A highly regioselective hydroformylation of an α-chiral olefin to produce a versatile trifunctionalised orthogonally protected C5 synthon

Article abstract of DOI:10.1016/j.tetlet.2011.04.062

This paper describes a highly regioselective hydroformylation of (R)-N-phthalimido-vinylglycinol, [(R)-PVG]. By judicious choice of the reaction conditions, catalyst-controlled preferential formation of the linear regioisomer could be achieved in excellent yield. The hydroformylation product cyclised to a hemi-acetal, which is an orthogonally protected trifunctionalised enantio-enriched C5 synthon. The value of this versatile intermediate was demonstrated by the ready formation of enantio-enriched amino-diols, diamino-alcohols and differentially protected (R)-3-aminopiperidine.

Full text of DOI:10.1016/j.tetlet.2011.04.062

Tetrahedron Letters 52 (2011) 3271–3274
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A highly regioselective hydroformylation of an
a-chiral olefin to produce
a versatile trifunctionalised orthogonally protected C5 synthon
Christopher Cobley a, Graham Meek a, , Cynthia Rand b
⇑
a Chirotech Technology Limited, Dr. Reddy’s Laboratories (EU) Limited, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK
b The Dow Chemical Company, Midland, MI 48674, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 January 2011
Revised 6 April 2011
Accepted 15 April 2011
Available online 23 April 2011
This paper describes a highly regioselective hydroformylation of (R)-N-phthalimido-vinylglycinol, [(R)-
PVG]. By judicious choice of the reaction conditions, catalyst-controlled preferential formation of the
linear regioisomer could be achieved in excellent yield. The hydroformylation product cyclised to a
hemi-acetal, which is an orthogonally protected trifunctionalised enantio-enriched C5 synthon. The value
of this versatile intermediate was demonstrated by the ready formation of enantio-enriched amino-diols,
diamino-alcohols and differentially protected (R)-3-aminopiperidine.
Keywords:
Regioselective hydroformylation
Trifunctionalised synthon
Ó 2011 Elsevier Ltd. All rights reserved.
Olefin hydroformylation to produce aldehydes is a highly atom-
economic process that is widely used in the commodity chemicals
industry to produce millions of tonnes per annum of basic feed-
stocks.1 Over 70 years of chemical and engineering know-how
have been accrued in order to make hydroformylation one of the
most heavily used homogenously-catalysed reactions practised to-
day. In spite of this, olefin hydroformylation remains relatively un-
der utilised for the production of fine chemicals and
pharmaceutical intermediates. Part of the reason for this is that
the majority of the vast wealth of knowledge around the applica-
tion of this chemistry has been gained from studying the behaviour
of very simple terminal alkenes, such as propene. Pharmaceutical
intermediates and fine chemicals by their very nature contain
more functionality, such as heteroatoms, unsaturated moieties
and other reducible groups. Furthermore, the synthesis of these
intermediates frequently requires control over the formation of
newly generated stereogenic centres. This higher degree of com-
plexity introduces more uncertainty into the outcome of the
hydroformylation reactions of such substrates. For the past several
years we,2 and others,3 have focussed on utilising olefin hydrofor-
mylation. This has been achieved in part by expanding the range of
available ligands to control chemo-, regio- and stereoselectivity as
well as exploring an increased substrate scope.
and the defined stereogenic centre, the single enantiomer 1 has
been used in the synthesis of a number of natural products and
pharmacologically active agents.5 The presence of the olefin unit,
in particular, allows for molecular complexity to be introduced
through reactions such as Heck couplings and metathesis. Like-
wise, we envisaged that hydroformylation of 1 would provide a
range of useful synthetic intermediates and undertook studies
determining the activity and selectivity of (R)-1 with a variety
of hydroformylation catalysts. The results are reported in this pa-
per. We also describe further reactions of the hydroformylation
product of (R)-1, a C5 orthogonally protected enantio-enriched
synthon, which illustrates the potential utility of this versatile
intermediate.
The hydroformylation of (R)-1 was examined using several
ligands (Fig. 1). We wished to avoid the complication of introduc-
ing a new stereocentre which would be observed with the
branched aldehyde and, therefore, focussed on formation of the
linear regioisomeric product. The achiral bidentate ligands biphe-
phos, 2 and 3, were chosen because they are generally selective
for the desired linear aldehyde. DoverPHOS and triphenyl phos-
phite were examined in order to ascertain the effects of using
monodentate ligands in this reaction. A reaction using no ligand
was also undertaken in order to determine the inherent regioselec-
tivity imparted by the substrate. These initial studies were carried
out at a molar substrate to catalyst ratio (S/C) of 250 using 10 bar
pressure of syngas (1:1 CO/H2).
(R)-N-phthalimido-vinylglycinol, (R)-1, is readily available
from epoxybutene using a palladium-catalysed dynamic kinetic
asymmetric transformation, which has been performed on a kilo-
gram scale using 0.1 mol % of catalyst in 88% ee.4 Owing to the
three distinct functional groups in the four-carbon framework
The results (Table 1) show that there was no substrate control
in this reaction as the ligand-free system provided an equal mix-
ture of the regioisomeric products 4 and 5, which arise through
cyclisation of the aldehydes 6 and 7, respectively (entry 1). As
anticipated, the catalytic system also benefitted from the use of a
⇑
Corresponding author.
E-mail address: gmeek@drreddys.com (G. Meek).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.062

3272
C. Cobley et al. / Tetrahedron Letters 52 (2011) 3271–3274
tBu
tBu
tBu
O
O
O
O
P
P
O
O
tBu
tBu
tBu
DoverPHOS
Triphenylphosphite
MeO
OMe
tBu
tBu
tBu
SiMe3
SiMe3
tBu
tBu
O
P
O
tBu
O
O
tBu
O
O
O
tBu
O
O
tBu
O
O
O
O
P
O
P
P
P
P
MeO
O
O
O
O
Me3Si
tBu
SiMe3
Biphepos
2
3
Figure 1. Ligands examined for the hydroformylation of (R)-1.
Table 1
Hydroformylation of (R)-1
NPhth
OH
NPhth
OH
Rh(CO)2(acac), Ligand
NPhth
OH
+
Toluene, CO/H2 (10 bar),
40 ºC, 18 h, S/C 250
O
O
H
H
7
6
(R)-1
NPhth
NPhth
+
HO
HO
O
O
4
5
Entry
Ligand
Conv. (%)a
4:5a
1
2
3
4
5
6
—
16
1:1
1:1
2:3
7:1
1:4
1:2
Biphephos
2
3
DoverPHOS
P(OPh)3
>95
>95
92
>95
>95
a
Determined by 1H NMR spectroscopy.
ligand in terms of enhanced activity and conversion when com-
pared to the ligand-free system. Ligand 3, which was developed
to favour linear selectivity,6 was the only example that favoured
preferential formation of the desired regioisomer 4 (entry 6).
Buoyed by these results we sought to enhance the regioselectiv-
ity to favour the linear product by examining the effects of pres-
sure and temperature using the ligand 3 at the same level of
overall catalyst loading (Table 2). Some insight into the regiochem-
ical influence of the hydroxy group was probed using both (R)-1
and the mesylate derivative, (R)-8. Increasing the temperature
with (R)-1 gratifyingly provided a higher regioselectivity for the
linear product 4 (entry 2), which is in accordance with previous
findings.7 The effect of temperature on the regioselectivity of the
reaction using (R)-8 was convoluted by the pressure effects (entry
4). Most noteworthy is that under the same conditions (R)-1 (entry
2) provides a higher level of regioselectivity than (R)-8 (entry 5)

C. Cobley et al. / Tetrahedron Letters 52 (2011) 3271–3274
3273
Table 2
Effect of pressure and temperature on the hydroformylation of (R)-1 and (R)-8
NPhth
OMs
NPhth
OMs
+
O
O
H
9
H
10
NPhth
3
Rh(CO)2(acac),
OR
Toluene, CO/H2,18 h,
S/C 250
NPhth
NPhth
OR
+
(R)-1, R = H
(R)- R = Ms
HO
8,
HO
O
O
4
5
Entry
Substrate
Pressure (bar)
Temp. (°C)
Conv. (%)a
4:5 or 9:10a
1
2
3
4
5
(R)-1
(R)-1
(R)-8
(R)-8
(R)-8
10
10
25
25
10
40
80
40
80
80
92
>95
66
>95
>95
7:1
16:1
5:1
4:1
7:1
a
Determined by 1H NMR spectroscopy.
NPhth
OH
H2NOH.HCl, BaCO3
EtOH, 96%
HO
N
11
12
NPhth
OH
NPhth
1) Rh(CO)2(acac), 3
NPhth
H2 (10 bar)
10wt% Pt/C
Toluene, CO/H2 (10 bar),
HO
OH
80 ºC,17 h, S/C 500
2) MTBE slurry
76-81%
HO
O
MeOH, 40 ºC
quantitative
4
(R)-1
NPhth
OH
RR'NH, NaBH(OAc)3,
1,2-DCE
RR'N
13 R = R' = Bn, 100%
14 R,R' = (CH2)5, 96%
15 R = Bn, R' = H, 40%
Scheme 1. Hydroformylation of (R)-1 and synthetic utility.
which points to the potential interaction of the hydroxy group in
(R)-1 with the catalyst system, and is also consistent with previous
findings.8
being equivalent to a masked aldehyde and alcohol, 4 is a versatile
synthon that could potentially be used to produce a diverse array
of synthetically-appealing intermediates. Furthermore, the pres-
ence of the differentiated functional groups potentially allows for
a high degree of control in subsequent reactions in which the ste-
reodefined centre could induce asymmetry.
In order to evaluate the potential of 4 we initially investigated
the chemistry of the hemi-acetal functionality. Oximes are known
precursors to nitrile oxides and hence isoxazoles and isoxazo-
lines,10 and treatment of 4 under standard conditions produced
the oxime 11 in excellent yield. Reduction of 4 to the amino-diol
12 was achieved using hydrogen in combination with a heteroge-
neous catalyst as the use of sodium borohydride resulted in the
formation of by-products from interaction with the phthalimide
group. Reductive amination using sodium triacetoxyborohydride11
proceeded smoothly to produce the tertiary amines 13 and 14,
On the basis of these results, the hydroformylation of (R)-1 was
carried-out in a single-well pressure vessel in order to study more
effectively the effect of a decrease in the catalyst loading (Scheme
1).9 The hydroformylation took 40 min to reach completion, as
determined by syngas uptake, but in order to ensure complete cyc-
lisation the reaction was run for 17 h. Longer reaction times did not
have a deleterious effect on the purity of the products and a similar
regioselectivity and yield to that previously obtained was ob-
served. The crude reaction mixture consisting of two diastereoiso-
mers of 4 and four diastereoisomers of 5 was purified by trituration
using methyl tert-butyl ether (MTBE) to provide >95% pure 4 as a
3:2 diastereoisomeric mixture in 76–81% yield. With the stereode-
fined centre, protected amine and the hemi-acetal functionality

3274
C. Cobley et al. / Tetrahedron Letters 52 (2011) 3271–3274
Proc. Res. Dev. 2002, 6, 379; (t) Gual, A.; Godard, C.; Castillon, S.; Claver, C. Adv.
Synth. Catal. 2010, 352, 463; (u) Cossu, S.; Peluso, P.; Alberico, E.; Marchetti, M.
Tetrahedron Lett. 2006, 47, 2569; (v) Zhang, X.; Cao, B.; Yu, S.; Zhang, X. Angew.
Chem., Int. Ed. 2010, 49, 4047; (w) Noonan, G. M.; Cobley, C. J.; Lebl, T.; Clarke,
M. L. Chem. Eur. J. 2010, 16, 12788; (x) Worthy, A. D.; Joe, C. L.; Lightburn, T. E.;
Tan, K. L. J. Am. Chem. Soc. 2010, 132, 14757; (y) Worthy, A. D.; Gagnon, M. M.;
Dombrowski, M. T.; Tan, K. L. Org. Lett. 2009, 11, 2764; (z) Lightburn, T. E.;
Dombrowski, M. T.; Tan, K. L. J. Am. Chem. Soc. 2008, 130, 9210.
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Lett. 2000, 41, 3187.
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12, 6607; (d) Llaveria, J.; Diaz, Y.; Mathue, M. I.; Castillión, S. Org. Lett. 2009, 11,
205.
whilst the secondary amine 15 was formed in moderate yield ow-
ing to further reaction of this initial product. Nevertheless, these
reactions produced enantio-enriched amino-diols and diamino-
alcohols in a straightforward fashion.
Enantiopure 3-aminopiperidine is a constituent of several phar-
maceutical agents, such as alogliptin12 and linagliptin,13 as well as
the investigational substances AZD-776214 and PCI-32765,15
amongst others. There are several known procedures to this mate-
rial based on resolution16 and use of the chiral pool.17 Both of these
approaches have their limitations and there is a need for new
methods to produce enantiopure 3-aminopiperidine. Treatment
of 15 under Mitsonobu conditions provided the orthogonally pro-
tected 3-aminopiperidine 16 in good yield (Eq. (1)).18
6. Peng, W. -J; Holladay, J. E. WO2004/035595, 2004, Chem. Abstr. 2004, 140,
357510.
7. van Leeuwen, P. W. N. M.; Claver, C. Rhodium Catalysed Hydroformylation;
Kluwer Academic: Dordrecht, 2000.
NPhth
NPhth
OH
DIAD, PPh3, THF
8. Whiteker, G. T. Top. Catal. 2010, 53, 1025.
9. Experimental procedure:
0.0202 mmol) and secured in
charged with nitrogen to a pressure of 10 bar and subsequently vented. This
charge/vent cycle was repeated three times. solution of
A
glass liner was charged with ligand
3 (22 mg,
succinimide
77%
ð1Þ
N
a
300 ml pressure vessel. The vessel was
BnHN
Bn
15
16
A
(acetylacetonato)dicarbonylrhodium(I) in deoxygenated toluene (20 ml of a
0.923 mM solution, 0.0184 mmol) was then added to the pressure vessel, which
was subsequently charged with syngas to a pressure of 10 bar and slowly
vented. This charge/vent cycle with syngas was repeated two times, after which
the vessel was charged with syngas to a pressure of 10 bar, stirring was initiated
and the vessel was heated to 40 °C. After 20 min at this temperature, the stirring
was stopped and the pressure vessel was vented. A solution of (R)-1 (2.00 g,
9.21 mmol) in deoxygenated toluene (80 ml) was then added to the pressure
vessel, which was subsequently charged with syngas to a pressure of 10 bar and
then vented. This charge/vent cycle with syngas was repeated two times. The
pressure vessel was then charged with syngas to a pressure of 9 bar, stirring was
initiated and the solution heated to 80 °C. The pressure within the vessel was
maintained between 9 and 10 bar by further addition of syngas, as necessary
(stirring was stopped during gas addition). After 90 min, no further uptake of
syngas occurred. After 17 h the heating was discontinued and the vessel vented.
The vessel was then charged with nitrogen to a pressure of 10 bar and stirred for
20 min and then vented. This charge/stir/vent cycle with nitrogen was repeated
three times. The solution was concentrated in vacuo to provide the crude
product as a light-tan solid (2.26 g, 99%) as an approximate 16:1 mixture of
regioisomers, as determined by 1H NMR analysis. The crude product was
purified via trituration by stirring as a suspension in MTBE (30 ml) for 17 h
followed by filtration and washing with fresh MTBE (20 ml) to provide 4 as a
white solid (1.73 g, 76%) as a 6:4 anomeric mixture. 1H NMR analysis revealed
>95% regioisomeric purity.
In conclusion, this paper reports the highly regioselective
hydroformylation of (R)-N-phthalimido-vinylglycinol, an -chiral
a
olefin bearing a hydroxy group b to the olefin. The hydroxy group
played a role in producing the observed regioselectivity in combi-
nation with the appropriate ligand. A simple purification of the
hydroformylation product provided access to an orthogonally pro-
tected, enantio-enriched, trifunctionalised C5 synthon. This highly
versatile intermediate could provide access to a multitude of prod-
uct types by exploiting the known chemistry of the functional
groups present. We chose to illustrate the potential of this synthon
by transformations into amino-diols, a diamino alcohol and an
oxime. We also reported the preparation of a differentially pro-
tected, enantio-enriched derivative of 3-aminopiperidine. Further
work on exploiting the utility of this synthon is ongoing.
Acknowledgement
We thank Wei Peng for supplying ligand
discussions.
3 and useful
1H NMR (400 MHz, CDCl3) (major diastereoisomer) d 7.83 (2H, dd, J 8 and 4 Hz),
7.72 (2H, dd, J 8 and 4 Hz), 4.92 (1H, ddd, J 9, 6 and 2 Hz), 4.43–4.35 (1H, m), 4.26
(1H, t, J 12 Hz), 3.90–3.85 (1H, m), 2.96 (1H, d, J 2 Hz), 2.60–2.50 (1H, m), 2.13–
2.07 (1H, m), 1.94–1.88 (1H, m) and 1.68–1.58 (1H, m); (minor diastereoisomer)
d 7.83 (2H, dd, J 8 and 4 Hz), 7.72 (2H, dd, J 8 and 4 Hz), 5.32 (1H, m), 4.67 (1H, t, J
12 Hz), 4.43–4.34 (1H, m), 3.52 (1H, ddd, J 10, 4 and 2 Hz), 2.90–2.79 (1H, m),
2.61–2.50 (1H, m), 2.02–1.96 (1H, m) and 1.68–1.58 (1H, m).
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