1. No category

SAMPLE PROBLEM:
Consider the structure below. Develop two enantioselective, retrosynthetic solutions to
the synthetic problem and describe one forward synthesis in detail.
H2N
H2N
NH2
NH2
CHE535 Synthetic Organic Chemistry Problem 1
page 1
ID Numbers
497-81-9926
890-78-5634
Retrosynthetic analysis 1:
H2N
NH2
H2N
N3
a
N3
ActO
b
HN Proc Proc NH
NH2 Proc NH
O
O
Proc NH
d
O
HN Proc
e
O
O
O
OSO2CF3
F3CO2SO
HN Proc
Proc NH
4
c
3
2
1
OAct
HN Proc
6
5
This retrosynthetic analysis uses tartaric acid-derived 6 as a source of the stereogenic centers needed
in the 1,2-diamine functionality in 1. The optically pure (R,R) and the (S,S) stereoisomers of tartrate are
both available commercially. The triple bonds in structure 5 are convenient to acidify the termini of the
three carbon unit bearing the primary amine to allow nucleophilic substitution. In the processes described
by retroarrow a, protection of the amines (NH-Proc) that allows transformations from structures 5 to 2 will
be sought. Nucleophilic substitution will be used to displace the oxygen atoms after the chain is elongated
in retrosynthetic arrow b. OAct indicates activation of the oxygen atoms as leaving groups.
Since I have chosen to present this retrosynthesis as a forward synthesis I will leave the description
sketchy and refer to referenced literature in the forward synthesis.
Retrosynthetic analysis 2:
7
H2N
NH2
f
TBSO
OEt
8
N
N H
g
9
TBSO
h
10
O
(EtO)2OP
H2N
NH2 TBSO
OTBS
TBSO
11
TBSO
Another feasible stereoselective retrosynthesis involves net addition of two nitrogen atoms across
the double bond which should generate structure 8 from 9.1 The diastereoselectivity is controlled at this
point but there will be a racemic mixture (two enantiomers in the reaction vessel) once the synthesis is
complete. The resolution of similar mixtures to a single enantiomer has been accomplish for a variety of
chiral 1,2-diamines.2
This protocol reduces the molecular complexity to the stereo control of a 1,2-disubstituted alkene.
Stereocontrol can be effectively accomplished by the selective coupling of ylide 10 with aldehyde 11.3
Retrosynthetic analysis 2 is less atom economical than retrosynthetic analysis 1 because half the
material is discarded in the resolution. Resolving the 1,2-dimamine at the earliest possible stage in the
synthesis would be desirable from the stand point of atom economy.
CHE535 Synthetic Organic Chemistry Problem 1
page 2
ID Numbers
497-81-9926
890-78-5634
O
Trif. Anhyd.
O
HO
13
O
°
Et2O, 0 C
Hunig's Base
OH
12
Ph
LiCC(CH2)NBn2
O
THF-DMPU, -78 oC
OSO2CF3
F3CO2SO
Ph
Ph
Ph
N
N
15
14
O
O
N3
N3
1) 0.1 N HCl/ MeCN
2) MsCl, Pyr
3) NaN3/ DMF
Ph
N
Ph
O
N3
O
BnO
OBn
3
3
1
Ph
N
Ph
H2 / Pd/ C
N3
BnO
OBn
3
3
FORWARD SYNTHESIS of retrosynthetic analysis 1.
The synthesis begins with compound 12 available from a three-step synthesis starting with the (l)
isomer of tartaric acid.2 Upon triflation the primary alcohols are activated to SN2 displacement by
carbanions.4 In the sited example the sodium salt of an amide enolate displaces the triflate of 13.
Homologation of the chains in two directions simultaneously takes advantage of the fact that the structure
is C2 symmetric. Hydrolysis of the 1,3-dioxolane protection of the 1,2-diol, mesylation and substitution
with sodium azide should furnish 15.5 These operations were performed on 16 to furnish 17 in the cited
reference. Note that the substitution reaction occurs with inversion at the carbinol carbon atom. In the last
step all three functionalities azide, triple bond and benzylamine should reduce under heterogeneous
catalysis with H2 and Pd.5,6
1
Jung, S.-H.; Kohn, H. "Stereoselective Synthesis of Vicinal Diamines from Alkenes and Cyanamide" J.
Am. Chem. Soc. 1985, 107, 2931-2943.
2
Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B. “1,4-Di-O-Alkyl Threitols From Tartaric
Acid: 1,4-Di-O-Benzyl-L-Threitol [2,3-Butanediol, 1,4-bis(phenylmethoxy)- [S-(R*,R*)]“ Organic
Synthesis, Coll. Vol. 8, 155.
3
(a) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. "The Wittig and related reactions in natural
product synthesis." Liebigs Ann. Chem. 1997, 1283-1301. (b) Kryshtal, G. V.; Serebryakov, E. P. "Regioand stereoselectivity in the addition reactions of CH-acids to aldehydes under the conditions of phasetransfer catalysis." Russian Chemical Bulletin 1995, 44, 1785-1804. (c) Clayden, J.; Warren, S.
"Stereocontrol in organic synthesis using the diphenylphosphoryl group." Angew. Chem., Int. Ed. Engl.
1996, 35, 241-270.
4
Overman, L. E.; Larrow, J. F.; Stearns, B. A.; Vance, J. M. "Enantioselective Construction of Vicinal
Stereogenic Quaternary Centers by Dialkylation: Practical Total Syntheses of (+)- and mesoChimonanthine" Angew. Chem. Int. Ed. 2000, 39, 213-216.
CHE535 Synthetic Organic Chemistry Problem 1
page 3
ID Numbers
497-81-9926
890-78-5634
5
Kotsuki, H.; Kuzume, H.; Gohda, T.; Fukuhara, M.; Ochi, M.; Oishi, T.; Hirama, M.; Shiro, M. "New
Convient, Enantiospecific Synthesis of (S,S)- and (R,R)-2,2'-Bipyrrolidine Derivatives" Tetrahedron:
Asymmetry 1995, 6, 2227-2236.
6
Siegel, S. “Heterogeneous Catalytic Hydrogenation of C=C and Alkynes.”In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, p 417.