Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
Disclaimer
This group meeting is in no way meant to be
comprehensive. There is an enormous body
of literature featuring sugar starting
materials in total synthesis of which this group
meeting is only a sample. Any comparison
made between syntheses are for educational
and discussion purposes only.
Molecular Target Categories
The target structure can be broken down into three categories based
on how easily it can be traced back to the chiral carbohydrate pool.
Total Synthesis of Natural Products:
The "Chiron Approach"
Stephen Hanessian ISBN-10: 0080307159
SEt
HO
O
OH OH
O
diacetonide
Tracking Treasure Down:
Hanessian's "Rule of Five"
1) Select an sp, sp2, or sp3-hybridized carbon atom in
target structure
2) Move five bonds away and look for a heteroatom
regardless of functionality in between. These two
internal reference points correspond to the anomeric
C-1 and the C-5 oxygen atoms in the
hexapyranose structure
3) Look at only that carbon chain and try to imagine
a suitible chiral sugar SM.
HO
MeOH/H +
70%
OH
MeO
OH
O
glucoside
HO
OH
O
1) Ac2O
2) Br 2
3) Zn/AcOH
70%
OAc
OAc
OAc
glucal
Cat. 3: Totally Hidden Carbohydrates
Identification of carb. SM unlikely. Usually
based around application of in-house
methodology.
*These are my simplified definitions based
on Hanessians own in depth definitions,
examples and analysis.
EtSH/H +
70%
Important Reactions to Keep In Mind
Type I Ferrier reaction
OH
O
OH
An Example:
OH
C5 H H
OH
HO
HO
SEt
dithioacetal
Me 2CO/ZnCl2
90%
Organic Synthesis with Carbohydrates
Geert-Jan Boons ISBN-10: 1850759138
Is sugar derived chirality right for me?
- End differentiated oxidation state
- Stereochemical diversity
- Carbon chain length varying between 3-7 carbons
- Strong conformational bias
- Ability to introduce other heteroatoms (N, S, X) with inversion
or retention of configuration
- Ability to branch using a C nucleophile
- Excellent conformational bias and stereoelectronic effects
maximize predictive outcomes based on models
OH OH
O
O
Design and Strategy in Organic Synthesis
Stephen Hanessian ISBN-10: 3527319646
ACS Symposium Series 841 2003, 47.
OH
O
Cat. 1: Apparent Carbohydrates
Usually a lightly modified carbohydrate
appended to a structure via glycosidation.
Very easy to spot.
Cat 2: Partially hidden carbohydrates
One or two chiral centers may have been
removed. Still contains carb. oxidation
pattern. Identification likely requires
squinting.
Typical Reaction Channels
Working from a feedstock carbohydrate is difficult, time consuming
and wasteful. Entry into any reaction channel toward an enantiopure
building block is mostly limited to chemistry dating back over 100
years in the carbohydrate literature. The initial stage always involves
the fixation of the sugar in the respective tautomeric form.
Resources
The following books and reviews are excellent
resources and were very helpful in the
preparation of this group meeting.
Natural Abundance
Carbohydrates are the single most abundant class of organic
compounds associated with living matter.
Baran Group Meeting
06/30/14
R1
1) BzCl
2) Br 2
3) Et 2NH
L.A.
Nuc.
O
R2
O
R1
Nuc
R2
LG
85%
OBz
OBz
BzO
Type II Ferrier rearrangement
O
O
OR4
OBz
hydroxyglucal
R1
R3
R2
L.A.
H 2O
O
OH
R1
R3
R2
H H
OR Arguably the Most Useful Sugar Based "Chiron" for Modern Total Synthesis
S
NH 2
Why don't we see more syntheses based on chiral sugars?
C1
N
(R)-2,3-O-isopropylideneglyceraldehyde For every one unit of D-mannitol
HO 2C NH 2
- Overfunctionaliztion with hydroxyl groups that
subjected to protection/oxidative
O
OH OH
have similar or identical reactivity
CO2H
cleavage two desired aldehydes are
2 steps
O
- Number of chiral centers present on starting
formed. The resulting aldehyde is higly
OH
thienamycin
O
HO
carbohydrate often excessive for the synthetic chemist
NH 2
O
prone to polymerization and hydrolysis.
- Lack of suitible functional groups (olefin, carbonyl)
Long term storage is not recommended
OH
OH OH
to which modern organic techniques can be applied
25g $53.00 (Oakwood)
For full, indepth explanation
C1
C5
- Outcome of chemical transformations are unique to
For (S)-derivative see:
D-mannitol
with details see pg. 236 in:
available in 2 steps from D-mannitol
HO
O
each sugar based on individual stereochemistry
Org. Syn. 1995, 72, 1.
100g $16 (Oakwood)
Design
and
Strategy
in
Organic
Synthesis
Org.
Syn.
1998,
9,
450.
- Development of outstanding asymmetric methodology
Synlett 2001, 10 , 1565.
OH
Stephen Hanessian ISBN-10: 3527319646
Some Easily Accessible/Commercial/Useful Sugar Based Chirons
Full exploitation of sugar starting materials
OH
OH
OH
OH
OH
- Retention of the carbon-chain of the sugar
OH
HO
OBz TsO
- Reaction sequence should be simple, high yielding with no
HO
Cl
N3
Cl HO
OH
Different
Representations
chromatography. Focus on generating crystaline products.
- Avoid protecting groups or use simple, easy to remove PGs
O
O
MeO
MeO
O
O
MeO
MeO
OH
O
HO
- Cost.
OH
O
OTs
Br
HO 5 O
Cl
OH
HO
OH
5
O
On practicality: reality vs. raw concept
3
OAc
OH 1
HO
HO
HO
1 5
HO
HO
There are a huge variety of chiral carbohydrates available in
1
OR
HO
OAc
O
O
O
OH
O
HO
O
principle. However, the pool shrinks immensely when practical
OH
3
3
OH
OH
and operational considerations are applied leaving a relatively
OH
O
O
O
RO
O
OR
MeO
small number of realistic chiral sugar starting materials.
MeO
α-D-glucopyranose
HO
Me
HO
Br
OAc
OAc
C5
C1
OH
Total Synthesis of (+)-Ambruticin
Kende's chiral sugar approach
5
Kende, A. J. Am. Chem. Soc. 1990, 112, 9645.
1
OBn
BnO
MeO
1) TBDPSCl, Im
2) Im 2CS then
OH
Bu 3SnH
BnO
O
OH
12
O
CO 2H
15
8
MeO
O
O
Me
OH
O
O
OTBDPS
OH
Total Synthesis of (+)-Ambruticin
Jacobsen's asymmetric catalysis approach
Jacobsen J. Am. Chem. Soc. 2001, 123, 10772.
Me
Me
OTBS
Me 24
Me
(+)-Ambruticin (Cat. 1: apparent carbohydrate)
OBn
1) (COCl) 2, DMF(cat.)
1) TBAF
BnO
then CH 2N 2
2) PDC
OBn
MeO
+
OBn
OBn
BnO
catalyst 1 (10 mol%)
H
OTBDPS
64%
97% ee
OBn
Et 2NSF 3
HO
92%
O
MeO
TESO
N
OBn
MenO 2C
CO 2Men
O
CO 2Me
1) pTSA(cat.)
2) DMP
H
OTBS
Me
C
OTES
Me
O
OTBS
Me
1) BH 3THF
then 10% HCl
2) Swern ox.
O
Me
1) Ph 3P, CBr 4
2) DIBAL
73% over
3) TrCl, DMAP, four steps
TEA
4) n-BuLi
OBn
1) DIBAL
O
CO 2Me
Me
B
O
I
Me
Me1) Bu 3SnCu(Bu)CNLi2
MeI, DMPU
2) I 2
O
Me
Me
71%
O
Me
Me
TMSC(Li)N2
Me
O
O
Me
Me
OBn
O
CO 2Men
O
Me
OBn
OBn
Cl
CH 2CHMgBr
Me Pd(PPh ) (5 mol%)
3 4
3) Swern ox.
45%
Men = l-menthyl
as a single diastereomer
see: JACS 1985, 107, 3343.
+
Me
CO 2Me
1) 10% KOH
(EtOH/H 2O, 9:1)
CO 2Men 2) B H /THF
2 6
MenO 2C
catalyst 1
(5 mol%)
87%
99% ee
O
O
73:27 β: α
Cl
LiTMP
then
Me
Br
O
Cr
O
CO 2Me
A
H
O
Me
catalyst 1
O
CO 2Me
OTBS
OTBS
3) Pd/C, H 2
4) TPAP (cat.), NMO
OBn
TBDPSO
O
TBDPSO
2) h ν
53% over
two steps
1) Ac2O, H 2SO 4 (cat.)
BnO
2) NaOMe, MeOH
BnO
1) BH 3THF then
30% H 2O 2, 3 N NaOH
2) TBSOTf, 2,6-lutidine
OTBS
O
Name rxn?
F
Baran Group Meeting
06/30/14
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
OTr
2)
Rh(acac)(CO) 2
(S, R)-BINAPHOS
H 2/CO
CrCl 2, CHI3
OTr
A
Me
I
R
O
Me
Me
1) ethyl acrylate
Pd(OAc) 2 (10 mol%)
Ag2CO3
Me
O
Me
Me
Me
R
HO
2) DIBAL
Me
R
Name rxn?
dr = 96:4
Zn(CH3CHI) 2 DME
L*
Me
1)
O
O
HO
H
HO 2C
hydroquinone (cat.)
2) chiral
resolution
(+)-Ambruticin
1) n-BuLi then
2) Na(Hg)
B
3) LiOH THF/H2O H
4) Li, NH 3 (l), EtOH
O
Me then Me
[Pd] cat.
HMPA
Me
SO2Tol
O
Me
Me
Me
LiHMDS, DMF/HMPA
Me
(COCl) 2,
DMF (cat.)
Me
Me
Me
SnMe3
C
Tol
O
O
O
R
O
Me
Me
1) MeMgBr
2) Ac2O, DMAP, TEA
3) LDA then TBSCl, HMPA
then acid
4) CH 2N 2
OTBS
OTBS
Me
1) LDA
then PTSF
2) (Me) 4N +-OAc MeO 2C
HMPA
S
O
Me
Me
Me
Me
O
OTBDPS
O
Me
Me
Me
Me
PPh 3, PTSH, DEAD
then Mo(VI)/H 2O 2
Me
R
HO
Me
1)TBAF
2) Pt, O 2 H 2O/acetone
(+)-Ambruticin
Me
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
HO
Synthesis of Trehazolin from D -Glucose:
following a plausible biosynthesis
Giese, B. J. Org. Chem. 1998, 63, 5877.
Trehazolin from trehazolamine is known in the literature
see J. Org. Chem. 1994, 59, 813.
OH
HO
HO
OH
MeO
N
HO
OH
N
H
O
O
OBn
O
Trehazolin
OH
O
HO
HO
HO
HO
+CO2
-2 H 2O
O
HO
HO
N
N
O
N
1
N
HO
3
HO
3
5
OH
HN
O
O
Li
O Al
H
H
O
then
N
O
O
TBSO
OH
Ph
OTBS
K 2CO 3
MeOH
OAc
OTBS
1) DMDO
2) CSA
HO
O
BnO
BnO
Ph
O
1) MeONH 2•HCl, py
2) DMP
O
OH
O
BnO
BnO
SmI2 (5 equiv.)
t-BuOH(2.5 equiv.)
O
NOMe
84%
single diast.
O
BnO
BnO
O
O
OH
NHOMe
OTBS
O
OH
OH
HO
NH 2
trehazolamine
Na, NH 3 (l) BnO
BnO
O
Ph
Ph
OH
O
OH
NHOMe
O
4) DBU
Bn
OTBS
OAc
1) Na naphthalide
2) (Boc) 2O, TEA, DMAP
O
1) K 2CO 3, MeOH
2) LAH, NaOMe BnO
BnO
O
61% over two steps
NH
O
3) Cs2CO 3, MeOH
4) Ac2O, TEA, DMAP
NHBoc
N
Ts
O
O
1) Ac2O, py, DMAP
2) Pb(OAc) 4
HO
HO
1) LiBH 4, MeOH
2) TsNCO
3) I 2, K 2CO 3
O
O
N
92% for RCM step
Bn
H
1) TBSOTf
2,6-lutidine
2) Grubbs' I
O
Giese's reductive cyclization approach
O
OH
NHOMe
BnO
63%
HO
Ph
O
BnO
H
OH O
Bu 2BOTf
TEA
OH
O
OH OH
OH
O
BnO MeON
Bn
O
N
OH
Trehazolin
NOMe
N
selective
oxidation
HO
N
N
OH
O
O
HO
HO
pinacol type
coupling
HO
O
BnO
The Crimmins' Synthesis of Trehazolin: The chiral auxiliary and RCM approach
J. Org. Chem. 2001, 66, 4012.
OH
O
Ph
O
OH
HO
OH
NHOMe
BnO
Ph
LAH
BnO
OH
OH
O
O
O
O
OH
5
HO
HO
O
O
BnO
Ph
BnO
1
O
MeO
Ph
HO
HO
C
NH 2
OBn
HO
O
HO
HO
Ph
O
Ph
OH
OH
SmIII
N
SmI2
O
O
A speculated biosynthesis
BnO
OBn
N
H
Baran Group Meeting
06/30/14
NH
O
OH
HO
2) H 2O2
OsO4, NMO
O
BnO
OBn
SCN
OAc
OH
NH
O
O
OBn
NOMe
AcO
HO
known steps
formal synthesis
see J. Org. Chem. 1994, 59, 813.
OAc
AcO
OAc
AcO
NHAc
peracylated
trehazolamine
OH
HO
O
NH
O
trehazolin
TBSO
OTBS
1)o-NO2C6H 4SeCN
n-Bu3P
1) 2 N KOH, EtOH
2) Ac2O, py, DMAP
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
Baran Group Meeting
06/30/14
OH
OH
Total Synthesis of (+)-Lycoricidine from D -Glucose
Ogawa, S. J. Org. Chem. 1993, 58, 4441.
O
O
Total Synthesis of Echinosporin
Smith III, A. J. Am. Chem. Soc. 1989, 111 , 8039.
HO
O
CONH2
O
H
H
(–)-Echinosporin
O
Lycoricidine
Br
O
OH
O
1) MOMCl
2) DBU
MeO
OH
N3
Carbohydr. Res. 1974, 35, 175.
OMOM 1) Hg(TFA) 2 (1 mol %)
O
MeO
OMOM
OMOM
HO
N3
HO
MsCl, TEA
OMOM
HO
N3
Br
O
OH
O
O
OPMB
OMOM
OH
L -ascorbic acid
O
1) Luche red.
2) PMBCl, NaH
OMOM
1)LDA,
2)Tf2NPh (72%)
3) Pd(OAc) 2, PPh 3, CO
TEA, MeOH, DMF (83%)
2) MPMCl, NaH
2
Pd(OAc) 2 (10 mol%)
DPPE, TlOAc (2 equiv)
DMF
O
OMOM
NMPM
O
O
CO2Me
H
OH
O
C2 inversion via
Mitsunobu
O
O
deprotection
5 steps
OH
H
H
(10 eq.)
O
O
O
h υ, uranium filter
50%
1) Swern ox.
2) NH 2NHTs
3) Na, (CH 2OH)2
O
O
O
Name rxn?
O
O
Lycoricidine
CO2Me
H
OMOM
NMPM
O
O
O
H
HO
HO
O
O
50%
OH
CO2Me
H
H
OMOM
NMPM
O
not observed!
CO2Me
OH
H
Parikh-Doering ox.
O
OMPM
OMOM
syn-elimination
HO
NH
formal anti-elimination?
Br
Pd
O
H
Pd(DBA) 3•CHCl 3
diallyl carbonate
OH
90%
O
O
CONH2
Br
H OPMB
Pd
OMOM
H
OMOM
NMPM
O
O
O
CO2Me
1) KHMDS, HMPA
then Davis oxaziridine HO
H
2) acidic resin
O
OH
HO
OPMB
OMOM
O
OTHP
O
OPMB
OMOM
O
HO
N3
N3
O
O
CO2Me
O
OMOM
OMOM
1) DIBAL
2) MeOH, PPTS
3) Me 2CO, H 2SO 4
O
3) DHP, PPTS
4) Me 2SO 4, NaHCO 3
H
(EtO) 2P(O)CN, TEA
OMOM
NMPM
1) Me 2CO, Me 2C(OMe)2
O 2) 30% H 2O2 (aq.), CaCO 3
then Pd/C
O
HO
1) LAH then
Br
O
OPMB
OMOM
O
OH
NH
CONH2
46%
H
OH
O
HO
1) 3.6 N HCl
2) Bu 3P, DEAD (28%)
O
CONH2
O
H
H
(–)-Echinosporin
NH 4OH, MeOH
86%
OH
O
O
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
Total Synthesis of (–)-Tetracycline
Tatsuta, K. Chem. Lett. 2000, 647.
Total Synthesis of Fomannosin
Paquette, L. Angew. Chem. Int. Ed. 2007, 46, 7817.
MeO 2C
O
HO
MeO 2C
4) PMB protect.
5) LDA, CH2O
O
TsO
Tetracycline from a sugar?
1) DBU
2) Pd/C, H 2
3) MeOH, acid
O
1) TBDPSCl
OMe 2) DIBAL
O
OPMB
TBDPSO
OMe
3) Swern ox
4) Wittig olefination
OPMB
OBn
BzN
OTBDPS
t-BuLi
PMBO
3) PDC
4) TMSCH2Li
5)TsOH
OTBS
OH
O
PMBO
1) Cp2ZrCl2, n-BuLi
2) TBSCl, imid.
Me OH
1) TBSCl
2) Oxidation
3) Wittig
4) HCl
H
MeO
2) BH 3•THF then MeO
H 2O2, NaOH
OH 3) BnBr
O
NBz
H
OBn
OBn
Me
OBn
O
O
OH
OH
O
1)
NBz
LDA
1) HgCl 2
2) MsCl, TEA
OBn 3) DBU
BzN
PBU 3
OBn
OMe OH O
SeCN
BzN
54% 2 steps
OTBS
OBn
OBn
OH
1) O3, Sudan III
PPh 3
2)
I
NO 2
1)
O
MeO
OTBDPS
Baran Group Meeting
06/30/14
NBz
OBn
OTBS
OBn
DBMP
2) acidic oxidation
O
OMe O
1) Grubbs II
2) TBAF
OH
PMBO
1) HO 2CCH2COSEt, EDCI
2) IBX
3) Pd/C, Et 3SiH
4) NaBH 4, KH 2PO 4
MeOH/AcOH
5) TBSCl
OH
1) OsO4
2) Swern ox.
O
PMBO HO
Me
SOCl2, TEA
O
H
Me OH
H
NBz
OBn
H
NMe 2
23 steps
NH 2
OBn
OTBS
OMe OH O
OH
HO
O HO O
H O
Tetracycline
O
1) Tf2O
2) DBU
3) TBAF
O
O
1) SmI2, t-BuOH
2) TFA
3) SOCl2, TEA
4) DBU
O
O
O
HO
OH
O
HO
O
O
PMBO HO
OTBS
OTBS
Fomannosin
PGO
O
OMe Cp2ZrCl2
OPMB
PGO
Cp
Zr
Cp
O
Cp
Zr Cp
O
OMe
OPMB
OPG
OPG
PMBO
OPMB
PMBO
O
OTBS
OPG
J. Organomet. Chem. 2006, 691, 2083.
OH
ZrL2
O
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
Synthesis of DS-8108b: from chiral aux to sugar and back
Daiichi Sankyo Co. Org. Process Res. Dev. 2013, 17 , 1430.
DS-8108b continued
Sugars: just a bridesmaid, back to the chiral auxiliary
Can your sugar do this?
Early-stage synthesis
O
O
1) NaHMDS
O
BnO
N
O
O
Br
O
Shi's catalyst
OBn oxone
HO
O
O
HO
2) LiOH, H 2O2
O
LiH, Cl
NH
Bn
O
O
O
1) Pd/C, H 2
2) NsCl, TEA
NsHN
HO
Ph
O
O
O
O
O
O
NsHN
Cl
O
K 2CO 3
NH
O
O
N
conc. HCl
HCl
O
N
N
Br
N
O
NsCl
NaHCO 3
O
O
NHNs
N
H
N
1) 1-decanethiol, K 2CO 3 NsHN
2) fumaric acid
3) recrystalization
O
N
82%
N
1) NaIO 4, KHCO 3, H 2O
OH
2)
OH
O
3) NaOH
Br
N
Br
NHNs
O
OH
OH
H 2N
O
O
O
N
O
OH
H 2N
0.2 eq Py-OH
0.3 eq TEA
cat. 2-hydroxypyridine
cat. TEA
NsHN
O
Cl
NH
N
N
OH
Ph 3P
O
O
So where does the sugar come in?
Avoiding chromatography en route to A
O
HMTA
N
N
O
Cl
Ph
N
Br
O
Ph
63%
AcOi-Pr
O
Br
N
Ph
OH
O
O
O
Ph
N
Cl
MsO
DS-8108b
N
O
NH 2
N
89% from A
NsN
2 eq
O
Ph
NsHN
N
O
O
Br
Br
Ph
BnO
O
O
1) MsCl, TEA
2) NaN 3
N3
O
A
LHMDS
O
BnO
MsCl, TEA
AcOiPr
Baran Group Meeting
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OH
O
Ph
O
O
1) Pd/C, cyclohexylamine
HCOONH 4
dicyclohexylamine (DCHA) dr = 67:33
CO2H
OH
2) acetone slurry
H
N
NsHN
OH
60%
70%
67%
Cl
O
N
O
1) Decanethiol
K 2CO 3, acetone-H2O
2) fumaric acid
N
N3
O
Ph
O
NaN 3, TBAC
CO2Me
1) Pd/C, H 2
2) NsCl, TEA
3) HCl, MeOH
80%
64%
O
Ph
1) MeI, NaHCO 3
2) MsCl, TEA
OMs
O
CO2Me
91%
OH
O
Ph
O
Cl
OH
CO2H
O
O
O
NsHN
HO
- 20% overall yield for the sequence
- no chromatography
- Sequence cost prohibitive (sugar SM)
- Insufficient dr
H
N
H 2N
No chromatography
24% overall yield
N
O
N
Cl
DS-8108b
OH
Creativity From The Chiral Pool: Sugar Edition
Ruben Martinez
Sugars: What are they good for?
SGLT2 inhibitors. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of drugs for the
treatment of type 2 diabetes. Type 2 diabetes affects 23 million Americans making this area
particularly interesting for the development of novel treatments.
Cl
Me
O
HO
HO
Process R & D synthetic route: a tale of two protecting groups
O
HO
O
O
HO
F
HO
OH
Cl
HO
TMSO
>90%
OH
O
TMSO
OTMS
OTMS
OH
O
O
TMSO
OH
TMSO
OTMS
OTMS
>70%
Et
OH
Empagliflozin
limited European approval
OEt
O
AcO
PhMe/Ac 2O
TEA/DMAP
90%
OMe
AcO
O
OAc
HO
OH
O
OH
83%
OH
Et
Et
OH
1) MSA/MeOH
2) NaHCO 3
OMe
HO
OAc
HO
n-BuLi
A
O
OH
OH
Canagliflozin
FDA approved
TMSCl/ NMM
THF/PhMe
O
HO
S
Baran Group Meeting
06/30/14
Dapagliflozin
limited European approval
SGLT2 inhibitors, how do they work?
The SGLT family includes the Na/glucose co-transporter SGLT1, which is mainly expressed in the
GI tract and is responsible for glucose absorption from the food intake. SGLT2 is mainly
expressed in the kidneys. SGLT2 is responsible for ~90% of glucose reabsorption in humans.
SGLT2 inhibitors work by blocking the reabsorption of glucose in the kidneys. This prevents the build
up of glucose in the blood and allows for excess glucose to be eliminated via urination. One of the
most common side effects is genital infection.
1) Et 3SiH/BF 3•OEt2/H2O
2) 2,2-dimethoxypropane
O
AcO
AcO
aq. NaOH/EtOH
OAc
3) EtOH crystallization
O
HO
HO
OAc
74%
Et
>20:1 β:α in the crude
crystallization purges the α isomer crystalline final intermediate
OH
OH
amorphous API
For an indepth discussion see: Current Pharmaceutical Design 2014, 20, 3647.
O
HO
Development of a large scale synthesis of an SGLT-2 inhibitor
Bristol-Myers Squibb OPRD 2012, 16 , 577.
HO
HO
OH
OH
First-generation synthesis
O
OH
The target
API
BnO
TEMPO/bleach
NaHCO 3
BnO
O
BnO
OBn
O
Br
OBn
BnO
A
n-BuLi
OBn
OBn
Et
O
OH
OBn
BnO
OBn
O
H 2, Pd/C
HO
OH
BnO
O
BF 3•OEt2/i-Pr3SiH
BnO
OH
OBn
OBn
Et
Et
COO
H 2O
OH
NH 3
OH
Et
Et
HO
Ph
HO
Et
BnO
O
L-phenylalanine
EtOH/H 2O
Et