Stereocontrolled addition of boron enolates to trans α,β- aziridine aldehydes. A new route to anti-1,2-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2004.01.059

A study of the addition of boron enolates of methyl ketones to trans α,β-aziridine aldehydes is reported. The reaction proceeds with excellent anti stereoselectivity furnishing functionalized products, capable of other controlled transformations, some of which are described.

Full text of DOI:10.1016/j.tetlet.2004.01.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2103–2106
Stereocontrolled addition of boron enolates to trans a,b-aziridine
aldehydes. A new route to anti-1,2-amino alcohols
Giuliana Righi* and Simona Ciambrone
Istituto di Chimica Biomolecolare-Sezione di Roma, c/o Dipartimento di Chimica, Universitꢀa ‘La Sapienza’,
P.le A. Moro 5, 00185 Roma, Italy
Received 14 October 2003; revised 9 January2004; accepted 14 January2004
Abstract—A studyof the addition of boron enolates of methyl ketones to trans a,b-aziridine aldehydes is reported. The reaction
proceeds with excellent anti stereoselectivityfurnishing functionalized products, capable of other controlled transformations, some
of which are described.
Ó 2004 Elsevier Ltd. All rights reserved.
Functionalized chiral aziridines can be considered
attractive compounds due to their reactivity, mainly as a
result of their ring strain.1 Indeed, chemo-, regio- and
stereocontrolled openings of aziridines with a varietyof
The stereoselective addition of enolates to a,b-aziridine-
2-carbaldehydes, which, to the best of our knowledge,
has never been exploited, could provide structures,
which are suitablyfunctionalized for selective elabora-
tion to aminopolyhydroxylated structures (e.g., regio-
selective aziridine ring opening or diastereoselective
carbonyl reductions6). Our preliminarystudies were
restricted, for convenience, to racemic compounds and
we chose, as the standard test reaction, the addition of
the enolate of pinacolone to trans-1-tert-butoxycar-
bonyl-3-propylaziridine-2-carbaldehyde. At first, lith-
ium diisopropylamide was used to generate the enolate,
however, a 1:1 mixture of diastereomeric aldols resulted.
2
nucleophiles have been widelyreported; in particular,
metal halides have been extensivelyused to ring-open
aziridines, often functionalized with hydroxyl and car-
boxyl groups.3 Moreover, it is known that the aziridine
ring of a,b-aziridine aldehydes, which are easily
obtainable in opticallyactive form from the corre-
sponding trans allylic alcohols, strongly influences the
stereochemistryof nucleophilic additions to the car-
bonyl group. In fact, the reaction between these sub-
strates and organometallic reagents generallyresults in
the formation of syn aziridino alcohols in quite good
yields and with good to excellent diastereomeric ratios.4
For example, using Grignard reagents and N-Boc-acti-
vated aziridines onlythe syn stereoisomer was obtained,
which can be explained byinvoking a ꢀcyclic chelate
modelꢁ for the T.S.5
In light of this unsatisfactoryresult, it was decided to
adopt the methodologyused in a recent similar study
aimed at the stereocontrolled aldol addition to trans a,b-
7
epoxyaldehdyes, namelythe use of boron enolates,
which had led to an excellent diastereoselection.
The reaction conditions were optimized bystudying the
addition of the dibutylboron enolate (formed by adding
Bu2BOTf and DPEA to pinacolone at 0 °C for 30 min)
to trans-1-tert-butoxycarbonyl-3-propylaziridine-2-carb-
aldehyde 1, at )78 °C, using CH2Cl2 as solvent (Et2O
and THF gave some side products) (Scheme 1).
Prompted bythese results, we decided to explore the
stereochemistryof the aldol addition of ketone enolates
to trans a,b-aziridine aldehydes, the configurational
stabilityof which overcomes the difficultyof using
configurationallyunstable a-amino aldehydes.
When the reaction mixture was allowed to warm slowly
from )78 °C to room temperature, onlyone diastereo-
isomer was detected.
Keywords: a,b-Aziridine aldehydes; Boron enolates; Aldol condensa-
tion; 1,2-Amino alcohols.
Stereochemical assignments for the aziridino alcohols
obtained were based on their spectral properties. It is
* Corresponding author. Tel.: +39-6490422; fax: +39-649913628;
e-mail: giuliana.righi@uniromal.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.059

2104
G.Righi, S.Ciambrone / Tetrahedron Letters 45 (2004) 2103–2106
OBBu2
Boc
OH
Boc
OH
Boc
N
O
O
R'
N
N
(2 eq.)
CH2Cl2, -78 to 25 °C
CHO
+
R
R'
R
R'
R
syn
3'- 6'
anti
3 - 6
1, 2
Scheme 1.
known that in their NMR spectra the methine hydro-
gens of the CHOH groups of anti isomers are always
shifted to lower field than those of the corresponding syn
isomers.4a Consistent with this general trend, the reso-
nance of the CHOH of 3 (d 3.95) is shifted by0.35 ppm
downfield relative to the corresponding resonance of the
CHOH of 30 (d 3.61).6 Consequently, we attributed the
anti configuration to 3 and the syn configuration to 30.
this metal halide to open the aziridine rings of the aldol
products.
The reaction was performed at room temperature on
compounds 4 and 6 and afforded the expected bromo
derivatives as single regio- and stereoisomers, indepen-
dent of the substituent at C-3 (Scheme 2).11 The regio-
chemistryof the ring opening was established bymeans
of NMR spectroscopy, employing a spin–spin decou-
pling technique.12 Furthermore, the high reactivityof
the bromides 7 and 8 can be utilized for further elabo-
ration: for example, radical reduction allowed the
preparation of 4-keto-1,2-amino alcohols with various
substituents.13 Thus compounds 7 and 8 were reduced
with tris(trimethylsilyl)silane14 to give the corresponding
anti-4-keto-1,2-amino alcohols 9 and 10 in good yields.15
Moreover, this procedure is selective for the anti 1,2-
amino alcohols, rather than the more accessible syn
compounds.16
The diastereoselectivityobserved in favour of the anti
isomers can be explained invoking the Felkin–Ahn
model for the T.S. We can assume that the incoming
nucleophile attacks the carbonyl in an anti-periplanar
manner with respect to the aziridine ring, which can be
considered the largest group attached to the stereogenic
centre at C-2, thus leading to the anti isomer (see Fig.
1).9
This methodologywas then tested on trans-1-tert-
butoxycarbonyl-3-cyclohexylaziridine-2-carbaldehyde 2,
where a stericallydemanding substituent is present at
the C-3 position. Besides pinacolone, 3-methyl-2-buta-
none, a ketone having two different enolizable sites, was
also used. As shown in Table 1, the results were satis-
factoryand demonstrated the general application of the
methodology.
In conclusion, the aldol condensation of boron enolates
with trans a,b-aziridine aldehydes proceeds with excel-
lent stereoselectivityin favour of the anti diastereoiso-
mer, consistent with the Felkin–Ahn model. Moreover,
these functionalized compounds can be elaborated,
through regio- and stereocontrolled transformations, to
1,2-amino alcohols, a structural feature characteristic of
manynatural products and drugs, 17 often utilized in the
synthesis of biologically active molecules such as pro-
tease inhibitors,18 glycosphingolipids19 or polyhydroxyl-
ated nitrogen heterocycles.20
The aziridino alcohols obtained bythis aldol addition
can be used for further transformations. Since MgBr2
has been extensivelyemployed in regio- and stereocon-
trolled ring openings of a,b-aziridino alcohols,10 it was
deemed appropriate to explore the possibilityof using
Table 1. Addition of boron enolates to a,b-aziridine aldehydes8
H
a,b-Aziridine
aldehyde
R
R0
Product Yield
(%)
anti/syna
O
H
O
Boc
N
M
S
R
N Boc
1
2
n-Pr
t-Bu
i-Pr
3
4
62
63
>95:5
>95:5
R
R'
L
OH
anti
O
H
c-Hexyl
t-Bu
i-Pr
5
6
64
67
>95:5
>95:5
H
Felkin-Ahn model
a The diastereomeric ratio was determined on crude mixtures,
employing the integrations of the CHOH.
Figure 1.
Boc
OH
Br
O
O
OH
OH
O
N
TTMSS (1 mmol)
AIBN, benzene, ∆
MgBr2 (2 mmol)
Et2O, rt
R
R
R
NHBoc
NHBoc
4
6
R = Pr
R = c-hexyl
7
R = Pr (75%)
9
R = Pr (65%)
8
R = c-hexyl (72%)
10 R = c-hexyl (68%)
Scheme 2.

G.Righi, S.Ciambrone / Tetrahedron Letters 45 (2004) 2103–2106
2105
9H), 0.9 (t, J 6.9 Hz, 3H). 13C NMR (50.3 MHz, CDCl3): d
215.4, 160.5, 81.1, 67.6, 45.6, 41.8, 40.9, 32.6, 28.3, 28.0,
26.2, 20.4, 13.7. Compound 4: 1H NMR (200 MHz,
CDCl3): d 4.01–3.92 (m, 1H), 3.38 (br d, J 3.7 Hz, 1H),
2.86 (dd, J 17.0, 7.2 Hz, 1H), 2.69 (dd, J 17.0, 5.3 Hz, 1H),
2.62 (q, J 6.9 Hz, 1H), 2.5–2.42 (m, 1H), 2.29 (dd, J 6,
3.3 Hz, 1H), 1.46 (s, 9H), 1.60–1.20 (m, 4H), 1.1 (d, J
6.9 Hz, 6H), 0.9 (t, J 7.1 Hz, 3H). 13C NMR (50.3 MHz,
CDCl3): d 213.1, 161.4, 81.6, 67.5, 47.1, 44.8, 41.5, 41.3,
Acknowledgements
The authors thank MIUR (Ministryof Universityand
Research––Rome) for partial financial support (Project
FIRB RBNE017F8N).
1
32.8, 27.9, 20.2, 18.3, 17.8, 13.7. Compound 5: H NMR
References and notes
(200 MHz, CDCl3): d 3.87 (ddd, J 12.4, 6.6, 2.9 Hz, 1H),
3.78 (br d, J 2.9 Hz, 1H), 2.95 (dd, J 17.6, 7.3 Hz, 1H), 2.67
(dd, J 17.6, 5.9 Hz, 1H), 2.37–2.25 (m, 2H), 1.98–1.84 (m,
1H), 1.80–1.00 (m, 10H), 1.46 (s, 9H), 1.15 (s, 9H); 13C
NMR (50.3 MHz, CDCl3): d 212.4, 161.7, 81.6, 68.5, 46.5,
46.2, 44.2, 41.3, 39.5, 30.5, 30.0, 28.3, 27.9, 26.2, 26.0, 25.6.
1. Reviews: (a) Davis, F. A.; McCoull, W. Synthesis 2000,
1347–1365; (b) Atkinson, R. S. Tetrahedron 1999, 55,
1519–1561; (c) Zwanenburg, B. Pure Appl.Chem. 1999, 71,
423–430; (d) Tanner, D. Angew.Chem,. Int.Ed.Engl.
1994, 33, 599–619.
2. (a) Lee, K. D.; Suh, J. M.; Park, J. H.; Ha, H. J.; Cha, H.
G.; Park, G. S.; Chang, J. W.; Lee, W. K.; Dong, Y.; Yun,
H. Tetrahedron 2001, 57, 8267–8276; (b) Righi, G.;
Chionne, A.; DꢁAchille, R.; Bonini, C. Tetrahedron:
Asymmetry 1997, 8, 903–907; (c) Tanner, D.; Gautun, O.
R. Tetrahedron 1995, 51, 8279–8287; (d) Tanner, D.;
Somfai, P. Bioorg.Med.Chem.Lett. 1993, 3, 2415–2417.
3. Righi, G.; Bonini, C. Functionalized Epoxides and Azir-
idines: Reactivitywith Metal Halides and Snythetic
Applications. In Targets in Heterocyclic Systems; Atta-
nasi, O. A., Spinelli, D., Eds.; Italian Societyof Chemistry,
2000; p 139–165.
4. (a) Hwang, G.-I.; Chung, J.-H.; Lee, W. K. J.Org.Chem.
1996, 61, 6183–6188; (b) Andres, J. M.; de Elena, N.;
Pedrosa, R.; Prez-Encabo, A. Tetrahedron 1999, 55,
14137–14144.
5. Righi, G.; Pietrantonio, S.; Bonini, C. Tetrahedron 2001,
57, 10039–10046.
6. (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986,
27, 5939–5942; (b) Chen, K.; Gunderson, K. G.; Hardt-
mann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Chem.
Lett. 1987, 1923–1926.
7. Righi, G.; Spirito, F.; Bonini, C. Tetrahedron Lett. 2002,
43, 4737–4740.
8. General procedure for the aldol condensation: Di-n-
butylboryl triflate (1 M in CH2Cl2, 2.6 mmol) was added
dropwise to a stirred solution of the ketone (2 mmol) in
4 mL of CH2Cl2 at 0 °C. After 10 min, diisopropylethyl-
amine (4 mmol in 1 mL of CH2Cl2) was added dropwise.
The reaction mixture was stirred at 0 °C for 30 min and
then cooled to )78 °C. To the above enolate solution was
added a solution of aziridine aldehyde (1 mmol) in 2 mL of
CH2Cl2. After a few minutes the reaction was allowed to
warm to room temperature and was then quenched with a
mixture of MeOH (6 mL), aqueous phosphate buffer
(4 mL, pH ¼ 7) and H2O2 (4 mL of a 30% solution). The
aqueous layer was extracted with two portions of AcOEt
and the combined organic extracts dried (Na2SO4) and
concentrated. GenerallyTLC monitoring revealed about
20% of unreacted aldehyde also after a longer reaction
time. The residue was purified on silica gel (petroleum
ether/EtOAC 9:1).
1
Compound 6: H NMR (200 MHz, CDCl3): d 3.84 (q, J
7.3 Hz, 1H), 3.76 (br s, 1H), 2.88 (dd, J 16.8, 6.6 Hz, 1H),
2.70–2.54 (m, 2H), 2.33 (dd, J 7.3, 2.9 Hz, 1H), 2.27–2.21
(m, 1H), 1.98–1.85 (m, 1H), 1.81–1.6 (m, 4H), 1.72–0.84
(m, 6H), 1.46 (s, 9H), 1.1 (d, J 7.3 Hz, 6H). 13C NMR
(50.3 MHz, CDCl3): d 212.5, 161.8, 81.8, 68.8, 46.5, 46.4,
44.8, 41.5, 39.5, 30.5, 29.9, 27.8, 26.0, 25.6, 25.4, 18.0,
17.9.
9. Trost, B. M.; Fleming, I. In Comprehensive Organic
Synthesis; Pergamon: Oxford, 1991; Vol. 1, p 49.
10. Righi, G.; Franchini, T.; Bonini, C. Tetrahedron Lett.
1998, 39, 2385–2388.
11. General procedure for the opening of the aldol with
MgBr2: To a solution of the aldol (1 mmol) in dryEt O
2
(10 mL) was added MgBr2ÆEt2O (516.5 mg, 2 mmol). The
solution was stirred at room temperature for 6 h (TLC
monitoring), then filtered trough a Celite pad and the
solvent evaporated in vacuo. The residue was chromato-
graphed on silica gel (petroleum ether/EtOAc).
NMR data for representative compounds. Compound 7:
1H NMR (200 MHz, CDCl3): d 5.12 (br d, J 9.3 Hz, 1H),
4.31 (ddd, J 8, 5.6, 1.1 Hz, 1H), 4.14–4.03 (m, 1H), 3.64
(ddd, J 9, 8.2, 0.8 Hz, 1H), 2.81–2.53 (m, 3H), 1.91–1.55
(m, 3H), 1.45 (s, 9H), 1.32–1.15 (2H, m), 1.15 (d, J 6.9 Hz,
6H), 0.88 (3H, t, J 7.1 Hz). 13C NMR (50.3 MHz, CDCl3):
d 216.1, 155.4, 79.7, 68.4, 58.7, 57.6, 43.5, 41.5, 37.2, 28.3,
1
20.8, 17.9, 17.7, 13.4. Compound 8: H NMR (200 MHz,
CDCl3): d 4.96 (br d, J 10.3 Hz, 1H), 4.76 (dd, J 8.7, 3.2 Hz,
1H), 4.15–4.05 (m, 1H), 3.87–3.73 (dt, J 10.3, 0.7 Hz, 1H),
3.5 (br s, 1H), 2.6–2.54 (m, 3H), 1.90–0.83 (m, 11H), 1.46
(s, 9H), 1.12 (d, J 1.1 Hz, 3H), 1.09 (d, J 1.1 Hz, 3H). 13C
NMR (200 MHz, CDCl3): d 216.2, 155.3, 79.8, 67.2, 63.3,
55.7, 43.7, 41.5, 39.6, 32.3, 28.3, 27.4, 26.4, 26.2, 25.9, 17.9.
12. ꢀSpin–spin decouplingꢁ data for compound 8:
dirr
CHOH 4.78
d (ddd, J 8.7;
3.2; 0.6)
CHBr 4.12
d (dd, J 10.4;
1.6)
CHNH 3.83
d (ddd, J 10.4;
10.3; 0.6)
2.64 (CH2CO)
4.96 (NH)
d, J 0.6
dd, J 10.4; 0.6
1.8 (CH2CHCH2)
d, J 10.4
NMR data for representative compounds. Compound 3:
1H NMR (200 MHz, CDCl3): d 3.98 (q, J 6.1 Hz, 1H), 3.41
(br s, 1H), 2.92 (dd, J 17.6, 7.3 Hz, 1H), 2.74 (dd, J 17.6,
5.1 Hz, 1H), 2.53–2.44 (m, 1H), 2.3 (dd, J 5.9, 3.7 Hz, 1H),
1.8–1.5 (m, 4H), 1.47 (s, 9H), 1.15 (s, 9H), 0.9 (t, J 6.9 Hz,
3H). 13C NMR (50.3 MHz, CDCl3): d 216.7, 161.3, 81.5,
67.5, 47.1, 41.4, 41.3, 32.9, 28.3, 27.9, 26.1, 20.2, 13.7.
Compound 30: 1H NMR (200 MHz, CDCl3): d 3.62 (m,
1H), 3.19 (br d, J 3.6 Hz, 1H), 2.88 (dd, J 17.6, 2.2 Hz,
1H), 2.79 (t, J 10.2 Hz, 1H), 2.53–2.44 (m, 1H), 2.26 (dd, J
5.9, 3.7 Hz, 1 H), 1.8–1.5 (m, 4H), 1.47 (s, 9H), 1.15 (s,
.
13. The direct reductive opening of the aziridine ring by
catalytic hydrogenation resulted in different products.
14. Chatgilialoglu, C. Acc.Chem.Res. 1992, 25, 188–204.
15. General procedure for the radical reduction of the bromo
derivatives: To a solution of the bromo derivative (1 mmol)
in benzene (10 mL) tris(trimethylsilyl)silane (0.31 mL,
1 mmol) and a catalytic amount of AIBN were added.
The solution was refluxed for ꢀ5 h (TLC monitoring),
then evaporated in vacuo. The crude mixture was purified
byflash chromatography(petroleum ether/EtOAc, 9:1).

2106
G.Righi, S.Ciambrone / Tetrahedron Letters 45 (2004) 2103–2106
NMR data for representative compounds. Compound 9:
16. (a) Kolb, H. C.; Sharpless, K. B. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
New York, 1998; p 243; (b) OꢁBrien, P. Angew.Chem., Int.
Ed. 1999, 38, 326–332, and Refs. 5,6.
17. Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Eur.J.
Org.Chem. 1998, 1771–1792, and references cited therein.
18. Kempf, D.; Sham, H. Curr.Pharm.Des. 1996, 2, 225–261.
19. Peterson, M. A.; Polt, R. J.Org.Chem. 1993, 58, 4309–
4314, and references cited therein.
20. (a) Hummer, W.; Dubois, E.; Gracza, T.; Jager, V.
Synthesis 1997, 634–642; (b) Du Bois, J.; Tomooka, C.
S.; Hong, J.; Carreira, E. M. J.Am.Chem.Soc. 1997, 119,
3179–3180, and references cited therein.
1H NMR (200 MHz, CDCl3): d 4.58 (br d, J 8.0 Hz, 1H),
3.82–3.66 (m, 1H), 3.61–3.44 (m, 1H), 2.78–2.48 (m, 3H),
2.28 (quintet, J 6.9 Hz, 1H), 1.62–0.98 (m, 6H), 1.42 (s,
9H), 1.18 (d, J 6.9 Hz, 6H), 0.88 (t, J 6.6 Hz, 3H). 13C
NMR (50.3 MHz, CDCl3): d 216.3, 155.1, 79.1, 70.6, 56.4,
43.9, 41.5, 31.6, 27.9, 22.8, 22.4, 18.0, 13.9. Compound 10:
1H NMR (200 MHz, CDCl3): d 4.68 (br d, J 10.2 Hz, 1H),
4.04–3.94 (m, 1H), 3.66–3.52 (m, 1H), 3.38 (br s, 1H),
2.78–2.52 (m, 2H), 2.32 (quintet, J 6.9 Hz, 1H), 2.12–0.88
(m, 13H), 1.44 (s, 9H), 1.08 (d, 6H). 13C NMR (50.3 MHz,
CDCl3): d 216.2, 156.0, 79.6, 69.4, 51.4, 43.9, 41.5, 34.2,
29.6, 28.3, 27.2, 26.5, 17.9.