-
The Career of Stuart Schreiber
Part 1: Organic Chemist
Group Meeting: April 1, 2009
Benjamin D Horning
■ For a complete listing of Dr. Schreiber’s publications,
including pdf links, please visit
http://www.broad.harvard.edu/chembio/lab_schreiber/smdb/smdbPublicationsDissertationsForm.php
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The (Chemistry) Career of Stuart L. Schreiber
Biographical
Notes
■ Education (b. 1956 - Virginia)
B.A. : University of Virginia (1977); R. J. Sundberg –
Photocyclization of Indole Derivatives
Ph.D.: Harvard (1981); R. B. Woodward and Y. Kishi – oxidation
of tertiary amines• Hydrgogen Transfer from Tertiary Amines to
Trifluoroacetic Anhydride. Tetrahedron 1980, 21, 1027 •
Fragmentation Reactions of α-alkoxy Hdroperoxides and Application
to the Synthesis of (±)-Recifeiolide. J. Am. Chem. Soc. 1980, 102,
6163• Oxidation of Tertiary Amines. II. Peroxides in Organic
Synthesis. Ph.D. Thesis, Harvard University, 1981
■ Career
Assistant Professor (1981-84); Associate Professor (tenured)
(1984-86); Professor (1986-88); Department of Chemistry,
YaleProfessor (1988-1998); Morris Loeb Professor (1998-);
Department of Chemistry and Chemical Biology, HarvardDepartment
Chair (2001-2004); Director, Chemical Biology, and Founding Core
Member of the Broad Institute of Harvard And MIT (2003-);
Investigator, Howard Hughes Medical Institute (1994-); Affiliate,
Department of Cell Biology, Harvard Medical School (1994-2004);
Member, Graduate Programs in Biophysics and Immunology (1988-),
Harvard
■ Notable Awards (chemistry)
Dreyfus Newly Appointed Faculty Award, 1981; Searle Scholar,
1982; Dreyfus Teacher-Scholar Award, 1985; Fellow of the Alfred P.
Sloan Foundation, 1985; NSF Presidential Young Investigator Award,
1985; ICI Pharmaceuticals Award for Excellence in Chemistry, 1986;
Arthur C. Cope Scholar Award, American Chemical Society (ACS),
1986; Award in Pure Chemistry, ACS, 1989; Arun Guthikonda Memorial
Award, Columbia University, 1990; Thieme-IUPAC Award in Synthetic
Organic Chemistry, 1992; NIH Merit Award, 1992, Rhone-Poulenc
Silver Medal, Royal Society of Chemistry, 1992; Award for Creative
Work in Synthetic Chemistry, ACS, 1994; Elected to the National
Academy of Sciences and the American Academy of Arts &
Sciences, 1996
■ Publications:
>425 invited lectures
>400 publications (h-index = 109)
■ Companies
Founder, Forma Therapeutics, Inc. (2008-); Founder, Co-Chair of
the Scientific Advisory Board, Infinity Pharmaceuticals (2002-06);
Founder and Chair of the Board of Scientific and Medical Advisers,
ARIAD Pharmaceuticals (1991-); Founder, ARIAD Gene Therapeutics
(1994-2008); Founder and Scientific Advisory Board Member, Vertex
Pharmaceuticals (1988-90); Adviser, Theravance, 2000-04;
Consultant, Pfizer, 1983-91
http://www.broad.harvard.edu/chembio/lab_schreiber/members/smdbSchreiberBio.php
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The (Chemistry) Career of Stuart L. Schreiber
H-index
http://www.rsc.org/chemistryworld/News/2007/April/23040701.asp
Ad Bax is the only living chemist who is both younger and has a
higher H-index
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The (Chemistry) Career of Stuart L. Schreiber
Ex-Group
Members
■ Amir Hoveyda (1981-1986) (Ph.D.)
Dissertation: “The Furan-Carbonyl Photocycloaddition
Reaction
and its Applications in Organic Synthesis”
Currently Joseph T. Vanderslice Professor, Boston College■ Tim
Jamison (1992-1997) (Ph.D.)
Dissertation: “I. Consecutive Use of Two Reactions of
Alkyne-Co2(CO)6 Complexes in the Total Synthesis of
(+)-Epoxydictymene
II. Studies Directed Toward the Synthesis of the
Diazonamide Marine Natural Products Using Benzofuran
Epoxidation-Rearrangements”
Currently Paul M. Cook Career Development Associate Professor
of
Chemistry, MIT
■ Glenn Micalizio (2000-2003) (post-doc)
Currently Associate Professor, Scripps Florida■ James Morken
(1995-1997) (post-doc)
Currently Professor, Boston College■ John A. Porco Jr.
(1985-1992) (Ph.D.)
Dissertation: “Studies Toward the Synthesis of the Enediyne
Antibiotics”
Currently Assistant Professor of Chemistry, Boston University■
Daniel Romo (1991-1993) (post-doc)
Currently Professor, Texas A&M University■ Scott Rychnovsky
(1987-1988) (post-doc)
Currently Professor, University of California, Irivine■ Matthew
Shair (1995-1997) (post-doc)
Currently Professor, Harvard University■ Martin Burke
(2000-2004) (Ph.D.)
Currently Assistant Professor, University of Illinois,
Urbana-Champaign■ John Wood (1991-1993) (post-doc)
Currently A.I. Meyers Professor of Chemistry, Colorado State
University■ Marc Snapper (1990-1993) (post-doc)
Currently Professor, Boston College
http://www.broad.harvard.edu/chembio/lab_schreiber/smdb/smdbFormerMembersForm.php
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The (Chemistry) Career of Stuart L. Schreiber
Timeline
■ Research theme:
To develop chemical transformations that can be used as
springboards for the synthesis of complex natural products
1981Assistant Professor
at Yale
1982Ozonolytic cleavage of
cycloalkenes to terminally differentiated products
Tetrahedron Letters 1982, 23, 3867
1986Macrolide epoxidation
strategy towards Monensin
JACS 1986, 108, 2106
1993First Synthesis of Discodermolide
JACS 1993, 115, 12621
O
HO
Me Me
Me
OH
Me
OCONH2
Me
Me
OH
O
Me
OH
Me
H
CH(OR)2
CHO
1984Total Synthesis of
Periplanone-B
JACS 1984, 106, 4038
OO
O
O
O
O O
Me
Me
Me
CO2Me
O O
O O
O
MeMe
MeH
Me
H
MeKOH, HCl,
acetone
1989Type II Diels-Alder
towards Calichemicin
Tetrahedron Letters 1989, 30, 3765
OH
OH
H
TBSO
OMs
OH
OH
H
H
TBSO Et2AlCl
1988Professor,Harvard
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The (Chemistry) Career of Stuart L. Schreiber
Outline
■ The use of α-alkoxy hydroperoxides in organic synthesis
Schreiber Ozonolysis
Alkene Baeyer-Villiger
Macrolide synthesis
■ Utilization of [2+2} photocycloaddition reactions in total
synthesis
Periplanone B
Furan Paterno-Büchi, “photoaldol”
Total synthesis of Asteltoxin
■ Verging on enamine catalysis
OO
O
R OOH
OR'
CHO
ORO
O
Me
O
O
Me
OMe
O
O
CHO
CHOO
HN
Me
Ph
t-Bu
H
HN
O
Me
Ph
t-BuScaleability“Springboard”
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3
OO
Oreductive
workup
oxidative
workup CHO
CHO
CO2H
CO2H
O
O O
MeOH,
NaHCO3
MeOH,
PTSA
O
OOH
OMe
CH(OMe)2
OOH
OMe
-
α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3
OO
Oreductive
workup
oxidative
workup CHO
CHO
CO2H
CO2H
O
O O
MeOH,
NaHCO3
MeOH,
PTSA
O
OOH
OMe
CH(OMe)2
OOH
OMe
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3, ROH,
NaHCO3
CHO
OOHRO
Ac2O,
Et3N
CHO
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
Ac2O,
Et3N
CH(OR)2
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
NaHCO3
Me2S
CH(OR)2
CHO
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3, ROH,
NaHCO3
CHO
OOHRO
Ac2O,
Et3N
CHO
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
Ac2O,
Et3N
CH(OR)2
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
NaHCO3
Me2S
CH(OR)2
CHO
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3, ROH,
NaHCO3
CHO
OOHRO
Ac2O,
Et3N
CHO
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
Ac2O,
Et3N
CH(OR)2
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
NaHCO3
Me2S
CH(OR)2
CHO
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3, ROH,
NaHCO3
CHO
OOHRO
Ac2O,
Et3N
CHO
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
Ac2O,
Et3N
CH(OR)2
ORO
O3, ROH,
PTSA
CH(OR)2
OOHRO
NaHCO3
Me2S
CH(OR)2
CHO
■ Ozonolysis modification allows access to terminally
differentiated products
Schreiber et al. Organic Synthesis 1984, 64, 168 and Schreiber
et al. Tetrahedron, 1982, 23, 38676
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α-Alkoxy Hydroperoxides in Organic Synthesis
Schreiber
Ozonolysis
O3, MeOH,
NaHCO3
CHO
OAc OAc
O
O
O
OAc
CHO
OAc
retro 2+3
OO
OOHOMe
1,3 addition
of methanol
■ Differentially substituted alkenes can be selectively
functionalized
■ Ester formation depends upon hydride migration
OR
OR
O Me
OH
OR
R O
O Me
O
H
OR
R O
HO Me
O
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 660
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α-Alkoxy Hydroperoxides in Organic Synthesis
Baeyer-Villiger
■ Criegee rearrangement of alkoxy-hydroperoxides derived from
1,1-disubstituted olefins
O3, MeOH,
NaHCO3
Ac2O,
Et3NO
Me
Me
O
Me
Me
OOH
OMeO
Me
O
O
Me
Me2S
O
Me
Me
O
MCPBAO
Me
O
O
Me
Schreiber et al. Tetrahedron 1983, 24, 2363
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α-Alkoxy Hydroperoxides in Organic Synthesis
Baeyer-Villiger
■ Criegee rearrangement of alkoxy-hydroperoxides derived from
1,1-disubstituted olefins
O3, MeOH,
NaHCO3
Ac2O,
Et3NO
Me
Me
O
Me
Me
OOH
OMeO
Me
O
O
Me
Me2S
O
Me
Me
O
MCPBAO
Me
O
O
Me
Schreiber et al. Tetrahedron 1983, 24, 2363
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α-Alkoxy Hydroperoxides in Organic Synthesis
Iron/Copper
mediated peroxide reduction/fragmentation
■ Reduction of intermediate alkoxy hydroperoxides generates a
highly fragmentable radical species
O3, MeOH,
NaHCO3
FeSO4,
Cu(OAc)2O
Me
Me
O
Me
Me
OOH
OMeO
Me
-Cu(OAc),AcOH
O
Me
Me
OOHO
Me
Me
O
OMeO
Me
Cu(OAc)2
Fe2+!Fe3+
OMe
Cu(OAc)2
-AcOMe
Schreiber et al. J. Am. Chem. Soc. 1980, 102, 6163
-
α-Alkoxy Hydroperoxides in Organic Synthesis
Iron/Copper
mediated peroxide reduction/fragmentation
■ Reduction of intermediate alkoxy hydroperoxides generates a
highly fragmentable radical species
O3, MeOH,
NaHCO3
FeSO4,
Cu(OAc)2O
Me
Me
O
Me
Me
OOH
OMeO
Me
-Cu(OAc),AcOH
O
Me
Me
OOHO
Me
Me
O
OMeO
Me
Cu(OAc)2
Fe2+!Fe3+
OMe
Cu(OAc)2
-AcOMe
Schreiber et al. J. Am. Chem. Soc. 1980, 102, 6163
-
α-Alkoxy Hydroperoxides in Organic Synthesis
Application in
macrolide synthesis
■ Fragmentation of cyclic alkoxy-hydroperoxides can yield
macrocycles
LDA, Me3Al,
80%
H2O2, AcOH
56%OO
OOH
Me
O
Me
HOO
O
Me
HOO
FeSO4,
Cu(OAc)296%
O
Me
O OMe
O
recifeiolide
OCu
Me
O
H
H
H H
H■ Single olefin regio- and geometrical olefin isomer
observed
Schreiber et al. J. Am. Chem. Soc. 1980, 102, 6163
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α-Alkoxy Hydroperoxides in Organic Synthesis
Application in
macrolide synthesis
■ Fragmentation of cyclic alkoxy-hydroperoxides can yield
macrocycles
LDA, Me3Al,
80%
H2O2, AcOH
56%OO
OOH
Me
O
Me
HOO
O
Me
HOO
FeSO4,
Cu(OAc)296%
O
Me
O OMe
O
recifeiolide
OCu
Me
O
H
H
H H
H■ Single olefin regio- and geometrical olefin isomer
observed
O
Cu
Me
O
H
H
HH
H
Schreiber et al. J. Am. Chem. Soc. 1980, 102, 6163
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[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ Cockroach sex pheromone, used by female cockroaches to
stimulate males by olfactory communication
■ Isolation (
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ Schreiber plans on utilizing a similar end-game as found in
the Still Synthesis
OO
O
Me
Me
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
OO
O
Me
Me
Me
Me
O
peroxideepoxidation
Selena-Pummerer
Corey-Chaykovsky
Me
Me
O
Me
Me
OH
grignardaddition
Me
Me
O
H
H
[2+2] Photocycloaddition
Me
Me
O
•
H
H
■ Schreiber plans on utilizing a similar end-game as found in
the Still Synthesis
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
OO
O
Me
Me
Me
Me
O
peroxideepoxidation
Selena-Pummerer
Corey-Chaykovsky
Me
Me
O
Me
Me
OH
grignardaddition
Me
Me
O
H
H
[2+2] Photocycloaddition
Me
Me
O
•
H
H
electrocyclic ring openingolefin photoisomerization
■ A clever synthon for a diene
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
OO
O
Me
Me
Me
Me
O
peroxideepoxidation
Selena-Pummerer
Corey-Chaykovsky
Me
Me
O
Me
Me
OH
Me
Me
O
H
H
[2+2] Photocycloaddition
Me
Me
O
•
H
H
electrocyclic ring openingolefin photoisomerization anionic
oxy-cope
■ The now-classical method for forming cyclodecanes, with a
twist
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
OO
O
Me
Me
Me
Me
O
peroxideepoxidation
Selena-Pummerer
Corey-Chaykovsky
Me
Me
O
Me
Me
OH
grignardaddition
Me
Me
O
H
H
[2+2] Photocycloaddition
Me
Me
O
•
H
H
electrocyclic ring openingolefin photoisomerization anionic
oxy-cope
■ [2+2] photocycloaddition to start things off
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ [2+2] photocycloaddition to start things off
Me
Me
O
• Me
Me
O
H
H
h!, Et2O,
72%
Et2O,
63%
2:1 anti:syn
MgBr
Me
Me
OH
H
H
Me
Me
OH
H
H
KH, 18-c-6
60 °C75%
Me
Me
O
H
H
O
Me
Me
+ H+
O
Me
Me
PhMe
175 °C77%
O
Me
Me
h!, PhH
82%
O
Me
Me
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ Heat and light play a commanding role in Schreiber’s early
steps
Me
Me
O
• Me
Me
O
H
H
h!, Et2O,
72%
Et2O,
63%
2:1 anti:syn
MgBr
Me
Me
OH
H
H
Me
Me
OH
H
H
KH, 18-c-6
60 °C75%
Me
Me
O
H
H
O
Me
Me
+ H+
O
Me
Me
PhMe
175 °C77%
O
Me
Me
h!, PhH
82%
O
Me
Me
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ Selective enolization/trapping allows desired olefin
installation
Me
Me
LHMDS,
-78 °C;PhSSO2Ph16:1 selectivity
MeOH, NaIO4;
PhMe, 110 °C32% (3 steps)
O
Me
Me
OSPh
Me
Me
O
O
Me
MeO
C
H H
H
H CO
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Periplanone B
OO
O
Me
Me
■ A series of oxidations (utilizing peripheral attack) installs
the remaining functionality
Me
Me
t-BuOOH, KH
83%
LHMDS, THF;
PhSeBr83%
O
Me
Me
O
Me
Me
OOSePh
O
O
Me
Me
H H
O
Me
Me
H H
O
O
Me
Me
OO
H2O2, THF, 97%THF, Ac2O, NaOAc;
MeOH, H2O, K2CO3, 60%
O
(Me)3SI, NaH,
DMSO, THF,
62%
OO
O
Me
Me
■ Synthesis is completed in 13 steps, 2% yield
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
-
[2+2] photocycloaddition reactions in natural product
synthesis
Furan-aldehyde photocycloaddition, “photoaldol”
O
+
Ph
O
h!
OO
H
H
PhH
■ Paterno-Büchi reaction between a furan and an aldehyde
proceeds with good head-to-head and exo- selectivity
■ Products serve as protected threo aldol products between a
1,4-dicarbonyl and an aldehyde
■ Unfortunately, only symmetrically substituted furans are
serviceable; Unsymmetrically subsituted ones proceed with low
chemoselectivity
■ Products serve as protected threo aldol products between a
1,4-dicarbonyl and an aldehyde
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 660
-
OO
R'
R
PhH
R
R'
dilute HCl
CSA, MeOH
H2,Rh/Al2O3
R=H, R'=MeR=Me, R'=H
Me
O
Ph
OH
MeO
OPh
Me
Me
O
OMe
Me
OH
Ph
OH
MeO
mCPBA
BH3•THF;H2O2
CH(CHO)3
O OO
OH
HOH
H
H
H
H
Ph
OO
Me
H
PhH
ArCO2
Me
HO
O
H
Me
HOPh
OHMe
[2+2] photocycloaddition reactions in natural product
synthesis
Furan-aldehyde photocycloaddition, “photoaldol”
O
+
Ph
O
h!
OO
H
H
PhH
OO
H
Me
PhH
Me
B
BH2
H
O
H
Me
B
Me
Ph
O BH2
H
O
H
Me
B
Me
Ph
O BH2O
O
R
R'R
R'
PhH
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 660
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
Asteltoxin
O
Me
H
HO
Me
Me O
OH
O
Me OMe
O
■ Stereochemically complex bis-tetrahydrofuran region connection
by an all-trans triene linker to a pyrone region
■ Inhibitor of oxidative phosphorylation, serves as a
fluorescent probe of mitochondrial F1- and bacterial BF1-ATPase
■ No total synthesis prior to 1984
■ Relative stereochemistry (and vicinal methyl groups) lends to
construction via furan-aldehyde Paterno-Büchi
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me
O
Me
H
HO
Me
Me O
OH
O
Me OMe
O
O
O
CHO
Me
Me
+
+
O
O
Me OMe
O
Me
Asteltoxin
O
Me
H
HO
Me
Me O
OH
O
Me OMe
O
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
+O
h!, PhH
OO
Me
H
HMe
Me OBnOBnMe
mCPBA,
NaHCO345% (2 steps)
OO
Me
H
H OBnMe
HO
ArCO2
THF : 3N HCl 3 : 1
O
OH
Me
HO
Me
X
H
OBn
X=O
X=NNMe2
Me2NNH2,MgSO472% (2 steps)
EtMgBr, THF
Me OBn
OH
OH
Me
H
H
Me OH
NNMe2
acetone,
CuSO4, CSA55% (2 steps)
O
Me
H
HO
Me
Me O
OMe
Me
OBn
O
Me
H
HO
Me
Me O
OH
R
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
Springboard stepScaleable
Used to set all relative stereochemistry
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
O
OH
Me
HO
Me
X
H
OBn
X=O
X=NNMe2
Me2NNH2,MgSO472% (2 steps)
EtMgBr, THF
Me OBn
OH
OH
Me
H
H
Me OH
NNMe2
acetone,
CuSO4, CSA55% (2 steps)
O
Me
H
HO
Me
Me O
OMe
Me
OBn
R
Me O
OHMg
EtMgBr
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
BuLi, THF, PhSCl
OH OS
Ph
SPhO
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
1. ArSeCn, PBu3, THF
2. H2O2, THF 81% (2 steps)
O3, CH2Cl2,
MeOH, Me2S92%
O
Me
H
HO
Me
Me O
OMe
Me
OR
R=Bn
R=H
Li, NH398%
O
Me
H
HO
Me
Me O
OMe
Me
O
Me
H
HO
Me
Me O
OMe
Me
O
SOPh
O
Me
H
HO
Me
Me O
OMe
Me
HOSOPh
CSA
77%
BuLi, THF88% (3:1)
O
Me
H
HO
Me
Me O
OH
SOPh
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
1. ArSeCn, PBu3, THF
2. H2O2, THF 81% (2 steps)
O3, CH2Cl2,
MeOH, Me2S92%
O
Me
H
HO
Me
Me O
OMe
Me
OR
R=Bn
R=H
Li, NH398%
O
Me
H
HO
Me
Me O
OMe
Me
O
Me
H
HO
Me
Me O
OMe
Me
O
SOPh
O
Me
H
HO
Me
Me O
OMe
Me
HO
BuLi, THF88% (3:1)
SPh O
O
Me
H
HO
Me
Me O
OMe
Me
HO
OS
Ph
O
Me
H
HO
Me
Me O
OMe
Me
HO
SPhO
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
1. ArSeCn, PBu3, THF
2. H2O2, THF 81% (2 steps)
O3, CH2Cl2,
MeOH, Me2S92%
O
Me
H
HO
Me
Me O
OMe
Me
OR
R=Bn
R=H
Li, NH398%
O
Me
H
HO
Me
Me O
OMe
Me
O
Me
H
HO
Me
Me O
OMe
Me
O
SOPh
O
Me
H
HO
Me
Me O
OMe
Me
HOSOPh
CSA
77%
BuLi, THF88% (3:1)
O
Me
H
HO
Me
Me O
OH
SOPh
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
BuLi, THF, PhSC
OH OS
Ph
SPhO
Me Me
OO1. MeI, K2CO3, acetone
2. NaNH2, NH3,
Et2O, CO2
Me
OO
Me
CO2H
1. CDI, THF
2. (MeO)2SO2, K2CO3, acetone
O
O
Me
Me
OMe
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
O
Me
H
HO
Me
Me O
OH
R
80%O
O
Me
Me
OMe
LDA, HMPA,
THF
O
O
Me
OMe
TsCl, DMAP,
Et3N, CH2Cl282%
O
Me
H
HO
Me
Me O
OH
OH
O
O
OMeMe
O
Me
H
HO
Me
Me O
OH
O
Me OMe
O
O
Me
H
HO
Me
Me O
OH
SOPh
1. CF3CO2COCH3, Ac2O, 2,6-lut
2. HgCl2, CaCO3, CH3CN, H2O 60%
O
Me
H
HO
Me
Me O
OH
O
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Asteltoxin
Asteltoxin
O
Me
H
HO
Me
Me O
OH
O
Me OMe
O
■ Synthesis completed in 16 steps, 4% overall yield
■ Key steps include a furan-aldehyde Paterno-Büchi, several
diastereoselective additions to aldehydes, and an addition/double
2,3-rearrangement to give net dienal addition
■ Symmetrically substituted furan partner a necessary
retrosynthetic fragment
Schreiber et al. J. Am. Chem. Soc. 1983, 105, 6723 and Schreiber
et al. J. Am. Chem. Soc. 1984, 106, 4186
-
[2+2] photocycloaddition reactions in natural product
synthesis
Unsymmetrically substituted furan partners
O
+
Ph
O
h!
OO
H
H
PhH
O
+
R2
O
h!
OO
H
H
PhH
R1 R1 +O
O
H
R1
PhH
H
R1 = SiMe3 1.2 : 1
R1 = Sii-Pr3 20 : 1
R1 = SnBu3 2.5 : 1
R1 = SnBu3 20 : 1 (CO2Bu instead of Ph)
Schreiber et al. Tetrahedron Letters. 1988, 29, 6689
-
Verging on enamine catalysis
Diastereoselective enal/enone
intramolecular 4+2
OHC R4
O
R1 R2 R3
MeNHPhO
R2
R1
H
HN(Me)Ph
R3
R4
Schreiber et al. J. Am. Chem. Soc. 1986, 108, 8274 and Schreiber
et al. J. Am. Chem. Soc. 1988, 110, 5198
O3, MeOH;
PTSA; NaHCO3,Me2S
CH(OMe)2
CHO
CHO
CHO
CHO
C(O)Me
CHO
CHO
Me
66g
-
Verging on enamine catalysis
Diastereoselective enal/enone
intramolecular 4+2
CHO
C(O)Me
CHO
CHO
Me
Starting material product yield d.r.
O
H
HN(Me)Ph
CHO
CHO
O
H
HN(Me)Ph
Me
O
H
HN(Me)Ph
Me
CHO
CHO
CHO
CHO
Me
Me
Me
O
H
HN(Me)Ph
H
O
H
HN(Me)Ph
Me
Me
Me
73
60
60
86
84
>25:1
>25:1
4:1(>25:1 after 10h)
14:1(>25:1 after 10h)
10:1(>25:1 after 10h)
Schreiber et al. J. Am. Chem. Soc. 1986, 108, 8274 and Schreiber
et al. J. Am. Chem. Soc. 1988, 110, 5198
-
Verging on enamine catalysis
Comparison with more recent
studies
CHO
CHO
Me
O
H
HN(Me)Ph
H
Me
86% yield14:1 dr
(>25:1 after 10h)
1 eq. MeNHPh
Et2O
CHO
CHO
Me
O
H
HMe
87% yield0.3 eq. MeNHPh
CHCl3
TBDPSO TBDPSO
O
CHO
CHO
Me
O
H
HMe
83% yield0.3 eq. D-proline
DMSO
TBDPSO TBDPSO
CHO
CHO
Me
O
H
HMe
91% yield0.3 eq. L-proline
DMSO
TBDPSO TBDPSO
OH
O
Schreiber et al. J. Am. Chem. Soc. 1988, 110, 5198 and MacMillan
et al. J. Am. Chem. Soc. 2005, 127, 3696
-
Verging on enamine catalysis
Induction of asymmetry
1. O3, MeOH; Me2S
2. 1N HCl, acetone CHO
CHO+
O
HN
Me
Ph
t-Bu
3:2 cis:trans
Et2O, rt
75%O
H
HN
O
Me
Ph
t-Bu
CHO
N
O
Me
Pht-Bu
NOCHO
t-Bu
MePh
Schreiber et al. J. Am. Chem. Soc. 1988, 110, 5198
17:1 cis:trans
-
Verging on enamine catalysis
Synthesis of Brefeldin C
1. m-CPBA; NaBH4
2. 1N HCl 31% (2 steps)
O
H
HN
O
Me
Ph
t-Bu
CHO
H
H
OH
OH
1. HS(CH2)2SH, TiCl4
2. NaIO4, aq. t-BuOH3. DBU, 14% (3 steps)
CHOH
1. BuLi, BF3•OEt22. Na(Hg), MeOH 48% (2 steps)3. PTSA, MeOH,
83%
SS
+SO2Ph
Me
OTHP
H
SS
OH
Me
+CO2MeI
Sn
HO Sn
O
O
Sn
Sn
OH
NCS
BuBuBu Bu
Bu BuBuBu
SCN
1. PhMe, !
2. MeI, aq. acetone 76% (2 steps)
HCHO
O
Me
I
O
Schreiber et al. J. Am. Chem. Soc. 1988, 110, 5198
-
Verging on enamine catalysis
Synthesis of Brefeldin C
CrCl2, 0.1% wt/wt
Ni(acac)2, DMF60%
HCHO
O
Me
I
O
HCHO
O
Me
I
O
CrCl2, 0.1% wt/wt
Ni(acac)2, DMF
70%
O
O Me
H
H
HO
O
O Me
H
H
HO
Schreiber et al. J. Am. Chem. Soc. 1988, 110, 5198
O
OMe
H
H
HO
Brefeldin C
4:1 d.r. at alcohol
(wrong way)
10:1 d.r. at alcohol
-
Stay tuned for part II: Stuart Schreiber, biologist
■ Stuart Schreiber worked alongside the best in the field during
the 1980s
■ His synthetic work continued into the 1990s, though his focus
switched mostly to biology
■ His synthetic work continues today, but is focused on the
synthesis of small molecules of biological interest
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