the career of stuart schreiber part 1: organic chemist · pdf filethe career of stuart...
TRANSCRIPT
The Career of Stuart SchreiberPart 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
The (Chemistry) Career of Stuart L. SchreiberBiographical 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, Yale Professor (1988-1998); Morris Loeb Professor (1998-); Department of Chemistry and Chemical Biology, Harvard Department 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
The (Chemistry) Career of Stuart L. SchreiberH-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
The (Chemistry) Career of Stuart L. SchreiberEx-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
The (Chemistry) Career of Stuart L. SchreiberTimeline
■ Research theme:
To develop chemical transformations that can be used as springboards for the synthesis of complex natural products
1981 Assistant Professor
at Yale
1982 Ozonolytic cleavage of
cycloalkenes to terminally differentiated products
Tetrahedron Letters 1982, 23, 3867
1986 Macrolide epoxidation
strategy towards Monensin
JACS 1986, 108, 2106
1993 First 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
1984 Total 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
1989 Type II Diels-Alder
towards Calichemicin
Tetrahedron Letters 1989, 30, 3765
OH
OH
H
TBSO
OMs
OH
OH
H
H
TBSO Et2AlCl
1988 Professor, Harvard
The (Chemistry) Career of Stuart L. SchreiberOutline
■ 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”
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
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
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
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
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
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
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
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
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
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
[2+2] photocycloaddition reactions in natural product synthesisPeriplanone B
OO
O
Me
Me
■ Cockroach sex pheromone, used by female cockroaches to stimulate males by olfactory communication
■ Isolation (<<1μg/insect) achieved by via dissection of 35,000 cockroach alimentary tracts and extraction of midguts, as well as fecal recovery and extraction from an additional 20,000 cockroaches, yielded 200 μg Periplanone B
■ First synthesis and relative stereochemistry by W. C. Still in 1979
■ Cyclodecanone structure containing two epoxides (one spirocyclic), two olefins and an isopropyl substituent
■ First step scaleable (10.6g), involves photocycloaddition
Schreiber et al. J. Am. Chem. Soc. 1984, 106, 4038
[2+2] photocycloaddition reactions in natural product synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisPeriplanone 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 synthesisFuran-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 synthesisFuran-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 synthesisAsteltoxin
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 synthesisAsteltoxin
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 synthesisAsteltoxin
O
+O
h!, PhH
OO
Me
H
HMe
Me OBnOBnMe
mCPBA,
NaHCO3
45% (2 steps)O
O
Me
H
H OBnMe
HO
ArCO2
THF : 3N HCl 3 : 1
O
OH
Me
HO
Me
X
H
OBn
X=O
X=NNMe2
Me2NNH2,MgSO4
72% (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 step Scaleable
Used to set all relative stereochemistry
[2+2] photocycloaddition reactions in natural product synthesisAsteltoxin
O
Me
H
HO
Me
Me O
OH
R
O
OH
Me
HO
Me
X
H
OBn
X=O
X=NNMe2
Me2NNH2,MgSO4
72% (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 synthesisAsteltoxin
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 synthesisAsteltoxin
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, NH3
98%
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 synthesisAsteltoxin
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, NH3
98%
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 synthesisAsteltoxin
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, NH3
98%
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 synthesisAsteltoxin
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 synthesisAsteltoxin
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 synthesisAsteltoxin
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 synthesisUnsymmetrically 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 catalysisDiastereoselective 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 catalysisDiastereoselective 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 catalysisComparison 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 catalysisInduction 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 catalysisSynthesis 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 catalysisSynthesis 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