Asymmetric synthesis of protected α-alkyl-β-amino-δ-hydroxy esters by stereocontrolled elaboration of THYM*

Article abstract of DOI:10.1016/S0040-4039(00)00351-8

Highly diastereoselective internal Michael addition of the carbamate moiety of enoate 1b [derived from asymmetrized tris(hydroxymethyl)methane (THYM*)] leads to oxazinone 4, which can, in turn, be alkylated with moderate to good diastereoselectivity in th

Full text of DOI:10.1016/S0040-4039(00)00351-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3203–3207
Asymmetric synthesis of protected α-alkyl-β-amino-δ-hydroxy
esters by stereocontrolled elaboration of THYM*
Giuseppe Guanti,∗ Alberto Moro and Enrica Narisano
Dipartimento di Chimica e Chimica Industriale dell’Università and CNR Centro di Studio per la Chimica dei Composti
Cicloalifatici ed Aromatici, Via Dodecaneso 31, I-16146 Genova, Italy
Received 13 December 1999; accepted 28 February 2000
Abstract
Highly diastereoselective internal Michael addition of the carbamate moiety of enoate 1b [derived from
asymmetrized tris(hydroxymethyl)methane (THYM*)] leads to oxazinone 4, which can, in turn, be alkylated with
moderate to good diastereoselectivity in the position α to the ester moiety to give protected anti,anti α-alkyl-β-
amino-δ-hydroxy esters. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: intramolecular Michael-type amination; α-alkylation of esters.
β-Amino acids are very valuable compounds: not only do they constitute one of the more obvious
starting materials to β-lactams, but also some of them have pharmaceutical properties or are part of
peptides acting as enzymatic inhibitors or as antitumor agents.1 Several methods are known for the
synthesis of β-amino acids, and most of these can also be applied to the synthesis of non–racemic
products. Among them, the Michael addition of an N-nucleophile to an α,β-unsaturated ester is widely
used,1 with the chirality placed either in the nucleophile2,3 or in the unsaturated ester,4 or in both.5
Tandem or sequential electrophilic attack at the α-carbon has also been studied and further functionalized
β-amino esters1–5 have been successfully achieved.
While, to our knowledge, the intermolecular addition of lithium salts of acylamides to α,β-unsaturated
esters has not been reported, the intramolecular process, involving an allylic or homoallylic carbamate
moiety is well known.6–8
Taking advantage of the synthetic opportunities offered by asymmetrized tris(hydroxymethyl)methane
THYM*, a highly versatile chiral building block recently introduced by us and utilized in many
asymmetric syntheses,9 we planned to use this unit as the starting material for synthesizing some
branched β-amino-δ-hydroxyacids and their α-alkylated derivatives.
To this purpose, we prepared the α,β-unsaturated t-butyl10 ester (R)-1a (E:Z ratio=9:1), starting from
THYM* via oxidation to the corresponding aldehyde and subsequent Wittig olefination,9 and, as a first
∗
Corresponding author. Tel/fax: +39 10 353 6105; e-mail: guanti@chimica.unige.it (G. Guanti)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00351-8
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approach, we studied that addition of the achiral lithium N-benzyltrimethylsilylamide (LSA)11 (Scheme
1). This silylated amine was chosen taking into account the good chemical and stereochemical results
generally obtained when using this nucleophile in similar Michael-type additions.4,11 Unfortunately, in
our case, the outcome was rather discouraging: not only was 2 isolated in rather low chemical yield
(not exceeding 35% when the reaction was run in THF), but also, even at low temperature (−78°C), the
stereochemical control on 1a was disappointingly poor [the diastereoisomeric ratio of 2 was about 3:2 in
favour of the less polar (TLC) isomer] and quite large amounts of amide 3 (derived from 1,2- instead of
1,4-attack) were detected, notwithstanding use of the t-butyl ester. Also, a deconjugated β,γ-unsaturated
ester (derived from deprotonation at the γ position of 1a) was formed,11 along with by-products from the
protecting group removal.
Scheme 1. (a) (i) (COCl)2, DMSO, i-Pr2NH, 92%; (ii) Ph3P_CHCO2But, 92% (two steps); (b) Bn(TMS)NLi, THF, −78°C;
(c) Bu4NF, 80%; ClSO2NCO, then H2O, 85%; (d) t-BuOK (see text); (e) base, RX (see Table 1); (f) (i) Boc2O, Et3N, DMAP,
CH2Cl2, 94%; (ii) Cs2CO3, MeOH, 88%; (iii) KOH, EtOH, 77%; (iv) TIPS–Cl, DBU, MeCN, 59%; (v) (PyS)2, PPh3, MeCN,
90%; (vi) TBAF, THF, 44%; (vii) DME, BF3·Et2O, CH2Cl2, 39%
Since better results, especially in terms of asymmetric induction, could reasonably be expected
from an intramolecular process, we turned to the synthesis of alkene (R)-1b, following already known
standard procedures7,12 (Scheme 1). A perusal of literature data regarding the intramolecular addition
of homoallylic O-carbamates to α,β-unsaturated esters having stereocentres at both the γ- and the δ-
carbon, indicates that diastereoselectivity mainly depends on the chirality of γ-carbon (1,2-anti induction
predominates) when an oxygenated functional group is present at the γ-carbon itself.7 On the contrary,
when a fluorine is present at the γ-carbon, the stereochemistry of the newly formed chiral carbon seems to
depend only on the chirality of the δ-carbon (1,3-syn induction predominates).8 Although cyclization of
homoallylic carbamates having chirality only at the δ-carbon are known,7a to the best of our knowledge
no example has been reported on homoallylic carbamates having chirality only at the γ-carbon, such as
1b.
Base-induced cyclization of (R)-1b was at first assayed using t-BuOK as a base, in THF for 20 min

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at 0°C,7e which afforded the oxazinone 4 with 59% chemical yield. With the aim of improving this
result, we examined the effect of various parameters: base, temperature, reaction time. While oxazinone
4 was reasonably stable under the reaction conditions, a major problem arises from the base-sensitivity
of substrate 1b. Potassium t-butoxide seemed to be the base of choice, notwithstanding the claimed
little importance of employed base,7a and a compromise between a lower temperature and extended
reaction time was used in order to suppress undesirable side reactions. Finally, 70% of purified 4 was
obtained when the reaction was run in THF, using a slight excess of base (t-BuOK) for 3 h at −50°C.
1
TLC analysis using a variety of eluents and H and 13C NMR spectra indicated that 4 was present in
only one diastereomeric form,13 with trans relative configuration14 of the two substituents. As a further
confirmation of this result, we benzylated the raw product of cycloaddition to achieve the N-benzylated
derivative 7, both diastereomeric forms of which being available starting from amino ester 2: only a trace
(≤4%) of the cis-diastereomer could be detected (Scheme 2).
Scheme 2.
Table 1
Alkylation of doubly deprotonated 4
With the protected β-amino ester in hand, we turned our attention to its elaboration. Herein, we report
the results of alkylation in the α-position with respect to the ester moiety (Scheme 1).
The reaction with methyl iodide was chosen as a probe in order to find best alkylation conditions: some
selected results are reported in Table 1. Using lithium diisopropylamide (LDA) as a base15 to doubly
deprotonate 4, resulted in decomposition of substrate, accompanied by only traces of the N-methylated
product. On the contrary, LiHMDS as a base furnished the desired product, in yields depending on the
time of alkylation and on the order of mixing of reagents. An excess of alkylating agent is deleterious,
probably due to a side reaction between methyl iodide and LiHMDS, and added hexamethylphosphoric

3206
amide (HMPA)16 or lithium chloride15 had no beneficial effect. The conditions of choice involved
premixing the substrate with about an equivalent of MeI and then adding a slight (5–10%) excess of
base (entry 2); diastereoisomeric excess is about 35%.
Other alkylating agents were then tested and in some cases they gave both satisfactory chemical and
stereochemical yields (entries 5 and 6 of Table 1, diastereoisomeric excess ≥90%). As for the methylation
reaction, the conditions of choice were always addition of base (LiHMDS) to a mixture of substrate, but
an excess of alkylating agent had to be employed, in order to improve the chemical yields (cf. entries 4
and 5). Different order of addition and different bases (LDA, KHMDS)16 gave worse results.17
On the basis of the coupling constant values (JH-6/H-7=1.5 Hz and JH-5/H-6=9.9 Hz) of the β-lactam 6,
obtained from 5 after deblocking and successive cyclization (see Scheme 1), the relative configuration of
the two stereocentres, in the main diastereomer of 5, was established to be anti,anti by comparison with
literature data.18
Reaction with other electrophiles, as well as further elaboration of 5, will be reported in a forthcoming
paper.
Acknowledgements
We thank MURST (Cofin 98), the University of Genova, and CNR for financial support.
References
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3–11. (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117–128.
2. (a) Burke, A. J.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1996, 621–622, and references cited therein. (b) Davies, S. G.;
Smyth, G. D. Tetrahedron: Asymmetry 1996, 7, 1001–1004. (c) Davies, S. G.; Fenwick, D. R.; Ichihara, O. Tetrahedron:
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Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595–1596. (c) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1996, 7,
1919–1992.
6. Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321–3408.
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T.; Yamazaki, Y.; Ito, S. Tetrahedron 1985, 26, 4133–4136. (c) Hirama, M.; Shigemoto, T.; Ito, S. Tetrahedron 1985, 26,
4137–4140. (d) Hirama, M.; Nishizaki, I.; Shigemoto, T.; Ito, S. J. Chem. Soc., Chem. Comm. 1986, 393–394. (e) Hirama,
M.; Shigemoto, T.; Ito, S. J. Org. Chem. 1987, 52, 3342–3346, and references cited therein.
8. Kitazume, T.; Kobayashi, T.; Yamamoto, T.; Yamazaki, T. J. Org. Chem. 1987, 52, 3218–3223.
9. Guanti, G.; Banfi, L. Eur. J. Org. Chem. 1998, 745–757.
10. Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994, 2373–2384, and
references cited therein.
11. Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1988, 44, 4173–4180.
12. Guanti, G.; Banfi, L.; Merlo, V.; Narisano, E.; Thea, S. Tetrahedron 1993, 49, 9501–9516.
13. For an α,β-unsaturated ester of E configuration, this is quite a notable result (see Ref. 7d).
14. The relative configuration of C-4 and C-5 in the oxazinone ring was established to be trans, after many unsuccessful efforts
(coupling constant JH-4/H-5 of 4 could not be determined, even with double resonance experiments), by transforming 4 into
acetate I [(i) MeI, t-BuOH, −30°C; (ii) DDQ, t-BuOH, CH2Cl2, rt; (iii) Ac2O, pyridine, 0°C], which showed JH-4/H-5 about
0
1.5 Hz and JH-5/H-6 and JH-5/H-6 1.5 and 3.3 Hz, respectively [see: (a) Bando, T.; Harayama, H.; Fukazawa, Y.; Shiro, M.;

3207
Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1994, 59, 1465–1474. (b) Seebach, D.; Abele, S.; Gademan, K.; Guichard,
G.; Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1998,
81, 932–982].
15. Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824–1839.
16. Wolf, J. P.; Rapoport, H. J. Org. Chem. 1989, 54, 3164–3163.
17. Some selected analytical data for compounds 1a,b and 4 are here reported (optical rotatory powers are taken at 22°C in
CHCl3, 1H NMR spectra in CDCl3). Compound (R)-(E)-1a: [α]D=+1.2 (c 0.94); 1H NMR: 1.04–1.09 [m, 21H, (Me2CH)3Si],
1.47 (s, 9H, Me3C), 2.55–2.75 (m, 1H, CHCH2OPMBOM), 3.65–3.80 (m, 4H, CH2OPMBOM and CH2OSi), 4.52 (s, 2H,
OCH2Ar), 4.72 (s, 2H, OCH2O), 5.86 (dd, J=15.8 and 1.0, 1H, ButOCOCH_), 6.87 (dd, J =5.8 and 8.3, 1H, CHCH_),
6.86–6.90 (m, 2H) and 7.25–7.29 (m, 2H) (ArH). Compound (R)-(E)-1b: [α]D=−3.8 (c 0.98); 1H NMR: 1.48 (s, 9H,
Me3C), 2.75–2.91 (m, 1H, CHCH2OCO), 3.65 (d, J=5.9, 2H, CH2OPMBOM), 3.81 (s, 3H, MeO), 4.19 (app. dd, J=6.2
and 2.1, 2H, CH2OCONH2), 4.52 (s, 2H, CH2Ar), 4.6 (broad s, 2H, NH2), 4.72 (s, 2H, OCH2O), 5.89 (dd, J=15.8 and 1.2,
1H, ButOCOCH_), 6.81 (dd, J=15.8 and 7.7, 1H, CHCH_), 6.86–6.92 (m, 2H) and 7.25–7.32 (m, 2H) (ArH). Compound
(4S, 5R)-4: [α]D=−37.1 (c 2.06); 1 H NMR: 1.46 (s, 9H, Me3C), 1.90–2.04 (m, 1H, CHCHNH), 2.43 and 2.59 (AB part of
an ABX system, JAB=16.9, JAX=10.4, JBX=2.9, 2H, CH2OCO2But), 3.60 and 3.62 (AB part of an ABX system, JAB=10.4,
JAX=9.1, JBX=3.6, 2H, CH2OPMBOM), 3.68–3.81 (m, 1H, CHNH), 3.81 (s, 3H, MeO), 4.19 and 4.28 (AB part of an ABX
system, JAB=11.4, JAX=7.5, JBX=3.6, 2H, CH2OCONH), 4.52 (s, 2H, CH2Ar), 4.72 (s, 2H, OCH2O), 5.83 (broad s, 1H,
NH), 6.87–6.92 (m, 2H) and 7.24–7.28 (m, 2H) (ArH). The optical purity of both (R)-(E)-1a and (4S, 5R)-4 was checked
via NMR spectra of Mosher’s esters prepared from alcohols obtained by removing a protecting group from 1a (TIPS) and 4
(PMBOM) and was found to be comparable with optical purity of starting THYM* (ee›90%).
18. Shih, D. H.; Fayter, J. A.; Cama, L. D.; Christensen, B. G.; Hirshfield, J. Tetrahedron Lett. 1985, 26, 583–586.