Addition of allyltrichlorostannanes to aldehydes: application in the synthesis of 4-N-Boc-amino-3-hydroxy ketones

Article abstract of DOI:10.1016/j.tetlet.2007.11.072

We wish to describe here the diastereoselective reaction between chiral N-Boc-α-amino aldehydes and achiral allyltrichlorostannanes leading to 1,2-syn-N-Boc-α-amino alcohols, which are treated with catalytic amounts of OsO₄ in the presence of N

Full text of DOI:10.1016/j.tetlet.2007.11.072

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 557–561
Addition of allyltrichlorostannanes to aldehydes: application
in the synthesis of 4-N-Boc-amino-3-hydroxy ketones
Luiz C. Dias,* Juliana Fattori and Carla Cristina Perez
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP C.P. 6154, 13084-971, Campinas, SP, Brazil
Received 22 August 2007; revised 12 November 2007; accepted 13 November 2007
Available online 19 November 2007
Abstract—We wish to describe here the diastereoselective reaction between chiral N-Boc-a-amino aldehydes and achiral allyltrichloro-
stannanes leading to 1,2-syn-N-Boc-a-amino alcohols, which are treated with catalytic amounts of OsO4 in the presence of NaIO4 to
provide the corresponding 4-N-Boc-amino-3-hydroxy ketones.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
OH OH
C13H27
OH
OH OH
C13H27
Me
Me
HO
C13H27
3
Sphingolipids are a class of lipids derived from the
aliphatic amino alcohol sphingosine (1) (Fig. 1).1 Sphin-
golipids are often found in neural tissues, and play an
important role in both signal transmission and cell
recognition.2,3 This diverse family of biomolecules is
structurally characterized by a long carbon chain
‘sphingoid’ base that is derivatized with amide linked
fatty acids and various polar head groups.4 These com-
pounds were found to possess a wide range of biological
properties, being important in the chemistry of cellular
membranes, cell growth differentiation and apoptosis.5,6
The 1,2-amino alcohol moiety is present in sphingo-
lipids, and recently, the 1-deoxy-5-hydroxy sphingosine
analogues 2 and 3 have been identified as a potential
new class of anticancer principles (Fig. 1).5,6 Encour-
aged by this, and to provide material for further biolo-
gical studies as well as access to novel analogues with
potential pharmacological activities, we developed a
short and efficient route for the synthesis of 4-N-Boc-
amino-3-hydroxy ketones, which are potential precur-
sors for the synthesis of sphingolipid derivatives. We
wish to describe here the diastereoselective reaction
between chiral N-Boc-a-amino aldehydes and achiral
allyltrichlorostannanes leading to 1,2-syn-N-Boc-a-
amino alcohols, which are easily converted to the
corresponding 4-N-Boc-amino-3-hydroxy ketones.7,8
2
NH2
NH2
NH2
sphingosine (1)
Figure 1. Sphingosine (1) and 1-deoxy-analogues 2 and 3.
To our surprise, there is no general and efficient
approach to 4-N-Boc-amino-3-hydroxy ketones
described in the literature.9
2. Results and discussion
To prepare the corresponding allyltrichlorostannanes,
the methyl esters 4 and 7 were treated with cerium(III)
chloride and trimethylsilylmethylmagnesium chloride
(3.0 equiv) to give an intermediate bis(trimethylsilyl-
methyl)carbinol which, after treatment with Amberlyst
15ꢁ resin in n-hexane, followed by filtration, gave allyl-
silanes 5 and 8 in 88% and 68% yield, respectively, for
the two-step sequence (Scheme 1).7,10
The next step involved the reactions of allylsilanes 5 and
8 with SnCl4 (Scheme 1). Allylsilanes 5 and 8 were
reacted with SnCl4 to promote ligand exchange, provid-
ing the corresponding allyltrichlorostannanes 6 and 9,
respectively. These reactions were followed by 1H
NMR spectroscopy.8 For allyltrimethylsilane 5, the
ligand exchange producing allyltrichlorostannane 6
and TMSCl is complete after 60 min at room tempera-
ture (Scheme 1). Upon the addition of SnCl4 to a solu-
tion of allylsilane 8 in CDCl3, at 25 ꢂC, a slightly
Keywords: Allyltrichlorostannane; Allylsilanes; Aminoketones;
Oxazolidinones.
*
Corresponding author. Tel.: +55 019 3521 3097; fax: +55 019 3521
3023; e-mail: ldias@iqm.unicamp.br
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.072

558
L. C. Dias et al. / Tetrahedron Letters 49 (2008) 557–561
O
a
88%
b
TMS
TMS
Cl3Sn
Cl3Sn
60 min.
rt
MeO
5
8
4
6
9
a
O
b
68%
10 min.
MeO
C13H27
C13H27
C13H27
rt
7
Scheme 1. Preparation of allyltrichlorostannanes 6 and 9. Reagents and conditions: (a) (i) CeCl3, TMSCH2MgCl, THF, À78 ꢂC, 18 h; (ii) Amberlyst
15, n-hexane, 25 ꢂC, 3 h; (b) SnCl4, CH2Cl2.
OH
O
CH2Cl2
Cl3Sn
R
R
+
H
-78 °C
6
NHBoc
NHBoc
10a - R = Me
10b - R = i-Pr
10c - R = i-Bu
10d - R = Bn
10e - R = CH2OTBS
10f - R = CH3S(CH2)2
11a - R = Me, 61%, ds 84:16
11b - R = i-Pr, 50%, ds > 95:5
11c - R = i-Bu, 40%, ds > 95:5
11d - R = Bn, 40%, ds > 95:5
11e - R = CH2OTBS, 62%, ds 75:25
11f - R = CH3S(CH2)2, 40%, ds 86:14
(yields for the two-step sequence)
H
R
O
H
O
H
Boc N
Boc
HN
BocHN
R
(Cl)3
Sn
O
H
H
Nu
B
Nu
A
R
H
R
H
C
1,2-syn
Scheme 2. Allyltrichlorostannane additions.
1,2-anti
yellow homogeneous solution was obtained.7,8 The
resulting 1H NMR spectra showed the formation of
TMSCl and complete consumption of the allylsilane 8
within 10 min to give allyltrichlorostannane 9.
(Scheme 2). When the form A predominates (bulkier R
groups), the syn-isomer is favored, whereas the preva-
lence of the B-like conformer (smaller R groups) leads
to the anti-isomer. The nucleophile selects the less hin-
dered Si-face, forming a six-member transition state C
where the chiral residue of the aldehyde occupies a pseu-
do-equatorial position.
We next moved to investigate the allyltrichlorostannane
additions to (S)-N-Boc-a-amino aldehydes 10a–f
(Scheme 2).7–13 Addition of aldehydes 10a–f to a
CH2Cl2 solution of allyltrichlorostannane 6 at À78 ꢂC
gave the 1,2-syn-amino alcohols 11a–f (anti-Felkin addi-
tion) in good yields and with moderate to high levels of
diastereoselectivity for the two-step sequence (prepara-
tion of the aldehyde and coupling with allyltrichlorost-
annane 6) (Scheme 2).14,15
The 1,2-syn relative stereochemistry of the major
products was unambiguously established by spectro-
scopic analysis of the corresponding trans-oxazolidinon-
es 12b–d (Scheme 3).16,17 Treatment of homoallylic
alcohols 11b–d with trifluoroacetic acid (TFA) followed
by cyclization with triphosgene gave 12b–d in good
yields.16,17 Observed average coupling constants
(3J = 4.9 Hz for 12b, 5.5 Hz for 12c and 5.1 Hz for
It is essential to promote the ligand exchange reaction
before the addition of the aldehyde to get good yields
and selectivities. This reaction benefits from the fact that
the real nucleophile is the allyltrichlorostannane and not
the allylsilane itself. If the allyltrichlorostannane addi-
tion reaction is carried out from À78 ꢂC to room tem-
perature, we have observed loss of the Boc protecting
group with the corresponding deprotected homoallylic
alcohols being isolated in good yields and having essen-
tially the same selectivities.
O
OH
HN
O
a
b
R
R
Ha Hb
NHBoc
11b, R = i-Pr
11c, R = i-Bu
11d, R = Bn
12b, R = i-Pr, 45% (JHa/Hb = 4.9 Hz)
12c, R = i-Bu, 53% (JHa/Hb = 5.5 Hz)
12d, R = Bn, 70% (JHa/Hb = 5.1 Hz)
Scheme 3. Proof of the relative stereochemistry. Reagents and
conditions: (a) TFA, 1,2-ethanedithiol, rt, 50 min; (b) triphosgene,
CH2Cl2, 0 ꢂC, 1 h, then rt, 2 h.
We believe that the observed selectivity can be explained
by an equilibrium between the intramolecular hydrogen
bond conformer A and the non-bonded conformer B

L. C. Dias et al. / Tetrahedron Letters 49 (2008) 557–561
559
i. OsO4(cat.)
Et2O/H2O (1:1), 2 h
OH
OH
O
R
R
ii. then NaIO4, 18 h
NHBoc
NHBoc
11a, R = Me
13a, R = Me (95%)
13b, R = i-Pr (95%)
13c, R= i-Bu (95%)
13d, R = Bn (95%)
11b, R = i-Pr
11c, R= i-Bu
11d, R = Bn
i. OsO4
Et2O/H2O (1:1), 2 h
OH
O
S
OH O
MeS
Me
Me
ii. then NaIO4, 18 h
89%
O
NHBoc
NHBoc
11f
14
OH
O3, Me2S
+ 13a (58% yield)
Me
N
11a
Boc
NHBoc
15 (20% yield)
Scheme 4. Synthesis of 4-N-Boc-amino-3-hydroxy ketones.
O
OH
CH2Cl2
SnCl3
R
R
C13H27
H
C13H27
-78 °C
9
NHBoc
NHBoc
10a, R = Me
16a, R = Me, 45%, ds 94:06
10b, R =
10c, R =
i
-Pr
16b, R =
16c, R =
i
-Pr, 46%, ds >95:05
i
-Bu
i
-Bu, 32%, ds >95:05
10d, R = Bn
16d, R = Bn, 60%, ds >95:05
10g, R = CH2OBn
16g, R = CH2OBn, 50%, ds 70:30
(yields for the two-step sequence)
Scheme 5. Coupling with allyltrichlorostannane 9.
12d), upon irradiation of the hydrogens adjacent to Ha
and Hb, indicated that hydrogens Ha and Hb are on the
opposite faces of the heterocyclic ring, and therefore, the
oxazolidinones are derived from 1,2-syn adducts.16–18
10a–d and 10g gave adducts 16a–d and 16g, respectively,
in good yields and with high levels of diastereoselectivity
for the two-step sequence (preparation of the aldehyde
and coupling with allyltrichlorostannane 9) (Scheme
5).15 The stereoinduction observed in these reactions
again shows that the reaction favored the anti-Felkin
product, indicating that there is an inherent selectivity
toward the 1,2-syn product by the resident a-stereogenic
center of the aldehydes.14,15
We were delighted to find that the oxidation of the
homoallylic alcohols 11a–d proceeded smoothly in the
presence of osmium tetroxide (catalytic) and sodium
periodate in Et2O/H2O to give the corresponding
4-N-Boc-amino-3-hydroxy ketones 13a–d in excellent
yields (Scheme 4).9,19 It is very important to point out
that, to the best of our knowledge, there is no useful
and general approach to 4-N-Boc-amino-3-hydroxy
ketones described in the literature and this methodology
stands as the most efficient approach to this class of
molecules.9 Attempts to prepare the corresponding
ketone from amino alcohol 11f led to ketone 14 with
concomitant oxidation to the sulfone in 89% yield
(Scheme 4).
The relative stereochemistry was determined after the
conversion of 16b and 16d to the corresponding
N-Boc-oxazolidinones 17b (49%) and 17d (53%),
respectively, by treatment of 16b,d with triphosgene
followed by 1H NMR coupling constant analysis
(Scheme 6). The observed coupling constants
(JHa/Hb = 2.4 Hz for 17b and 2.3 Hz for 17d) indicates
that hydrogens Ha and Hb are on opposite faces of
the heterocyclic ring (Scheme 6).16,17
It is also important to point out that our initial attempts
to promote the double bond oxidation in homoallylic
alcohol 11a by ozonolysis led to the desired product
13a (58% yield) together with a by-product which we
assigned as pyrrol derivative 15 (20% yield) (Scheme 4).20
O
OH
triphosgene
CH2Cl2, rt
O
BocN
R
C13H27
R
Ha
NHBoc
Hb
C13H27
16b, R = i-Pr
16d, R = Bn
17b, R = i-Pr, 49% (JHa/Hb = 2.4 Hz)
17d, R = Bn, 53% (JHa/Hb = 2.3 Hz)
We next moved to investigate the addition of allyltri-
chlorostannane 9 to a-aminoaldehydes (Scheme 5).
The addition of allyltrichlorostannane 9 to aldehydes
Scheme 6. Oxazolidinone formation.

560
L. C. Dias et al. / Tetrahedron Letters 49 (2008) 557–561
354; (c) Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta,
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OH
i. OsO4(cat.)
Et2O/H2O (1:1), 2 h
OH
O
R
R
C13H27
C13H27
ii. then NaIO4, 18 h
NHBoc
NHBoc
16a-d and 16g
18a, R = Me, 92%
18b, R = i-Pr, 80%
18c, R = i-Bu, 94%
18d, R = Bn, 89%
18g, R = CH2OBn, 92%
Scheme 7. Synthesis of 4-N-Boc-amino-3-hydroxy ketones.
6. Symolon, H.; Schmelz, E. M.; Dillehay, D. L.; Merrill, A.
H., Jr. J. Nutr. 2004, 134, 1157.
Treatment of homoallylic alcohols 16a–d and 16g with
OsO4/NaIO4 gave 4-N-Boc-amino-3-hydroxy ketones
18a–d and 18g in good yields (Scheme 7).
7. (a) Dias, L. C.; Ferreira, E. Tetrahedron Lett. 2001, 42,
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R.; Ferreira, E.; Diaz, G.; Steil, L. J.; Meira, P. R. R.;
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Again, to the best of our knowledge, this is the
best methodology available for the preparation of
these kinds of compounds with high levels of
diastereoselectivities.19,21
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1, 1335.
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3. Conclusions
We have described here that high levels of substrate-
based, 1,2-syn-stereocontrol could be achieved in the
achiral allyltrichlorostannane addition reactions to
N-Boc-a-amino aldehydes, leading to the anti-Felkin
products, which were easily converted to the corre-
sponding 4-N-Boc-amino-3-hydroxy ketones in good
yields. This methodology stands as a new and very effi-
cient approach to 4-N-Boc-amino-3-hydroxy ketones.
This synthetic methodology allows compounds with
programmed variations of substituents to be synthesized
and is particularly important in the screening of
pharmacological activity and in the study of structure-
activity relationships directed toward the design of
new classes of anticancer principles. Further studies in
this direction are underway to explore their generality
and origin and will be described in a full account of this
work together with our results related to the reductions
of these 4-N-Boc-amino-3-hydroxy ketones to the corre-
sponding 1,3-syn and 1,3-anti diols.21
13. The optical purity of aldehydes 10 was estimated to be
1
greater than 96% ee from the H NMR spectrum of the
Acknowledgments
Mosher ester prepared from 10 via NaBH4 reduction
followed by esterification.
We are grateful to FAEP-UNICAMP, FAPESP (Fun-
´
14. (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
`
dac¸ao de Amparo a Pesquisa do Estado de Sao Paulo)
˜
˜
1968, 18, 2199; (b) Anh, N. T.; Eisenstein, O. Nouv. J.
Chem. 1977, 1, 61; (c) We use the ‘Felkin’ descriptor to
refer to the diastereomer predicted by the Felkin–Ahn
paradigm. The ‘anti-Felkin’ descriptor refers to diastereo-
mers not predicted by this transition state model.
15. (a) The ratios were determined by 1H and 13C NMR
spectroscopic analysis of the unpurified product mixture;
(b) All of the percentage values represent data obtained
from at least three individual trials.
and CNPq (Conselho Nacional de Desenvolvimento
´
´
Cientıfico e Tecnologico) for financial support. We also
thank Professor Carol H. Collins for helpful suggestions
about English grammar and style.
References and notes
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18. Having confirmed the 1,2-syn relationship, the absolute
stereochemistry of the newly formed hydroxyl substituent
was determined by ascertaining its relationship to the
known stereocenter originating from the aldehydes.
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resulting solution was stirred at rt for 2 h and then cooled
to À78 ꢂC when a solution of aminoaldehydes (1.2 mmol)
in CH2Cl2 (2 mL) was added. This mixture was stirred for
2 h at À78 ꢂC and quenched by the slow addition of a satd
aq solution of NaHCO3 (5 mL) followed by CH2Cl2
(5 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 · 5 mL). The combined
organic layers were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash chromatography on
silica gel (30% EtOAc–hexane) gave the corresponding
homoallylic alcohols 11 and 16.
21. Homoallylic alcohols 11 and 16: general procedure: To a
solution of the corresponding allylsilane (1.5 mmol) in
CH2Cl2 (5 mL) at rt was added SnCl4 (1.1 mmol). The