Chromium(II) chloride-mediated coupling reactions of Garner aldehyde with allyl bromides: Facile asymmetric synthesis of (2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine

Article abstract of DOI:10.1039/a805998e

Chromium(II) chloride-mediated coupling reactions of 1,1-dimethylethyl (S)- and (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylates [(S)- and (R)-Garner aldehydes] (1a,b) with allyl bromides 2a-c proceeded with moderate to good stereoselectivity to give t

Full text of DOI:10.1039/a805998e

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Chromium(II) chloride-mediated coupling reactions of Garner
aldehyde with allyl bromides: facile asymmetric synthesis of
(2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine
Yutaka Aoyagi, Haruko Inaba, Yukiko Hiraiwa, Asako Kuroda and Akihiro Ohta*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, Japan. Fax: ϩ81-426-76-3040; E-mail ohtaa@ps.toyaku.ac.jp
Received 30th July 1998, Accepted 30th September 1998
Chromium() chloride-mediated coupling reactions of 1,1-dimethylethyl (S)- and (R)-4-formyl-2,2-dimethyl-
oxazolidine-3-carboxylates [(S)- and (R)-Garner aldehydes ] (1a,b) with allyl bromides 2a–c proceeded with moderate
to good stereoselectivity to give the corresponding homoallyl alcohols 3a–d in good yields. The homoallyl alcohol 3b
was easily transformed to (2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine 8.
TMEDA did not give better chemical yields but did give better
Introduction
diastereoselectivity (entry 12 in the Table). No beneficial effect
Recently, a lot of attention has been devoted to the design and
was observed when HMPA and Et2AlCl were added (entries 10
synthesis of azasugars such as polyhydroxylated pyrrolidines,1,2
and 13 in the Table). Methods B and C were also found to give
pyrrolizidines,3 indolizidines,4 and quinolizidines,5 in view of
very poor diastereoselectivity (entries 14 and 15 in the Table).
their remarkable inhibitory activity against glucosidases and
The reaction conditions of entry 4 were found to be best in
mannosidases.6 Therefore, they are known to possess a variety
of beneficial therapeutic effects against tumor metastasis,7
Table 1 Coupling reactions of 1a with 2a under different reaction
metabolic disorder,8,9 and viral infections.10
conditions
During our investigation on one-electron reducing agents,
O
OH
such as low valent tantalum (LVT)11 and samarium diiodide
(SmI2),12–16 we decided to explore chromium chloride-mediated
coupling reactions (Hiyama–Nozaki reaction),17–19 which pro-
ceeded under mild conditions to give the corresponding
coupling products. Though allylation of (S)- and (R)-Garner
aldehydes (1a,b)20–22 with allyl metals such as chiral titanium23
and Grignard reagents24 has been reported, there is little
known about the Hiyama–Nozaki reaction between allyl
halides and 1a,b. The Garner aldehyde is a well known chiral
synthon and has been converted to β,γ-alkynylglycine deriv-
atives,25 γ-hydroxy-β-amino alcohols and β-hydroxy amino-
acids,26 sphingosines,24 azasugars,27 fulleropyrrolidines,28
and more complex natural products such as phorboxazole,29
micropines,30 and curacin A.31 (S)-Garner aldehyde (1) and
its antipode [(R)-1] can be easily prepared from -serine20,21 and
-serine,26 respectively. To demonstrate further the versatility of
these aldehydes, we decided to develop the coupling reactions
of 1a,b and the facile transformation of the coupling products
to biologically active compounds.
H
CrCl2
Br
2a
O
NBoc
O
NBoc
Me
1a
Me
Me
Me
syn-3a
OH
O
NBoc
Me
Me
anti-3a
Total
yield
(%)b
Entry Methoda
T/ЊC
Ϫ78
0
0
rt
Solvent
Additive
Ratioc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
A
A
A
A
A
A
A
A
A
A
A
A
A
B
THF
THF
THF
THF
THF
none
none
none
none
none
none
none
none
none
Et2AlCl
ButOH
N.R.
5
—
—
In this paper, we would like to report the chromium()
chloride-mediated coupling reactions of 1a,b with allyl halides
and a facile transformation of the coupling products to
(2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine.
36d
98
54
72e
0
45/55
37/63
49/51
49/51
—
48/52
45/55
40/60
45/55
27/73
32/68
46/54
45/55
40
reflux THF
rt
rt
rt
rt
rt
rt
0
CH2Cl2
DMF
toluene
THF
THF
THF
THF
THF
THF
61
56
60
42
Results and discussion
First, we examined the coupling reactions of 1a with allyl
bromide (2a) under several reaction conditions. The addition of
TMEDA 18f
HMPA
none
25f
88
80
O
O
rt
rt
C
none
H
H
a Method A: To a THF suspension of CrCl2, a mixture of 1a and 2a was
added; Method B: 1a was added to a mixture of CrCl2 and 2a; Method
C: 2a was added to a mixture of CrCl2 and 1a. b Isolated yields. c Ratio
(syn/anti) was determined by HPLC by using chiral column AD (Daisel
Chemical Co Ltd.). d Reaction time is 72 h. e Reaction time is 0.2 h.
f Reaction time is 15 h.
O
NBoc
Me
O
NBoc
Me
Me
Me
(S)-Garner aldehyde (1a)
(R)-Garner aldehyde(1b)
Fig. 1
J. Chem. Soc., Perkin Trans. 1, 1998, 3975–3978
3975

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O
terms of both chemical yield and diastereoselectivity. Namely,
to a suspension of chromium chloride in THF, a THF solution
of 1a and crotyl bromide (2b) was added at room temperature
under an argon atmosphere to give the corresponding coupling
products in 98% total yield and 37:63 dr. At this stage, the
diastereomers could not be separated by silica gel flash chrom-
atography. To synthesize the title pyrrolidine alkaloid 8, using
1b, which was prepared from nonproteinogenic -serine, the
coupling reaction was carried out. To determine the structures
of the coupling products and separate the diastereomers (4b1
and 4b2), cyclic O,OЈ-acetals 4b1 and 4b2 were prepared from
the coupling products (3b) and the coupling constants were
measured by 1H NMR.32
H
Me
Br
O
NBoc
2b
Me
Me 1a
80%
(85:15)
i)
HO
HO
Me
Me
O
NBoc
Me
O
NBoc
Me
3c1
Me
Me
3c2
O
(expected)
OH
ii),iii)
ii),iii)
53%
52%
H
CrCl2
98%
i), ii)
61%
Br
O
NBoc
Me
O
NBoc
Me
Me
O
Me
O
Me
O
Me
O
Me
Me
(R)-1
3b
Me
Me
O
Me
O
Me
O
BocHN
Me
(expected)
BocHN
Me
4c2
4c1
O
O
63:37
NHBoc
NHBoc
4b2
Me
4b1
H
Scheme 1 Coupling reaction of 1b with 2a and transacetalization of
homoallyl alcohol 3b to compound 4b1 and b2. Reagents and conditions:
i) p-TsOHؒH2O; ii) 2,2-dimethoxypropane, p-TsOHؒH2O.
Me
Br
O
NBoc
Me
2c
Me
1a
Based on the coupling constants (J4,5) between the protons at
C-4 and C-5 of the compounds 4b1 (major diastereomer) and
4b2 (minor diastereomer), of 10.0 Hz and 1.9 Hz respectively,
the structures of 4b1 and 4b2 were determined as shown in
Scheme 1. Further, the physical and spectral data were identical
with those reported.32
60% i)
HO
Me
Me
ii),iii)
45%
O
O
Me
Me
O
NBoc
Next, we tried to examine the coupling reactions of allyl
bromides 2b,c with 1a under the reaction conditions of entry 11
in the Table (Scheme 2). The coupling reaction of 1a with 2b
gave a mixture of two diastereomers in 80% total yield, which
were easily separated. To determine the structures, each coupling
product (3c1 and 3c2) was converted to the cyclic O,OЈ-acetal
(4c1 and 4c2).
Me
Me
BocHN
Me
Me
4d
3d
Scheme 2 Chromium() chloride-mediated coupling reactions of 1a
with substituted allyl bromides (2b and c). Reagents and conditions: i)
CrCl2, THF, 2.5 h; ii) p-TsOH, MeOH; iii) 2,2-dimethoxypropane,
p-TsOH.
The coupling constants (J4,5) between the protons at C-4
and C-5 of compounds 4c1 (major diastereomer) and 4c2 (minor
diastereomer) were 9.6 Hz and 2.0 Hz, respectively. By
comparison with previous work,22 the relative configuration of
C-4 and C-5 on the 1,3-dioxolane ring could be determined.
Namely, since the H–H coupling constant (J4,5) is known to be
about 9 Hz for the trans configuration and ca. 1.5 Hz for the
cis one,22 the relative configuration of C-4 and C-5 in the
compound 4c1 has to be trans and that in 4c2 cis. The physical
data of 4c2 were identical with those reported.22 So, the
structure of 4c2 has been established. In general, it is known
that the Nozaki–Hiyama reactions of aldehydes with crotyl
halides proceed via the chair form transition state to give only
anti isomers in good yields.33 Though in this paper we have not
determined the structure of 4c1 completely, it is reasonable to
think that the relative configuration between C-4 and C1Ј is anti
and therefore the configuration between C-4, C-5, and C-1Ј in
the compound 4c1 is all-trans. The structures of 3c1 and 3c2 are
deduced to be as shown in Scheme 2.
As a result, the chromium mediated coupling reactions of
(S)- and (R)-Garner aldehydes (1a,b) with allyl bromides (2a,
b, and c) proceeded via a Cram transition state to give anti-
compounds predominantly, as for the coupling reactions of
glyceraldehyde with allyl bromides.34,35
With the diastereomerically pure acetal 4b1 in hand, we
examined the transformation of compound 4b1 to the pyrro-
lidine derivative. Ozonolysis of 4b1, followed by reductive
treatment of the ozonide with sodium borohydride36 gave the
alcohol 5 in 93% yield. After tosylation of the alcohol, the
treatment with sodium hydride gave the corresponding pyrro-
lidine (7) in 84% yield.
Finally, removal of the acetonide was accomplished under
acidic conditions to give (2R,3S)-3-hydroxy-2-hydroxymethyl-
pyrrolidine (8) in 76% yield. The melting point, optical rotation,
and some spectral data such as 1H NMR and IR of synthetic 8
were completely identical with those reported.37
In summary, we have described the chromium() chloride
coupling reactions of 1a,b with allyl bromides. The coupling
reaction proceeded in good chemical yields to give the anti-
products predominantly. Further, the effective transformation
of the coupling product 4b1 to (2R,3S)-3-hydroxy-2-hydroxy-
methylpyrrolidine (8) was accomplished. The route included
8 steps from 1a and the overall yield was 23%. As both
enantiomers of 1a,b were prepared easily and are commercially
available, this synthetic procedure promises easy access to the
The coupling reaction of 1a with isopentenyl bromide (2c)
gave a sole product in 60% yield. After conversion of the
1
coupling product 3d to 4d, the H NMR spectrum of com-
pound 4d was measured. The coupling constant (J4,5) between
the protons at C-4 and C-5 of compound 4d was 8.8 Hz, and
therefore, the orientation between 5-NH group and 4-alkoxy
group might be anti.
3976
J. Chem. Soc., Perkin Trans. 1, 1998, 3975–3978

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products. As the diastereomeric mixture of the coupling
products could not be separated at this stage, this mixture was
submitted to the next reaction.
Me
O
Me
O
Me
O
Me
O
i),ii)
To a MeOH solution (85 cm3) of the coupling product 3
(9.1 mmol), p-TsOHؒH2O (0.48 g, 2.5 mmol) was added. The
resulting mixture was stirred at room temperature for 2 h. After
evaporation of the solvent, sat. NaHCO3–H2O (1:1) solution
(30 cm3) was added to the residue. The aqueous phase was
extracted with AcOEt (30 cm3 × 3), and the combined organic
layer was washed with sat. NaCl (40 cm3 × 3), dried over
Na2SO4, filtered, and evaporated to give an oily residue. The
residue was purified with silica gel flash chromatography
(hexanes:AcOEt = 1:1) to give a diastereomeric mixture of the
amino diols as an oil (1.75 g, 83% yield).
93%
OH
NHBoc
4b1
5
NHBoc
iii)
95%
Me
Me
O
Me
O
O
Me
iv)
84%
O
OTs
N
Boc
7
NHBoc
6
To a solution of the amino diols (1.63 g, 7.1 mmol) and 2,2-
dimethoxypropane (100 cm3), p-TsOHؒH2O (0.28 g, 1.49 mmol)
was added. After the reaction mixture was stirred at room
temperature for 2 h, sat. NaHCO3 (50 cm3) was added. The
aqueous phase was extracted with AcOEt (50 cm3 × 3), and the
organic layer was dried over Na2SO4, filtered, and evaporated to
give an oily residue, which was purified with MPLC (hexanes:
Et2O:acetone = 20:1:1) to give compound 4b2 (less polar
component: 0.54 g, 28% yield) and 4b1 (0.88 g, 46% yield),
respectively. The physical data and spectral data were identical
with those reported.32
v)
76%
HO
HO
+
Cl–
N
H2
8
Scheme 3 Transformation of cyclic acetal 4b1 to (2R,3S)-3-hydroxy-2-
hydroxymethylpyrrolidine 8. Reagents and conditions: i) O3, MeOH; ii)
NaBH4; iii) TsCl, Et3N, DMAP; iv) NaH; v) 5 M HCl.
Preparation of O,OЈ-acetals 4c1
enantiomer of compound 8. Now, using the coupling products,
we are trying to prepare polysubstitued pyrrolidine antibiotics
and will report the results in the near future.
The coupling product 3c1 (0.184 g, 68%) was obtained from 1b
(0.229 g, 1.0 mmol) and 2a (0.270 g, 2.0 mmol). The homoallyl
alcohol 3c1 (0.662 g, 2.3 mmol) was transformed to compound
4c1 (0.344 g, 53%) according to the method for the synthesis
of 4b1 and 4b2. Colorless solid (36% yield from 1a); mp 81 ЊC
(CH2Cl2); [α]D ϩ15.6 (CHCl3, c 0.90); νmax/cmϪ1 (KBr) 1680
Experimental
General methods
(C᎐O); δ (pyridine-d , 400 MHz, 300 K) 6.12 (1H, ddd, J 17.0,
᎐
H
5
10.3, and 8.2), 5.26 (1H, d, J 17.0), 5.17 (1H, dd, J 10.3 and 2.1),
4.09 (1H, dd, J 11.8 and 2.0), 3.96 (1H, dd, J 11.8 and 1.9), 3.91
(1H, m), 3.78 (1H, dd, J 9.6 and 2.0), 2.75 (1H, m), 1.52 (9H, s),
1.47 (6H, s), 1.19 (3H, d, J 6.9); m/z (CI) 286 (Mϩ ϩ H) (Found:
C, 62.95; H, 9.60; N, 4.90. C15H27NO4 requires C, 63.13; H,
9.54; N, 4.91%).
Melting points were measured on a Yanagimoto micro melting
point apparatus and are uncorrected. 1H (300 MHz) and 13C (75
MHz) NMR spectra were obtained on a Varian Gemini A-300.
Chemical shifts are reported in parts per million downfield
from the internal standard. Infrared spectra were recorded on a
Japan Spectroscopic Co.A-100 and were recorded as λmax in
cmϪ1. Optical rotations were obtained on a Japan Spectroscopic
Co.DIP-360. Specific rotations [α]D are reported in degrees per
decimetre at 25 ЊC and the concentration (c) is given in grams
per 100 mL in the specified solvent. Mass spectra were obtained
on a Hitachi M-80B or Fisons VG Auto Spec instrument.
Column chromatography and flash chromatography were
performed with Merck silica gel Kieselgel 60 (230–400 mesh).
MPLC was conducted with a Merck silica gel Kieselgel 60.
Preparative thin layer chromatography (PTLC) was carried
out with Merck Kieselgel 60 F254 precoated glass (either 0.25
or 0.50 mm). All solvents were commercial grade and were
distilled and dried as follows: tetrahydrofuran (THF) and
diethyl ether from sodium benzophenone ketyl; MeCN from
P2O5; CH2Cl2 from CaH2. Garner aldehydes were prepared in
accordance with the reported manner by Garner et al.20,21
Chromium() chloride was purchased from Aldrich Chemical
Co. and used without further purification.
Preparation of O,OЈ-acetals 4c2
The coupling product 3c2 (0.032 g, 12%) was obtained from1b
(0.229 g, 1.0 mmol) and 2a (0.270 g, 2.0 mmol). The homoallyl
alcohol 3c2 (0.286 g, 1.0 mmol) was transformed to compound
4c2 (0.148 g, 52%) according to the same procedure for the
synthesis of 4b1 and 4b2. Colorless oil (6.2% yield from 1a);
[α]D Ϫ7.72 (CHCl3, c 1.01). The physical and spectral data of
compound 4c2 were identical with those reported.22
Preparation of O,OЈ-acetals 4d
The title acetal was prepared from 1a (0.229 g, 1.0 mmol) and
2c (0.298 g, 2.0 mmol) in 2 steps. Colorless solid [27% yield
from (S)-1]; mp 65 ЊC (CH2Cl2); [α]D ϩ22.0 (CHCl3, c 0.30);
νmax/cmϪ1 (KBr) 1700 (C᎐O); δH (pyridine-d5, 300 MHz, 300 K)
᎐
7.75 (1H, d, J 8.6), 6.17 (1H, dd, J 17.6 and 10.8), 5.15 (1H, dd,
J 17.6 and 1.4), 5.09 (1H, dd, J 10.8 and 1.4), 4.17 (1H, m), 3.98
(1H, dd, J 11.5 and 4.8), 3.80 (1H, dd, J 11.5, and 5.2), 3.73
(1H, d, J 8.8), 1.50 (9H, s), 1.45 (3H, s), 1.41 (3H, s), 1.23 (3H,
s), 1.20 (3H, s); m/z (CI) 300 (Mϩ ϩ H) (Found: C, 64.30; H,
9.72; N, 4.68. C16H29NO4 requires C, 64.18; H, 9.76; N, 4.68%).
Preparation of O,OЈ-acetals 4b1 and 4b2
A THF solution (5 cm3) of 1b (0.229 g, 1.0 mmol) and 2a (0.242
g, 2.0 mmol) was added dropwise to a suspension of CrCl2
(0.61 g, 6.0 mmol) in dry THF (10 cm3). After stirring for 2.5 h
at room temperature, sat. NaHCO3 (10 cm3) was added, and
the organic layer was separated. The aqueous solution was
extracted with AcOEt (2 × 10 cm3). The combined organic
phase was dried over NaSO4, filtered, and evaporated in
vacuo to give an oily residue, which was purified by flash
chromatography (hexanes–AcOEt) to give the coupling
Preparation of alcohol 5
A dry MeOH solution (26 cm3) of compound 4b1 (0.66 g, 2.4
mmol) was bubbled with O3 at Ϫ78 ЊC until the solution turned
blue. Excess O3 was removed by bubbling with an Ar stream.
To the reaction mixture, NaBH4 (0.45 g, 11.8 mmol) was
added carefully at the same temperature and the solvent was
J. Chem. Soc., Perkin Trans. 1, 1998, 3975–3978
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evaporated under reduced pressure to give an oily residue. To
the residue, H2O (16 cm3) was added. The reaction mixture was
stirred at room temperature for 15 h and then extracted with
Et2O (15 cm3 × 3), and the organic layer was dried over Na2SO4,
filtered, and evaporated to give an oily residue, which was puri-
fied by silica gel flash chromatography (hexanes:AcOEt = 2:1)
to give an alcohol 5 as a colorless solid (0.65 g, 98% yield); mp
77 ЊC (hexanes); [α]D Ϫ33.9 (CHCl3, c 1.06); νmax/cmϪ1 (CH2Cl2)
c 0.33) (lit.,36 [α]D ϩ45.7;. The spectral data were completely
identical with those reported.36)
Acknowledgements
The authors are very grateful to the Ministry of Education,
Science and Culture, Japan for Grant-in-Aid.
3450 (OH, NH), 1690 (C᎐O); δH (DMSO-d6, 300 MHz, 340 K)
᎐
References
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11.4), 3.55–3.40 (2H, m), 3.26 (1H, ddd, J 19.2, 9.5, and 6.2),
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(C᎐O); δ (CDCl3, 300 MHz, 300 K) 7.79 (2H, d, J 8.3), 7.35
᎐
H
(2H, d, J 8.3), 4.33 (1H, br d), 4.22–4.04 (2H, m), 3.89–3.83
(1H, m), 3.63 (1H, br t), 3.49 (2H, m), 2.45 (3H, s), 2.10
(1H, m), 1.68 (1H, m), 1.42 (9H, s), 1.32 (3H, s), 1.30 (3H, s);
m/z 430 (Mϩ ϩ H) (Found: C, 55.42; H, 7.25; N, 3.28.
C20H31NO7S requires C, 55.92; H, 7.28; N, 3.26%).
Preparation of pyrrolidine 7
The tosylate 6 (1.56 g, 3.63 mmol) in dry THF (7.0 cm3)
was added dropwise to a dry THF solution (7.0 cm3) of NaH
(ca. 60% dispersion in mineral oil, 0.44 g, 11 mmol) at 0 ЊC.
After stirring at room temperature for 1 h, the resulting reaction
mixture was poured into ice–water (30 cm3) and extracted
with Et2O (30 cm3 × 3). The organic layer was washed with sat.
NaCl (30 cm3 × 3), dried over Na2SO4, filtered, and evaporated
to give an oily residue, which was purified by silica gel flash
chromatography (hexanes:AcOEt = 4:1) to give the corre-
sponding pyrrolidine 7 as a colorless oil (0.78 g, 84% yield);
[α]D Ϫ83 (CHCl3, c 0.63); νmax/cmϪ1 (film) 1700 (C᎐O);
᎐
δH (CDCl3, 300 MHz, 300 K) 4.75–4.4 (1H, br s), 3.86 (1H, br
t), 3.75 (1H, ddd, J 11.0, 9.6, and 5.7), 3.50 (1H, br d), 3.31 (1H,
ddd, J 11.0, 11.0, and 7.0), 3.00 (1H, br t), 2.10 (1H, m), 1.78
(1H, m), 1.50 (9H, s), 1.45 (3H, s), 1.44 (3H, s); m/z 258
(Mϩ ϩ H) (Found: C, 60.38; H, 8.91; N, 5.41. C13H23NO4
requires C, 60.68; H, 9.01; N, 5.44%).
Preparation of (2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine 8
To a MeOH solution (9.0 cm3) of compound 7 (0.257 g, 1.0
mmol), 5.0 M HCl (30 cm3) was added at room temperature.
The reaction mixture was stirred at 60 ЊC for 2 h. The solvent
was evaporated under reduced pressure to give a residue. After
addition of H2O (15 cm3), the mixture was lyophilized to give
a residue, which was evaporated azeotropically with EtOH–
benzene (3:2, 15 cm3). The solid was recrystallized from
EtOH–AcOEt at Ϫ30 ЊC for 5 days to give the title compound 8
hydrochloride as colorless crystals (0.116 g, 76% yield); mp
118 ЊC (EtOH–AcOEt) (lit.,37 mp 120 ЊC); [α]D ϩ43.4 (H2O,
Paper 8/05998E
3978
J. Chem. Soc., Perkin Trans. 1, 1998, 3975–3978