Highly diastereoselective synthesis of β-amino alcohols

Article abstract of DOI:10.1039/b108254j

The highly diastereoselective synthesis of β-amino alcohols was presented. The several substituted β-amino alcohols were synthesized via a novel highly versatile intermediate, involving a combination of N-acyliminium ion and Weinreb amide chemistry. It was found that in the resulting five-membered ring, the allyl group blocks the top face of the molecule, thus forcing the incoming nucleophile to attack from the opposite side of the ring giving rise to the syn-β-amino alcohol as the main product.

Full text of DOI:10.1039/b108254j

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Highly diastereoselective synthesis of ꢀ-amino alcohols
Wim J. N. Meester,a Rudmer van Dijk,a Jan H. van Maarseveen,a Floris P. J. T. Rutjes,*a,b
Pedro H. H. Hermkensc and Henk Hiemstra*a
1
a Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
b Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1,
6525 ED Nijmegen, The Netherlands
c Lead Discovery Unit, NV Organon, P.O. Box 20, 5340 BH Oss, The Netherlands
Received (in Cambridge, UK) 2nd September 2001, Accepted 10th October 2001
First published as an Advance Article on the web 25th October 2001
Several substituted ꢀ-amino alcohols 1 were synthesised in
a diastereoselective manner via the novel highly versatile
intermediate 8b, involving a combination of N-acyl-
iminium ion and Weinreb amide chemistry.
Both N-acyliminium ion chemistry1 and additions of Grignard
reagents to Weinreb (N-methoxy-N-methyl) amides2 are widely
recognised as effective tools to construct CC bonds. A large
variety of π-nucleophiles can be introduced via addition to N-
acyliminium ions, while a virtually infinite number of Grignard
reagents can be applied to functionalise the Weinreb amide.
Considering the extensive experience with N-acyliminium
ion chemistry in our group,3 its combination with Weinreb
technology would further increase its potential to form a broad
range of highly functionalised molecules containing both
oxygen and nitrogen. In this article, we wish to report a straight-
forward synthesis of β-amino alcohols 14 via such a com-
bination, i.e. a subsequent diastereoselective, double addition
of Grignard reagents to Weinreb amides 2,2b,5,6 preceded by the
addition of a suitable nucleophile to the N-acyliminium ion 3
(Scheme 1). In addition, an efficient route towards the key
intermediate 2 starting from benzyl carbamate (4) will be
Scheme 2 Reagents and conditions: (i) MeNHOMeؒHCl, AlMe3, CH2-
Cl2; (ii) 1) KOH, EtOH; 2) diisopropylethylamine (DIPEA), 1,3-diiso-
propylcarbodiimide (DIPCDI), HOBt, MeNHOMeؒHCl; (iii) 4 Å MS,
CH2Cl2, reflux; (iv) p-TsOH, MeOH; (v) BF3ؒOEt2, CH2Cl2.
discussed.
organometallic additions) in three subsequent reaction steps
resulting in highly functionalised compounds.
The most straightforward route to 8b would be to condense
benzyl carbamate 4 with the corresponding hemiacetal 7,
which requires an efficient synthesis of the latter species. It was
found that the best way to synthesise hemiacetal 7 was to start
from fumaroyl chloride (9, Scheme 3); double reaction of the
Scheme 1
In a first approach we synthesised the Weinreb amide 6 from
the corresponding methyl ester 53b,7 (Scheme 2). Slight optimis-
ation of standard conditions2b to construct the Weinreb amide
from methyl ester 5 (4 equiv. of AlMe3 and MeNHOMeؒHCl
and a reaction time of 4 days) resulted in a yield of 70%. An
alternative way of introducing the Weinreb amide in a two step
procedure starting with hydrolysis of methyl ester 5, followed
by reaction with N,O-dimethylhydroxylamine using standard
peptide coupling methodology, appeared to give no improve-
ment with respect to the yield of Weinreb amide 6.8
We then worked on a more elegant route involving the novel
Weinreb amide 8b which contains both precursor function-
alities for N-acyliminium ion and Weinreb amide chemistry.
Hence, via this species three different functionalities can be
introduced (one via N-acyliminium ion chemistry and two by
Scheme 3 Reagents and conditions: (i) MeNHOMeؒHCl, pyr, CH2Cl2;
(ii) 1) O3, CH2Cl2–MeOH; 2) DMS.
acid chloride to form the bis-Weinreb amide 10, followed by
ozonolysis in a CH2Cl2–MeOH solvent mixture gave the desired
hemiacetal 7 in high yield.9
At this point, hemiacetal 7 was coupled to benzyl carbamate
and after acid-catalysed methanolysis the desired N-acyl-
iminium ion precursor 8b was obtained in virtually quantitative
overall yield.10 Allyltrimethylsilane was used as the nucleophile
in the Lewis acid-catalysed N-acyliminium ion reaction to afford
homoallylic carbamate 6 in excellent yield, thus underlining the
usefulness of this versatile intermediate.
DOI: 10.1039/b108254j
J. Chem. Soc., Perkin Trans. 1, 2001, 2909–2911
This journal is © The Royal Society of Chemistry 2001
2909

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Table 1 Grignard additions to Weinreb amide 6
Entry
RMgX
Product
yield
1
2
3
4
5
6
MeMgBr
EtMgBr
11a
11b
11c
11d
11e
11f
97%
78%
86%a
83%
36%
24%
AllylMgBr
᎐
PhC᎐CMgBr
᎐
iPrMgCl
cPentMgCl
Scheme 4
a The corresponding isomerised α,β-unsaturated ketone was also
obtained (10%).
the diene was reacted in a ring-closing metathesis reaction with
Grubbs’ catalyst (Scheme 4).12 After cyclisation, the configur-
ation of the main product could be assigned as the trans-
1
Table 2 Grignard additions to ketone 11a
cyclohexene using a H-NMR NOE experiment. The major
isomer gave an NOE effect of 0.7% of the methyl group upon
irradiation of the α-H proton, whereas in the minor isomer a
2.8% enhancement of the Me signal was observed.
The high diastereoselectivity is consistent with a chelation-
controlled reaction mechanism in which magnesium most
probably chelates between the nitrogen and ketone function of
the starting material. In the resulting five-membered ring 12 the
allyl group blocks the top face of the molecule, thus forcing
the incoming nucleophile to attack from the opposite side of
the ring giving rise to the syn-β-amino alcohol 1c as the main
product.
In conclusion, we have developed efficient syntheses of the
Weinreb amide 7 and the versatile intermediate 8b, which were
successfully applied in the diastereoselective preparation of β-
amino alcohols 1. A combinatorial solid phase approach of the
methodology reported herein is currently under investigation.
Entry
R1MgX
Product
Yield
syn : antia
1
2
3
4
5
6
MeMgBr
EtMgBr
1a
1b
1c
1d
1e
—
72%
82%
89%
9%b
23%
0%
—
> 98 : 2
70 : 30
> 98 : 2
> 98 : 2
—
AllylMgBr
᎐
PhC᎐CMgBr
᎐
iPrMgCl
cPentMgCl
a Ratio determined by 1H-NMR. b The reaction was carried out at
80 ЊC; the deprotected β-amino alcohol was obtained as the main
product (65%, 82 : 18 ratio of syn : anti isomers).
Acknowledgements
This research has been financially supported by the Council
for Chemical Sciences of the Netherlands Organization for
Scientific Research (CW–NWO).
The Weinreb amide 6 was used as a substrate in the diastereo-
selective double addition of Grignard reagents to obtain β-
amino alcohols. The first addition to Weinreb amide 62b,5
yielded, after acidic work-up, the corresponding protected
amino ketones 11 in reasonable to high yields (Table 1). The
best results were obtained by using an excess (3 equiv.) of
the Grignard reagents at room temperature. With one equiv.
of the Grignard reagent, the reaction does not proceed. This
result demonstrates that deprotonation of the carbamate by the
Grignard reagent under these conditions is faster than nucleo-
philic addition.11
On changing from primary to secondary Grignard reagents
the decreasing yields (entries 1–4 to entries 5 and 6) most likely
reflect the increasing steric bulk of the organometallic reagents.
The second addition of a Grignard reagent to the methyl
ketone 11a6 was carried out at lower temperatures using an
excess of the organometallic reagent and yielded α-amino
alcohols 1 in high diastereoselectivity (Table 2). Similarly, the
difference in yields between entries 1–3 and 5 and 6 can be
explained by the increased steric bulk of the Grignard reagent.
The low yield of amino alcohol 1d (entry 4) can be explained by
the need to use a higher reaction temperature (80 ЊC) in order
to circumvent the initial precipitation of the Grignard reagent
at lower reaction temperatures. However, at this higher tem-
perature a side reaction resulted in the formation of 65%
of the Cbz-deprotected amino alcohol (82 : 18 diastereomeric
ratio).
References
1 For a recent review, see: W. N. Speckamp and M. J. Moolenaar,
Tetrahedron, 2000, 56, 3817.
2 (a) S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815;
(b) M. P. Sibi, Org. Prep. Proced. Int., 1993, 25, 15.
3 (a) H. H. Mooiweer, H. Hiemstra and W. N. Speckamp, Tetrahedron,
1989, 45, 4627; (b) E. C. Roos, H. H. Mooiweer, H. Hiemstra and
W. N. Speckamp, J. Org. Chem., 1992, 57, 6769 . For applications
in the area of solid phase chemistry, see: (c) W. J. N. Meester,
F. P. J. T. Rutjes, P. H. H. Hermkens and H. Hiemstra, Tetrahedron
Lett., 1999, 40, 1601; (d ) J. H. van Maarseveen, W. J. N. Meester,
J. N. Veerman, C. G. Kruse, P. H. H. Hermkens, F. P. J. T. Rutjes and
H. Hiemstra, J. Chem. Soc., Perkin Trans. 1, 2001, 994.
4 For a recent review, see: S. C. Bergmeier, Tetrahedron, 2000, 56, 2561.
5 For
a recent example of additions to amino acid-derived
Weinreb amides, see, for example: M. Kratzel, R. Hiessböck and
A. Bernkop-Schnürch, J. Med. Chem., 1998, 41, 2339.
6 For a recent example of additions to α-keto carbamates, see,
for example: M. A. Blaskovich, G. Evindar, N. G. W. Rose,
S. Wilkinson, Y. Luo and G. A. Lajoie, J. Org. Chem., 1998, 63,
3631.
7 U. Zoller and D. Ben-Ishai, Tetrahedron, 1975, 31, 863. Using
an optimised procedure for additions of hemiacetals to carbamates
by R. A. T. M. van Benthem, H. Hiemstra and W. N. Speckamp,
J. Org. Chem., 1992, 57, 6085.
8 All compounds were obtained as analytically pure samples and
adequately characterized using spectroscopic techniques (IR, 1H-
and 13C-NMR and HRMS).
In order to establish the configuration of the diastereo-
isomers and to functionalise the obtained β-amino alcohol 1c,
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9 Experimental procedure for the synthesis of hemiacetal 7: 6.0 mL
(55.5 mmol) fumaroyl chloride and 13.5 g (13.8 mmol) N,O-
dimethylhydroxylamine HCl salt in 50 mL CH2Cl2 were cooled to
0 ЊC and 22.5 mL (278 mmol) pyridine was carefully added to the
reaction mixture. The resulting dark purple reaction mixture was
allowed to warm up to rt and was stirred for 18 h at this temperature.
50 mL of a saturated NH4Cl solution was added and the layers were
separated. The aqueous phase was extracted several times with
CH2Cl2 (20 mL) until the organic phase was colorless. The combined
organic layers were dried (MgSO4), concentrated in vacuo and puri-
fied using flash chromatography (EtOAc–petroleum ether (PE) 50 :
10 Experimental procedure for the synthesis of Weinreb amide 8b using
hemiacetal 7: 200 mg (1.32 mmol) benzyl carbamate and 591 mg
(3.97 mmol) hemiacetal 7 in 7.5 mL CH2Cl2 were heated to reflux
temperature. The reflux condenser was placed on top of a pressure-
equalising dropping funnel filled with 4 Å MS. After refluxing for
18 h the solvent was evaporated to obtain the crude N,O-hemiacetal
8a, which was dissolved in 7.5 mL MeOH. A catalytic amount
(50.0 mg, 0.26 mmol) of p-TsOH was added, the solution was stirred
for 18 h at rt and concentrated in vacuo. The residue was dissolved
in CH2Cl2, washed with a saturated NaHCO3 solution (15 mL), a
saturated NaCl solution (15 mL), dried (MgSO4) and concentrated
in vacuo. The crude product was purified using flash chroma-
tography (EtOAc–PE, 50 : 50) to afford 349 mg (1.24 mmol, 94%)
of 8b. Data for 8b: 1H-NMR (400 MHz, CDCl3) δ 7.34–7.26 (m, 5H,
Ar-H), 6.26 (br s, 1H, NH), 5.77–5.74 (m, 1H, CH), 5.13 (s, 2H,
OCH2), 3.75 (s, 3H, NOCH3), 3.43 (s, 3H, OCH3), 3.19 (NCH3).
13C-NMR (100 MHz, CDCl3) δ 170.0 (CON(OMe)Me), 155.8
(OCON), 135.8, 128.3, 128.0, 127.8 (Ar-C), 85.2 (CH), 66.8
(OCH2), 61.5 (NOCH3), 55.0 (OCH3), 31.9 (NCH3). νmax/cmϪ1
3310, 3032, 2940, 1724, 1681. m/z (FAB) 283.1309 (Mϩ ϩ H.
C13H19N2O5 requires 283.1294).
50
100 : 0) to afford 8.29 g (41.0 mmol, 73%) of bis-Weinreb
amide 10. Data for 10: 1H-NMR (400 MHz, CDCl3) δ 7.40 (s,
2H HC᎐CH), 3.66 (s, 6H, OCH3), 3.20 (s, 6H, NCH3). 13C-NMR
᎐
(100 MHz, CDCl3) δ 165.0 (CO), 130.2 (HC᎐CH), 61.9 (OCH3),
᎐
32.1 (NCH3). νmax/cmϪ1 2971, 1640. m/z (FAB) 203.1053 (Mϩ ϩ H.
C8H15N2O4 requires 203.1032). 4.55 g (22.5 mmol) of the bis-
Weinreb amide 12 was dissolved in 75 mL CH2Cl2–MeOH (1 : 1) and
cooled to Ϫ78 ЊC. O3 was bubbled through the cold solution until
the reaction mixture turned blue, then some O2 was bubbled through
until the reaction mixture turned colorless again and a large excess
of S(CH3)2 (17 mL, 230 mmol) was added. The solution was allowed
to warm up to rt and stirred for 18 h. The solvents were concentrated
in vacuo and the resulting hemiacetal 7 (8.03 g, 42.6 mmol, 95% of
a 1 : 0.5 mixture of 7 and DMSO) was used without further purifica-
11 Reaction of Weinreb amide 6 with 1 equiv. of MeMgBr for 1 h
did not lead to any product formation. Upon addition of
a second equiv. of EtMgBr complete formation of ethyl ketone
11b was observed. This clearly proves that the first equiv. of
the Grignard reagent is consumed by the deprotonation of the
carbamate, while the second equiv. is used for the nucleophilic
addition.
1
tion. Data for 7: H-NMR (400 MHz, CDCl3) δ 5.18 (s, 1H, CH),
4.41 (br s, 1H, OH), 3.73 (s, 3H, NOCH3), 3.44 (s, 3H, OCH3), 3.21
(s, 3H, NCH3), 2.58 (s, 6H, DMSO). 13C-NMR (100 MHz, CDCl3)
δ 168.8 (CO), 90.41 (CH), 61.5 (NOCH3), 54.6 (OCH3), 40.8
(DMSO), 32.3 (NCH3). νmax/cmϪ1 3452, 2941, 1667.
12 For a recent review, see: A. Fürstner, Angew. Chem., Int. Ed., 2000,
39, 3013.
J. Chem. Soc., Perkin Trans. 1, 2001, 2909–2911
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