Studies toward the syntheses of carbohydrate analogs containing a phosphonate group via
oxaphospholene chemistry
by Todd Aksel Madsen
A thesis submitted in partial fulfillment of the requirements for the degree of Masters of Science in
Chemistry
Montana State University
© Copyright by Todd Aksel Madsen (2002)
Abstract:
Previous studies toward 3-deoxy-3-phosphonomethyl-D-arabinose using oxaphospholene methodology
have found a problem in a crucial step of the synthesis. In an attempt to fix this problem, a new aminal
protecting group was pursued. The new aminal proved to be too bulky to react with the
oxaphospholene. However, in the process of making the aminal there was room for variation that
should produce an aminal that is less hindered and should therefore react with the oxaphospholene.
Another issue addressed is the stereochemistry of the aldol condensation of a chiral aldehyde and the
oxaphospholene. The product of this reaction is a β-hydroxy ketone phosphonate with two new
stereocenters. The aldehyde is chiral and derived from 5-ethyl lactate and contains a protected alcohol.
The method envisioned for the determination of the stereochemistry is protection of the hydroxyl group
of the β-hydroxy ketone then deprotection of the alcohol. This should then cyclize onto the
phosphonate yielding a six membered cyclic phosphonate otherwise known as a phostone. The six
membered phostones are known in literature and the J coupling values for the protons around the ring
are published. Thus, by comparison of the J coupling values from the phostone that we make to the
literature references we will know the stereochemistry of the six membered phostone, which we could
then relate back to the aldol product. STUDIES TOWARD THE SYNTHESES OF CARBOHYDRATE ANALOGS
CONTAINING A PHOSPHONATE GROUP VIA OXAPHOSPHOLENE CHEMISTRY
by
Todd Aksel Madsen
A thesis submitted in partial fulfillment
of the requirements for the degree
of
Masters of Science
in
Chemistry
MONTANA STATE UNIVERSITY
Bozeman Montana
June 2002
ii
APPROVAL
of a thesis submitted by
Todd Aksel Madsen
This thesis has been read by each member of the thesis committee and has been
found to satisfactory regarding content, English usage, format, citations, bibliographic
style, and consistency, and is ready for submission to the College of Graduate Studies.
Dr. Cynthia McClure
Approved for the Department of Chemistry
S
Dr. Paul Grieco
>ignatup<0
Date
Approved for the College of Graduate Studies
/ rS
Dr. Bruce Mcleod
(Signature)
Date
ZL
iii
STATEMENT OF PERMISSON TO USE
In presenting this thesis in partial fulfillment of the requirements for a Master’s
degree at Montana State University, I agree that the Library shall make it available to
borrowers under rules of the library.
If I have indicated my intention to copyright this thesis by including a copyright
notice page, copying is allowable only for scholarly purposes, consistent with “fair use”
as prescribed in the U.S. Copyright Law. Requests for permission for extended quotation
from or reproduction of this thesis in whole or in parts may be granted only by the
copyright holder.
Date
iv '
TABLE OF CONTENTS
I . INTRODUCTION.................................................................................................. I
Background......................................
I
Classical Methods for the Synthesis of Phosphonates........................................... 2
Pentacovalent Oxaphospholene Methodology....... ...... :........................................ 3 '
Proposed Target.................................................................................
6
2. STUDIES OF THE CONDENSATIONS OF OXAPHOSPHOLENES AND
ALDEHYDES TOWARD D-ARABINOSE AND STEREOCONTROL OF
PRODUCTS..............................................................................,............................ 9
Retrosynthetic Analysis.......................................................................................... 9
Previous Work...................................................................................................... 11
Chiral Aminal........................................................................................................ 12
Chiral Oxazolidine................................................................................................ 17
3. PREPARATION AND CONDENSATION REACTIONS OF A CHIRAL
ALDEHYDE........................
20
20
Overview...............................................................
The Aldehyde........................................................................................................ 21
Determination of stereochemistry.......... ..............
23
Deprotection.............................................
24
Conclusions and Future Work................
26
4. EXPERIMENTAL..................................................... J........................................ 27
General Information...............................................................................
27
Experimentals....................................................................................................... 30
Preparation of 2,2,2-triethoxy-2,2-dihydro5-methyl-1,2,X,45-oxaphospho-4-lene.............................................
30
Preparation of N,N’-diisopropyl-diimine.............................................................. 30
Preparation of <i/-N,N’-diisopropyl-1,2-diphenylethylene-1,2-diamine............... 31
Preparation of N,N’-bis-o-tolyl-diimine............................................................... 32
Preparation of 1,3-diisopropyl-4,5-diphenyl-2-imidazolidinecarboxaldhyde......33
Preparation of 3-(diethoxy)phonomethyl-5-?-butyldiphenyIsilyloxy-hexan-4-ol-2-one....................................................................... 34
Preparation of N-methyl benzil monoimine......................................................... 36
Preparation of 2-N-methyl-1,2-diphenyl-ethylene-1-ol........................................ 37
REFERENCES CfTED......................................................................................... 38
vi
LIST OF TABLES
Table
.
Page
2.1 Synthesisof N,N’-dimethyl-1,2-diphenylethylene-diamine 8b.......................13
2.2 Reaction of aminal 4b and oxaphospholene I ...................... ........................ 14
2.3 Reaction of aminal 4a and oxaphospholene I ...............................................16
2.4 Diimines......................................................................................................... 17
3.1 Deprotection of the silyl ether........................................................................ 25
3.2 Deprotection of 20.......'................................................................................. 26
vii
LIST OF FIGURES
Figure
Page
LI Phosphates vs. Phosphonates.......................................................................... 2
1.2 D-Arabinose and KDO.................................................................................... 7
1.3 3-Deoxy-3-Phosphonomethyl-D-Arabinose.................................................... 8
2.1 Oxaphospholenes............................................................................................. 9
2.2 l,3-Diphenyl-2-imidazolidinecarboxaldehyde 4c...........................................11
3.1 Product of TBAF Deprotection....................
25
viii
LIST OF SCHEMES
Scheme
Page
LI Alternative Methods to Prepare Phosphonates................................................3
1.2 Reaction of Oxaphospholene and an Electrophile.............................. ............ 4
1.3 Synthesis of a Pentacovalent Oxaphospholene............................................... 4
1.4 Proposed Nucleophilic Addition Mechanism..................................................5
1.5 Pentacovalent Oxaphospholene Methodology.................... ........................... 5
1.6 Biosynthesis of Lipopolysaccharide................................................................ 8
2.1 Retrosynthesis of 3-Deoxy-3-Phosphonomethyl-D-Arabinose...... ...............10
2.2 Reduction of Ketone 5...................................................................................10
2.3 Preparation of the Chiral Diamine............ .................................................... 12
2.4 Preparation of the Aminal............................................................................. 13
2.5 Transfomation of Diimine 10 to Diamine 8a..................................................15
2.6 Proposed Synthesis of an Oxazolidine from Benzil......................... .............19
3.1 Condensations of Oxaphospholenes and Substitited Aldehydes...................20
3.2 Synthesis of Chiral Aldehyde Derived from S -Ethyl Lactate......................21
3.3 Condensation of Aldehyde 16 and 1,2X5-oxaphospholene 1........................22
3.4 Formation of the Five Membered Cyclic Phosphonate.................... ;........... 23
3.5 Proposed Synthesis of a Phostone
,24
ix
ABSTRACT
Previous studies toward 3-deoxy-3-phosphonomethyl-D-arabinose using
oxaphospholene methodology have found a problem in a crucial step of the synthesis. In
an attempt to fix this problem, a new aminal protecting group was pursued. The new
aminal proved to be too bulky to react with the oxaphospholene. However, in the process
of making the aminal there was room for variation that should produce an aminal that is
less hindered and should therefore react with the oxaphospholene.
Another issue addressed is the stereochemistry of the aldol condensation of a
chiral aldehyde and the oxaphospholene. The product of this reaction is a P-hydroxy
ketone phosphonate with two new stereocenters. The aldehyde is chiral and derived from
5-ethyl lactate and contains a protected alcohol. The method envisioned for the
determination of the stereochemistry is protection of the hydroxyl group of the P-hydroxy
ketone then deprotection of the alcohol. This should then cyclize onto the phosphonate
yielding a six membered cyclic phosphonate otherwise known as a phostone. The six
membered phostones are known in literature and the J coupling values for the protons
around the ring are published. Thus, by comparison of the J coupling values from the
phostone that we make to the literature references we will know the stereochemistry of
the six membered phostone, which we could then relate back to, the aldol product.
I
I
CHAPTER I
INTRODUCTION
Background
Organic phosphates play important roles in biological systems. Phosphates form
the backbone of DNA and RNA. The loss of a phosphate group in the conversion of
adenosine triphosphate (ATP) to adenosine diphosphate (ADP) liberates free energy that
is used to drive reactions such as muscle contraction.1 Phosphates play a large role in
glycolysis and gluconeogenesis. Phospholipids are one of two main types of lipids that
occur in biological membranes.2 The role of phosphates makes them key targets in
controlling or inhibiting metabolic functions.2
Phosphonates differ from phosphates by replacing the labile oxygen-phosphorus
bond with a carbon-phosphorus bond (see Figure LI). This difference could be exploited
by using phosphonate analogs of phosphates to interrupt biological pathways.3
Phosphonate derivatives of naturally occurring compounds can be used to inhibit or
perturb biosynthetic pathways, because the carbon-phosphorus bond cannot be
hydrolyzed like the oxygen-phosphorus bond.3c Our research group is exploring the
synthesis of phosphonate analog targets using pentacovalent oxaphospholene
methodology.
2
Figure 1.1 Phosphates vs. Phosphonates
Phosphate
Phosphonate
Labile P-O bond
Non-Iabile
P-C bond
The course of study described herein is the exploration of a possible route to
carbohydrate derivatives containing phosphonate moieties via the condensation of an
aminal protected glyoxal derivative with a pentacovalent oxaphospholene. A study of
stereocontrol using chiral aldehydes in condensation reactions with pentacovalent
oxaphospholenes to affect the stereochemistry of the final products is also presented.
Classical Methods for Phosphonates
There are several classical methods available to make phosphonates. The
Arbuzov or Michaelis-Arbuzov reaction is simply the reaction of a trialkyl phosphite and
an alkyl halide to provide the phosphonate. A variation on this theme is the MichaelisBecker reaction, which involves a displacement of a halide ion from a saturated carbon
by a dialkyl phosphite anion. The Abramov reaction is the treatment of an aldehyde with
trialkyl phosphite. The Pudovik is a variation of the Abramov using a dialkyl phosphite
anion in place of the trialkyl phosphite. These reactions are shown in Scheme LI.4
These classical methods only produce the carbon-phosphorus bond.
3
Scheme 1.1 Alternative Methods to Prepare Phosphonates
RX
+
(RO)3P
RP(O)(OR)2
+
RX
+
$ P(OR)2
R1P(O)(OR)2
+
X"
Arbuzov
RX
M ichaelis-Becker
O
Il
R1CHO
+
(RO)3P
(RO)2PCHR'
OR
Abramov
O
_ Il
R1CHO
+
JP(OR)2
O OH
Il I
-► (RO)2P -C H R 1
Pudovik
Pentacovalent Oxaphospholene Methodology
The methodology developed in our group uses a pentacovalent 1,2X5oxaphospholene that is condensed with an electrophile to produce a phosphonate
(Scheme 1.2).5 A benefit of this methodology is that it can be done in one pot if desired
(e.g. the oxaphospholene generated in situ, then the electrophile added) to produce a
carbon-phosphorus bond and a carbon-carbon, carbon-nitrogen, carbon-oxygen, or
carbon-bromine bond.5
4
Scheme 1.2 Reaction of Oxaphospholene and an Electrophile
O
E+
</
OR
Pentacovalent 1,2X5-oxaphospholene I (or simply oxaphospholene) is the product
of the reaction of a trialkyl phosphite with an a,|3-unsaturated ketone (Scheme 1.3).
Scheme 1.3 Synthesis of a Pentacovalent Oxaphospholene
Neat
P(OR)3
+
»
rS ^ P (O R )3
1_ R = Et1 R' = Me
The resultant oxaphospholene is then condensed with an electrophile resulting in a
phosphonate compound. The proposed mechanism is shown in Scheme 1.4. The
pentacovalent oxaphospholenes can be distilled and kept stored in a freezer sealed under
argon for months with little or no degradation.
5
Scheme 1.4 Proposed Nucleophilic Addition Mechanism
Various electrophiles have been explored in this reaction, several of which are
illustrated in Scheme 1.5. The formation of bisphosphonates is also possible using this
methodology by subjecting a keto vinyl (3-phosphonate (produced from the reaction of the
oxaphospholene and bromine followed by subsequent elimination) to a trialkyl phosphite.
Scheme 1.5 Pentacovalent Oxaphospholene Methodology
O
OH
R11CHO
PO(OR)2
6
The product would then be a pentacovalent oxaphospholene containing a phosphonate.
There are many choices of electrophiles as shown in Scheme 1.5. My research,
however, has focused on using aldehydes as the electrophiles. Condensations with
aldehydes produce P-hydroxy ketone phosphonates containing two new chiral centers.
With the proper choices of R’ and R”, the condensation product can be transformed into
an acyclic carbohydrate. With this in mind, two goals are presented; first an easy route to
a carbohydrate with a phosphonate group in place of a hydroxyl group, and secondly,
stereocontrol of the newly formed chiral centers from the aldol condensation. The first
goal involves choosing the appropriate vinyl ketone and aldehyde moieties that could be
deprotected or modified to give the desired acyclic carbohydrate. The second goal
involves the use of a chiral aldehyde to see if chirality transfers to the condensation
product from the aldehyde.
Proposed Target
Our target is the 3-deoxy-3-phosphonomethyl-D-arabinose derivative. Gram­
negative bacteria use D-arabinose (Figure 1.2) to produce 3-deoxy-D-manno-2octulosonic acid (KDO) (Figure 1.2). KDO is the key component used to make the
lipopolysaccharides that constitute the outer membrane of gram-negative bacteria.
7
Figure 1.2
HO— H
HO
O
CO2H
OH
D-Arabinose
3-Deoxy-D-M anno-2-Octulosonic Acid
KDO
The KDO pathway is exclusive to gram-negative bacteria and therefore is an
attractive candidate for inhibition. The biosynthesis of KDO is shown in Scheme 1.6.6
Any inhibition of the biosynthesis of KDO would affect the formation of
lipopolysaccharides, which would compromise the integrity of the outer membrane of the
bacteria and allow it to be more vulnerable to outside attack from either the host’s natural
defenses or other antibiotics.
As shown in Scheme 1.6, KDO is formed from D-arabinose 5-phosphate. From
labeling studies, it was found that the hydroxyl group at the three position of D-arabinose
becomes the ring oxygen in KDO. With this in mind, one possible route to inhibit the
KDO 8-phosphate synthetase enzyme is by replacing the 3- hydroxyl group with a
phosphonomethyl moiety (Figure 1.3). The stronger carbon-phosphorus bond should
prevent the enzyme from hydrolyzing off the phosphonate. This would prevent the
formation of KDO and the subsequent formation of the lipopolysaccharide.
8
Scheme 1.6 Biosynthesis of Lipopolysaccharide
D-Arabinose
5-Phosohate
H2O3P
.OPO3H2
^
PEP
P-Pl
CTP
"V
CMP-KDO
I Synthetase
UH
HO------ H
CMP-KDO
Figure 1.3 3-Deoxy-3-Phosphonomethyl-D-Arabinose
HOi
Y
_n_OH
0^
(HO)2OP
2
OH
9
CHAPTER 2
STUDIES OF CONDENSATIONS OF OXAPHOSPHOLENES AND ALDEHYDES
TOWARD THE SYNTHESES OF D-ARABINOSE DERIVATIVES AND
STEREOCONTROL OF PRODUCTS
Retrosynthetic Analysis
In order to test our hypothesis, we needed to prepare 3-deoxy-3phosphonomethyl-D-arabinose 2. To meet the goal the following retrosynthetic analysis
was envisioned (Scheme 2.1). One of the key intermediates of our synthesis is the (3hydroxy ketone 5. The formation of syn stereochemistry is crucial. With this in mind,
the condensation reaction of the oxaphospholene 3 and the aminal 4c is the key step of
the retrosynthesis as shown. The model system (methyl instead of the CH20Si(tBu)(Ph)2 group) was used because of the ease of preparing the oxaphospholene and the
low cost of the reagents. The reactvity of the silyl protected alcohol derivative 3 has been
shown to be on the same order as I (Figure 2.2).
Figure 2.1 Oxaphospholenes
p IrS u 0
Rh
3
I
10
Scheme 2.1 Retrosynthesis of 3-Deoxy-3-Phosphonomethyl-D-Arabinose
OH
0
Ph
Ha Y n)
Rh' " ' 7
Another critical step is the selective reduction of the ketone in 5 to give the I, 3anti diol 6 (Scheme 2.2). This is followed by deprotection of the aminal protecting
group, which should lead to cyclization to form the arabinose derivative. The desilyation
and dealkylation of the phosphonate would then be done by standard methods.
Scheme 2.2 Reduction of Ketone 5
O
T B D PS-O ^ J L
(EtO)2OP
OH
R
OH
OH
R
T B D P S -O ^ ^ /L /N
J
N
R'
5
N
(EtO)2OP
R
6
11
Previous Work
A previous attempt at this synthesis was with the aminal I, 3-diphenyl-2imidazolidinecarboxaldehyde 4c (Figure 2.3) made from dianilinoethane and glyoxal.
While the selectivity of the condensation with both oxaphospholenes (I and 3) was 9:1
syn vs. anti and 14:1 syn vs. anti respectively, a problem arose in the selective reduction
of the ketone. The diol 6 has to be anti in order to have the proper stereochemistry to go
on to the D-arabinose. Here the Gribble reagent (Me4NHB(OAc)3), that had been used
previously in the McClure laboratories on reductions of (3-hydroxy ketone phosphonate
analogs with excellent diastereomeric ratios gave no preference for the anti diol.
Figure 2.2 l,3-diphenyl-2-imidazolidinecarboxaldehyde 4c
O
Rh
4c
The problem of the selectivity of the reduction of the ketone to an alcohol was
thought to be due to steric interactions. The phenyl groups on the aminal nitrogens were
preventing the chelation of the reducing agents with the (3-hydroxyl group, and thus the
selectivity of the reduction was lost. It became apparent that a less bulky aminal needed
to be studied. It was decided to prepare aminals based on diamines which had phenyls on
the ethylene bridge and methyls on the nitrogen. This new aminal would possibly
12
accomplish two goals, the reduction of steric hindrance around the nitrogen and the
introduction of chirality to the condensation product.
Chiral Aminal
The preparation of the chiral diamine involved the coupling of N-methyl
benzylimine (Scheme 2.3)7 This resulted in a mixture of isomers {dl and meso) of the
diamine and some benzylamine from the reduction of the benzylimine. The dl diamine
could be separated from the meso diamine by doing a resolution with ^/-tartaric acid.7b
Scheme 2.3 Preparation of the Chiral Diamine
R -N H HN -R
P lf
R = isopropyl
R = CHg
Ph
R -N H HN -R
Ph
Ph
dl
Meso
8a: R = isopropyl
8b: R = CHg
R = isopropyl
R = CHg
/
HN
Pli
Reduction
R = isopropyl
R = CHg
Conditions = (A) 1. HgCI2, Mg, THF1 RT 20min. 2. TiCI4lO0-RT
(B) Zn, 1,2-Brom oethane, TMSCI1 MeCN
(C) Zn, 10% NaOH
The use of Li and isoprene isomerized the meso isomer into the dl isomer.7b The meso
isomer did not react with glyoxal to form the aminal (4b). Even though this was a
literature preparation7^ the results were not satisfactory. The purification and isolation of
the dl isomer was difficult as shown in Table 2.1. The use of column chromatography
with bascified silica gel resulted in large losses of product. The benzylamine was very
13
difficult to separate from the diamine, and all methods attempted (resolution with dl
tartaric acid, distillation, column chromatography) met with little success.
Table 2.1 Synthesis of N,N’-Dimethyl-l,2-diphenylethylene-diamine (8b)
R -N H H N -R
J
^
PlT
Ph
dl
R = CH3
8b: R = CH3
R -N H HN -R
Ph
Ph
+
Meso
7
p \f
Reduction
R = CH3
R = CH3
Conditions
Yield
Note
Reference
I
HgCl2ZMg & TiCl4
32% d/
C o lu m n 3% M e O H /D C M
7a
2
Zn, Me3SiCl
74%
dl & meso
7b
3
Zn, 10% aq. NaOH
92% Crude
2:1:1 re&.di.meso
7c
The formation of the aminal was from the reaction of glyoxal and the diamine
(Scheme 2.4). The lack of success at obtaining the diamine 8b continued with the aminal
4b. It was found that 4b could not be purified and had to be used directly from the
reaction.8
Scheme 2.4 Preparation of the Aminal
R-NH HN-R
Ph^Ph
+
R
8a: R = isopropyl
8 b : R = CH3
4a: R = isopropyl
4b: R = CH3
14
The inability to purify the aminal 4b proved to be a problem as the
oxaphospholene condensation reaction is very sensitive to contamination in the reaction
mixture. TLC and/or phosphorus NMR were used to follow the condensation reactions
(Table 2.2). Entry 2 in table 2.2 did show one product by 31P NMR, but it could not be
isolated by HPLC.
Table 2.2 Reaction of Aminal 4b and Oxaphospholene I
OH
0 > (O E t)3
R
+
I: R1= CH3
4b: R = CH
Conditions
Yield
I
DCM, RT
N.R.
2
CDCl3 , RT
Note
Product- Hydrolysis of the Oxaphospholene
NMR scale reaction
71% Crude
Product- 31P peak at 30.9 not isolable by HPLC
Larger scale reaction
3
CDCl3, RT
N.R.
Product- Hydrolysis of the Oxaphospholene
In the same article8 was information on the aminal 4a with an isopropyl group on
the amines. This could be purified by flash column chromatography. The initial efforts
at producing the diamine by the Alexakis procedure^ were as successful as before. A
15
reference that used a diimine that could then react with two equivalents of Grignard
reagent giving the desired chiral diamine was found.9
The diimine 10 was the product of a primary amine and glyoxal catalyzed by
formic acid9. This stable compound was purified by sublimation and kept refrigerated.
When the diimine was subjected to two equivalents of phenyl magnesium bromide
Grignard reagent only the dl diamine 8a product was observed with no evidence of the
meso isomer (Scheme 2.5).
The reaction of glyoxal and diamine 8a to the aminal 4a was accomplished
according to the literature6, and purified by column chromatography to provide
approximately 50 % yield, which corresponded with literature values.
Scheme 2.5 Transformation of Diimine (10) to Diamine (8a)
10
+
10
PhMgBr
8a
Once the chiral aminal 4a was prepared, the condensation of 4a and the
oxaphospholene I was examined. Unfortunately, the condensation reactions were
unsuccessful as shown in Table 2.3. Steric interactions of the bulky isopropyl groups on
the nitrogen would not allow the oxaphospholene access to the aldehyde moiety. Aminal
16
4a would eventually decompose at room temperature after days in the reaction mixture.
Lewis acid assisted conditions were attempted using magnesium bromide dietherate
(MgBrz OEtz). The Lewis acid assisted condensations gave several products, which were
not separable by column chromatography, radial chromatography, or H.P.L.C.
Table 2.3 Reaction of Aminal 4a and Oxaphospholene I
O
I
,'P(OEt)3
+
O
R
OH
H 'J1v S ' " Ph
r1
N _>
(EtO)2O P ^
R
I: R1= CH3
Ph
4a: R = isopropyl
/Ay
S
R
X
rV xph
N -C
R'
>ph
9a: R1= isop rop yl, R = CH
Conditions
Yield
Note
I
DCM O0C
N.R.
Hydrolysis of the Oxaphospholene
3
DCM RT
N.R.
Hydrolysis of the Oxaphospholene
4
MgBr2 OEt2, -7B0C
22% crude
2 peaks by jlP NMR 31.515 & 28.575
5
MgBr2 OEt2, -78°C
13% crude
2 peaks by jlP NMR 29.967 & 26.657
6
MgBr2 OEt2, O0C
19% crude
2 peaks by jlP NMR 33.819 & 30.600
N.R.
Hydrolysis of the Oxaphospholene
MgBr2 OEt2,
7
-7 B0C to RT
In an attempt to reduce the bulk around the nitrogens, an investigation of another
series of diimines was started. These are shown in Table 2.4. Efforts to provide diimines
with various degrees of steric bulk proved to be difficult. The use of I0 and 2° alkyl
17
groups attached to the amine did not afford the desired diimines (Table 2.4, entries 2 and
4). However, amines containing 3° and 4° carbon centers yielded the related diimine
(Table 2.4, entries I and 3). The diimine formed from o-toluidine and glyoxal gave
beautiful yellow crystals in 58% yield. It became apparent that to have a less bulky
group on the nitrogens something more substituted than glyoxal needed to be used in
order to stabilize the diimine.
Table 2.4 Diimines
R-NH2 +
R-N
0^ J d
V -*
N-R
R=
Yield
Clean up
I
Isopropylamine 10
35%
Sublimation
2
Methylamine
N.R.
3
o-Toluidine 11
58%
4
Benzylamine
N.R.
Recrystalization
Chiral Oxazolidine
Our initial efforts to develop chiral diamines with less bulky groups on the amine
were unsuccessful and the focus was directed towards another route. This research has
shown that as the steric bulk of the nitrogen increases, the accessibility of the aldehyde
18
moiety of the aminal decreases. Therefore, it is important to reduce the steric hindrance
around the nitrogen. As a result, an effort to make N-methyl diimine continued. It was
thought that by treating aqueous methyl amine with benzil would afford the N-methyl
diimine. This diimine could be reduced with sodium borohyride (NaBEU) to give the
desired diamine.
Unfortunately, the only product of the reaction of benzil and methylamine was not
the diimine, but instead the ketimine 12, in quantitative yield however (Scheme 2.6).
While this was disappointing, not all was lost. A reference to an aldehyde produced from
the reaction of d-pseudoephedrine and glyoxal was found.10 Thus, a new aldehyde was
envisioned from the reduction product of the ketimine 12. The ketimine was reduced
with sodium borohydride to yield the aminol 13 as white crystals. The aminol 13 was
treated with glyoxal, however all attempts thus far have failed to produce the desired
oxazolidinal 14. The conditions attempted included those from the reference 10 as well
as the conditions that had worked previously with the diamines. Another reason could be
that there is some meso isomer present which, from previous experience with the
diamines, does not form the aminal. In mixtures of the dl and meso, the meso isomer
inhibits the dl isomer from forming the aminal.
Scheme 2.6 Proposed Synthesis of an Oxazolidine from Benzil
q
o
DCMt
+
Ph
O
N-
Rh
Rh
MeNH2
99%
Rh
12
EtOH
NaBH4
Il
HO
HN-
Rh
Rh
13
20
CHAPTER 3
PREPARATION AND CONDENSATION REACTIONS OF A CHIRAL
ALDEHYDE
Overview
Early work done in the McClure laboratories has demonstrated that the
condensation of 1,2X5-oxaphospholenes I with simple aldehydes indicated a lack of
stereocontrol in the reaction. Syn : anti ratios of 1.3:1 - 5:1 were found from the
condensation5. Furthermore, it was determined that the condensation of I with more
substituted aldehydes led to products having 9-20:1 syn : anti ratios (Scheme 3.1)."
Scheme 3.1 Condensations of oxaphospholenes and substituted aldehydes
O
R
OH
Rh
^ P (O E t)3
(EtO)2OP
5b R = CH3 (9:1, symanti)
S a R = CH2O Si(Ph)2(I-Bu)
(14:1, symanti)
1_ R = CH3
3 R = CH2OSi(Ph)2(I-Bu)
Kv
pi^ P ( O E t ) 3
16
O
rW 4L
(EtO)2O P ^
15 R = TMS
OH
u
V
17 R = TMS (15-20:1, syiranti)
21
The Aldehyde
The results shown in Scheme 3.1 show that there is some chirality transfer from
the chiral glyceraldehyde 16 to the condensation product 17. The symanti ratio is better
than the product of the bulky aminal 4c and the oxaphospholene 3. Thus by altering the
nature of the aldehyde it is possible to change the stereochemistry of the “aldol”
condensation product. The key feature that we want for the aldehyde is the inclusion of
chirality in the carbon backbone. In this case, the starting material for the aldehyde was
S-ethyl lactate.
The alcohol of the S-ethyl lactate was protected with f-butyldiphenylsilylchloride
(TBDPSC1). This was followed by a reduction of the ester with diisobutylaluminum
hydride (DIBAL-H) to yield the aldehyde 19 (Scheme 3.2).12 Purification of the
aldehyde was done by either column chromatography or radial chromatography.
Scheme 3.2 Synthesis of Chiral Aldehyde Derived from Ethyl Lactate
DiBAIH
22
When the aldehyde 19 is subjected to the 1,2X5-oxaphospholene I under Lewis
acid assisted conditions at -78° C the products were two diastereomers 20a,b in a 2 to 3
ratio (by 31P NMR) in a 67% yield (Scheme 3.3). This is a better result than if the
condensation is done at room temperature with no Lewis acid. Here there is still a 2:3
ratio of the same diastereomers 20a,b, as well as another diastereomer of 20c and a fivemembered cyclic phosphonate 21 as well. The five-membered cyclic phosphonate has
been seen as a byproduct of other condensations done at room temperature. The fivemembered cyclic phosphonate occurs when the oxygen from the aldehyde cyclizes onto
the phosphorus Scheme 3.4. The separation and isolation of diastereomers is possible by
column chromatography or HPLC.
Scheme 3.3 Condensation of aldehyde 16 and 1,2X5-oxaphospholene I
O
OH
(EtO)2OP
20b
1
MaBroeOEto
19
2 isom ers 2:3 ratio
23
Scheme 3.4 Formation of the five member cyclic phosphonate
Determination of stereochemistry
The determination of the absolute stereoshemistry of the diastereomers of 20 is to
be done by removal of the silyl group, which should lead to cyclization of the deprotected
oxygen onto the phosphorus producing a six-membered cyclic phosphonate (also known
as a phostone). See Scheme 3.5. The six-membered phostones are known and the Jvalues for the coupling of the protons on the ring are published.13 Then by comparing the
values from literature to the values we obtain, the relative stereochemistry around the ring
could be determined. Once the stereochemistry around the ring is determined, then this
could be then translated back to the condensation products 20. Therefore having a known
chiral center present in 20 provides a “handle” to determine relative stereochemistry from
the /-values.
24
Scheme 3.5 Proposed Synthesis of a Phostone
OTBDPS
V
o
x ^ P ( O E t )3 _|_
H^ Y (
OTBDPS
The alcohol moiety on the condensation product 20 needed to be protected before
the silyl group could be removed. Unfortunately, this can only be accomplished with an
acetate group. A benzyl protecting group has been tried but with no success. Silyl
groups had been attempted on other condensation products, but in this case as there is
already a silyl protected alcohol present, so this was not attempted.
Deprotection
All attempts at the deprotection thus far have met with little success (Table 3.1).
The attempt at deprotection with tetra n-butylammonium fluoride (TBAF) resulted in
deprotection of the silyl ether as expected but resulted in the acetate “walking” to that
oxygen and loss of the other alcohol (figure 3.1).
25
Table 3.1 Deprotection of the Silyl Ether
A
O
O
A
OTBDPS
(EtO)2OP
2
Reagent
Tetrabutylammonium Fluoride
Cerium Chloride & Sodium Iodide
3
Cesium Fluoride
4
Pyridine-Hydrogen Fluoride
I
Result
24
Multiple products none
were isol able
Multiple products none
were isolable
Multiple products none
were isolable
Figure 3.1 Product of TBAF Deprotection
O
aTY'
A
(EtO)2OP
The problem of the acetate walking to the next oxygen after the desilylation was
not unexpected as this would be a five membered transition state. Also of note is that an
acetate group can only be put on one of the major isomers of the condensation reaction.
This has been tried on both a mixture of isomers and on the individual isomers with the
same results. Obviously the alcohol of the condensation product is hindered enough to
26
prevent access. This presents two problems. One is which groups can protect the alcohol
in the condensation product. Second is the choice of protecting groups and the conditions
required for deprotection of the groups, e.g., where removal of one will not affect the
other.
The removal of the siIyl ether without protecting the alcohol has been attempted.
This has not given any satisfactory results as of yet as shown in Table 3.2.
Table 3.2 Deprotection on 20
OH
OTBDPS
(EtO)2OP
(EtO)2OP
Reagent
Result
I
Cesium Fluoride in Deuterated Chloroform
2
TBAF
3
Pyridine-Hydrogen Fluoride
Multiple products none
were isolable
Multiple products none
were isolable
Multiple products none
were isolable
Conclusions and Future Work
The alcohol of 20 presents a problem in the choice of protecting groups. What
needs to be determined is exactly what groups can be used and if they can work on both
isomers. The choice of groups has to include their inability to “walk” to the next alcohol
27
when the other alcohol is deprotected. In addition, determining why the acetate only
works on one of the major diastereomers and not the other is another interesting problem.
When a protecting group for the alcohol of the condensation product is found then the
alcohol of the 5-ethyl lactate will be protected with a suitable group that can be
deprotected in the presence of the other group. This should then lead directly to the
desired phostone.
28
CHAPTER 4
EXPERIMENTAL
General Information
1H NMR spectra were recorded on either the Broker DRX-250 (250 MHz),
Broker DPX-300 (300 MHz), or Broker DRX-500 (500 MHz) spectrometer. Chemical
shifts are reported in ppm downfield from tetramethylsilane, with the residual hydrogen
bearing solvent resonance acting as the internal standard (deuterochloroform (CDCI3):
8
7.24 ppm). Data is reported as follows: chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, sep = septet,, m = multiplet, etc.), coupling
constant (Hz) and assignment. 13C NMR spectra were recorded on either the Broker
DPX-300 (75 MHz), or Broker DRX-500 (125 MHz) spectrometer. Chemical shifts are
reported in ppm downfield from tetramethylsilane with solvent as the internal standard
(deuterochloroform (CDCl3): 8 77.0 ppm). Data is reported as follows: chemical shift,
multiplicity, coupling constant (Hz) and assignment. 31P NMR spectra were recorded on
the Bruker DPX-300 (121 MHz) with complete proton decoupling. Chemical shifts are
reported in ppm from 85% phosphoric acid (H3PO4) with H3PO4 as an external standard
(8
0.00 ppm). A Mel-Temp 13 apparatus equipped with a digital thermometer was used
for obtaining the melting points and are uncorrected. A Perkin Elmer 1600 series FT-IR
29
was used for recording infrared spectra. Standard NaCl plates were used for oil samples
and KBr pellet procedures for solids.
Thin-layer chromatography (TLC) was performed on Analtech 250 micron silica
gel plates with fluorescent indicator. The TLC plates were visualized by UV-light,
iodine, and ninhydrin solution. Chromatatron (radial chromatography) plates were made
from Merck silica gel TLC grade 7749 with fluorescent indicator. Column
chromatography was performed on Whatman silica gel 60 230-400 mesh or 70-230
mesh. High-pressure liquid chromatography (HPLC) was performed on either SSI model
222B with SS I500 variable UV detector, or Varian Prostar model 215 with Dynmax
variable UV detector. All solvent systems used for either column chromatography,
radial chromatography dr H.P.L.C. are reported in volume-to-volume mixtures.
All reagents were purified according to Perrin and Perrin14 or other applicable
methods. All solvents used were distilled prior to use. DichloromCthane, acetonitrile,
toluene and hexanes were distilled from calcium hydride. Tetrahydrofuran and diethyl
ether were distilled from sodium benzophenone ketyl. Unless otherwise stated, all
glassware is either oven dried or flame dried and cooled under argon. All experiments
were performed under an argon atmosphere.
30
Experimentals
Preparation of 2,2,2-triethoxv-2,2-dihydro-5-methvl-E2A5-oxaphospho-4-lene I
9
10
An oven dried 50 mL, round bottom flask equipped with an oven dried stirbar and
cooled under argon was charged with methyl vinyl ketone (5mL, 60.1 mmol). Triethyl
phosphite (12 mL, 70 mmol) was added via syringe and reaction flask covered with foil
and allowed to stir 2 days under argon at room temperature. The excess triethyl
phosphite was then removed under high vacuum overnight. The remaining liquid was
then distilled under vacuum. A clear oil was collected at 50°C at 0.4 mm Hg. Yield and
spectral data were the same as reported in ref. 5.
Preparation of N.N’-diisopropvl-diimine 10
Isopropyl amine (40 mL, 469.6 mmol) was added to a stirred solution of glyoxal
(40% weight solution in water 20 mL, 174.4 mmol) in dichloromethane (90 mL) in a 500
mL Erlenmeyer flask. Formic acid (LI mL, 29.2 mmol) was then added followed by
31
magnesium sulfate (40.4 g, 335.6 mmol). The reaction was stirred 20 min., then filtered
through celite, and the solvent removed under reduced pressure. After sublimation, a
white crystalline compound was obtained ( 12.3 g, 88.2 mmol, 51 % yield). Spectral data
conforms to literature values. 15 Melting point 56-57° C (after sublimation); literature
melting point 58-59° C (after sublimation at room temperature and 0.1 torr); 1H NMR:
7.90 ( 2H, S1 H o n C l), 3.48 (2H, septet, J = 6.3 Hz, H on C2), 1.20 (12H, d, 7 = 6.3 Hz,
H on C3). 13C NMR: 159.6 ppm (Cl), 61.1 ppm (C2), 23.7 ppm (C3). IR (KBr pellet)
2970 cm ', 1616 cm ', 1376 cm'1.
Preparation of 7/-N,N’-diisopropvl-l,2-diphenvlethvlene-l.2-diamine 8a
Rh
Rh
8a racemic
To an oven dried 50 mL round bottom flask equipped with a stirbar and water
condenser and flushed with argon was added magnesium turnings (0.4361 g, 17.9 mmol)
and a single crystal of iodine. The flask was heated with a heat gun to see the purple
haze, and diethyl ether (5 mL) was added and stirring started. Phenyl bromide (1.5 mL,
14.2 mmol) in diethyl ether ( 8 mL) was added via an addition funnel slowly to maintain
the reaction at a reflux. The reaction stirred 15 min. after addition of the phenyl bromide.
The diimine 11 (1.006 g, 7.2 mmol) dissolved in hexane (12 mL) was added via an
addition funnel slowly over 5 min. After stirring 30 min. at room temperature, the
reaction was quenched with 12 mL of saturated NH4Cl solution and stirred 30 min. more.
32
The organic layer was separated and the aqueous layer was extracted with diethyl ether (2
x 20 mL). The combined organic layers were dried over K2CO3 and filtered through
silica gel. The solvent was removed under reduced pressure. The crude oil (2.2318 g)
was then dissolved in 55 mL ethanol in a 250 mL round bottom flask, to which is added
J/-tartaric acid (1.1294 g, 7.5 mmol). The flask was equipped with a water condenser
and the reaction was heated to reflux. After refluxing 10 min., the reaction was cooled to
room temperature for I hour and the crystals that formed were filtered and washed with
ethanol (10 mL). The crystals were added to a solution of 24 mL 35% NaOH solution,
80 mL H2O, and 80 mL diethyl ether and stirred for two hours. The organic layer was
then separated, and the aqueous layer was extracted with diethyl ether (2 x 50mL), dried
over K2CO3, filtered and solvent removed under reduced pressure to yield a clear oil
(0.8379 g, 2.8 mmol, 39 % yield). Spectral data conformed to literature values.8 The
registry no. is as follows: 55079-98-6. 1H NMR: 7.2-6.9 ppm (10H, m, H on phenyl
rings), 3.7 (2H, S1H o n C l and CS), 2.5 (2H, septet, J = 6.3 Hz, H on C2 and C6 ), 0.97
(6 H, d, 7 = 6.3 Hz, H on C4 and CS), 0.92 (6 H, d, 7 = 6.3 Hz, H on C3 and Cl).
Preparation of N,N’-bis-o-tolvl-diimine 11
15
16
9
1
8
7
H
Glyoxal (40% weight solution in water 2.5 mL, 21.8 mmol) was added to a stirred
solution of o-toluidine
(6
mL, 56.2 mmol) in 10 mL dichloromethane, and the reaction
33
was allowed to stir. After 30 min., 10 mL dichloromethane was added, and the organic
layer separated. Saturated aq. NaCl solution (10 mL) was added to the aqueous layer and
extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried
over MgSCL, filtered, and the solvent removed under reduced pressure. The crude
product was then recrystalized from methanol yielding bright yellow crystals (2.99 g,
12.6 mmol, 58% yield). Spectral data conforms to literature values. 16 Melting point 125126°C; literature melting point 122-124° C; 1H NMR: 8.29 (2H, s, H on Cl and C9),
7.24-6.98 ( 8 H, m, phenyl H), 2.38 ppm (6 H, s, H on C4 and C12); 13C NMR: 159.7 (Cl
& C9), 149.5, 132.8, 130.6, 127.3, 126.8, 117.3, 17.8 (C4); IR 2972 c m 1, 1604 c m 1,
1461 cm"1.
Preparation of L3-diisopropvl-4,5-diphenvl-2-imidazolidinecarboxaldehvde 4a
7
4a
The diamine 6a (0.8495 g, 2.9 mmol) in diethyl ether ( 23 mL) was added to a
stirred solution of glyoxal (40% weight solution in water 50 mL, 435.9 mmol) at room
temperature and allowed to stir for 3 hours. The organic layer was separated and the
aqueous layer extracted with diethyl ether (3 x 30 mL), dried over K2CO3 , filtered and
solvent removed under reduced pressure. Purification by radial chromatography (4 mm
plate, 30% ethyl acetate / hexane) yielded a pale yellow oil (0.3275 g, 0.97 mmol, 33 %
34
yield). Spectral data conformed to literature values. 8 1H NMR: 9.76 (1H d, 7 = 6.9 Hz,
on CIO), 7.27-7.12 (IOH, m, phenyl H), 4.37 ( 1H, d, 7 = 6.9 Hz, on C9), [4.13 (1H d, 7 =
7.9 Hz), 3.99 (1H d, 7 = 7.9 Hz)] both are on Cl or CS, [3.00 (1H sep, 7 = 6 . 6 Hz ), 2.94
(1H sep, 7 = 6.7 Hz)] both are on C2 and C6 , [1.12 (3H, d, 7 = 6.9), 1.04 (3H, d, 7 = 6.4),
0.99 (3H, d, 7 = 6.7), 0.87 (3H, d, 7 = 6 .6 )] C3, C4, Cl, and CS.
One Pot Preparation of 3-(diethoxv)phosphonomethvl-5-/-butvldiphenvlsilvloxv-hexan-4-ol-2-one 20
Methyl vinyl ketone (0.35 mL, 4.2 mmol) was added via syringe to triethyl
phosphite (0.75 mL, 4.4 mmol) in an oven dried 3-necked round bottom flask equipped
with a stirbar and flushed with argon. The flask was covered with foil and allowed to stir
under argon for 3 days. Dichloromethane (IOmL) was then added and the reaction flask
equipped with an addition funnel. The reaction was then cooled to -78°C (CO2 / acetone)
and magnesium dibromide diethyl etherate (1.0581 g, 4.1 mmol) dissolved in
dichloromethane (10 mL) and diethyl ether (10 mL) was added via cannula. The
aldehyde 16 (1.2791 g, 4.1 mmol) was added to the addition funnel followed bylO mL
dichloromethane, and this solution was then added drop wise slowly over
10
minutes to
35
the reaction mixture at -78°C. After stirring for 30 min., the reaction was quenched at 78°C with pH 7.2 phosphate buffer solution (10 mL) and warmed to room temperature
over I hour. The reaction mixture was extracted with dichloromethane (3 x 30 mL), the
combined organic layers washed with saturated aq. NaCl solution (30 mL) and dried over
MgSC>4 . The organic layer was filtered and solvents removed under reduced pressure.
Purification by column chromatography (65 mm column, 215 g silica gel (230-400
mesh), 2% methanol/ dichloromethane) yielded a yellow oil consisting of two isomers.
Minor isomer (by 31P NMR) after column chromatography: 0.7620 g, 1.5 mmol, 36%
yield. 1H NMR: 7.64-7.34 (m, 10H on phenyl rings), 3.99 (qd, 4H 7 = 7.5 Hz, J ph = 3.0
Hz, CS and CIO), 3.84 (dq, J = 6.2, 4.0Hz, C5), 3.51 (ddd, 1H, J = 7.1, 4.5, 3.9 Hz, C4),
3.06 (ddt, Jph =11.6 Hz, J = 7.4, 2.9 Hz, C3), 2.97 (d, 1H, J = 4.8 Hz, OH), 2.28 (s, 3H,
Cl), 2.06 (ddd, 1H, Jph = 13.0 Hz, J = 11.0, 3.7 Hz, C7), 1.47 (dt, 1H, Jph = 19.3 Hz, J =
15.6, 3.1 Hz, Cl), 1.25 (td, 6H, J = 7.0 Hz, Jm = 3.5 Hz, C9 and CU), 1.04 (d, 3H, J =
5.8 Hz, C6), 1.03. (s, 9H, C13, C14, and C15). 13C NMR: 210.6 (C2), 136.2,136.2,
134.1, 133.4, 130.4, 130.3, 128.2, 128.0, 78.4 (C4), 71.0 (C5), 62.4 (d, Jpc = 6.0 Hz, CS
or CIO), 62.1 (d, Jpc = 6.0 Hz, CS or CIO), 46.3 (d, Jpc = 3.0 Hz, C3), 30.1 (Cl), 27.4
(C13, C14, and C15), 25.0 (d, Jpc = 142.6 Hz, C7),19.6 (C12), 17.4 (C6), 16.7 (d, Jpc =
3.0 Hz, C9 or CU). 31P NMR: 29.66. IR (NaCl, cm"1): 3364, 2986, 1718. HRMS
calculated for C27H4IO6PSiNa+: 543.6680, found 543.228600.
Major isomer (by 31P NMR) after column chromatography: 0.6595 g, 1.3 mmol, 31%
yield). 1H NMR: 7.66-7.33 (m, 10H on phenyl rings), 4.00 (qd, 2H J = 7.1 Hz, Jph = 7.0
Hz, CS and CIO), 3.99 (dq, 2H J =.7.1 Hz, Jph = 7.0 Hz, CS and CIO), 3.71 (appt. pent,
36
1H7 = 6.0 Hz, C5), 3.62 (appt. pent.d, 1H, 7 = 5.1, 3.7 Hz, C4), 3.14 (d appt.pent, 1H,
yHP = 13.7 Hz, J = 4.8 Hz, C3), 2.84 (d, 1H, J = 3.6 Hz, OH), 2.13 (s, 3H, Cl), 2.12-2.01
(m, 2H, Cl), 1.26 (t, 6H,7 = 7.1 Hz, C9,C11), 1.07 (d, 3H, 7=6.1 Hz, C6 ), 1.04 (s, 9H,
C13, C14, C15). 13C NMR: 209.6 (C2), 135.8, 135.8, 133.9, 133.1, 130.0, 129.8, 127.6,
75.0 (C4), 70.5 C5, 61.9 (d, Jvc = 6.2 Hz, CS or CIO), 61.6 (d, Jvc = 6.4 Hz, CS or CIO),
48.3 (C3), 30.1 (Cl), 27.0 (C13, CM, C15), 23.2 (d, J pc = 142.5 Hz, Cl), 19.2 (Cl2),
18.3 (C6 ), 16.3 (d, 7pc = 5.0 Hz, C9 or Cl I), 16.3 (d, Jvc = 5.0 Hz, C9 or Cl I). 31P
NMR: 31.29. IR (NaCl, cm"1): 3345, 2931, 1715. HRMS calculated for
C27H4 IO6PSiNa+: 543.6680, found 543.233700.
Preparation of N-methvl benzil mono!mine 12
Q
N -2
3^
(Z1
Ph
Ph
12
Benzil (10.0 g, 47.6 mmol) was dissolved in 75 mL dichloromethane in a 250 mL
round bottom flask equipped with a stirbar. Methylamine (40% weight solution in water
25 mL, 290.4 mmol) was then added in one portion. The reaction was allowed to stir I1A
hours. The layers separated, and aqueous layer was extracted with dichloromethane (2 x
50 mL). The combined organic layers were dried over MgSO4, filtered and solvent
removed under reduced pressure. Purification by radial chromatography with
dichloromethane as the solvent yielded a yellow oil (10.52 g, 47.1 mmol, 99% yield).
Spectral data conforms to literature values. 17 1H NMR: 7.3-7.95 (IOH, m, H on phenyl
37
ring), 3.3 (3H, s, H on Cl); 13C NMR: 199.4 (C3), 168.5 (Cl), 135.6, 135.1, 135.0, 131.2,
129.7 , 129.5, 129.0, 127.5, 41.4 (C2).
Preparation of 2-N-methvl-l,2-diphenyl-ethylene-l-ol 13
HO
HN- 2
13
The ketimine 12 (0.7375 g, 3.3 mmol) was added to a solution of NaBH4 (0.8782
g, 23.2 mmol) in 30 mL ethanol in a IOOmL round bottom flask equipped with a stirbar
and a water condenser. The reaction mixture was heated to reflux for 3 hours. The
ethanol was distilled from the reaction and the residue was taken up in water (50mL).
The aqueous solution was extracted with dichloromethane (3 x 25 mL), washed with
saturated aq. NaCl solution (50 mL), organic layers dried over MgSO4, filtered and
solvent removed under reduced pressure. Recrystallization from ethanol yielded a white
solid (0.7079 g, 3.1 mmol, 94% yield). Spectral data conforms to literature values. 18
Melting point 130-131°C; literature melting point 135-138°C; 1H NMR: 7.25-7.12 (IOH,
m, phenyl H), 4.79 (1H, d, 7 = 5.5 Hz, on C3), 3.73 (1H, d, 7 = 5.5 Hz, on Cl), 3.21 (1H,
s, NH), 2.24 (3H, s, C2); 13C NMR: 141.1, 139.5, 128.7, 128.6, 128.4, 128.0, 127.9,
127.2, 77.0 (C3), 71.4 (Cl), 34.7 (C2); IR: 3024 cm' 1 broad, 1449 cm"1, 1055 cm'1.
38
REFERENCES CITED
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K . Y .; J o u r n a l o f O r g a n i c C h e m i s tr y , 1 9 9 1 , 5 6 , 2 3 2 6 -2 3 3 2 . (c ) M c C lu r e , C . K .; H e r z o g , K . J.; B ru ch , M .
D .; T e t r a h e d r o n L e t t e r s , 1 9 9 6 , 3 7 , 2 1 5 3 -2 1 5 6 . (d ) M c C lu r e , C . K .; M ish ra , P .K .; G ra te, C . W .; J o u r n a l o f
O r g a n ic C h e m is tr y , 1 9 9 7 , 6 2 , 2 4 3 7 -2 4 4 1 .
6 (a ) A n d e r so n , L .; U n g e r , F .M .; “A C S S y m p . S e r .” , 1 9 8 3 , 2 3 1 , 1 4 1 -1 6 9 . (b ) U n g e r , F .M .; “A d v a n c e s in
C a r b o h y d r a t e C h e m i s t r y a n d B i o c h e m i s t r y ” , 1 9 8 1 , 3 8 , 3 2 3 -3 8 8 .
7 (a) M a n g e n e y , P .; T e je r o , T .; A le x a k is , A .; G rosjean , F .; N o rm a n t, J.; S y n th e s is , 1 9 8 8 , 3 , 2 5 5 -2 5 7 .
(b ) A le x a k is , A .; A u jard , I.; K a n g er, T .; M a n g e n e y , P .; O r g a n i c S y n th e s e s , 1 9 9 8 , 7 6 , 2 3 -3 5 . (c) D utta,
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8 A le x a k is , A .; T ra n ch ier, J. P .; L e n se n , N .; M a n g e n e y , P .; J. A m . C h e m . S o c ., 1 9 9 5 , 1 1 7 , 1 0 7 6 7 -1 0 7 6 8 .
9 R o la n d , S .; M a n g e n e y , P .; A le x a k is , A .; S y n th e s is , 1 9 9 9 ,2 2 8 - 2 3 0 .
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11 M c C lu r e , C .K ., A le g r ia , L .; B o e h lo w , T .R .; M a d se n , T A . ; W ilk in s o n , R A . ; P h o s p h o r u s , S u l f u r a n d
S i l i c o n , 1 9 9 9 , 1 4 4 - 1 4 6 , 1 7 7 -1 8 0 .
12 C h ia c c h io , U .; C o rsa ro , A .; G u m in a , G .; R e sc iE n a , A .; Ia n n a z z o , D .; P ip e r n o , A .; R o m e o , G .; R o m e o ,
R.
; J .O . C . , 1 9 9 9 , 6 4 , 9 3 2 1 -9 3 2 7 . 13
13 (a ) S h ib u y a , S .; Y o k o m a tsu , T .; S h io y a , Y .; Iw a sa w a , H .; H e t e r o c y c l e s , 1 9 9 7 , 4 6 , 4 6 3 - 4 7 2 . (b ) W e ile r ,
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; H a r v e y , T .C .; S im ia n d , C .; W ith ers, S .G .; J o u r n a l o f O r g a n i c C h e m i s t r y , 1 9 9 7 , 6 2 , 6 7 2 2 -6 7 2 5 . (c)
H a n e ssia n , S .; R o g e l, O .; B i o o r g a n i c & M e d i c i n a l C h e m i s t r y L e t t e r s , 1 9 9 9 , 9 , 2 4 4 1 - 2 4 4 6 . (d ) H a n essia n ,
S . ; R o g e l, O .; J o u r n a l o f O r g a n i c C h e m i s tr y , 2 0 0 0 , 6 5 , 2 6 6 7 - 2 6 7 4 . (e ) H a n so n , P .R .; S to ia n o v a , D .S .;
O r g a n i c L e t t e r s , 2 0 0 1 , 3 „ 3 2 8 5 -3 2 8 8 .
39
14 P errin , D . D .; A r m a r e g o , W . L . F .; “P u r i f i c a t i o n o f L a b o r a t o r y C h e m i c a l s ” , P e r g a m o n P r e ss L td.
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15 (a ) M e lo t, J. M .; T e x ie r -b o u lle t, F .; F o u ca n d , A .; S y n th e s is , 1 9 8 8 ,5 5 8 - 5 6 0 . (b ) B a r n e s, R . K .; K lie g m a n ,
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S tu fk e n s, D . J.; O sk a m , A .; F raanje , J.; G o u b its, K .; J o u r n a l o f O r g a n o m e t a l l i c C h e m i s t r y , 1 9 9 5 , 4 9 3 , 1 5 3 1 6 2 . (d ) H s ie h , A .T .T .; W e sr , B .O .; J o u r n a l o f O r g a n o m e t a l l i c C h e m i s t r y , 1 9 7 6 , 1 1 2 , 2 8 5 -2 9 6 .
16 (a) B a r n e s, R . K .; K lie g m a n , J. M .; J o u r n a l o f O r g a n i c C h e m i s t r y , 1 9 7 0 , 3 5 , 3 1 4 0 - 3 1 4 3 . (b ) E xn er, O .;
K lie g m a n , J. M .; J o u r n a l o f O r g a n i c C h e m i s tr y , 1 9 7 1 , 3 6 , 2 0 1 4 -2 0 1 5 .
17 W h e a tle y , W . B .; F itz g ib b o n , W . E .; C h e n e y , L . C .; J o u r n a l o f O r g a n i c C h e m i s t r y , 1 9 5 3 , 1 8 , 1 5 6 4 -1 5 7 1 .
18 L o u , R .; M i, A .; J ia n g , Y .; Q in , Y .; L i, Z .; P u , F .; C h an , A . S . C .; T e t r a h e d r o n , 2 0 0 0 , 5 6 , 5 8 5 7 -5 8 6 3 .
MONTANA STATE UNIVERSITY - BOZEMAN
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