Highly stereoselective oxy-Michael additions to α,β- disubstituted nitro olefins: Asymmetric synthesis of pseudo-norephedrine derivatives and THP protected α-hydroxy ketones

Article abstract of DOI:10.1039/b406804c

The "naked" anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to α,β-disubstituted nitro olefins to give the THP* protected Henry products with excellent (95→98% de) stereocontrol at the β-position and moderate (up to 3:1) stereo

Full text of DOI:10.1039/b406804c

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A R T I C L E
Highly stereoselective oxy-Michael additions to a,b-disubstituted
nitro olefins: asymmetric synthesis of pseudo-norephedrine
derivatives and THP* protected a-hydroxy ketones†
David J. Buchanan, Darren J. Dixon* and Felix A. Hernandez-Juan
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: djd26@cam.ac.uk; Fax: +44 336 362; Tel: +44 763 965
Received 5th May 2004, Accepted 30th July 2004
First published as an Advance Article on the web 22nd September 2004
The “naked” anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to a,b-disubstituted nitro
olefins to give the THP* protected Henry products with excellent (95→98% de) stereocontrol at the b-position and
moderate (up to 3:1) stereocontrol at the a-position in favour of the syn-diastereoisomer. Nitro group reduction
with in situ N-Boc protection and THP* removal provides a,b-disubstituted ethanolamine derivatives, while
treatment with tetrapropylammonium perruthenate gives THP* protected a-hydroxy ketone derivatives in high
diasteromeric excess.
Table 1 Dependence of alpha stereocontrol on nature of the acid
quench
Introduction
The stereoselective oxy-Michael addition to nitro olefin accep-
tors provides a direct route to O-protected Henry products.1–3
When the chiral water equivalent is readily available in both
enantiomeric forms, it imparts high levels of stereocontrol
on addition, and becomes a desirable protecting group, this
approach can be considered as complementary in many respects
to the enantioselective nitro aldol reaction.4
We have recently reported the highly diastereoselective oxy-
Michael addition of the “naked” anion of (S)-6-methyl delta
lactol to b-substituted nitro olefins. This work provided the basis
of an efficient method for the synthesis of enantiomerically
enriched amino alcohol products after nitro group reduction
and removal of the THP* ether protecting group.
Entry
HA
2a:2ba
1
2
3
4
5
6
MeOH
NH4Cl
2,4-dinitrophenol
CF3COOH
CCl3COOH
CH3COOH
1:1.4
1.2:1
1:1
1.1:1
1:1.2
3.0:1
1
a Measured by analysis of the 400 or 600 MHz H nmr spectra of the
crude reaction product.
Encouraged by these results we were keen to investigate
whether the high levels of control and reaction efficiency could
be maintained in additions to a-substituted nitro olefin accep-
tors as the products of these reactions would have considerable
utility in synthesis. Here we wish to report our findings on the
addition of the naked lactol anion to a,b-disubstituted nitro
olefins and the application of these additions to the synthesis
of a,b-disubstituted ethanolamine derivatives5 and to protected
a-hydroxy ketones via Nef-type oxidation.
Results and discussion
Preliminary studies using the “naked” alkoxide of (S)-6-methyl
delta lactol 1 [formed by deprotonation with KHMDS (1.0 eq)
and subsequent addition of 18-crown-6 (1.0 eq)] were performed
on E-b-methyl-b-nitro styrene6 at −78 °C in THF to ascertain
reactivity and diastereocontrol at the three newly formed
stereocentres on quenching with a range of proton sources. The
screened acids included, acetic acid, trichloroacetic acid, tri-
fluoroacetic acid, methanol, 2,4-dinitrophenol and ammonium
chloride and were added neat via syringe or as solutions in THF
or water as appropriate. In all cases only two, of the possible
eight diastereomeric products were observed in the reaction
mixtures post aqueous work-up. In all-but-one case, 2a and 2b
were formed in 1:1 ratio. The optimal conditions used neat
acetic acid (2.0 eq) injected directly into the −78 °C reaction mix-
ture and gave rise to 2a and 2b in the ratio of 3:1, respectively
(Scheme 1, Table 1). These two products, 2a and 2b, epimeric
at the a-centre were consistent with the lactol anion reacting
Scheme 1 Reagents and conditions: (a) KHMDS (1.0 eq),
THF, −78 °C then 18-crown-6 (1.0 eq) then (E)-PhCHC(Me)NO2
(0.67 eq), 1 h. (b) HA, −78 °C.
predominantly cis across the (S)-6-methyl tetrahydropyranyl
(THP*) ring and to the Re-face of the nitro olefin acceptor in
agreement with our previous work.2 Unambiguous proof of
the relative syn-stereochemistry of 2a was established by single
crystal X-ray diffraction.‡
‡ Crystal data for 2a. C15H21N1O4, M = 279.33, monoclinic, a =
19.5297(6), b = 5.7494(2), c = 13.7124(6) Å, U = 1485.65(9) Å3, T =
180(2) K, space group C2, Z = 4, l(Mo–Ka) = 0.090 mm−1, 3197
reflections measured. The final R1(F2) was 0.0708 (all data). The
Flack parameter was 0.9(12); Crystal data for 5a. C14H21N1O4S1, M =
299.38, monoclinic, a = 21.0458(9), b = 5.9725(2), c = 13.3797(7) Å,
U = 1578.12(12) Å3, T = 180(2) K, space group C2, Z = 4, l(Mo–Ka) =
0.217 mm−1, 3195 reflections measured. The final R1(F2) was 0.0836
(all data). The Flack parameter was 0.06(13). CCDC reference
numbers 238145 for 5a and 238146 for 2a. See http://www.rsc.org/
suppdata/ob/b4/b406804c/ for crystallographic data in .CIF or other
electronic format.
† Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for all new compounds. See
http://www.rsc.org/suppdata/ob/b4/b406804c/
2 9 3 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 3 2 – 2 9 3 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Yields and selectivities for the addition of the “naked” lactol
alkoxide to a,b-unsaturated nitro olefins
Entry
R1, R2
de (b)a
dr (a)a
Adduct
Yieldb
1
2
3
4
, Me
, Me
, Me
, Et
>98%
>98%
96%
3.0:1
2.8:1
2.0:1
2.8:1
2
3
4
5
99%
89%
66%
84%
Fig. 1 X-ray crystal structures of compounds 2a and 5a.
>98%
As well as demonstrating that the “naked” delta lactol
anion is capable of addition to a,b-disubstituted nitro olefins
with high stereocontrol, these reactions provide access to
important products in only a few steps. Thus, nickel boride
reduction7 and in situ N-Boc protection of isomerically pure
2a gave 9 in good yield. Removal of the THP* using polymer
supported sulfonic acid resin and methanol occurred smoothly
and afforded N-Boc–pseudo-norephedrine 10. The relative
5
, Et
, Et
97%
2.6:1
6
7
78%
6
7
96%
95%
2.3:1
1:1
89%
78%
, Et
8
and absolute stereochemistry of 10 was confirmed by com-
1
a Measured by analysis of the 400, 500 or 600 MHz H nmr spectra of
1
parison of the H nmr8 and the specific rotation [a]25 −35.1
the crude reaction product. b Reaction yield after purification.
D
(c 1.0, CHCl3) [Lit.;9 [a]20 −35.2 (c 0.47, CHCl3)] with the
D
literature and was consistent with the stereochemistry of
the oxy-Michael adduct. The same sequence, when applied
to diastereoisomerically pure 7a, afforded N-Boc protected
a-ethyl, b-furanyl ethanolamine product 12 in good yield
over the three step transformation.10 Gratifyingly, no loss of
stereochemical integrity was observed in either of the nickel
boride reduction reactions (Scheme 3).
The optimal conditions were applied to a range of a,b-
disubstituted nitro olefins and the results are presented in
Scheme 2, Table 2. The diastereoselectivity at the b-centre
was uniformly good to excellent for branched alkyl, aryl and
heteroaryl groups with the best control arising in the aryl and
heteroaryl cases [95→98% de (b)]. The selectivity at the a-
centre ranged from absent in one case (entry 7, dr (a) = 1:1)
to moderate (entries 1–6, dr (a) = 2.0–3.1:1) in favour of the
syn-diastereoisomer.§ The reaction yields were uniformly good
to excellent.¶
Scheme 2 Reagents and conditions: (a) 1, KHMDS (1.0 eq),
THF, −78 °C, then 18-crown-6 (1.0 eq) then (E)-nitro olefin (0.67 eq),
1 h. (b) AcOH (2 eq), −78 °C.
Single crystal X-ray diffraction allowed unambiguous deter-
mination of the stereochemistry of product 5a.‡ Taken with
the known stereochemistry of 2a and through analysis of the
1H nmr spectra of both relative to their minor anti-diastereo-
isomeric products, it was possible by comparison to assign the
stereochemistry of all the products in Table 2 (Fig. 1).
Subjection of single diastereoisomers 2a, 5a and 5b to simu-
lated post-quench end-of-reaction conditions followed by the
usual reaction work up resulted in little (<5%) or no epimeri-
sation at the a-centre, indicating the observed a-selectivity is a
result of kinetic control.
Scheme 3 Reagents and conditions: (a) NiCl2·6H2O, NaBH4, MeOH,
THF, 0 °C then Boc2O, 0 °C to rt. (b) MP–TsOH II, MeOH, rt.
The Nef oxidation of nitro alkanes to ketones is frequently
performed under either strongly basic or strongly acidic (or
Lewis acidic) conditions.11 Both extremes of conditions are
incompatible with the oxy-Michael adducts listed in Table 2.
Under acidic conditions, the THP* is labile to deprotection,
whereas under basic conditions at high temperatures, the
adducts are prone to degradative retro-Michael addition.
However, oxidation of O-THP* protected Henry products
2, 3, 5, 6 was possible under near-neutral conditions. Thus
treatment with excess tetrapropylammonium perruthenate12
(TPAP) in DCM at room temperature overnight furnished
the THP* protected a-hydroxy ketones in good to excellent
yields and with little or no compromise to the stereochemical
§ In related work, a predominance for the anti-diastereoisomers was
noted when O-benzyl protected Henry products were treated with
potassium tert-butoxide in THF at −78 °C followed by quenching with
AcOH; see ref. 5.
¶ Interestingly, in the cases of adducts 2 and 3 only, purification by
filtration through silica gel and evaporation facilitated a dynamic
epimerisation—crystallisation process resulting in the isolation of 2a
and 3a as essentially single diastereoisomeric products in high yield.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 3 2 – 2 9 3 4
2 9 3 3

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Table 3 Results of TPAP mediated Nef-type oxidation
Acknowledgements
R1
R2
Product
dea
Yield
We gratefully acknowledge GlaxoSmithKline (to djb), EPSRC
(to fah-j), Dr J. E. Davies for X-ray crystallography, EPSRC
National Mass Spectrometry Service Centre, Swansea and
Prof. S. V. Ley.
Entry
1
Me
Me
13
14
>98%
>98%
66%
50%
2b
References and notes
3
Et
15
98%
48%
1 (a) D. Enders, A. Haertwig, G. Raabe and J. Runsink, Angew.
Chem., Int. Ed., 1996, 35, 2388–2390; (b) D. Enders, A. Haertwig,
G. Raabe and J. Runsink, Eur. J. Org. Chem., 1998, 1771–1792;
(c) D. Enders, A. Haertwig and J. Runsink, Eur. J. Org. Chem., 1998,
1793–1802.
2 (a) N. J. Adderley, D. J. Buchanan, D. J. Dixon and D. I. Lainé,
Angew. Chem., Int. Ed., 2003, 42, 4241–4244; (b) D. J. Buchanan,
D. J. Dixon, M. S. Scott and D. I. Lainé, Tetrahedron: Asymmetry,
2004, 15, 195–197.
4
Et
16
98%
83%
a Measured by analysis of the 400, 500 or 600 MHz H nmr spectra
of the purified reaction product. b Reaction performed for 3 h at rt in
the presence of 2,6-di-tert-butyl-4-methylpyridine (1.0 eq).
1
3 For early studies into the oxy-Michael (racemic, unstereoselective)
see J. L. Duffy, J. A. Kurth and M. J. Kurth, Tetrahedron Lett.,
1993, 34, 1259–1260 and references cited therein.
4 (a) H. Sasai, N. Itoh, T. Suzuki and M. Shibasaki, Tetrahedron
Lett., 1993, 34, 855–858; (b) H. Sasai, N. Itoh, T. Suzuki, S. Arai
and M. Shibasaki, Tetrahedron Lett., 1993, 34, 2657–2660;
(c) R. Chinchilla, C. Najera and P. Sanchez-Agullo, Tetrahedron:
Asymmetry, 1994, 5, 1393–1402; (d) M. Shibasaki, H. Sasai and
T. Arai, Angew. Chem., Int. Ed., 1997, 36, 1236–1256; (e) H. Sasai,
T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh and M. Shibasaki,
J. Org. Chem., 1995, 60, 7388–7389; (f) B. M. Trost, V. S. C. Yeh,
H. Ito and N. Bremeyer, Org. Lett., 2002, 4, 2621–2623.
5 A. Kamimura and N. Ono, Tetrahedron Lett., 1989, 30, 731–734.
6 a,b-Disubstituted nitro olefins are readily prepared by the
condensation of nitroalkanes with aldehydes. See for example:
Y. Kawai, Y. Inaba and N. Tokitoh, Tetrahedron: Asymmetry,
2001, 12, 309–318.
7 (a) A. Nose and T. Kudo, Chem. Pharm. Bull., 1981, 29, 1159–1161;
(b) A. Nose and T. Kudo, Chem. Pharm. Bull., 1988, 36, 1529–1533;
(c) A. Nose and T. Kudo, Chem. Pharm. Bull., 1989, 37, 816–818;
(d) J. O. Osby and B. Ganem, Tetrahedron Lett., 1985, 26,
6413–6416.
8 P. Besse, H. Veschambre, M. Dickman and R. Chênevert, J. Org.
Chem., 1994, 59, 8288–8291.
Scheme 4 Reagents and conditions: (a) TPAP (xs), CH2Cl2, RT, o/n.
integrity of the b-stereocentre formed in the oxy-Michael
reaction (Scheme 4, Table 3).
This method worked well, albeit slowly, for the b-aryl and
b-heteroaryl oxy-Michael adducts, but interestingly no reaction
was observed when the b-alkyl adduct 8 was subjected to the
same reaction conditions.
In summary, the naked alkoxide of (S)-6-methyl delta
lactol adds efficiently and with excellent b-selectivity to a,b-
disubstituted nitro olefins. Diastereofacial protonation of the
generated nitronate anions with acetic acid allows moderate
control of the a-stereocentre (1:1→3:1 favouring the syn-
products). These materials can be reduced with nickel boride
to give the amino alcohol products, or oxidized via the Nef-type
reaction to give the protected a-hydroxy ketones in high dia-
stereoisomeric excess. The origins of stereocontrol at both the
a- and b-centres, as well as various applications of this work
will be reported in due course.
9 C. Agami, F. Couty, L. Hamon and O. Venier, Bull. Soc. Chim.
Fr., 1995, 132, 808–814.
10 The stereochemistry of 12 was predicted by analogy with that
of 10.
11 R. C. Larock, Comprehensive Organic Transformations; VCH
Publishers, Inc., 1989, pp. 603–604.
12 Y. Tokunaga, M. Ihara and K. Fukumoto, J. Chem. Soc., Perkin
Trans. 1, 1997, 207–209.
2 9 3 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 3 2 – 2 9 3 4