004, 101, 12036-12041
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Shairs retrosynthetic analysis
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Shairs retrosynthetic analysis
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Shairs retrosynthetic analysis
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Shairs retrosynthetic analysis
It is interesting to note that the diene and
dienophile are obtained from the same precursor,
and is subject to similar chemistry
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Shairs retrosynthetic analysis
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Shairs retrosynthetic analysis
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Ene-yne metathesis

• Intramolecular ene-yne metathesis affords
  1,2-disubstituted dienes
• Intermolecular ene-yne metathesis affords
  1,3-disubstituted dienes
• What will happen for a macro-intramolecular?

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Ene-yne metathesis control

• Assumed macrocyclization would resemble
  intermolecular reaction
• Hence a 1,3-disubstituted diene
• Since the resulting 12-paracyclophane is less
  strained than a 11-paracyclophane (from a
  1,2-disubstituted diene)

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Ene-yne metathesis

• 1,3 observed especially for ring sizes of 12 and
  greater
• Only 5 to 8 membered had been tested previously
• First report of macro-ene-yne RCM
• But how to control which atropisomer is obtained

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Vancomycin

• Nicolaou successfully used removable directing
  groups to direct an atropselective
  macrocyclization.
• Evans group also used the same strategy
• Directing groups govern the transition state
  adopted during enyne metathesis
• The A(1,3) interaction is worth several kcal/mol
  more and hence will be the disfavored conformer

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Vancomycin
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Atropisomerism control

• Strategic benzylic hydroxyl groups should favor A
  C and disfavor B D due to A(1,3) strain
• Benzylic hydroxyl groups can then be removed
  reductively
• Absence of this control group led to
  non-selective ring closure

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Negishi-type cross-coupling

• Directing group installed via asymmetric
  alkenylation of an aldehyde
• Can then be removed by hydride displacement or
  acid-mediated lysis
• This starting material was derived from a
  Negishi-type Pd cross-coupling reaction

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Total Synthesis
oxidation
protection
Z selective Wittig via unstabalized ylide
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Total Synthesis
Halogen metal exchange
reduction
Conversion to zinc bromide species
quench
Exchange of BzOH for Br
Aryl lithiation
Pd-Negishi cross-coupling reaction
Differentiation of two aryl methoxy groups!!!
quench
Usually nearly impossible! but aldehyde can
coordinate with L.A. catalyst, directing it to
its adjacent methyl ether hence activating it
for preferential cleavage!!!
reprotection
Also, increases the electronic effect. The lone
pair of the adjacent oxygen can be delocalized
into aldehyde
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Total Synthesis
Lithium alkoxide serves as highly competent
chiral auxiliarly
Stable complex with lithium trans to Ar
Lithiation
transmetallation
Partial reduction hydrogenation via Lindlars
catalyst selective for terminal alkyne, TIPS
deprotection
Stereoselectively orchestrates the uniion of
aldehyde 14 and nucleophilic vinylzinc
TBS protection
TMS, TBS selective deprotection
Transition state aldehyde coordinates to lithium
trans to the distal pphenyl ring. Alkenyl
transfer occurs via 6-membered transition state.
-recovery of auxiliary via extraction. Completion
achieved with equimolar aldehyde and bromozinc
hence material economy
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Total Synthesis
Major by-productloss of 1 carbon -propene formed
with carbene
Grubbs
TBS deprotection
Complete selectivity for both olefin geometry and
atropisomerism. 42 yield due to formation of
major byproduct.
Hydride displacement via NaBH3CN using TFA as
benzylic alcohol activation into a good leaving
group followed by reprotection.
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Total Synthesis
Install vinyl iodide side chain as before
Global desilylation, followed by alcohol
protection
Macrocyclization provide exclusively the 1,3
disubstituted diene product
Lithiation, transmetallation, stable complex
Alcohol protection, allylation
However, less atropselective (less steric
differentiation) and failed to completely control
endocyclic olefin geometry
oxidation
Ionic type reduction of benzylic directing group
via H- (silane) H(TFA), PPTS deprotects alcohol
Thermally stable up to 100C implies can
activate Diels Alder reaction at higher
temperatures
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Total Synthesis
First attempt failed. 15 h at RT, heating and
LAs also did not work
Desilylation of 2 phenolic TBS groups, followed
by oxidation with iodosylbenzene to give rise to
bis quinone
After much screening, reaction conditions were
found giving complete endo selectivity but not
facially selective, giving rise to both
diastereomers (aldehyde and H down) favoring the
non-natural configuration -this supports
possibility of enzymatic assistance proposed by
Schmitz
Ie.diels-alderase
Amazingly, adduct started to slowly convert into
Longithorine A at RT without being isolated
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Summary

• Total synthesis
• 32 operations overall
• 19 steps in the longest linear sequence
• Unique example of chirality transfer in complex
  molecule synthesis
• Stereogenic centers are used to control planar
  chirality
• Removal of chiral centers
• Planar chirality is then in return used to
  regenerate stereogenic centers

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Summary

• Challenges overcome
• Biosynthesis is feasible
• Atropselectivity acheived
• Macrocyclic ring closing enyne metathesis gave
  disubstituted 1,3 diene (first example)
• Diels-Alder reaction gave endo product only
• But was not facially selective (hence 2
  diastereoisomers)
• Benzylic alcohols were installed highly
  enantioselectively via vinylzinc additions

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Thank you