Total synthesis of clavaminol A, C and H

Article abstract of DOI:10.1039/c1ob06060k

The first total synthesis of clavaminol A and C, (2R,3S)-2-amino-3-alkanols from the Mediterranean ascidian Clavelina phlegraea has been achieved in 29% overall yield. The key step involved a palladium(ii)-catalysed directed Overman rearrangement to create the C-N bond and install the erythro configuration while a one-pot, tributyltin hydride-mediated reduction allowed simultaneous formation of the methyl side-chain and N-acetyl group. Similarly, the first total synthesis of clavaminol H was completed in 48% overall yield using an approach that also provided the cytotoxic des-acetyl analogue. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06060k

Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 9 | Number 23 | 7 December 2011 | Pages 7953–8204
ISSN 1477-0520
PAPER
Ahmed M. Zead
and Andrew Sutherland
Total synthesis of clavaminol A,
C and H
1477-0520(2011)9:23;1-S

Organic &
Biomolecular
Chemistry
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Cite this: Org. Biomol. Chem., 2011, 9, 8030
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PAPER
Total synthesis of clavaminol A, C and H†
Ahmed M. Zaed and Andrew Sutherland*
Received 1st July 2011, Accepted 27th July 2011
DOI: 10.1039/c1ob06060k
The first total synthesis of clavaminol A and C, (2R,3S)-2-amino-3-alkanols from the Mediterranean
ascidian Clavelina phlegraea has been achieved in 29% overall yield. The key step involved a
palladium(II)-catalysed directed Overman rearrangement to create the C–N bond and install the erythro
configuration while a one-pot, tributyltin hydride-mediated reduction allowed simultaneous formation
of the methyl side-chain and N-acetyl group. Similarly, the first total synthesis of clavaminol H was
completed in 48% overall yield using an approach that also provided the cytotoxic des-acetyl analogue.
Introduction
Clavaminols are a new class of 2-amino-3-alkanols recently
isolated from the Mediterranean ascidian Clavelina phlegraea.1,2
As well as the usual spectroscopic techniques used for their char-
acterisation, comparison of the CD spectra of benzoyl derivatives
with stereoisomers of known standards3 allowed determination
of the absolute configuration of these compounds. Interestingly,
the 2-amino-3-alkanols isolated from Clavelina phlegraea were
found to have (2R,3S)-configuration, the opposite absolute con-
figuration to that of the well-known sphingolipids4 or other
2-amino-3-alkanols such as (2S,3R)-2-aminododecan-3-ol,3 an
antifungal agent isolated from Clavelina oblonga and (2S,3R)-2-
aminotetradecan-3-ol, an inhibitor of cell proliferation isolated
from Spisula polynima.5
Fig. 1 Structures of (-)-clavaminol A (1), (+)-clavaminol C (2) and
(+)-clavaminol H (3).
in this approach involved using a palladium(II)-catalysed directed
Overman rearrangement to install the crucial C–N bond. As well
as the synthesis of the (2R,3S)-stereoisomers, we also report the
synthesis of the (2S,3R)-enantiomers, allowing confirmation of
the original absolute stereochemical assignment of these natural
products.7
Despite having (2R,3S)-configuration, biological testing of the
clavaminols showed these natural products to be cytotoxic.1
In particular, (-)-clavaminol A (1) was found to be the most
active, inducing cell death in three different cell lines (A549, lung
carcinoma; T47D, breast carcinoma and AGS, gastric carcinoma)
by activation of the apoptotic machinery.6 (+)-Clavaminol H (3)
showed no significant activity, although its des-acetyl form was
active against AGS gastric carcinoma.2 These results suggested
that a free amino group at C-2 and a free hydroxyl group at C-3
was necessary for cytotoxic activity, while a C-1 hydroxyl group
made the compounds less active but more selective.
Due to the unusual stereochemical configuration of these
natural products and the potential interest in their cytotoxic
activity, we were interested in developing an efficient route for
their synthesis. We now report a new general, stereoselective
approach for the preparation of erythro amino alkanols that
has led to the first total synthesis of (-)-clavaminol A (1), (+)-
clavaminol C (2) and (+)-clavaminol H (3) (Fig. 1). The key step
Results and discussion
Our strategy for the synthesis of the clavaminols involved using
a directed Overman rearrangement of a suitably derived allylic
alcohol. As such, allylic alcohol 9 was prepared in seven steps
as outlined in Scheme 1. Protection of (R)-glycidol (4) as the
tert-butyldimethylsilyl ether was followed by a regioselective ring
opening reaction with octylmagnesium bromide in the presence
of a copper(I) salt that gave alcohol 5 in 94% yield. Protection of
the secondary hydroxyl as the MOM-ether followed by removal of
the silyl ether under standard conditions gave primary alcohol
7 in quantitative yield. A one-pot Swern oxidation/Horner–
Wadsworth–Emmons reaction8 of alcohol 7 gave exclusively E-
a,b-unsaturated ester 8.9 Reduction of the ester moiety with
DIBAL-H completed the synthesis of allylic alcohol 9 in 85%
overall yield.
Allylic alcohol 9 was then subjected to an Overman re-
arrangement (Scheme 2).10 Initially, allylic trichloroacetimidate
10 was prepared using a catalytic amount of DBU and
trichloroacetonitrile.11 Diastereoselective MOM-ether directed
Overman rearrangement12 of 10 using bis(acetonitrile)palla-
dium(II) chloride (10 mol%) in the presence of p-benzoquinone13
gave the erythro and threo-allylic trichloroacetamides in a
13 : 1 ratio, respectively. Column chromatography allowed the
WestCHEM, School of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK G12 8QQ. E-mail: Andrew.Sutherland@
glasgow.ac.uk; Fax: +44 (0)141 330 4888; Tel: +44 (0)141 330 5936
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for all new compounds. See DOI: 10.1039/c1ob06060k
8030 | Org. Biomol. Chem., 2011, 9, 8030–8037
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trichloroacetamides,15 at 0 ◦C only clean reduction of the ozonide
to give alcohol 12 was observed.
To access the methyl side chain required for (-)-clavaminol A (1)
and (+)-clavaminol C (2), a two stage process involving conversion
of alcohol 12 to the corresponding bromide followed by a tin-
mediated reduction was proposed. An advantage of using this
mild and selective method for reduction of the C–Br bond meant
that the N-acetyl group required from clavaminol C could also be
formed by simultaneous in situ reduction of the trichloroacetamide
group.
Bromide 13 was prepared in two steps in good yield from alcohol
12 by conversion to the mesylate followed by reaction with sodium
bromide (Scheme 3). The one-pot cleavage of the C–Br bond and
reduction of the N-trichloroacetyl to the N-acetyl group under
neutral conditions with n-tributyltin hydride in the presence of
AIBN led to the formation of 14 in 85% yield.16 The synthesis
of (-)-clavaminol A (1) was completed by treatment of 14 with
6 M hydrochloric acid at 60 ◦C. This gave (-)-clavaminol A (1) in
29% overall yield after 14 steps. Selective removal of the MOM-
protecting group of 14 using 2 M hydrochloric acid at room
temperature gave (+)-clavaminol C (2) in the same overall yield
after 14 steps.
Scheme 1 Reagents and conditions: i. TBDMSCl, imidazole, THF, rt,
100%; ii. Me(CH2)7MgBr, CuBr·SMe2, THF, -78 ◦C, 94%; iii. MOMBr,
EtN(i-Pr)2, CH2Cl2, D, 100%; iv. TBAF, THF, 0 ◦C, 100%; v. (COCl)2,
DMSO, Et3N, CH2Cl2, -78 ◦C; vi. (EtO)2P(O)CH2CO2Et, DBU, LiCl,
MeCN, rt, 95% over two steps; vii. DIBAL-H, Et2O, -78 ◦C, 95%.
Scheme 3 Reagents and conditions: i. MsCl, Et3N, DMAP, CH2Cl2, rt,
87%; ii. NaBr, DMSO, 60 ◦C, 75%; iii. n-Bu3SnH, AIBN, toluene, DMA,
D, 85%; iv. 6 M HCl, 60 ◦C, 100%; v. 2 M HCl, rt, 100%.
Scheme 2 Reagents and conditions: i. Cl3CCN, DBU, CH2Cl2, rt; ii.
PdCl2(MeCN)2, p-benzoquinone, toluene, 45 ◦C, 70% from 9; iii. O3,
MeOH, CH2Cl2, -78 ◦C, then NaBH4, 0 ◦C, 88%.
The cytotoxic amine, (+)-des-acetyl-clavaminol H 15 was pre-
pared directly from 12 in quantitative yield by the removal of both
protecting groups using 6 M hydrochloric acid (Scheme 4). To
access the N-acetyl group required for (+)-clavaminol H (3), the N-
trichloroacetyl group was again reduced under neutral conditions
with n-tributyltin hydride.16 This gave N-acetyl derivative 16 in
91% yield. Selective removal of the MOM-protecting group using
2 M hydrochloric acid completed the total synthesis of (+)-
clavaminol H (3) in 12 steps and 48% overall yield.
straightforward isolation of the major erythro-diastereomer 11
in 70% overall yield from allylic alcohol 9. To form the methyl
or methylene hydroxyl side chains required for the clavaminols,
allylic trichloroacetamide 11 was subjected to ozonolysis under
reductive conditions.14
This gave the corresponding alcohol 12 in 88% yield. It should
be noted that although sodium borohydride is known to reduce
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Org. Biomol. Chem., 2011, 9, 8030–8037 | 8031
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NMR signals are based on two-dimensional COSY and DEPT
experiments, respectively. Infrared spectra were recorded using
Golden Gate apparatus on a JASCO FTIR 410 spectrometer and
mass spectra were obtained using a JEOL JMS-700 spectrometer.
Melting points were determined on a Reichert platform melting
point apparatus. Optical rotations were determined as solutions
irradiating with the sodium D line (l = 589 nm) using an Autopol V
polarimeter. [a]D values are given in units 10-1 deg cm2 g-1.
(2S)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxypropane18
A mixture of (R)-(+)-glycidol (4) (4.61 g, 60.7 mmol), tert-
butyldimethylsilyl chloride (9.15 g, 60.7 mmol) and imidazole
(4.13 g, 60.7 mmol) were dissolved in tetrahydrofuran (300 mL)
and stirred overnight at room temperature. A white precipitate was
removed by filtration and washed with diethyl ether (200 mL). The
combined filtrate was concentrated and purified by flash column
chromatography using (diethyl ether/petroleum ether, 1 : 10),
which gave (2S)-1-(tert-butyldimethylsilyloxy)-2,3-epoxypropane
(11.7 g, 100%) as a colourless oil. Spectroscopic data consistent
with literature.18 [a]D23 -6.1 (c 1.3, CHCl3); dH (400 MHz, CDCl3)
0.09 (3H, s, SiCH3), 0.10 (3H, s, SiCH3), 0.81 (9H, s, SiC(CH3)3),
2.56 (1H, dd, J 5.1, 2.6 Hz, 1-HH), 2.70 (1H, dd, J 5.1, 4.1 Hz,
1-HH), 2.98–3.03 (1H, m, 2-H), 3.60 (1H, dd, J 11.9, 4.8 Hz, 3-
HH), 3.80 (1H, dd, J 11.9, 3.1 Hz, 3-HH); dC (100 MHz, CDCl3)
-5.3 (CH3), -5.2 (CH3), 18.4 (C), 25.9 (3 ¥ CH3), 44.5 (CH2), 52.5
(CH), 63.8 (CH2); m/z (CI) 189.1309 (MH+. C9H22O2Si requires
189.1311), 145 (35%), 131 (50), 89 (62), 73 (12).
Scheme 4 Reagents and conditions: i. 6 M HCl, 60 ◦C, 100%; ii. n-Bu3SnH,
AIBN, toluene, DMA, D, 91%; iii. 2 M HCl, rt, 100%.
Spectroscopic data for (-)-clavaminol A (1), (+)-clavaminol C
(2) and (+)-clavaminol H (3) matched that reported for the natural
products.1,2 The optical rotation of 1, 2 and 3 were also in close
agreement with previously reported data, thus confirming the
(2R,3S)-stereochemical assignment of these natural products.1,2 In
the course of this study, the enantiomers of 1, 2 and 3 were prepared
in a similar manner as described above except starting from
(S)-glycidol.17 As expected, the optical rotation of the (2S,3R)-
enantiomers of 1, 2 and 3 were of similar value and of opposite
sign to that observed for the (2R,3S)-natural products.
(2R)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxypropane19
Conclusions
The reaction was carried out according to the procedure
described above using (S)-(-)-glycidol (9.93 g, 134.0 mmol).
This gave (2R)-1-(tert-butyldimethylsilyloxy)-2,3-epoxypropane
(22.9 g, 91%) as a colourless oil. [a]2D4 +2.6 (c 1.0, CHCl3). All
other spectroscopic data as previously reported for (2S)-1-(tert-
butyldimethylsilyloxy)-2,3-epoxypropane.
In summary, we have developed the first total synthesis of (-)-
clavaminol A (1) and (+)-clavaminol C (2) in an efficient manner
from (R)-glycidol. The key steps involved a palladium(II)-catalysed
directed Overman rearrangement to install the key C–N bond and
create the erthyro-configuration as well as a tin-mediated reduction
for simultaneous formation of the N-acetyl group and the methyl
side chain. In similar fashion, the first total synthesis of (+)-
clavaminol H (3) was completed in 12 steps and 48% overall yield.
Comparison of the optical data of these compounds with their
enantiomers prepared from (S)-glycidol confirmed the (2R,3S)-
absolute configuration of the natural products.7 Work is currently
underway to expand this general approach for the preparation of
other biologically active 2-amino-3-alkanols.
(2S)-1-(tert-Butyldimethylsilyloxy)undecan-2-ol (5)
A solution of octylmagnesium bromide (2.0 M in diethyl ether)
(26.6 mL, 53.1 mmol) was added dropwise to a solution of
copper(I) bromide·dimethyl sulfide (6.01 g, 29.2 mmol) in THF
(300 mL) at -78 ◦C and the white suspension was stirred for
1 h. (2S)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxypropane (5.00 g,
26.6 mmol) in tetrahydrofuran (30 mL) was then added and the
reaction mixture was warmed to 0 ◦C and stirred for 3 h. The
reaction mixture was quenched by the addition of a saturated
solution of ammonium chloride (50 mL) and extracted with ethyl
acetate (3 ¥ 100 mL). The organic layers were combined, dried
(MgSO4) and concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/diethyl ether, 30 : 1) gave (2S)-
1-(tert-butyldimethylsilyloxy)undecan-2-ol (5) (7.55 g, 94%) as a
colourless oil. nmax/cm-1 (NaCl) 3423 (OH), 2927 (CH), 1464,
1254, 1109, 837, 777; [a]2D3 -19.4 (c 2.7, CHCl3); dH (400 MHz,
CDCl3) 0.07 (6H, s, 2 ¥ SiCH3), 0.80–0.84 (12H, m, 11-H3 and
SiC(CH3)3), 1.22–1.44 (16H, m, 3-H2, 4-H2, 5-H2, 6-H2, 7-H2, 8-
H2, 9-H2, and 10-H2), 2.42 (1H, d, J 3.2 Hz, OH), 3.38 (1H, dd,
J 10.8, 8.4 Hz, 1-HH), 3.60–3.65 (2H, m, 1-HH and 2-H); dC
(100 MHz, CDCl3) -5.4 (CH3), -5.3 (CH3), 14.1 (CH3), 18.3 (C),
Experimental
All reagents and starting materials were obtained from commercial
sources and used as received. All dry solvents were purified using
a PureSolv 500 MD solvent purification system. All reactions
were performed under an atmosphere of argon unless otherwise
mentioned. Brine refers to a saturated solution of sodium chloride.
Flash column chromatography was carried out using Fisher matrix
silica 60. Macherey-Nagel aluminium-backed plates pre-coated
with silica gel 60 (UV254) were used for thin layer chromatography
and were visualised by staining with potassium permanganate. 1H
NMR and 13C NMR spectra were recorded on a Bruker DPX
400 spectrometer with chemical shift values in ppm relative to
tetramethylsilane as the standard. Assignment of 1H and 13C
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22.7 (CH2), 25.6 (CH2), 25.9 (3 ¥ CH3), 29.3 (CH2), 29.6 (2 ¥ CH2),
29.7 (CH2), 32.0 (CH2), 32.8 (CH2), 67.3 (CH2), 71.8 (CH); m/z
(CI) 303.2722 (MH+. C17H39O2Si requires 303.2719), 285 (24%),
185 (10), 133 (11), 113 (14), 69 (60).
reaction mixture was warmed to room temperature and stirred
overnight. The reaction mixture was then concentrated and the
resulting residue was re-suspended in diethyl ether (200 mL). The
solution was washed with water (100 mL) and the aqueous layer
was then extracted with diethyl ether (3 ¥ 100 mL). The combined
organic extracts were dried (MgSO4), concentrated and purified by
flash column chromatography (petroleum ether/diethyl ether, 5 : 2)
to give (2S)-2-(methoxymethoxy)undecan-1-ol (7) as a colourless
oil (3.35 g, 100%). nmax/cm-1 (NaCl) 3435 (OH), 2925 (CH), 1466,
1106, 1037, 918; [a]D23 +6.7 (c 1.2, CHCl3); dH (400 MHz, CDCl3)
0.90 (3H, t, J 6.8 Hz, 11-H3), 1.26–1.52 (16H, m, 3-H2, 4-H2, 5-H2,
6-H2, 7-H2, 8-H2, 9-H2, and 10-H2), 3.15 (1H, dd, J 8.8, 3.2 Hz,
OH), 3.43 (3H, s, OCH3), 3.46–3.62 (3H, m, 1-H2 and 2-H), 4.70
(1H, d, J 6.9 Hz, OCHHO), 4.75 (1H, d, J 6.9 Hz, OCHHO);
dC (100 MHz, CDCl3) 14.1 (CH3), 22.6 (CH2), 25.5 (CH2), 29.3
(CH2), 29.5 (CH2), 29.6 (2 ¥ CH2), 31.6 (CH2), 31.8 (CH2), 55.6
(CH3), 65.7 (CH2), 82.5 (CH), 97.0 (CH2); m/z (CI) 233.2119
(MH+. C13H29O3 requires 233.2117), 215 (10%), 201 (94), 183 (38),
171 (100), 153 (14), 113 (6), 81 (18), 69 (26).
(2R)-1-(tert-Butyldimethylsilyloxy)undecan-2-ol
The reaction was carried out according to the procedure
described above using (2R)-1-(tert-butyldimethylsilyloxy)-2,3-
epoxypropane (5.00 g, 26.6 mmol). This gave (2R)-1-(tert-butyl-
dimethylsilyloxy)undecan-2-ol (8.1 g, 100%) as a colourless oil.
[a]2D3 +19.0 (c 1.0, CHCl3). All other spectroscopic data as previ-
ously reported for (2S)-1-(tert-butyldimethylsilyloxy)undecan-2-
ol (5).
(2S)-1-(tert-Butyldimethylsilyloxy)-2-(methoxymethoxy)undecane
(6)
A solution of (2S)-1-(tert-butyldimethylsilyloxy)undecan-2-ol (5)
(5.00 g, 16.6 mmol) was dissolved in dichloromethane (300 mL)
and cooled to 0 ◦C. Diisopropylethylamine (8.63 mL, 50.0 mmol)
was then added followed by bromomethyl methyl ether (2.76 mL,
33.8 mmol). The solution was stirred for 0.5 h at 0 ◦C then
heated under reflux overnight. The reaction mixture was cooled
to room temperature, acidified with 1.0 M hydrochloric acid
(15 mL) and extracted with dichloromethane (3 ¥ 100 mL).
After removal of the solvent under reduced pressure, the
resulting material was purified by flash column chromatog-
raphy (petroleum ether/diethyl ether, 30 : 1) to give (2S)-1-
(tert-butyldimethylsilyloxy)-2-(methoxymethoxy)undecane (6) as
a colourless oil (5.72 g, 100%). (Found: C, 65.92; H, 12.23.
C19H42O3Si requires C, 65.90; H, 12.14%); nmax/cm-1 (NaCl) 2927
(CH), 1465, 1254, 1113, 1040, 837, 776; [a]2D3 +49.9 (c 1.4, CHCl3);
dH (400 MHz, CDCl3) 0.01 (6H, s, Si(CH3)2), 0.83–0.85 (12H, m,
11-H3 and SiC(CH3)3), 1.18–1.44 (16H, m, 3-H2, 4-H2, 5-H2, 6-H2,
7-H2, 8-H2, 9-H2, and 10-H2), 3.32 (3H, s, OCH3), 3.48–3.60 (3H,
m, 1-H2 and 2-H), 4.59 (1H, d, J 6.8 Hz, OCHHO), 4.72 (1H,
d, J 6.8 Hz, OCHHO); dC (100 MHz, CDCl3) -5.1 (2 ¥ CH3),
14.1 (CH3), 18.3 (C), 22.7 (CH2), 25.4 (CH2), 25.9 (3 ¥ CH3),
29.3 (CH2), 29.6 (2 ¥ CH2), 29.7 (CH2), 31.7 (CH2), 31.9 (CH2),
55.4 (CH3), 65.9 (CH2), 78.2 (CH), 96.3 (CH2); m/z (CI) 347.2983
(MH+. C19H43O3Si requires 347.2981), 315 (100%), 285 (24), 259
(8), 221 (6), 133 (7), 97 (18), 81 (52), 69 (68).
(2R)-2-(Methoxymethoxy)undecan-1-ol
The reaction was carried out according to the proce-
dure described above using (2R)-1-(tert-butyldimethylsilyloxy)-2-
(methoxymethoxy)undecane (3.38 g, 9.75 mmol). This gave (2R)-
2-methoxymethoxy)undecan-1-ol (2.13 g, 94%) as a colourless oil.
[a]2D3 -7.1 (c 1.0, CHCl3). All other spectroscopic data as previously
reported for (2S)-2-(methoxymethoxy)undecan-1-ol (7).
Ethyl (2E,4S)-4-(methoxymethoxy)tridecan-2-enoate (8)
Dimethyl sulfoxide (4.10 mL, 57.8 mmol) was added to a
stirred solution of oxalyl chloride (2.83 mL, 32.4 mmol) in
◦
dichloromethane (200 mL) at -78 C. The reaction mixture was
stirred for 0.3 h before (2S)-2-(methoxymethoxy)undecan-1-ol (7)
(5.38 g, 23.1 mmol) in dichloromethane (50 mL) was slowly added.
The mixture was stirred for a further 0.3 h before triethylamine
(16.1 mL, 115.7 mmol) was added. This reaction mixture was
stirred for 0.5 h at -78 ◦C and then allowed to warm to room
temperature and stirred for a further 2 h. Meanwhile, a solution of
lithium chloride (1.77 g, 41.8 mmol), triethyl phosphonoacetate
(6.88 mL, 34.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(4.88 mL, 34.7 mmol) in acetonitrile (200 mL) was prepared and
stirred for 1.0 h. The Swern solution was concentrated in vacuo
and the Horner–Wadsworth–Emmons solution was added. The
reaction mixture was stirred at room temperature overnight. The
reaction mixture was quenched by the addition of a saturated
solution of ammonium chloride (50 mL) and concentrated to
give an orange residue, which was then extracted with diethyl
ether (4 ¥ 100 mL). The organic layers were combined, dried
(MgSO4) and concentrated to give an orange oil. Purification
by flash column chromatography using (diethyl ether/petroleum
ether, 1 : 10) yielded ethyl (2E,4S)-4-(methoxymethoxy)tridecan-
2-enoate (8) (6.61 g, 95%) as a colourless oil. (Found: C, 67.85; H,
10.86. C17H32O4 requires C, 68.00; H, 10.67%); nmax/cm-1 (NaCl)
2927 (CH), 1724 (CO), 1658 (C C), 1467, 1368, 1268, 1154,
1035, 722; [a]2D3 -62.1 (c 1.1, CHCl3); dH (400 MHz, CDCl3) 0.88
(3H, t, J 6.8 Hz, 13-H3), 1.21–1.62 (19H, m, 5-H2, 6-H2, 7-H2,
8-H2, 9-H2, 10-H2, 11-H2, 12-H2 and OCH2CH3), 3.38 (3H, s,
(2R)-1-(tert-Butyldimethylsilyloxy)-2-(methoxymethoxy)undecane
The reaction was carried out according to the procedure de-
scribed above using (2R)-1-(tert-butyldimethylsilyloxy)undecan-
2-ol (5.00 g, 16.53 mmol). This gave (2R)-1-(tert-butyldimethylsily-
loxy)-2-(methoxymethoxy)undecane (5.70 g, 100%) as a colourless
oil. [a]2D3 -49.5 (c 1.4, CHCl3). All other spectroscopic data
as previously reported for (2S)-1-(tert-butyldimethylsilyloxy)-2-
(methoxymethoxy)undecane (6).
(2S)-2-(Methoxymethoxy)undecan-1-ol (7)
A solution of tetrabutylammonium fluoride (1.0 M in tetrahydro-
furan) (17.3 mL, 17.3 mmol) was added to a solution of (2S)-
1-(tert-butyldimethylsilyloxy)-2-(methoxymethoxy)undecane (6)
(5.00 g, 14.5 mmol) in tetrahydrofuran (300 mL) at 0 ◦C. The
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8030–8037 | 8033
©

OCH3), 4.16–4.24 (3H, m, 4-H and OCH2CH3), 4.58 (1H, d,
J 6.8 Hz, OCHHO), 4.64 (1H, d, J 6.8 Hz, OCHHO), 5.97
(1H, dd, J 16.0, 1.2 Hz, 2-H), 6.82 (1H, dd, J 16.0, 6.4 Hz, 3-
H); dC (100 MHz, CDCl3) 14.2 (CH3), 14.3 (CH3), 22.7 (CH2),
25.2 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 31.9
(CH2), 34.9 (CH2), 55.7 (CH3), 60.5 (CH2), 75.2 (CH), 94.6 (CH2),
121.8 (CH), 148.0 (CH), 166.4 (C); m/z (CI) 301.2378 (MH+.
C17H33O4 requires 301.2379), 271 (15%), 239 (100), 173 (6), 145 (5),
69 (17).
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-
(methoxymethoxy)tridecan-1-ene (11)
(2E,4S)-4-(Methoxymethoxy)tridecan-2-ene-1-ol (9) (2.55 g,
9.90 mmol) was dissolved in dichloromethane (200 mL) and cooled
to 0 ◦C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.34 mL, 2.47 mmol)
was then added to the solution followed by trichloroacetonitrile
(1.48 mL, 14.8 mmol). The reaction mixture was warmed to room
temperature and stirred for 2 h. The reaction mixture was then
filtered through a short pad of silica gel and washed with diethyl
ether (200 mL). The resulting filtrate was then concentrated to give
allylic trichloroacetimidate 10, which was used without further
purification. The resulting allylic trichloroacetimidate 10 was
dissolved in toluene (100 mL) and bis(acetonitrile)palladium(II)
chloride (0.38 g, 1.48 mmol) and p-benzoquinone (2.13 g,
19.8 mmol) were added. The reaction mixture was stirred at 45 ◦C
for 24 h. The reaction mixture was concentrated and purifica-
tion by flash column chromatography (diethyl ether/petroleum
ether, 1 : 20) gave (3R,4S)-3-(trichloromethylcarbonylamino)-4-
(methoxymethoxy)tridecan-1-ene (11) as a colourless oil (2.78 g,
70% over 2 steps). nmax/cm-1 (NaCl) 3287 (NH), 2855 (CH), 1717
(CO), 1643 (C C), 1517, 1237, 1036, 822, 758; [a]2D3 +66.0 (c 1.1,
CHCl3); dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.8 Hz, 13-H3),
1.24–1.65 (16H, m, 5-H2, 6-H2, 7-H2, 8-H2, 9-H2, 10-H2, 11-H2
and 12-H2), 3.43 (3H, s, OCH3), 3.56 (1H, ddd, J 8.4, 4.8, 2.0 Hz,
4-H), 4.36–4.41 (1H, m, 3-H), 4.65 (1H, d, J 6.8 Hz, OCHHO),
4.74 (1H, d, J 6.8 Hz, OCHHO), 5.30–5.36 (2H, m, 1-H2), 5.85
(1H, ddd, J 17.2, 10.4, 6.8 Hz, 2-H), 8.24 (1H, br d, J 7.6 Hz, NH);
dC (100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 25.7 (CH2), 29.3
(CH2), 29.5 (2 ¥ CH2), 29.5 (CH2), 31.9 (CH2), 33.0 (CH2), 55.9
(CH), 56.7 (CH3), 83.9 (CH), 93.0 (C), 98.2 (CH2), 118.9 (CH2),
131.6 (CH), 161.4 (C); m/z (CI) 402.1369 (MH+. C17H3135Cl3NO3
requires 402.1370), 370 (100%), 336 (36), 308 (25), 270 (19), 214
(60), 180 (19), 85 (20), 69 (31).
Ethyl (2E,4R)-4-(methoxymethoxy)tridecan-2-enoate
The reaction was carried out according to the proce-
dure described above using (2R)-2-(methoxymethoxy)undecan-
1-ol (5.38 g, 23.14 mmol). This gave ethyl (2E,4R)-4-
(methoxymethoxy)tridecan-2-enoate (7.10 g, 100%) as a colourless
oil. [a]2D3 +63.2 (c 1.1, CHCl3). All other spectroscopic data as pre-
viously reported for ethyl (2E,4S)-4-(methoxymethoxy)tridecan-
2-enoate (8).
(2E,4S)-4-(Methoxymethoxy)tridecan-2-ene-1-ol (9)
Ethyl (2E,4S)-4-(methoxymethoxy)tridecan-2-enoate (8) (4.70 g,
15.7◦mmol) was dissolved in diethyl ether (350 mL) and cooled to
-78 C. DIBAL-H (1.0 M in hexane) (34.5 mL, 34.5 mmol) was
added dropwise and the reaction mixture was stirred at -78 ◦C
for 3 h, before warming to room temperature. The solution was
cooled to 0 ◦C and quenched by the addition of a saturated
solution of ammonium chloride (50 mL) and warmed to room
temperature with vigorous stirring over 1 h. The reaction mixture
R
was filtered through a pad of Celiteꢀ and washed with diethyl ether
(400 mL). The filtrate was then dried (MgSO4) and concentrated
in vacuo. Flash column chromatography (diethyl ether/petroleum
ether, 2 : 5) gave (2E,4S)-4-(methoxymethoxy)tridecan-2-ene-1-ol
(9) (3.84 g, 95%) as a colourless oil. (Found: C, 70.15; H, 11.99.
C15H30O3 requires C, 69.77; H, 11.63%); nmax/cm-1 (NaCl) 3399
(OH), 2925 (CH), 2855, 1466, 1377, 1213, 1152, 1128, 1096, 1036,
973; [a]2D3 -87.3 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.88 (3H,
t, J 6.4 Hz, 13-H3), 1.26–1.62 (17H, m, 5-H2, 6-H2, 7-H2, 8-H2,
9-H2, 10-H2, 11-H2, 12-H2 and OH), 3.37 (3H, s, OCH3), 4.01 (1H,
q, J 7.0 Hz, 4-H), 4.16 (2H, td, J 5.6, 1.2 Hz, 1-H2), 4.53 (1H, d,
J 6.8 Hz, OCHHO), 4.70 (1H, d, J 6.8 Hz, OCHHO), 5.56 (1H,
ddt, J 15.6, 7.0, 1.2 Hz, 3-H), 5.81 (1H, dt, J 15.6, 5.6 Hz, 2-H);
dC (100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 25.4 (CH2), 29.3
(CH2), 29.6 (2 ¥ CH2), 29.6 (CH2), 31.9 (CH2), 35.6 (CH2), 55.4
(CH3), 62.9 (CH2), 76.3 (CH), 93.8 (CH2), 131.7 (CH), 131.9 (CH);
m/z (CI) 241.2166 (MH+ - H2O. C15H29O2 requires 241.2168), 197
(100%), 179 (33), 155 (14), 131 (21), 85 (28).
(3S,4R)-3-(Trichloromethylcarbonylamino)-4-
(methoxymethoxy)tridecan-1-ene
The reaction was carried out according to the procedure
described above using (2E,4R)-4-(methoxymethoxy)tridecan-
2-ene-1-ol (2.55 g, 9.90 mmol). This gave (3S,4R)-3-
(trichloromethylcarbonylamino)-4-(methoxymethoxy)tridecan-1-
ene (2.80 g, 70%) as a colourless oil. [a]2D3 -65.8 (c 1.0, CHCl3).
All other spectroscopic data as previously reported for (3R,4S)-
3-(trichloromethylcarbonylamino)-4-(methoxymethoxy)tridecan-
1-ene (11).
(2R,3S)-2-(Trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecan-1-ol (12)
( 3R , 4S ) - 3 - ( Trichloromethylcarbonylamino ) - 4 - ( methoxyme-
thoxy)tridecan-1-ene (11) (0.94 g, 2.33 mmol) was dissolved in a
mixture of dichloromethane (40 mL) and methanol (20 mL) and
cooled to -78 ◦C. Ozone was bubbled through the reaction mixture
until the solution turned slightly blue. After excess ozone was
purged with argon gas, sodium borohydride (0.08 g, 2.33 mmol)
was added in portions. The solution was stirred for 1.5 h at 0 ◦C,
then acidified with 1 M hydrochloric acid (10 ml). The reaction
was quenched by the addition of water (20 mL) and then extracted
with diethyl ether (4 ¥ 50 mL). The organic layers were combined,
(2E,4R)-4-(Methoxymethoxy)tridecan-2-ene-1-ol
The reaction was carried out according to the procedure de-
scribed above using ethyl (2E,4R)-4-(methoxymethoxy)tridecan-
2-enoate (4.80 g, 16.0 mmol). This gave (2E,4R)-4-(methoxy-
methoxy)tridecan-2-ene-1-ol (4.00 g, 97%) as a colourless oil.
[a]2D3 +87.6 (c 1.0, CHCl3). All other spectroscopic data as previ-
ously reported for (2E,4S)-4-(methoxymethoxy)tridecan-2-ene-1-
ol (9).
8034 | Org. Biomol. Chem., 2011, 9, 8030–8037
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©

dried (MgSO4) and concentrated to give an orange oil. Purification
by flash column chromatography using (diethyl ether/petroleum
ether, 5 : 5) yielded (2R,3S)-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecan-1-ol (12) (0.84 g, 88% over 2 steps) as
a colourless oil. (Found: C, 47.26; H, 7.45; N, 3.32. C16H30Cl3NO4
requires C, 47.23; H, 7.38; N, 3.44%); nmax/cm-1 (NaCl) 3416 (NH),
2926 (CH), 1712 (CO), 1522, 1467, 1214, 1034, 906, 822, 756; [a]D23
+23.3 (c 1.3, CHCl3); dH (400 MHz, CDCl3) 0.91 (3H, t, J 6.8 Hz,
12-H3), 1.25–1.78 (16H, m, 4-H2, 5-H2, 6-H2, 7-H2, 8-H2, 9-H2,
10-H2, and 11-H2), 2.70 (1H, dd, J 9.6, 3.6 Hz, OH), 3.47 (3H, s,
OCH3), 3.74–3.84 (2H, m, 1-HH and 3-H), 3.95 (1H, dq, J 8.2,
3.6 Hz, 2-H), 4.08 (1H, dt, J 12.0, 3.6 Hz, 1-HH), 4.65 (1H, d, J
6.8 Hz, OCHHO), 4.73 (1H, d, J 6.8 Hz, OCHHO), 8.01 (1H, br
d, J 8.2 Hz, NH); dC (100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2),
25.7 (CH2), 29.3 (CH2), 29.5 (CH2), 29.5 (2 ¥ CH2), 31.9 (CH2),
32.9 (CH2), 54.7 (CH), 56.1 (CH3), 61.2 (CH2), 82.6 (CH), 92.7 (C),
97.9 (CH2), 162.2 (C); m/z (CI) 406.1317 (MH+. C16H3135Cl3NO4
requires 406.1319), 374 (100%), 340 (43), 288 (14), 272 (6), 183 (4),
121 (3), 81 (6).
m/z (CI) 484.1089 (MH+. C17H3335Cl3NO6S requires 484.1094),
452 (83%), 418 (19), 388 (100), 354 (85), 322 (44), 279 (74), 201
(10), 153 (6), 85 (11).
(2S,3R)-1-Methanesulfonate-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecane
The reaction was carried out according to the procedure de-
scribed above using (2S,3R)-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecan-1-ol (0.23 g, 0.56 mmol). This gave
(2S,3R)-1-methanesulfonate-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecane (0.23 g, 88%) as
a colour-
less oil. [a]2D3 -25.4 (c 1.0, CHCl3). All other spectroscopic
data as previously reported for (2R,3S)-1-methanesulfonate-2-
(trichloromethylcarbonylamino)-3-(methoxymethoxy)dodecane.
(2R,3S)-1-Bromo-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecane (13)
(2R,3S)-1-Methanesulfonate-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecane (0.41 g, 0.85 mmol) was dissolved
in dimethyl sulfoxide (20 mL), then sodium bromide (0.44 g,
4.26 mmol) was added and the reaction mixture was heated
under reflux overnight. The reaction mixture was cooled and
concentrated in vacuo. The resulting residue was dissolved in
diethyl ether (20 mL) and washed with water (2 ¥ 30 mL).
The organic layer was dried and concentrated in vacuo. Purifi-
cation by column chromatography (petroleum ether/diethyl ether,
14 : 1) gave (2R,3S)-1-bromo-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecane (13) (0.30 g, 75%) as a colourless
oil. nmax/cm-1 (NaCl) 3337 (NH), 2925 (CH), 1718 (CO), 1523,
1148, 1034, 821; [a]D23 +32.8 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
0.81 (3H, t, J 6.8 Hz, 12-H3), 1.16–1.59 (16H, m, 4-H2, 5-H2, 6-
H2, 7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 3.37 (3H, s, OCH3), 3.50
(1H, dd, J 10.8, 7.6 Hz, 1-HH), 3.56–3.61 (2H, m, 1-HH and
3-H), 4.16–4.23 (1H, m, 2-H), 4.57 (1H, d, J 6.8 Hz, OCHHO),
4.65 (1H, d, J 6.8 Hz, OCHHO), 7.62 (1H, br d, J 9.2 Hz, NH);
dC (100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2), 25.4 (CH2), 29.3
(CH2), 29.5 (CH2), 29.5 (2 ¥ CH2), 31.4 (CH2), 31.9 (CH2), 32.5
(CH2), 54.6 (CH), 56.1 (CH3), 81.7 (CH), 92.7 (C), 97.8 (CH2),
161.8 (C); m/z (CI) 470.0442 (MH+. C16H3081Br35Cl3NO3 requires
470.0451), 438 (100%), 436 (63), 408 (16), 354 (9), 201 (4), 171 (3),
95 (2), 69 (8).
(2S,3R)-2-(Trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecan-1-ol
The reaction was carried out according to the procedure described
above using (3S,4R)-3-(trichloromethylcarbonylamino)-4-(me-
thoxymethoxy)tridecan-1-ene (0.50 g, 1.24 mmol). This gave
(2S,3R)-2-(trichloromethylcarbonylamino)-3-(methoxymethoxy)-
dodecan-1-ol (0.38 g, 76%) as a colourless oil. [a]2D3 -23.7
(c 1.3, CHCl3). All other spectroscopic data as previously
reported
for
(2R,3S)-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecan-1-ol (12).
(2R,3S)-1-Methanesulfonate-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecane
A
solution of (2R,3S)-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecan-1-ol (12) (0.38 g, 0.95 mmol) was
dissolved in dichloromethane (40 mL). Methanesulfonyl chloride
(0.16 mL, 1.47 mmol), triethylamine (0.29 mL, 2.16 mmol)
and 4-dimethylaminopyridine (DMAP, catalytic) were added
at 0 ◦C and the solution stirred at room temperature for
24 h. The reaction mixture was then washed with water
(20 mL), extracted with dichloromethane (3 ¥ 30 mL). The
resulting organic layer was dried (MgSO4) and concentrated to
give the crude product, which was purified by flash column
chromatography (diethyl ether/petroleum ether, 2 : 3) to give
(2R,3S)-1-methanesulfonate-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecane (0.39 g, 87%) as a colourless oil.
(2S,3R)-1-Bromo-2-(trichloromethylcarbonylamino)-3-
(methoxymethoxy)dodecane
The reaction was carried out according to the procedure
described above using (2S,3R)-1-methanesulfonate-2-(trichlo-
romethylcarbonylamino)-3-(methoxymethoxy)dodecane (0.41 g,
0.85 mmol). This gave (2S,3R)-1-bromo-2-(trichloromethyl-
carbonylamino)-3-(methoxymethoxy)dodecane (0.31 g, 75%) as
a colourless oil. [a]2D3 -34.0 (c 1.0, CHCl3). All other spectro-
scopic data as previously reported for (2R,3S)-1-bromo-2-(trichlo-
romethylcarbonylamino)-3-(methoxymethoxy)dodecane (13).
n
max/cm-1 (NaCl) 3346 (NH), 2926 (CH), 1716 (CO), 1524, 1359,
1177, 1034, 823; [a]D23 +25.8 (c 1.7, CHCl3); dH (400 MHz, CDCl3)
0.88 (3H, t, J 7.2 Hz, 12-H3), 1.21–1.72 (16H, m, 4-H2, 5-H2, 6-H2,
7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 3.06 (3H, s, OSO2CH3), 3.45
(3H, s, OCH3), 3.59–3.65 (1H, m, 3-H), 4.23–4.29 (1H, m, 2-H),
4.34 (1H, dd, J 10.4, 7.8 Hz, 1-HH), 4.50 (1H, dd, J 10.4, 4.4 Hz,
1-HH), 4.63 (1H, d, J 6.8 Hz, OCHHO), 4.74 (1H, d, J 6.8 Hz,
OCHHO), 8.15 (1H, br d, J 8.4 Hz, NH); dC (100 MHz, CDCl3)
14.1 (CH3), 22.7 (CH2), 25.8 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5
(2 ¥ CH2), 31.9 (CH2), 33.0 (CH2), 37.8 (CH3), 53.2 (CH), 56.0
(CH3), 66.4 (CH2), 82.4 (CH), 92.6 (C), 98.3 (CH2), 162.2 (C);
(2R,3S)-2-Acetylamino-3-(methoxymethoxy)dodecane (14)
A
mixture of (2R,3S)-1-bromo-2-(trichloromethylcarbonyl-
amino)-3-(methoxymethoxy)dodecane (13) (0.14 g, 0.29 mmol),
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8030–8037 | 8035
©

tributyltin hydride (1.01 mL, 3.47 mmol), AIBN (0.02 g) in toluene
(9 mL) and N,N-dimethylacetamide (3 mL) were degassed under
argon for 0.3 h and then heated under reflux for 24 h. The reaction
mixture was cooled, washed with water (20 mL), extracted with
diethyl ether (3 ¥ 20 mL) and concentrated in vacuo. Purification
by flash column chromatography (petroleum ether/diethyl ether,
1 : 8) gave (2R,3S)-2-acetylamino-3-(methoxymethoxy)dodecane
(14) (0.07 g, 85%) as a white solid. Mp 35–37 ◦C; nmax/cm-1 (NaCl)
3290 (NH), 2925 (CH), 1648 (CO), 1546, 1374, 1038, 920; [a]D23
+46.1 (c 1.7, CHCl3); dH (400 MHz, CDCl3) 0.90 (3H, t, J 7.2 Hz,
12-H3), 1.11 (3H, d, J 6.8 Hz, 1-H3), 1.28–1.62 (16H, m, 4-H2, 5-H2,
6-H2, 7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 1.98 (3H, s, COCH3),
3.43–3.48 (4H, m, OCH3 and 3-H), 3.98–4.06 (1H, m, 2-H), 4.64
(1H, d, J 6.8 Hz, OCHHO), 4.74 (1H, d, J 6.8 Hz, OCHHO),
6.65 (1H, br d, J 7.6 Hz, NH); dC (100 MHz, CDCl3) 14.0 (CH3),
14.1 (CH3), 22.7 (CH2), 23.6 (CH3), 25.9 (CH2), 29.3 (CH2), 29.5
(CH2), 29.6 (CH2), 29.7 (CH2), 31.9 (CH2), 32.7 (CH2), 47.2 (CH),
55.7 (CH3), 84.4 (CH), 98.1 (CH2), 169.1 (C); m/z (CI) 288.2543
(MH+. C16H34NO3 requires 288.2539), 256 (29%), 226 (9), 184 (3),
131 (4), 86 (5).
(2R,3S)-2-Acetylaminododecan-3-ol (clavaminol C) (2)1
(2R,3S)-2-Acetylamino-3-(methoxymethoxy)dodecane
(14)
(0.02 g, 0.07 mmol) was dissolved in 2 M hydrochloric acid
(10 mL) and stirred at room temperature for 24 h. The reaction
mixture was washed with diethyl ether (3 ¥ 10 mL) and the
organic layers were concentrated in vacuo. Purification by flash
column chromatography (diethyl ether/methanol, 15 : 1) yielded
(2R,3S)-2-acetylaminododecan-3-ol (2) (0.02 g, 100%) as a white
solid. Mp 103–105 ◦C; nmax/cm-1 (NaCl) 3283 (NH), 2918 (CH),
1645 (CO), 1558, 1467, 1126, 747; [a]2D3 +11.1 (c 2.1, MeOH),
lit.1 [a]D25 +11.4 (c 0.0022, MeOH); dH (400 MHz, CDCl3) 0.81
(3H, t, J 7.2 Hz, 12-H3), 1.03 (3H, d, J 6.8 Hz, 1-H3), 1.17–1.43
(16H, m, 4-H2, 5-H2, 6-H2, 7-H2, 8-H2, 9-H2, 10-H2, and 11-H2),
1.92 (3H, s, COCH3), 2.12 (1H, d, J 6.0 Hz, OH), 3.54–3.61
(1H, m, 3-H), 3.90–3.98 (1H, m, 2-H), 5.71 (1H, br d, J 7.2 Hz,
NH); dC (100 MHz, CDCl3) 14.0 (CH3), 14.2 (CH3), 22.7 (CH2),
23.5 (CH3), 26.0 (CH2), 29.3 (CH2), 29.6 (CH2), 29.6 (CH2), 29.7
(CH2), 31.9 (CH2), 33.6 (CH2), 49.5 (CH), 74.3 (CH), 170.0 (C);
m/z (CI) 244.2275 (MH+. C14H30NO2 requires 244.2277), 226
(5%), 151 (5), 113 (5), 85 (39), 69 (58).
(2S,3R)-2-Acetylamino-3-(methoxymethoxy)dodecane
(2S,3R)-2-Acetylaminododecan-3-ol
The reaction was carried out according to the procedure described
above using (2S,3R)-1-bromo-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecane (0.05 g, 0.10 mmol). This gave
(2S,3R)-2-acetylamino-3-(methoxymethoxy)dodecane (0.03 g,
100%) as a white solid. [a]D23 -45.7 (c 1.0, CHCl3). All other spec-
troscopic data as previously reported for (2R,3S)-2-acetylamino-
3-(methoxymethoxy)dodecane (14).
The reaction was carried out according to the proce-
dure described above using (2S,3R)-2-acetylamino-3-(methoxy-
methoxy)dodecane (0.027 g, 0.24 mmol). This gave (2S,3R)-2-
acetylaminododecan-3-ol (0.018 g, 81%) as a white solid. [a]D23
-13.3 (c 1.0, MeOH). All other spectroscopic data as previously
reported for (2R,3S)-2-acetylaminododecan-3-ol (2).
(2R,3S)-2-Aminododecan-1,3-diol (15)
(2R,3S)-2-Aminododecan-3-ol (clavaminol A) (1)1
(2R,3S)-2-(Trichloromethylcarbonylamino)-3-(methoxymethoxy)-
dodecan-1-ol (12) (0.04 g, 0.10 mmol) was dissolved in 6 M
hydrochloric acid (10 mL) and heated to 60 ◦C for 24 h. The
reaction mixture was then cooled before being washed with
diethyl ether (3 ¥ 10 mL). The water layer was concentrated to
give (2R,3S)-2-aminododecan-1,3-diol (0.02 g, 100%) (15) as a
colourless oil. nmax/cm-1 (NaCl) 3348 (NH/OH), 2924 (CH),
1600, 1467, 1051; [a]D23 +6.6 (c 0.6, MeOH); dH (400 MHz,
CD3OD) 0.92 (3H, t, J 6.8 Hz, 12-H3), 1.25–1.58 (16H, m, 4-H2,
5-H2, 6-H2, 7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 3.33–3.35 (1H,
m, 2-H), 3.73 (1H, dd, J 11.6, 8.8 Hz, 1-HH), 3.79–3.85 (1H,
m, 3-H), 3.87 (1H, dd, J 11.6, 3.6 Hz, 1-HH); dC (100 MHz,
CD3OD) 14.5 (CH3), 23.8 (CH2), 27.1 (CH2), 30.5 (CH2), 30.6
(CH2), 30.7 (2 ¥ CH2), 33.1 (CH2), 34.2 (CH2), 58.5 (CH), 58.9
(CH2), 70.3 (CH); m/z (CI) 218.2113 (MH+. C12H28NO2 requires
218.2120), 200 (4%), 186 (3), 171 (4), 81 (5), 69 (6).
(2R,3S)-2-Acetylamino-3-(methoxymethoxy)dodecane
(14)
(0.02 g, 0.06 mmol) was dissolved in 6 M hydrochloric acid
(10 mL) and heated to 60 ◦C for 24 h. The reaction mixture
was then cooled before being washed with diethyl ether (3 ¥
10 mL). The aqueous layer was concentrated to give (2R,3S)-
2-aminododecan-3-ol (1) (0.014 g, 100%) as a white solid. Mp
107–109 ◦C; nmax/cm-1 (NaCl) 3389 (NH), 2928 (CH), 1610, 1500,
1025, 721; [a]2D3 -4.5 (c 1.5, MeOH), lit.1 [a]2D5 -4.25 (c 0.0094,
MeOH); dH (400 MHz, CD3OD) 0.93 (3H, t, J 7.2 Hz, 12-H3),
1.24 (3H, d, J 6.8 Hz, 1-H3), 1.31–1.59 (16H, m, 4-H2, 5-H2, 6-H2,
7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 3.30 (1H, qd, J 6.8, 3.2 Hz,
2-H), 3.70–3.75 (1H, m, 3-H); dC (100 MHz, CD3OD) 12.1 (CH3),
14.5 (CH3), 23.8 (CH2), 27.0 (CH2), 30.5 (CH2), 30.7 (CH2), 30.7
(2 ¥ CH2), 33.1 (CH2), 34.0 (CH2), 52.6 (CH), 71.7 (CH); m/z
(CI) 202.2175 (MH+. C12H28NO requires 202.2171), 184 (15%),
156 (10), 97 (4), 85 (6), 71 (7).
(2S,3R)-2-Aminododecan-1,3-diol7b
(2S,3R)-2-Aminododecan-3-ol
The reaction was carried out according to the procedure de-
scribed above using (2S,3R)-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecan-1-ol (0.10 g, 0.24 mmol). This gave
(2S,3R)-2-aminododecan-1,3-diol (0.05 g, 100%) as a colourless
oil. [a]2D3 -6.3 (c 1.0, MeOH), lit.7b [a]2D0 -6.0 (c 0.1, MeOH). All
other spectroscopic data as previously reported for (2R,3S)-2-
aminododecan-1,3-diol (15).
The reaction was carried out according to the proce-
dure described above using (2S,3R)-2-acetylamino-3-(methoxy-
methoxy)dodecane (0.015 g, 0.05 mmol). This gave (2S,3R)-2-
aminododecan-3-ol (0.011 g, 100%) as a white solid. [a]2D3 +5.4 (c
1.0, MeOH). All other spectroscopic data as reported above for
(2R,3S)-2-aminododecan-3-ol (1).
8036 | Org. Biomol. Chem., 2011, 9, 8030–8037
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The Royal Society of Chemistry 2011
©

(2R,3S)-2-Acetylamino-3-(methoxymethoxy)dodecan-1-ol (16)
mixture of (2R,3S)-2-(trichloromethylcarbonylamino)-3-
(2S,3R)-2-Acetylaminododecan-1,3-diol
A
The reaction was carried out according to the proce-
dure described above using (2S,3R)-2-acetylamino-3-(methoxy-
methoxy)dodecan-1-ol (0.03 g, 0.08 mmol). This gave (2S,3R)-2-
acetylaminododecan-1,3-diol (0.03 g, 100%) as a white solid. [a]D23
-4.1 (c 1.0, MeOH). All other spectroscopic data as previously
reported for (2R,3S)-2-acetylaminododecan-1,3-diol (3).
(methoxymethoxy)dodecan-1-ol (12) (0.30 g, 0.73 mmol), trib-
utyltin hydride (2.50 mL, 8.85 mmol), AIBN (0.02 g) in toluene
(9 mL) and N,N-dimethylacetamide (3 mL) were degassed under
argon for 0.3 h and then heated under reflux for 24 h. The
reaction mixture was cooled, washed with water (20 mL), ex-
tracted with diethyl ether (3 ¥ 20 mL) and the organic layers
were concentrated in vacuo. Flash column chromatography using
(diethyl ether/methanol, 15 : 1) yielded (2R,3S)-2-acetylamino-3-
(methoxymethoxy)dodecan-1-ol (16) (0.20 g, 91%) as a colourless
oil. nmax/cm-1 (NaCl) 3297 (NH/OH), 2925 (CH), 1656 (CO),
1551, 1376, 1035; [a]D23 +34.6 (c 2.5, CHCl3); dH (400 MHz, CDCl3)
0.75 (3H, t, J 6.8 Hz, 12-H3), 1.10–1.52 (16H, m, 4-H2, 5-H2, 6-H2,
7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 1.89 (3H, s, COCH3), 3.18
(1H, dd, J 8.6, 3.2 Hz, OH), 3.29 (3H, s, OCH3), 3.48 (1H, ddd, J
8.4, 4.8, 3.2 Hz, 3-H), 3.55 (1H, ddd, J 11.2, 8.6, 3.2 Hz, 1-HH),
3.71–3.77 (1H, m, 1-HH), 3.80–3.86 (1H, m, 2-H), 4.47 (1H, d, J
6.8 Hz, OCHHO), 4.54 (1H, d, J 6.8 Hz, OCHHO), 6.60 (1H, br
d, J 8.0 Hz, NH); dC (100 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2),
23.4 (CH3), 25.8 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (2 ¥ CH2),
31.9 (CH2), 32.7 (CH2), 53.3 (CH), 56.0 (CH3), 62.4 (CH2), 82.7
(CH), 98.0 (CH2), 170.6 (C); m/z (CI) 304.2483 (MH+. C16H34NO4
requires 304.2488), 272 (58%), 242 (8), 200 (3), 147 (4), 102 (4), 85
(4).
Acknowledgements
The authors gratefully acknowledge financial support from the
Libyan People’s Bureau, London (studentship to A.M.Z.) and the
University of Glasgow.
Notes and references
1 A. Aiello, E. Fattorusso, A. Giordano, M. Menna, C. Navarrete and
E. Mun˜oz, Bioorg. Med. Chem., 2007, 15, 2920.
2 A. Aiello, E. Fattorusso, A. Giordano, M. Menna, C. Navarrete and
E. Mun˜oz, Tetrahedron, 2009, 65, 4384.
3 M. H. Kossuga, J. B. MacMillan, E. W. Rogers, T. F. Molinski, G. G. F.
Nascimento, R. M. Rocha and R. G. S. Berlinck, J. Nat. Prod., 2004,
67, 1879.
4 For reviews, see: (a) P. M. Koskinen and A. M. P. Koskinen, Synthesis,
1998, 1075; (b) A. R. Howell, R. C. So and S. K. Richardson,
Tetrahedron, 2004, 60, 11327.
5 R. Cuadros, E. Montejo de Garcini, F. Wandosell, G. Faircloth, J. M.
Ferna´ndez-Sousa and J. Avila, Cancer Lett., 2000, 152, 23.
6 Clavaminol A has an IC50 value of approximately 5 mg mL-1 against
AGS cells. It has a similar level of cytotoxicity against T47D and A549
cells.
(2S,3R)-2-Acetylamino-3-(methoxymethoxy)dodecan-1-ol
7 There are reports in the literature of a synthesis of clavaminol H (see
reference 7a) and the des-acetyl form of clavaminol H (see reference 7a
and 7b). However, the products prepared in both of these papers have
(2S,3R)-absolute configuration, the opposite of the natural product.
(a) R. Ait-Youcef, X. Moreau and C. Greck, J. Org. Chem., 2010, 75,
5312; (b) C. Se´guin, F. Ferreira, C. Botuha, F. Chemla and A. Pe´rez-
Luna, J. Org. Chem., 2009, 74, 6986.
8 R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
9 The Masamune–Roush conditions were used for the HWE step: M. A.
Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R.
Roush and T. Sakai, Tetrahedron Lett., 1984, 25, 2183.
10 L. E. Overman and N. E. Carpenter, In Organic Reactions, L. E. Over-
man; Ed.; Wiley, Hoboken, NJ, 2005; Vol. 66, 1–107 and references
therein.
The reaction was carried out according to the procedure de-
scribed above using (2S,3R)-2-(trichloromethylcarbonylamino)-
3-(methoxymethoxy)dodecan-1-ol (0.10 g, 0.24 mmol). This
gave (2S,3R)-2-acetylamino-3-(methoxymethoxy)dodecan-1ol as
a colourless oil (0.07 g, 84%). [a]2D3 -32.8 (c 1.0, CHCl3). All
other spectroscopic data as previously reported for (2R,3S)-2-
acetylamino-3-(methoxymethoxy)dodecan-1-ol (16).
(2R,3S)-2-Acetylaminododecan-1,3-diol (clavaminol H) (3)2
(2R,3S)-2-Acetylamino-3-(methoxymethoxy)dodecan-1-ol (16)
(0.02 g, 0.08 mmol) was dissolved in 2 M hydrochloric acid
(10 mL) and stirred at room temperature for 24 h. The reaction
mixture was washed with diethyl ether (3 ¥ 10 mL) and
the organic layers were concentrated in vacuo. Flash column
chromatography using (diethyl ether/methanol, 15 : 1) yielded
(2R,3S)-2-acetylaminododecan-1,3-diol (3) (0.02 g, 100%) as a
11 C. E. Anderson, L. E. Overman and M. P. Watson, Org. Synth., 2005,
82, 134.
12 (a) A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3,
735; (b) A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2006,
4, 2932; (c) M. D. Swift and A. Sutherland, Org. Biomol. Chem., 2006,
4, 3889; (d) A. G. Jamieson and A. Sutherland, Org. Lett., 2007, 9,
1609; (e) A. G. Jamieson and A. Sutherland, Tetrahedron, 2007, 63,
2123; (f) M. D. Swift, A. Donaldson and A. Sutherland, Tetrahedron
Lett., 2009, 50, 3241.
◦
white solid. Mp 107–109 C; nmax/cm-1 (NaCl) 3289 (NH/OH),
2917 (CH), 1650 (CO), 1551, 1371, 1091; [a]2D3 +3.3 (c 1.4, MeOH),
lit.2 [a]D25 +3.19 (c 0.0013, MeOH); dH (400 MHz, CDCl3) 0.81
(3H, t, J 6.8 Hz, 12-H3), 1.14–1.53 (16H, m, 4-H2, 5-H2, 6-H2,
7-H2, 8-H2, 9-H2, 10-H2, and 11-H2), 1.99 (3H, s, COCH3), 2.44
(1H, d, J 6.8 Hz, 3-OH), 2.53 (1H, dd, J 6.8, 3.6 Hz, 1-OH),
3.66–3.80 (3H, m, 1-HH, 2-H and 3-H), 3.96 (1H, dt, J 11.2,
3.6 Hz, 1-HH), 6.35 (1H, br d, J 7.2 Hz, NH); dC (100 MHz,
CDCl3) 14.1 (CH3), 22.7 (CH2), 23.5 (CH3), 26.0 (CH2), 29.3 (2 ¥
CH2), 29.6 (2 ¥ CH2), 31.9 (CH2), 34.6 (CH2), 53.6 (CH), 62.5
(CH2), 74.4 (CH), 170.4 (C); m/z (CI) 260 (MH+, 100%), 242
(29), 228 (6), 186 (4), 102 (3), 85 (18).
13 We have shown previously that the use of p-benzoquinone during the
Overman rearrangement of bulky substrates prevents the formation
of the [1,3]-product via a Pd(0)-catalysed process: (a) K. N. Fanning,
A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3, 3749;
(b) A. M. Zaed and A. Sutherland, Org. Biomol. Chem., 2010, 8, 4394.
14 M. Watanabe and N. Harada, J. Org. Chem., 1995, 60, 7372.
15 F. Weygand and E. Frauendorfer, Chem. Ber., 1970, 103, 2437.
16 G. Blatter, J.-M. Beau and J.-C. Jacquinet, Carbohydr. Res., 1994, 260,
189.
17 For full details of the synthesis of the (2S,3R)-enantiomers of 1, 2 and
3 as well as their optical data, see experimental section.
18 M.-T. Lai, E. Oh, Y. Shih and H.-W. Liu, J. Org. Chem., 1992, 57, 2471.
19 C. L. Cywin, F. X. Webster and J. Kallmerten, J. Org. Chem., 1991, 56,
2953.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8030–8037 | 8037
©