An enantioselective total synthesis of pinnaic acid

Article abstract of DOI:10.1016/j.tet.2007.03.031

An enantioselective and convergent total synthesis of marine natural product pinnaic acid has been achieved. Our general synthetic approach is featured with an asymmetric hydrogenation of racemic γ-keto ester 3, a diastereoselective methylation on the α-m

Full text of DOI:10.1016/j.tet.2007.03.031

Tetrahedron 63 (2007) 6454–6461
An enantioselective total synthesis of pinnaic acid
*
Hao Wu, Honglu Zhang and Gang Zhao
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 FengLin Lu, Shanghai 200032, China
Received 6 January 2007; revised 28 February 2007; accepted 2 March 2007
Available online 12 March 2007
Abstract—An enantioselective and convergent total synthesis of marine natural product pinnaic acid has been achieved. Our general syn-
thetic approach is featured with an asymmetric hydrogenation of racemic g-keto ester 3, a diastereoselective methylation on the a-methylene
of the (1R,5R)-lactone 4, and a diastereoselective Michael addition of the tertiary nitro cyclopentane. The central azaspiro[4.5]decane was
constructed utilizing reductive cyclization of the d-nitroketone followed by highly stereoselective reduction of the cyclic imine with
NaBH4. Ultimately, successive use of triethyl-2-phosphonopropionate and Heathcock’s phosphorane 18 to elaborate C5 and C13 side chains
completed the total synthesis of pinnaic acid.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
azaspirobicyclic and azaspirotricyclic cores.4–7 However,
only racemic azaspirobicyclic and azaspirotricyclic cores
were obtained in most present synthetic work. To the best
of our knowledge, only two total syntheses of halichlor-
ine,8,9 three of pinnaic acid9–11 have been reported so far
in the literature. Among them, Danishefsky and co-workers
were first to complete the enantioselective syntheses of
halichlorine and pinnaic acid, and simultaneously assigned
the stereochemistry at C14 and C17 of pinnaic acid. In our
efforts directed toward the enantioselective synthesis of
these alkaloids, we have previously presented an efficient
and enantioselective synthesis of the azaspirobicyclic core.7b
Herein, we would like to report an enantioselective total syn-
thesis of pinnaic acid featured by an improved preparation of
the azaspiro[4.5]decane ring system. The improvements
achieved in the pinnaic acid synthesis made the synthetic
work convenient, short, and executable.
Naturally occurring marine alkaloids halichlorine 1 and pin-
naic acid 2 bearing a highly functionalized azaspiro[4.5]-
decane ring system (Fig. 1) were found in Halichondria
okadai kadota and Pinna muricata, respectively, in 1996
by Uemura and co-workers.1 Halichlorine 1 inhibits the
expression of vascular cell adhesion molecule-1 (VCAM-1)
with an IC50 of 7 mg/mL and consequently has potential
for the treatment of arteriosclerosis, asthma, and cancer.2
Pinnaic acid 2 is a specific inhibitor of cytosolic phospho-
lipase A2 (cPLA2) with an in vitro IC50 of 0.2 mM. cPLA2
is involved in regulating inflammation and thus represents
a potential target for drug discovery.3 Because of their bio-
logical activities and unique structures, these alkaloids are
challenging and attractive synthetic targets. To date, many
groups have reported their synthetic approaches toward the
total synthesis of the two compounds, particularly for the
2. Results and discussion
H
In our previous work, the bicyclolactone 4 was prepared
through Lipase PS-catalyzed selective acylation. Though
the Lipase PS method could help us get the bicyclolactone
4, a new more efficient method to obtain this useful com-
pound 4 is still being required and will be interesting to syn-
thetic chemists. The BINAP–Ru complex is an efficient
catalyst for the asymmetric hydrogenation of b-keto ester.12
In this synthesis, hydrogenation of the g-keto ester 3 to bi-
cyclolactone 4 was explored with this catalyst, and a satisfac-
tory result was obtained. Thus, hydrogenation of racemic
g-keto ester 3 in the presence of [(R)-BINAP-RuCl2](DMF)n
as a catalyst was completely explored, and we were pleased
to find that the desired (1R,5R)-lactone 4 could be obtained
in gram scale with 61% yield and 90% ee. The yield of the
H
5
N
HOOC
Cl OH
O
9
5
HN
H
9
H
13
O
13
HO
Cl
OH
Pinnaic acid (2)
Halichlorine (1)
Figure 1. Structures of halichlorine and pinnaic acid.
Keywords: Total synthesis; Pinnaic acid; Asymmetric reduction; Michael
addition.
* Corresponding author. Fax: +86 21 64166128; e-mail: zhaog@mail.sioc.
ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.031

H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
6455
desired lactone 4 is higher than 50%, indicating that some
deracemization occurred at the a-position of the carbonyl
group under the reaction conditions. The key intermediate
of nitro cyclopentane 8 was synthesized by a sequence of
steps as outlined in Scheme 1. Substrate-induced asymmet-
ric methylation of the bicyclolactone 4 using LDA as a base
at ꢀ78 ꢁC led to 6 as a sole product in 77% yield. As
expected, methyl group approaches from the less stereo-
hindered face of the fused bicyclic ring system. Reduction
of 6 with LAH, followed by site-selective protection of the
primary alcohol with benzyl bromide, and oxidation of the
secondary alcohol using PCC in CH2Cl2 afforded the corre-
sponding cyclopentanone 7. Condensation of hydroxyl-
amine with ketone 7 followed by m-CPBA oxidation
afforded the nitro cyclopentane 8 in 64% yield over two
steps.13 Compound 8 was a pair of diastereoisomers that
needed no further separation.
(Scheme 2). Thus, the stage was now set for the Michael
addition of nitrocyclopentane 8 with methyl acrylate to
construct the spirocenter. Pleasingly, the desired nitro ester
9 was obtained in 97% yield as a single diastereoisomer,7b,14
which could be explained by presuming the acrylate ap-
proaching from the less hindered face of 8. Reduction of
the nitro ester 9 with LiBH4, followed by mesylation and
iodination, led to the iodide 10. Subsequent metalation of
the dithiane 1115 with t-BuLi and then alkylation with the
iodide 10,7b,16 followed by the deprotection of dithiane in
the presence of I2 and NaHCO3 in acetone, gave the ketone
12 that is the critical precursor for the piperidine ring cycli-
zation. In order to form the piperidine ring by intramolecular
condensation of d-aminoketone, the tertiary nitro group in
12 should be reduced to an amino group. We had reported
that reduction of the nitro group using the Ni2B method
afforded the corresponding nitrone, which was converted
into the desired piperidine by successive further reduction
with NaBH4 and TiCl3.7b Herein, we would like to contribute
a more direct and concise route, via catalytic hydrogenation
of the nitro compound 12. Previous work7b showed that the
nitro group of 12 was intact to hydrogenation over Pd/C, and
while hydrogenation over Raney nickel in MeOH under
5 atm pressure of H2 did give the desired spiropiperidine
core structure, silyl group was partially cleaved. We pre-
sumed that over hydrogenation and partial TBS loss were
due to the high pressure and the solvent chosen. Thus, Raney
nickel and 1 atm pressure of H2 were found to be an ideal
condition, and different solvents such as MeOH, EtOAc,
and cyclohexane were screened (Table 1). The results dem-
onstrated that the solvents exerted a great influence on this
reaction. Only trace amounts of the expected spiropiperidine
13 were produced in MeOH and low yield was obtained
in EtOAc (30%). To our delight, cyclohexane provided a
moderate yield of product 13 (61%). It indicated that when
decreasing the polarity of the solvents, the catalytic activity
and the rate of the reaction were reduced, and the TBS loss
problem was avoided. Further optimization of the reaction
conditions led to a superior yield of 93% by adding a small
amount of Et3N to the reaction system. The benzyl and TBS
groups remained intact under this condition. Subsequent
reduction of the cyclic imine 13 with NaBH4 in a mixed
solvent (CH2Cl2/MeOH, v/v, 1:1) generated the desired
H
O
OH
O
a
+
O
MeO2C
CO2Me
H
racemic ( )-3
5
4
H
O
H
O
b
c, d, e
BnO
4
O
H
6
7
NO2
H
f, g
BnO
8
Scheme 1. Reagents and conditions: (a) [(R)-BINAP-RuCl2](DMF)n, H2,
MeOH, 25 atm, 100 ꢁC, 61% yield for 4, 90% ee for 4, 13% yield for 5,
91% ee for 5; (b) LDA, MeI, THF, ꢀ78 ꢁC, 6 h, 77%; (c) LiAlH4, THF,
reflux, 4 h; (d) NaH, BnBr, THF, rt, 10 h, 63% over two steps; (e) PCC,
Celite, CH2Cl2, rt, 4 h, 95%; (f) NH2OH$HCl, K2CO3, MeOH, rt,
4 h, 90%; (g) m-CPBA, Na2HPO4, crushed urea, MeCN, 80 ꢁC, 76%.
BINAP¼2,20-bis(diphenylphosphino)-1,10-binaphthyl, PCC¼pyridinium
chlorochromate.
With success achieved in the initial sequence, our attention
was directed to the synthesis of the azaspirocyclic core 14
O2N
H
O2N
CO2Me
I
a
H
b, c, d
8
BnO
BnO
9
10
S
S
OTBS
e,f
11
H
TBSO
TBSO
TBSO
O
HN
H
N
h
g
O2N
H
H
BnO
BnO
BnO
13
14
12
Scheme 2. Reagents and conditions: (a) Triton B, methyl acrylate, t-BuOH, THF, rt, 48 h, 97%; (b) LiBH4, THF, rt, 24 h, 99%; (c) Et3N, DMAP, CH2Cl2, MsCl,
0 ꢁC to rt, 2 h; (d) NaI, NaHCO3, acetone, rt, 24 h, 99% over two steps; (e) 11, t-BuLi, HMPA, THF, ꢀ78 ꢁC, 3 h, 98%; (f) I2, NaHCO3, acetone/H2O (v/v, 5:1),
rt, 87%; (g) Raney Ni, cyclohexane/Et3N (v/v, 50:1), 1 atm H2, 93%; (h) NaBH4, MeOH, 0 ꢁC to rt, 98%. Triton B¼benzyltrimethylammonium hydroxide,
40 wt % solution in methanol.

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H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
Table 1. Reductive condensation of 12 under 1 atm H2
most likely because of the hindered steric environment.
Horner–Wadsworth–Emmons reaction of aldehyde 16 with
Weinreb’s phosphonate 175a produced trace product. The de-
sired dienone 19 was finally obtained in moderate yield
(60%) by heating aldehyde 16 with Heathcock’s phosphor-
ane 189 in benzene. Reduction of the ketone group under Lu-
che’s conditions19 resulted in a 3:1 mixture favoring the
desired diastereomer 20. Deprotection of the TBS group
with HF$Py complex produced alcohol 21. Reductive cleav-
age of trifluoroacetamide followed by hydrolysis of ethyl
ester in the presence of LiOH gave the lithium carboxylate
salt of 2. Dissolving the salt in aqueous pH 7 buffer, extract-
ing with 1-butanol, and purifying by flash chromatography
gave the presumed zwitterion 2 (Scheme 3). Eventually, the
enantioselective synthesis of pinnaic acid was completed
(Tables 2 and 3).
Entry
Catalyst
Solvent
Isolated yield
of 13 (%)
1
2
3
4
5
6
10% Pd/C
Pd(OH)2
Raney Ni
Raney Ni
Raney Ni
Raney Ni
CH3OH
CH3OH
CH3OH
EtOAc
Cyclohexane
Cyclohexane/Et3N (v/v, 50:1)
—
—
Trace
30
61
93
diastereoisomer 14 exclusively. The excellent selectivity
could be attributed to hydride attack from the less hindered
face of 13. Thus, we successfully constructed the azaspiro-
cyclic core.
Subsequently, we began to study the challenging elaboration
of both the C5 and C13 side chains. Protection of the second-
ary amino group in 14 with trifluoroacetic anhydride,10 de-
protection of the TBS group, and oxidation by DMP17
afforded an aldehyde, which was converted into compound
15 through Horner–Wadsworth–Emmons reaction.18 Subse-
quent removal of the benzyl group using BBr3 in CH2Cl2 at
ꢀ78 ꢁC, and DMP oxidation resulted in the desired aldehyde
16. Introduction of the C13 side chain proved to be quite
challenging. Both Julia coupling and cross coupling olefina-
tion were explored in turn. However, each of these failed,
3. Conclusion
In summary, we presented herein an efficient and highly
stereoselective total synthesis of pinnaic acid. The unique
feature of the work was the use of Ru complex catalyzed
asymmetric hydrogenation of g-keto ester to efficiently
generate chiral bicyclolactone 4. Key steps of this synthesis
included a highly diastereoselective Michael addition of ni-
tro cyclopentane 8 to methyl acrylate and an intramolecular
H
H
EtO2C
EtO2C
a-d
e, f
TFAN
H
TFAN
H
14
H
BnO
O
16
15
g or h
H
H
H
EtO2C
Cl
EtO2C
Cl OH
EtO2C
i
TFAN
H
TFAN
H
TFAN
H
O
+
Cl
OH
TBSO
TBSO
TBSO
19
20
17-epi-20
j
H
H
HN
EtO2C
EtO2C
k
TFAN
H
l, m
Cl
OH
2
Cl
OH
H
HO
HO
Pinnaic acid
22
21
PO(OEt)2
PPh3
O
Cl
O
O
Cl
O
TBS
TBS
17
18
Scheme 3. Reagents and conditions: (a) (CF3CO)2O, i-Pr2NEt, 1,2-dichloroethane, 0 ꢁC, 1 h, 89%; (b) HF$Py, THF, rt, 97%; (c) DMP, CH2Cl2; (d) NaH,
triethyl-2-phosphonopropionate, THF, 87% over two steps; (e) BBr3, CH2Cl2, ꢀ78 ꢁC, >99%; (f) DMP, CH2Cl2, rt, 92%; (g) phosphonate 17, LiHMDS,
THF, ꢀ78 ꢁC, 0.5 h, then 16, ꢀ78 to 25 ꢁC, 2 days, trace product; (h) phosphorane 18, benzene, 60–65 ꢁC, 60%; (i) NaBH4, CeCl3$7H2O, MeOH, 0 ꢁC,
80% (dr¼3:1), isomers were separated by column chromatograph; (j) HF$Py, THF, 0 ꢁC, 24 h, 97%; (k) NaBH4, EtOH, 0 ꢁC, 82%, (l) LiOH, THF/MeOH/
H2O (v/v/v, 6:2:1), 30 ꢁC, 10 h; (m) pH 7 buffer/n-BuOH extract, 63% over two steps.

H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
6457
Table 2. 1H NMR spectral data of pinnaic acid
Position Natural
(400 MHz, in CD3CD) (carboxylate, 600 MHz, in CD3CD)
Uemura group’s data (ꢂ)-pinnaic acid Heathcock group’s data (ꢂ)-pinnaic acid Our group’s data (ꢀ)-pinnaic acid
(500 MHz, in CD3CD)
dH (J in hertz)
(500 MHz, in CD3CD)
dH (J in hertz)
dH (J in hertz)
dH (J in hertz)
3
4
6.45 (t, 7.5)
2.56 (br)
2.40 (m)
6.35 (t, 7.2)
2.49 (br s)
2.32 (m)
5.75 (dd, 9.6, 15.6)
5.60 (dd, 6.6, 15.6)
4.96 (8.4)
5.76 (d, 8.4)
2.56 (t, 6.0)
3.73 (m)
1.06 (d, 6.6)
1.86 (s)
6.35 (t, 7.5)
2.47–2.55
2.33 (m)
5.79 (dd, 9.5, 15.6)
5.62 (dd, 7.0, 15.5)
4.96 (t, 7.0)
5.78 (d, 8.0)
2.57 (t, 6.5)
3.70–3.79
6.36 (t, 7.5)
2.49 (t, 6.5)
2.33 (m)
14
15
16
17
18
20
21
22
23
5.82 (dd, 8.8, 15.6)
5.64 (dd, 6.8, 15.6)
5.03 (dd, 6.8, 7.9)
5.72 (d, 7.9)
2.55 (t, 6.5)
3.78 (t, 6.5)
1.08 (d, 7.0)
1.88 (s)
5.77 (dd, 10.0, 15.6)
5.62 (dd, 6.6, 15.5)
4.98 (t, 7.1)
5.76 (d, 7.9)
2.56 (t, 6.3)
3.71–3.76 (m)
1.06 (d, 6.6)
1.85 (s)
1.07 (d, 6.5)
1.87 (s)
Table 3. 13C NMR spectral data of pinnaic acid
Position Natural
Our group’s data (ꢀ)-pinnaic acid
10ꢀ1 deg cm3 gꢀ1. (ꢂ)-Methyl 2-(2-oxocyclopentyl)acetate
3 was prepared according to the previously described proce-
dure.20
(100 MHz, in CD3CD) (75 MHz, in CD3CD)
dc
dc
4.2. (3aR,6aR)-Hexahydrocyclopenta[b]furan-
2-one (4)7b
1
2
3
4
5
6
7
8
170.14
134.51
127.71
31.53
53.46
27.20
19.46
34.17
68.48
33.70
21.66
28.54
54.21
36.37
136.97
130.75
68.84
128.22
132.01
41.65
58.06
19.03
11.86
174.94
137.60
127.90
32.48
53.54
28.40
20.52
35.25
67.57
34.95
22.41
29.44
55.04
37.19
137.95
130.89
69.54
128.76
132.29
42.13
58.63
19.76
12.91
To a solution of keto ester 3 (3.2 g, 20.5 mmol) in MeOH
(30 mL) was added [(R)-BINAP-RuCl2](DMF)n (65 mg).
12
The reaction mixture was stirred under H2 (25 atm) at
100 ꢁC for 24 h. Then, cooled, filtered through Celite, and
concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, EtOAc/hexane 1:3) to provide
lactone 4 as colorless oil (1.57 g, 61%, 90% ee, the analytical
sample was converted to benzoate in two steps, first reduced
with LAH and then protected the primary alcohol with BzCl.
The benzoate was determined by HPLC on Chiralcel AD
column, eluant: Vhexane/Vi-PrOH¼4:1) and the alcohol 5 as
colorless oil (430 mg, 13%, 91% ee, the analytical sample
was converted to benzoate and determined by HPLC on
Chiralcel OD column, eluant: Vhexane/Vi-PrOH¼9:1).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4.2.1. Lactone 4. [a]D24 51.7 (c 1.00, MeOH) (lit.7b [a]2D0 59.7
(c 1.28, MeOH)); Rf¼0.33 (EtOAc/hexane 1:3); IR (film,
1
cmꢀ1): 2961, 2872, 1773, 1177, 984; H NMR (300 MHz,
reductive condensation reaction, which formed the azaspiro
cyclic core. In addition, elaboration of the C13 side chain
was completed, and finally the synthesis of pinnaic acid
was achieved. Efforts toward the total synthesis of halichlo-
rine are currently underway.
CDCl3) d 5.01 (t, J¼5.2 Hz, 1H), 2.92–2.82 (m, 1H), 2.79
(d, J¼10.3 Hz, 1H), 2.29 (d, J¼17.5 Hz, 1H), 2.07–2.02
(m, 1H), 1.90–1.66 (m, 4H), 1.58–1.51 (m, 1H).
4.2.2. Alcohol 5. [a]D20 ꢀ41.2 (c 1.20, MeOH); Rf¼0.24
(EtOAc/hexane 1:3); IR (film, cmꢀ1): 3435, 2954, 2874,
1737, 1438, 1344, 1268, 1195, 1175; H NMR (300 MHz,
1
4. Experimental section
4.1. General
CDCl3) d 3.86 (q, J¼6.3 Hz, 1H), 3.69 (s, 3H), 2.95 (s,
1H), 2.44 (d, J¼2.5 Hz, 1H), 2.42 (s, 1H), 2.13–2.06
(m, 1H), 1.98–1.95 (m, 2H), 1.74–1.61 (m, 3H), 1.28–1.15
(m, 1H).
All reactions were conducted under Ar atmosphere unless
stated otherwise and monitored by TLC on precoated silica
gel HSGF254 plates (Yantai Chemical Co., Ltd). Column
chromatography was performed on silica gel 300–400
mesh (Yantai Chemical Co., Ltd) and eluted with hexane
and ethyl acetate mixtures. All solvents were refluxed and
distilled from sodium benzophenone ketyl (THF, Et2O) or
CaH2 (CH2Cl2, ClCH2CH2Cl). The NMR spectra (1H:
300 MHz, 13C: 75.0 MHz) are reported in d units (parts
per million) and J values (hertz) with Me4Si as the internal
standard. Infrared (IR) spectra are reported in wave numbers
(cmꢀ1). Optical rotations are reported in units of
4.3. 3-(R)-Methyl-hexahydrocyclopenta[b]furan-
2-one (6)7b
To a solution of lithium diisopropylamide, prepared from
a solution of diisopropylamine (8.2 mL, 58 mmol) in
150 mL of THF and n-BuLi (1.6 M in hexane, 36.3 mL,
58 mmol) at ꢀ78 ꢁC, was added a solution of lactone 4
(6.69 g, 53 mmol) in 10 mL of THF. After stirring for an
additional 30 min at ꢀ78 ꢁC, methyl iodide (3.46 mL,
55 mmol) was added. The reaction mixture was stirred at
ꢀ78 ꢁC for 6 h, quenched with water, and acidified with

6458
H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
concentrated hydrochloric acid to pH¼3–4, the organic
layer was separated, and the aqueous layer was extracted
with ethyl acetate (3ꢃ100 mL). The combined extracts
were dried over anhydrous sodium sulfate, concentrated,
and purified by flash chromatography (silica gel, EtOAc/
hexane 1:5) to afford 6 (5.72 g, 77%) as a colorless oil.
warm to room temperature, and poured into a solution of
5% aqueous sodium bicarbonate solution. The methane-
sulfonate ester was isolated by extraction with CH2Cl2 and
removal of solvent. The crude mesylate was then stirred
with sodium iodide (25.5 g, 0.17 mol) and sodium bicarbon-
ate (2.86 g, 34 mmol) in acetone (200 mL) for 24 h at room
temperature. The solvent was removed in vacuo, the residue
was redissolved in water, and extracted with ethyl acetate
(3ꢃ50 mL). The combined organic phase was dried over an-
hydrous sodium sulfate, concentrated, and purified by flash
chromatography (silica gel, EtOAc/hexane 1:30) to generate
the corresponding iodide 10 (7.34 g, 99%) as a colorless oil.
[a]D21 68.8 (c 1.40, MeOH) (lit.7b [a]2D0 68.6 (c 1.64, MeOH));
Rf¼0.50 (EtOAc/hexane 1:3); IR (film, cmꢀ1): 2964, 2874,
1
1767, 1191, 984; H NMR (300 MHz, CDCl3) d 4.98 (t,
J¼5.7 Hz, 1H), 2.55–2.50 (m, 1H), 2.39–2.34 (m, 1H),
2.04–1.99 (m, 1H), 1.87–1.57 (m, 5H), 1.32 (d, J¼7.8 Hz,
3H).
[a]2D5 34.6 (c 1.35, CHCl3) (lit.7b [a]D20 32.5 (c 1.02, CHCl3));
Rf¼0.68 (EtOAc/hexane 1:3); IR (film, cmꢀ1): 2960, 2874,
4.4. 3-[10-(S)-Nitro-20-(R)-(200-benzyloxy-100-(R)-methyl-
ethyl)-cyclopentyl]-propionic acid methyl ester (9)7b
1530, 1096, 737; H NMR (300 MHz, CDCl3) d 7.39–7.26
1
(m, 5H), 4.55 (d, J¼12.1 Hz, 1H), 4.47 (d, J¼11.7 Hz, 1H),
3.44 (dd, J¼5.0, 9.4 Hz, 1H), 3.28–3.19 (m, 2H), 3.18–3.06
(m, 1H), 2.60–2.47 (m, 2H), 2.24–2.17 (m, 1H), 2.06–1.96
(m, 2H), 1.91–1.59 (m, 7H), 0.75 (d, J¼6.6 Hz, 3H).
4.6. 1-(R)-(20-Benzyloxy-10-(R)-methyl-ethyl)-2-(S)-
nitro-2-(S)-[600-(tert-butyl-dimethyl-silanyloxy)-400-
oxo-hexyl]-cyclopentane (12)7b
Methyl acrylate (1.46 mL, 16.3 mmol) and Triton B (40% in
MeOH, 0.8 mL) were added to a solution of 8 (4.0 g,
15.2 mmol) in dry THF (30 mL) and t-BuOH (70 mL), and
the mixture was stirred under Ar atmosphere at room tem-
perature for 48 h. The solution was evaporated to a residue,
which was subjected to column chromatography (silica gel,
EtOAc/hexane 1:10) to give nitro ester 9 (5.12 g, 97%) as
a colorless oil.
To a solution of dithiane 1115 (6.52 g, 23 mmol) in 150 mL
of THF at ꢀ78 ꢁC were added t-BuLi (1.5 M solution in
pentane, 15.6 mL, 23.4 mmol) and HMPA (5.43 mL,
31.2 mmol). After stirring for an additional 30 min at
ꢀ78 ꢁC, iodide 10 (6.73 g, 15.6 mmol) in THF (30 mL)
was added dropwise. The reaction mixture was stirred at
ꢀ78 ꢁC for 3 h, quenched with saturated aqueous ammo-
nium chloride solution (50 mL), and extracted with ethyl
acetate (3ꢃ50 mL), dried over anhydrous sodium sulfate,
concentrated, and purified by flash chromatography (silica
gel, EtOAc/hexane 1:20) to give dithiane (8.94 g, 98%) as
a pale-yellow oil.
[a]2D5 26.6 (c 1.15, CHCl3) (lit.7b [a]D20 27.6 (c 0.98, CHCl3));
Rf¼0.48 (EtOAc/hexane 1:3); IR (film, cmꢀ1): 2952, 2877,
1740, 1532, 738, 699; 1H NMR (300 MHz, CDCl3)
d 7.34–7.27 (m, 5H), 4.52 (d, J¼11.9 Hz, 1H), 4.44 (d,
J¼12.0 Hz, 1H), 3.66 (s, 3H), 3.40 (dd, J¼5.0, 9.4 Hz,
1H), 3.24 (dd, J¼6.8, 9.3 Hz, 1H), 2.85–2.75 (m, 1H),
2.57–2.48 (m, 1H), 2.35 (t, J¼8.0 Hz, 2H), 2.25–2.15 (m,
1H), 2.11–1.60 (m, 7H), 0.75 (d, J¼6.9 Hz, 3H).
4.5. 1-(R)-(20-Benzyloxy-10-(R)-methyl-ethyl)-2-(S)-
(300-iodo-propyl)-2-(S)-nitro-cyclopentane (10)7b
To a stirred solution of the nitro ester 9 (11.85 g, 34 mmol) in
THF (200 mL) was added LiBH4 (4.0 M solution in THF,
42 mL, 0.17 mol). Stirring was continued for 24 h at room
temperature. The mixture was quenched with saturated
aqueous ammonium chloride solution under ice cooling
and extracted with ethyl acetate. The combined extracts
were washed with water and brine, and then dried over anhy-
drous sodium sulfate, concentrated, and purified by flash
chromatography (silica gel, EtOAc/hexane 1:3) to yield nitro
alcohol (10.85 g, 99%) as a colorless oil.
[a]2D3 20.1 (c 1.35, CHCl3) (lit.7b [a]D20 18.5 (c 1.03, CHCl3));
Rf¼0.56 (EtOAc/hexane 1:10); IR (film, cmꢀ1): 2953, 2856,
1532, 1095, 837, 777; 1H NMR (300 MHz, CDCl3) d 7.29–
7.19 (m, 5H), 4.46 (d, J¼12.2 Hz, 1H), 4.40 (d, J¼
12.2 Hz, 1H), 3.70 (t, J¼7.2 Hz, 2H), 3.33 (dd, J¼5.4,
9.3 Hz, 1H), 3.17 (dd, J¼7.0, 9.6 Hz, 1H), 2.76–2.69 (m,
4H), 2.55–2.31 (m, 2H), 2.09–2.03 (m, 3H), 1.98–1.36 (m,
13H), 0.82 (s, 9H), 0.66 (d, J¼6.9 Hz, 3H), 0.01 (s, 6H).
To a solution of dithiane (4.51 g, 7.75 mmol) in acetone/H2O
(v/v, 5:1, 120 mL) at 0 ꢁC were added iodide (7.87 g,
31 mmol) and NaHCO3 (5.86 g, 69.8 mmol). The resulting
mixture was stirred at 0 ꢁC for 1 h and quenched by addition
of saturated aqueous Na2S2O3 (50 mL). The organic phase
was separated, the aqueous phase was extracted with ethyl
acetate (3ꢃ60 mL), the combined extracts were dried over
anhydrous sodium sulfate, and concentrated in vacuo to
give a residue, which was subjected to column chromato-
graphy (silica gel, EtOAc/hexane 1:10) to give 12 (3.34 g,
87%) as a pale-yellow oil.
[a]2D4 36.0 (c 0.97, CHCl3) (lit.7b [a]D20 36.2 (c 1.26, CHCl3));
Rf¼0.10 (EtOAc/hexane 1:3); IR (film, cmꢀ1): 3395, 2958,
1
2875, 1530, 1097, 738, 699; H NMR (300 MHz, CDCl3)
d 7.37–7.26 (m, 5H), 4.51 (d, J¼12.1 Hz, 1H), 4.46 (d, J¼
12.0 Hz, 1H), 3.64–3.54 (m, 2H), 3.39 (dd, J¼5.0, 9.3 Hz,
1H), 3.24 (dd, J¼7.2, 9.2 Hz, 1H), 2.61–2.42 (m, 2H),
2.22–2.15 (m, 1H), 2.08–1.98 (m, 3H), 1.91–1.81 (m, 1H),
1.77–1.45 (m, 6H), 0.74 (d, J¼7.0 Hz, 3H).
The above nitro alcohol (5.42 g, 16.9 mmol), triethylamine
(7.1 mL, 51 mmol), and DMAP (500 mg) were dissolved
in CH2Cl2 (200 mL) at 0 ꢁC, and methanesulfonyl chloride
(2.6 mL, 34 mmol) was added dropwise with stirring. The
reaction mixture was stirred at 0 ꢁC for 1 h, allowed to
[a]2D3 26.1 (c 1.00, CHCl3) (lit.7b [a]D20 23.9 (c 0.91, CHCl3));
Rf¼0.22 (EtOAc/hexane 1:10); IR (film, cmꢀ1): 2955, 2856,
1716, 1532, 1096, 836; 1H NMR (300 MHz, CDCl3) d 7.31–
7.22 (m, 5H), 4.46 (d, J¼12.3 Hz, 1H), 4.41 (d, J¼11.9 Hz,

H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
6459
1H), 3.82 (t, J¼6.3 Hz, 2H), 3.33 (dd, J¼5.0, 9.2 Hz, 1H),
3.19 (dd, J¼7.1, 9.5 Hz, 1H), 2.54–2.30 (m, 6H), 2.13–
2.08 (m, 1H), 2.00–1.89 (m, 3H), 1.70–1.47 (m, 6H), 0.83
(s, 9H), 0.68 (d, J¼6.9 Hz, 3H), 0.01 (s, 6H).
hexane 1:10) to afford the corresponding aldehyde as a
colorless oil. Sodium hydride (60%, 40.8 mg, 1.02 mmol)
was added to triethyl-2-phosphonopropionate (0.18 mL,
0.85 mmol) in THF (5 mL) at 0 ꢁC. After stirring for
30 min, the resulting aldehyde (143 mg, 0.34 mmol) in
THF (5 mL) was added. After 30 min, the mixture was
warmed to room temperature and reacted for 12 h and satu-
rated ammonium chloride was added to the solution and
extracted with ethyl acetate. The extract was washed with
water and brine, dried over anhydrous sodium sulfate,
concentrated, and purified by flash chromatography (silica
gel, EtOAc/hexane 1:10) to afford 15 (150 mg, 87%) as a
colorless oil.
4.7. Imine (13)
Raney nickel catalyst was prepared according to the litera-
ture.21 To a solution of 12 (300 mg, 0.61 mmol) in cyclo-
hexane (30 mL) were added Raney nickel (100 mg) and
Et3N (0.6 mL). The mixture was stirred at 25 ꢁC under
1 atm pressure of H2 for 4 h. The catalyst was filtered off,
the filtrate was then concentrated, and purified by flash chro-
matography (silica gel, EtOAc/hexane 1:10) to give 13
(253 mg, 93%) as a colorless oil.
[a]2D4 ꢀ21.4 (c 0.70, CHCl3) (lit.7b [a]2D0 ꢀ21.6 (c 0.95,
CHCl3)); Rf 0.35 (EtOAc/hexane 1:10); IR (film, cmꢀ1):
1712, 1690, 1652, 1260, 1200, 1139 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 7.35–7.32 (m, 5H), 6.54 (t, J¼
7.2 Hz, 1H), 4.48 (q, J¼12.6 Hz, 2H), 4.22 (q, J¼7.1 Hz,
2H), 3.92 (d, J¼9.3 Hz, 1H), 3.40–3.32 (t, J¼4.8 Hz, 2H),
2.59–2.37 (m, 2H), 2.25–2.05 (m, 3H), 1.86–1.57 (m,
14H), 1.28 (t, J¼7.2 Hz, 3H), 0.96 (d, J¼6.3 Hz, 3H).
[a]2D6 21.3 (c 1.10, CHCl3); Rf¼0.44 (EtOAc/hexane 1:3); IR
(film, cmꢀ1): 3064, 2928, 2856, 1655, 1496, 1461, 1361,
1255, 1093, 836, 776, 734, 697; 1H NMR (300 MHz,
CDCl3) d 7.34–7.26 (m, 5H), 4.47 (s, 2H), 3.87–3.77 (m,
1H), 3.29–3.17 (m, 1H), 2.31 (m, 1H), 2.13–2.06 (m, 1H),
1.95–1.85 (m, 2H), 1.72–1.41 (m, 13H), 0.97 (d, J¼
7.2 Hz, 3H), 0.88 (m, 9H), 0.04 (m, 6H). 13C NMR
(75 MHz, CDCl3) d 164.8, 138.9, 128.2, 127.5, 127.3,
75.5, 72.7, 65.4, 61.5, 52.0, 43.7, 42.0, 33.8, 32.8, 30.1,
28.4, 25.9, 23.4, 18.2, 18.0, 15.8, ꢀ5.4; MS (MALDI)
444.3 [M+H]+; HRMS (MALDI) calcd for C27H46NO2Si
[M+H]+: 444.3312, found: 444.3292.
4.10. Aldehyde 16
To a stirring solution of alcohol (132 mg, 0.31 mmol) in
CH2Cl2 (10 mL) was added DMP (267 mg, 0.63 mmol).
After stirring at room temperature for 5 h, the mixture was
diluted with CH2Cl2 (10 mL) and quenched by addition of
saturated aqueous Na2S2O3 (10 mL). The aqueous phase
was extracted with CH2Cl2 (3ꢃ10 mL). The combined
extracts were dried over anhydrous sodium sulfate, con-
centrated, and purified by flash chromatography (silica gel,
EtOAc/hexane 1:10) to provide 120 mg (92%) of aldehyde
16 as a colorless oil.
4.8. 1-(R)-(20-Benzyloxy-10-(R)-methyl-ethyl)-7-(R)-
[200-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-aza-5-
(S)-spiro[4.5]decane (14)7b
To imine 13 (1.0 g, 2.24 mmol) in CH2Cl2/MeOH (v/v, 1:1,
20 mL), NaBH4 (426 mg, 11.2 mmol) was added at 0 ꢁC and
stirred for 1 h. The solution was evaporated, the residue was
diluted with water, and extracted with ethyl acetate
(3ꢃ15 mL). The combined organic layer was washed with
water and brine, dried over anhydrous sodium sulfate, con-
centrated, and purified by flash chromatography (silica gel,
MeOH/EtOAc 1:10) to afford 14 (1.05 g, 98%) as a pale-
yellow oil.
[a]2D5 ꢀ16.2 (c 0.3, CHCl3); Rf¼0.35 (EtOAc/hexane 1:10);
IR (film, cmꢀ1): 2958, 2929, 1726, 1684, 1463, 1425, 1260,
1201, 1142, 1101, 1020, 836, 801; H NMR (300 MHz,
1
CDCl3) d 9.66 (d, J¼3.3 Hz, 1H), 6.56 (t, J¼7.5 Hz, 1H),
4.21 (q, J¼6.9 Hz, 2H), 3.93 (d, J¼9.9 Hz, 1H), 2.62–2.03
(m, 9H), 1.93–1.67 (m, 10H), 1.48–1.44 (m, 1H), 1.32 (t,
J¼6.9 Hz, 3H), 1.05 (d, J¼6.9 Hz, 3H).
[a]2D6 ꢀ25.6 (c 1.10, CHCl3) (lit.7b [a]2D0 ꢀ29.4 (c 1.14,
CHCl3)); Rf¼0.50 (MeOH/EtOAc 1:10); IR (film, cmꢀ1):
3342, 2931, 2858, 1255, 1095, 836, 776; 1H NMR
(300 MHz, CDCl3) d 7.36–7.25 (m, 5H), 4.50 (s, 2H),
3.70–3.62 (m, 2H), 3.51 (dd, J¼5.9, 9.0 Hz, 1H), 3.35–3.30
(m, 1H), 2.76–2.73 (m, 1H), 2.05 (m, 1H), 1.77–1.22 (m,
16H), 0.96 (d, J¼6.9 Hz, 3H), 0.88 (s, 9H), 0.003 (s, 3H).
4.9. (10R,50S,70R,100R)-4-{10-[200-Benzyloxy-100-methyl-
ethyl]-60-trifluoroacetyl-60-aza-50-spiro[4.5]dec-70-yl}-
2-methylbut-2E-enoic acid ethyl ester (15)7b
4.11. Ketone 19
A solution of aldehyde 16 (95.0 mg, 0.228 mmol) and
phosphorane 189 (178 mg, 0.34 mmol) in benzene (5 mL)
was heated at reflux. After 24 h, more phosphorane 18
(130 mg, 0.25 mmol) was added, as a solution in benzene
(1 mL). After 48 h, the additional phosphorane 18
(130 mg, 0.25 mmol) was added, as a solution in benzene
(1 mL). After 48 h, the reaction mixture was allowed to
cool and then evaporated. Flash chromatography with 1:20
EtOAc/hexane afforded 90 mg (60%) of enone 19 as
a pale-yellow oil.
To the alcohol (145 mg, 0.34 mmol) in CH2Cl2 (10 mL) was
added DMP (288 mg, 0.68 mmol) at room temperature.
After stirring at room temperature for 5 h, the mixture was
diluted with CH2Cl2 (10 mL) and quenched by addition of
saturated aqueous Na2S2O3 (10 mL). The aqueous phase
was extracted with CH2Cl2 (3ꢃ10 mL). The combined ex-
tracts were dried over anhydrous Na2SO4, concentrated,
and purified by flash chromatography (silica gel, EtOAc/
[a]2D4 ꢀ75.4 (c 1.15, CHCl3); Rf¼0.44 (EtOAc/hexane 1:8);
IR (film, cmꢀ1): 2954, 2930, 1713, 1688, 1621, 1471, 1424,
1367, 1258, 1200, 1141, 1110, 837, 778; 1H NMR
(300 MHz, CDCl3) d 6.92 (dd, J¼9.6, 15.3 Hz, 1H), 6.49
(t, J¼6.9 Hz, 1H), 6.34 (s, 1H), 6.25 (d, J¼15.3 Hz, 1H),
4.18 (q, J¼6.9 Hz, 2H), 3.84 (t, J¼6.0 Hz, 3H), 2.63–2.44

6460
H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
(m, 5H), 2.18 (m, 4H), 1.88–1.60 (m, 15H), 1.32–1.26 (m,
6H), 1.00 (d, J¼6.3 Hz, 3H), 0.87 (s, 9H), 0.04 (s, 6H);
13C NMR (75 MHz, CDCl3) d 187.3, 167.8, 157.8, 157.6,
154.2, 144.4, 136.7, 130.3, 128.7, 125.4, 118.0, 115.7,
68.7, 60.6, 60.1, 59.9, 53.7, 44.7, 38.2, 35.9, 35.0, 34.7,
31.7, 29.7, 25.8, 24.4, 23.1, 22.0, 18.2, 14.2, 12.6, ꢀ5.5;
MS (MALDI) 684.3 [M+Na]+; HRMS (MALDI) calcd for
C33H51F3NO5SiClNa [M+Na]+: 684.3069, found: 684.3086.
(1 M THF solution, 0.3 mL, 0.3 mmol). The mixture was
stirred for 24 h at 0 ꢁC and diluted with EtOAc (2 mL).
The organic layer was washed with brine, dried over anhy-
drous sodium sulfate, concentrated, and purified by flash
chromatography (silica gel, EtOAc/hexane 1:2) to afford
21 (16 mg, 97%) as a colorless oil.
[a]2D5 ꢀ19.5 (c 0.70, CHCl3); Rf¼0.30 (EtOAc/hexane 1:1);
IR (film, cmꢀ1): 3460, 2925, 2855, 1713, 1689, 1446, 1369,
1263, 1200, 1140; 1H NMR (300 MHz, CDCl3) d 6.58
(t, J¼7.5 Hz, 1H), 5.72 (dd, J¼8.4, 15.6 Hz, 1H), 5.60 (d,
J¼8.1 Hz, 1H), 5.38 (dd, J¼6.0, 15.6 Hz, 1H), 5.00 (t,
J¼6.9 Hz, 1H), 4.20 (q, J¼7.5 Hz, 2H), 3.93 (br m, 1H),
3.84–3.71 (m, 2H), 2.72 (m, 2H), 2.51 (q, J¼6.0 Hz, 2H),
2.46–2.13 (m, 6H), 1.90–1.62 (m, 11H), 1.51–1.25 (m,
6H), 0.94 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 167.9, 157.8, 157.4, 139.3, 137.1, 132.6, 130.3, 129.8,
128.8, 118.4, 115.6, 69.9, 68.8, 60.8, 60.0, 59.6, 53.5,
42.6, 37.1, 36.1, 35.3, 34.7, 31.7, 29.7, 24.5, 23.3, 22.2,
14.2, 12.7; MS (MALDI) 572.2 [M+Na]+; HRMS (MALDI)
calcd for C27H39F3NO5ClNa [M+Na]+: 572.2361, found:
572.2387.
4.12. Alcohols 20 and 17-epi-20
To a stirring solution of CeCl3$7H2O (120 mg, 0.35 mmol)
and enone 19 (50 mg, 0.075 mmol) in methanol (2 mL) at
0 ꢁC was added sodium borohydride (13 mg, 0.35 mmol),
in one portion. The mixture was stirred at 0 ꢁC for 1 h.
The reaction mixture was shaken with saturated NH4Cl
(5 mL) and Et2O (5 mL), and the layers were separated.
The cloudy aqueous solution was extracted with Et2O
(5 mL). Addition of a few drops of 1 N HCl to the aqueous
solution made it homogeneous and it was extracted again
(Et2O, 3ꢃ5 mL). The combined organic solution was dried
(MgSO4) and evaporated. Chromatography with 1:10
EtOAc/hexane afforded 30 mg (60%) of alcohol 20 and
10 mg (21%) of alcohol 17-epi-20 as colorless oils.
4.14. Diol 22
4.12.1. Alcohol 20. [a]2D0 ꢀ21.8 (c 0.80, CHCl3); Rf¼0.31
(EtOAc/hexane 1:8); IR (film, cmꢀ1): 3502, 2955, 2927,
1713, 1689, 1463, 1446, 1368, 1288, 1258, 1201, 1140, 1112,
980, 837, 778; 1H NMR (300 MHz, CDCl3) d 6.58 (t,
J¼7.5 Hz, 1H), 5.72 (dd, J¼8.1, 15.0 Hz, 1H), 5.59 (d, J¼
7.5 Hz, 1H), 5.38 (dd, J¼6.0, 15.0 Hz, 1H), 4.99 (t, J¼6.6,
1H), 4.20 (q, J¼7.2 Hz, 2H), 3.94 (br m, 1H), 3.77 (t,
J¼6.0 Hz, 2H), 2.70 (m, 2H), 2.50 (t, J¼6.0 Hz, 2H),
2.27–2.14 (m, 4H), 1.90–1.63 (m, 13H), 1.33–1.26 (m,
4H), 0.94 (d, J¼6.3 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H);
13C NMR (75 MHz, CDCl3) d 167.8, 157.8, 157.5, 139.3,
137.0, 133.2, 130.3, 129.1, 128.3, 118.2, 115.9, 70.2, 68.8,
60.7, 60.2, 60.0, 53.6, 42.9, 36.9, 36.1, 35.3, 34.6, 31.7,
29.7, 25.9, 24.5, 22.7, 21.9, 18.3, 14.2, 12.7, ꢀ5.3; MS
(MALDI) 686.3 [M+Na]+; HRMS (MALDI) calcd for
C33H53F3NO5SiClNa [M+Na]+: 686.3226, found: 686.3237.
To diol 21 (15 mg, 0.027 mmol) in EtOH (1 mL), NaBH4
(5.2 mg, 0.136 mmol) was added at 0 ꢁC and stirred for
1 h. The solution was evaporated, the residue was diluted
with water, extracted with ethyl acetate (3ꢃ5 mL), and dried
over anhydrous sodium sulfate. Concentrated and purified
by flash chromatography (silica gel, MeOH/EtOAc 1:10)
to afford 22 (10 mg, 82%) as a colorless oil.
[a]2D5 ꢀ14.2 (c 0.40, CHCl3); Rf¼0.38 (MeOH/EtOAc 1:10);
IR (film, cmꢀ1): 3396, 2927, 2862, 1709, 1651, 1456, 1368,
1279, 1257, 1096, 985; H NMR (500 MHz, C6D6) d 7.13
1
(td, J¼7.4, 1.0 Hz, 1H), 5.85 (dd, J¼9.0, 15.5 Hz, 1H),
5.78 (d, J¼8.0 Hz, 1H), 5.66 (dd, J¼6.3, 15.5 Hz, 1H),
5.26 (t, J¼7.1 Hz, 1H), 4.07 (q, J¼7.1 Hz, 2H), 3.66 (m,
1H), 3.52 (m, 1H), 2.67 (m, 1H), 2.41–2.32 (m, 2H), 2.26–
2.10 (m, 3H), 1.93 (s, 3H), 1.80–1.60 (m, 5H), 1.45–1.30
(m, 6H), 1.25–1.07 (m, 3H), 1.03 (t, J¼7.1 Hz, 3H), 0.98
(d, J¼6.7 Hz, 3H); 13C NMR (125 MHz, C6D6) d 168.7,
140.3, 139.4, 132.7, 131.1, 130.0, 129.4, 70.8, 63.8, 61.0,
59.6, 56.1, 51.7, 43.5, 38.4, 37.4, 37.2, 37.0, 32.8, 30.7,
23.7, 23.1, 21.4, 14.7, 13.3; HRMS (MALDI) calcd for
C25H41NO4Cl [M+H]+: 454.2719, found: 454.2709.
4.12.2. 17-epi-20. [a]2D1 ꢀ53.6 (c 0.30, CHCl3); Rf¼0.23
(EtOAc/hexane 1:8); IR (film, cmꢀ1): 3502, 2955, 2926,
2855, 1713, 1689, 1463, 1258, 1200, 1140, 1108, 980, 837,
778; 1H NMR (300 MHz, CDCl3) d 6.57 (t, J¼7.5 Hz, 1H),
5.79 (dd, J¼8.7, 15 Hz, 1H), 5.54 (d, J¼8.1 Hz, 1H), 5.36
(dd, J¼6.0, 15.0 Hz, 1H), 5.00 (t, J¼6.0 Hz, 1H), 4.21 (q,
J¼6.9 Hz, 2H), 3.93 (br m, 1H), 3.77 (t, J¼6.0 Hz, 2H),
2.67 (m, 2H), 2.48 (t, J¼6.6 Hz, 2H), 2.27–2.14 (m, 4H),
1.90–1.65 (m, 13H), 1.34–1.23 (m, 4H), 0.95 (d, J¼6.9 Hz,
3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 167.8, 157.8, 157.3, 138.2, 137.1, 133.6, 130.2,
129.0, 128.0, 118.9, 115.0, 69.3, 68.8, 60.7, 60.2, 60.1,
53.6, 42.8, 37.3, 36.1, 35.0, 34.7, 31.8, 29.7, 25.9, 24.5,
23.3, 22.3, 18.3, 14.2, 12.7, ꢀ5.3; MS (MALDI) 686.3
[M+Na]+; HRMS (MALDI) calcd for C33H53F3NO5SiClNa
[M+Na]+: 686.3226, found: 686.3234.
4.15. Pinnaic acid (2)
Ethyl ester 22 (10 mg, 0.022 mmol) was dissolved in THF/
MeOH/H2O (v/v/v 6:2:1, 0.9 mL). LiOH$H2O (9.24 mg,
0.22 mmol) was added. After stirring for 3 h at room temper-
ature, the solution was heated to 30 ꢁC. After 4 h, no ester
could be detected by TLC. The reaction mixture was loaded
onto a short flash column, which was eluted with 1:7 MeOH/
CH2Cl2 to yield (presumed) pinnaic acid lithium salt 10 mg
(88%) as a colorless oil. The sample was dissolved in excess
pH 7.00 buffer (NaH2PO4/Na2HPO4/H2O). The aqueous so-
lution was extracted three times with n-BuOH and the com-
bined n-BuOH was evaporated. Purification of the resulting
product by flash chromatography (silica gel, MeOH/CH2Cl2
1:7) affords pinnaic acid 2 (7 mg, 72%) as a colorless oil.
4.13. Diol 21
A stirring solution of amine 20 (20 mg, 0.03 mmol) in THF
(2 mL) was cooled to 0 ꢁC. To the solution was added HF$Py

H. Wu et al. / Tetrahedron 63 (2007) 6454–6461
6461
[a]2D5 ꢀ19.3 (c 0.49, MeOH); Rf¼0.30 (MeOH/CH2Cl2 1:7);
1H NMR (500 MHz, CD3OD) d 6.36 (t, J¼7.5 Hz, 1H), 5.77
(dd, J¼10.0, 15.6 Hz, 1H), 5.76 (d, J¼7.9 Hz, 1H), 5.62 (dd,
J¼6.6, 15.6 Hz, 1H), 4.98 (t, J¼7.1 Hz, 1H), 3.76–3.71 (m,
2H), 3.27 (m, 1H), 2.56 (t, J¼6.3 Hz, 2H), 2.49 (t, J¼6.5 Hz,
2H), 2.33 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.85 (s, 3H),
1.85–1.75 (overlapping signals, 5H), 1.67–1.65 (m, 2H),
1.57–1.49 (m, 3H), 1.40–1.38 (m, 1H), 1.06 (d, J¼6.6 Hz,
3H); 13C NMR (75 MHz, CD3OD) d 174.9, 138.0, 137.6,
132.3, 130.9, 128.8, 127.9, 69.5, 67.6, 58.6, 55.0, 53.5,
42.1, 37.2, 35.2, 34.9, 32.5, 29.4, 28.4, 22.4, 20.5, 19.7,
12.9; MS (MALDI) 426.2 [M+H]+; HRMS (MALDI) calcd
for C23H3735Cl NO4 [M+H]+: 426.2406, found: 426.2417.
D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847;
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4.16. 1H NMR of pinnaic acid trifluoroacetate salt
A drop of TFA was added to a CD3OD solution (0.5 mL) of
(presumed) pinnaic acid zwitterion 2, 1H NMR was recorded
1
after 0.5 h. H NMR (500 MHz, CD3OD): d 6.68 (t, J¼
7.9 Hz, 1H), 5.84 (dd, J¼9.0 Hz, 15.7, 1H), 5.74–5.69 (m,
2H), 5.03 (t, J¼7.0 Hz, 1H), 3.77–3.71 (m, 2H), 3.44 (m,
1H), 2.75–2.70 (m, 1H), 2.65–2.58 (m, 1H), 2.55 (t, J¼
6.3 Hz, 2H), 2.50–2.40 (m, 1H), 2.15–2.10 (m, 1H), 2.00–
1.75 (m, 10H), 1.70–1.50 (m, 4H), 1.42 (m, 1H), 1.09 (d,
J¼6.6 Hz, 3H).
6. For synthetic works on pinnaic acid and halichlorine in 2005, see:
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Acknowledgements
We are grateful to National Natural Science Foundation of
China for financial support (nos. 20525208, 203900502,
20532040, and 20672135), QT program and Shanghai
Natural Science Council.
8. Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3542.
9. Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 12079.
Supplementary data
10. (a) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4450; (b)
Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4453.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.03.031.
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