Ligand-mediated enantioselective synthesis of acyclic pyrrole carbinols

Article abstract of DOI:10.1055/s-2005-872698

The enantioselective synthesis of acyclic pyrrole carbinols via ligand-mediated addition of lithium pyrrolate to aldehydes, and subsequent exploitation of the resulting stereocentre as a stereodirecting group in syn- or anti-selective 1,3-reductions of ketone functionality in the parent aldehyde is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872698

2420
LETTER
Ligand-Mediated Enantioselective Synthesis of Acyclic Pyrrole Carbinols
Enantioselective
S
a
ynthesis of
r
A
cyclic
rPyrrole
e
Carbinols n J. Dixon,*a Mark S. Scott,b Chris A. Luckhurstc
a
b
c
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Fax +44(161)2754939; E-mail: Darren.Dixon@man.ac.uk
Received 8 July 2005
enantioselective
lithium pyrrolate
addition
stereoselective
reduction
Abstract: The enantioselective synthesis of acyclic pyrrole
carbinols via ligand-mediated addition of lithium pyrrolate to
aldehydes, and subsequent exploitation of the resulting stereocentre
as a stereodirecting group in syn- or anti-selective 1,3-reductions of
ketone functionality in the parent aldehyde is described.
OH OH
O
O
OH
O
N
H
N
1i
2i
4a
Key words: aldehydes, asymmetric synthesis, ligands, lithium,
pyrrole carbinol
Scheme 2
additions of N-centred nucleophiles, such as lithium
amides to conjugate acceptors have recently been report-
ed.8 Although the enantiomeric excesses vary consider-
ably, certain ligands have revealed themselves as
excellent for these additions. However, in the case of
aldehyde substrates, temperatures below –100 °C are of-
ten required to achieve good to excellent selectivity.9
Additionally, most examples of additions to aldehydes
lack substrate generality and many use lithium amides/
alkoxides as the chiral controller via co-aggregation
resulting in the need for excess quantities of organolithi-
um reagents.10 We hoped that the lower reactivity of
lithium pyrrolate compared to organolithiums would
allow for improved control in the reactions. Ligand-medi-
ated addition reactions offer considerable potential for the
asymmetric synthesis of enantioenriched pyrrole
carbinols and herein we report our preliminary findings.
The chemoselective addition of lithium pyrrolate to alde-
hydes 1 which furnishes the N-pyrrole carbinols in good
yield has recently been reported by our group.1 The
metastable pyrrole carbinol adducts 2 can tolerate mildly
acidic, basic and reductive conditions and may be purified
by silica gel chromatography. Under strongly basic condi-
tions, however, the adducts are unstable and revert back to
the parent aldehydes and pyrrole.1,2 This may be conduct-
ed in the presence of carbon-centred nucleophiles and
one-pot sequences can afford olefin products 3 in good
yields (Scheme 1).1,3,4
O
P
O
OH
OR'
O
NLi
EtO
EtO
OR'
N
R
1.
O
R
R
2. H+
base
1
2
3
Our initial work employed a wide screen of multidentate
ether and/or amine ligands for the addition of lithium pyr-
rolate to isobutyraldehyde as a model system (Scheme 3,
Table 1). Lithium pyrrolate was formed by the addition of
n-butyllithium to a solution of pyrrole 5 at 0 °C. The re-
sulting white precipitate was then treated with the ligand
6–10 (Figure 1) at 22 °C and homogeneity was restored.11
Ligation of the lithium pyrrolate was assumed, and the re-
action mixture allowed to mature for 25 minutes then
cooled to –78 °C and isobutyraldehyde was added. After
stirring for 30 minutes, the reactions were quenched with
acetic acid (1 M in THF), passed though a short silica plug
Scheme 1
It was envisaged that this method of aldehyde protection
could be extended to a new approach for the asymmetric
synthesis of chiral aldehydes. The concept requires an
enantioselective addition reaction followed by exploita-
tion of the newly formed stereocentre in a diastereoselec-
tive transformation of a second prochiral group present in
the aldehyde starting material (i.e. 2i to 4a).5 Subsequent
collapse of the metastable pyrrole carbinol could reveal
the desymmetrised aldehyde ready for further synthetic
transformations, in situ or stepwise (Scheme 2).
1
and analysed by H NMR and chiral stationary phase
HPLC.
It was envisaged that the enantioselective synthesis of the
pyrrole carbinols could be effected by a chiral ligand-me-
diated addition.6 Such reactions have been reported for the
addition of organolithium nucleophiles to Michael accep-
tors, imines and aldehydes.7 In addition, ligand-mediated
The initial study was performed in toluene due to its
limited ability to solvate lithium pyrrolate. These
reactions gave disappointing results with sparteine 6 (en-
try a), and the bisoxazoline 8 (entry c). Performing the ad-
dition with (1R,2R)-1,2-dimethoxy-1,2-diphenylethane
(7a,12 entry b) gave a promising 63% ee in favour of the
R-enantiomer13 and it was hoped that further optimisation
would be possible.
SYNLETT 2005, No. 16, pp 2420–2424
0
4
.1
0
.2
0
0
5
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872698; Art ID: D19005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Synthesis of Acyclic Pyrrole Carbinols
2421
OH
H
N
H
a
O
O
NH
N
(R)
N
N
N
5
2a
RO
OR
(–)-sparteine
7a R = Me
7b R = Et
7c R = MOM
Scheme 3 Reagents and conditions: a) i) n-BuLi (1 equiv), 0 °C; ii)
ligand, 22 °C, 25 min; iii) (CH3)2CHCHO (1 equiv), –78 °C; iv)
AcOH (1.5 equiv, 1 M in THF), –78 °C
6
8
Table 1 Ligand Identificationa
O
O
Entry
Ligand Equiv
Solvent
ee (%)b
Conversion
(%)c
RO OR
10a R = Me
10b R = MOM
9
a
6
7a
8
1
1
1
1
1
1
2
2
1
1
1
1
1
1
PhMe
PhMe
PhMe
THF
20
90
80
78
86
75
68
79
73
82
74
76
84
83
65
Figure 1 Chiral ligands 6–10
b
cd
d
e
63
16
66% ee at –95 °C) was observed using ligand 7a in tolu-
ene (entries b, g and n). Having exhausted all the readily
available ligand classes, it was decided to explore the
optimal system for substrate generality.
7a
7a
7a
7a
7a
9
12
Et2O
60
f
Hexane
PhMe
Et2O
45
OH
O
g
h
i
63
a
N
R
(R)
R
56
1a–i
2a–i
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
50
Scheme 4 Reagents and conditions: a) i) 5 (1.05 equiv), n-BuLi (1
equiv), 0 °C; ii) 7a (1 equiv), 22 °C, 25 min; then 1 (1 equiv), –78 °C;
iii) AcOH (1.5 equiv, 1 M in THF), –78 °C
j
7b
7c
10a
10b
7a
<10
<10
<10
26
k
l
The results of the lithium pyrrolate addition to a range of
aldehydes in the presence of dimethyl ether ligand 7a
(Scheme 4) are shown in Table 2. The moderate to good
levels of enantiocontrol were maintained in the additions
to linear, branched and bulky aldehydes (entries a–e, i).
With a,b-unsaturated aldehydes, such as cinnamaldehyde
1h, the enantiocontrol dropped to 34% ee (entries g–h).
m
ne
66
a Reactions performed on 1 mmol scale.
b Enantiomeric excesses were determined by chiral stationary phase
HPLC and the R-enantiomer was dominant in each case.13
c Conversion determined by 1H NMR using an internal standard.
d Reaction performed on 0.25 mmol scale.
The stereochemical outcome of these reactions is consis-
tent with the stereochemical model proposed by Tomioka
for the 7a-mediated addition of organolithiums to imines
and a,b-unsaturated esters.14 Here, it is postulated that the
reacting complex has the lithium ligated by the two ethe-
real oxygen atoms of 7a. The methyl groups adopt a con-
formation that minimises steric clash with the vicinal
phenyl groups, shown by 11a. This relays the chirality of
the backbone to the ligating ethers generating a chiral
space around the bound lithium ion. Two diastereomeric
transition states are then possible by attack to either the re
(12a) or si (12b) face of the aldehyde complexed to the
lithium ion. An unfavourable steric clash between the
methyl group and the aldehyde in 12a destabilises this
structure, with respect to 12b, and results in a preferential
formation of the R-isomer (Figure 2). Increasing the size
of the ether substituents on the hydrobenzoin backbone
presumably results in a pseudo achiral complex, 11b,
where steric clash between the ligated pyrrolate and these
groups is minimised. Such a complex would give rise to
lower enantioselectivities.14
e Reaction performed at –95 °C.
In fact, toluene was found to be the optimal solvent for 7a-
mediated additions. In diethyl ether an almost identical
enantioselectivity was observed but the conversion was
slightly diminished (entry e). The use of THF or hexane as
solvent resulted in lower enantioselectivities (entries d
and f).
Performing the same reaction with two equivalents of
ligand 7a in both toluene and diethyl ether led to a negli-
gible change in selectivity implying that a single equiva-
lent of ligand was sufficient for complete ligation of the
lithium pyrrolate (entries g, h).
Attempts to increase the enantioselectivity by structural
modifications to ligand 7a were not successful (entries i–
m). Notably, increasing the steric bulk by substituting the
methyl for ethyl groups in 7b, or changing to a binaphthol
motif led to almost complete loss of selectivity (entries l,
m). The highest enantioselectivity (63% ee at –78 °C and
Synlett 2005, No. 16, 2420–2424 © Thieme Stuttgart · New York

2422
D. J. Dixon et al.
LETTER
Table 2 Addition of 7a Ligated Lithium Pyrrolate to Aldehydesa
Entry
a
Adduct 2b
ee (%)c Conversion (%)d
O
O
O
O
OH
63
63
64
62
80
78
83
84
Li
N
Li
N
N
N
N
N
N
N
b
c
d
e
f
OH
OH
OH
OH
OH
11a
11b
O
O
O
O
O
O
Li
N
Li
N
12a
12b
Figure 2 Proposed stereochemical models
55
87
73
80
75
86f
ethyl ether afforded the syn-1,3-diol as the major dia-
stereomer in
pleasing 94:6 dr (entry a).16,17
a
e
–
Alternatively, treatment with Me4NBH(OAc)3 gave the
anti-1,3-diol in a ratio of 95:5 (entry b).18 Subsequent
treatment of these pyrrole carbinols with our deprotective
HWE conditions allowed access to both enantiomers of
the a,b-unsaturated product 13 in good yield.1,19
g
h
i
29
34
50
OH
OH
OH
N
N
N
OH OH
OH OH
a
2i
N
N
+
46% ee
Ph
4a
4b
b
b
O
O
OH
O
OH
tBuO
a Reactions performed on 1 mmol scale.
tBuO
b The absolute stereochemistry of the major enantiomer of adduct 2
was assigned as R.13
(R)-13
97% Yield,
[α]D25 = 4.9 (c 1.0, CHCl3)
(S)-13
97% Yield,
c Enantiomeric excesses were determined by chiral stationary phase
HPLC.
[α]D25 = –5.1 (c 1.1, CHCl3)
d Conversion determined by 1H NMR using an internal standard.
e Attempts to separate the enantiomers by HPLC have so far failed.
f Isolated yield.
Scheme
5 Reagents and conditions: a) See Table 3; b)
(EtO)2P(=O)CH2CO2t-Bu, NaH, THF
In conclusion, the first direct formation of enantioen-
riched pyrrole carbinols via chiral ligand-mediated addi-
tion has been achieved. With a range of aldehydes,
moderate to good levels of stereocontrol are obtained
using the dimethyl ether of hydrobenzoin, 7a, as a chiral
The utility of the enantioselective addition is effectively
demonstrated by manipulation of pyrrole carbinol 2i
(Scheme 5, Table 3). This was prepared on 10 mmol scale
at 46% ee.15 Treatment of 2i with zinc borohydride in di-
Table 3 Diastereoselective Reduction of 2i
Entry
Reductant
Solvent
Temperature (°C)
4a:4ba
94:6
Yield (%)b
a
Zn(BH4)2
Et2O
–35
–25
90
84
b
Me4NBH (OAc)3
MeCN–AcOH
5:95
a Determined by 1H NMR. Relative stereochemistry assigned by the method of Rychnovsky.20
b The diastereomers were not separable by silica gel chromatography.
Synlett 2005, No. 16, 2420–2424 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Acyclic Pyrrole Carbinols
2423
Mosher ester method, see: Seco, J. M.; Quiñoá, E.; Riguera,
R. Chem. Rev. 2004, 104, 17.
(14) (a) Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron
2000, 56, 10153. (b) Shindo, M.; Koga, K.; Tomioka, K. J.
Org. Chem. 1998, 63, 9351.
ligand for lithium pyrrolate. The newly formed stereocen-
tre may be used as a stereochemical handle in diastereose-
lective reductions of proximal ketone groups giving
access to either the syn-1,3- or anti-1,3-diol motif depend-
ing on reagent choice. Exploiting the metastability of the
pyrrole carbinol group in a tandem deprotection olefina-
tion sequence affords either enantiomer of the alcohol.
Thus, a stereodivergent strategy is presented where only
one enantiomer of the ligand is required to access either
enantiomer of 13. Other enantioselective approaches to
acyclic pyrrole carbinols and their application in synthesis
are under investigation and will be reported in due course.
(15) (R)-1-Hydroxy-2,2-dimethyl-1-pyrrol-1-yl-pentan-3-one
(2i).
To a rapidly stirred solution of pyrrole (730 mL, 10.5 mmol)
in toluene (100 mL) was added n-BuLi (4.0 mL, 10 mmol,
2.5 M in hexane) at 0 °C. The solution was allowed to warm
to room temperature over 5 min before 7a (2.42 g, 10.0
mmol) was added in one portion. The reaction was allowed
to stir for 25 min at this temperature before cooling to –78 °C
and the aldehyde 1i (1.28 g, 10 mmol) was added over 5 s via
syringe. After 30 min at this temperature the reaction was
quenched by the rapid addition of a pre-cooled solution of
AcOH (15 mmol) in THF (15 mL). After a further 30 min the
reaction was allowed to warm to 0 °C over 15 min before
being filtered though a pad of silica (6 cm × 6 cm) and
concentrated under reduced pressure to give the crude
product. 1H NMR and HPLC analysis indicated a conversion
of 95% and ee of 46%. Purification by flash column
chromatography eluting with hexane–EtOAc (20:1 to 1:5)
yielded 2i as a pale brown oil (1.56 g, 80%), 7a as a white
Acknowledgment
We thank the EPSRC (MSS), AstraZeneca (MSS) and Trinity Col-
lege (MSS) for funding and the National Mass Spectrometry Ser-
vice Swansea for analysis. DJD would like to thank Merck, Sharp
and Dohme, Terlings Park, UK for generous donations to the group.
References
solid (2 g, 70%) together with further 2i (13%) contaminated
(1) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A. Synlett 2003,
2317.
(2) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem. Int. Ed.
2002, 41, 3188.
25
with 7a (25%). HPLC indicated no change in ee. [a]D
=
+18.2 (c 1.1, CDCl3). 1H NMR (400 MHz): d = 6.71 (2 H, t,
J = 2.2 Hz, CHCHN), 6.13 (2 H, t, J = 2.2 Hz, CHCHN),
5.43 (1 H, br d, J = 3.9 Hz, NCHOH), 4.36 (1 H, br, OH),
2.52–2.41 (2 H, m, CH2), 1.8 (3 H, s, CH3), 1.13 (3 H, s,
CH3), 1.02 (3 H, t, J = 7.1 Hz, CH2CH3). 13C NMR (100
MHz): d = 217.8 (C), 120.3 (CH), 108.2 (CH), 87.8 (CH),
52.4 (C), 32.4 (CH2), 22.9 (CH3), 19.5 (CH3), 7.5 (CH3). IR
(film): nmax = 3445 (br), 2978, 1698, 1472, 1261, 1081 cm–1.
MS (ESI): m/z calcd for C13H13NO+: 196.1332. Found:
196.1335 [MH+].
(3) For similar transformations of N-1¢-hydroxyalkyl-
oxazolidin-2-ones see for example: (a) Bach, J.; Bull, S. D.;
Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A.
D. Tetrahedron Lett. 1999, 40, 6677. (b) Bach, J.; Blachere,
C.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Price, P. D.;
Sanganee, H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1,
2001. (c) Gaul, C.; Seebach, D. Helv. Chim. Acta 2002, 85,
772.
(4) (a) Dixon, D. J.; Lucas, A. C. Synlett 2004, 1092.
(b) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559.
(c) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2005, 44, 4365.
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307.
(6) (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
(b) Asymmetric Catalysis in Organic Synthesis; Noyori, R.,
Ed.; Wiley: New York, 1994.
(16) (a) Freiser, H. Acc. Chem. Res. 1984, 17, 126. (b) Oishi, T.;
Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(17) (1R,3R)-2,2-Dimethyl-1-pyrrol-1-yl-pentane-1,3-diol
(4a).
To a solution of 2i (231 mg, 1.18 mmol) in Et2O (6 mL) was
added freshly prepared zinc borohydride (24 mL, 3.6 mmol,
ca. 0.15 M in Et2O) at –35 °C. After stirring for 8 h the
reaction was quenched with MeOH (5 mL) followed by the
addition of sodium potassium tartrate solution (15 mL) and
EtOAc (25 mL) then stirred for 10 min. The layers were
separated and the aqueous phase further extracted with
EtOAc (2 × 50 mL). The combined organics were washed
with brine (15 mL), dried (MgSO4) and the solvent removed
under reduced pressure. Analysis of the crude material by 1H
NMR gave a selectivity of 94:6. The crude product was
purified by flash column chromatography eluting with
hexane–EtOAc (20:1 to 1:5) gave 4a as a colourless oil (209
mg, 90%) as a 16.6:1 mixture of diastereomers. [a]D25 = +5.2
(c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3): d = 6.81 (2 H,
t, J = 2.0 Hz, CH=CHN), 6.14 (2 H, t, J = 2.0 Hz, CH=CHN),
5.33 (1 H, s, NCHOH), 4.26 (1 H, br, OH), 3.26 [1 H, dd,
J = 10.5, 1.9 Hz, CH(OH)CH2], 2.69 (1 H, br, OH), 1.55 (1
H, dqd, J = 14.1, 7.1, 1.8 Hz, CHaHbCH3), 1.40–1.28 (1 H,
ddq, J = 14.1, 10.5, 7.1 Hz, CHaHbCH3), 1.00 (3 H, s, CCH3),
(7) Organolithiums in Enantioselective Synthesis; Hodgson, D.
M., Ed.; Springer: Berlin, 2003.
(8) (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K.
J. Am. Chem. Soc. 2003, 125, 2886. (b) Doi, H.; Sakai, T.;
Yamada, K.; Tomioka, K. Chem. Commun. 2004, 1850.
(c) Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.;
Tomioka, K. Tetrahedron Lett. 2004, 45, 9261.
(9) See: Granander, J.; Sott, R.; Hilmersson, G. Tetrahedron:
Asymmetry 2003, 14, 439; and references cited therein.
(10) Müller, P.; Allenbach, Y. F.; Bernardinelli, G. Helv. Chim.
Acta 2003, 86, 3164.
(11) Lithium pyrrolate shows low solubility in non-polar
solvents, marginally higher solubility in ethereal solvents.
Almost complete dissolution is observed at the operating
concentration of 0.1 M.
0.98 (3 H, t, J = 7.1 Hz, CH2CH3), 0.67 (3 H, s, CCH3). 13
C
NMR (100 MHz, CDCl3): d = 119.7 (CH), 107.5 (CH), 89.2
(CH), 79.3 (CH), 43.6 (C), 24.2 (CH2), 20.5 (CH3), 14.3
(CH3), 11.0 (CH3). IR (film): nmax = 3399 (br), 2972, 1472,
(12) Ligand 7a was synthesised by the methods of Sharpless and
Tomioka: Wang, Z. M.; Sharpless, K. B. J. Org. Chem.
1994, 59, 8302; and ref. 14.
(13) The absolute stereochemistry of 2a and 2c–i was assigned by
analogy to that of 2b which was established using the
+
1261, 1077, 969 cm–1. MS (ESI): m/z calcd for C11H20NO2 :
198.1489. Found: 198.1492 [MH+].
Synlett 2005, No. 16, 2420–2424 © Thieme Stuttgart · New York

2424
D. J. Dixon et al.
LETTER
(18) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(19) (R)-5-Hydroxy-4,4-dimethyl-hept-2-enoic Acid tert-
Butyl Ester (13).
+4.9 (c 1.0, CHCl3). 1H NMR (400 MHz): d = 6.87 (1 H, d,
J = 16.0 Hz, CH=CH), 5.72 (1 H, d, J = 16.0 Hz, CH=CH),
3.24 [1 H, br dd, J = 10.4, 2.0 Hz, CH(OH)], 1.55 [1 H, m,
CH(OH)CHaHb], 1.48 [9H, s, C(CH3)3], 1.24 [1 H, m,
CH(OH)CHaHb], 1.05 [6 H, s, C(CH3)2], 0.98 (3 H, t, J = 7.3
Hz, CH2CH3). 13C NMR (100 MHz): d = 166.3 (C), 154.1
(CH), 121.3 (CH), 80.3 (C), 80.0 (CH), 41.7 (C), 28.1 (CH3),
24.7 (CH2), 22.8 (CH3), 22.4 (CH3), 11.2 (CH3). IR (film):
To a suspension of NaH (17 mg, 0.42 mmol, 60% in mineral
oils) in THF (1 mL) was added tert-butyl diethylphos-
phonoacetate (0.12 mL, 0.5 mmol) at 0 °C. A solution of 4a
(55 mg, 0.28 mmol) in THF (1 mL) was added dropwise and
stirred for 20 min. The reaction was then filtered through a
plug of silica (4 cm × 4 cm) and eluted with Et2O.
Concentration under reduced pressure followed by flash
n
max = 3418 (br), 2968, 1715, 1696, 1646, 1461, 1367, 1317,
1160, 976 cm–1. MS (ESI): m/z calcd for C13H25NO3 :
246.2064. Found: 246.2063 [MH+].
+
column chromatography eluting with hexane–Et2O (20:1 to
(20) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc.
Chem. Res. 1998, 31, 9.
25
1:5) gave (R)-13 as a colourless oil (61 mg, 97%). [a]D
=
Synlett 2005, No. 16, 2420–2424 © Thieme Stuttgart · New York