Acarbose

Konyin Adewumi
Jacquelyn Ferguson
Shawn Gupta
Roma Luthra
Mariah Ondeck

Heidy Pardo
Shalini Ray
Diego Schaps
JusDn Wong

A discussion of acarbose
Why do people use it?
Historical perspecDve
Design consideraDons
New synthesis

Acarbose is used to control glucose levels for

people with type 2 diabetes5

Acarbose works to slow breakdown

of complex sugars1
Decreased rate of digesDon slower increase
of blood glucose levels
Taken 3 Dmes a day, prior to each meal
Intermediate step between dieDng and insulin
injecDons

ConcepDon of acarbose through target-directed

screening1
Discovered by Bayer in 1970s
Glucobay in 1990s
EecDveness seen outside US
Side eects:
- light headedness
- loose bowel movements
Awareness

CH 3

HO
CH 3OH

OH

O
H

HO
H
H

OH

OH

OH

Cyclase

OH

OH

OH

HO

OH

HO

H 2N

HO

(R Group)
OH

OH

OH

HO

CH2O

HO

Sedoheptulose 7-phosphate2
HO

HO

HO

OH

OH

OH

OH

R
N

OH

OH
OH

OH

OH

N
OH

H 2O

OH

H-OH

HO

HO

HO

HO

HO
HO

HO
OH

OH

OH

OH

z-epimerization

OH

R
N

N
N
OH
OH

HO

OH

N
OH

H
HO

HO

OH

HO

OH

OH

OH

OH

NaBH4
CH 3

H3O

OH

CH 3
OH

N
OH

HO
OH

OH

CH2OH

HO
OH

OH

CH2OH

O
HO

HCl

OH

O
HO

OH

OH
OH
CH 3
OH

N
OH

CH2OH

HO
OH

CH2OH

HO
HO
OH

O
HO
OH

OH

O
H

Our teams synthesis focuses on lowering cost

and improving funcDonality
StarDng material is glucose
Decreasing costs allows companies to increase
producDon, or make a larger revenue
Valiolone can make valienamine which are
important pharmaceuDcal compounds

Our teams synthesis focuses on lowering cost

and improving funcDonality
CH2BnO

CH2BnO

CH2OH

OBn

OBn

HO

CH2BnO

CH2BnO

CH2BnO

Cl

OBn

OH

Cl

CH2BnO

BnO

CH2BnO

Cl
Cl

BnO

OH

HO

OBn
O

OH

CH2OH

OH

OBn

OBn
BnO

Cl

OBn

BnO

OH

OBn

Cl

OBn

BnO

Cl

OBn

OBn
Cl

OBn

OH

BnO

BnO

OH

OH

Cl

OBn

OBn

HO

Cl

HO

OH

OH

CH2OH

OH

CH 3

O
HO
HO
OH

Reference: Gloria Silva

N
H

HO

HO

HO
OH

OH

OH

OH

Step 0:

H
CH2OH

HO

Cr

CH2OH

OH

HO

HO

HO

OH

Cr

HO

OH

OH

OH

OH
O

CH2OH
O

CH2OH
O

HO
HO

OH

OH

HO
OH

Cr

HO

OH

Cr

O
O
H

H
CH2OH
O
HO

HO
OH

Reference: Gloria Silva

OH
O

HOH 2C

BnOH 2C
O

Step 1:

OBn
OBn

O
BnO
BnO

O
OBn

HOH 2C

OBn

OH2C

NaH

O
HO
HO

O
OH

Deprotonates
Alcohol

O
O
O

O
O

Br

BnOH 2C
O
BnO
BnO

Reference: Gloria Silva

O
OBn

OBnH2C

OBnH2C
Cl

Step 2:

OBn
OBn

Cl

LDA

OBn
OBn

OBn

(LDA)
OBnH2C

Cl
OBn

OH

OBnH2C

Li
N

O
OBn
OBn

Cl
O

OBn
OBn

O
OBn
Cl

Cl
O

OBn

Cl
O

Cl

Protonation
of Alcohol
OBnH2C

Cl
O

OBn
OBn

Reference: Gloria Silva

OBn

Cl
OH

CH2BnO

CH2BnO

Step 3:

O
OBn

OBn

OH

Cl

O
CH2BnO

CH2BnO

Cl

OH

OH

OBn

OBn

OBn

Cl

OBn

OBn

OBn

Cl
BnO

BnO
OH

Cl

BnO

BnO

Cl
OBn

Cl

OBn

CH2BnO

OH

HCl

Cl

OH

BnO

Cl

OH

CH2BnO

CH2BnO

OH

OH

Cl

OBn

Cl

OBn
OBn
Cl

BnO
O

OBn
Cl

BnO
OH

Cl

Reference: Gloria Silva

CH2OBn
OH

OBn
OBn

Step 4:

CH2OBn

DMSO, Et3N, (COCl)2

R

BnO

BnO

CH2OBn
Me

OH

Me

OBn
OBn

S
R

BnO

CH2OBn
OBn
OBn

OBn
OBn

R
BnO

Me
S

Cl

Me

Cl

NEt3
H
CH2OBn
OBn
OBn

CH2OBn

CH2OBn

OBn
OBn

R
BnO

Reference: Gloria Silva

OBn
OBn

Me
S

R
BnO

S
R

BnO

Me

Cl

Step 5:

CH2OBn

R
O

OBnH2C

CH2OBn

OBn
R
BnO

R
R

OBn

BnO

BnO

OH

OBn

OBn

BnO

BnO
O

CH2OBn
BnOH 2C

O
OBn
BnO
H

BnO

Cl

OH

BnO

Cl

BnO

Cl

Cl

BnO
O

OH

H
Cl
BnOH 2C

BnOH 2C

Cl

Bno

O
Cl

Bno

OBn
BnO

Reference: Gloria Silva

Cl

OH

OBn
BnO

CH 2BnO Cl

CH 2BnO

HSnBu3 +AIBN

Cl

OBn

OBn

Step 6:

OH

OBn

N
N

CH 2BnO

CH 3

CH 3

H
N

BnO

H 3C

OH

OBn

BnO

OBn

CH 3

OH

OBn

BnO

SnBu 3

N
C
CH 2BnO H
H
OBn
OBn
H

OH

CH 2BnO H

SnBu3

BnO

SnBu3

SnBu3

OBn

CH 2BnO Cl

OBn

Cl

OH

BnO

OBn
OBn

OH
BnO

O
CH 2BnO

SnBu3

CH 2BnO H

Cl
OBn
OBn

Reference: Gloria Silva

SnBu3
Cl

OBn
OH
BnO

OBn

OH
BnO

Step 7:

Reference: Gloria Silva

Step 8: PreparaDon of the chain for abachment

N

NH

Cl

Si

NH

Si

Cl

O
H

O
O

OH
HO
Si

Cl
OH

Si

NH

NH

Cl

NH

NH

OH
HO

OH

Si
O

OH

R=

HO

O
OH
HO

Reference: Gloria Silva

HO

Step 9:

Reference: Gloria Silva

Cost analysis: glucose7

25,000g/$214
117g/dollar
To create acarbose product (15% yield)
- 3750g/$214
- 17.52g/dollar

Reference: Sigma Aldrich

Cost analysis: materials for original synthesis7

D-Sedoheptulose 7-phosphate D-Sedoheptulose 7-phosphate
lithium salt
barium salt
- 5mg/$503
- 5mg/$485
- 1g/$100,600
- 1g/$97,000
- Almost 800,000 Dmes
- Almost 750,000 Dmes
more expensive than
more expensive than
glucose!
glucose!

Acarbose is a useful drug and

our synthesis is cost eecDve
Use for controlling glucose for type 2 diabetes
Current synthesis:
- D-sepoheptulose 7-phosphate as starDng material
- Costly!
Our synthesis
- Glucose as starDng material
- Cost-eect, abundant, comparable synthesis
- Can be scaled up using large reactors
- Could be a Dmely process

Works Cited
1. Organic Chemistry, Solomons and Fryhle, 10th EdiDon
2. hbp://onlinelibrary.wiley.com/doi/10.1002/tcr.1015/full
3. hbp://www.sciencedirect.com/science/arDcle/pii/S000862150300315X#
4. hbp://pubs.acs.org/doi/pdf/10.1021/jo00039a025
5. hbp://www.metacure.com/about-diabetes-2/type-2-diabetes-mellitus-t2dm/
6. hbp://www.businessweek.com/news/2011-11-28/china-s-thirst-for-new-diabetes-drugs-
threatens-bayer-s-lead.html
7. Sigma Aldrich website

References
Priyanka Nawathe, Bayer ScienDst
Gloria Silva, Organic Chemistry Professor
Mabhew Mackenzie, Organic Chemistry Teaching Assistant
Susan Graul, Organic Chemistry (Lab 2) Professor
Phil Campbell, Physiology Professor

Pentose Pathway too long

Pentose Pathway too long