Stereo- and regioselective synthesis of 2-amino-3,5-diols via stereospecific crotyl transfer and regioselective aminohydroxylation

Article abstract of DOI:10.1055/s-0032-1316805

A short synthesis of 2-amino-3,5-diols is described, including the all-S isomer enigmol, a synthetic anticancer compound inspired by the structure of fumonisin B The synthetic route features 1) stereospecific crotyl transfer to tetradecanal via pericyclic

Full text of DOI:10.1055/s-0032-1316805

PAPER
▌3639
paper
Stereo- and Regioselective Synthesis of 2-Amino-3,5-diols via Stereospecific
Crotyl Transfer and Regioselective Aminohydroxylation
Synthesis of 2-Amino-3,5-diols
Frank E. McDonald,* Claney L. Pereira
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Fax +1(404)7276586; E-mail: fmcdona@emory.edu
Received: 06.08.2012; Accepted after revision: 26.09.2012
Several syntheses of enigmol have been reported featur-
Abstract: A short synthesis of 2-amino-3,5-diols is described, in-
ing a variety of key disconnections ranging from aldol re-
cluding the all-S isomer enigmol, a synthetic anticancer compound
actions,6 diastereoselective allylations,7 and cross-
inspired by the structure of fumonisin B1. The synthetic route fea-
tures 1) stereospecific crotyl transfer to tetradecanal via pericyclic
coupling reactions.8 In each of these syntheses, the C2-chi-
oxonia-Cope rearrangement; 2) stereoselective epoxidation of the ral center is potentially prone to epimerization.6b In order
alkene; 3) regioselective epoxide opening with azide; and 4) reduc-
tion of azide to amine. This manuscript also corrects a structure as-
to avoid this problem with epimerization, we developed a
complementary synthesis of enigmol (4) involving C4–C5
signment error in a previously reported synthesis of one of the
bond formation by stereo- and regioselective crotyl group
diastereomers of enigmol.
transfer9 to provide the homoallylic alcohol 7 (Scheme 1),
Key words: allylation, rearrangement, regioselectivity, sphingolip-
ids, stereoselective synthesis
featuring oxacyclization of the epoxycarbonate 8 with in-
version of configuration at C3.10 The position of the cyclic
carbonate 9 protected the oxygens at C3 and C5, allowing
for regioselective formation of the C2 mesylate followed
by stereospecific substitution with azide with inversion of
configuration at C2, which upon methanolysis of the cy-
Fumonisin B1 (1, Figure 1) is a fungal toxin produced by
Fusarium verticillioides, which has been found as a con-
taminant in corn and other food grains.1,2 The toxicity of
clic carbonate and hydrogenolysis of the azide afforded a
reliable route to provide gram quantities of enigmol (4).10a
fumonisin B1 as well as the potency of activity as a ce-
ramide synthase inhibitor is reduced upon basic hydroly-
sis of the ester side chains to the aminopentol (2).3,4
Compound 2 and its N-palmitoyl derivative 3 exhibit in
vitro cytotoxicity to HT29 (colon cancer) cells along with
enhanced ceramide synthase inhibition activity.3 Based on
these findings, several laboratories have studied simpler
analogues containing only the 2-amino-3,5-diol substruc-
ture of fumonisin B1, especially the all-S stereoisomer 4
(dubbed enigmol), which has shown promising in vivo
studies on suppression of colon and prostate tumor growth
in mouse models.5
tetradecanal (6)
p-TsOH (0.5 equiv)
Me
i-Pr
OH
5
3
Me
Me
n-C13H27
2
CH2Cl2, 24 h
(68%)
OH
7 (13:1 er)
5 (12:1 dr)
2 equiv
Ot-Bu
BF3-OEt2
CH2Cl2, –40 °C
1. n-BuLi, Boc2O
2. Shi epoxidation
O
3
O
5
Me
n-C13H27
2
O
8
1731 cm–1
O
OH OH
OR1
1. MsCl, Et3N
2. NaN3, DMF
Me
2
O
3
O
5
OH OH
3
5
Me
Me
Me
HN R2
OH
fumonisin B1 (1) R1
OR1 OH
2
2
Me
O
3
5
n-C13H27
n-C13H27
4, enigmol
3. K2CO3, MeOH
4. H2, Pd/C
HO
H2N
R2 = H
=
CO2H
9
CO2H
Scheme 1 Our previous (2005) synthesis of enigmol10
aminopentol (2) R1 = R2 = H
n-C15H31
N-palmitoylaminopentol (3) R1 = H, R2
=
However, we subsequently observed that the correspond-
ing reaction sequence from the C5-diastereomer 10 failed
due to carbonate migration to afford the five-membered-
ring carbonate 12 (Scheme 2).10b,11 Presumably the trans-
substitution pattern of an initial six-membered-ring car-
bonate 11 (never observed) would place the C2 oxygen in
proximity to the carbonyl, so that intramolecular acyl
transfer provided isomer 12. Compound 12 exhibited an
infrared stretch of 1792 cm–1, consistent with the in-
creased ring strain of a five-membered ring versus the six-
membered ring of compound 9. Unfortunately, the signif-
O
OH OH
2
Me
3
5
Me
NH2
enigmol (4)
Figure 1 Structures of 1-deoxysphingolipids
SYNTHESIS 2012, 44, 3639–3648
Advanced online publication: 24.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316805; Art ID: SS-2012-M0648-OP
© Georg Thieme Verlag Stuttgart · New York

3640
F. E. McDonald, C. L. Pereira
PAPER
icance of the infrared spectrum was initially overlooked conversion of aldehyde 6, even with excess reagent 16. As
and so compound 12 was subjected to the same sequence the proposed mechanism for crotyl transfer is an oxonia-
of steps as for compound 9. As the cyclic carbonate of 12 Cope pericyclic rearrangement of oxonium ion 18 to 19
protected the C2 and C3 oxygens, the azide substitution re- (Scheme 4), we considered that some of the extraneous
action now occurred at C5, resulting in the aminodiol re- features of the camphor skeleton might be responsible for
gioisomer 13.10b
diminishing the reaction rate.15
O-t-Bu
Me
Me
tetradecanal (6)
OH
5
1. n-BuLi, Boc2O
2. Shi epoxidation
BF3-OEt2
CH2Cl2
CSA (0.1 equiv)
3
O
3
O
5
2
n-C13H27
OH
ent-7
Me
CH2Cl2, 6 d
(66%)
Me
n-C13H27
(ref. 10a)
2
Me
–40 °C
O
Me
10
17 (>95:5 er)
+ H2O
– H2O
1792 cm–1
OH
16 (2.3:1 dr)
3 equiv
O
H
HO
H
Me
2
O
5
O
C13H27
Me
C13H27
n-C13H27
O
Me
O
2
3
5
O
O
n-C13H27
12 (61%)
OH NH2
3
O
H
Me
Me
Me
H
H
H
H
11
H
H
Me
Me
Me
Me
1. MsCl, Et3N
2. NaN3, DMF, 70 °C
19
18
Me
2
3
5
n-C13H27
Scheme 4 Oxonia-Cope rearrangement mechanism for crotyl group
3. K2CO3, MeOH
4. H2, Pd/C
HO
transfer
13 (75%, 4 steps)
Scheme 2 Divergent behavior of diastereomeric epoxycarbonate 10 To this end, a structurally simpler reagent 20 (arising from
enantio- and diastereoselective crotylboration of 4-silyl-
oxybutanal) was designed,16,17 bearing a tethered nucleo-
The identities of our synthetic aminodiols were confirmed
phile designed to trap the product oxonium ion.18 For the
by selective N-acylation followed by acetonide protection
of the diols (Scheme 3). The acetonide 14 exhibited a 13C
resonance for the acetal carbon at 107.7 ppm, consistent
with a five-membered-ring acetonide,12 whereas the cor-
responding acetonide 15 arising from enigmol (4) exhib-
ited a 13C resonance at 98.5 ppm as expected for a six-
membered-ring acetonide. Moreover, compound 15 was
crystalline so that its structure was unambiguously con-
firmed by X-ray crystallography.13
reaction of one equivalent of 20 with tetradecanal (6), the
best results were achieved with stoichiometric camphor-
sulfonic acid (CSA), providing the alkenyl alcohol 17
with high enantiomeric purity (>95:5 er) as well as com-
plete cis-alkene selectivity (Scheme 5). The formation of
product 17 was accompanied by small amounts of the O-
tetrahydrofuranyl derivative 21. Under the same reaction
conditions, the reaction of tetradecanal with the anti-dia-
stereomer 23 provided the corresponding trans-alkenyl
alcohol ent-7 and the corresponding tetrahydrofuranyl de-
rivative 24.19,20
107.7 ppm
1. Ac2O, Et3N
2. (MeO)2CMe2
p-TsOH (cat.)
Me
Me
O
OH NH2
NHAc
5
1
The crotyl transfer reaction of 20 was monitored by H
O
Me
2
3
3
5
n-C13H27
n-C13H27
2
NMR spectroscopy, revealing the rapid formation of a
seven-membered-ring acetal intermediate 25, which
could even be isolated as a mixture of diastereomers when
the reaction was stopped after 30 minutes (Scheme 6). The
stereospecificity of each crotyl transfer process is consis-
tent with acid-catalyzed opening of the seven-membered-
ring acetal of 25 to form oxonium ion 26, which then un-
dergoes oxonia-Cope rearrangement to product oxonium
ion 27. The tetrahydrofuranyl acetal 21 presumably arises
from cyclization of the primary hydroxyl onto the product
oxonium ion 27. Notably, we have not found conditions
by which the tetrahydrofuranyl derivative 21 is formed as
the major product, and thus the mechanistic pathway for
the formation of alcohol 17 has not been conclusively es-
tablished. However, protonation of the acyclic oxygen of
acetal 21 and elimination of volatile dihydrofuran may di-
minish the yield of 21 in favor of the desired alcohol prod-
uct 17.
Me
HO
13
14
Me
Me
1. Ac2O, Et3N
2. (MeO)2CMe2
p-TsOH (cat.)
98.5 ppm
OH OH
O
3
O
5
Me
Me
2
2
3
5
n-C13H27
4, enigmol
n-C13H27
H2N
AcN
H
15
Scheme 3 Structural confirmation of acetonides 14 and 15
In rethinking the synthetic route for enigmol diastereo-
mers from homoallylic alcohols, we considered that azide
nucleophile might be directly added to the C2–C3 epoxide.
For enigmol itself, this would require preparation of the
cis-alkene isomer 17, which was prepared by crotyl trans-
fer to tetradecanal (6) using the camphor-derived reagent
16.14 However, the reaction was extremely slow, and reac-
tion times of six to seven days were required for complete
Synthesis 2012, 44, 3639–3648
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,5-diols
3641
O
O
tetradecanal (6)
OH
OH
CSA, CH2Cl2, 24 h
TBSO
+
n-C13H27
n-C13H27
Me
Me
Me
20
17 (52%)
21 (17%)
p-nitrobenzoic acid
Ph3P, DIAD (53%)
O
O
OH
OR
tetradecanal (6)
CSA, CH2Cl2, 24 h
TBSO
Me
Me
+
n-C13H27
n-C13H27
24 (14%)
Me
ent-7 (62%)
22 R = 4-O2NC6H4C(O)
23 R = H
DIBAL-H
(79%)
Scheme 5 Crotyl group transfer with reagents 20 and 23
n-C13H27
O
tetradecanal (6)
CSA, CH2Cl2, 0.5 h
OH
O
H+
TBSO
Me
Me
20
25
O
C13H27
C13H27
Me
Me
OH
O
O
O
+
n-C13H27
n-C13H27
HO
HO
H
H
H
H
Me
Me
H
H
H
H
17
21
26
27
Scheme 6 Proposed oxonia-Cope mechanism for crotyl transfer with reagent 20
Returning to the synthesis of enigmol, we utilized hydrox- moted azide addition provided predominantly 33 as the
yl-directed vanadium-catalyzed epoxidation of the cis-ho- penultimate precursor to the aminodiol diastereomer 35.
moallylic alcohol 17, providing the epoxy alcohol 28 with
In light of the previous erroneous claim of compound 35
high diastereoselectivity.21 Ti(Oi-Pr)2(N3)2-promoted ad-
from our laboratory,10 we now carefully established the
dition of azide to epoxy alcohol 28 exhibited modest
relative stereochemistry of the diol moiety of 35 generated
regioselectivity in favor of the azidodiol 29,22 and lithium
in this work by forming the acetonide 36 from the azido-
aluminum hydride reduction of the azide afforded enig-
mol (4), which matched the physical and spectroscopic
characteristics of enigmol prepared by our previous syn-
diol 33 (Scheme 8). The 13C NMR acetal resonance at
100.9 ppm and methyl resonances at 24.6 ppm and 24.5
ppm were consistent with a six-membered-ring acetonide
thesis (Scheme 7). Diastereomer 32 was synthesized by
with anti-stereochemistry of the oxygens at C3 and C5.23
Mitsunobu inversion from 28 followed by methanolysis
Moreover, compound 35 was converted into the triacetyl
of the acetate ester intermediate 31. Ti(Oi-Pr)2(N3)2-pro-
derivative 37, for which the 13C NMR resonance for C1 at
18.6 ppm was consistent with the 18 ppm resonance re-
VO(acac)2 (cat.)
TBHP
N3
3
OH
5
OH OH
OH
5
Ti(O-i-Pr)2(N3)2
O
3
Me
Me
2
2
+
17
3
5
2
n-C13H27
n-C13H27
n-C13H27
benzene, 80 °C
87%
X
HO
Me
28
29 X = N3 (53%)
4 X = NH2 (71%)
30 (15%)
LiAlH4
Ph3P, DIAD, AcOH
(81%)
N3
OH
5
OH OH
2
OR
5
Ti(O-i-Pr)2(N3)2
O
3
2
Me
Me
+
2
3
3
5
n-C13H27
n-C13H27
n-C13H27
benzene, 80 °C
X
HO
Me
33 X = N3 (52%)
35 X = NH2 (79%)
34 (26%)
K2CO3, MeOH
(88%)
31 R = Ac
32 R = H
LiAlH4
Scheme 7 Preparation of enigmol (4) and diastereomer 35
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3639–3648

3642
F. E. McDonald, C. L. Pereira
PAPER
ported for the reference compound 38 bearing syn-rela- we have undertaken preliminary work towards new re-
tionship between the C2 nitrogen and C3 oxygen.24,25
agents for stereoselective crotyl group transfer with gen-
erality for both cis- and trans-disubstituted homoallylic
alcohols, as well as uncovering the regioselectivities of
azide-openings with epoxy alcohols arising from homoal-
lylic alcohols.27
24.5, 24.6 ppm
Me
Me
100.9 ppm (this work)
O
O
Me
2
3
5
n-C13H27
1H NMR and 13C NMR spectra were recorded in deuterated solvents
on Varian INOVA 600, Unity 600, and INOVA 400 spectrometers.
Chemical shift values were recorded in parts per million relative to
N3
36
residual H and 13C in CDCl3 (7.27 ppm for H, 77.23 for 13C),
CD3OD (3.31 ppm for 1H, 49.3 ppm for 13C), or C6D6 (7.16 ppm for
1H, 128.23 ppm for 13C), and coupling constants in hertz. IR spectra
were recorded on a Mattson Genesis II FT-IR spectrometer as neat
films on NaCl discs. Mass spectral data (high resolution EI, ESI and
APCI) were recorded on a Finnigan LTQ FT-mass spectrometer.
Optical rotations were measured on a PerkinElmer 341 polarimeter
(concentration in g/100 mL). Flash column chromatography was
conducted with silica gel 60 (230–400 mesh ASTM) from EM Sci-
ence. All reactions were conducted with anhydrous solvents in
oven-dried or flame-dried and argon-charged glassware. Anhyd sol-
vents were dried with 4 Å molecular sieves and tested for trace H2O
content with Coulometric KF titrator from Denver Instruments.
1
1
AcO
OAc
1
Me
18.6 ppm
2
(this work)
3
5
n-C13H27
AcNH
37
AcO
OAc
5
1
Me
~18 ppm
(ref. 24)
2
3
OAc
AcNH
38
Scheme 8 Confirmation of relative stereochemistry for derivatives
36 and 37
(4S,5R)-4-[(R)-2-Hydroxypentadecyl]-5-methyl-1,3-dioxolan-2-
one (12)
For the trans-epoxide diastereomers 39 and 43 (arising
from Shi epoxidation of 7 and ent-7, respectively),26 the
azide addition proceeded with nearly exclusive formation
of the C2-azide regioisomers 40 and 44, respectively (see
Scheme 9), with formation of less than 5% of the C3-azide
Epoxycarbonate 10 (0.513 g, 1.34 mmol) was dissolved in anhyd
CH2Cl2 (27 mL) under argon atmosphere. The solution was cooled
to –40 °C, and a 0.195 M Et2O·BF3 solution in CH2Cl2 (7.0 mL,
1.36 mmol) was added in one portion. The solution was stirred vig-
orously at –40 °C for 5 min, and then quenched with sat. aq
regioisomer in either case. Although the choice of reagent NaHCO3 (7 mL). The organic layer was separated, and aqueous
phase was extracted with CH2Cl2 (2 × 10 mL). The organic layers
were combined and washed with H2O (20 mL), dried (Na2SO4), and
concentrated by rotary evaporation. Chromatography on silica gel
Ti(Oi-Pr)2(N3)2 was originally viewed as an extended ap-
plication of the method described earlier by Sharpless in
the analogous reactions of 2,3-epoxy-1-alcohols,27 the dif-
with hexanes–EtOAc (1: 1) gave 12 (0.27 g, 61%) as a white solid;
mp 63–63.5 °C; [α]D25 –33.6 (c 1.0 CH2Cl2).
ferences in regioselectivity may arise from differing steric
factors upon nucleophilic additions to C2 versus C3 in
trans- versus cis-disubstituted epoxides.28 Lithium alumi-
num hydride reduction of azides 40 and 44 afforded the
corresponding 2-amino-3,5-diol diastereomers 41 and 45.
The relative stereochemistry was confirmed by 13C NMR
analysis of the corresponding acetonides 42 and 46.23
IR (thin film, CH2Cl2): 3402, 2918, 2849, 1792, 1763, 1063 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.01 (ddd, J = 10.2, 7.2, 3.0 Hz, 1
H), 4.88 (m, J = 6.6 Hz, 1 H), 3.87 (m, J = 4.2, 2.4, 1.8 Hz, 1 H),
1.82 (ddd, J = 13.8, 3.6, 1.8 Hz, 1 H), 1.63 (br s, 1 H), 1.57 (ddd, J =
13.8, 10.8, 3.0 Hz, 1 H), 1.50 (q, J = 7.2 Hz, 2 H), 1.42 (br m, 1 H),
1.37 (d, J = 6.6 Hz, 3 H), 1.27 (br s, 21 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (400 MHz, CDCl3): δ = 154.8, 76.3, 68.1, 38.5, 36.2, 32.1,
29.83, 29.73, 29.66, 29.54, 25.6, 22.9, 15.1, 14.3.
In conclusion, we have developed a synthetic route pro-
viding all diastereomers of 2-amino-3,5-dihydroxyocta-
decane, including enigmol (4). In the course of this work,
HRMS (EI): m/z calcd for C19H36O4: 335.2774; found: 335.2771.
24.7, 24.8 ppm
Me
Me
100.7 ppm
(MeO)2CMe2
p-TsOH (cat.)
OH
OH OH
O
3
O
5
Shi epoxidation
78%, dr 14:1
Ti(Oi-Pr)2(N3)2
3
Me
Me
Me
2
2
7
5
3
5
n-C13H27
n-C13H27
n-C13H27
2
benzene, 80 °C
O
X
N3
39
40 X = N3 (54%)
41 X = NH2 (73%)
42
LiAlH4
30.2 ppm
98.8 ppm
19.9 ppm
Me
O
Me
O
(MeO)2CMe2
p-TsOH (cat.)
OH
5
OH OH
Ti(Oi-Pr)2(N3)2
Shi epoxidation
70%, dr 11:1
3
Me
Me
Me
2
2
ent-7
3
3
5
5
n-C13H27
n-C13H27
n-C13H27
2
benzene, 80 °C
O
X
N3
43
44 X = N3 (65%)
45 X = NH2 (70%)
46
LiAlH4
Scheme 9 Preparation of enigmol diastereomers 41 and 45
Synthesis 2012, 44, 3639–3648
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,5-diols
3643
Anal. Calcd for C19H36O4: C, 69.47; H, 11.05. Found: C, 69.47; H,
11.16.
the reaction. The mixture was extracted with Et2O (2 × 2 mL), the
combined Et2O layers were dried (MgSO4), filtered, and concentrat-
ed by rotary evaporation to obtain a colorless oil. This material was
purified by silica gel chromatography using 0.5% MeOH in CH2Cl2
as the eluent, to provide compound 14 (3 mg, 44%) as a colorless
oil, which solidified upon standing.
1H NMR (600 MHz, CDCl3): δ = 5.43 (d, J = 8.4 Hz, 1 H), 4.26 (dq,
J = 6.3 Hz, 1 H), 4.09 (ddd, J = 4.8, 8.4 Hz, 1 H), 4.02–3.96 (m, 1
H), 1.97 (s, 3 H), 1.69 (ddd, J = 4.8, 14.4 Hz, 1 H), 1.57–1.50 (m, 3
H), 1.45 (s, 3 H), 1.31 (s, 3 H), 1.25 (br s, 27 H), 1.15 (d, J = 6.6 Hz,
3 H), 0.88 (t, J = 7.2 Hz, 3 H).
(2R,3S,5S)-5-Aminooctadecane-2,3-diol (13)
Compound 18 (0.27 g, 0.82 mmol) was dissolved in anhyd CH2Cl2
(10 mL) and cooled to 0 °C under argon atmosphere. Et3N (120 μL,
0.9 mmol) was added followed by dropwise addition of MsCl (100
μL, 0.8 mmol) over 10 min. The reaction mixture gradually warmed
to r.t. and was stirred for 6 h. The mixture was then partitioned be-
tween CH2Cl2 (10 mL) and H2O (10 mL), the organic layer was sep-
arated, the aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
the organic layers were combined, dried (Na2SO4), and concentrat-
ed by rotary evaporation. The crude mesylate was dissolved in DMF
(15 mL), and NaN3 (0.37 g, 5.7 mmol) was added. The reaction
mixture was stirred at 68 °C for 24 h, then cooled to r.t. and diluted
with CH2Cl2 (30 mL) and H2O (30 mL). The organic layer was sep-
arated, the aqueous layer was extracted with CH2Cl2 (2 × 25 mL),
the organic layers were combined, dried (Na2SO4), and concentrat-
ed by rotary evaporation. Chromatography on silica gel with eluent
of hexanes–EtOAc (1: 1) afforded the azidocarbonate (0.252 g,
87%, 2 steps) as a clear colorless oil. A portion of this azidocarbon-
ate (0.118 g, 0.33 mmol) was dissolved in anhyd MeOH (7 mL),
K2CO3 (0.32 g, 2.34 mmol) was added, and the reaction mixture
was stirred at r.t. for 12 h. The mixture was then diluted with CH2Cl2
(15 mL) and H2O (15 mL), the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com-
bined organic layers were dried (Na2SO4), and concentrated by ro-
tary evaporation to provide the crude azidodiol (99 mg). Without
further purification, the crude azidodiol was mixed with 10% Pd/C
(24 mg, 20% by mass), and the reaction vessel was evacuated under
high vacuum for 5 min, and then filled with H2 atmosphere. This cy-
cle of evacuation and H2 filling was repeated three more times.
Then, 95% EtOH (7 mL) was added, and the reaction mixture was
degassed by three cycles of partial evacuation and filling with H2 at-
mosphere. The mixture was stirred at r.t. for 6 h under a positive
pressure of H2 gas delivered by a balloon. The mixture was then fil-
tered through a 1 cm plug of packed Celite, washing with CH2Cl2
(20 mL). The filtrate was dried (Na2SO4) and concentrated by rotary
evaporation to afford aminodiol 13 (93 mg, 86%, 2 steps) as a white
solid; mp 65–66 °C; [α]D25 +3.1 (c 1.0, CH2Cl2).
13C NMR (150 MHz, CDCl3): δ = 170.0, 107.7, 75.9, 74.1, 48.1,
35.7, 35.1, 32.1, 30.2, 29.8, 29.7, 29.5, 28.7, 26.0, 25.9, 23.8, 22.9,
15.9, 14.3.
N-{(S)-1-[(4S,6S)-2,2-Dimethyl-6-tridecyl-1,3-dioxan-4-yl]eth-
yl}acetamide (15)
Following the procedure described above for compound 14, a sam-
ple of enigmol (4; 25 mg, 80 mmol) prepared as previously
reported10a was converted into compound 15 (18 mg, 28%, 2 steps,
unoptimized) as a colorless oil, which solidified upon standing. The
compound was dissolved in a small quantity of CH2Cl2 (2 mL) and
refrigerated (ca. 4 °C) for approximately one week, after which
crystals were harvested for structural confirmation by X-ray crystal-
lography;13 mp 61–62 °C.
1H NMR (400 MHz, CDCl3): δ = 5.76 (d, J = 8.8 Hz, 1 H), 3.97 (dq,
J = 2.0, 7.2 Hz, 1 H), 3.83–3.77 (m, 2 H), 2.00 (s, 3 H), 1.42 (s, 3
H), 1.39 (s, 3 H), 1.40–1.36 (m, 2 H), 1.25 (br s, 23 H), 1.16 (d,
J = 6.8 Hz, 3 H), 0.88 (t, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 98.5, 71.5, 68.9, 48.1, 36.6,
33.8, 32.1, 30.2, 29.8 (2 C), 29.7, 29.6, 29.5, 25.1, 23.7, 22.9, 19.9,
18.4, 14.3.
(3R,4R)-7-[(tert-Butyldimethylsilyl)oxy)-3-methylhept-1-en-4-
ol (20)
By Ipc2B-Mediated Crotylboration: cis-But-2-ene (3.7 g, 65.9
mmol) was added to a cooled solution of t-BuOK (1.8 g, 16.0 mmol)
in THF (34 mL) at –78 °C. n-BuLi (1.02 g, 16.0 mmol, 2.5 M in
hexanes) was then added, and the yellow reaction mixture was
warmed to –45 °C and stirred for 10 min. After cooling back to
–78 °C, [(+)Ipc]2BOMe (5.0 g, 16.0 mmol) in THF (27 mL) was
then added and the mixture was stirred for 30 min. Et2O·BF3 (2.27
g, 16.0 mmol) was then added, followed by 4-[(tert-butyldimethyl-
silyl)oxy]butanal (2.7 g, 13.3 mmol),29 and the mixture was stirred
for 5 h. The mixture was quenched by addition of aq 3 M NaOH
(13.5 mL), followed by 30% H2O2 (10.0 mL), and stirring at r.t. for
18 h. The aqueous layer was then extracted with EtOAc (3 × 50
mL), dried (MgSO4), filtered, and concentrated to obtain an oil. The
crude product was purified by flash chromatography using 8%
EtOAc in hexanes to obtain compound 20 (1.7 g, 50%) as a color-
less oil.
IR (thin film, CH2Cl2): 3331, 2918, 2850, 1467 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.77 (m, J = 3.6, 2.4 Hz, 1 H), 3.73
(d, J = 10.2 Hz, 1 H), 3.2 (br s, 4 H), 2.81 (m, J = 5.4 Hz, 1 H), 1.57
(d, J = 14.4 Hz, 1 H), 1.43 (m, 3 H), 1.24 (br s, 22 H), 1.11 (d, J =
6.0 Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (400 MHz, CDCl3): δ = 76.4, 70.1, 52.4, 41.2, 35.4, 32.1,
29.80, 29.75, 29.67, 29.51, 25.8, 22.8, 17.4, 14.3.
HRMS (EI): m/z calcd for C18H40NO2: 302.30543; found:
302.30536.
Anal. Calcd for C18H39NO2: C, 71.70; H, 13.04; N. 4.65. Found: C,
71.47; H, 12.93; N, 4.49.
By VIVOL-Catalyzed Crotylboration: A mixture of preactivated 4Å
molecular sieves (0.11 g), (S,S)-VIVOL catalyst (0.028 g, 0.064
mmol),17 and anhyd Na2CO3 (0.01 g, 0.049 mmol) was suspended
in toluene (2.0 mL). After stirring for 5 min at r.t., SnCl4 (0.012 g,
0.049 mmol) was added, and the reaction mixture was cooled to
–75 °C, and stirred for 15 min. (Z)-2-(But-2-en-1-yl)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (0.10 g, 0.54 mmol) was then added
and the mixture was stirred for 30 min at –75 °C, followed by
addition of 4-[(tert-butyldimethylsilyl)oxy]butanal (0.10 g, 0.49
mmol).29 The mixture was stirred at –67 °C for 19 h before quench-
ing with DIBAL (0.9 mL, 1.0 M in toluene). After stirring for 15
min, the cold bath was removed, aq 1.0 M HCl (1.8 mL) was added,
and the mixture was stirred at r.t. for 1 h. The aqueous layer was ex-
tracted with hexanes (2 × 5 mL), the combined organic layers were
dried (MgSO4), filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel (6% EtOAc in hex-
N-{(S)-1-[(4S,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl]pentadec-
an-2-yl}acetamide (14)
A solution of aminodiol 13 (50 mg, 0.17 mmol) in anhyd CH2Cl2
(2.2 mL) under argon atmosphere was cooled to 0 °C. Et3N (46 μL,
0.33 mmol) was added with stirring, and after 5 min,Ac2O (15 μL,
0.16 mmol) was added dropwise. The reaction mixture was stirred
at 0 °C for 1 h, after which time aq 1 N HCl (1 mL) was added to
quench the reaction. The organic layer was separated and subse-
quently washed with aq 1 N NaOH (2 mL), H2O (2 mL), and brine
(2 mL), dried (MgSO4), filtered, and concentrated by rotary evapo-
ration to provide the crude N-acetyldiol (16 mg) as a white solid.
Without further purification, a portion of this N-acetyldiol (6 mg)
was dissolved in 2,2-dimethoxypropane (0.19 mL) and cooled to
0 °C under argon atmosphere. p-TsOH (0.9 mg) was added and the
reaction mixture was stirred at 0 °C for 15 min, after which Et3N
(0.5 mL) and a few drops of sat. aq NaHCO3 was added to quench
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3639–3648

3644
F. E. McDonald, C. L. Pereira
PAPER
anes) to provide compound 20 as a colorless oil (70 mg, 55%);
[α]D25 –17.4 (c 1.14, CHCl3).
IR (film): 3367, 2954, 2857, 1471, 1253, 1095, 995, 832, 773 cm–1.
1H NMR (600 MHz, CDCl3): δ = 5.80 (ddd, J = 7.2, 10.5, 17.4 Hz,
1 H), 5.08–5.04 (m, 2 H), 3.66 (t, J = 5.7 Hz, 2 H), 3.50–3.46 (m, 1
H), 2.45 (d, J = 4.2 Hz, 1 H), 2.29–2.26 (m, 1 H), 1.68–1.61 (m, 3
H), 1.42–1.37 (m, 1 H), 1.04 (d, J = 6.6 Hz, 3 H), 0.90 (s, 9 H), 0.07
(s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 141.4, 115.0, 74.7, 63.6, 43.8,
31.4, 29.5, 26.1, 18.5, 14.9, –5.1.
HRMS (ESI): m/z calcd for C14H31O2Si (M + H+): 259.2088; found:
259.2087.
rotary evaporation to obtain a colorless oil. This was purified by
flash chromatography using 6% EtOAc in hexanes as eluent to ob-
tain compound 17 as a white solid (3.3 g, 66%); mp 28–29 °C;
[α]D25 –2.7 (c 1.03, CHCl3).
IR (film, CH2Cl2): 3345, 3021, 2915, 2848, 1469 cm–1.
1H NMR (600 MHz, CDCl3): δ = 5.66 (dqt, J = 10.8, 6.6, 1.8 Hz, 1
H), 5.44 (dtq, J = 10.8, 7.8, 1.8 Hz, 1 H), 3.63 (br pent, J = 4.8 Hz,
1 H), 2.22 (app t, J = 6.6 Hz, 2 H), 1.64 (dd, J = 1.2, 6.6 Hz, 3 H),
1.58 (s, 1 H), 1.49–1.44 (m, 3 H), 1.31–1.26 (m, 21 H), 0.88 (t,
J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 127.4, 126.4, 71.7, 37.0, 35.1,
32.1, 29.9, 29.8, 29.5, 25.9, 22.9, 14.3, 13.2.
HRMS (APCI): m/z calcd for C18H35O (M+): 267.2682; found:
267.2683.
(3R,4S)-7-[(tert-Butyldimethylsilyl)oxy]-3-methylhept-1-en-4-ol
p-Nitrobenzoate Ester (22)
The absolute stereochemistry and enantioselectivity was deter-
mined by Mosher (MTPA) ester analysis.30 Each Mosher ester was
diastereomerically pure, that is, uncontaminated by any evidence of
the other diastereomer. Resonances were clearly assignable for H1–
H5 (Table 1).
Compound 20 (0.80 g, 3.0 mmol), Ph3P (1.6 g, 6.19 mmol), and p-
nitrobenzoic acid (1.0 g, 6.19 mmol) were dissolved in benzene (40
mL) at r.t. DIAD (1.25 g, 6.19 mmol) was added, and the reaction
mixture was stirred for 24 h. The solvents were then removed by ro-
tary evaporation to obtain the crude product as a semisolid, which
was purified by flash chromatography using 1% Et2O in hexanes to
afford the nitrobenzoate ester 22 (0.67 g, 53%) as an oil; [α]D25 +9.7
(c 0.875, CHCl3).
Table 1 Diagnostic Resonances for Mosher Esters of 17
R-Ester, from
(S)-MTPACl
S-Ester, from
(R)-MTPACl
Δδ
(R–S)
IR (film): 2954, 2856, 1721, 1528, 1318, 1270, 1098, 872, 831, 717
cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.29 (d, J = 8.4 Hz, 2 H), 8.20 (d,
J = 9.6 Hz, 2 H), 5.80 (ddd, J = 7.8, 10.2, 17.7 Hz, 1 H), 5.15 (ddd,
J = 4.8, 9.0 Hz, 1 H), 5.08 (dd, J = 16.8, 18.3 Hz, 2 H), 3.65–3.59
(m, 2 H), 2.59–2.53 (m, 1 H), 1.81–1.70 (m, 2 H), 1.60–1.51 (m, 2
H), 1.08 (d, J = 6.6 Hz, 3 H), 0.08 (s, 9 H), 0.03 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 164.5, 150.6, 139.2, 136.2, 130.8,
123.7, 116.2, 78.8, 62.7, 42.0, 28.9, 28.0, 26.1, 18.5, 16.3, –5.1.
H1
H2
H3
H4
H4′
H5
1.49 ppm
5.47 ppm
5.22 ppm
2.35 ppm
2.26 ppm
5.08 ppm
1.56 ppm
5.54 ppm
5.34 ppm
2.42 ppm
2.32 ppm
5.09 ppm
–0.07 ppm
–0.07 ppm
–0.12 ppm
–0.07 ppm
–0.06 ppm
not applicable
HRMS (ESI): m/z calcd for C21H34NO5Si (M + H+): 408.2200;
found: 408.2202.
(3R,4S)-7-[(tert-Butyldimethylsilyl)oxy]-3-methylhept-1-en-4-ol
(23)
From 20: Tetradecanal (6; 0.25 g, 1.17 mmol) and compound 20
(0.34 g, 1.29 mmol) were dissolved in CH2Cl2 (8 mL) at r.t., and
CSA (0.33 g, 1.4 mmol) was added. The reaction mixture was
stirred for 24 h. The mixture was then quenched with MeOH (0.1
mL) and stirred for 1 h, before evaporating solvents by rotary evap-
oration. The crude product was purified by flash chromatography
using a gradient of 2–3% EtOAc in hexanes to obtain compound 17
as a white solid (160 mg, 52%).
A solution of compound 22 (0.67 g, 1.64 mmol) in CH2Cl2 (21 mL)
was cooled to –78 °C, and DIBAL (4.9 mL, 4.9 mmol, 1.0 M in hex-
anes) was added. The reaction mixture was stirred for 30 min at
–78 °C, after which the reaction was quenched with EtOH (0.5 mL)
at –78 °C and saturated Rochelle salt (25 mL). After stirring the
mixture at r.t. for 1 h, the organic layer was separated, and the aque-
ous layer was extracted with CH2Cl2 (2 × 20 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and concentrated to
obtain the crude product as an oil, which was purified by silica gel
chromatography using a gradient of 2–5% EtOAc in hexanes to pro-
(R,E)-Octadec-2-en-5-ol (ent-7)
Following the procedures described above for reactions with 20, the
reaction of compound 23 (0.24 g, 0.93 mmol), tetradecanal (6; 0.18
g, 0.84 mmol), and CSA (0.24 g, 1.01 mmol) in CH2Cl2 (5.5 mL)
for 24 h provided the trans-homoallylic alcohol ent-7 as a white sol-
id (0.14 g, 62%). The physical and spectroscopic properties
matched those reported earlier.10a
25
vide compound 23 (0.27 g, 79%) as a colorless oil; [α]D +0.8 (c
0.625, CHCl3).
IR (film): 3399, 2954, 2856, 1471, 1253, 1094, 832, 773 cm–1.
1H NMR (600 MHz, CDCl3): δ = 5.79 (ddd, J = 9.0, 19.2 Hz, 1 H),
5.10–5.07 (m, 2 H), 3.69–3.63 (m, 2 H), 3.45–3.43 (m, 1 H), 2.38
(d, J = 3.6 Hz, 1 H), 2.26–2.20 (m, 1 H), 1.68–1.62 (m, 3 H), 1.44–
1.38 (m, 1 H), 1.04 (d, J = 6.6 Hz, 3 H), 0.90 (s, 9 H), 0.06 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 140.8, 115.9, 74.7, 63.6, 44.2,
31.2, 29.3, 26.1, 18.5, 16.2, –5.1.
(S)-1-[(2S,3R)-3-Methyloxiran-2-yl]pentadecan-2-ol (28)
The homoallylic alcohol 17 (3.25 g, 12.1 mmol) and VO(acac)2
(0.16 g, 0.60 mmol) were dissolved in CH2Cl2 (120 mL), and the re-
sulting solution was cooled to 0 °C. tert-Butyl hydroperoxide
(TBHP, 5.5 M in decane, 3.3 mL, 18.1 mmol) was then added drop-
wise, and the reaction mixture was stirred at 0 °C for 3 h before
warming to r.t. and stirring for 24 h at r.t. The mixture was then di-
luted with aq 10% Na2S2O3 (25 mL). The organic layer was separat-
ed, washed with brine (50 mL), dried (MgSO4), filtered, and
concentrated to obtain the crude product as a brown oil, which was
purified by flash chromatography using 20% EtOAc in hexanes as
eluent to obtain epoxy alcohol 28 (3.0 g, 87%) as a colorless oil,
HRMS (ESI): m/z calcd for C14H31O2Si (M + H+): 259.2088; found:
259.2086.
(S,Z)-Octadec-2-en-5-ol (17)
From Camphor-Derived 16: Tetradecanal (6; 4.00 g, 18.8 mmol)
and compound 16 (11.7 g, 56.1 mmol)14 were dissolved in CH2Cl2
(3 mL). CSA (0.44 g, 1.9 mmol) was then added and the reaction
mixture was stirred at r.t. for 6 days. The mixture was then diluted
with CH2Cl2 (15 mL), dried (MgSO4), filtered, and concentrated by
25
which solidified upon standing; mp 32–33 °C; [α]D –3.2 (c 1.05,
CHCl3).
Synthesis 2012, 44, 3639–3648
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,5-diols
3645
IR (film, CH2Cl2): 3415, 2994, 2923, 2854, 1463 cm–1.
evaporation to obtain the crude acetate intermediate as a yellow oil.
Purification by flash chromatography using 10% EtOAc in hexanes
as eluent afforded the epoxy acetate intermediate 31 (2.8 g, 81%) as
a colorless oil; [α]D25 +7.2 (c 1.04, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 3.93–3.87 (m, 1 H), 3.12–3.09 (m,
1 H), 3.07–3.04 (m, 1 H), 2.29 (s, 1 H), 1.56–1.40 (m, 4 H), 1.30–
1.25 (m, 25 H), 0.87 (t, J = 6.6 Hz, 3 H).
IR (film): 2994, 2925, 2854, 1739 1465, 1373, 1240, 1022, 829
cm–1.
1H NMR (600 MHz, CDCl3): δ = 5.06–5.02 (m, 1 H), 3.06–3.02 (m,
1 H), 2.97–2.94 (m, 1 H), 2.05 (s, 3 H), 1.78–1.76 (m, 2 H), 1.64–
1.59 (m, 2 H), 1.29–1.25 (m, 26 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 71.0, 55.5, 52.1, 37.6, 34.6, 32.1,
29.85, 29.8, 29.5, 25.7, 22.8, 14.3, 13.5.
HRMS (ESI): m/z calcd for C18H37O2 (M + H+): 285.2788; found:
285.2785.
13C NMR (150 MHz, CDCl3): δ = 170.8, 72.4, 54.1, 52.5, 34.5, 32.7,
(2S,3S,5S)-2-Azidooctadecane-3,5-diol (29)
Me3SiN3 (0.4 g, 3.47 mmol) was added to a solution of Ti(Oi-Pr)
(0.49 g, 1.72 mmol) in benzene (12.5 mL) and the solution was heat-
ed to 80 °C for 5 h. A solution of epoxy alcohol 28 (0.50 g, 1.75
mmol) in benzene (5 mL) was then added and the reaction mixture
was stirred for 15 min before cooling to r.t. Benzene was removed
under vacuum and the crude product was diluted with Et2O (20 mL).
Aq 5% H2SO4 (10 mL) was then added and the resulting solution
was stirred for 1 h at r.t. The organic layer was separated, and the
aqueous phase was extracted with Et2O (2 × 25 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated by
rotary evaporation to obtain a brown oil. The crude product was pu-
rified by flash chromatography using 25% EtOAc in hexanes as el-
uent to obtain the azidodiol 29 (0.30 g, 53%) as a colorless oil which
solidified on standing; mp 42–44 °C; [α]D25 +31.0 (c 1.07, CHCl3).
The C3-azide regioisomer 30 was also formed (0.085 g, 15%).
32.1, 29.8 (2 C), 29.7 (2 C), 29.6 29.5, 25.4, 22.8, 21.4, 14.3, 13.5.
HRMS (ESI): m/z calcd for C20H39O3 (M + H+): 327.2893; found:
327.2886.
(R)-1-[(2S,3R)-3-Methyloxiran-2-yl]pentadecan-2-ol (32)
The epoxy acetate 31 (0.30 g, 0.91 mmol) was dissolved in MeOH
(3 mL). K2CO3 (63 mg, 0.45 mmol) was then added and the reaction
mixture was stirred at r.t. for 4 h. MeOH was removed by rotary
evaporation and the crude product mixture was dissolved in H2O (5
mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and
the combined organic layers were dried (MgSO4), filtered, and con-
centrated to obtain the crude product as a white solid. Purification
by flash chromatography using 20% EtOAc in hexanes as eluent
gave the epoxy alcohol 32 (0.23 g, 88%) as a white solid; mp 48–
49 °C; [α]D25 –13.2 (c 1.0, CHCl3).
IR (thin film, CH2Cl2): 3390, 2923, 2854, 2109, 1463, 1261, 1066
cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.88–3.84 (m, 1 H), 3.75–3.72 (m,
1 H), 3.58 (br s, 1 H), 3.43–3.39 (m, 1 H), 2.89 (br s, 1 H), 1.60–
1.55 (m, 2 H), 1.54–1.44 (m, 2 H), 1.43–1.38 (m, 1 H), 1.31–1.25
(m, 24 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 75.6, 72.7, 62.1, 39.2, 38.4, 32.1,
29.85, 29.8, 29.5, 25.5, 22.8, 15.3, 14.3.
HRMS (ESI): m/z calcd for C18H38N3O2 (M + H+): 328.2958; found:
328.2952.
IR (thin film, CH2Cl2): 3334, 3257, 2915, 2848, 1467, 721 cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.88–3.83 (m, 1 H), 3.15–3.09 (m,
1 H), 3.07–3.04 (m, 1 H), 1.74–1.70 (m, 2 H), 1.62–1.58 (ddd,
J = 3.6, 7.8, 14.4 Hz, 1 H), 1.55–1.51 (m, 2 H), 1.48–1.44 (m, 1 H),
1.29 (d, J = 6.6 Hz, 3 H), 1.25 (br s, 22 H), 0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 70.3, 54.6, 52.9, 37.9, 35.0, 32.1,
29.8 (2 C), 29.5, 25.8, 22.9, 14.3, 13.6.
HRMS (ESI): m/z calcd for C18H37O2 (M + H+): 285.2788; found:
285.2785.
(2S,3S,5R)-2-Azidooctadecane-3,5-diol (33)
(2S,3S,5S)-2-Aminooctadecane-3,5-diol (Enigmol, 4)
Following the procedure described above for compound 29, epoxy
alcohol 32 (0.2 g, 0.7 mmol) was converted into azidodiol 33 (0.12
g, 52%); mp 56–58 °C; [α]D25 +17.2 (c 0.52, CHCl3). The C3-azide
regioisomer 34 was also formed (0.06 g, 26%).
LiAlH4 (2.0 M in THF, 0.23 g, 3 mL, 6.0 mmol) was added to THF
(3.2 mL) at r.t. A solution of azidodiol 29 (0.1 g, 0.3 mmol) in THF
(0.75 mL) was then added dropwise and the reaction mixture stirred
at r.t. for 15 min. The reaction was quenched by dropwise addition
of aq Rochelle salt (5 mL). The biphasic solution was stirred for 30
min at r.t., before separating the organic layer. The aqueous layer
was extracted with EtOAc (2 × 10 mL) and the combined organic
layers were dried (MgSO4), filtered, and concentrated to obtain the
aminodiol enigmol (4) as a white solid (65 mg, 71%); mp 71–72 °C;
[α]D25 –12.1 (c 1.05, MeOH).
IR (thin film, CH2Cl2): 3305, 2954, 2913, 2848, 2123, 1469, 1022,
981 cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.97–3.91 (m, 1 H), 3.81–3.76 (m,
1 H), 3.49–3.45 (m, 1 H), 2.63 (d, J = 4.2 Hz, 1 H), 2.08 (s, 1 H),
1.70 (ddd, J = 3.0, 9.6, 14.2 Hz, 1 H), 1.60–1.51 (m, 2 H), 1.49–1.40
(m, 2 H), 1.32–1.26 (m, 24 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 72.2, 69.2, 62.6, 39.5, 37.6, 32.1,
29.8 (2 C), 29.5, 25.9, 22.9, 15.8, 14.3.
IR (thin film, CH2Cl2): 3402, 3328, 3277, 2917, 2846, 1598, 1463,
984 cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.87 (m, 1 H), 3.45 (t, J = 7.2 Hz,
1 H), 2.76–2.74 (br m, 1 H), 1.64 (d, J = 13.8 Hz, 1 H), 1.53–1.48
(m, 1 H), 1.44–1.39 (m, 3 H), 1.25 (br s, 22 H), 1.12 (d, J = 6.6 Hz,
3 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 76.6, 72.1, 51.7, 40.5, 38.2, 32.1,
29.8, 29.5, 25.7, 22.9, 21.1, 14.3.
HRMS (ESI): m/z calcd for C18H38N3O2 (M + H+): 328.2958; found:
328.2952.
(2S,3S,5R)-2-Aminooctadecane-3,5-diol (35)
Following the procedure described for compound 4, azidodiol 33
(0.05 g, 0.15 mmol) was converted into aminodiol 35 (36 mg, 79%);
mp 64–66 °C; [α]D25 –2.7 (c 0.87, CHCl3).
(R)-1-[(2S,3R)-3-Methyloxiran-2-yl]pentadecan-2-ol Acetate
Ester (31)
IR (thin film, CH2Cl2): 3359, 3307, 2917, 2850, 1592, 1467, 1064
cm–1.
To a solution of epoxy alcohol 28 (3.0 g, 10.5 mmol) in anhyd Et2O
(190 mL) were added Ph3P (5.5 g, 21.0 mmol) and AcOH (1.26 g,
21.0 mmol) and the mixture was cooled to 0 °C. Diisopropyl azodi-
carboxylate (4.26 g, 21.0 mmol) was then added, and the reaction
mixture was stirred at 0 °C for 2 h. The mixture was diluted with
H2O (75 mL), the organic layer was separated, and the aqueous lay-
er was extracted with Et2O (2 × 50 mL). The combined organic lay-
ers were dried (MgSO4), filtered, and concentrated by rotary
1H NMR (600 MHz, CDCl3): δ = 3.92–3.87 (m, 1 H), 3.52–3.49 (m,
1 H), 2.85–2.81 (m, 1 H), 2.78–2.20 (br s, 3 H), 1.66–1.50 (m, 3 H),
1.47–1.39 (m, 2 H), 1.36–1.25 (br s, 22 H), 1.11 (d, J = 6.6 Hz, 3
H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 73.7, 69.2, 51.2, 39.6, 37.8, 32.1,
29.8, 29.5, 26.0, 22.9, 20.8, 14.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3639–3648

3646
F. E. McDonald, C. L. Pereira
PAPER
HRMS (ESI): m/z calcd for C18H40NO2 (M + H+): 302.3053; found:
302.3047.
54%); mp 57–59 °C; [α]D25 +29.8 (c 1.04, CHCl3). Traces of the C3-
azide regioisomer (0.01 g, 2%) were also observed.
IR (thin film, CH2Cl2): 3297, 2954, 2913, 2848, 2129, 1469, 1259,
1022 cm–1.
(4S,6R)-4-[(1S)-1-Azidoethyl]-2,2-dimethyl-6-(tridecyl)-1,3-di-
oxane (36)
1H NMR (600 MHz, CDCl3): δ = 3.98–3.94 (m, 1 H), 3.90–3.87 (m,
1 H), 3.59–3.55 (m, 1 H), 2.85 (br s, 1 H), 1.69 (ddd, J = 3.0, 9.6,
14.1 Hz, 1 H), 1.58–1.46 (m, 3 H), 1.44–1.39 (m, 1 H), 1.29 (d,
J = 6.6 Hz, 3 H), 1.26 (br s, 21 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 71.5, 69.6, 61.9 38.1, 37.6, 32.1,
29.8, 29.7, 29.5, 25.9, 22.9, 14.5, 14.3.
The anti-diol stereochemistry of 33 was confirmed by converting a
portion of azidodiol 33 (10 mg) into the 3,5-acetonide 36 (8 mg) us-
ing dimethoxypropane and catalytic p-TsOH, as described for the
preparation of compound 15. The 13C NMR acetal resonance at
100.9 ppm and methyl resonances at 24.6 ppm and 24.5 ppm were
consistent with a six-membered-ring acetonide with anti-stereo-
chemistry of the oxygens at C3 and C5.23
1H NMR (600 MHz, CDCl3): δ = 3.80–3.74 (m, 2 H), 3.39–3.34 (m,
1 H), 1.73 (ddd, J = 6.0, 9.9, 12.6 Hz, 1 H), 1.54–1.49 (m, 2 H), 1.38
(s, 3 H), 1.37 (s, 3 H), 1.30–1.26 (m, 23 H), 1.18 (d, J = 7.2 Hz, 3
H), 0.89 (t, J = 6.0 Hz, 3 H).
HRMS (ESI): m/z calcd for C18H38N3O2 (M + H+): 328.2958; found:
328.2953.
(2S,3S,5R)-2-Aminooctadecane-3,5-diol (41)
Following the procedure described for compound 4, azidodiol 40
(75 mg, 0.22 mmol) was converted into aminodiol 41 as a white sol-
id (50 mg, 73%); mp 71–73 °C; [α]D25 +13.9 (c 0.55, CHCl3).
13C NMR (150 MHz, CDCl3): δ = 100.9, 70.8, 66.9, 60.2, 36.06,
36.04, 32.1, 29.87, 29.81, 29.7, 29.5, 25.5, 24.6, 24.5, 22.9, 15.3,
14.3.
IR (thin film, CH2Cl2): 3307, 2915, 2848, 1469, 1051 cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.94–3.88 (m, 1 H), 3.78–3.74 (m,
1 H), 2.96–2.92 (m, 1 H), 1.65–1.60 (m, 1 H), 1.55–1.41 (m, 4 H),
1.32–1.25 (br s, 22 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.88 (t, J = 6.6 Hz,
3 H).
13C NMR (150 MHz, CDCl3): δ = 71.8, 69.2, 51.1, 39.0, 37.8, 32.1,
29.9, 29.8, 29.5, 26.1, 22.9, 18.3, 14.3.
(2S,3S,5R)-2-Acetamidooctadecane-3,5-diol 3,5-Bisacetoxy Di-
ester (37)
The syn-stereochemistry of the C2 and C3 amino alcohol was con-
firmed from a portion of aminodiol 35 (6 mg), which was dissolved
in anhyd CH2Cl2 (0.7 mL) under argon, to which Et3N (13 μL) was
added. This mixture was cooled to 0 °C after which Ac2O (4 μL)
was added. After stirring for 30 min, TLC showed that the reaction
was complete. The reaction mixture was quenched with aq 1 N HCl
(0.5 mL), the organic layer was separated, and washed with brine (2
mL). The organic layer was dried (MgSO4), filtered, and concen-
trated by rotary evaporation to give compound 37 as a white solid
(6 mg, 80%).
HRMS (ESI): m/z calcd for C18H40NO2 (M + H+): 302.3053; found:
302.3051.
(4R,6S)-4-[(1S)-1-Azidoethyl]-2,2-dimethyl-6-(tridecyl)-1,3-di-
oxane (42)
The anti-diol stereochemistry of 40 was confirmed by converting a
portion of azidodiol 40 (15 mg) into the 3,5-acetonide 42 (12 mg)
using dimethoxypropane and catalytic p-TsOH, as described for the
preparation of compound 15. The 13C NMR acetal resonance at
100.7 ppm and methyl resonances at 24.8 ppm and 24.7 ppm were
consistent with a six-membered-ring acetonide with anti-stereo-
chemistry of the oxygens at C3 and C5.23
1H NMR (400 MHz, CDCl3): δ = 5.57 (d, J = 9.2 Hz, 1 H), 4.99–
4.95 (m, 1 H), 4.91–4.85 (m, 1 H), 4.20–4.11 (m, 1 H), 2.07 (s, 3 H),
2.02 (s, 3 H), 1.99 (s, 3 H), 1.79–1.76 (m, 2 H), 1.51 (br s, 2 H), 1.24
(br s, 25 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.7, 169.6, 72.2, 70.0,
48.4, 45.0, 36.2, 35.0, 32.1, 29.8, 29.7, 29.5, 25.3, 23.6, 22.9, 21.3,
21.1, 18.6, 14.3.
1H NMR (600 MHz, CDCl3): δ = 3.79–3.75 (m, 2 H), 3.56–3.51 (m,
1 H), 1.81 (ddd, J = 5.4, 12.6 Hz, 1 H), 1.57–1.50 (m, 2 H), 1.46–
1.39 (m, 2 H), 1.35 (s, 6 H), 1.30–1.26 (m, 21 H), 1.20 (d, J = 6.6
Hz, 3 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 100.7, 69.9, 66.9, 60.4, 36.0, 34.2,
32.1, 29.87, 29.81, 29.7, 29.5, 25.5, 24.8, 24.7, 22.9, 15.3, 14.3.
(2S,3R,5S)-2-Azidooctadecane-3,5-diol (40)
The homoallylic alcohol 7 (0.30 g, 1.1 mmol) was dissolved in di-
methoxymethane (16.8 mL) and MeCN (8.4 mL). A solution of
Na2B4O7·10 H2O (16.2 mL, 0.05 M in 4 × 10–4 M Na2EDTA solu-
tion) was added, followed by Bu4NHSO4 (15 mg, 44 mmol) and D-
epoxone (86 mg, 0.33 mmol).26 The reaction mixture was cooled to
(2S,3R,5R)-2-Azidooctadecane-3,5-diol (44)
0 °C. Solutions of Oxone (1.09 g, 1.78 mmol) in 4 × 10–4
M
Using the same procedure as described for 39, compound ent-7
(0.50 g, 1.86 mmol) was converted into epoxy alcohol 43 (0.345 g,
65%), and a portion of this epoxy alcohol (0.20 g) was further con-
verted into azidodiol 44 (0.15 g, 65%); mp 31–33 °C; [α]D25 +10.8
(c 0.86, CHCl3). Traces of the C3-azide regioisomer (0.01 g, 4%)
were also observed.
Na2EDTA (5 mL) and K2CO3 (1.04 g, 7.53 mmol) in H2O (5 mL)
were simultaneously added dropwise over a period of 1.5 h, as the
reaction mixture was stirred at 0 °C. The mixture was stirred at 0 °C
for 30 min more after the additions were completed. The mixture
was then diluted with hexanes (25 mL), the organic layer was sepa-
rated, and the aqueous layer was extracted with hexanes (2 × 25
mL). The organic layers were combined, dried (MgSO4), filtered,
and concentrated by rotary evaporation, and the crude product was
purified by silica gel chromatography using a gradient of 5–10%
EtOAc in hexanes as eluent. The resulting epoxy alcohol 39 (0.20
g, 63%) was added to an 80 °C benzene solution of Ti(Oi-Pr2)(N3)2
[prepared from Me3SiN3 (0.4 g, 3.47 mmol) and Ti(Oi-Pr)3 (0.49 g,
1.72 mmol) which had been refluxed in benzene (12.5 mL) for 5 h],
and the reaction mixture was stirred for 15 min before cooling to r.t.
Benzene was removed under vacuum and the crude product was di-
luted with Et2O (25 mL). Aq 5% H2SO4 (10 mL) was then added
and the resulting solution was stirred for 1 h at r.t. The organic layer
was separated, and the aqueous phase was extracted with Et2O (2 ×
25 mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated by rotary evaporation to obtain a brown oil. The
crude product was purified by flash chromatography using 25%
EtOAc in hexanes as eluent to obtain the azidodiol 40 (0.125 g,
IR (thin film, CH2Cl2): 3369, 2923, 2854, 2115, 2098, 1461, 1261,
1051 cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.89–3.85 (m, 1 H), 3.83–3.80 (m,
1 H), 3.52–3.48 (m, 1 H), 2.57 (br s, 1 H), 1.68–1.66 (m, 1 H), 1.53–
1.47 (m, 3 H), 1.41–1.37 (m, 1 H), 1.30–1.26 (m, 21 H), 0.88 (t,
J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 75.5, 73.3, 61.9 38.5, 38.3, 32.1,
29.8, 29.7, 29.5, 25.9, 22.8, 14.3 (2 C).
HRMS (ESI): m/z calcd for C18H38N3O2 (M + H+): 328.2958; found:
328.2959.
(2S,3R,5R)-2-Aminooctadecane-3,5-diol (45)
Following the procedure described for compound 4, azidodiol 44
(75 mg, 0.22 mmol) was converted into aminodiol 45 (50 mg, 70%);
mp 82–83 °C; [α]D25 +3.1 (c 0.98, CHCl3).
Synthesis 2012, 44, 3639–3648
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Amino-3,5-diols
3647
IR (thin film, CH2Cl2): 3340, 2917, 2848, 1461, 1076 cm–1.
Lorente, A.; Romea, P.; Urpí, F.; Ríos-Luci, C.; Padrón, J.
M. Eur. J. Org. Chem. 2011, 960.
(7) Dias, L. C.; Fattori, J.; Perez, C. C.; de Oliveira, V. M.;
Aguilar, A. M. Tetrahedron 2008, 64, 5891.
1H NMR (600 MHz, CDCl3): δ = 3.99–3.83 (m, 1 H), 3.74–3.70 (m,
1 H), 3.03–2.99 (m, 1 H), 2.90–2.00 (br s, 3 H), 1.58–1.40 (m, 5 H),
1.30–1.26 (br s, 21 H), 1.57 (d, J = 6.6 Hz, 3 H), 0.88 (t, J = 7.2 Hz,
3 H).
13C NMR (150 MHz, CDCl3): δ = 75.7, 72.0, 50.7, 38.3, 38.0, 32.1,
29.8, 29.5, 25.7, 22.9, 18.0, 14.3.
(8) Garnier-Amblard, E. C.; Mays, S. G.; Arrendale, R. F.;
Baillie, M. T.; Bushnev, A. S.; Culver, D. G.; Evers, T. J.;
Holt, J. J.; Howard, R. B.; Liebeskind, L. S.; Menaldino, D.
S.; Natchus, M. G.; Petros, J. A.; Ramaraju, H.; Reddy, G.
P.; Liotta, D. C. ACS Med. Chem. Lett. 2011, 2, 438.
(9) (a) Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y. Angew. Chem. Int. Ed.
2001, 40, 2921. (b) Nokami, J.; Ohga, M.; Nakamoto, H.;
Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem. Soc.
2001, 123, 9168.
(10) (a) Wiseman, J. M.; McDonald, F. E.; Liotta, D. C. Org.
Lett. 2005, 7, 3155. (b) Correction: Wiseman, J. M.;
McDonald, F. E.; Liotta, D. C. Org. Lett. 2007, 9, 2959.
(11) Carbonate migration has been observed on several occasions
between two five-membered-ring isomers: (a) Roush, W. R.;
Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48, 5083.
(b) Wang, Z.; Schreiber, S. L. Tetrahedron Lett. 1990, 31,
31.
HRMS (ESI): m/z calcd for C18H40NO2 (M + H+): 302.3053; found:
302.3050.
(4R,6R)-4-[(1S)-1-Azidoethyl]-2,2-dimethyl-6-(tridecyl)-1,3-di-
oxane (46)
The syn-diol stereochemistry of 44 was confirmed by converting a
portion of azidodiol 44 (15 mg) into the 3,5-acetonide 46 (10 mg)
using dimethoxypropane and catalytic p-TsOH, as described for the
preparation of compound 15. The 13C NMR acetal resonance at 98.8
ppm and methyl resonances at 30.2 ppm and 19.9 ppm were consis-
tent with a six-membered-ring acetonide with syn-stereochemistry
of the oxygens at C3 and C5.23
1H NMR (600 MHz, CDCl3): δ = 3.80–3.75 (m, 2 H), 3.45–3.41 (m,
1 H), 1.57–1.53 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.31–1.26 (m,
22 H), 1.22 (d, J = 6.6 Hz, 3 H), 0.89 (t, J = 6.6 Hz, 3 H).
(12) Buchanan, J. G.; Chacón-Fuertes, M. E.; Edgar, A. R.;
Moorhouse, S. J.; Rawson, D. I.; Wightman, R. H.
Tetrahedron Lett. 1980, 21, 1793.
13C NMR (150 MHz, CDCl3): δ = 98.8, 72.4, 68.9, 60.8, 36.6, 32.4,
32.1, 30.2, 29.8, 29.7, 29.5, 25.5, 22.9, 19.9, 15.1, 14.3.
(13) Crystal structure data for compound 15 have been deposited
under the deposition number CCDC 894289 at the
Cambridge Crystallographic Data Centre. These data can be
obtained free of charge at
Acknowledgment
www.ccdc.cam.ac.uk/conts/retrieving.html or by writing to
the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033;
E-mail: deposit@ccdc.cam.ac.uk.
We thank Prof. Dennis Liotta (Emory University) and Prof. Alfred
Merrill (Georgia Institute of Technology) for their support and
encouragement in this work. We also thank Dr. Yi-Hung Chen
(Emory University) for first alerting us to the possibility of carbo-
nate migration leading to formation of compound 12. We thank
Prof. Dennis Hall and Dr. Vivek Raumiyar (University of Alberta)
for generous gifts of VIVOL catalysts. Crystallographic analysis of
the enigmol derivative 15 was conducted by Dr. Kenneth I.
Hardcastle and Dr. Rui Cao (Emory University X-ray Crystallogra-
phy Center). We thank Mr. Noah Setterholm (Emory University)
for his assistance in completing characterization of several com-
pounds.
(14) Lee, C. K.; Lee, C. A.; Tan, K.; Loh, T.-P. Org. Lett. 2004,
6, 1281.
(15) (a) Nokami, J.; Nomiyama, K.; Shafi, S. M.; Kataoka, K.
Org. Lett. 2004, 6, 1261. (b) The reaction of Nokami’s
isomenthone-derived reagent with tetradecanal (6) required
only 24 h; however, the minor diastereomer of this reagent
was difficult to separate from the major diastereomer, and
crotyl-transfer reactions with the mixture of diastereomers
provided a mixture of cis- and trans-alkene products.
(16) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570.
(17) (a) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc.
2008, 130, 8481. (b) Rauniyar, V.; Hall, D. G. J. Org. Chem.
2009, 74, 4236.
(18) (a) Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125,
4990. (b) Chen, Y.-H.; McDonald, F. E. J. Am. Chem. Soc.
2006, 128, 4568.
References
(1) Bezuidenhout, S. C.; Gelderblom, W. C. A.; Gorst-Allman,
C. P.; Horak, R. M.; Marasas, W. F. O.; Spiteller, G.;
Vleggaar, R. J. Chem. Soc., Chem. Commun. 1988, 743.
(2) Stockmann-Juvala, H.; Savolainen, K. Human Exp. Toxicol.
2008, 27, 799.
(3) (a) Humpf, H.-U.; Schmelz, E. M.; Meredith, F. I.; Vesper,
H.; Vales, T. R.; Wang, E.; Menaldino, D. S.; Liotta, D. C.;
Merrill, A. H. J. Biol. Chem. 1998, 273, 19060.
(b) Seiferlein, M.; Humpf, H.-U.; Voss, K. A.; Sullards, M.
C.; Allegood, J. C.; Wang, E.; Merrill, A. H. Mol. Nutr. Food
Res. 2007, 51, 1120.
(4) For the first synthesis of fumonisin B1, see: Pereira, C. L.;
Chen, Y.-H.; McDonald, F. E. J. Am. Chem. Soc. 2009, 131,
6066.
(19) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(20) (a) The Mitsunobu inversion of compound 20 proved to be
the most reliable approach to preparing stereochemically
homogeneous 24. Enantioselective crotylboration directly to
the diastereomer 24 proceeded with lower yields (ref. 20b)
or less-than-perfect anti-diastereoselectivity (ref. 16).
(b) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321.
(5) Symolon, H.; Bushnev, A.; Peng, Q.; Ramaraju, H.; Mays,
S. G.; Allegood, J. C.; Pruett, S. T.; Sullards, M. C.;
Dillehay, D. L.; Liotta, D. C.; Merrill, A. H. Mol. Cancer
Ther. 2011, 10, 648.
(6) (a) Menaldino, D. S.; Bushnev, A.; Sun, A.; 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. Pharmacol. Res. 2003, 47, 373. (b) Bushnev, A. S.;
Baillie, M. T.; Holt, J. J.; Menaldino, D. S.; Merrill, A. H.;
Liotta, D. C. ARKIVOC 2010, (viii), 263. (c) Esteve, J.;
(21) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem.
Soc. 1981, 103, 7690.
(22) (a) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1988, 53, 5185. (b) Literature reports on the use of
Ti(Oi-Pr)2(N3)2 have previously been limited to epoxy
alcohols arising from allylic alcohols.
(23) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3639–3648

3648
F. E. McDonald, C. L. Pereira
PAPER
Macchia, F.; Pineschi, M. Tetrahedron 1995, 51, 10601.
(b) Benedetti, F.; Berti, F.; Norbedo, S. Tetrahedron Lett.
1998, 39, 7971. (c) McCleland, B. W.; Nugent, W. A.; Finn,
M. G. J. Org. Chem. 1998, 63, 6656.
(24) Harmange, J.-C.; Boyle, C. D.; Kishi, Y. Tetrahedron Lett.
1994, 35, 6819.
(25) (a) Saikia, P. P.; Goswami, A.; Baishya, G.; Barua, N. C.
Tetrahedron Lett. 2009, 50, 1328. (b) The characterization
data reported for compound 35 in reference 25a matched the
data provided in reference 10a; however, the structure of this
compound was misassigned, as briefly noted in reference
10b and described more fully herein. Thus, we recommend
that this work should be reinvestigated.
(26) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y.
J. Am. Chem. Soc. 1997, 119, 11224. (b) Wong, O. A.; Shi,
Y. Chem. Rev. 2008, 108, 3958.
(28) Portions of this work have been previously communicated:
(a) McDonald, F. E.; Pereira, C. L.; Chen, Y.-H. Pure Appl.
Chem. 2011, 83, 445. (b) Pereira, C. L. Ph.D. Dissertation;
Emory University: USA, 2010.
(29) (a) Kumarn, S.; Oelke, A. J.; Shaw, D. M.; Longbottom, D.
A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2678.
(b) Chandrasekhar, S.; Kiranmai, N. Tetrahedron Lett. 2010,
51, 4058.
(27) Other reagents including enantioselective catalysts for azide
addition to epoxides gave poorer regioselectivities and/or
yields: (a) Azzena, F.; Calvani, F.; Crotti, P.; Gardelli, C.;
(30) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2,
2451.
Synthesis 2012, 44, 3639–3648
© Georg Thieme Verlag Stuttgart · New York