An efficient procedure for the synthesis of 2-N-Boc-amino-3,5-diols

Article abstract of DOI:10.1016/j.tet.2008.04.049

We wish to describe here the diastereoselective reaction between chiral N-Boc-α-amino aldehydes with both achiral allyltrichlorostannanes leading to 1,2-syn-N-Boc-α-amino alcohols, which are easily converted to the corresponding 4-N-Boc-amino-3-hydroxy ketones after treatment with catalytic amounts of OsO₄ in the presence of NaIO₄. After reduction of the carbonyl function, these 4-N-Boc-amino-3-hydroxy ketones were converted to 1-deoxy-5-hydroxy sphingosine analogues.

Full text of DOI:10.1016/j.tet.2008.04.049

Tetrahedron 64 (2008) 5891–5903
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient procedure for the synthesis of 2-N-Boc-amino-3,5-diols
y
*
Luiz C. Dias , Juliana Fattori, Carla C. Perez, Vanda M. de Oliveira, Andrea M. Aguilar
Instituto de Qu´ımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971, Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We wish to describe here the diastereoselective reaction between chiral N-Boc-a-amino aldehydes with
Received 15 February 2008
Received in revised form 10 April 2008
Accepted 11 April 2008
both achiral allyltrichlorostannanes leading to 1,2-syn-N-Boc-a-amino alcohols, which are easily con-
verted to the corresponding 4-N-Boc-amino-3-hydroxy ketones after treatment with catalytic amounts
of OsO4 in the presence of NaIO4. After reduction of the carbonyl function, these 4-N-Boc-amino-3-
hydroxy ketones were converted to 1-deoxy-5-hydroxy sphingosine analogues.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 16 April 2008
Keywords:
Allylsilanes
Allylstannanes
Catalytic dihydroxylation
Aminoketones
Sphingolipids
Aldol reaction
Boron enolates
1. Introduction
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
Sphingolipids, a class of lipids derived from the aliphatic amino
alcohol sphingosine (1) are a diverse family of biomolecules struc-
turally characterized by a long carbon chain ‘sphingoid’ base that is
derivatized with amide-linked fatty acids and various polar head
groups (Fig. 1).1–4 Sphingolipids have been found to possess a wide
range of biological properties, being important in the chemistry of
The primary hydroxyl group of sphingosine is phosphorylated in
vivo, which results in undesired mitogenic/anti-apoptotic activity.
Menaldino and co-workers3c,4 have proposed that 1-deoxy-5-
hydroxy sphingosine analogues like 2 and 3, designed by moving
the hydroxyl group to the 5-position, showed similar lipophilicity
to sphingosine while decreasing phosphorylation.
cellular membranes, cell growth differentiation, and apoptosis.5,6
A
Encouraged by this, we developed a general and efficient ap-
proach to 4-N-Boc-amino-3-hydroxy ketones, which provides
1,2-amino-alcohol moiety is present in sphingolipids, and recently,
OH
HO
Me
NH2
sphingosine (1)
OH OH
OH OH
Me
Me
Me
Me
3
2
NH2
NH2
Figure 1. Sphingosine (1) and 1-deoxy-analogues 2 and 3.
* Corresponding author. Tel.: þ55 19 3521 3097; fax: þ55 19 3521 3023.
E-mail address: ldias@iqm.unicamp.br (L.C. Dias).
Present address: Universidade Federal de Sa˜o Paulo, UNIFESP, Campus Diadema, Departamento de Cieˆncias Exatas e da Terra, R. Prof. Artur Ridel, 275, 09972-270,
Diadema, SP, Brazil.
y
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.049

5892
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
Table 1
access to aminopolyhydroxylated structures analogous to 2 and 3,
after selective reduction of the carbonyl group.7
Boron enolate additions to a-aminoaldehydes 10a–c
Entry
Ketone
(R0)
Aldehyde
(10) (R)
Aldol adducts
dsa
(syn/anti)
Yield (%)
(two steps)
2. Results and discussion
1
2
3
4
5
6
7
C
13H27
Me
i-Pr
Me
i-Pr
Bn
Me
i-Pr
Bn
9a/15a
95:05
66:34
75:25
95:05
95:05
95:05
95:05
95:05
50:50
20
43
38
15
92
41
30
10
42
C13H27
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
t-Bu
9b/15b
12a/15c
12b/15d
12c/15e
13a/15f
13b/15g
13c/15h
14/15i
Our strategy to prepare the 2-amino-3,5-diols of type 4–7 is
based on the selective syn or anti reduction of 4-N-Boc-amino-3-
hydroxy ketones 8 (R0¼Bn) and 9 (R0¼C13H27) (Scheme 1). These
aminoketones are viewed as arising either from the addition of
dicyclohexylboron enolates or from the addition of allyltri-
8
a
-aminoaldehydes 10.8,9 In the case of allyltri-
911
i-Pr
chlorostannes to
chlorostanne addition, the resulting double bond in the homoallylic
alcohol should be converted to the ketone carbonyl function.
a
Refers to the ratio of isolated syn/anti aldol products.
trimethylsilylmethylmagnesium chloride followed by reaction with
Amberlyst 15Ò resin in n-hexane to give allylsilanes 17 and 20 in
88% and 70% yield, respectively (Scheme 3).19
OH OH
R
R'
NHBoc
4, R' = Bn
5, R' = C13H27
Treatment of allylsilanes 17 and 20 with SnCl4 provided the
corresponding allyltrichlorostannanes 18 and 21, respectively.17,18
The coupling reaction of aldehydes 10a–g with allyltri-
chlorostannane 18 proceeded smoothly at ꢁ78 ꢀC to give 1,2-syn
amino alcohols 22a–g (anti-Felkin addition) in good yields and with
moderate to high levels of diastereoselectivity for the two-step
sequence (preparation of the aldehyde and addition reaction with
18) (Scheme 4).15–18
The observed sense of induction can be explained by the six-
member transition state A where the chiral residue of the aldehyde
occupies a pseudo-equatorial position and the nucleophile ap-
proaches from the less hindered Si-face (Scheme 4).17
In order to determine the relative stereochemistry, homoallylic
alcohols 22b–d were converted to the corresponding trans-oxazo-
lidinones 23b–d (Scheme 5).20,21 Treatment of 22b–d with tri-
fluoroacetic acid (TFA) followed by cyclization with triphosgene
gave oxazolidinones 23b–d in good yields. Observed coupling con-
stants (3J¼4.9 Hz for 23b, 5.1 Hz for 23c and 5.5 Hz for 23d), upon
irradiation of the hydrogens adjacent to Ha and Hb, indicated that
hydrogens Ha and Hb are on opposite faces of the heterocyclic ring,
and the oxazolidinones are derived from 1,2-syn adducts.16,20,21
We next moved to the preparation of the desired 4-N-Boc-
amino-3-hydroxy ketones. Our initial attempts to promote the
double bond oxidation in homoallylic alcohol 22a by ozonolysis led
to the desired product 8a in 48% yield together with the N-Boc
pyrrol derivative 24 as a by-product in 19% yield (Scheme 6).22,23
After several other unsuccessful attempts, we found that oxi-
dation of the homoallylic alcohols 22a–d proceeded smoothly in
the presence of sodium periodate and catalytic amounts of osmium
tetroxide in Et2O/H2O to give the corresponding 4-N-Boc-amino-3-
hydroxy ketones 8a–d in excellent yields (Scheme 7).22,24 Based on
these results, we suggest that this methodology stands as probably
the most efficient method to prepare this class of molecules.7,11,12
OBc-Hex2
R'
OH
O
O
R
R
or
and
+
R'
H
NHBoc
NHBoc
10
OH OH
Cl3Sn
R
R'
8, R' = Bn
9, R' = C13H27
R'
NHBoc
6, R' = Bn
7, R' = C13H27
Scheme 1. Synthetic strategy for the preparation of amino-3,5-diols.
Our first approach to prepare the desired 4-N-Boc-amino-3-
hydroxy ketones 8 and 9 involved the aldol addition of boron eno-
lates generated from methyl ketones 11a–d to -aminoaldehydes
a
10a–c.10–13 The reaction conditions were optimized by studying the
additions of the dicyclohexylboron enolate (formed by adding
c-Hex2BCl and Et3N to the methyl ketones 11a–d in Et2O at 0 ꢀC for
30 min) to the aldehydes 10a–c at ꢁ78 ꢀC in Et2O as solvent (Scheme
2, Table 1).13 The corresponding yields are forthe two-step sequence,
preparation of the aldehyde and coupling with the boron enolate.
When achiral boron enolates were used, selectivities ranged
from very low to good in favor of the 1,2-syn (anti-Felkin) product.14
Stereochemical assignments for the aldol adducts were based on
their spectral properties by chemical correlation with known
compounds or by comparison of their 1H and 13C NMR spectra with
those of 1,2-syn products prepared in this work.7,11 Although good
levels of diastereoselectivity were obtained in some cases, un-
fortunately, we were not able to get better yields than those pre-
sented in Table 1.15,16
In light of these results, we decided to investigate the addition of
allyltrichlorostannanes to
began with the preparation of allylsilanes 17 and 20 (Scheme 3).
The methyl esters 16 and 19 were treated with CeCl3 and
a
-amino aldehydes.17,18 Our strategy
O
R
OH
O
OH
O
H
OBc-Hex2
R'
R
R
O
c-Hex2BCl
+
R'
1,2-syn
R'
1,2-anti
NHBoc
Et3N
NHBoc
NHBoc
Me
R'
Et2O, -78 °C
O, 0 °C
Et2
10a, R = Me
10b, R = i-Pr
10c, R = Bn
9a, R = Me, R' = C13H27
9b, R = i-Pr, R' = C13H27
12a, R = Me, R' = i-Pr
12b, R = i-Pr, R' = i-Pr
12c, R = Bn, R' = i-Pr
13a, R = Me, R' = Ph
13b, R = i-Pr, R' = Ph
13c, R = Bn, R' = Ph
14, R = i-Pr, R' = t-Bu
15a, R = Me, R' = C13H27
15b, R = i-Pr, R' = C13H27
15c, R = Me, R' = i-Pr
15d, R = i-Pr, R' = i-Pr
15e, R = Bn, R' = i-Pr
15f, R = Me, R' = Ph
15g, R = i-Pr, R' = Ph
15h, R = Bn, R' = Ph
15i, R = i-Pr, R' = t-Bu
11a, R' = C13H27
11b, R' = i-Pr
11c, R' = Bn
11d, R' = t-Bu
Scheme 2. Boron enolate additions to a-aminoaldehydes 10a–c.

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5893
i.CeCl3, TMSCH2MgCl
SnCl4
THF, -78 °C, 1 h
then, rt, 18h
O
CH2Cl2
Cl3Sn
TMS
TMS
60 min.
rt
MeO
MeO
ii.Amberlyst 15
n-hexane, 25 °C, 3h
88 %
16
18
17
SnCl4
CH2Cl2
10 min.
rt
O
i.CeCl3, TMSCH2MgCl
THF, -78 °C, 18h
ii.Amberlyst 15
n-hexane, 25 °C, 3h
Cl3Sn
C13H27
21
C13H27
19
C13H27
20
70%
Scheme 3. Preparation of allyltrichlorostannanes 18 and 21.
Cl3Sn
18
OH
Boc
HN
+
O
(Cl)n
Sn
R
CH2Cl2
-78 ºC
O
R
R
1,2-syn
NHBoc
H
H
R
H
NHBoc
A
10a - R = Me
10b - R = i-Pr
10c - R = Bn
10d - R = i-Bu
10e - R = CH2OTBS
10f - R = CH3S(CH2)2
10g - R = CH2OTBDPS
22a - R = Me, 61%, ds 86:14
22b - R = i-Pr, 50%, ds > 95:5
22c - R = Bn, 40%, ds > 95:5
22d - R = i-Bu, 40%, ds > 95:5
22e - R = CH2OTBS, 62%, ds 75:25
22f - R = CH3S(CH2)2, 34%, ds 86:14
22g - R = CH2OTBDPS, 58%, ds > 95:5
Scheme 4. Coupling reaction of aldehydes 10a–g with allyltrichlorostannane 18.
O
OH
HN
O
R
i. TFA, 1,2-ethanedithiol
rt, 50 min.
ii. triphosgene, CH2Cl2
0 °C, 1 h, then rt, 2 h
R
Ha Hb
NHBoc
22b, R = i-Pr
23b, R = i-Pr, 45% (JHa/Hb = 4.9 Hz)
23c, R = Bn, 70% (JHa/Hb = 5.1 Hz)
23d, R = i-Bu, 53% (JHa/Hb = 5.5 Hz)
22c, R = Bn
22d, R = i-Bu
Scheme 5. Proof of the relative stereochemistry for 22b–d.
OH
O
OH
O3, Me2S
CH2Cl2
+
Me
Me
Me
N
22a
NHBoc
Boc
NHBoc
8a (48%)
24 (19%)
Scheme 6. Ozonolysis of homoallylic alcohol 22a.
Treatment of amino alcohol 22f under the same oxidation re-
action conditions provided ketone 8f with concomitant oxidation
to the sulfone in 89% yield (Scheme 7).25
chemical shifts at 24.8, 28.4, and 100.3 ppm are characteristic of
a 1,3-anti dimethyl acetonide.
The coupling reaction of allyltrichlorostannane 21 with a-ami-
Diastereoselective reduction of hydroxyketones 8a–d using
a slight modification of the Narasaka protocol (n-Bu3B/LiBH4) pro-
vided the desired 1,3-syn diols 4a–d in good yields and with ex-
cellent diastereoselectivities (Scheme 7).26–28
The relative stereochemistry of the 1,3-diols was determined
after analysis of acetonides 25 and 26, easily prepared from diols 4b
and 4c, respectively (Scheme 8).29 Analysis of the 13C NMR spectra
showed resonances at 19.5, 30.3, and 98.5 for 25 and 19.8, 30.0, and
98.8 for 26, characteristic of 1-3-syn acetonides.29,30
noaldehydes 10a–d and 10h led to the anti-Felkin homoallylic
alcohols 28a–d and 28h, respectively, in good yields and with
high levels of diastereoselectivity (for the two steps, preparation of
the aldehyde and coupling with allyltrichlorostannane 21)
(Scheme 10).7,15
The relative stereochemistry was determined after conversion
of 28a–c to the corresponding N-Boc-oxazolidinones 29a (55%),
29b (49%), and 29c (53%), respectively, by treatment of 28a–c with
triphosgene (Scheme 11). The observed coupling constants in the
1H NMR spectra (JHa/Hb¼3.6 Hz for 29a, J 2.4 Hz for 29b and 2.3 Hz
for 29c) unambiguously established that hydrogens Ha and Hb are
on opposite faces of the heterocyclic ring (Scheme 11).16,21
As observed before, attempts to promote double bond oxidation
in homoallylic alcohol 28a by ozonolysis led to low yields of the
Treatment of aminoketones 8b and 8f with with Me4NBH(OAc)3
in CH3CN provided the corresponding 1,3-anti diols 6b (ds>95:05)
and 6f (ds 60:40) in good yields (Scheme 9).31
The relative stereochemistry for diol 6b was ascertained by its
conversion to acetonide 27 (Scheme 9). The observed 13C NMR

5894
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
i. OsO4(cat.)
OH
O
OH
Et2O/H2O (1:1), 2h
R
R
ii. then NaIO4, 18h
NHBoc
NHBoc
8a, R = Me
8b, R = i-Pr
8c, R = Bn
8d, R= i-Bu
22a, R = Me
22b, R = i-Pr
22c, R = Bn
22d, R= i-Bu
Li
H
H
B
H
OH OH
H
R
H
(n-Bu)3B, rt, 2h
LiBH4, -78 °C, THF
nBu
B
NHBoc
R
H
H
O
O
nBu
4a, R = Me, 89%, ds >95:5
4b, R = i-Pr, 40%, ds >95:5
4c, R = Bn, 69%, ds >95:5
4d, R= i-Bu, 60%, ds >95:5
Bn
i. OsO4
O
S
O
OH O
OH
Et2O/H2O (1:1), 2h
MeS
Me
ii. then NaIO4, 18h
89%
NHBoc
NHBoc
8f
22f
Scheme 7. Synthesis of 4-N-Boc-amino-3-hydroxy ketones and diastereoselective reduction to 1,3-syn diols.
syn (5) and 1,3-anti (7) diols in good yields. Treatment of ketones
Me OH OH
OH OH
9a–d with Zn(BH4)2 in CH2Cl2 gave 1,3-syn diols 5a–d with mod-
erate to high levels of diastereoselectivity in good yields for the
two-step sequence (oxidation of the double bond and reduction).30
The 1,3-syn (5) and 1,3-anti (7) diols are separated by flash chro-
matography (Scheme 13).14,26
The relative stereochemistry of the 1,3-syn diols was de-
termined after analysis of acetonide 31, prepared from diol 5c
(Scheme 13). Analysis of the 13C NMR spectra showed resonances at
19.8, 30.1, and 98.6 for 31, characteristic of a 1,3-syn acetonide.29
The corresponding 1,3-anti diols 7a–d were obtained in good
yields and good levels of diastereoselectivity after reduction of
aminoketones 9a–d with Me4NBH(OAc)3 in CH3CN as solvent
(Scheme 14).31
Me
NHBoc
NHBoc
4c
4b
Me2C(OMe)2
CSAcat., 2h
97%
Me2C(OMe)2
CSAcat., 2h
92%
δ 98.8 ppm
δ 98.5 ppm
δ 30.0 ppm
δ 19.8 ppm
δ 30.3 ppm
δ 19.5 ppm
Me Me
Me Me
O
O
Me
O
O
Me
25
NHBoc
26
NHBoc
The relative stereochemistry of the 1,3-diols was established
after analysis of acetonide 32, prepared from diol 7d (Scheme 14).
13C NMR chemical shifts at 24.6, 25.4, and 100.3 for 32, confirmed
the 1-3-anti relationship.29
Scheme 8. Proof of the relative stereochemistry for diols 4b and 4c.
desired product 9a (10% yield) together with pyrrol derivative 30 in
13% yield (Scheme 12).23
Again, as noted for 22a–d, the best way to promote this double
bond oxidation is by treatment of homoallylic alcohols 28a–d and
28h with OsO4/NaIO4. This protocol led to 4-N-Boc-amino-3-
hydroxy ketones 9a–d and 9h in good yields (Scheme 13).7,22,24
However, attempts to reduce these aminoketones using the
modified Narasaka26 conditions led to low yields and low diaster-
eoselectivities and the use of DIBAL-H gave a 50:50 mixture of 1,3-
3. Conclusions
We have described herein that high levels of substrate-based
1,2-syn-stereocontrol could be achieved in the achiral allyltri-
chlorostannane addition reactions to N-Boc-a-amino aldehydes
leading to the anti-Felkin products, which were easily converted
Me OH
NHBoc
O
Me OH OH
Me4NBH(OAc)3
Me
Me
CH3CN, -40 °C
AcOH, 18h
1,3-anti (6b)
NHBoc
8b
68%, ds >95:05
O
S
O
OH OH
O
S
O
OH O
Me4NBH(OAc)3
Me
Me
CH3CN, -40 °C
AcOH, 18h
NHBoc
1,3-anti (6f)
NHBoc
8f
73%, ds 60:40
δ 24.8 ppm
δ 28.4 ppm
Me Me
δ 100.3 ppm
Me
OH OH
O
O
Me
Me2C(OMe)2
CSAcat., 2h
72%
Me
Me
NHBoc
6b
NHBoc
27
Scheme 9. 1,3-anti Diols 6b and 6f and proof of the relative stereochemistry for 6b.

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5895
Cl3Sn
Me
21
OH
CH2Cl2
-78 °C
O
R
Me
R
H
NHBoc
NHBoc
10a, R = Me
28a, R = Me, 45%, ds 90:10
10b, R = i-Pr
10c, R = Bn
28b, R = i-Pr, 46%, ds >95:05
28c, R = Bn, 60%, ds >95:05
28d, R = i-Bu, 42%, ds >95:05
28h, R = CH2OBn, 50%, ds 70:30
10d, R = i-Bu
10h, R = CH2OBn
Scheme 10. Coupling reaction with of allyltrichlorostannane 21 with a-aminoaldehydes.
O
OH
O
BocN
R
triphosgene
CH2Cl2, rt
R
Me
Me
NHBoc
Ha Hb
28a, R = Me
28b, R = i-Pr
28c, R = Bn
29a, R = Me, 55% (JHa/Hb = 3.6 Hz)
29b, R = i-Pr, 49% (JHa/Hb = 2.4 Hz)
29c, R = Bn, 53% (JHa/Hb = 2.3 Hz)
Scheme 11. Oxazolidinone formation.
OH
Me
O
Me
OH
NHBoc
9a (10%)
O3, Me2S
Me
Me
+
CH2Cl2
28a
NHBoc
Me
Me
N
Boc
30 (13%)
Scheme 12. Ozonolysis of homoallylic alcohol 28a.
to the corresponding 4-N-Boc-amino-3-hydroxy ketones in good
yields. This methodology stands as a new and very efficient ap-
proach to 4-N-Boc-amino-3-hydroxy ketones. After reduction of
the carbonyl function, these ketones were converted to 1-deoxy-
5-hydroxy sphingosine analogues. 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 anti-
cancer principles. Further studies in this direction are
underway.32
OH
i. OsO4(cat.)
OH
O
Et2O/H2O (1:1), 2h
R
R
C13H27
C13H27
ii. then NaIO4, 18h
NHBoc
NHBoc
9a, R = Me, 92%
9b, R = i-Pr, 80%
9c, R = Bn, 89%
9d, R = i-Bu, 94%
9h, R = CH2OBn, 92%
28a-d and 28h
OH OH
OH OH
C13H27
NHBoc
1,3-anti (7)
OH
O
OH OH
C13H27
NHBoc
1,3-anti (7)
Zn(BH4)2
R
+
Me4NBH(OAc)3
CH3CN, -40 °C
AcOH, 18 h
R
R
R
C13H27
NHBoc
1,3-syn (5)
C13H27
CH2Cl2, -20 °C, 2 days
NHBoc
9a, R = Me
a, R = Me, 48%, ds 92:08
b, R = i-Pr, 53%, ds 75:25
c, R = Bn, 49%, ds > 95:05
d, R = i-Bu, 78%, ds 70:30
9b, R = i-Pr
9c, R = Bn
9d, R = i-Bu
a, R = Me, 57%, ds 96:04
b, R = i-Pr, 42%, ds 95:05
c, R = Bn, 40%, ds 90:10
d, R = i-Bu, 42%, ds 92:08
δ 30.1 ppm
δ 19.8 ppm
δ 24.6 ppm
δ 25.4 ppm
Me Me
Me Me
OH OH
C13H27
5c
OH OH
C13H27
O
O
O
O
δ 98.6 ppm
δ 100.3 ppm
Me
Me2C(OMe)2
Me2C(OMe)2
Me
C13H27
31
C13H27
32
CSAcat., 2 h
CSAcat., 2 h
87%
NHBoc
Me NHBoc
NHBoc
Me
NHBoc
7d
97%
Scheme 13. Synthesis of 1,3-syn diols 5a–d and proof of stereochemistry of diol 5c.
Scheme 14. Synthesis of 1,3-anti diols 7a–d and proof of stereochemistry of diol 7d.

5896
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
4. Experimental
4.2.3. tert-Butyl (2S,3S)-3-hydroxy-6-methyl-5-oxo-1-
phenylheptan-2-ylcarbamate (12c)
4.1. General information
Yield: 92%; ds 95:05 (syn/anti); 1H NMR (C6D6, 300 MHz):
d 7.26–
6.87 (m, 5H), 5.00 (d, J 10.8 Hz, 1H), 3.99 (d, J 9.5 Hz, 1H), 3.87 (q, J
6.5 Hz, 1H), 3.75 (s, 1H), 2.96 (dd, J 4.8, 16.6 Hz, 1H), 2.93 (dd, J 3.3,
16.6 Hz, 1H), 2.44 (dd, J 9.9, 17.9 Hz, 1H), 2.10 (dd, J 2.4, 17.9 Hz, 1H),
1.90 (sept, J 6.9 Hz, 1H), 1.43 (s, 9H), 0.72 (d, J 6.9 Hz, 3H), 0.69 (d, J
All reactions were carried out under an atmosphere of argon or
nitrogen in flame-dried glassware with magnetic stirring.
Dichloromethane, triethylamine, 2,6-lutidine, diisopropylamine,
dimethylformamide, and N-methylpyrrolidone were distilled from
CaH2. Dimethyl sulfoxide was distilled under reduced pressure
from calcium hydride and stored over molecular sieves. THF and
toluene were distilled from sodium/benzophenone ketyl. Oxalyl
chloride was distilled immediately prior to use. MeOH was distilled
from Mg(OMe)2. Petrol ether refers to the fraction boiling between
40–60 ꢀC. Purification of reaction products was carried out by flash
chromatography using silica gel (230–400 mesh). Analytical thin
layer chromatography was performed on silica gel 60 and GF (5–
6.9 Hz, 3H); 13C NMR (C6D6, 62.5 MHz):
d
215.8, 198.4, 156.0, 139.0,
129.8, 128.7, 126.6, 78.8, 67.1, 56.1, 44.0, 41.2, 39.1, 28.4, 17.8, 17.7; IR
(film):
n 3388, 2971, 2918, 2846, 1701, 1497, 1445, 1365, 1254, 1169,
1043, 866 cmꢁ1. HRMS (ESI TOF-MS ESþ): calcd for C19H30NO4:
336.2175; found: 336.2176.
4.2.4. tert-Butyl (3S,4S)-4-hydroxy-2,7,7-trimethyl-6-oxooctan-
3-ylcarbamate (14)
Yield: 42%; ds 50:50 (1,2-syn); 1H NMR (CDCl3, 300 MHz):
d 4.85
40-
m
m thickness) plates. Visualization was accomplished with UV
(d, J 9.3 Hz, 1H), 4.23 (d, J 9.0 Hz, 1H), 3.12 (t, J 9.3 Hz, 1H), 2.73 (dd, J
2.7, 18.0 Hz, 1H), 2.58 (dd, J 9.6, 18.0 Hz, 1H), 1.85 (m, 1H), 1.45 (s,
light and anisaldehyde, ceric ammonium nitrate stain or phos-
phomolybdic acid followed by heating or I2 staining. 1H NMR
spectra were taken in CDCl3 at 250 MHz, 300 MHz or 500 MHz and
are reported in parts per million using solvent as an internal
standard (CDCl3 at 7.26 ppm) unless otherwise indicated. Data are
reported as ap¼apparent, s¼singlet, d¼doublet, t¼triplet,
q¼quartet, quint¼quintet, sext¼sextet, ap t¼apparent triplet,
m¼multiplet, br¼broad, td¼triplet of doublets, quint d¼quintet of
doublets, coupling constant(s) in hertz; integration. Proton-
decoupled 13C NMR spectra were taken in CDCl3 at 62.5 MHz,
75 MHz or 125 MHz and are recorded in parts per million using
solvent as an internal standard (CDCl3 at 77.0 ppm) unless other-
wise indicated.
9H), 1.14 (s, 9H), 0.97 (t, J 6.9 Hz, 6H); IR (film):
n 3446, 2935, 2864,
1709, 1502, 1367, 1217, 1171, 1081, 1020 cmꢁ1
.
4.2.5. tert-Butyl (3S,4R)-4-hydroxy-2,7,7-trimethyl-6-oxooctan-
3-ylcarbamate (15i)
Yield: 42%; ds 50:50 (1,2-anti); 1H NMR (CDCl3, 300 MHz):
d 4.32
(d, J 9.5 Hz, 1H), 3.77 (dt, J 7.5, 2.8 Hz, 1H), 3.41 (dt, J 10.0, 2.3 Hz,
1H), 2.71 (dd, J 8.5, 2.5 Hz, 1H), 2.55 (dd, J 8.5, 2.5 Hz, 1H), 2.12 (m,
1H), 1.35 (s, 9H), 1.04 (s, 9H), 0.84 (d, J 6.75 Hz, 3H), 0.76 (d, J
6.75 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d
218.2, 156.2, 79.3,
69.0, 58.2, 44.4, 40.4, 28.3, 27.0, 26.3, 20.2, 15.6; IR (film): 3446,
3013, 2968, 2935, 2875, 1699, 1506, 1367, 1313, 1217, 1072, 925,
872 cmꢁ1
n
.
4.2. Representative procedure for methyl ketone aldol
reactions
4.2.6. tert-Butyl (2S,3S)-3-hydroxy-5-oxo-5-phenylpentan-
2-ylcarbamate (13a)
Yield: 41%; ds (95:05); 1H NMR (C6D6, 250 MHz):
d 7.80–6.85 (m,
To a solution of the corresponding methyl ketone (0.592 mmol)
in Et2O (5.0 mL) under an argon atmosphere at ꢁ10 ꢀC was added
dropwise (c-Hex)2BCl (1.776 mmol). After this, Et3N (2.5 equiv,
2.072 mmol) was added dropwise. The resulting mixture was stir-
red for 1 h at 0 ꢀC. The solution was cooled to ꢁ78 ꢀC and the al-
dehyde (1.0 equiv, 0.296 mmol) was added dropwise to the enolate
solution. The resulting mixture was stirred for 3 h at ꢁ78 ꢀC. The
reaction was quenched by addition of 4.0 mL of MeOH and warmed
to rt. The solvent was removed under reduced pressure, and the
resulting oil was purified by flash chromatography (silica gel 230–
400 mesh), providing the aldol adducts.
5H), 4.92 (d, J 9.8 Hz, 1H), 3.85 (d, J 8.8 Hz, 1H), 3.73 (t, J 7.0 Hz, 1H),
3.54 (s, 1H), 2.85 (dd, J 9.25, 18.0 Hz, 1H), 2.69 (dd, J 3.0, 18.0 Hz,
1H), 1.45 (s, 9H) 1.17 (d, J 6.8 Hz, 3H); 13C NMR (C6D6, 75 MHz):
d
200.8, 156.0, 137.1, 133.2, 78.7, 70.4, 50.3, 42.7, 28.5, 27.9, 18.7.
HRMS (ESI TOF-MS ESþ): calcd for C16H24NO4: 294.1705; found:
294.1620.
4.2.7. tert-Butyl (3S,4S)-4-hydroxy-2-methyl-6-oxo-6-
phenylhexan-3-ylcarbamate (13b)
Yield: 30%; ds 95:05 (syn/anti); 1H NMR (C6D6, 250 MHz):
d
7.79–6.98 (m, 5H), 5.16 (d, J 10.3 Hz, 1H), 4.37 (d, J 7.8 Hz, 1H), 3.7
4.2.1. tert-Butyl (3S,4R)-4-hydroxy-2-methyl-6-oxononadecan-
3-ylcarbamate (15b)
(t, J 8.8 Hz, 1H), 3.02 (dd, J 9.0, 18.0 Hz, 1H), 2.90 (dd, J 3.3, 18.0 Hz,
1H), 1.95 (m, 1H), 1.46 (s, 9H), 1.02 (d, J 6.8 Hz, 3H), 0.96 (d, J 6.5 Hz,
Minor isomer; ds 66:34 (syn/anti); 1H NMR (C6D6, 300 MHz):
3H); 13C NMR (C6D6, 62.5 MHz):
d
201.2, 156.7, 137.1, 133.2, 128.6,
78.6, 67.3, 50.0, 30.7, 28.5, 20.0, 19.9, 8.7. IR (film): 3487, 3055,
2985, 2930, 2852, 1670, 1600, 1448, 1373, 1265, 1212, 1085,
1010 cmꢁ1 HRMS (ESI TOF-MS ESþ): calcd for C18H28NO4:
d
4.31 (d, J 9.5 Hz, 1H), 3.85 (m, 2H), 3.53 (d, J 4.5 Hz, 1H), 2.49 (d,
n
J 4.5 Hz, 2H), 2.27 (m, 1H), 2.15 (dt, J 6.25, 3.0 Hz, 2H), 1.55 (br s,
11H), 1.40 (s, 20H), 1.01 (t, J 6.8 Hz, 3H), 1.00 (d, J 6.8 Hz, 6H); 13C
.
NMR (C6D6, 75 MHz):
d 211.7, 156.4, 78.9, 69.2, 58.8, 46.3, 32.3,
322.2018; found: 322.1960.
30.2, 30.1, 30.1, 30.1, 29.9, 29.8, 29.5, 28.5, 27.5, 23.7, 23.1, 20.4,
15.8, 14.4.
4.2.8. tert-Butyl (2S,3S)-3-hydroxy-5-oxo-1,5-diphenylpentan-
2-ylcarbamate (13c)
4.2.2. tert-Butyl (3S,4S)-4-hydroxy-2,7-dimethyl-6-oxooctan-
Yield: 10%; ds 95:05 (syn/anti); 1H NMR (CDCl3, 300 MHz):
3-ylcarbamate (12b)
Yield: 15%; ds 95:05 (syn/anti); 1H NMR (C6D6, 300 MHz):
d 4.88
d
7.69–7.01 (m, 10H), 5.19 (d, J 9.5 Hz, 1H), 4.21 (d, J 8.5 Hz, 1H), 4.00
(t, J 8.5 Hz, 1H), 3.11 (dd, J 3.8, 7.5 Hz, 1H), 2.95 (dd, J 9.8, 18.3 Hz,
1H), 2.72 (dd, J 9.8, 3.8 Hz,1H), 2.60 (dd, J 7.3, 2.5 Hz, 1H), 1.43 (s,
(d, J 8.5 Hz, 1H), 4.19 (d, J 9.0 Hz, 1H), 3.44 (br s, 1H), 3.29 (t, J 9.1 Hz,
1H), 2.50 (dd, J 9.6, 18.3 Hz, 1H), 2.34 (dd, J 2.7, 18.3 Hz, 1H), 2.03 (m,
1H), 1.86 (m, 1H), 0.98 (d, J 6.6 Hz, 3H), 0.92 (d, J 6.6 Hz, 3H), 0.80 (d,
9H); 13C NMR (CDCl3, 75 MHz):
d
201.2, 139.1, 136.9, 133.1, 129.9,
129.5, 128.8, 128.5, 126.5, 78.8, 67.1, 56.3, 42.4, 39.1, 28.3; IR (film):
3487, 3055, 2985, 2930, 2852, 1670, 1600, 1448, 1373, 1265, 1212,
1085, 1010 cmꢁ1
J 6.9 Hz, 6H); 13C NMR (CDCl3, 75 MHz):
d
215.8, 156.5, 78.5, 67.2,
60.0, 44.6, 41.3, 30.8, 28.5, 19.8, 17.9; IR (film): 3443, 2971, 2924,
1703, 1500, 1217, 1166, 1041, 926 cmꢁ1
n
n
.
.

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5897
4.3. Allylsilanes 17 and 20 (general procedure)
In 3-necked 500 mL round-bottomed flask powdered
4.4. Homoallylic alcohols: general procedure
a
To a solution of the corresponding allylsilane (1.5 mmol) in
CH2Cl2 (5 mL) at rt was added SnCl4 (1.1 mmol). The resulting
solution was stirred at 0 ꢀC for 2 h and then cooled to ꢁ78 ꢀC
when a solution of aminoaldehydes (1.2 mmol) in CH2Cl2 (2 mL)
was added. This mixture was stirred for 2 h at ꢁ78 ꢀC and
quenched by the slow addition of CH2Cl2 (5 mL) and satd aq
solution of NH4Cl (5 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢂ5 mL). The com-
bined organic layers were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash chromatography on silica gel
(30% EtOAc in hexane) gave the corresponding homoallylic
alcohols.
CeCl3$H2O (15.44 g, 41.4 mmol) was heated under vacuum (1 Torr)
at 160 ꢀC for 12 h with vigorous stirring, resulting in the formation
of a free flowing white solid. The reaction flask was flushed with
argon and allowed to cool to rt when anhydrous THF (65 mL) was
added to the vigorously stirred anhydrous cerium(III) chloride
forming a uniform white suspension, which was kept under stirring
for 2 h. During this time, a separate three-necked 100 mL flask,
fitted with a condenser and a pressure-equalizing dropping funnel,
was charged with Mg turnings (1 g, 41.4 mmol) and the whole
apparatus was flame dried under a flow of argon. To this flask was
added dropwise a solution of ClCH2SiMe3 (5.8 mL, 41.4 mmol) in
anhydrous THF (27 mL). This mixture was stirred for 3 h until al-
most all of the Mg had dissolved. The anhydrous CeCl3 suspension
was now cooled to ꢁ78 ꢀC. To this suspension was added dropwise
the previously prepared Grignard reagent forming an off-white
suspension that was stirred at ꢁ78 ꢀC for 2 h. At this time, a solu-
tion of the corresponding ester 16 or 19 (13.8 mmol) in anhydrous
THF (8 mL) was added to the Grignard–cerium chloride complex
dropwise over 5 min, and the resulting mixture was warmed
gradually to rt. When consumption of the starting ester was com-
plete, as determined by TLC (3 h), the resulting gray solution was
cooled to 0 ꢀC and quenched by the addition of a satd aq solution of
NH4Cl (30 mL). The organic layer was separated, and the aqueous
layer was extracted with Et2O (2ꢂ50 mL). The combined organic
layers were washed with brine (2ꢂ50 mL) and dried (MgSO4). After
filtration, the solvent was removed under reduced pressure to give
a slightly yellow liquid that was dissolved in CH2Cl2 (100 mL). To
this flask was added Amberlyst 15 (1.0 g) and this mixture was
stirred at rt until complete consumption of starting material. The
resin was then removed by filtration and washed with CH2Cl2
(100 mL). The solvent was removed under reduced pressure to give
allylsilanes 17 and 20.
4.4.1. tert-Butyl (2S,3S)-5-benzyl-3-hydroxyhex-5-en-2-
ylcarbamate (22a)
Yield: 61% (two steps); ds 86:14; TLC: Rf 0.39 (20% EtOAc in
hexane); 1H NMR (CDCl3, 300 MHz):
d 1.16 (d, 3H, J 7.0 Hz), 1.44 (s,
9H), 2.16 (m, 2H), 2.28 (br s, 1H), 3.33 (d, 1H, J 15.0 Hz), 3.41 (d, 1H, J
15.4 Hz), 3.64 (m, 2H), 4.82 (br s, 1H), 4.91 (s, 1H), 4.95 (s, 1H), 7.16–
7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d
18.6, 28.4, 40.5, 42.9, 49.8,
71.6, 79.1, 114.6, 126.1, 128.2, 128.8, 138.8, 145.3, 155.7; IR (film):
n
3431, 3060, 2978, 2931, 1691, 1497, 1451, 1365, 1169, 1029 cmꢁ1
.
HRMS (ESI TOF-MS ESþ): calcd for C18H28NO3: 306.1991; found:
306.1984.
4.4.2. tert-Butyl (3S,4S)-6-benzyl-4-hydroxy-2-methylhept-6-en-3-
ylcarbamate (22b)
Yield: 50% (two steps); ds >95:05; TLC: Rf 0.48 (30% EtOAc in
20
hexane); [
d
a
]
D
ꢁ14.0 (c 1.62, CH2Cl2); 1H NMR (CDCl3, 300 MHz):
0.94 (d, 6H, J 7.0 Hz), 1.43 (s, 9H), 1.75–1.85 (m, 2H), 2.16 (d, J
6.6 Hz, 2H), 3.12 (apt, 1H, J 8.8 Hz), 3.38 (br s, 2H), 3.83 (apt, 1H, J
6.2 Hz), 4.78 (br d, 1H, J 9.8 Hz), 4.94 (br s, 2H), 7.16–7.31 (m, 5H);
13C NMR (CDCl3, 75 MHz):
d
19.3, 19.7, 28.4, 30.6, 41.4, 43.1, 59.5,
67.9, 78.9, 114.8, 126.1, 128.4, 128.9, 139.0, 145.5, 156.4; IR (film):
3439, 3026, 2976, 2929, 2873, 1689, 1497, 1367, 1243, 1171,
1044 cmꢁ1 HRMS (ESI TOF-MS ESþ): calcd for C20H32NO3:
4.3.1. 2-Benzyl(allyl)trimethylsilane (17)
n
Colorless liquid; Yield: 88%; TLC: Rf 0.60 (hexane); 1H NMR
.
(CDCl3, 300 MHz):
d
0.0 (s, 9H), 1.44 (s, 2H), 3.23 (s, 2H), 4.53 (br s,
334.2382; found: 334.2177.
1H), 4.58 (br s, 1H), 7.10–7.25 (m, 5H); 13C NMR (C6D6, 75 MHz):
d
ꢁ1.0, 26.3, 45.6, 110.0, 126.4, 128.6,129.5, 140.0, 146.8; MS (70 eV):
4.4.3. tert-Butyl (2S,3S)-3-hydroxy-5-methylene-1,6-
diphenylhexan-2-ylcarbamate (22c)
m/z (%)¼204 (Mþ, 12), 189 (2), 173 (5), 147 (40), 134 (21), 115 (24),
104 (7), 91 (87), 73 (100); IR (film):
n
3074, 3026, 2955, 2897, 1633,
Yield: 40% (two steps); ds >95:05; TLC: Rf 0.48 (30% EtOAc in
20
1495, 1452, 1248, 1160, 1074, 1030 cmꢁ1; HRMS: m/z calcd for
C13H20Si: 204.1334, found: 204.1354; Anal. Calcd for C13H20Si: C,
76.40; H, 9.86; Si, 13.74. Found: C, 76.32; H, 9.81.
hexane); [
d
a
]
ꢁ18.0 (c 1.32, CH2Cl2); 1H NMR (CDCl3, 300 MHz):
D
1.40 (s, 9H), 2.03 (dd, 1H, J 5.3, 8.3 Hz), 2.19 (dd, 1H, J 9.1, 9.4 Hz),
2.61 (dd, 1H, J 8.3, 13.3 Hz), 2.80 (dd, 1H, J 6.5, 13.3 Hz), 3.07 (br s,
1H), 3.19 (br s, 1H), 3.71 (m, 2H), 3.86 (m, 1H), 4.79 (br s, 1H), 4.91
(br d, 1H, J 9.9 Hz), 6.96–7.12 (m, 2H), 7.16–7.31 (m, 8H); 13C NMR
4.3.2. Trimethyl(2-methylenepentadecyl)silane (20)
Yellow oil; Yield: 70%; TLC: Rf 0.68 (5% EtOAc in hexane); 1H
(CDCl3, 75 MHz):
126.1, 128.3, 129.0, 129.4, 138.7, 139.1, 144.2, 155.4; IR (film):
3055, 2982, 2361, 1707, 1495, 1366, 1265, 1171, 1061, 845, 739 cmꢁ1
d
28.5, 39.2, 40.5, 42.9, 53.5, 70.3, 78.9, 115.4,
NMR (CDCl3, 300 MHz):
s, 20H), 1.46 (m, 2H), 1.57 (s, 2H), 1.97 (t, J 7.0 Hz, 2H), 4.52 (br s, 1H),
4.60 (d, J 1.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
2.1, 14.2, 22.5,
22.8, 27.8, 29.4, 29.6, 29.8, 32.0, 37.9, 109.4, 146.2; IR (film): 3072,
2953, 2926, 2854, 1633, 1466, 1248, 1157 cmꢁ1
d
0.04 (s, 9H), 0.91 (t, J 7.0 Hz, 3H), 1.29 (br
n
3439,
;
d
HRMS: m/z calcd for C24H31NO3: 381.2304, found: 290.1804
n
(Mþꢁ91); Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19; N, 3.67.
.
Found: C, 75.30; H, 8.20; N, 3.63.
4.3.3. 2-Benzyl(allyl)trichlorostannane (18)
1H NMR (CDCl3, 300 MHz):
1.64 (s, 2H), 3.1 (s, 2H), 5.15 (s, 1H),
4.4.4. tert-Butyl (4S,5S)-7-benzyl-5-hydroxy-2-methyloct-7-en-4-
ylcarbamate (22d)
d
5.23 (s, 1H), 7.20–7.40 (m, 5H) (Obs. The signal at
responds to TMSCl).
d
0.45 ppm cor-
Yield: 40% (two steps); ds >95:05; TLC: Rf 0.48 (30% EtOAc in
hexane); 1H NMR (CDCl3, 300 MHz):
d 0.91 (d, 3H, J 3.2 Hz), 0.92 (d,
3H, J 6.6 Hz),1.30 (m,1H),1.43 (s, 9H),1.60 (m,1H),1.92 (m,1H), 2.18
(m, 2H), 3.35 (d, 1H, J 15.0 Hz), 3.40 (d, 1H, J 15.0 Hz), 3.57 (m, 1H),
3.65 (m, 1H), 4.64 (br d, 1H, J 9.2 Hz), 4.92 (br s, 1H), 4.95 (br s, 1H),
4.3.4. Trichloro(2-methylenepentadecyl)stannane (21)
1H NMR (CDCl3, 300 MHz):
0.89 (t, J 6.0 Hz, 3H),1.30 (br s, 20H),
1.51 (m, 2H), 2.14 (t, J 8.0 Hz, 2H), 3.15 (s, 2H), 5.07(br s,1H), 5.10 (br s,
1H) (Obs. The signal at
0.45 ppm corresponds to TMSCl); 13C NMR
(CDCl3, 75 MHz): 14.2, 22.7, 27.4, 29.1, 29.4, 29.7, 32.0, 37.4, 40.0,
116.0, 139.0 (Obs. The signal at 3.3 ppm corresponds to TMSCl).
d
7.16–7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d
22.3, 23.2, 24.9, 28.4,
40.8, 42.0, 43.0, 52.1, 70.6, 79.0, 114.7, 126.3, 128.4, 128.9, 138.9,
145.5, 156.0; IR (film): 3439, 3055, 2985, 1707, 1643, 1504, 1265,
1167 cmꢁ1
d
d
n
d
.

5898
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
4.4.5. tert-Butyl (2S,3S)-5-benzyl-1-(tert-butyldimethylsilyloxy)-3-
hydroxyhex-5-en-2-ylcarbamate (22e)
(m, 2H), 2.88 (dd, J 8.4, 13.4 Hz, 1H), 3.02 (dd, J 7.5, 13.4 Hz, 1H), 3.66
(m, 1H), 4.01 (dd, J 7.5, 16.5 Hz, 1H), 4.72 (br s, 1H), 4.78 (br s, 1H),
4.90 (d, J 9.3 Hz, 1H), 7.03–7.26 (m, 5H); 13C NMR (C6D6, 75 MHz):
Yield: 62% (two steps); ds 75:25; TLC: Rf 0.53 (30% EtOAc in
hexane); 1H NMR (CDCl3, 300 MHz):
d
0.08 (s, 6H), 0.91 (s, 9H), 1.45
d
14.6, 23.4, 28.3, 28.7, 30.0, 30.1, 30.2, 30.4, 32.6, 36.5, 39.8, 42.1,
(s, 9H), 2.17 (d, 1H, J 6.2 Hz), 2.25 (d, 1H, J 6.6 Hz), 3.13 (m, 1H), 3.36
(d, 1H, J 15.0 Hz), 3.41 (d, 1H, J 15.0 Hz), 3.52 (m, 1H), 3.73 (m, 1H),
3.87 (m, 1H), 4.11 (apt, 1H, J 6.6 Hz), 4.91 (br s, 1H), 4.95 (br s, 1H),
5.14 (d, 1H, J 8.8 Hz), 7.18–7.31 (m, 5H); 13C NMR (CDCl3, 75 MHz):
55.9, 68.7, 79.1, 112.6, 126.8, 128.9, 130.0, 139.4, 146.9, 156.3; IR
(film): n 3439, 3054, 2928, 1693, 1635, 1496, 1453, 1368, 1265, 1169,
897 cmꢁ1; HRMS (ESI TOF-MS ESþ): calcd for C30H52NO3: 474.3947;
found: 474.3982.
d
ꢁ5.5, 18.2, 25.9, 28.4, 40.7, 43.0, 53.2, 63.1, 70.6, 79.2, 114.6, 126.1,
128.3, 128.9, 139.1, 145.0, 155.7; IR (film): 3443, 3060, 2983, 2960,
2931, 2858, 1707, 1648, 1497, 1367, 1265, 1171, 1087 cmꢁ1
n
4.4.11. tert-Butyl (4S,5S)-5-hydroxy-2-methyl-7-methyleneicosan-
4-ylcarbamate (28d)
.
Yield: 42% (two steps); ds >95:05; TLC: Rf 0.62 (20% EtOAc in
20
4.4.6. tert-Butyl (3S,4S)-6-benzyl-4-hydroxy-1-(methylthio)hept-
6-en-3-ylcarbamate (22f)
hexane); [
d
a
]
ꢁ8.0 (c 1.70, CH2Cl2); 1H NMR (CDCl3, 250 MHz):
D
0.88 (t, J 6.9 Hz, 3H), 0.92 (d, J 2.7 Hz, 3H), 0.95 (d, J 2.7 Hz, 3H),
Yield: 34% (two steps); ds 86:14; TLC: Rf 0.31 (30% EtOAc in
1.26 (br s, 22H), 1.45 (s, 9H), 1.52 (m, 2H), 1.67 (m, 2H), 2.02 (apt, J
7.4 Hz, 2H), 2.20 (m, 2H), 3.65 (m, 2H), 4.67 (br d, J 9.8 Hz 1H), 4.83
hexane); 1H NMR (CDCl3, 300 MHz):
d 1.44 (s, 9H), 1.81 (m, 2H),
2.05–2.19 (m, 2H), 2.10 (s, 3H), 2.50 (m, 2H), 3.34 (d, 1H, J 15.4 Hz),
3.41 (d, 1H, J 15.4 Hz), 3.59 (m, 1H), 3.69 (m, 1H), 4.79 (br d, 1H, J
8.1 Hz), 4.94 (br s, 1H), 4.96 (br s, 1H), 7.17–7.32 (m, 5H); 13C NMR
(br s, 1H), 4.89 (br s, 1H); 13C NMR (CDCl3, 75 MHz):
d
14.0, 22.1,
22.6, 23.1, 24.7, 27.6, 28.3, 29.3, 29.4, 29.6, 31.8, 35.7, 41.4, 42.3, 52.1,
70.3, 77.1, 78.9, 112.4, 156.0; IR (film):
n 3439, 3055, 2926, 2852,
(CDCl3, 75 MHz):
115.0, 126.3, 128.5, 128.9, 138.9, 145.3, 156.1; IR (film):
2982, 2918, 1707, 1498, 1445, 1362, 1265, 1169, 1045 cmꢁ1
d
15.5, 28.3, 30.8, 32.7, 40.7, 42.9, 53.2, 70.0, 79.3,
2305, 1693, 1504, 1367, 1270, 1170, 1054, 890 cmꢁ1; HRMS (ESI TOF-
MS ESþ): calcd for C27H54NO2: 440.4104; found: 440.4051.
n
3435, 3055,
.
4.4.12. tert-Butyl (2S,3S)-1-(benzyloxy)-3-hydroxy-5-
methyleneoctadecan-2-ylcarbamate (28h)
4.4.7. tert-Butyl (2S,3S)-5-benzyl-1-(tert-butyldiphenylsilyloxy)-3-
hydroxyhex-5-en-2-ylcarbamate (22g)
Yield: 50% (two steps); ds 70:30; TLC: Rf 0.46 (20% EtOAc in
Yield: 58% (two steps); ds >95:5; TLC: Rf 0.45 (30% EtOAc in
hexane); 1H NMR (CDCl3, 250 MHz):
d 0.95 (t, 3H, J 6.9 Hz), 1.35 (br
20
hexane); [
d
a
]
D
þ9.5 (c 3.01, CH2Cl2); 1H NMR (CDCl3, 250 MHz):
s, 22H), 1.45 (s, 9H), 2.02 (t, 2H, J 7.5 Hz), 2.34 (t, 1H, J 6.0 Hz), 2.50–
2.57 (m, 1H), 3.44–3.66 (m, 1H), 3.69–3.75 (m, 1H), 3.96–4.21 (m,
2H), 4.85 (br s, 1H), 4.89 (br s, 1H), 4.92 (s, 2H), 5.25 (br d, 1H, J
1.07 (s, 9H),1.43 (s, 9H), 2.18 (apd, 2H, J 5.5 Hz), 2.72 (br s,1H), 3.34
(d, 1H, J 15.0 Hz), 3.37 (d, 1H, J 15.0 Hz), 3.62 (m, 1H), 3.73 (m, 2H),
4.12 (m, 1H), 4.91 (br s, 1H), 4.94 (br s, 1H), 5.08 (br d, 1H, J 9.0 Hz),
7.16–7.30 (m, 5H), 7.37–7.45 (m, 6H), 7.63–7.66 (m, 4H); 13C NMR
9.2 Hz), 7.13–7.19 (m, 5H); 13C NMR (CDCl3, 125 MHz):
d
14.4, 23.1,
28.1, 28.4, 29.8, 30.1, 32.3, 36.5, 41.1, 41.8, 53.0, 69.9, 72.1, 73.3, 78.9,
105.0, 112.3, 128.3, 128.5, 138.4, 146.6, 156.0; IR (film): 3445, 2926,
2854, 2359, 1714, 1504, 1367, 1265, 1170, 1093, 741 cmꢁ1
(CDCl3, 62.5 MHz):
d
19.2, 26.8, 28.4, 40.1, 42.9, 53.7, 66.0, 69.6, 79.2,
n
114.8, 126.2, 127.8, 128.4, 129.0, 129.9, 132.8, 135.5, 139.1, 145.1,
.
155.8; IR (film):
n 3439, 3053, 2932, 2858, 2361, 1711, 1497, 1429,
1367, 1265, 1171, 1113, 897, 823, 739 cmꢁ1. HRMS (ESI TOF-MS ESþ):
calcd for C34H45NO4Si: 560.3118; found: 560.3107.
4.5. Oxazolidinone formation (general procedure)
A mixture of 60 mg of homoallylic alcohol and 0.2 mL of 1,2-
ethanedithiol in 2 mL of trifluoroacetic acid was stirred for 10 min
at 0 ꢀC and then for 50 min at rt. The mixture was quenched by the
addition of 10 mL of pH 5.0 phosphate buffer, and the organic layer
was extracted with Et2O and dried with MgSO4. To a solution of the
amino alcohols (0.213 mmol) in CH2Cl2 (1.2 mL) at 0 ꢀC was added
slowly a solution of triphosgene (76 mg, 0.256 mmol) in CH2Cl2
(1.2 mL). The mixture was stirred for 3 h at rt, diluted with CH2Cl2
(10 mL), and washed with satd aq. NaHCO3 (5 mL). The aqueous
phase was extracted with CH2Cl2 (2ꢂ10 mL) and the organic layer
dried (MgSO4) and concentrated to provide the crude product,
which was purified by flash chromatography (20% EtOAc in
hexane).
4.4.8. tert-Butyl (2S,3S)-3-hydroxy-5-methyleneoctadecan-2-
ylcarbamate (28a)
Yield: 45% (two steps); ds 90:10; TLC: Rf 0.36 (20% EtOAc in
20
hexane); [
d
a
]
ꢁ1.0 (c 2.4, CH2Cl2); 1H NMR (CDCl3, 250 MHz):
D
0.88 (t, J 6.6 Hz, 3H), 1.21 (d, J 7.0 Hz, 3H), 1.25 (br s, 19H), 1.41 (m,
2H), 1.45 (s, 9H), 1.65 (m, 2H), 2.02 (t, J 7.8 Hz, 2H), 2.12 (dd, J 9.6,
13.7 Hz, 1H), 2.24 (dd, J 3.0, 13.7 Hz, 1H), 3.61 (m, 2H), 4.78 (m, 2H),
4.83 (br s, 1H), 4.89 (br s, 1H); 13C NMR (C6D6, 75 MHz):
d
14.5, 18.9,
23.2, 28.2, 28.6, 29.9, 30.1, 30.3, 32.4, 36.4, 41.7, 50.2, 71.9, 78.7,
112.3, 146.8, 156.9; IR (film):
n 3439, 2924, 2848, 1688, 1504, 1368,
1247, 1171 cmꢁ1; HRMS (ESI TOF-MS ESþ): calcd for C24H48NO3:
398.3634; found: 398.3564.
4.4.9. tert-Butyl (3S,4S)-4-hydroxy-2-methyl-6-
methylenenonadecan-3-ylcarbamate (28b)
4.5.1. (4S,5S)-5-(2-Benzylallyl)-4-isopropyloxazolidin-2-one (23b)
Yield: 45% (two steps); TLC: Rf 0.20 (30% EtOAc in hexane); 1H
Yield: 46% (two steps); ds >95:05; TLC: Rf 0.47 (20% EtOAc in
NMR (CDCl3, 300 MHz): d 0.83 (d, 3H, J 6.8 Hz), 0.88 (d, 3H, J 6.7 Hz),
20
hexane); [
a]
ꢁ12.0 (c 0.24, CH2Cl2); 1H NMR (CDCl3, 300 MHz):
1.64 (m, 1H), 2.22 (dd, 1H, J 4.8, 14.8 Hz), 2.40 (dd, 1H, J 8.1, 14.8 Hz),
2.65 (m, 1H), 3.17 (apt, 1H, J 4.9 Hz), 3.40 (s, 2H), 4.34 (dt, 1H, J 4.8,
4.9 Hz), 4.94 (br s, 1H), 4.98 (br s, 1H), 7.17–7.31 (m, 6H).
D
d
0.88 (t, J 7.0 Hz, 3H), 0.98 (apt, J 7.0 Hz, 6H), 1.26 (br s, 22H), 1.45 (s,
9H), 1.82 (m, 2H), 2.02 (m, 2H), 2.18 (m, 2H), 3.19 (t, J 9.0 Hz, 1H),
3.78 (m, 1H), 4.83 (br s, 2H), 4.89 (br s, 1H); 13C NMR (CDCl3,
75 MHz):
31.9, 35.8, 42.0, 59.5, 67.6, 78.9, 112.5, 146.5, 156.5; IR (film):
3079, 2924, 2854, 1688, 1501, 1498, 1370, 1368, 1247, 1173 cmꢁ1
d
14.1, 19.4,19.9, 22.7, 27.7, 28.4, 29.3, 29.5, 29.6, 29.7, 30.8,
4.5.2. (4S,5S)-4-Benzyl-5-(2-benzylprop-2-enyl)-1,3-oxazolidin-2-
one (23c)
n
3441,
.
Yield: 46 mg (70%); Rf 0.52 (50% EtOAc in hexane); 1H NMR
(CDCl3, 300 MHz): d 2.10 (dd, 1H, J 14.6, 6.0 Hz), 2.33 (dd, 1H, J 14.6,
4.4.10. tert-Butyl (2S,3S)-3-hydroxy-5-methylene-1-
phenyloctadecan-2-ylcarbamate (28c)
7.3 Hz), 2.72 (dd, 1H, J 13.4, 6.3 Hz), 2.81 (dd, 1H, J 13.4, 7.0 Hz), 3.20
(d,1H, J 15.4 Hz), 3.26 (d, 1H, J 15.4 Hz), 3.63 (q,1H, J 6.0 Hz), 4.37 (q,
1H, J 6.0 Hz), 4.86 (s, 1H), 4.89 (s, 1H), 5.98 (br s, 1H), 7.08–7.33 (m,
Yield: 60% (two steps); ds >95:05; TLC: Rf 0.37 (20% EtOAc in
20
hexane); [
d
a
]
D
ꢁ3.1 (c 3.50, CH2Cl2); 1H NMR (C6D6, 300 MHz):
10H); 13C NMR (CDCl3, 75 MHz):
d
40.1, 41.4, 43.0, 58.5, 79.9, 115.4,
0.93 (t, J 7.0 Hz, 3H), 1.33 (br s, 22H), 1.43 (s, 9H), 1.79 (m, 2H), 2.22
126.3, 127.1, 128.3, 128.8, 128.9, 135.7, 138.5, 142.9, 158.5; IR (film):

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5899
3278, 3068, 3028, 2917, 2852, 1754, 1644, 1600, 1494, 1456, 1389,
29.7, 31.9, 83.2, 108.9, 110.1, 131.2, 136.2, 150.5; IR (film):
n
2926,
1246, 1096, 1013, 902, 735, 703 cmꢁ1; HRMS (ESI TOF-MS ESþ):
calcd for C31H49NO4Na: 522.3560; found: 522.3676.
2852, 1740, 1514, 1462, 1389, 1327, 1254, 1176, 1122, 1028 cmꢁ1
.
4.5.3. (4S,5S)-5-(2-Benzylallyl)-4-isobutyloxazolidin-2-one (23d)
Yield: 53% (two steps); TLC: Rf 0.26 (30% EtOAc in hexane); 1H
4.6. Homoallylic alcohol oxidation (general procedure)
NMR (CDCl3, 300 MHz):
d
0.89 (d, 3H, J 6.2 Hz), 0.91 (d, 3H, J 6.2 Hz),
To a solution of 0.78 mmol of the corresponding homoallylic al-
cohol in a mixture of 5 mL of water and 5 mL of ether at rt was added
0.016 mmol of osmium tetroxide. This mixture was stirred for 2 h at
rt, then 3.1 mmol of sodium periodate was added and the mixture
was stirred for another 24 h. The layers were separated and the
aqueous layer was extracted with ether (2ꢂ15 mL). The combined
organic layer was dried with MgSO4, filtered, and concentrated in
vacuo. Yields refer to the unpurified 4-N-Boc-amino-3-hydroxy
ketones. These4-N-Boc-amino-3-hydroxy ketonesareveryunstable
to flash chromatography and were reduced immediately after
preparation. The listedspectroscopic data are for the crude products.
1.23 (m, 1H), 1.45 (dt, 1H, J 5.5, 8.8 Hz), 1.59 (m, 1H), 2.25 (dd, 1H, J
5.5, 15.0 Hz), 2.42 (dd, 1H, J 7.7, 15.0 Hz), 3.40 (s, 2H), 3.48 (dt, 1H, J
5.5, 8.8 Hz), 4.22 (dt, 1H, J 5.5, 7.7 Hz), 4.95 (br s, 1H), 4.98 (br s, 1H),
6.82 (br s, 1H), 7.17–7.32 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d
21.8,
23.1, 24.9, 40.0, 43.3, 44.3, 55.7, 81.3, 115.4, 126.4, 128.5, 129.0, 138.7,
143.2, 159.0; IR (film):
n
3261, 3057, 2958, 2930, 1751, 1388, 1261,
HRMS (ESI TOF-MS ESþ): calcd for
1076, 1016, 750 cmꢁ1
.
C
17H24NO2: 274.3772; found: 274.1772.
4.5.4. (4S,5S)-tert-Butyl 4-methyl-5-(2-methylenepentadecyl)-2-
oxooxazolidine-3-carboxylate (29a)
Yield: 55%; Rf 0.65 (20% EtOAc in hexane); 1H NMR (CDCl3,
4.6.1. tert-Butyl (2S,3S)-3-hydroxy-5-oxo-6-phenylhexan-2-
300 MHz):
d
0.87 (t, 3H, J 6.9 Hz), 1.25 (br s, 20H), 1.35–1.43 (m, 2H),
ylcarbamate (8a)
20
1.38 (d, 3H, J 7.1 Hz), 1.54 (s, 9H), 1.99–2.08 (m, 2H), 2.26 (dd, 1H, J
7.0, 4.5 Hz), 2.46 (dd, 1H, J 7.0, 14.5 Hz), 3.96 (dd, 1H, J 3.6, 7.0 Hz),
4.16 (dt, 1H, J 3.6, 7.0 Hz), 4.81 (br s, 1H), 4.90 (d, 1H, J 1.1 Hz); 13C
TLC: Rf 0.16 (30% EtOAc in hexane); [
1H NMR (CDCl3, 300 MHz):
(m, 2H), 3.60 (m,1H), 3.71 (s, 2H), 3.96 (m,1H), 4.84 (d,1H, J 9.2 Hz),
7.16–7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz):
18.4, 28.4, 45.8, 49.7,
50.7, 70.3, 79.3, 127.4, 128.6, 129.3, 133.3, 155.7, 209.3; IR (film):
3396, 2976, 2931, 1707, 1498, 1367, 1167, 1030 cmꢁ1
a]
ꢁ20.0 (c 1.76, CH2Cl2);
D
d
1.17 (d, 3H, J 7.0 Hz), 1.44 (s, 9H), 2.66
NMR (CDCl3, 75 MHz):
d
14.1, 19.7, 22.7, 27.6, 28.0, 29.6, 29.64, 31.9,
d
36.2, 40.5, 55.7, 79.6, 83.7, 113.2, 143.4, 149.5, 151.6; IR (film): 2925,
2854, 2366, 1820, 1803, 1725, 1461, 1369, 1259, 1222, 1078,
n
.
750 cmꢁ1
.
4.6.2. tert-Butyl (3S,4S)-4-hydroxy-2-methyl-6-oxo-7-
phenylheptan-3-ylcarbamate (8b)
4.5.5. (4S,5S)-tert-Butyl 4-isopropyl-5-(2-methylenepentadecyl)-2-
oxooxazolidine-3-carboxylate (29b)
TLC: Rf 0.32 (30% EtOAc in hexane); 1H NMR (C6D6, 300 MHz):
Yield: 49%; Rf 0.70 (20% EtOAc in hexane); 1H NMR (CDCl3,
d 0.85 (d, 3H, J 7.0 Hz), 0.93 (d, 3H, J 6.6 Hz), 1.46 (s, 9H), 1.79 (m, 1H),
300 MHz):
d
0.60 (d, 3H, J 7.0 Hz), 0.70 (d, 3H, J 7.0 Hz), 0.92 (t, 3H, J
2.34(dd,1H, J2.9,15.0 Hz), 2.51(dd,1H,9.5,15.0 Hz), 3.19(m,1H), 3.20
(s, 2H), 4.10 (br d, 1H, J 8.0 Hz), 4.80 (d, 1H, J 10.3 Hz), 6.99–7.12 (m,
7.0 Hz), 1.33 (br s, 22H), 1.48 (s, 9H), 1.85 (t, 2H, J 7.0 Hz), 1.86 (dd,
1H, J 7.0, 14.0 Hz), 2.11 (dd, 1H, J 7.0, 14.0 Hz), 2.23 (m, 1H), 3.90 (dd,
1H, J 2.4, 4.5 Hz), 4.04 (dt, 1H, J 2.4, 7.0 Hz), 4.70 (s, 1H), 4.80 (d, 1H, J
5H); 13C NMR (C6D6, 75 MHz):
d 19.8, 20.0, 28.6, 30.8, 46.5, 50.5, 59.9,
67.2, 78.6, 127.2, 128.8, 129.7, 134.2, 156.4, 209.0; IR (film):
n
3435,
.
0.9 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.7, 15.7, 18.0, 23.5, 28.3, 28.4,
2974, 2935, 2882, 1705, 1498, 1451, 1367, 1260, 1171, 1040 cmꢁ1
29.8, 30.0, 30.2, 30.3, 30.5, 30.6, 32.7, 36.7, 42.2, 63.8, 73.2, 83.4,
114.1, 127.4, 144.3, 151.3, 151.5; IR (film): 2926, 2855, 1815, 1722,
1466, 1371, 1323, 1265, 1160, 1070 cmꢁ1; HRMS (ESI TOF-MS ESþ):
calcd for C27H49NO4Na: 474.3559; found: 474.3471.
4.6.3. tert-Butyl (2S,3S)-3-hydroxy-5-oxo-1,6-diphenylhexan-2-
ylcarbamate (8c)
TLC: Rf 0.48 (30% EtOAc in hexane); 1H NMR (CDCl3, 300 MHz):
d
1.40 (s, 9H), 2.59 (dd, 1H, J 2.4, 2.8 Hz), 2.69 (dd, 1H, J 2.4, 9.8 Hz),
4.5.6. (4S,5S)-tert-Butyl 4-benzyl-5-(2-methylenepentadecyl)-2-
oxooxazolidine-3-carboxylate (29c)
2.88 (d, 2H, J 7.6 Hz), 3.50 (br s, 1H), 3.67 (s, 2H), 3.71 (s, 1H), 3.98 (d,
1H, J 9.1 Hz), 4.94 (d, 1H, J 9.8 Hz), 7.13–7.36 (m, 10H); 13C NMR
Yield: 53%; Rf 0.80 (20% EtOAc in hexane); 1H NMR (CDCl3,
(CDCl3, 75 MHz):
129.3, 129.4, 133.3, 138.1, 155.9, 210.1; IR (film):
2931, 1707, 1497, 1366, 1265, 1167, 1114 cmꢁ1
d
28.3, 38.4, 45.7, 50.6, 55.3, 66.8, 79.4, 128.4,
300 MHz):
d
0.80 (t, 3H, J 6.9 Hz), 1.17 (br s, 22H), 1.37 (m, 2H), 1.51
n
3433, 3055, 2981,
(s, 9H), 1.93 (dd, 1H, J 8.0, 14.0 Hz), 2.22 (dd, 1H, J 6.6, 14.0 Hz), 2.64
(dd, 1H, J 10.0, 13.3 Hz), 3.22 (dd, 1H, J 3.6, 13.3 Hz), 4.04 (ddd, 1H, J
2.3, 3.6, 10.0 Hz), 4.19 (ddd, 1H, J 2.34, 6.6, 8.0 Hz), 4.48 (s, 1H), 4.61
(s, 1H), 7.25–7.06 (m, 5H); IR (film): 3055, 2926, 2854, 1815, 1722,
1454, 1323, 1263, 1159, 1072 cmꢁ1; HRMS (ESI TOF-MS ESþ): calcd
for C31H49NO4Na: 522.3560, found: 522.3676.
.
4.6.4. tert-Butyl (4S,5S)-5-hydroxy-2-methyl-7-oxo-8-
phenyloctan-4-ylcarbamate (8d)
TLC: Rf 0.38 (30% EtOAc in hexane); 1H NMR (C6D6, 300 MHz):
d
0.87 (d, 3H, J 6.2 Hz), 0.95 (d, 3H, J 6.2 Hz),1.20 (m,1H),1.45 (s, 9H),
1.54 (m, 2H), 2.37 (dd, 1H, J 3.3, 17.9 Hz), 2.52 (dd, 1H, J 8.8, 17.9 Hz),
3.25 (s, 2H), 3.67 (m,1H), 3.84 (m,1H), 4.69 (d,1H, J 9.9 Hz), 6.99–7.13
4.5.7. tert-Butyl 2-benzyl-5-methyl-1H-pyrrole-1-carboxylate (24)
Yield: 19%; TLC: Rf 0.70 (30% EtOAc in hexane). 1H NMR (CDCl3,
(m, 5H); 13C NMR (C6D6, 75 MHz):
d
22.3, 23.3, 25.0, 28.5, 42.0, 46.1,
50.4, 53.2, 69.7, 78.6,127.2,128.8,129.8,134.3,156.2, 208.8; IR (film):
3435, 3055, 2960, 2874, 1707, 1499, 1368, 1265, 1166 cmꢁ1
250 MHz):
3.8 Hz), 5.83 (apd, 1H, J 1.02 Hz), 7.12–7.28 (m, 5H). 13C NMR (CDCl3,
125 MHz): 16.4, 27.8, 35.7, 83.4, 110.1, 111.6, 125.9, 128.2, 128.6,
d 1.45 (s, 9H), 2.40 (s, 3H), 4.17 (s, 2H), 5.67 (dt, 1H, J
n
d
132.0, 133.6, 140.2, 150.3; IR (film):
n
3066, 3030, 2979, 2930, 1738,
4.6.5. tert-Butyl (3S,4S)-4-hydroxy-1-(methylsulfonyl)-6-oxo-7-
phenylheptan-3-ylcarbamate (8f)
1605, 1535, 1457, 1389, 1329, 1257, 1171, 1120, 1020 cmꢁ1. See
Ref. 23.
Yield: 89%; TLC: Rf 0.35 (60% EtOAc in hexane); 1H NMR (CDCl3,
300 MHz):
d 1.43 (s, 9H), 1.62 (br s, 1H), 2.15 (m, 2H), 2.65 (m, 2H),
4.5.8. tert-Butyl 2-methyl-5-tridecyl-1H-pyrrole-1-carboxylate (30)
Yield: 53%; TLC: Rf 0.62 (20% EtOAc in hexane). 1H NMR (CDCl3,
2.90 (s, 3H), 3.09 (apt, 2H, J 8.0 Hz), 3.58 (m, 1H), 3.72 (br s, 2H), 4.12
(m, 1H), 4.92 (br d, 1H, J 9.5 Hz), 7.17–7.36 (m, 5H); 13C NMR (CDCl3,
250 MHz):
(s, 9H), 2.37 (s, 3H), 2.76 (t, J 7.3 Hz, 2H), 5.80 (s, 2H); 13C NMR
(CDCl3, 75 MHz): 14.1, 16.5, 22.7, 28.1, 29.3, 29.4, 29.5, 29.6, 29.61,
d
0.88 (t, J 6.4 Hz, 3H), 1.26 (br s, 20H), 1.57 (m, 2H), 1.59
75 MHz):
128.9, 129.4, 133.2, 156.1, 209.5; IR (film):
1707, 1498, 1457, 1267, 1167, 1134 cmꢁ1
d
25.9, 28.3, 40.7, 45.3, 50.7, 51.9, 52.5, 68.8, 80.0, 127.4,
n
3427, 3061, 2980, 2930,
d
.

5900
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
4.6.6. tert-Butyl (2S,3S)-3-hydroxy-5-oxooctadecan-2-ylcarbamate
(9a)
4.8.
LiBH4)
b-Hydroxyketone reduction (diethylmethoxyborane/
Yield: 92%, TLC: Rf 0.28 (20% EtOAc in hexane); 1H NMR (C6D6,
250 MHz):
d
4.79 (d, J 8.3 Hz, 1H), 3.60–3.80 (m, 2H), 3.43 (br s, 1H),
A solution of 0.25 mL of diethylmethoxyborane and 0.46 g of the
corresponding -hydroxyketone in 18.0 mL of tetrahydrofuran and
2.33 (dd, J 9.8, 17.5 Hz, 1H), 2.11 (dd, J 2.8, 17.5 Hz, 1H), 1.91 (t, J 7.0
Hz, 2H), 1.47 (s, 9H), 1.45 (m, 2H), 1.32 (br s, 20H), 1.10 (d, J 6.8 Hz,
b
3.5 mL of methanol was stirred at ꢁ78 ꢀC for 30 min. Thenwas added
1.8 mL of lithium borohydride solution (2 mol/L). After 2 h the mix-
turewasquenched withamixtureof4.1 mLofpH7phosphatebuffer,
6.2 mL of methanol, and 2.5 mL of 25% hydrogen peroxide. This
mixturewas stirred at rt for 18 h. The organic solvent was evaporated
invacuo and the organic layers were extracted withether (2ꢂ15 mL).
The combined organic layer was dried with MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (silica
gel, 30% EtOAc in hexane) afforded the corresponding 1,3-syn-diol.
3H), 0.92 (t, J 6.0 Hz, 3H); 13C NMR (C6D6, 75 MHz):
d 211.5, 155.9,
78.7, 70.4, 50.0, 46.4, 44.4, 32.3, 30.8, 30.1, 30.1, 30.1, 29.9, 29.8, 29.4,
29.3, 28.5, 28.3, 27.9, 27.8, 24.1, 23.7, 23.3, 23.1, 21.9, 18.6, 14.3; IR
(film):
n
3441, 3020, 2928, 2852, 1705, 1504, 1456, 1367, 1215,
.
1165 cmꢁ1
HRMS (ESI TOF-MS ESþ): calcd for C23H46NO4:
400.3427; found: 400.3280.
4.6.7. tert-Butyl (3S,4S)-4-hydroxy-2-methyl-6-oxononadecan-3-
ylcarbamate (9b)
20
Yield: 80%; TLC: Rf 0.34 (60% EtOAc in hexane); [
a
]
D
ꢁ28.0 (c
4.8.1. tert-Butyl (2S,3S,5S)-3,5-dihydroxy-6-phenylhexan-2-
ylcarbamate (4a)
1.13, CH2Cl2); 1H NMR (CDCl3, 300 MHz):
d
0.92 (t, 3H, J 6.5 Hz), 0.93
(d, 3H, J 6.7 Hz), 0.99 (d, 3H, J 6.7 Hz), 1.12–1.26 (m, 2H), 1.32 (br s,
20H),1.49 (s, 9H),1.80–1.93 (m, 3H), 2.23 (dd,1H, J 2.6,17.8 Hz), 2.46
(dd,1H, J 9.6, 17.8 Hz), 3.27 (apt,1H, J 9.6 Hz), 3.45 (br s, 1H), 4.20 (br
d, 1H, J 9.6 Hz), 4.90 (br d, 1H, J 9.6 Hz); 13C NMR (CDCl3, 75 MHz):
Yield: 89%; ds >95:05; TLC: Rf 0.08 (30% EtOAc in hexane); 1H
NMR (CDCl3, 300 MHz): d 1.17 (d, 3H, J 7.0 Hz), 1.45 (s, 9H), 1.67 (apt,
2H, J 7.7 Hz), 2.76 (m, 2H), 3.20–3.40 (br s, 2H), 3.67 (m, 1H), 3.78
(m, 1H), 4.10 (m, 1H), 4.85 (m, 1H), 7.16–7.31 (m, 5H); 13C NMR
d
14.4, 19.8, 20.0, 23.1, 23.7, 28.5, 29.5, 29.8, 30.0, 30.1, 30.12, 30.14,
(CDCl3, 75 MHz):
128.6, 129.3, 137.5, 156.0. HRMS (ESI TOF-MS ESþ): calcd for
C17H28NO4: 310.1940; found: 310.1926.
d 18.3, 28.5, 39.5, 44.8, 50.8, 73.5, 75.3, 79.3, 126.6,
30.2, 30.9, 32.3, 43.4, 59.9, 67.1, 78.5, 156.5, 212.2; IR (film): n 3441,
2926, 2854, 1701, 1501, 1265, 1259, 1170 cmꢁ1. HRMS (ESI TOF-MS
ESþ): calcd for C25H50NO4: 428.3740; found: 428.3690.
4.8.2. tert-Butyl (3S,4S,6S)-4,6-dihydroxy-2-methyl-7-
phenylheptan-3-ylcarbamate (4b)
4.6.8. tert-Butyl (2S,3S)-3-hydroxy-5-oxo-1-phenyloctadecan-2-
ylcarbamate (9c)
Yield: 40%; ds >95:05; TLC: Rf 0.21 (30% EtOAc in hexane); 1H
Yield: 89%; TLC: Rf 0.40 (60% EtOAc in hexane); 1H NMR (CDCl3,
NMR (CDCl3, 300 MHz): d 0.94 (d, 3H, J 6.9 Hz), 0.97 (d, 3H, J 6.6 Hz),
300 MHz):
d
0.92 (t, 3H, J 6.9 Hz), 1.11–1.26 (m, 2H), 1.31 (br s, 20H),
1.46 (s, 9H), 1.68 (apdd, 2H, J 2.9, 5.9 Hz), 1.83 (m, 1H), 2.70 (dd, 1H, J
8.4, 13.6 Hz), 2.84 (dd, 1H, J 4.4, 13.6 Hz), 3.10 (apt, 1H, J 9.9 Hz), 4.10
(m, 2H), 4.90 (br d, 1H, J 9.9 Hz), 7.18–7.34 (m, 5H); 13C NMR (CDCl3,
1.44 (s, 9H),1.80 (t, 2H, J 7.2 Hz), 2.02 (dd,1H, J 2.1, 17.9 Hz), 2.40 (dd,
1H, J 10.0, 17.9 Hz), 2.94 (d, 2H, J 7.6 Hz), 3.85 (dd, 2H, J 8.3, 17.9 Hz),
4.01 (d, 1H, J 9.7 Hz), 5.13 (d, 1H, J 9.7 Hz), 7.05–7.29 (m, 5H); 13C
NMR (CDCl3, 75 MHz):
38.9, 43.1, 46.1, 55.9, 67.0, 78.8, 126.3, 128.4, 128.5, 129.3, 129.6,
138.8, 155.9, 211.8; IR (film): 3445, 3055, 2854, 1699, 1645, 1506,
1265, 1169 cmꢁ1
75 MHz):
126.8, 128.7, 129.4, 137.5, 156.7; IR (film):
1713, 1520, 1454, 1367, 1265, 1169, 1045 cmꢁ1
d
19.5, 19.8, 28.4, 30.0, 40.2, 44.8, 60.6, 71.5, 73.8, 79.0,
d
14.3, 23.0, 28.4, 29.3, 29.7, 29.8, 30.0, 32.2,
n
3418, 3057, 2947, 2872,
.
n
.
4.8.3. tert-Butyl (2S,3S,5S)-3,5-dihydroxy-1,6-diphenylhexan-2-
ylcarbamate (4c)
4.6.9. tert-Butyl (4S,5S)-5-hydroxy-2-methyl-7-oxoicosan-4-
ylcarbamate (9d)
Yield: 69%; ds >95:05; TLC: Rf 0.15 (30% EtOAc in hexane); 1H
NMR (CDCl3, 300 MHz):
d 1.43 (s, 9H), 1.59 (m, 1H), 1.74 (m, 1H),
Yield: 94%; TLC: Rf 0.52 (20% EtOAc in hexane); 1H NMR (CDCl3,
2.64 (m, 3H), 2.72 (dd, 1H, J 8.1, 4.4 Hz), 2.84 (d, 2H, J 4.4 Hz), 3.68
(m, 1H), 3.82 (d, 1H, J 9.8 Hz), 4.02 (m, 1H), 5.01 (br d, 1H, J 8.1 Hz),
300 MHz):
d 0.92 (t, J 6.76 Hz, 3H), 0.93 (d, J 6.8 Hz, 3H), 0.99 (d, J
6.2 Hz, 3H), 1.32 (br s, 22H), 1.47 (s, 9H), 1.60 (m, 3H), 1.92 (apt, J
8.06 Hz, 2H), 2.24 (m, 1H), 2.44 (dd, J 9.3, 17.6 Hz, 1H), 3.30 (m, 1H),
3.70 (m, 1H), 3.90 (d, J 8.8 Hz, 1H), 4.70 (d, J 9.3 Hz, 1H); 13C NMR
(CDCl3, 75 MHz):
30.07, 30.09, 30.13, 32.3, 42.3, 43.3, 46.4, 52.2, 69.7, 78.6, 156.2,
211.9; IR (film): 3445, 3055, 2926, 2858, 1716, 1505, 1469, 1367,
1260, 1171, 1123, 1045 cmꢁ1
7.14–7.32 (m, 10H); 13C NMR (CDCl3, 75 MHz):
d
28.5, 38.5, 39.8,
44.8, 56.4, 71.5, 73.7, 79.3, 126.1, 126.7, 128.3, 128.6, 129.3, 137.6,
138.4; IR (film): 3343, 3055, 2985, 1655, 1496, 1373, 1265,
1167 cmꢁ1 HRMS (ESI TOF-MS ESþ): calcd for C23H32NO4:
n
d
14.3, 22.3, 23.1, 23.3, 23.7, 25.0, 28.5, 29.4, 29.81,
.
386.2253; found: 386.2221.
n
.
4.8.4. tert-Butyl (4S,5S,7S)-5,7-dihydroxy-2-methyl-8-
phenyloctan-4-ylcarbamate (4d)
Yield: 60%; ds >95:05; TLC: Rf 0.24 (30% EtOAc in hexane); 1H
4.7.
b-Hydroxyketone reduction (n-Bu3B/LiBH4)
NMR (CDCl3, 300 MHz): d 0.91 (d, 6H, J 6.6 Hz), 1.29 (m, 1H), 1.45 (s,
9H), 1.65 (m, 3H), 2.70 (dd, 1H, J 8.1, 13.6 Hz), 2.81 (dd, 1H, J 4.4,
13.6 Hz), 3.04 (br s, 2H), 3.56 (m,1H), 3.82 (m,1H), 4.10 (m,1H), 4.76
(br d, 1H, J 9.2 Hz), 7.18–7.33 (m, 5H); 13C NMR (CDCl3, 75 MHz):
To a solution of 0.60 mmol of tributylborane and 0.41 mmol of
the corresponding -hydroxyketone in 2.5 mL of tetrahydrofuran
b
was bubbled a small amount of air and the solution was stirred at
rt for 2 h. Then the mixture was cooled to ꢁ78 ꢀC and treated with
0.60 mmol of lithium borohydride. After 4 h the mixture was
quenched with a mixture of 4.1 mL of pH 7 phosphate buffer,
6.2 mL of methanol, and 2.5 mL of 30% hydrogen peroxide. This
mixture was stirred at rt for 18 h. The organic solvent was evap-
orated in vacuo and the organic layers were extracted with ether
(2ꢂ15 mL). The combined organic layer was dried with MgSO4,
filtered, and concentrated in vacuo. Purification by flash chroma-
tography (silica gel, 30% EtOAc in hexane) afforded the corre-
sponding 1,3-syn-diol.
d
22.2, 23.1, 24.7, 28.4, 39.5, 41.5, 44.8, 52.9, 73.6, 74.3, 79.1, 126.7,
128.7, 129.4, 137.6, 156.3; IR (film): 3435, 3055, 2958, 2870, 1693,
1506, 1451, 1368, 1265, 1169, 1081 cmꢁ1
n
.
4.8.5. tert-Butyl (2S,3S,5S)-3,5-dihydroxyoctadecan-2-ylcarbamate
(5a)
Yield: 48% (two steps); ds 94:06; TLC: Rf 0.10 (20% EtOAc in
20
hexane); white solid (mp 55.1–58.0 ꢀC); [
a
]
ꢁ3.0 (c 0.84, CHCl3);
D
1H NMR (CDCl3, 300 MHz):
d 0.88 (t, J 6.6 Hz, 3H), 1.19 (d, J 6.6 Hz,
3H), 1.26 (br s, 22H), 1.45 (s, 9H), 1.58 (m, 2H), 3.61 (br s, 1H), 3.78
(m, 1H), 3.88 (m, 2H), 4.82 (d, J 8.4 Hz, 1H); 13C NMR (CDCl3,

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5901
75 MHz):
40.0, 50.6, 69.5, 79.4, 156.1; IR (film):
1451, 1367, 1265, 1169, 1022 cmꢁ1
d
14.1, 18.2, 22.7, 25.3, 28.4, 29.4, 29.6, 29.7, 31.9, 38.4,
28.2, 30.1, 40.2, 43.9, 60.5, 68.3, 70.5, 79.2, 126.6, 128.7, 129.3, 138.2,
156.9; IR (film): 3414, 3057, 2945, 2870, 1711, 1496, 1434, 1362,
1265, 1170, 1043, 1021, 902 cmꢁ1. HRMS (ESI TOF-MS ESþ): calcd for
19H32NO4: 338.2331; found: 338.2235.
n
3435, 2927, 2852, 1691, 1502,
n
.
C
4.8.6. tert-Butyl (3S,4S,6S)-4,6-dihydroxy-2-methylnonadecan-3-
ylcarbamate (5b)
4.9.2. tert-Butyl (3S,4S,6R)-4,6-dihydroxy-1-methylsulfonyl-7-
phenylheptan-3-ylcarbamate (6f)
Yield: 53% (two steps); ds 75:25; TLC: Rf 0.20 (20% EtOAc in
20
hexane); [
d
a
]
ꢁ15.0 (c 1.14, CH2Cl2); 1H NMR (CDCl3, 300 MHz):
Yield: 73%; ds 60:40; TLC: Rf 0.15 (60% EtOAc in hexane); 1H
D
0.88 (t, J 6.0 Hz, 3H), 0.95 (m, 6H), 1.25 (br s, 22H), 1.45 (s, 9H), 1.59
NMR (CDCl3, 300 MHz): d 1.43 (s, 9H), 1.61 (br s, 4H), 1.78 (m, 1H),
(m, 2H), 1.86 (sept, J 9.0 Hz, 1H), 3.21 (apt, J 9.0 Hz, 1H), 4.20 (dd, J
2.08 (m, 2H), 2.78 (m, 2H), 2.91 (s, 3H), 3.12 (apt, 2H, J 7.9 Hz), 3.61
(m, 1H), 4.04 (br d, 1H, J 9.2 Hz), 4.11 (m, 1H), 4.99 (d, 1H, J 8.8 Hz),
10.0, 18.0 Hz, 1H), 4.60 (dd, J 9.0, 12.0 Hz, 1H); 13C NMR (CDCl3,
75 MHz):
d
14.1,19.4, 20.0, 22.7, 26.6, 27.4, 28.4, 28.7, 29.3, 29.6, 30.4,
7.18–7.33 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d
25.8, 28.3, 39.3, 40.7,
43.7, 52.0, 53.6, 69.9, 70.3, 79.9, 126.8, 128.8, 129.3, 137.8, 156.8; IR
(film): 3425, 3055, 2986, 2687, 2307, 1705, 1498, 1421, 1267, 1167,
1022, 964, 897, 784 cmꢁ1
31.9, 32.3, 34.6, 36.1, 37.5, 39.3, 59.7, 70.5, 75.1, 79.0, 156.4; IR (film):
n
3445, 2926, 2853, 1693, 1504, 1392, 1301, 1173, 1016 cmꢁ1; HRMS
n
(ESI TOF-MS ESþ): calcd for C25H52NO4: 430.3896; found: 430.3917.
.
4.8.7. tert-Butyl (2S,3S,5S)-3,5-dihydroxy-1-phenyloctadecan-2-
4.9.3. tert-Butyl (2S,3S,5R)-3,5-dihydroxyoctadecan-2-ylcarbamate
ylcarbamate (5c)
(7a)
Yield: 49% (two steps); ds 95:05; TLC: Rf 0.20 (20% EtOAc in
Yield: 57%; ds 96:04; TLC: Rf 0.15 (20% EtOAc in hexane); white
20
20
hexane); white solid (mp 63.4–66.2 ꢀC); [
a
]
D
ꢁ117.0 (c 1.30,
solid (mp 55.5–56.4 ꢀC); [
a]
ꢁ7.0 (c 1.08, CH2Cl2); 1H NMR (CDCl3,
D
CH2Cl2); 1H NMR (CDCl3, 300 MHz):
d
0.87 (t, J 6.3 Hz, 3H), 1.24 (br
250 MHz): d 0.88 (t, J 6.3 Hz, 3H), 1.18 (d, J 7.5 Hz, 3H), 1.15–1.20 (m,
s, 22H), 1.41 (s, 9H), 1.51 (m, 2H), 2.88 (d, J 7.2 Hz, 2H), 3.67 (apd, J
7.8 Hz, 1H), 3.82 (d, J 9.9 Hz, 2H), 5.01 (d, J 9.3 Hz, 1H), 7.18–7.31 (m,
2H), 1.26 (br s, 20H), 1.45 (s, 9H), 1.49–1.579 (m, 2H), 1.69–1.78 (m,
2H), 2.52 (br, 1H), 3.05 (br,1H), 3.63 (m, 1H), 3.79–3.89 (m, 2H), 4.74
5H); 13C NMR (CDCl3, 75 MHz):
d
14.1, 22.7, 25.2, 28.3, 29.3, 29.5,
(d, J 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d
14.1, 22.7, 25.8, 28.3,
29.3, 29.6, 31.9, 37.3, 38.5, 40.1, 56.3, 68.8, 69.5, 79.4, 126.3, 128.4,
129.3, 138.4, 156.4; IR (film): 3435, 3049, 2926, 2852, 1687, 1506,
1547, 1265, 1165, 1045 cmꢁ1; HRMS (ESI TOF-MS ESþ): calcd for
29H52NO4: 478.3896; found: 478.3915.
29.6, 31.9, 38.5, 40.0, 56.5, 71.9, 73.1, 79.3, 126.2, 128.4, 129.4, 138.5,
156.1; IR (film):
n
3435, 3055, 2928, 2858, 1693, 1497, 1451, 1368,
n
1265, 1169 cmꢁ1; HRMS (ESI TOF-MS ESþ): calcd for C29H52NO4:
478.3896; found: 478.3741.
C
4.8.8. tert-Butyl (4S,5S,7S)-5,7-dihydroxy-2-methylicosan-4-
4.9.4. tert-Butyl (3S,4S,6R)-4,6-dihydroxy-2-methylnonadecan-3-
ylcarbamate (5d)
Yield: 78% (two steps); ds 70:30; TLC: Rf 0.23 (20% EtOAc in
hexane); white solid (mp 60.2–62.7 ꢀC); [
ylcarbamate (7b)
20
Yield: 42%; ds 95:05; TLC: Rf 0.11 (20% EtOAc in hexane); [a]
D
20
a
]
D
ꢁ4.0 (c 1.3, CH2Cl2);
ꢁ11.0 (c 2.4, CH2Cl2); 1H NMR (CDCl3, 250 MHz):
d 0.88 (t, J 7.0 Hz,
1H NMR (CDCl3, 300 MHz):
6.7 Hz, 6H), 1.25 (br s, 22H), 1.44 (s, 9H), 1.50 (m, 3H), 1.59 (m, 2H),
3.01 (br s, 2H), 3.60 (m, 1H), 3.90 (m, 2H), 4.76 (d, J 9.7 Hz, 1H); 13
NMR (CDCl3, 75 MHz): 14.1, 22.2, 22.7, 23.2, 24.8, 25.3, 28.4, 29.4,
29.6, 29.7, 31.9, 38.5, 39.8, 41.4, 53.1, 73.0, 74.7, 79.2, 156.4; IR (film):
d
0.88 (t, J 6.9 Hz, 3H), 0.92 (apd, J
3H), 0.94 (d, J 6.5 Hz, 3H), 0.98 (d, J 6.5 Hz, 3H), 1.23 (d, J 6.5 Hz, 2H),
1.25 (br s, 20H), 1.44 (s, 9H), 1.54–1.57 (m, 2H), 1.80–1.87 (m, 1H),
3.10 (apt, J 9.0 Hz,1H), 3.91–3.97 (m, 2H), 4.07–4.04 (m, 2H), 4.86 (d,
C
d
J 11 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d
14.1, 19.4, 19.9, 22.7, 24.2,
25.2, 25.3, 28.4, 29.4, 29.6, 29.7, 29.9, 31.9, 38.3, 38.6, 40.5, 44.7,
n
3435, 3055, 2852, 1693, 1502, 1368, 1265, 1169, 1045, 913 cmꢁ1
;
60.7, 71.9, 73.2, 79.0,156.7; IR (film): n 3437, 2926, 2852, 2306, 1693,
HRMS (ESI TOF-MS ESþ): m/z calcd for C26H54NO4: 444.4053,
1504, 1469, 1367, 1265, 1171, 1045; HRMS (ESI TOF-MS ESþ): calcd
for C25H52NO4: 430.3896; found: 430.3927.
found: 444.4015.
4.9.
b
-Hydroxyketone reduction (Me4NBH(OAc)3)
4.9.5. tert-Butyl (2S,3S,5R)-3,5-dihydroxy-1-phenyloctadecan-2-
ylcarbamate (7c)
Acetic acid (1.0 mL) was added to a stirred suspension of
Me4NHB(OAc)3 (1.58 mmol) in acetonitrile (0.55 mL) at rt. The
resulting mixture was stirred for 30 min and then cooled to ꢁ40 ꢀC.
The corresponding hydroxyketone (0.197 mmol) dissolved in ace-
Yield: 40%; ds 90:10; TLC: Rf 0.15 (20% EtOAc in hexane); 1H NMR
(CDCl3, 250 MHz):
11H), 1.77 (m, 1H), 2.88 (d, 3H, J 7.5 Hz), 3.72–3.87 (m, 3H), 3.93
(apd, 1H, J 9.6 Hz, 1H), 4.96 (d, 1H, J 9.5 Hz), 7.21–7.28 (m, 5H); 13
NMR (CDCl3, 75 MHz): 14.1, 22.7, 25.8, 28.3, 29.3, 29.6, 31.9, 37.3,
38.5, 40.1, 56.3, 68.8, 69.5, 79.4, 126.3, 128.4, 129.3, 138.4, 156.4; IR
(film): 3435, 3055, 2928, 2858, 1693, 1497, 1451, 1368, 1265,
1169 cmꢁ1 HRMS (ESI TOF-MS ESþ): calcd for C29H52NO4:
d 0.88 (t, 3H, J 7.0 Hz), 1.25 (br s, 22H), 1.39 (br s,
C
tonitrile (0.55 mL) was added dropwise.
A
solution of CSA
d
(0.098 mmol), acetic acid (0.55 mL), and acetonitrile (0.55 mL) was
added and the mixture was stirred for 18 h at ꢁ22 ꢀC. The reaction
was quenched by addition of aqueous sodium bicarbonate solution
(10 mL) followed by aqueous potassium tartrate solution (10 mL)
and Et2O (30 mL) stirring vigorously at rt for 3 h. The combined
organic phase was dried over MgSO4. The solvent was removed
under reduced pressure and the resulting oil was purified by flash
chromatography (silica gel 230–400 mesh, using 25% EtOAc in
hexane) providing the corresponding 1,3-anti aminodiols.
n
;
478.3896; found: 478.3915.
4.9.6. tert-Butyl (4S,5S,7R)-5,7-dihydroxy-2-methylicosan-4-
ylcarbamate (7d)
Yield: 42%; ds 92:08; TLC: Rf 0.13 (20% EtOAc in hexane); white
20
solid (mp 99.3–103.0 ꢀC); [
(CDCl3, 250 MHz):
a]
ꢁ2.0 (c 0.71, CH2Cl2); 1H NMR
D
d 0.88 (t, J 6.6 Hz, 3H), 0.93 (d, J 6.6 Hz, 6H), 1.25
4.9.1. tert-Butyl (3S,4S,6R)-4,6-dihydroxy-2-methyl-7-
phenylheptan-3-ylcarbamate (6b)
(br, 22H), 1.44 (s, 9H), 1.45 (m, 2H), 1.69–1.72 (m, 2H), 2.36 (br, 2H),
3.60 (m, 1H), 3.85–3.88 (m, 2H), 4.68 (d, J 9.9 Hz, 1H); 13C NMR
Yield: 68%; ds >95:05; TLC: Rf 0.18 (30% EtOAc in hexane); 1H
(CDCl3, 75 MHz):
d 14.1, 22.1, 22.7, 23.3, 24.8, 25.8, 28.4, 29.3, 29.6,
NMR (CDCl3, 300 MHz): d 0.92 (d, 3H, J 6.7 Hz), 0.97 (d, 3H, J 6.7 Hz),
29.7, 31.9, 37.4, 39.9, 41.5, 53.1, 69.7, 71.2, 79.3, 156.6; IR (film):
1.43 (s, 9H), 1.57 (m, 1H), 1.82 (m, 2H), 2.80 (d, 1H, J 2.1 Hz), 2.86 (d,
1H, J 4.0 Hz), 3.16 (apt, 1H, J 8.9 Hz), 4.14 (m, 2H), 4.80 (br d, 1H, J
n ;
3437, 2928, 2852, 1707, 1508, 1421, 1361, 1267, 1170, 1045 cmꢁ1
HRMS (ESI TOF-MS ESþ): calcd for C26H54NO4: 444.4053; found:
444.3849.
9.4 Hz), 7.19–7.32 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d 18.8, 19.9,

5902
L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
4.10. Acetonide formation (general procedure)
HRMS (ESI TOF-MS ESþ): calcd for C29H58NO4: 484.4366; found:
484.4251.
To a solution of 0.74 mmol of aminodiol in 8 mL of 2,2-dime-
thoxypropane was added 5 mg of CSA. This mixture was stirred
under an argon atmosphere for about 48 h at rt. The layers were
separated and the organic layer was washed with satd aq. NaHCO3
and extracted with ether (2ꢂ10 mL). The combined organic layer
was dried with MgSO4, filtered and concentrated in vacuo. Purifi-
cation by flash chromatography (silica gel, 30% EtOAc in hexane)
afforded the corresponding acetonide.
Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP (Fundaça˜o de
`
˜
´
Amparo a Pesquisa do Estado de Sao Paulo), and CNPq (Conselho
´
Nacional de Desenvolvimento Cientıfico e Tecnologico) for fellow-
ships and financial support. We also thank Prof. Carol H. Collins for
helpful suggestions about English grammar and style.
4.10.1. tert-Butyl-(S)-1-((4S,6S)-6-benzyl-2,2-dimethyl-1,3-dioxan-
4-yl)-methylpropylcarbamate (25)
References and notes
Yield: 92%; TLC: Rf 0.58 (30% EtOAc in hexane); 1H NMR (CDCl3,
1. Biochemistry, 2nd ed.; Voet, D., Voet, J. G., Eds.; Wiley: New York, NY, 1995.
2. (a) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H., Jr.; Bell, R. M. J. Biol. Chem. 1986,
261, 12604; (b) Merrill, A. H., Jr.; Sereni, A. M.; Stevens, V. L.; Hannun, Y. A.; Bell,
R. M.; Kinkade, J. M., Jr. J. Biol. Chem. 1986, 261, 12610.
3. (a) Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 11061; (b) Herold, P.
Helv. Chim. Acta 1988, 71, 354; (c) Nimkar, S.; Menaldino, D.; Merrill, A. H.;
Liotta, D. Tetrahedron Lett. 1997, 38, 7687.
4. (a) Menaldino, D. S.; Bushnev, A.; Sun, A.-M.; Liotta, D. C.; Symolon, H.; Desai,
K.; Dillehay, D. L.; Peng, Q.; Wang, E.; Allegood, J.; Trotman-Pruett, S.; Sullards,
M. C.; Merrill, A. H. Pharm. Res. 2003, 47, 373.
5. (a) Wiseman, J. M.; McDonald, F. E.; Liotta, D. C. Org. Lett. 2005, 7, 3155; (b)
Dougherty, A. M.; McDonald, F. E.; Liotta, D. C.; Moody, S. J.; Pallas, D. C.; Pack,
C. D.; Merrill, A. H., Jr. Org. Lett. 2006, 8, 649.
300 MHz):
d 0.90 (d, 3H, J 6.6 Hz), 0.93 (d, 3H, J 7.0 Hz), 1.30–1.50
(m, 2H), 1.39 (s, 3H), 1.42 (s, 3H), 1.49 (s, 9H), 1.79 (m, 1H), 2.61 (dd,
1H, J 7.0, 13.6 Hz), 2.91 (dd, 1H, J 5.8, 13.6 Hz), 3.14 (apt, 1H, J
9.9 Hz), 4.05 (m, 2H), 4.86 (d, 1H, J 9.3 Hz), 7.18–7.31 (m, 5H); 13C
NMR (CDCl3, 75 MHz):
d 19.4, 19.5, 28.4, 29.9, 30.3, 33.1, 43.0, 58.9,
67.8, 70.1, 78.8, 98.5, 126.2, 128.2, 129.3, 137.7, 156.3; IR (film):
n
3454, 2974, 2935, 2874, 1716, 1497, 1367, 1255, 1169, 1045 cmꢁ1
;
HRMS (ESI TOF-MS ESþ): calcd for C22H36NO4: 378.2566; found:
378.2498.
6. Symolon, H.; Schmelz, E. M.; Dillehay, D. L.; Merrill, A. H., Jr. J. Nutr. 2004, 134,
1157.
7. Dias, L. C.; Fattori, J.; Perez, C. C. Tetrahedron Lett. 2008, 49, 557.
8. (a) Einhorn, J.; Einhorn, C.; Luche, J. L. Synlett 1991, 37; (b) Prasad, J. V. N. V.;
Rich, D. H. Tetrahedron Lett. 1990, 31, 1803.
4.10.2. tert-Butyl-(S)-1-((4S,6S)-6-benzyl-2,2-dimethyl-1,3-dioxan-
4-yl)-phenylethylcarbamate (26)
Yield: 97%; TLC: Rf 0.48 (30% EtOAc in hexane); 1H NMR (CDCl3,
9. (a) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676; (b) Golebiowski, A.; Jacobsson,
U.; Jurczak, J. Tetrahedron 1987, 43, 3063; (c) Jurczak, J.; Golebiowski, A. Chem.
Rev. 1989, 89, 149; (d) Stanfield, C. F.; Parker, J. E.; Kanellis, P. J. Org. Chem. 1981,
46, 4797; (e) Prasad, J. N. V. N.; Rich, D. H. Tetrahedron Lett. 1991, 32, 5857; (f)
Braibante, M. E. F.; Braibante, H. T. S.; Morel, A. F.; Costa, C. C.; Lima, M. G. J. Braz.
Chem. Soc. 2006, 17, 184.
10. The optical purity of aldehydes 10 was estimated to be greater than 96% ee
from the 1H NMR spectrum of the Mosher ester prepared from 10 via LiBH4
reduction followed by esterification.
300 MHz): d 1.35 (s, 3H), 1.47 (s, 3H), 1.49 (s, 9H), 1.54 (m, 2H), 2.58
(dd, 1H, J 7.3, 10.5 Hz), 2.78 (dd, 1H, J 9.8, 12.8 Hz), 2.89 (dd, 2H, J 5.5,
13.7 Hz), 3.68 (m, 2H), 3.94 (m, 1H), 5.02 (d, 1H, J 9.5 Hz), 7.13–7.28
(m, 10H); 13C NMR (CDCl3, 75 MHz):
d 19.8, 28.4, 30.0, 32.6, 38.2,
42.9, 55.2, 66.9, 69.9, 79.2, 98.8, 126.2, 126.3, 128.2, 128.3, 129.3,
129.5, 137.6, 138.4, 155.8.
11. (a) Righi, G.; Ciambrone, S. Tetrahedron Lett. 2004, 45, 2103; (b) Lou, S.;
Westbrook, J. A.; Schaus, S. E. J. Am. Chem. Soc. 2004, 126, 11440; (c) Machado,
M. A.; Harris, M. I. N. C.; Braga, A. C. H. J. Braz. Chem. Soc. 2006, 17, 1440; (d)
Zhang, Z.-W.; Hu, J.-Y. J. Braz. Chem. Soc. 2006, 17, 1447.
12. (a) Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60, 6248; (b) Reetz, M. T.
Chem. Rev. 1999, 99, 1121.
4.10.3. tert-Butyl-(S)-1-((4S,6R)-6-benzyl-2,2-dimethyl-1,3-
dioxan-4-yl)-ethylpropylcarbamate (27)
Yield: 72%; TLC: Rf 0.48 (30% EtOAc in hexane); 1H NMR (CDCl3,
300 MHz): d 1.35 (s, 3H), 1.47 (s, 3H), 1.49 (s, 9H), 1.54 (m, 2H), 2.58
(dd, 1H, J 7.3, 10.5 Hz), 2.78 (dd, 1H, J 9.8, 12.8 Hz), 2.89 (dd, 2H, J 5.5,
13.7 Hz), 3.68 (m, 2H), 3.94 (m, 1H), 5.02 (d, 1H, J 9.5 Hz), 7.13–7.28
13. (a) Dias, L. C.; Aguilar, A. M. Chem. Soc. Rev. 2008, 37, 451; (b) Dias, L. C.; Aguilar,
A. M. Quim. Nova 2007, 30, 2007.
(m, 10H); 13C NMR (CDCl3, 75 MHz):
d
19.4, 24.8, 28.4, 30.8, 35.2,
42.2, 58.6, 65.5, 68.2, 78.8, 100.3, 126.2, 128.0, 129.2, 138.4, 156.8; IR
(film): 3853, 3736, 3446, 2974, 2930, 2361, 1711, 1624, 1498, 1456,
1367, 1265, 1169, 1047, 941, 741 cmꢁ1
14. (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199; (b) Anh,
N. T.; Eisenstein, O. Nouv. J. Chim. 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 diastereomers 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 averages
obtained from at least three individual trials.
16. 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.
17. (a) Dias, L. C.; Ferreira, E. Tetrahedron Lett. 2001, 42, 7159; (b) Dias, L. C.; Ferreira,
A. A.; Diaz, G. Synlett 2002, 1845; (c) Dias, L. C.; Diaz, G.; Ferreira, A. A.; Meira, P.
R. R.; Ferreira, E. Synthesis 2003, 4, 603; (d) Dias, L. C.; Santos, D. R.; Steil, L. J.
Tetrahedron Lett. 2003, 44, 6861; (e) Dias, L. C.; Ferreira, A. A.; Santos, D. R.;
Ferreira, E.; Diaz, G.; Steil, L. J.; Meira, P. R. R.; Giacomini, R. Arkivoc 2003, 10, 240.
18. (a) Dias, L. C.; Meira, P. R. R.; Ferreira, E. Org. Lett. 1999, 1, 1335; (b) Dias, L. C.;
Giacomini, R. Tetrahedron Lett. 1998, 39, 5343; (c) Dias, L. C.; Meira, P. R. R.
Synlett 2000, 37.
19. (a) Bunnelle, W. H.; Narayanan, B. A. Tetrahedron Lett. 1987, 28, 6261; (b)
Mickelson, T. J.; Koviach, J. L.; Forsyth, C. J. J. Org. Chem. 1996, 61, 9617.
20. (a) Masui, Y.; Chino, N.; Sakakibara, S. Bull. Chem. Soc. Jpn. 1980, 63, 464; (b)
Correa, A.; Denis, J. N.; Greene, A. E. Synth. Commun. 1991, 21, 1.
21. Futagawa, S.; Inui, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1973, 46, 3308.
22. (a) Knorr, A.; Daub, J. Angew. Chem., Int. Ed. 1997, 36, 2817; (b) Schroeder, M.
Chem. Rev. 1980, 80, 187; (c) DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K.
B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907;
(d) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6, 2587.
n
.
4.10.4. tert-Butyl (S)-1-((4S,6S)-2,2-dimethyl-6-tridecyl-1,3-
dioxan-4-yl)-2-phenylethylcarbamate (31)
20
Yield: 97%; TLC: Rf 0.80 (20% EtOAc in hexane); [
a]
ꢁ1.0 (c 0.97,
D
CH2Cl2); 1H NMR (CDCl3, 300 MHz):
d
0.88 (t, J 6.3 Hz, 3H), 1.23 (br
s, 22H), 1.35 (s, 3H), 1.43 (s, 3H), 1.45 (s, 9H), 1.59 (br s, 2H), 2.82 (m,
2H), 3.70 (m, 2H), 5.00 (d, J 9.3 Hz, 1H), 7.21–7.31 (m, 5H); 13C NMR
(CDCl3, 75 MHz): d 14.1, 19.8, 22.7, 24.9, 28.4, 29.3, 29.5, 29.54, 29.6,
29.7, 30.1, 31.9, 33.2, 36.4, 38.3, 55.3, 67.2, 68.7, 77.2, 79.2, 98.6,
126.3, 128.3, 129.6, 138.5, 155.9; HRMS (ESI TOF-MS ESþ): m/z calcd
for C32H56NO4: 518.4209, found: 518.4333.
4.10.5. tert-Butyl (S)-1-((4S,6R)-2,2-dimethyl-6-tridecyl-1,3-
dioxan-4-yl)-3-methylbutylcarbamate (32)
20
Yield: 87%; TLC: Rf 0.88 (20% EtOAc in hexane); [
a
]
ꢁ14.0
D
(c 1.08, CH2Cl2); 1H NMR (CDCl3, 250 MHz):
d
0.91 (t, J 6.7 Hz,
3H), 0.89 (d, J 6.5 Hz, 3H), 0.92 (d, J 6.5 Hz, 3H), 1.23 (br, 22H),
1.29 (s, 6H), 1.43 (s, 9H), 1.50–1.53 (m, 2H), 1.57 (br s, 2H), 3.51–
3.80 (m, 3H), 4.66 (d, J 9.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
23. (a) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996, 61, 4999; (b) Konieczny, M.;
Cushman, M. Tetrahedron Lett. 1992, 33, 6939.
24. Yields refer to the unpurified 4-N-Boc-amino-3-hydroxy ketones. Attempts to
flash chromatograph these aminoketones led to low recovered yields and
formation of the corresponding pyrrol derivatives. These 4-N-Boc-amino-3-
hydroxy ketones are very unstable to flash chromatography and were reduced
immediately after preparation.
d
14.1, 22.5, 22.7, 23.0, 24.6, 25.4, 28.4, 29.3, 29.5, 29.6, 29.65,
29.7, 32.0, 35.1, 36.0, 42.0, 51.3, 67.3, 68.0, 77.2, 79.0, 100.3, 156.3;
IR (film):
2925, 2855, 1718, 1499, 1366, 1275, 1224, 1174 cmꢁ1
n
.

L.C. Dias et al. / Tetrahedron 64 (2008) 5891–5903
5903
25. Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis 1989, 3, 189.
26. (a) Narasaka, K.; Pai, F.-C. Chem. Lett. 1980, 1415; (b) Narasaka, K.; Pai, F.-C.
Tetrahedron 1984, 40, 2233; (c) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea,
P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287; (d) Paterson, I.; Tillyer, R. D.
J. Org. Chem. 1993, 58, 4182; (e) Dias, L. C.; de Oliveira, L. G.; Sousa, M. A. Org.
Lett. 2003, 5, 265; (f) Dias, L. C.; Meira, P. R. R. J. Org. Chem. 2005, 70, 4762.
27. (a) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338; (b) Dias, L. C.; Sousa, M. A.
Tetrahedron Lett. 2003, 44, 5625.
29. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945; (b) Evans,
D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099; (c) Rychnovsky, S.
D.; Rogers, B. N.; Richardson, T. I. Acc. Chem. Res. 1998, 31, 9; (d) Tormena, C. F.;
Dias, L. C.; Rittner, R. J. Phys. Chem. A 2005, 109, 6077.
30. (a) Chen, J. M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Chem. Lett. 1987, 1923; (b) Nicolaou, K. C.; Nold, A. L.; Milburn, R.
R.; Schindler, C. S.; Cole, K. P.; Yamaguchi, J. J. Am. Chem. Soc. 2007, 129,
1760.
28. (a) Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27, 282; (b) Ruff, F.; Kucsman,
A. J. Chem. Soc., Perkin Trans. 2 1985, 683; (c) Su, W. Tetrahedron Lett. 1994, 35,
4955; (d) Xu, W. L.; Li, Y. Z.; Zhang, Q. S.; Zhu, H. S. Synthesis 2004, 2, 227.
31. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
32. All new compounds were isolated as chromatographically pure materials
and exhibited acceptable 1H NMR, 13C NMR, IR, MS, and HRMS spectral data.