Stereoselective synthesis of the bicyclic guanidine alkaloid (+)-monanchorin

Article abstract of DOI:10.1039/c0ob00219d

A new approach for the stereoselective synthesis of the bicyclic guanidine alkaloid (+)-monanchorin has been developed using a palladium(ii)-catalysed MOM-ether directed Overman rearrangement to establish the second stereogenic centre and a cross metathesis reaction to generate the carbon backbone. In the final stage, a one-pot acid mediated deprotection of aldehyde, guanidine and hydroxyl groups gave an intermediate that underwent facile cyclisation to (+)-monanchorin.

Full text of DOI:10.1039/c0ob00219d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of the bicyclic guanidine alkaloid (+)-monanchorin†
Ahmed M. Zaed and Andrew Sutherland*
Received 6th June 2010, Accepted 30th June 2010
DOI: 10.1039/c0ob00219d
A new approach for the stereoselective synthesis of the bicyclic guanidine alkaloid (+)-monanchorin
has been developed using a palladium(II)-catalysed MOM-ether directed Overman rearrangement to
establish the second stereogenic centre and a cross metathesis reaction to generate the carbon
backbone. In the final stage, a one-pot acid mediated deprotection of aldehyde, guanidine and hydroxyl
groups gave an intermediate that underwent facile cyclisation to (+)-monanchorin.
Introduction
(+)-Monanchorin, a guanidine alkaloid with an unusual bicyclic
skeleton was isolated by McKee and co-workers from the sponge
Monanchora ungiculata collected in the Maldives islands.1 Using
2D NMR experiments, the carbon skeleton was assigned leading
to two possible aminal structures 1 and 2 (Fig. 1). Calculated 13
C
NMR shifts for 1 and 2, and comparison of data from known
bicyclic aminal natural products2 suggested that 1 was the likely
structure for monanchorin. The connectivity of the guanidine unit
to the carbon chain and the absolute stereochemistry of the natural
product was established by Yu and Snider who carried out the
first and only synthesis to date of (+)- and (-)-monanchorin.3
The key steps in their synthesis involved the ring opening of an
optically pure epoxide with sodium azide that led to a guanidino
alcohol, which was cyclised onto a pendant aldehyde side-chain
under acidic conditions to give the bicyclic aminal structure. By
synthesising both enantiomers, the absolute configuration of the
natural product (+)-monanchorin was established as shown for
structure 3.
Scheme
1 Proposed synthesis of (+)-monanchorin (3) using a
MOM-ether directed Overman rearrangement.
(+)-a-conhydrine.5f As shown in Scheme 1, we believed that our
MOM-ether directed Overman rearrangement could be used for a
stereoselective synthesis of (+)-monanchorin (3). The proposed
route involved preparation of allylic amide 5 using the ether-
directed Overman rearrangement of allylic trichloroacetimidate 6.
Cross metathesis of 5 with 2-vinyl-1,3-dioxolane would generate
the required carbon skeleton that would easily be converted
to the guanidine 4. A one-pot acid-mediated deprotection of
the aldehyde, guanidine and hydroxyl groups would give an
intermediate that could cyclise to give (+)-monanchorin (3). In
this paper, we now report a new stereoselective synthesis of (+)-
monanchorin from (R)-glycidol using the highly efficient MOM-
ether directed Overman rearrangement to establish the second key
stereogenic centre.
Fig.
1
Originally proposed (1) and actual structure (3) for
(+)-monanchorin.
In recent years, we have studied the palladium(II)-catalysed
Overman rearrangement of allylic trichloroacetimidates4 con-
taining adjacent stereogenic centres within the compound. This
work led to the development of a MOM-ether directed re-
arrangement that allows the formation of erythro-products in
diastereomeric ratios of up to 16 : 1.5 This process has been utilised
for the stereoselective synthesis of b- and g-hydroxy-a-amino
acids5b,d,g,h as well as for the preparation of the piperidine alkaloid
Results and discussion
The first stage of the synthesis involved the preparation of
allylic alcohol 12 required for the MOM-ether directed Overman
rearrangement (Scheme 2). Commercially available (R)-glycidol
(7) was protected as the tert-butyldimethylsilyl ether and then
subjected to a regioselective ring-opening reaction using n-
butyllithium and copper iodide. This gave 8 in 90% yield. The
secondary hydroxyl group of 8 was protected as the MOM-
ether using bromomethyl methyl ether and Hu¨nig’s base. Removal
WestCHEM, Department of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK G12 8QQ. E-mail: andrews@chem.gla.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/c0ob00219d
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Scheme 2 Reagents and conditions: i. TBDMSCl, imidazole, THF, rt,
88%; ii. n-BuLi, CuI, THF, -78 ◦C, 90%; iii. MOMBr, EtN(i-Pr)2, CH2Cl2,
D, 96%; iv. TBAF, THF, 0 ◦C, 100%; v. (COCl)2, DMSO, Et3N, CH2Cl2,
-78 ◦C; vi. (EtO)2POCH2CO2Et, DBU, LiCl, MeCN, rt, 86% over two
steps; vii. DIBAL-H, Et2O, -78 ◦C, 92%.
of the silyl ether was then effected using TBAF to give the
corresponding primary alcohol 10 in quantitative yield. A one-
pot Swern oxidation and Horner–Wadsworth–Emmons reaction
under Masamune–Roush conditions was used for the preparation
of E-a,b-unsaturated ester 11.6,7 Reduction of ester 11 using
DIBAL-H gave desired allylic alcohol 12 in 92% yield. While the
synthesis of allylic alcohol 12 requires seven steps, the reactions
involved are straightforward and generate 12 in good overall yield
(60%).
Scheme 3 Reagents and conditions: i. Cl3CCN, DBU, CH2Cl2, rt; ii.
PdCl2(MeCN)2, p-benzoquinone, toluene, 45 ◦C, 84% over two steps.
diastereomer 5 was easily isolated in 75% yield by flash column
chromatography.
Having generated allylic trichloroacetamide 5, initial attempts
at forming the required carbon backbone of (+)-monanchorin
(3) were achieved by direct cross coupling of 5 with metathesis
partners such as crotonaldehyde, acrolein and acrolein diethyl
acetal. While these gave the cross coupled products in vary-
ing yields, subsequent transformations in the presence of the
trichloroacetyl protecting grouping proved incompatible. Instead,
the trichloroacetyl group was replaced with the Cbz-protecting
group in a one-pot reaction involving hydrolysis of the amide
using sodium hydroxide followed by the addition of benzyl
chloroformate (Scheme 4). This gave carbamate 15 in 81% yield.
Cross metathesis of 15 was then investigated with 2-vinyl-1,3-
dioxolane 1611 in the presence of Grubbs’ 2nd generation catalyst
(10 mol%).12 On optimisation, this gave E-alkene 17 in 87% yield.
Treatment of 17 with palladium on carbon under an atmosphere
of hydrogen led to hydrogenation of the alkene and removal of the
Cbz-protecting group. The resulting amine 18 was then coupled
with commercially available N,N¢-bis(tert-butoxycarbonyl)-1H-
pyrazole-1-carboxamidine (19) in the presence of Hu¨nig’s base
which gave guanidine 4 in 87% yield.13,14 The synthesis of (+)-
monanchorin (3) was then completed by reaction of 4 with TFA
which led to the isolation of the natural product in 75% yield.
Spectroscopic data and optical activity was entirely consistent with
that previously published by the McKee and Snider groups.1,3,15
Allylic trichloroacetimidate 6 was prepared by reaction of allylic
alcohol 12 with trichloroacetonitrile and a catalytic amount of
DBU (Scheme 3).8 Allylic trichloroacetimidate 6 was initially
treated with bis(acetonitrile)palladium(II) chloride (10 mol%) in
the non-coordinating solvent, toluene.5c This gave the erythro-
and threo-allylic trichloroacetamides 5 and 13 in 55% yield over
the two steps and in a 12 : 1 ratio, respectively. Also isolated
in trace amounts was allylic trichloroacetamide 14. It is well-
known that the use of Pd(II) during Claisen-type rearrangements
gives exclusively the product of [3,3]-rearrangement (5 and 13)
while Pd(0), via a non-concerted ionisation pathway produces
predominantly the product of [1,3]-rearrangement (14).9,10 During
our studies on optimisation of the MOM-ether directed Overman
rearrangement, we found that allylic trichloroacetimidates with
bulky side-chains undergo slow rearrangement generating Pd(0)
in situ by a competing b-elimination.5b The Pd(0) formed then
catalyses the [1,3]-rearrangement, lowering the yield of the desired
product of the [3,3]-rearrangement. It was discovered however,
during our previous optimisation studies that the addition of
p-benzoquinone to the MOM-ether directed rearrangement of
bulky substrates results in the in situ oxidation of Pd(0) back to
Pd(II) and the isolation of the products of [3,3]-rearrangement
more cleanly and in higher yields.5b Thus, the rearrangement of
allylic trichloroacetimidate 6 was repeated in the presence of p-
benzoquinone and this again gave allylic trichloroacetamides 5
and 13 in a 12 : 1 ratio but in a substantially improved 84% yield
over the two steps (Scheme 3). Furthermore, the desired major
Conclusions
In summary, a fourteen-step synthesis of the bicyclic guanidine
alkaloid (+)-monanchorin (3) has been developed in an overall
yield of 15%. The key stages involved a highly efficient MOM-ether
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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-epoxypropane16
A mixture of (R)-(+)-glycidol (7) (4.61 g, 0.05 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 col-
umn chromatography using (diethyl ether/petroleum ether, 1 : 10)
which gave (2S)-1-(tert-butyldimethylsilyloxy)-2,3-epoxypropane
(11.5 g, 88%) as a colourless oil. Spectroscopic data consistent
with literature.16 [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), 2.98–3.02 (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), 26.0 (3 ¥ CH3), 44.5 (CH2), 52.4
(CH), 63.7 (CH2); m/z (CI) 189.1309 (MH+. C9H21O2Si requires
189.1311), 145 (35%), 131 (50), 89 (62), 73 (12).
(2S)-1-(tert-Butyldimethylsilyloxy)heptan-2-ol (8)17
Scheme 4 Reagents and conditions: i. 2 M NaOH, BnOCOCl, 45 ◦C, 81%;
ii. 16, Grubbs 2nd generation catalyst, CH2Cl2, D, 87%; iii. H2, Pd/C,
MeOH, rt, 71%; iv. 19, EtN(i-Pr)2, MeOH, rt, 87%; v. TFA, CH2Cl2, D,
75%.
A solution of n-butyllithium (2.5 M in hexane) (0.53 mL,
1.33 mmol) was added dropwise to a solution of copper iodide
(0.11 g, 0.58 mmol) in THF (15 mL) at -78 ◦C and the white
suspension was stirred for 1 h. (2S)-1-(tert-butyldimethylsilyloxy)-
2,3-epoxypropane (0.10 g, 0.53 mmol) in THF (10 mL) was then
added and the reaction mixture was warmed to 0 ◦C and stirred
for 3 h. The reaction was quenched by the addition of a saturated
solution of ammonium chloride (10 mL) and extracted with ethyl
acetate (3 ¥ 20 mL). The organic layers were combined, dried
(MgSO4) and concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/diethyl ether, 20 : 1) gave (2S)-
1-(tert-butyldimethylsilyloxy)heptan-2-ol (8) (0.12 g, 90%) as a
colourless oil. Spectroscopic data consistent with literature.17
directed Overman rearrangement that generated the second key
stereogenic centre. This was followed by a cross metathesis reaction
with 2-vinyl-1,3-dioxolane that allowed formation of the carbon
backbone of the natural product. Acid mediated deprotection of
the aldehyde, guanidine and hydroxyl groups gave an intermediate
that underwent facile cyclisation to give the natural product.
Investigation of new applications of the MOM-ether directed
Overman rearrangement for natural product synthesis is currently
under way.
n
max/cm-1 (NaCl) 3434 (OH), 2929 (CH), 1464, 1255, 1106, 837,
778; [a]2D3 +7.3 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.09 (6H, s,
2 ¥ SiCH3), 0.79–0.84 (12H, m, 7-H3 and SiC(CH3)3), 1.19–1.42
(8H, m, 3-H2, 4-H2, 5-H2 and 6-H2), 2.37 (1H, br s, OH), 3.31 (1H,
dd, J 10.4, 8.3 Hz, 1-HH), 3.51–3.60 (2H, m, 1-HH and 2-H); dC
(100 MHz, CDCl3) -5.4 (CH3), -5.3 (CH3), 14.1 (CH3), 18.3 (C),
22.6 (CH2), 25.3 (CH2), 25.9 (3 ¥ CH3), 32.0 (CH2), 32.8 (CH2),
67.3 (CH2), 71.9 (CH); m/z (CI) 247 (MH+, 11%), 206, (3), 150
(4), 88 (3), 52 (100).
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
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
(2S)-1-(tert-Butyldimethylsilyloxy)-2-(methoxymethoxy)heptane
(9)
A solution of (2S)-1-(tert-butyldimethylsilyloxy)heptan-2-ol (8)
(5.00 g, 20.3 mmol) was dissolved in dichloromethane (200 mL)
and cooled to 0 ◦C. Diisopropylethylamine (10.6 mL, 61.0 mmol)
was then added followed by bromomethyl methyl ether (3.40 mL,
41.7 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
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resulting material was purified by flash column chromatogra-
phy (petroleum ether/diethyl ether, 20 : 1) to give (2S)-1-(tert-
butyldimethylsilyloxy)-2-(methoxymethoxy)heptane (9) as a pale
yellow oil (5.70 g, 96%). nmax/cm-1 (NaCl) 2930 (CH), 1464, 1256,
1111, 1039, 838, 776; [a]2D3 -32.7 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 0.01 (6H, s, Si(CH3)2), 0.80–0.86 (12H, m, 7-H3 and
Si(CH3)3), 1.24–1.43 (8H, m, 3-H2, 4-H2, 5-H2 and 6-H2), 3.33
(3H, s, OCH3), 3.51–3.58 (3H, m, 1-H2 and 2-H), 4.60 (1H, d, J
6.7 Hz, OCHHO), 4.73 (1H, d, J 6.7 Hz, OCHHO); dC (100 MHz,
CDCl3) -6.5 (CH3), -6.4 (CH3), 13.0 (CH3), 17.3 (C), 21.6 (CH2),
24.0 (CH2), 24.9 (3 ¥ CH3), 30.7 (CH2), 31.0 (CH2), 54.4 (CH3),
64.9 (CH2), 77.2 (CH) 95.2 (CH2); m/z (CI) 291.2354 (MH+.
C15H35O3Si requires 291.2355), 259 (100), 229 (12), 203 (6), 133
(3), 85 (8).
organic layers were combined, dried (MgSO4) and concentrated
to give an orange oil. Purification by flash column chromatography
using (diethyl ether/petroleum ether, 2 : 5) yielded ethyl (2E,4S)-4-
(methoxymethoxy)nona-2-enoate (11) (4.62 g, 86%) as a colourless
oil. nmax/cm-1 (NaCl) 2934 (CH), 1723 (CO), 1658 (C C), 1467,
1368, 1273, 1156, 1038; [a]2D3 -67.7 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 0.89 (3H, t, J 6.7 Hz, 9-H3), 1.28–1.43 (9H, m, 6-H2, 7-H2,
8-H2 andOCH2CH3), 1.51–1.66 (2H, m, 5-H2), 3.38(3H, s, OCH3),
4.16–4.24 (3H, m, 4-H and OCH2CH3), 4.57 (1H, d, J 6.8 Hz,
OCHHO), 4.63 (1H, d, J 6.8 Hz, OCHHO), 5.92 (1H, d, J 15.7 Hz,
2-H), 6.82 (1H, dd, J 15.7, 6.4 Hz, 3-H); dC (100 MHz, CDCl3)
14.0 (CH3), 14.2 (CH3), 22.6 (CH2), 24.8 (CH2), 31.7 (CH2), 34.9
(CH2), 55.6 (CH3), 60.5 (CH2), 75.2 (CH), 94.6 (CH2), 121.8 (CH),
148.0 (CH), 166.3 (C); m/z (CI) 245.1752 (MH+. C13H25O4 requires
245.1753), 215 (22), 183 (100), 173 (10), 137 (4), 109 (4).
(2S)-2-(Methoxymethoxy)heptan-1-ol (10)
(2E,4S)-4-(Methoxymethoxy)nona-2-ene-1-ol (12)
A solution of tetrabutylammonium fluoride (1.0 M in THF)
(24.7 mL, 24.8 mmol) was added to a solution of (2S)-1-(tert-
butyldimethylsilyloxy)-2-(methoxymethoxy)heptane (9) (6.00 g,
Ethyl (2E,4S)-4-(Methoxymethoxy)nona-2-enoate (11) (4.56 g,
18.7 mmol) was dissolved in diethyl ether (350 mL) and cooled
to -78 ◦C. DIBAL-H (1.0 M in hexane) (46.1 mL, 46.1 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.
◦
20.7 mmol) in THF (300 mL) at 0 C. The 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)heptan-1-ol (10) as a colourless oil (3.65 g,
100%). nmax/cm-1 (NaCl) 3450 (OH), 2931 (CH), 1466, 1103, 1041;
[a]2D3 +57.1 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.90 (3H, t, J
7.0 Hz, 7-H3), 1.23–1.54 (8H, m, 3-H2, 4-H2, 5-H2 and 6-H2), 3.11
(1H, dd, J 8.7, 3.3 Hz, OH), 3.43 (3H, s, OCH3), 3.48–3.62 (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),
25.2 (CH2), 31.7 (CH2), 31.8 (CH2), 55.7 (CH3), 65.8 (CH2), 82.5
(CH), 97.0 (CH2); m/z (CI) 177.1491 (MH+. C9H21O3 requires
177.1491), 145 (100), 143 (8), 115 (42), 97 (18).
R
The reaction mixture 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 chro-
matography (diethyl ether/petroleum ether, 2 : 5) gave (2E,4S)-
4-(methoxymethoxy)nona-2-ene-1-ol (12) (3.50 g, 92%) as a
colourless oil. (Found: C, 65.18; H, 11.09. C11H22O3 requires C,
65.34; H, 10.89); nmax/cm-1 (NaCl) 3407 (OH), 2932 (CH), 1673
(C C), 1467, 1378, 1213, 1115, 1096, 1039, 920; [a]2D3 -69.8 (c
1.0, CHCl3); dH (400 MHz, CDCl3) 0.89 (3H, t, J 6.7 Hz, 9-H3),
1.27–1.55 (7H, m, 6-H2, 7-H2, 8-H2 and OH), 1.58–1.64 (2H, m,
5-H2), 3.37 (3H, s, OCH3), 3.99–4.06 (1H, m, 4-H), 4.16 (2H, td,
J 5.6, 1.4 Hz, 1-H2), 4.53 (1H, d, J 6.7 Hz, OCHHO), 4.70 (1H,
d, J 6.7 Hz, OCHHO), 5.56 (1H, ddt, J 15.5, 7.4, 1.4 Hz, 3-H),
5.82 (1H, dtd, J 15.5, 5.6, 0.6 Hz, 2-H); dC (100 MHz, CDCl3)
14.1 (CH3), 22.6 (CH2), 25.1 (CH2), 31.7 (CH2), 35.5 (CH2), 55.4
(CH3), 62.8 (CH2), 76.4 (CH), 93.6 (CH2), 131.5 (CH), 132.1 (CH);
m/z (CI) 203 (MH+, 10%), 185 (19), 142 (83), 138 (37), 124 (100),
100 (19), 83 (49).
Ethyl (2E,4S)-4-(methoxymethoxy)nona-2-enoate (11)
Dimethyl sulfoxide (3.35 mL, 47.4 mmol) was added to a
stirred solution of oxalyl chloride (2.32 mL, 26.5 mmol) in
◦
dichloromethane (100 mL) at -78 C. The reaction mixture was
stirred for 0.3 h before (2S)-2-(methoxymethoxy)heptan-1-ol (10)
(3.33 g, 19.0 mmol) in dichloromethane (50 mL) was slowly added.
The mixture was stirred for a further 0.3 h before triethylamine
(13.2 mL, 94.7 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 (1.45 g, 34.1 mmol), triethyl phosphonoacetate (5.63 mL,
28.4 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (4.28 mL,
28.4 mmol) in acetonitrile (100 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
was quenched by the addition of a saturated solution of ammo-
nium chloride (50 mL) and concentrated to give an orange residue,
which was then extracted with diethyl ether (4 ¥ 100 mL). The
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-
(methoxymethoxy)nona-1-ene (5)
(2E,4S)-4-(Methoxymethoxy)nona-2-ene-1-ol (12) (0.74 g,
3.66 mmol) was dissolved in dichloromethane (30 mL) and cooled
to 0 ◦C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.91 mmol)
was then added to the solution followed by trichloroacetonitrile
(0.55 mL, 5.50 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 (100 mL). The resulting filtrate was then concentrated to
give allylic trichloroacetimidate 6, which was used without further
purification. The resulting allylic trichloroacetimidate 6 was
dissolved in toluene (30 mL) and bis(acetonitrile)palladium(II)
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chloride (0.10 g, 0.36 mmol) and p-benzoquinone (0.21 g,
2.00 mmol) were added. The reaction mixture was stirred at 45 ◦C
for 24 h. The reaction mixture was concentrated and purification
by flash column chromatography (diethyl ether/petroleum ether,
1 : 20) and gave (3R,4S)-3-(trichloromethylcarbonylamino)-4-
(methoxymethoxy)nona-1-ene (5) as a colourless oil (0.90 g, 75%
over 2 steps). nmax/cm-1 (NaCl) 3284 (NH), 2933 (CH), 1715
(CO), 1644 (C C), 1517, 1236, 1100, 1037, 822; [a]2D3 +59.0 (c
1.0, CHCl3); dH (400 MHz, CDCl3) 0.89 (3H, t, J 6.8 Hz, 9-H3),
1.24–1.53 (6H, m, 6-H2, 7-H2 and 8-H2), 1.58–1.68 (2H, m, 5-H2),
3.43 (3H, s, OCH3), 3.54–3.59 (1H, m, 4-H), 4.36–4.42 (1H, m,
3-H), 4.74 (1H, d, J 6.8 Hz, OCHHO), 4.66 (1H, d, J 6.8 Hz,
OCHHO), 5.30–5.37 (2H, m, 1-H2), 5.85 (1H, ddd, J 16.8, 10.4,
6.7 Hz, 2-H), 8.27 (1H, br d, J 7.6 Hz, NH); dC (100 MHz,
CDCl3) 14.0 (CH3), 22.4 (CH2), 25.4 (CH2), 31.7 (CH2), 33.0
(CH2), 56.0 (CH), 56.7 (CH3), 83.9 (CH), 93.0 (C), 98.2 (CH2),
119.0 (CH2), 131.6 (CH), 161.5 (C); m/z (FAB) 346.0747 (MH+.
C13H2335Cl3NO3 requires 346.0744), 314 (57%), 284 (28), 213
(100), 201 (11), 179 (14), 123 (34).
etate, 1 : 1) gave 2-[(1E,3R,4S)-3-(benzyloxycarbonylamino)-4-
(methoxymethoxy)nona-2-enyl]-1,3-dioxolane (17) (0.11 g, 87%)
as a yellow oil. nmax/cm-1 (NaCl) 3338 (NH), 2953 (CH), 1722
(CO), 1522, 1235, 1149, 1037, 699; [a]2D3 +2.9 (c 1.5, CHCl3); dH
(400 MHz, CDCl3) 0.88 (3H, t, J 6.5 Hz, 9-H3), 1.27–1.58 (8H,
m, 5-H2, 6-H2, 7-H2 and 8-H2), 3.38 (3H, s, OCH3), 3.52–3.59
(1H, m, 4-H), 3.85–4.00 (4H, m, OCH2CH2O), 4.29–4.36 (1H, m,
3-H), 4.62 (1H, d, J 7.0 Hz, OCHHO), 4.70 (1H, d, J 7.0 Hz,
OCHHO), 5.07 (1H, d, J 12.0 Hz, OCHHPh), 5.12 (1H, d, J
12.0 Hz, OCHHPh), 5.29 (1H, d, J 5.9 Hz, OCHO), 5.70 (1H, dd,
J 15.9, 5.6 Hz, 2-H), 5.84 (1H, d, J 8.8 Hz, NH), 5.90 (1H, dd, J
15.9, 5.9 Hz, 1-H), 7.28–7.35 (5H, m, Ph); dC (100 MHz, CDCl3)
14.0 (CH3), 22.3 (CH2), 25.4 (CH2), 31.7 (CH2), 32.1 (CH2), 54.6
(CH), 55.9 (CH3), 64.8 (CH2), 65.0 (CH2), 66.6 (CH2), 82.7 (CH),
97.3 (CH2), 103.1 (CH), 128.1 (2 ¥ CH), 128.5 (3 ¥ CH), 129.4
(CH), 131.6 (CH), 136.6 (C), 155.8 (C); m/z (CI) 408.2381 (MH+.
C22H34NO6 requires 408.2386), 377 (21%), 300 (12), 284 (31), 246
(100), 214 (32), 145 (21), 91 (92).
2-[(3R,4S)-3-(N,N¢-Bis(tert-butoxycarbonyl)guanidino)-4-
(methoxymethoxy)nonyl]-1,3-dioxolane (4)
(3R,4S)-3-(Benzyloxycarbonylamino)-4-(methoxymethoxy)nona-
1-ene (15)
To a solution of 2-[(1E,3R,4S)-3-(benzyloxycarbonylamino)-
4-(methoxymethoxy)nona-2-enyl]-1,3-dioxolane (17) (0.02 g,
0.06 mmol) in methanol (5 mL) was added 10% palladium
on carbon (0.03 g). The reaction mixture was allowed to stir
under an atmosphere of hydrogen at room temperature for
18 h. The reaction mixture was filtered through a short pad of
A
solution of (3R,4S)-3-(trichloromethylcarbonylamino)-4-
(methoxymethoxy)nona-1-ene (5) (2.00 g, 5.77 mmol) was dis-
solved in 2.0 M sodium hydroxide solution (70 mL) and
heated at 45 ◦C overnight. The reaction mixture was cooled
to room temperature and benzyl chloroformate (3.25 mL,
23.1 mmol) was added and stirred overnight at room temper-
ature. The reaction mixture was extracted with ethyl acetate
(4 ¥ 100 mL) and the combined organic layers dried (MgSO4)
and concentrated in vacuo. Purification by flash column chro-
matography (diethyl ether/petroleum ether, 3 : 7) gave (3R,4S)-3-
(benzyloxycarbonylamino)-4-(methoxymethoxy)nona-1-ene (15)
(1.55 g, 81%) as a colourless oil. nmax/cm-1 (NaCl) 3339 (NH),
2933 (CH), 1722 (CO), 1519, 1234, 1099, 1038; [a]2D3 +48.7 (c 1.0,
CHCl3); dH (400 MHz, CDCl3) 0.88 (3H, t, J 6.9 Hz, 9-H3), 1.27–
1.60 (8H, m, 5-H2, 6-H2, 7-H2 and 8-H2), 3.39 (3H, s, OCH3),
3.54–3.57 (1H, m, 4-H), 4.24 (1H, t, J 7.0 Hz, 3-H), 4.63 (1H, d, J
7.0 Hz, OCHHO), 4.68 (2H, m, OCHHO and NH), 5.11 (2H, s,
PhCH2), 5.20–5.28 (2H, m, 1-H2), 5.76–5.89 (1H, m, 2-H), 7.28–
7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 14.0 (CH3), 22.3 (CH2),
25.3 (CH2), 31.5 (CH2), 32.1 (CH2), 55.8 (CH3), 56.0 (CH), 66.5
(CH2), 82.7 (CH), 97.3 (CH2), 117.4 (CH2), 128.0 (2 ¥ CH), 128.5
(3 ¥ CH), 133.8 (CH), 136.7 (C), 156.0 (C); m/z (CI) 336.2177
(MH+. C19H30NO4 requires 336.2175), 304 (45%), 260 (10), 228
(9), 181 (7), 147 (9), 91 (23).
R
Celiteꢀ which was washed with methanol (50 mL). The resulting
solution was concentrated in vacuo to give 2-[(3R,4S)-3-amino-
4-(methoxymethoxy)nonyl]-1,3-dioxolane (18) (0.01 g, 71%) as
a colourless oil which was used without further purification.
2-[(3R,4S)-3-Amino-4-(methoxymethoxy)nonyl]-1,3-dioxolane
(18) (0.01 g, 0.04 mmol) was dissolved in methanol (7 mL).
Diisopropylethylamine (0.06 mL, 0.33 mmol) and N,N¢-bis(tert-
butoxycarbonyl)-1H-pyrazole-1-carboxamidine (19) (0.02 g,
0.06 mmol) were then added. The reaction mixture was stirred
for 20 h at room temperature. The methanol was removed
in vacuo. The resulting residue was dissolved in ethyl acetate
(10 mL) and acidified with 0.2 M hydrochloric acid. The or-
ganic layer was washed with brine (10 mL), extracted with
ethyl acetate (2 ¥ 10 mL), dried (MgSO4) and concentrated
in vacuo. Purification by flash column chromatography (petroleum
ether/ethyl acetate, 10 : 1) gave 2-[(3R,4S)-3-(N,N¢-bis(tert-
butoxycarbonyl)guanidino)-4-(methoxymethoxy)nonyl]-1,3-dio-
xolane (4) (0.02 g, 87%) as a colourless oil. nmax/cm-1 (NaCl) 3325
(NH), 2933 (CH), 1795, 1720 (CO), 1638 (C N), 1332, 1155,
1034, 757; [a]2D3 -8.1 (c 1.5, CHCl3); dH (400 MHz, CDCl3) 0.89
(3H, t, J 6.7 Hz, 9-H3), 1.25–1.35 (6H, m, 6-H2, 7-H2 and 8-H2),
1.47 (9H, s, OtBu), 1.48 (9H, s, OtBu), 1.50–1.82 (6H, m, 1-H2, 2-H2
and 5-H2), 3.38 (3H, s, OCH3), 3.61–3.66 (1H, m, 4-H), 3.82–3.89
(2H, m, OCHHCHO), 3.94–3.99 (2H, m, OCHHCHHO), 4.34–
4.42 (1H, m, 3-H), 4.62 (1H, d, J 6.9 Hz, OCHHO), 4.69 (1H, d,
J 6.9 Hz, OCHHO), 4.88 (1H, t, J 4.4 Hz, OCHO), 8.44 (1H, d,
J 9.2 Hz, NH), 11.53 (1H, br s, NH); dC (100 MHz, CDCl3) 14.1
(CH3), 22.6 (CH2), 23.2 (CH2), 25.5 (CH2), 28.1 (3 ¥ CH3), 28.3
(3 ¥ CH3), 30.3 (CH2), 31.1 (CH2), 31.8 (CH2), 52.0 (CH), 55.8
(CH3), 64.8 (CH2), 64.9 (CH2), 78.8 (C), 79.7 (C), 82.8 (CH), 96.4
(CH2), 104.3 (CH), 153.1 (C), 156.1 (C), 163.8 (C); m/z (FAB)
2-[(1E,3R,4S)-3-(Benzyloxycarbonylamino)-4-
(methoxymethoxy)nona-2-enyl]-1,3-dioxolane (17)
A solution of (3R,4S)-3-(benzyloxycarbonylamino)-4-(methoxy-
methoxy)nona-1-ene (15) (0.10 g, 0.30 mmol) was dissolved
in dichloromethane (10 mL) and degassed with argon. 2-
Vinyl-1,3-dioxolane (16) (0.09 g, 0.90 mmol) and Grubbs
2nd generation catalyst (0.03 g, 0.03 mmol) were added.
The reaction mixture was heated under reflux overnight.
The mixture was concentrated under vacuum. Purification
by flash column chromatography (petroleum ether/ethyl ac-
4398 | Org. Biomol. Chem., 2010, 8, 4394–4399
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518.3443 (MH+. C25H48N3O8 requires 518.3441), 462 (9%), 406
(55), 362 (22), 311 (14), 260 (7), 199 (6), 111 (12).
4 L. E. Overman and N. E. Carpenter, in Organic Reactions, ed.
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(+)-Monanchorin (3)1,3
To a solution of 2-[(3R,4S)-3-(N,N’-bis(tert-butoxycarbonyl)-
guanidino)-4-(methoxymethoxy)nonyl]-1,3-dioxolane (4) (0.04 g,
0.07 mmol) in dichloromethane (5 mL) was added trifluoroacetic
acid (0.35 mL, 4.64 mmol). The reaction mixture was heated under
reflux for 12 h. The reaction was quenched with potassium carbon-
ate (0.10 g, 0.77 mmol), filtered and concentrated under vacuum.
Flash column chromatography (dichloromethane–methanol, 2 : 1)
gave the TFA salt of (+)-monanchorin (3) (0.01 g, 75%) as a
colourless oil. Spectroscopic data consistent with literature.1,3 [a]D22
+33.7 (c 0.8, MeOH), lit1 [a]D25 +39.0 (c 3.9, MeOH); dH (400 MHz,
CDCl3) 0.91 (3H, t, J 6.7 Hz, 3H, 15-H3), 1.22–1.35 (5H, m, 12-
HH, 13-H2 and 14-H2), 1.42–1.49 (2H, m, 2H, 11-HH, 12-HH),
1.60–1.66 (1H, m, 11-HH), 2.00–2.11 (2H, m, 8-HH and 9-HH),
2.19–2.23 (1H, m, 8-HH), 2.28–2.37 (1H, m, 9-HH), 3.23–3.27
(1H, m, 5-H), 4.29–4.35 (1H, m, 6-H), 4.84 (1H, t, J 6.2 Hz, 1-H),
8.56 (1H, br s, NH), 8.96 (1H, br s, NH); dC (100 MHz, CDCl3)
14.0 (CH3), 22.5 (CH2), 23.8 (CH2), 25.1 (CH2), 28.9 (CH2), 31.6
(CH2), 33.6 (CH2), 51.3 (CH), 76.7 (CH), 79.5 (CH), 159.1 (C);
m/z (CI) 212 (MH+, 85%), 170 (15), 129 (19), 113 (31), 81 (67).
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11 2-Vinyl-1,3-dioxolane 16 has been previously investigated as a substrate
for cross metathesis reactions. For examples, see: (a) D. J. O’Leary,
H. E. Blackwell, R. A. Washenfelder, K. Miura and R. H. Grubbs,
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A. K. Chatterjee, R. A. Washenfelder, D. A. Bussmann and R. H.
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L. Panella, F. L. van Delft, B. Kaptein, Q. B. Broxterman, H. E.
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13 (a) M. S. Bernatowicz, Y. Wu and G. R. Matsueda, J. Org. Chem.,
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Tetrahedron Lett., 1993, 34, 3389.
14 (a) D. J. Hamilton and A. Sutherland, Tetrahedron Lett., 2004, 45,
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Lett., 2005, 46, 7147; (c) C. M. Reid, C. Ebikeme, M. P. Barrett, E.-M.
Patzewitz, S. Mu¨ller, D. J. Robins and A. Sutherland, Bioorg. Med.
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Notes and references
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S. G. Franzblau, F. Zhang, O. Peraud, R. T. Hill and M. T. Hamann,
Tetrahedron, 2002, 58, 7397.
15 See the ESI† for 1H and 13C NMR spectra for (+)-monanchorin 3.
16 M.-T. Lai, E. Oh, Y. Shih and H.-W. Liu, J. Org. Chem., 1992, 57, 2471.
17 L. Poppe, K. Recseg and L. Nova´k, Synth. Commun., 1995, 25, 3993.
3 M. Yu and B. B. Snider, Org. Lett., 2009, 11, 1031.
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The Royal Society of Chemistry 2010
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