Synthesis of 2-amino-octa-4,7-dien-1-ol (2): Key intermediate for mycothiazole natural product and analogs

Article abstract of DOI:10.1081/SCC-200057988

Starting from L-aminoacids, facile methods for the preparation 2-aminocta-4,7-dien-ol with different stereochemistry have been developed as key intermediates of mycothiazole and analogs. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200057988

This article was downloaded by: [Georgetown University]
On: 01 May 2013, At: 09:19
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of
2‐Amino‐octa‐4,7‐Dien‐1‐ol
(2): Key Intermediate for
Mycothiazole Natural Product
and Analogs
Graciela Mahler a , Gloria Serra a & Eduardo Manta a
a Cátedra de Química Farmacéutica, Departamento
de Química Orgánica, Facultad de Química,
Montevideo, Uruguay
Published online: 17 Dec 2010.
To cite this article: Graciela Mahler , Gloria Serra & Eduardo Manta (2005): Synthesis
of 2‐Amino‐octa‐4,7‐Dien‐1‐ol (2): Key Intermediate for Mycothiazole Natural
Product and Analogs, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:11, 1481-1492
To link to this article: http://dx.doi.org/10.1081/SCC-200057988
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,

sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communicationsw, 35: 1481–1492, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057988
Synthesis of 2-Amino-octa-4,7-Dien-1-ol (2):
Key Intermediate for Mycothiazole Natural
Product and Analogs
Graciela Mahler, Gloria Serra, and Eduardo Manta
´
´
Facultad de Quımica, Udelar, Montevideo, Uruguay
´ ´
Catedra de Quımica Farmaceutica, Departamento de Quımica Organica,
´
´
Abstract: Starting from L-aminoacids, facile methods for the preparation 2-aminocta-
4,7-dien-ol with different stereochemistry have been developed as key intermediates of
mycothiazole and analogs.
Keywords: 1,2-Aminoalcohols, L-aminoacids, porcine kidney acetylase, Wittig
reaction
Compounds containing 1,2-aminoalcohols are of great interest because of
either their intrinsic properties or for their as powerful synthetic intermediates.
This particular function is present in many drugs and in serine protease
inhibitors.[1] Moreover, 1,2-aminoalcohols are useful as chiral ligands for
catalysts[2] or as chiral auxiliaries in asymmetric synthesis.[3] These types of
molecules have been employed to construct b-hydroxy amides and thioamides
as key intermediates in the synthesis of thiazolines and oxazolines.[4]
Many bioactive natural products and analogs to natural products have
been synthesized using cyclodehydration reactions of b-hydroxy amides or
thioamides such as trunkamide,[5a] mollamide,[5b] hennoxazole,[6] Lissoclinum
cyclopeptide alkaloids and analogs,[7] and curacin A analogs.[8]
Received in the USA January 27, 2005
Address correspondence to Eduardo Manta, Catedra de Quımica Farmaceutica,
´
´
´
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Udelar, General Flores
2124, Montevideo, Uruguay. Tel.: 598 2 924 4856. Fax: 598 2 924 1906; E-mail:
emanta@fq.edu.uy
1481

1482
G. Mahler, G. Serra, and E. Manta
The marine natural product mycothiazole (1, Figure 1) exhibited anthelmin-
tic activity[9] in vitro and selective toxicity toward lung cancer cells in the NCI in
vitro 60-cell line panel. Results of the National Cancer Institute Human Tumor
Cell Line Screen can be obtained at http:// dtp.nci.nih.gov/, NSC 647640.
As part of our work in the search for bioactive compound analogs to
marine natural products, we are interested in the synthesis of 1,2-aminoalco-
hols, intermediates for thiazolines/thiazoles and oxazolines/oxazoles analogs
of mycothiazole.[10]
In the total synthesis of mycothiazole, Sugiyama and coworkers con-
structed the C18-C14 diene fragment by two successive Stille couplings
using a bromide-containing thiazol intermediate.[11]
Our planned synthesis of 1 and its derivatives is based on a convergent
approach that combines aminoalcohols and acids, as shown in Scheme 1.
In this article, we describe our study on the synthesis of aminoalcohols
of type 2, key intermediates of 1 (C11-C18 fragment) and reduced analogs
thereof.
RESULTS AND DISCUSSION
Aminoalcohols of type 2, with various stereochemistries, were synthesized
using two methodologies: via Wittig reaction or by traditional aminoacid
synthesis. First we investigated the Wittig reaction between the homolo-
gated Garner’s aldehyde 7,[12] and the nonstabilized ylide obtained from the
Wittig salt 8, (Scheme 2).
The aldehyde 7 was synthesized as shown in Scheme 2, starting from
the oxazoline 3.[12] Reduction of the ester function using NaBH4/MeOH
gave the alcohol 4.[13] The best yield to perform the conversion of
compound 5 to the cyanide 6 was obtained using the mesyl oxazolidine 5c.
Reduction of compound 6 by DIBALH allowed us to obtain the homologated
Garner’s aldehyde (7).
Wittig coupling of compound 7 and homoallylthriphenylphosphonium
bromide (8) gave the protected aminoalcohols 9. These products were
obtained in variable yield and stereoselectivity depending on the experimental
conditions, as shown in Table 1.
The Z alkene was the major product under Boden conditions (method A)
as expected for a nonstabilized ylide.[14] Attempts to isomerize this Z alkene to
Figure 1.

2-Amino-octa-4,7-dien-1-ol
1483
Scheme 1.
the E isomer (present in the natural product) using the conditions reported by
matikainen and coworkers (method B) failed.[15] Nevertheless, the E alkene
could be obtained using Schlosser modification of the Wittig reaction.[16] In
this case, the product was obtained with the highest selectivity but the
lowest yield (20%).
Protecting groups of compound 9 were removed by treatment with HCl
10% and MeOH at 408C to give the Z or E isomer of (R) 2-aminocta-4,7-
dien-ol (2) in 90% yield.
To improve both yield and stereoselectivity, an alternative route was
investigated (Scheme 3).
The synthesis involved the alkylation of acetamidemalonic ester (11) with
alkenyl bromide 10.
Compound 10 was synthesized using Normant methodology, starting
from allylbromide and propargyl alcohol by a C-C coupling reaction.[17]
DMPU was used as solvent instead of HMPA. The selective reduction of
the alkynyl alcohol to the E double bound using LiAlH4 and a subsequent
substitution of the alcohol by a bromide allowed us to obtain the desired
product 10 in 65% overall yield.
Scheme 2. a) NaBH4, MeOH, rt, 12 h, 90% yield: b) CCl4, PPh3, benzene, reflux, 2 h,
61% yield; c) CBr4, CH2Cl2, 08C to rt, 63% yield; d) MsCl, Py, 0 to 408C, 4 h, 90%
yield; e) TosylCl, Py, 08C, 48 h, 50% yield; f) NaCN, DMF, 908C, 10 h, 70% yield;
g) DIBALH, CH2Cl2, 2 408C to rt, 4 h, 70% yield; h) K2CO3, 18-crown-6, CH2Cl2,
reflux, 4 h, 90% yield; i) K2CO3, hn, sodium/thioglycolate, dioxane/H2O, 60%
yield; j) PhLi, tBuOK, 2 78 to 2 308C, THF, 20% yield: k) MeOH, HCl 10%, 408C,
90% yield.

1484
G. Mahler, G. Serra, and E. Manta
Table 1. Synthesis of compound 9 using different conditions
Experimental
conditions
Time and T (8C) Solvent and T (8C) Z/Ea Yield (%)
A
B
K2CO3 (1.5 eq.), 4 h, reflux
18-crown-6
CH2Cl2
90:10
75:25
90
60
K2CO3 (1.5 eq.), 20 h, reflux
sodium
thioglycolate
Dioxane/H2O
C
PhLi (2 eq),
tBuOH-tBuOK
2 h, 278 to 230
THF
13:87
20
aThe Z/E ratio was determined by NMR spectroscopy on the crude reaction mixture.
The alkylation reaction of compound 11 proceeded with good yields,
giving the ester 12. To perform the decarboxylation, product 12 was first sapo-
nificated at room temperature with NaOH and the solution then acidificated
with HCl to pH 2. Finally the diacidic aduct was isolated to perform decar-
boxylation reaction in refluxing H2O/MeOH. Other decarboxylation media
led to decomposition products. (S)-Aminoacid 14 was obtained in excellent
yield from 13 by stereoespecific hydrolysis of the acetamide group with
porcine kidney acetylase (EC 3.5.1.14).[17] Attempts to perform the hydrolysis
Scheme 3. Cu2Cl2, K2CO3, K2CO3, Na2SO3, DMPU, reflux, 5 h, 0% yield; b)
LiAlH4, THF, reflux, 2 h, 80%; c) CBr4, Ph3, CH2Cl2, 108C, 2 h, 70% yield; d)
EtONa, EtOH, 5 h, 80% yield; e) NaOH, rt, 24 h; f) HCl pH ¼ 2; g) H2O/MeOH,
reflux, 6 h, 80% yield (e,f,g); h) Acylasa I (EC 3.5.1.14) Co(Ac)2, 378C, 24 h; 50%
yield; i) LiAlH4, THF, reflux, 2 h, 70% yield.

2-Amino-octa-4,7-dien-1-ol
1485
of compound 13 in NaOH at reflux failed because of the decomposition of the
reaction product. Finally the reduction of the acid group rendered the (2S, 4E)-
2-aminocta-4,7-dien-ol (2) in 20% overall yield.
The hydrolysis of the (R) N-acetyl-aminoacid (13) and reduction to
alcohol group provided the (2R, 4E) aminoalcohol 2.
Our results indicated that rac-aminoacid synthesis is more useful than the
Schlosser method to construct E aminoalcohol 2 because the sequence is
shorter and overall yield is higher.
EXPERIMENTAL
General Methods
Melting points were determined on a Gallenkamp capillary melting point
apparatus and are uncorrected. IR spectra were recorded on a Shimadzu
spectrophotometer. NMR spectra were recorded on Bruker Advance DPX-
400 (1H, 400 MHz; 13C, 100 MHz). Chemical shifts are relative to TMS
as internal standard. Low-resolution mass spectra (MS) were obtained on a
GCMS Shimadzu QP 1100-EX spectrometer. Elemental analyses were
obtained from vacuum-dried samples and performed on a Fisons EA 1108
CHNS-O analyzer. Flash column chromatography was carried out with
silica gel 60 (J. T. Baker, 40-mm average particle diameter). All reactions
and chromatographic separations were monitored by TLC analyses,
conducted on 0.25-mm silica-gel plastic sheets (Macherey–Nagel,
PolygramR SIL G/UV 254). Spots were visualised under 254-nm illumina-
tion, by iodine vapor, p-hydroxybenzaldehyde spray, or ninhydrine spray.
All reactions were carried out in dry, freshly distilled solvents under
anhydrous conditions unless otherwise stated. Yields are reported for chro-
matographically and spectroscopically (1H- and 13C-NMR) pure
compounds. The Z/E ratio was determined by NMR spectroscopy on the
crude reaction mixture.
(4R)-4-Hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid
tert-butyl ester (4). To a stirred solution of 3 (2.6 g, 9.7 mmol) in MeOH
(23 mL) was added in portions NaBH4 (1.2 g, 32 mmol) at rt. After 12 h, the
solvent was evaporated. To the residue, 5% HCl was added until pH 7. The
aqueous layer was extracted (5 ꢀ 30 mL) with AcOEt and the combined
organic layer dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography (silica gel, AcOEt/n-hexane, 1:2) afforded 2.2 g (90%) of 4.
(4R)-4-Methanesulfonyloxymethyl-2,2-dimethyl-oxazolidine-3-carb-
oxylic acid tert-butyl ester (5c). To a solution of 4 (3.3 g, 14.3 mmol) in
pyridine (47 mL) at 08C was added MsCl (2.24 mL, 14.8 mmol) and the
mixture was stirred at 08C for 1 h and then at 408C for 4 h. Two percent
HCl (100 mL) was added and the mixture extracted with Et2O
(3 ꢀ 100 mL). The combined organic layers were washed with 2% HCl

1486
G. Mahler, G. Serra, and E. Manta
(100 mL), saturated NaHCO3 (2 ꢀ 100 mL), and H2O (2 ꢀ 100 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography (silica gel, AcOEt/n-hexane, 1:2) afforded 5c (3.9 g, 90%).
1
mp: 75–768C, Rf ¼ 0.40 (AcOEt/n-hexane, 1:2). H-NMR (CDCl3) d: 1.48
(bs, 9H), 1.54 (s, 6H), 1.63 (s, 6H),ꢁ 3.03 (s, 3H), 3.99 (d, J ¼ 3.05 Hz,
2H), 4.08–4.16 (m, 2H), 4.32–4.34 (m, 1H); 13C-NMR (CDCl3) d: 152.6,
151.7,ꢁ 94.7,ꢁ 94.2, 81.4, 81.1,ꢁ 67.6, 65.3,ꢁ 65.0, 56.2, 37.9,ꢁ 37.6, 28.7,
27.7, 27.1,ꢁ 24.6, 23.3.ꢁ (ꢁ Asterisk denotes minor conformer peaks.) EIMS,
70 eV (%): 294 ([M-15]þ, 2.9), 194 (60.8), 138 (14.8), 57 (100). IR (KBr):
n ¼ 3380, 1680, 1520 cm21. Anal. calc. for C12H23NO6S: C, 46.59; H,
7.49; N, 4.53; S, 10.36. Found: C, 46.13; H, 7.65; N, 4.19; S, 10.77.
(4R)-4-Cyanomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-
butyl ester (6). To a solution of 5c (7 g, 22.7 mmol) in DMF (170 mL) was
added KCN (2.07 g, 31.8). The stirred reaction mixture was heated at 90–
958C for 10 h, then washed with water (100 mL), and extracted with AcOEt
(9 ꢀ 80 mL) and CHCl3 (3 ꢀ 70 mL). The combined organic layer was
washed with water (80 mL), dried (MgSO4), and concentrated in vacuo.
Flash chromatography (AcOEt/n-hexane, 1:2) afforded compound 6 (3.70 g,
70%). Solid, mp 85–878C, Rf ¼ 0.60 (AcOEt/n-hexane, 1:2); 1H-NMR
(CDCl3) d: 1.47 (bs, 9H), 1.58 (s, 6H), 1.63 (s, 3H), 2.72 (m, 2H), 3.92
13
(m, 1H), 4.09 (m, 2H); C-NMR (CDCl3) d: 152.4, 151.4,ꢁ 117.0, 95.2,ꢁ
94.7, 81.5, 81.3,ꢁ 67.2, 66.8,ꢁ 54.5, 54.2,ꢁ 28.7, 27.7, 27.1, 24.7, 24.0,ꢁ
22.4,ꢁ 21.4. (ꢁ Asterisk denotes minor conformer peaks.) EIMS (20 eV),
m/z (%), 225 (Mþ -CH3, 3.1), 125 (21.6), 57 (34.6), 44 (100.0). IR film
nmax: 3402, 2254, 1690. Anal. elem. calcd. for C12H20N2O3: C, 59.98; H,
8.39; N, 11.66. Found: C, 60.77; H, 8.63; N, 11.88.
(4R)-2,2-Dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-
butyl ester (7). To a stirred solution of compound 6 (1.8 g, 7.5 mmol) in
CH2Cl2 (45 mL) at 2408C was added a solution of 1 M of DIBAL-H in
hexane (13 mL, 12.9 mmol) in portions. After 2 h of stirring, MeOH (9 mL)
was added carefully and the mixture was allowed to warm up to room temp-
erature. The mixture was then poured into a solution of potassium sodium
tartrate (18.2 g) in H2O (48 mL) and the biphasic mixture stirred vigorously
for 2 h. The phases were separated and the aqueous layer extracted with
CH2Cl2 (5 ꢀ 20 mL). The combined organic layer was dried (MgSO4),
filtered, and concentrated. The residue was chromatographed on SiO2
(AcOEt/n-hexane, 1:3) to give compound 7 (1.3 g, 70% yield). Oil,
1
Rf ¼ 0.58 (AcOEt/n-hexane, 1:2). H-NMR (CDCl3) d: 1.50 (s, 9H), 1.57
(s, 6H), 1.62ꢁ (s, 6H), 2.59–2.78 (m, 2H), 2.81–3.07ꢁ (m, 2H), 3.75 (dd,
J1 ¼ 1.56, J2 ¼ 9.2 Hz, 1H), 4.09 (dd, J1 ¼ 1.6, J2 ¼ 9.1 Hz, 1H), 4.06-4.10
(dd J1 ¼ 6, J2 ¼ 9.1 Hz, 1H), 4.30 (bs, 1H), 4.38ꢁ (bs, 1H), 9.81 (s, 1H);
13C-NMR (CDCl3) d: 200.8, 151.7, 151.7,ꢁ 94.4,ꢁ 93.8, 81.0, 80.7,ꢁ 68.3,ꢁ
67.2, 53.1, 52.7,ꢁ 48.7,ꢁ 47.8, 28.8, 27.9, 27.1,ꢁ 24.9, 23.5ꢁ. (ꢁ Asterisk
denotes minor conformer peaks.) EIMS (20 eV), m/z (%), 244 ([M þ 1]þ,
10.5), 243 (Mþ, 0.2), 228 (9.8), 188 (7.9), 172 (12.8), 144 (33.4), 128

2-Amino-octa-4,7-dien-1-ol
1487
(15.1), 57 (100), 44 (78.5). IR film nmax: 3442.2, 1697.6. Anal. calcd. for
C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 58.99; H, 8.81; N, 5.80.
Triphenylhomoallylphosphine bromide (8). To a solution of 4-bromo-
butene (5 g, 37 mmol) in toluene (25 mL) was added PPh3 (9.71 g, 37 mmol).
The reaction mixture was stirred at 1008C for 24 h, cooled, filtered, and
washed with toluene. The solid was dried for 1 h at 508C and then overnight
in a vacuum dessicator. The resulted salt 13 (10 g, 68%) was used without
further purification.
(4S, 2Z)-4-Hexa-2,5-dienyl-2,2-dimethyl-oxazolidine-3-carboxylic
acid tert-butyl ester (9). Method A (Boden).
To a suspension of salt 8 (983 mg, 2.5 mmol) in CH2Cl2 (1.5 mL) was
added K2CO3 (2.5 mmol, 341 mg) and 18-crown-6 (4.2 mg). The mixture
reaction was stirred for 30 min and then a solution of compound 7
(1.65 mmol, 400 mg) in CH2Cl2 (1 mL) was added dropwise and refluxed
for 4 h. The reaction mixture was cooled, filtered through celite, and washed
with Et2O. The filtrate was concentrated and chromatographed on SiO2
(AcOEt/n-hexane, 1:6) to give alkenyl 9 (632 mg, 90% yield, Z/E: 90/10).
1
Oil, Rf ¼ 0.69 (AcOEt/n-hexane, 1:6). H-NMR (CDCl3) d: 1.50 (bs, 9H),
1.60 (bs, 3H), 1.61 (bs, 6H), 1.63ꢁ (bs, 3H), 2.20–2.57 (m, 2H), 2.87
(dd, J1 ¼ J2 ¼ 6.6 Hz, 2H3), 3.74–3.93 (m, 3H), 5.00–5.09 (m, 2H), 5.38–
5.48 (m, 1H), 5.50–5.57 (m, 1H), 5.76–5.89 (m, 1H); 13C-NMR (CDCl3)
d: 153.0, 136.9, 130.2, 126.5, 115.3, 94.3, 93.8,ꢁ 80.3, 80.2,ꢁ 66.9, 66.8,ꢁ
57.6, 32.0, 31.5, 30.7,ꢁ 28.9, 27.9, 27.1,ꢁ 24.9,ꢁ 23.7. (ꢁ Asterisk denotes
minor conformer peaks.) EIMS (20 eV), m/z (%), 281 (Mþ, 0.1), 200 (19.1),
100 (40.7), 83 (4.5), 57 (100). IR n max ¼ 3410, 1690 cm21. Anal. calcd.
for C16H27NO3: C, 68.29; H, 9.67; N, 4.98. Found: C, 67.99; H, 9.80; N, 5.09.
(4S, 2Z)-4-Hexa-2,5-dienyl-2,2-dimethyl-oxazolidine-3-carboxylic acid
tert-butyl ester (9). Method B (Hase).
A stirred mixture of salt 8 (0.19 mmol, 74mg), K2CO3 (0.18 mmol, 26mg),
aldhehyde 7 (0.12 mmol, 30mg), sodium thioglycolate (0.012mmol, 1.4 mg),
dioxane (1 mL), and H2O (3 ꢀ 1023 mL) were heated to reflux under
tungsten daylight lamp irradiation (75 W). After 20 h, the volatiles were
removed under reduced pressure and the residue chromatographed on SiO2
(AcOEt/n-hexane, 1:6) to give compound 9 (32 mg, 60% yield, Z/E: 75/25).
(4S, 2E)-4-Hexa-2,5-dienyl-2,2-dimethyl-oxazolidine-3-carboxylic
acid tert-butyl ester (9). Method C (Schlosser).
To a suspension of salt 8 (0.82 mmol, 326 mg) in THF (2 mL) cooled at
2788C was added PhLi (0.82 mmol, 1.06 M) and the mixture was stirred
for 30 min. Then a solution of aldehyde 7 (0.82 mmol, 200 mg) in Et2O
(2 mL) was added dropwise. The mixture turned orange after 45 min, and
then more PhLi (0.82 mmol, 1.06 M) was added and the reaction was allowed
to warm up to 2308C. At this temperature, tBuOK-tBuOH (complex 1:1)
(229 mg, 1.23 mmol) was added and the mixture was stirred for another
45 min and then filtered through celite, washed with Et2O, and concentrated
in vacuo. Purification by flash comatography on SiO2 (AcOEt/n-hexane,

1488
G. Mahler, G. Serra, and E. Manta
0.5:5) afforded compound 9 (46 mg, 20% yield, Z/E:13/87). Oil, Rf ¼ 0.69
(AcOEt/n-hexane, 1:6).1H-NMR (CDCl3) d: 1.50 (bs, 9H), 1.60 (bs, 6H),
2.22ꢁ (m), 2.47 (m, 2H), 2.77 (m, 2H), 3.78 (dd J1 ¼ 8.2, J2 ¼ 17 Hz, 1H),
3.91 (dd, J1 ¼ 8.2, J2 ¼ 5.7, 1H), 4.99–5.04 (m, 2H), 5.35–5.47 (m, 1H),
5.51–5.62 (m, 1H), 5.79–5.86 (m, 1H); 13C-NMR (CDCl3) d: 153.4, 137.3,
131.5, 130.2, 127.6, 126.5, 115.4, 66.9, 57.6, 37.1, 30.1, 28.7. (ꢁ asterisk
denotes minor conformer peaks.) EIMS (20 eV), m/z (%), 281 (Mþ, 0.3),
200 (22.7), 166 (1.7), 144 (12.3), 100 (42.8), 83 (4.5), 57 (100.0).
(2R, 4Z)-2-Amino-octa-4,7-dien-1-ol (2). To a solution of (2R, 4Z)
compound 9 (310 mg, 1.1 mmol) in MeOH (30 mL) was added 10% HCl
(15 mL). The reaction mixture was stirred at 408C for 6 h, quenched with
saturated solution of NaHCO3, and extracted with AcOEt (6 ꢀ 20 mL). The
combined organic layer was dried, filtered, concentrated in vacuo, and the
residue chromatographed on SiO2 (AcOEt/n-hexane, 1:4) to give (2R, 4Z)
compound 2 (139 mg, 90% yield). Oil, Rf ¼ 0.43 (CHCl3/MeOH 2:0.5).
1H-NMR (CDCl3) d: 1.99 (bs, 1H), 2.09–2.18 (m, 2H), 2.83 (dd,
J1 ¼ J2 ¼ 6.1 Hz, 2H), 2.90 (m, 1H), 3.34 (dd, J1 ¼ 7.3, J2 ¼ 10.6 Hz, 1H),
3.60 (dd, J1 ¼ 3.6, J2 ¼ 10.6 Hz, 1H), 4.98–5.08 (m, 2H), 5.46–5.50
(m, 1H), 5.19–5.50 (m, H), 5.78–5.85 (m, 1H); 13C-NMR (CDCl3,) d:
137.0, 130.1, 127.2, 115.2, 66.9, 53.1, 32.6, 32.0; EIMS 20 eV, m/z (%):
141 (Mþ, 0.1), 123 (Mþ-H2O, 0.4), 110 (Mþ-CH2OH, 12.5), 74 (8.7), 60
(100.0). IR(film) nmax 3422, 1637 cm21. C8H15NO: C, 68.04; H, 10.71; N,
9.92. Found: C, 68.45; H, 9.62; N, 11.63.
(2R, 4E)-2-Amino-octa-4,7-dien-1-ol (2). To a solution of (2R, 4E)
compound 9 (310 mg, 1.1 mmol) in MeOH (30 mL) was added 10% HCl
(15 mL). The reaction mixture was stirred at 408C for 6 h,quenched with
saturated solution of NaHCO3, and extracted with AcOEt (6 ꢀ 20 mL). The
combined organic layer was dried, filtered, concentrated in vacuo, and the
residue chromatographed on SiO2 (AcOEt/n-hexane, 1:4) to give (2R, 4E)
compound 2 (137 mg, 89% yield).Oil, Rf ¼ 0.43 (CHCl3/MeOH 2:0.5),
1H-NMR (MeOD) d: 2.36-2.41 (m, 2H), 2.82 (dd, J1 ¼ J2 ¼ 5.9 Hz, 2H),
3.22–3.26 (m, 1H), 3.56 (dd, J1 ¼ 7.0, J2 ¼ 11.6 Hz, 1H), 3.77 (dd,
J1 ¼ 3.7, J2 ¼ 11.6 Hz, 1H), 5.00–5.04 (m, 1H), 5.48 (m, 1H), 5.82–5.88
(m, 1H); 13C-NMR (CDCl3) d: 137.1, 132.1, 127.1, 115.7, 65.7, 53.0, 37.0,
30.1. EIMS (20 eV), m/z (%), 141 (Mþ, 0.1), 123 (Mþ-H2O, 0.42), 110
(Mþ-CH2OH, 12.5), 74 (8.7), 60 (100). IR (film) nmax 3422, 1637 cm21
.
Anal. calcd. for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 67.95; H,
9.79; N, 10.29.
(4E) 6-Bromo-hexa-1,4-diene (10). To a stirred solution of (4E)-6-
hydroxy-hexa-1,4-diene (6.3 g, 0.65 mol) in CH2Cl2 (80 mL) cooled at
2158C was added CBr4 (222 g, 0.67 mol) and PPh (18 g, 0.67 mmol).
3
After stirring 2 h, the solvent was removed under reduced pressure and the
residue chromatographed on SiO2 (AcOEt/n-hexane, 0.25:5) to give alkenyl-
bromide 10 (9.3 g, 90%).Oil, Rf ¼ 0.52 (AcOEt/n-hexane, 0.25:5); 1H-NMR
(CDCl3) d: 2.84 (t, J ¼ 6.3 Hz, 2H), 3.98–3.97 (m, 2H), 5.05–5.10 (m, 2H),

2-Amino-octa-4,7-dien-1-ol
1489
5.72–5.85 (m, 3H); 13C-NMR (CDCl3) d: 137.9, 134.2, 132.2, 116.5, 36.4,
33.4. EIMS (20 eV), m/z (%), 160 (Mþ, 0.5), 162 (Mþ þ 2, 0.4).
(2E)-2-Acetylamino-2-hexa-2,5-dienyl-malonic acid diethyl ester (12).
To a suspension of Na8 (1.3 g, 55.8 mmol) in EtOH (25 mL) a solution of
compound 11 (8 g, 36.4 mmol) in EtOH (15 mL) was added. The mixture
was stirred at reflux for 45 min and then cooled at room temperature.
Bromide 10 (6 g, 37.2 mmol) was added dropwise. The mixture was refluxed
for 8 h. H2O (20 mL) was added and the aqueous layer was extracted with
AcOEt (4 ꢀ 20 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography (silica gel,
AcOEt/n-hexane, 1:2) afforded 12 (8.8 g, 80% yield). Oil, Rf ¼ 0.75
1
(AcOEt/n-hexane, 1:1); H-NMR (CDCl3) d: 1.26 (t, J ¼ 7.1 Hz, 6H), 2.03
(s, 3H), 2.73 (t, J ¼ 36.4 Hz, 2H), 3.04 (m, 2H), 4.24 (c, J ¼ 7.1 Hz, 4H),
4.97–5.02 (m, 2H), 5.20–5.24 (m, 1H), 5.49–5.55 (m, 1H), 5.73–5.79
(m, 1H), 6.72 (s, 1HNH); 13C-NMR (CDCl3) d: 169.2, 168.1, 136.9, 133.8,
124.2, 115.7, 66.8, 62.9, 37.0, 36.2, 23.4, 14.4. EIMS (70 eV), m/z (%), 297
(Mþ, 2.5), 252 (Mþ -OEt, 7.7), 224 (13.3), 197 (50.3), 182 (42.5), 174
(48.7), 146 (23.5), 108 (22.5), 43 (100).
(4E) rac-2-Acetylamino-octa-4,7-dienoic acid (13). A solution of
alkenyl ester 12 (1.3 g, 4.4 mmol) in NaOH 2N (25 mL) was stirred
overnight at room temperature. The mixture was cooled at 48C, acidulated
with HCl to pH 1, and concentrated in vacuo. The residue was washed with
MeOH and filtered. The solution was concentrated in vacuo to 30 mL. H2O
(24 mL) was added and the mixture was refluxed for 6 h. The solvent was
removed under reduced pressure. Flash chromatography (silica gel, CHCl3/
MeOH/AcOH,3:0.3:0.01) afforded 13 (695 mg, 80% yield). Oil, Rf ¼ 0.58
(CHCl3/MeOH/AcOH, 3:0.3:0.01). 1H-NMR (CDCl3) d: 2.05 (s, 3H),
2.52–2.76 (m, 3H), 4.62–4.71 (m, 1H), 4.98–5.03 (m, 2H), 5.35–5.39
(m, 1H), 5.56–5.59 (m, 1H), 5.76–5.82 (m, 1H), 6.10–6.42 (m, 1HNH).
13C-NMR (CDCl3) d: 175.1, 171.7, 136.9, 133.4, 124.9, 116.3, 52.6, 36.9,
35.3, 23.3. EIMS (70 eV), m/z (%), 197 (Mþ, 0.8), 182 (5.5), 120 (22.7),
117 (19.1), 110 (16.8), 99 (29.1), 97 (39.7), 74 (100.0). Anal. elem. calcd.
for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 61.21; H, 7.15; N, 6.95.
(2S, 4E) 2-Amino-octa-4,7-dienoic acid (14). To a solution of compound
13 (200 mg, 1.1 mmol) in H2O (10 mL) was added NH4OH (conc.) to pH 7.5,
acylasa I (EC 3.5.1.14) (1 mg), and cobalt acetate (2 mg). After 20 h at 378C
more acylasa (0.1 mg) was added and the hydrolysis continued for 4 h. The
mixture was concentrated in vacuo. Flash chromatography (silica gel,
CHCl3/MeOH/NH3, 1.5:1.5:0.1) afforded 14 (85 mg, 50% yield). Solid, mp
52–538C. 1H-NMR (MeOD) d: 2.53–2.63 (m, 2H), 2.67–2.75 (m, 2H),
3.74–3.76 (m, 1H), 5.02–5.09 (m, 2H), 5.39–5.43 (m, 1H), 5.72–5.76
(m, 1H), 5.87–5.91 (m, 1H); 13C-NMR (CDCl3) d: 174.1, 137.7, 123.9,
115.7, 54.8, 36.4, 34.1.
(2S, 4E)-2-Amino-octa-4,7-octadien-1-ol (2). To a suspension of 14 (80 mg,
0.5 mmol) in THF (15 mL) cooled at 48C was added LiAlH4 (100 mg,

1490
G. Mahler, G. Serra, and E. Manta
2.6 mmol) in portions. The mixture was heated to reflux for 3 h and the excess
of LiAlH4 was destroyed with cooled AcOEt. The mixture was filtered
through celite and washed with MeOH. The filtrate was concentrated in
vacuo and the residue was purified by flash chromatography (silica gel,
CHCl3/MeOH, 3:0.5) to afford (2S, 4E) 2 (49 mg, 70% yield). The spectro-
scopic data were in agreement with those of aminoalcohol 2 synthesised
previously by Schlosser’s methodology.
CONCLUSIONS
In conclusion, we have developed two methodologies to obtain aminoalcohols
2, intermediates of mycothiazole, and their reduced analogs with different
stereochemistry.
The method that involves the homologated Garner’s aldehyde gave
(2R, 4Z)-2-aminocta-4,7-dien-ol (2) in high yield. In contrast, the (2R, 4E)
compound 2 was obtained in a moderate yield.
The aminoacid strategy provides the (2S, 4E) aminoalcohol 2 in good yield.
ACKNOWLEDGMENTS
This work was supported by grants from SAREC (Swedish Agency for
Research Cooperation with Developing Countries), PEDECIBA (Programa
´
de Desarrollo de Ciencias Basicas, Project URU/84/002), and NIH/FIRCA
(Fogarty International Research Collaboration Award).
REFERENCES
1. Occhiato, E.; Jones, J. B. Probing enzyme stereospecificity. Inhibition of a-chymo-
trypsin and subtilisin Carlsberg by chiral amine- and aminoalcohol derivatives.
Tetrahedron 1996, 52, 4199.
2. (a) Muchow, G.; Vannoorenberghe, Y.; Buono, G. Use of alkaloids and amino-
alcohols in catalytic asymmetric induction: Temperature effect on the addition
of diethylzinc to benzaldehyde. Tetrahedron Lett. 1987, 28 (49), 6163–6166;
(b) Hayashi, Y.; Rohde, J. J.; Corey, E. J. A novel chiral super-lewis acidic
catalyst for enantioselective synthesis. J. Am. Chem. Soc. 1996, 118, 5502.
3. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. 1,2-Amino alcohols and their hetero-
cyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem. Rev.
1996, 96 (2), 835; (b) Senanayake, C. H.; Fang, K.; Grover, P.; Bakale, R. P.;
Vandenbossche, C. P.; Wald, S. A. Rigid aminoalcohol backbone as a highly
defined chiral template for the preparation of optically active tertiary a-hydroxyl
acids. Tetrahedron Lett. 1999, 40, 819.
4. (a) Wipf, P.; Venkatraman, S. From aziridines to oxazolines and thiazolines: The
heterocyclic route to thiangazole. Synlett 1997, 1; (b) Wipf, P.; Fritch, P. C. Total
synthesis and assignment of configuration of lissoclinamide 7. J. Am. Chem. Soc.
1996, 118, 12358; (c) Wipf, P.; Lim, S. Total synthesis of the enantiomer of the

2-Amino-octa-4,7-dien-1-ol
1491
antiviral marine natural product hennoxazole. J. Am. Chem. Soc. 1995, 117, 558;
(d) Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M.; Williams, D. Synthesis of functio-
nalized oxazolines and oxazoles with DAST and deoxo-fluor. Org. Lett. 2000, 2,
1165; (e) Mahler, G.; Serra, G.; Antonow, D.; Manta, E. Deoxo-fluor mediated
cyclodehydration of b-hydroxy thioamides to the corresponding thiazolines.
Tetrahedron Lett. 2001, 42, 8143; (g) Scarone, L.; Sellanes, D.; Manta, E.;
Wipf, P.; Serra, G. Use of deoxo-fluor for double cyclization to bis-thiazolines.
Limitations of this agent for the synthesis of oxazolines. Heterocycles 2004, 63,
773.
5. (a) Mckeever, B.; Pattenden, G. Total synthesis of trunkamide A, a novel thiaz-
oline-based prenylated cyclopeptide metabolite from Lissoclinum sp. Tetrahedron
2003, 59, 2713–2727; (b) Mckeever, B.; Pattenden, G. Total synthesis of the
cytotoxic cyclopeptide mollamide, isolated from the sea squirt Didemnum molle.
Tetrahedron 2003, 59, 2701–2712.
6. Williams, D.; Brooks, D.; Berliner, M. Total synthesis of (–)-hennoxazole A.
J. Am. Chem. Soc. 1999, 121, 4924.
7. Wipf, P.; Miller, C.; Grant, C. Synthesis of cyclopeptide alkaloids by cyclooligo-
merization of dipeptidyl oxazolines. Tetrahedron 2000, 56, 9143.
8. Wipf, P.; Reeves, J.; Balachadran, R.; Day, B. Synthesis and biological evaluation
of structurally highly modified analogues of the antimitotic natural product
Curacin A. J. Med. Chem. 2002, 45 (9), 1901–1917.
`
9. (a) Crews, P.; Kakou, Y.; Quin˜oa, E. Mycothiazole, a polyketide heterocycle from
a marine sponge. J. Am. Chem. Soc. 1988, 110, 4365; (b) Cutignano, A.; Bruno, I.;
Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-Paloma, L.; Riccio, R. Dactylo-
lide, a new cytotoxic macrolide from the vanuatu sponge Dactylospongia sp.
Eur. J. Org. Chem. 2001, 66, 775–778.
´
10. (a) Serra, G.; Gonzalez, D.; Manta, E. A controlled stepwise oxidation of ethyl-2-
oxo-thiazolidine-4-carboxylate to the corresponding 2-hydroxythiazole. Hetero-
cycles 1995, 41, 2701; (b) Gordon, S.; Costa, L.; Incerti, M.; Manta, E.;
´
Saldan˜a, J.; Domınguez, L.; Mariezcurrena, R.; Suescun, L. Synthesis and in
vitro anthelmintic activity against Nipostrongylus brasiliensis of new 2-amino-
4-hydroxy-valerolactam derivatives. Il Farmaco 1997, 52, 603; (c) Serra, G. L.;
Mahler, G.; Manta, E. Preparation of methyl 2-(1,1-dimethyl-2-oxopropyl)-
thiazole and related 2,4-disubstituted thiazoles. Key intermediates in the
synthesis of anthelmintic agents based on marine natural products. Heterocycles
1998, 48, 2035.
11. Sugiyama, H.; Yokokawa, F.; Shioiri, T. Total synthesis of mycothiazole, a polike-
tide heterocycle from marine sponges. Tetrahedron 2003, 59, 6579–6593.
12. (a) Garner, P.; Park, J.-M. The synthesis and configurational stability of differen-
tially protected b-hydroxy-a-amino aldehydes. J. Org. Chem. 1987, 52, 2361;
(b) McKillop, A.; Taylor, R.; Watson, R.; Lewis, N. An improved procedure for
the preparation of the garner aldehyde and its use for the synthesis of
N-protected 1-halo-2-(R)-amino-3-butenes. Synthesis 1994, 31.
13. Brown, M.; Rapoport, H. The reduction of esters with sodium borohydride. J. Org.
Chem. 1963, 28, 3261.
14. (a) Boden, R. M. A mild method for preparing trans-alkenes; crown ether catalysis
´
´
of the Wittig reaction. Synthesis 1975, 784; (b) Pandolfi, E.; Lopez, G.; Dıas, E.;
Seoane, G. Solvent effect in the Wittig reaction under Boden’s conditions.
Synth. Commun. 2003, 20 (3), 2187–2196.
15. Matikainen, J.; Kaltia, S.; Hase, T. Wittig reaction under daylight lamp irradiation:
maximizing the yields of (E)-alkenes. Synlett 1994, 817.

1492
G. Mahler, G. Serra, and E. Manta
16. (a) Schlosser, M.; Mu¨ller, G.; Christmann, K. Trans-selective olefin synthesis.
Angew. Chem. Int. Ed. Eng 1966, 5, 667; (b) Schlosser, M.; Christmann, F. K.
Synthesis 1969, 38; (c) Schlosser, M.; Christmann, F. K.; Piskala, A.;
Coffinet, D. Synthesis 1971, 79.
´
´
´
´
17. Bourgain, M.; Normant. Reactivedes acetylures de cuivre dans l’hexamethylphos-
triamide. J. Bull. Soc. Chim. Fr. 1969, 2477.
18. Leukart, O.; Caviezel, M.; Eberle, A.; Escher, E.; Tun-Kyi, A.; Schwyzer, R.
Synthesis of L-propargylglycine and derivates. Helvet. Chim. Acta 1976, 59, 2181.