A concise and convergent (formal) total synthesis of huperzine A

Article abstract of DOI:10.1039/b615059d

The first convergent synthesis of the tricyclic skeleton of huperzine A is described and includes, as the key step, an efficient regioselective intramolecular Heck reaction of 2-(tert-butyldimethylsilyloxymethyl)-6-(2- methoxy-5-bromopyridin-6-yl)methylcy

Full text of DOI:10.1039/b615059d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A concise and convergent (formal) total synthesis of huperzine A†
Cathal Lucey, Sean A. Kelly and John Mann*
Received 16th October 2006, Accepted 16th November 2006
First published as an Advance Article on the web 30th November 2006
DOI: 10.1039/b615059d
The first convergent synthesis of the tricyclic skeleton of huperzine A is described and includes, as the
key step, an efficient regioselective intramolecular Heck reaction of
2
-(tert-butyldimethylsilyloxymethyl)-6-(2-methoxy-5-bromopyridin-6-yl)methylcyclohex-2-enol.
Introduction
There is considerable interest in the natural product huperzine A 1
(
Fig. 1) from the club moss Huperzia serrata, since this has proven
activity as an inhibitor of the enzyme acetylcholine esterase, and is
currently undergoing clinical evaluation in the USA as a potential
treatment for Alzheimer’s disease. In China it has already been
approved for this condition. To date the best synthesis of the
1
natural product is the route published by Kozikowski in 1993.
which has been used by his group and by others to prepare a large
number of analogues. Comprehensive reviews of structure–activity
2
data for these analogues have been provided by Kozikowski and
3
by Bai. The basic Kozikowski route is shown in Scheme 1 and
Scheme 1 Summary of Kozikowski’s synthesis.
is essentially linear in nature, thus making access to the widest
range of analogues more difficult. In 2003, we described a new
4
convergent approach to the basic skeleton of huperzine, but
hexenone 4. The synthesis of the substituted picoline derivative 5
4
this earlier approach did not allow access to the (apparently)
essential bridgehead amino functionality. In this paper we report a
modified approach that allows access to the full tricyclic skeleton
of huperzine A by a concise and convergent route to the key keto-
ester 2 used by Kozikowski in his ground-breaking synthesis.
was previously described in our 2003 paper. Alkylation of the
cyclohexenone 4 with the iodide 5 to yield the adduct 6 was
accomplished using sodium hexamethyldisilazide as base in THF
◦
at −50 C, although the best yield was only 65%. Attempted alky-
lations with LDA and with potassium tert-butoxide gave complex
reaction mixtures where proton removal had also occurred c to
the ketone group.
In our earlier studies with unsubstituted cycloehexenone and
also in the present work, attempts to carry out the intramolecular
Heck reaction resulted in a variety of products resulting from
bond formation both a and b to the carbonyl. In consequence,
6
we chose to reduce the ketone under Luche conditions, and this
Fig. 1 (−)-Huperzine A: structure and numbering.
provided a 92 : 8 ratio of the syn- and anti-alcohols 7a,b in good
yield. (These assignments were confirmed by NOE experiments
carried out on the Heck products 8 and 9). The intramolecular
Heck reaction now proceeded in good yield to produce exclusively
the desired huperzine A skeleton in the form of the two epimeric
alcohols 8 and 9, depending on the Heck substrate used (i.e. anti-
or syn-). Interestingly, when a microwave reactor was employed
the reaction times could be reduced from 24 hours to around 20
minutes with little diminution in the isolated yield, and Tables 1
and 2 provide a comparison of the various reaction conditions
employed.
Results and discussion
Our overall synthesis is shown in Scheme 2 and includes,
as its key step, a regioselective intramolecular Heck re-
action of 2-(tert-butyldimethylsilyloxymethyl)-6-(2-methoxy-5-
bromopyridin-6-yl)methylcyclohex-2-enol 7. The alicyclic portion
of this molecule was prepared from cyclohex-2-enone 3 using a
5
Baylis–Hillman reaction to insert the requisite hydroxymethyl
group, followed by protection of the hydroxyl as its tert-
butyldimethylsilyl ether, thus providing the 2-substituted cyclo-
The predominant epimer 9 was first converted into the bis-
TBS ether 10 and thence into the ketone 11. This oxidation was
most efficiently achieved via a one-pot process involving borane–
dimethylsulfide in THF followed by the N-methylmorpholine ox-
ide/tetrabutylammonium perruthenate combination introduced
School of Chemistry, Queen’s University Belfast, Stranmillis Road, Belfast,
BT9 5AG, UK. E-mail: j.mann@qub.ac.uk; Fax: +44 (0)28 9097 4890;
Tel: +44 (0)28 9097 5525
7
by Yates (60% overall yield on a 3.5 g scale). Several other methods
†
Electronic supplementary information (ESI) available: Additional exper-
imental data. See DOI: 10.1039/b615059d
were also explored including Wacker oxidation, formation of
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Scheme 2 Formal convergent synthesis of huperzine A. Reagents and conditions: (i) 37% aq. HCHO, DMAP, THF, r.t., 15 h, 63%; (ii) TBS-Cl, imidazole,
◦
◦
◦
DMF, r.t., 18 h, 74%; (iii) NaHMDS, THF, −78 C to −50 C, 2 h; then 5, −50 C, 3 h, 64%; (iv) NaBH
4
, CeCl
3
·7H
2
O, MeOH–DCM, r.t., 89%; (v)
·DMS, Et O,
O, r.t. to reflux, 24 h, 55% 12 and
, pyridine, 0 C, 3 h, 11% 13, 63% 14; (x) TBAF, THF, r.t., 15 h, 90%; (xi) PDC, DMF, r.t., 20 h, 53%; (xii) CH , Et O,
◦
◦
Pd(OAc)
2
(10 mol%), PPh
3
, Et
3
N, DMA, 167 C, 24 h, 72% 9 or 57% 8; (vi) TBS-OTf, DMAP, Et
7 C, 1 h; then NMO, crushed 4 A˚ mol. sieves, DCM, r.t., 1 h; then TPAP (5 mol%), r.t., 15 h, 60%; (viii) MeMgI, Et
3
N, DCM, 0 C to r.t., 18 h, 93%; (vii) BH
3
2
◦
3
3
0
2
◦
6% recovered 11; (ix) SOCl
C, 1 h, 80%.
2
2
N
2
2
◦
the epoxide and Lewis-acid-catalysed rearrangement, but none
of these proved successful. The ketone 11 was now reacted with
excess methyl magnesium iodide to produce the alcohol 12 (55%
yield with 36% recovery of starting material), which was efficiently
dehydrated using thionyl chloride and pyridine to provide the
alkenes 13 and 14 (11% and 63%), the latter alkene possessing
the complete tricyclic skeleton of huperzine A. Completion of the
formal total synthesis was achieved by removal of the silyl ether
protecting groups using TBAF and oxidation of the resultant diol
15 with PDC in DMF to yield keto acid 16 (53% unoptimised
yield). Esterification of this with diazomethane then provided the
keto ester 2 used by Kozikowski in his 1993 synthesis of huperzine
A, which employed a Curtius rearrangement to insert the requisite
bridgehead amino functionality and a Wittig reaction to provide
the required ethylidene group. Comparison of the NMR data for
Table 1 Study of intramolecular Heck cyclisation under standard heating
conditions
Yield (%)
Table 2 Study of intramolecular Heck cyclisation under microwave
heating conditions
a
b
Entry
Precursor
Ligand (equiv.)
8
9
1
2
3
4
5
6
7
(syn) 7a
(syn) 7a
(syn) 7a
(syn) 7a
(syn) 7a
(anti) 7b
(anti) 7b
PPh
PPh
PPh
PPh
3
3
3
3
(0.2)
(0.4)
(0.6)
(0.8)
—
—
—
—
—
57
53
22
56
72
63
30
—
—
Yield (%)
a
b
Entry
Precursor
Ligand (equiv.)
8
9
POT (0.2)
1
2
3
(syn) 7a
(syn) 7a
(anti) 7b
PPh
POT (0.2)
PPh (0.4)
3
(0.6)
—
—
55
54
30
—
PPh
PPh
3
(0.4)
(0.6)
3
3
a
a
Precursor, ligand, Pd(OAc)
2
(10 mol%) and Et
3
N (12 equiv.) were refluxed
2 3
Precursor, ligand, Pd(OAc) (10 mol%), Et N (12 equiv.) and DMA were
b
b
◦
in DMA for 24 h under standard heating conditions. POT = tri(o-
subjected to microwave radiation (200 W, 167 C) for 20 mins; POT =
tri(o-tolyl)phosphine.
tolyl)phosphine.
3
02 | Org. Biomol. Chem., 2007, 5, 301–306
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our product 2 and those reported by Kozikowski are shown in
Fig. 2.
produce the discrete enantiomers of 9. (We have not yet been
able to obtain crystals of (+)- and (−)-20 good enough for X-ray
characterisation.) This now opens up the possibility of preparing
stereochemically defined analogues of huperzine A.
Our convergent route yields not only the complete huperzine
A skeleton but also provides the key tricycle 9, which should
allow access to a wide range of analogues not hitherto available,
including a range of novel tricycles with one or more integral
nitrogen atoms produced via Beckmann rearrangements. Our
initial investigations in this area are shown in Scheme 3.
Finally, resolution of our key intermediate 9 was achieved
through formation of the camphanate esters 20 (Scheme 3)
which after separation by chromatography, were hydrolysed to
Experimental
Where possible, dry solvents were obtained from MBraun MB-
SPS dry solvent machines. Where this was not possible, solvents
were pre-dried according to procedures described in Purification
of Laboratory Chemicals (D. D. Perrin and W. L. F. Armarego, 3rd
1
13
Fig. 2 Comparison of H and C NMR data for 2 via the Mann synthesis and via the Kozikowski synthesis.
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Scheme 3 Resolution of key intermediate 9 and initial analogue investigation. Reagents and conditions: (i) NH
2
OH·HCl, pyridine, EtOH–H
2
O (1 : 1),
◦
◦
reflux, 3 h, 91%; (ii) MeSO
2
Cl, pyridine, DCM, −10 C to r.t., 18 h, 94% 17a or 72% 17b; (iii) aq. KH
2
PO
4
(pH 7.4), THF, 76 C, 20 h, 83% 18 or 84% 19;
◦
(
iv) (1S)-(−)-camphanic chloride, DMAP, DCM, 0 C to r.t., 18 h, 34% (+)-20 and 37% (−)-20; (v) K
2
CO
3
, MeOH, r.t., 24 h, 49% (+)-9 or 41% (−)-9.
edition, 1988). Anhydrous N,N-dimethylformamide (DMF) and
N,N-dimethylacetamide (DMA) were purchased from Aldrich
Chemical company and were supplied under argon in Sure-
Seal bottles. Thin layer chromatography was used to monitor
(250 ml) under argon. The reaction mixture was heated to reflux
and stirred at this temperature for 24 h. After cooling to room
temperature, the reaction was quenched with saturated aqueous
sodium bicarbonate solution (200 ml). The organic layer was
taken up with diethyl ether, washed with water and brine, dried
ꢀ
R
reactions using Polygram SIL G/UV254 precoated plastic sheets
with a 0.2 mm layer of silica gel containing fluorescent indicator
UV254. Plates were visualised using a 254 nm UV lamp and a
potassium permanganate stain. Flash column chromatography
over MgSO
4
and concentrated under reduced pressure to give
a crude brown oil. Purification by flash chromatography (40%
Et
2
O–pet. ether) yielded the pure Heck product 9 as a white solid
ꢀ
R
◦
was carried out using Sorbisil C60 silica gel (40–60 lm mesh).
(2.31 g, 73% yield), mp 96.5 C.
◦
Petroleum ether 40–60 C (pet. ether), diethyl ether, ethyl acetate,
Microwave Heck reaction: Syn-6-[(3-bromo-6-methoxypyridin-
2-yl)methyl]-2-[(tert-butyldimethylsilyloxy)methyl]cyclohex-2-en-
1-ol 7a (0.10 g, 0.23 mmol, 1 eq.) in anhydrous DMA (2 ml),
followed by freshly distilled triethylamine (0.38 ml, 2.72 mmol, 12
eq.) were added via syringe to a mixture of palladium(II) acetate
(0.005 g, 0.02 mmol, 10 mol%) and triphenylphosphine (0.04 g,
0.14 mmol, 0.6 eq.) in a sealed, inert microwave tube, which also
contained a magnetic stirring bar. The reaction mixture was then
dichloromethane and methanol were used as eluents. NMR
spectra were recorded on a Bruker DPX 300 or a Bruker DRX 500
spectrometer. Samples were dissolved in deuterated chloroform
with tetramethylsilane as a reference. Chemical shift values (d) are
given in ppm. IR spectra were recorded using a Perkin Elmer RX
1
FT-IR spectrophotometer. Melting points were recorded on a
Mettler Toledo FF62 melting point apparatus. EI-MS and CI-MS
experiments were carried out on a VG Autospec spectrometer.
Elemental analyses were carried out by ASEP (Queen’s University
Belfast) with a precision of 0.3%. Optical rotations were measured
◦
heated rapidly to 167 C under microwave radiation (200 W) and
maintained at this temperature for 20 min. On cooling to room
temperature, the reaction mixture was diluted with Et
washed successively with sodium bicarbonate, water and brine,
dried over MgSO and concentrated under reduced pressure.
2
O (3 ml),
◦
on a Perkin Elmer polarimeter (Na lamp (589 nm) at 20 C).
4
Intramolecular Heck cyclisation
Purification by flash chromatography (40% Et O–pet. ether) gave
2
the Heck product 9 (0.04 g, 54% yield).
The experimental procedures described below for the Heck
reaction, using either standard heating conditions or microwave
radiation, are general and can be applied to different Heck
substrates, catalysts, ligands, bases and solvents (for more details
see Results and discussion).
−
1
m
max/cm : 3480, 3054, 2956, 2930, 2859, 2305, 1594, 1447, 1427,
307, 1265, 1102, 1069, 1044, 837, 738; d (CDCl , 500 MHz): 0.00
3H, s, (CH )Si), 0.02 (3H, s, (CH )Si), 0.72 (9H, s, (CH CSi),
.99 (1H, dd, J = 18.0, 4.5 Hz, H-10), 2.37–2.45 (2H, m, H-9 and
1
(
1
H
3
3
3
)
3 3
H-10), 2.42 (1H, d, J = 19.0 Hz, H-8), 3.24 (1H, dd, J = 19.0,
(
13R)*-1-[(tert-Butyldimethylsilyloxy)methyl]-5-methoxy-6-aza-
8.0 Hz, H-8), 3.75 (3H, s, OCH
4.05 (1H, d, J = 3.5 Hz, H-13), 4.17 (1H, d, J = 10.5 Hz, H-14),
3
), 3.78 (1H, d, J = 10.5 Hz, H-14),
2
,7
tricyclo[7.3.1.0 ]trideca-2(7),3,5,11-tetraen-13-ol (9). Standard
heating: Freshly distilled triethylamine (14.55 ml, 104 mmol,
5.06–5.09 (1H, m, H-12), 5.47–5.50 (1H, m, H-11), 6.34 (1H, d,
1
2 eq.) was added via syringe to a stirred solution of syn-6-
J = 8.5 Hz, H-4), 7.23 (1H, d, J = 8.5 Hz, H-3); d
MHz): −5.66 (2CH , (CH Si), 18.05 (C, (CH C), 25.75 (3CH
(CH CSi), 31.71 (CH, C-9), 35.03 (CH , C-10), 36.94 (CH , C-
8), 43.74 (C, C-1), 53.26 (CH , OCH ), 68.38 (CH , C-14), 74.65
C
(CDCl
3
, 125
[
(3-bromo-6-methoxypyridin-2-yl)methyl]-2-[(tert-butyldimethyl-
3
3
)
2
3
)
3
3
,
silyloxy)methyl]cyclohex-2-en-1-ol 7a (3.85 g, 8.70 mmol, 1 eq.),
triphenylphosphine (1.37 g, 5.22 mmol, 0.6 eq.) and palladium(II)
acetate (0.20 g, 0.87 mmol, 10 mol%) in anhydrous DMA
3
)
3
2
2
3
3
2
(CH, C-13), 106.75 (CH, C-4), 125.32 (C, C-2), 126.51 (CH, C-11),
3
04 | Org. Biomol. Chem., 2007, 5, 301–306
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1
30.78 (CH, C-12), 135.49 (CH, C-3), 156.78 (C, C-7), 161.50 (C,
washed with Et
2
O. The combined organic phases were washed
+
C-5); m/z (EI): 362 (M , 74%), 361 (43), 347 (25), 346 (100), 328
with water and brine, dried over MgSO
reduced pressure. Purification by flash chromatography (40%
Et O–pet. ether) gave the pure tertiary alcohol 12 as a colourless
oil (0.06 g, 55% yield), and also recovered starting ketone 11
4
and concentrated under
(
(
41), 316 (17), 305 (16), 304 (69), 274 (29), 212 (57), 200 (41), 105
56), 75 (100); CHN Analysis required C 66.44, H 8.64, N 3.87%,
2
found C 66.22, H 8.57, N 3.79%.
(
0.03 g, 36%).
Alcohol 12: mmax/cm : 3445 (br.), 2955, 2929, 2857, 1596, 1477,
426, 1306, 1256, 1094, 1037, 836, 775; d (CDCl , 500 MHz): 0.05
)Si), 0.10 (3H, s, (CH )Si), 0.12
CSi), 0.95 (9H, s, (CH CSi),
), 1.69 (1H, dd, J = 14.4, 3.2 Hz, H-12), 1.83 (1H,
(
13R)*-1-[(tert-Butyldimethylsilyloxy)methyl]-5-methoxy-6-aza-
−
1
2
,7
1
3-(tert-butyldimethylsilyloxy)tricyclo[7.3.1.0 ]trideca-2(7),3,5-
trien-11-one (11). Borane–dimethyl sulfide (3.64 ml of a 2 M
solution, 7.276 mmol, 1 eq.) was added slowly via syringe to
a stirred solution of 10 (3.46 g, 7.28 mmol, 1 eq.) in dry Et
70 ml) at room temperature and under argon. The reaction
mixture was heated to a gentle reflux and refluxed for 1 h.
After cooling to room temperature, dry DCM (70 ml) was
added followed by crushed 4 A molecular sieves (ca. 0.5 g) and
N-methylmorpholine N-oxide (8.52 g, 72.76 mmol, 10 eq.). The
reaction mixture was stirred under argon at room temperature for
1
(
(
H
3
3H, s, (CH
3
)Si), 0.08 (3H, s, (CH
)Si), 0.75 (9H, s, (CH
3
3
3H, s, (CH
3
3
)
3
)
3 3
2
O
1
.11 (3H, s, CH
3
(
dd, J = 14.7, 4.8 Hz, H-10), 1.90 (1H, d, J = 14.4 Hz, H-12),
1
1
.92–1.96 (1H, m, H-10), 2.29–2.33 (1H, m, H-9), 2.77 (1H, d, J =
8.1 Hz, H-8), 3.24 (1H, dd, J = 18.1, 7.9 Hz, H-8), 3.73 (1H, d,
˚
J = 9.5 Hz, H-14), 3.84 (1H, d, J = 9.5 Hz, H-14), 3.87 (3H, s,
OCH
3
), 3.89 (1H, d, J = 3.9 Hz, H-13), 6.48 (1H, d, J = 8.5 Hz,
(CDCl
)Si), −4.56 (CH
)Si), 18.47 (C, (CH C), 18.88 (C, (CH
CSi), 26.52 (3CH , (CH CSi), 33.14 (CH
C-15), 34.66 (CH, C-9), 35.03 (CH , C-8), 42.98 (C, C-1), 45.02
CH , C-10), 47.90 (CH , C-12), 53.70 (CH , OCH ), 68.31 (CH
C-14), 70.10 (C, C-11), 72.94 (CH, C-13), 107.73 (CH, C-4), 128.00
H-4), 7.57 (1H, d, J = 8.5 Hz, H-3); d
C
3
, 125 MHz): −5.06
, (CH )Si),
C),
1
h. Tetra-n-butylammonium perruthenate (0.13 g, 0.364 mmol, 5
(CH
3
, (CH
3.81 (CH
6.15 (3CH
3
)Si), −4.74 (CH
, (CH
, (CH
3
, (CH
3
3
3
mol%) was then added and the reaction mixture stirred overnight.
The following morning, activated charcoal was added and the
reaction mixture filtered through Celite. The Celite was then
rinsed with ethyl acetate and the reaction mixture concentrated
under reduced pressure. The crude product was purified by flash
−
3
3
3
)
3
)
3 3
2
3
3
)
3
3
3
)
3
3
,
2
(
2
2
3
3
2
,
chromatography (35% Et
as a white solid (2.13 g, 60% yield), mp 128.4 C.
2
O–pet. ether) to give the pure ketone 11
(
(
4
7
C, C-2), 136.58 (CH, C-3), 155.52 (C, C-7), 162.04 (C, C-5); m/z
◦
+
EI): 507 (11%, M ), 490 (12), 475 (13), 474 (31), 452 (14), 451 (34),
−
1
m
max/cm : 2953, 2928, 2856, 1720, 1598, 1577, 1478, 1428, 1313,
257, 1096, 1028, 872, 834, 776; d (CDCl , 500 MHz): 0.11 (3H, s,
)Si), 0.14 (3H, s, (CH )Si), 0.15 (3H, s,
)Si), 0.81 (9H, s, (CH CSi), 0.96 (9H, s, (CH CSi), 2.20
50 (100), 432 (61), 244 (16), 226 (100), 212 (19), 160 (12), 147 (55),
1
H
3
+
3 (68); C27
H
49
O
4
Si
2
N [M ] required 507.3200, found 507.3206.
(
(
(
1
1
CH
CH
3
3
)Si), 0.12 (3H, s, (CH
3
3
3
)
3
)
3 3
(
13R)*-1-[(tert-Butyldimethylsilyloxy)methyl]-5-methoxy-6-aza-
1H, dd, J = 14.5, 3.0 Hz, H-12), 2.38 (1H, dd, J = 13.5, 3.0 Hz, H-
2
,7
1
2
6
0
1-methyl-13-(tert-butyldimethylsilyloxy)tricyclo[7.3.1.0 ]trideca-
(7),3,5,10-tetraene (14). Thionyl chloride (0.27 ml, 3.72 mmol,
eq.) was added dropwise via syringe to a solution of 12 (0.32 g,
0), 2.58 (1H, d, J = 18.0 Hz, H-8), 2.65–2.70 (2H, m, H-9 and H-
0), 2.58 (1H, d, J = 14.5 Hz, H-12), 3.33 (1H, dd, J = 18.0, 6.5 Hz,
H-8), 3.80 (1H, d, J = 10.0 Hz, H-14), 3.87 (3H, s, OCH
3
), 3.89
◦
.62 mmol, 1 eq.) in dry pyridine (0.6 ml) at 0 C under argon. The
(
(
1
(
(
1H, d, J = 10.0 Hz, H-14), 4.49 (1H, d, J = 3.5 Hz, H-13), 6.50
1H, d, J = 8.5 Hz, H-4), 7.41 (1H, d, J = 8.5 Hz, H-3); d (CDCl
25 MHz): −5.05 (CH , (CH )Si), −4.68 (CH , (CH )Si), −4.50
CH , (CH , (CH )Si), 18.52 (C, (CH C), 18.87
)Si), −3.80 (CH
C, (CH C), 26.18 (3CH , (CH CSi), 26.52 (3CH , (CH CSi),
5.32 (CH , C-8), 36.46 (CH, C-9), 46.14 (C, C-1), 47.31 (CH
C-10), 50.73 (CH , C-12), 53.64 (CH , OCH ), 66.44 (CH , C-
4), 70.82 (CH, C-13), 109.15 (CH, C-4), 125.77 (C, C-2), 136.60
◦
reaction mixture was stirred at 0 C for 3 h. It was then poured
C
3
,
onto ice and the organic layer taken up with Et
organic extracts were washed with brine, dried over MgSO
and concentrated under reduced pressure. Purification by flash
chromatography (5% Et O–pet. ether) gave the pure desired
alkene 14 (0.09 g, 28% yield) as a colourless oil, and also a 3 : 1
mixture of 14 and its isomer 13 as a colourless oil (0.14 g, 46%
yield).
2
O. Combined
3
3
3
3
4
3
3
3
3
)
3 3
3
)
3
3
3
)
3
3
)
3 3
2
3
2
2
,
2
3
3
2
1
(
CH, C-3), 152.10 (C, C-7), 162.42 (C, C-5), 210.04 (C=O, C-11);
−
1
Olefin 13: mmax/cm : 2929, 2857, 1597, 1477, 1307, 1253, 1097,
+
m/z (EI): 492 (56%, M ), 435 (42), 434 (100), 302 (15), 228 (24),
1
(
(
033, 835, 775; d
3H, s, (CH )Si), 0.11 (3H, s, (CH
9H, s, (CH CSi), 0.97 (9H, s, (CH
H
(CDCl
3
, 500 MHz): 0.07 (3H, s, (CH
3
)Si), 0.10
)Si), 0.82
+
2
00 (22), 186 (28), 160 (26), 147 (66), 74 (59); C26
required 491.2887, found 491.2882.
H
45
O
4
Si N [M ]
2
3
3
)Si), 0.13 (3H, s, (CH
3
3
)
3
3
)
3
CSi), 1.53 (3H, s, CH ), 1.83
3
(
13R)*-1-[(tert-Butyldimethylsilyloxy)methyl]-5-methoxy-6-aza-
(1H, d, J = 17.4 Hz, H-12), 2.50 (1H, d, J = 17.0 Hz, H-8), 2.53–
2
,7
1
2
1-methyl-13-(tert-butyldimethylsilyloxy)tricyclo[7.3.1.0 ]trideca-
(7),3,5-trien-11-ol (12). Freshly prepared methylmagnesium
iodide in Et
added dropwise to a solution of ketone 11 (0.097 g, 0.20 mmol)
in dry Et O at room temperature under argon. The reaction
mixture was stirred at room temperature for 3 h. A further 1
eq. of methylmagnesium iodide (0.13 ml of 1.47 M solution,
.20 mmol) was then added and the reaction mixture stirred at
room temperature overnight. In the morning, a further 2 eq. of the
Grignard reagent was added. The reaction mixture was heated to
gentle reflux and stirred at this temperature for 24 h. The reaction
was quenched with a saturated aqueous solution of ammonium
chloride. The two phases were separated and the aqueous phase
2.56 (2H, m, H-9 and H-12), 3.21 (1H, dd, J = 17.0, 5.2 Hz, H-8),
3.78 (1H, d, J = 9.6 Hz, H-14), 3.87 (4H, m, OCH
3
and H-14),
2
O (0.16 ml of 1.47 M solution, 0.24 mmol, 1.2 eq.) was
4.04 (1H, d, J = 4.6 Hz, H-13), 5.35–5.37 (1H, m, H-10), 6.50 (1H,
d, J = 8.5 Hz, H-4), 7.73 (1H, d, J = 8.5 Hz, H-3); d (CDCl
125 MHz): −4.99 (CH , (CH )Si), −4.78 (CH , (CH )Si), −4.52
(CH , (CH , (CH )Si), 18.56 (C, (CH C), 18.95
)Si), −3.68 (CH
(C, (CH C), 23.49 (CH , C-15), 26.29 (3CH , (CH CSi), 26.57
(3CH , (CH CSi), 34.28 (CH , C-8), 36.72 (CH, C-9), 42.86 (C,
C-1), 42.98 (CH , C-12), 53.60 (CH , OCH ), 68.36 (CH , C-14),
C
3
,
2
3
3
3
3
3
3
3
3
)
3 3
3
)
3
3
3
3 3
)
0
3
3
)
3
2
2
3
3
2
71.35 (CH, C-13), 108.02 (CH, C-4), 124.57 (CH, C-10), 129.57 (C,
C-2), 133.40 (C, C-11), 137.71 (CH, C-3), 153.88 (C, C-7), 162.09
+
(C, C-5); m/z (EI): 489 (51%, M ), 488 (26), 476 (15), 475 (37), 474
(100), 466 (12), 432 (37), 227 (20), 226 (100), 212 (13), 147 (44),
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 301–306 | 305

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+
+
7
3 (55); C27
H
47
O
3
Si
2
N [M ] required 489.3095, found 489.3108;
(M , 30%), 230 (25), 229 (100), 214 (40), 212 (53), 200 (62), 184
CHN Analysis required C 66.20, H 9.67, N 2.86%, found C 65.90,
H 9.75, N 2.49%.
(20), 170 (13), 149 (14), 128 (14), 115 (16), 85 (24), 77 (15), 69 (43),
+
63 (13), 58 (22); C15
74.1074.
H
16
O
4
N (ES) [MH ] required 274.1074, found
2
(
13R)*-1-Hydroxymethyl-5-methoxy-6-aza-11-methyltricyclo-
2
,7
2,7
[
7.3.1.0 ]trideca-2(7),3,5,10-tetraen-13-ol (15). A 1 M solution
5-Methoxy-6-aza-11-methyl-13-ketotricyclo[7.3.1.0 ]trideca-
of TBAF (0.7 ml, 0.7 mmol, 2.3 eq.) was added dropwise via
syringe to a solution of 13 (0.15 g, 0.3 mmol, 1 eq.) in dry THF
2(7),3,5,10-tetraen-14-oic acid methyl ester (2). A solution of 16
(0.02 g, 0.07 mmol) in 1 ml of a Et
2
O–DCM mixture (1 : 1)
◦
(
2 ml) at room temperature. The reaction mixture was stirred at
was cooled to 0 C and stirred at this temperature for 20 min
before the dropwise addition of a dilute ethereal solution of
diazomethane, which had been previously prepared and stored
room temperature for 15 h before being quenched with a saturated
aqueous solution of ammonium chloride. The organic layer was
taken up with ethyl acetate. The combined organic layers were then
◦
◦
at 0–4 C until use. The reaction mixture was stirred at 0 C for
1 h. Three to four drops of acetic acid were then carefully added.
Ethyl acetate (3 ml) was added followed by water (1 ml). The two
washed with water and brine, dried over MgSO
4
and concentrated
under reduced pressure. Purification by flash chromatography
(
80% ethyl acetate–pet. ether) gave the pure diol 15 as a white
phases were separated, and the organic phase dried over MgSO
and concentrated under reduced pressure. Purification by flash
chromatography (30% Et O–pet. ether) yielded keto ester 2 as a
colourless oil (0.017 g, 80% yield).
4
◦
solid (0.07 g, 90% yield), mp 160.1 C.
−
1
m
max/cm : 3367 (br.), 2915, 1596, 1476, 1423, 1310, 1031; d
H
2
(CDCl , 500 MHz): 1.52 (3H, s, CH
3
3
), 1.69 (1H, d, J = 17.2 Hz,
−
1
H-12), 2.13 (1H, d, J = 17.2 Hz, H-12), 2.61 (1H, d, J = 17.4 Hz,
m
max/cm : 2917, 2849, 1745, 1731, 1602, 1576, 1478, 1424, 1326,
1262, 1025, 831; d (CDCl , 500 MHz): 1.62 (3H, s, CH ), 2.51 (1H,
d, J = 17.5 Hz, H-12), 3.12–3.20 (2H, m, H-8 and H-9), 3.36–3.43
(2H, m, H-8 and H-12), 3.76 (3H, s, OCH , CO Me), 3.92 (3H, s,
OCH
), 5.42–5.44 (1H, m, H-10), 6.61 (1H, d, J = 8.5 Hz, H-4),
7.10 (1H, d, J = 8.5 Hz, H-3); d (CDCl , 125 MHz): 22.74 (CH
C-15), 40.87 (CH , C-8), 46.46 (CH, C-9), 47.34 (CH , C-12),
53.01 (CH , OCH , CO Me), 53.90 (CH , OCH ), 60.60 (C, C-1),
H-8), 2.64–2.66 (1H, m, H-9), 3.24 (1H, dd, J = 17.4, 5.5 Hz, H-8),
H
3
3
3
.90 (3H, s, OCH
3
), 3.98 (1H, d, J = 11.5 Hz, H-14), 4.00 (1H,
d, J = 11.5 Hz, H-14), 4.17 (1H, d, J = 4.6 Hz, H-13), 5.43 (1H,
3
2
d, J = 5.5 Hz, H-10), 6.60 (1H, d, J = 8.5 Hz, H-4), 7.47 (1H,
3
d, J = 8.5 Hz, H-3); d
C
(CDCl
3
, 125 MHz): 23.12 (CH
3
, C-15),
C
3
3
,
3
3.76 (CH
C-12), 53.77 (CH
09.11 (CH, C-4), 124.94 (CH, C-10), 125.50 (C, C-2), 132.13 (C,
C-11), 137.64 (CH, C-3), 154.62 (C, C-7), 162.65 (C, C-5); m/z
2
, C-8), 36.43 (CH, C-9), 42.22 (C, C-1), 43.33 (CH
2
,
2
2
3
, OCH ), 69.35 (CH , C-14), 74.64 (CH, C-13),
3
2
3
3
2
3
3
1
110.08 (CH, C-4), 124.24 (CH, C-10), 126.85 (C, C-2), 134.01 (C,
C-11), 138.13 (CH, C-3), 151.15 (C, C-7), 163.68 (C, C-5), 171.84
+
+
(
(
EI): 261 (M , 41%), 260 (15), 242 (18), 224 (22), 213 (18), 212
(CO
2
Me, C-14), 207.88 (C=O, C-13); m/z (EI): 287 (M , 83%),
+
100); C15
H
19
O
3
N [M ] required 261.1365, found 261.1361.
255 (86), 244 (16), 228 (65), 226 (16), 212 (15), 200 (100), 184 (43),
1
70 (25), 156 (18), 128 (20), 91 (12), 77 (16), 65 (15); C16
H
17
4
O N
2
,7
5
-Methoxy-6-aza-11-methyl-13-ketotricyclo[7.3.1.0 ]trideca-
+
[
M ] required 287.1158, found 287.1139.
2
(7),3,5,10-tetraen-14-oic acid (16). To a solution of 15 (0.04 g,
0
.17 mmol, 1 eq.) in DMF was added 0.62 g of pyridinium
Acknowledgements
dichromate (1.65 mmol, 10 eq.). The reaction mixture was stirred
at room temperature for 20 h. 10 ml of water was added followed
by extraction of the product several times with ethyl acetate. The
combined organic phases were then washed with brine, dried over
Cathal Lucey thanks the McClay Trust for his Ph.D. studentship.
References
MgSO
4
and concentrated under reduced pressure. Purification by
flash chromatography (40% ethyl acetate–pet. ether) gave the acid
1
G. Campiani, L.-Q. Sun, A. P. Kozikowski, P. Aagaard and M.
1
6 as a colourless oil (0.03 g, 53% yield).
m
McKinney, J. Org. Chem., 1993, 58, 7660.
−
1
2 A. P. Kozikowski and W. T u¨ ckmantel, Acc. Chem. Res., 1999, 32, 641.
3
4
max/cm : 3600–3100 (br), 2919, 2850, 1738 (br), 1601, 1478,
424, 1326, 1268, 1032; d (CDCl , 500 MHz): 1.55 (3H, s, CH ),
.50 (1H, d, J = 17.5 Hz, H-12), 3.12–3.16 (1H, m, H-9), 3.12 (1H,
D. L. Bai, X. C. Tang and X. C. He, Curr. Med. Chem., 2000, 7, 355.
S. A. Kelly, Y. Foricher, J. Mann and J. M. Bentley, Org. Biomol. Chem.,
1
2
H
3
3
2
003, 1, 2865. An earlier unsuccessful approach was reported in; V.
d, J = 17.5 Hz, H-8), 3.27 (1H, d, J = 17.5 Hz, H-12), 3.32 (1H,
dd, J = 17.5, 5.3 Hz, H-8), 3.85 (3H, s, OCH ), 5.36–5.38 (1H, m,
H-10), 6.58 (1H, d, J = 8.7 Hz, H-4), 7.27 (1H, d, J = 8.7 Hz,
H-3); d (CDCl , 125 MHz): 19.81 (CH , C-15), 39.73 (CH , C-8),
4.99 (CH, C-9), 45.88 (CH , C-12), 52.59 (CH , OCH ), 58.46
C, C-1), 108.71 (CH, C-4), 122.65 (CH, C-10), 124.83 (C, C-2),
32.48 (C, C-11), 137.08 (CH, C-3), 149.74 (C, C-7), 162.44 (C,
C-5), 173.42 (CO
H, C-14), 207.32 (C=O, C-13); m/z (EI): 273
Caprio and J. Mann, J. Chem. Soc., Perkin Trans. 1, 1998, 3151. Caprio
has now used some of this technology to provide a route to the core
structure of huperzine A: J. Ward and V. Caprio, Tetrahedron Lett.,
3
2
006, 47, 553, and this paper contains a comprehensive citliography for
C
3
3
2
synthetic endeavours.
5
6
F. Rezgui and M. M. El Gaied, Tetrahedron Lett., 1998, 39, 5965.
(a) J.-L. Luche, J. Am. Chem. Soc., 1978, 100, 2226; (b) J.-L. Luche, L.
Rodriguez-Hahn and P. Crabb e´ , J. Chem. Soc., Chem. Commun., 1978,
4
(
1
2
3
3
6
01.
7 M. H. Yates, Tetrahedron Lett., 1997, 38, 2813.
2
3
06 | Org. Biomol. Chem., 2007, 5, 301–306
This journal is © The Royal Society of Chemistry 2007