An efficient and enantioselective approach to the azaspirocyclic core of alkaloids: Formal synthesis of halichlorine and pinnaic acid

Article abstract of DOI:10.1021/jo047882v

A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase PS-catalyzed selective acylation, asymmetric methylation

Full text of DOI:10.1021/jo047882v

An Efficient and Enantioselective Approach to the Azaspirocyclic
Core of Alkaloids: Formal Synthesis of Halichlorine and Pinnaic
Acid
Hong-Lu Zhang, Gang Zhao,* Yu Ding,* and Bin Wu
Laboratory of Modern Organic Synthetic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P.R. China
dingyu@mail.sioc.ac.cn
Received November 30, 2004
A novel, highly stereoselective synthesis of an azaspirocyclic core, which contains four stereogenic
carbons consistent with structures of natural halichlorine and pinnaic acid, is presented. Lipase
PS-catalyzed selective acylation, asymmetric methylation on the R-methylene of the bicyclic lactone,
and an asymmetric Michael addition of the tertiary nitro cyclopentane were concisely used to conquer
the challenging problem of successfully constructing the C9 quarternary carbon center with complete
stereocontrol. The spiropiperidine ring was formed by reduction of the δ-nitroketone, intramolecular
condensation, and then highly stereoselective reduction of the cyclic nitrone with NaBH4. This
spirocyclic core is a key intermediate in Danishefsky’s synthesis of pinnaic acid and halichlorine.
Introduction
The naturally occurring marine alkaloids halichlorine
1 and pinnaic acid 2 (Figure 1) are found in halichondria
okadai kadota and pinna muricata, respectively.1,2 Be-
cause of their biological activity and unique structure, 1
and 2 have garnered much attention from the synthetic
community. Halichlorine 1 is a potent inhibitor of VCAM-
1, which is a potential target for the treatment of
inflammation and coronary heart disease.3 Pinnaic acid
2 is an inhibitor of cPLA2, and so has potential for
treatment of inflammatory disease.4 To date, considerable
effort has been directed toward the total synthesis of the
two compounds.5 Among others, Danishefsky’s group has
reported the total synthesis of halichlorine and pinnaic
acid and assigned simultaneously the stereochemistry at
C13 and C17 of pinnaic acid in a communication.6
Recently, Heathcock’s group reported their total synthe-
ses of (()-halichlorine, (()-pinnaic acid, and (()-tau-
FIGURE 1. Structures of halichlorine and pinnaic acid.
ropinnaic acid.7 Stimulated by the novel structures and
biological activity of these compounds, and with the aim
(5) Recent synthetic works on Pinnaic acid and Halichlorine: (a)
Keen, S. P.; Weinreb, S. M. J. Org. Chem. 1998, 63, 6739. (b) Martin-
Lopez, M. J.; Bermejo, F. Tetrahedron 1998, 54, 12379. (c) Lee, S.; Zhao,
Z. S. Org. Lett. 1999, 1, 681. (d) Lee, S.; Zhao, Z. S. Tetrahedron Lett.
1999, 40, 7921. (e) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999,
40, 8503. (f) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40,
8529. (g) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000,
2, 1847. (h) Shindo, M.; Fukuda, Y.; Shishido, K. Tetrahedron Lett.
2000, 41, 929. (i) Yokota, W.; Shindo, M.; Shishido, K. Heterocycles
2001, 54, 871. (j) Ciblat, S.; Canet, J. L.; Troin, Y. Tetrahedron Lett.
2001, 42, 4815. (k) Ito, T.; Yamazaki, N.; Kibayashi, C. Synlett. 2001,
1506. (l) White, J. D.; Blakemore, P. R.; Korf, E. A.; Yokochi, A. F. T.
Org. Lett. 2001, 3, 413. (m) Fenster, M. D. B.; Patrick, B. O.; Dake, G.
R. Org. Lett. 2001, 3, 2109. (n) Taber, D. F.; Mitten, J. V. J. Org. Chem.
2002, 67, 3847. (o) Hayakawa, I.; Arimoto, H.; Uemura, D. Heterocycles
2003, 59, 441. (p) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org Lett.
2003, 5, 3249. (q) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org Lett.
2004, 6, 965. (r) Takasu, K.; Ohsato, H.; Ihara, M. Org Lett. 2003, 5,
3017.
* Author to whom correspondence should be addressed. Fax: 86-
21-64166128.
(1) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867.
(2) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871.
(3) Postigo, A. A.; Teixido, J.; Sanchezmadrid, F. Res. Immunol.
1993, 144, 723.
(4) Nevalainen, T. J. Clin. Chem. (Washington, DC) 1993, 39, 2453.
10.1021/jo047882v CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/26/2005
4954
J. Org. Chem. 2005, 70, 4954-4961

Synthesis of Azaspirocyclic Core of Alkaloids
SCHEME 1a
FIGURE 2. Retrosynthetic analysis of azaspirocyclic core 3.
a Reaction conditions: (a) (i) NBS, H2O, rt, 2.5 h, (ii) NaOH,
H2O, 2-10 °C, 3 h, 65% over two steps; (b) Na, CH2(CO2Me)2,
MeOH, reflux, 6 h, 89%; (c) 2 eq. LiCl, 1 eq. H2O, DMSO, 140 °C,
3 h, 82%; (d) 5% Lipase PS, 2 eq. vinyl acetate, rt, 48 h, 43% for
(+) 6, 99.5% ee for (+) 6, 48% for 7; (e) MsCl, Et3N, DMAP, CH2Cl2,
0 °C to room temperature; (f) 5% aqueous NaOH, THF, 0 °C, 24
h, 89% over two steps; (g) LDA, MeI, THF, -78 °C, 6 h, 77%; (h)
LiAlH4, THF, reflux, 4 h; (i) 1.2 eq. BnBr, 1.3 eq. NaH, THF, rt,
10 h, 80% over two steps; (j) PCC, CH2Cl2, rt, 4 h, 90%.
to further confirm the absolute configuration in pinnaic
acid and to contribute a more efficient route to it, we
initiated a program to synthesize these two alkaloids with
complete stereocontrol. The key in the total synthesis of
halichlorine and pinnaic acid is the construction of the
azaspirocyclic core 3.
Three contiguous stereogenic carbons C9, C13, and C14
make the synthesis challenging, particularly the C9
which is a spirochiral center. We report herein the
methods we have developed for concisely dealing with
this challenge. The retrosynthetic scheme is shown in
Figure 2. Our strategy involves Lipase PS-catalyzed
irreversible transesterification to prepare the optical
intermediate (+) 68 with the desired configuration at C13;
asymmetric methylation of the bicyclic lactone 8 to
introduce the chiral center at C14; and asymmetric
Michael addition of the nitrocyclopentane 13 to install
the chiral spirocenter C9. Finally, the spiropiperidine
ring can be constructed through nitro reduction of 18,
followed by intramolecular condensation with simulta-
neous formation of the stereogenic C5.
the desired product (+) 6 (43% yield, 99.5% ee),11 which
was converted to the bicyclolactone 8 (89% yield) through
mesylation, hydrolysis, and cyclization.
Substrate-induced asymmetric methylation of the bi-
cyclolactone 8 using LDA as base at -78 °C led to 9 in
77% yield. Reduction of 9 with LiAlH4, followed by
regioselective protection of the primary alcohol with
benzylbromide, provided 10 (80% over two steps), which
was directly oxidized in 90% yield to the cyclopentanone
11 using PCC in CH2Cl2. Thus, the construction of two
stereogenic carbons C13 and C14 was completed. This
method for the preparation of optical cyclopentanone 11
with two adjacent stereocenters is very efficient and the
cyclopentanone can be prepared in large scale.
To construct the piperidine ring with a chiral spiro-
center, the strategy of intramolecular condensation be-
tween the amine and the carbonyl group was adopted.
The synthesis of the key intermediate 18, which is the
precursor for the intramolecular condensation and the
piperidine ring formation, is shown in Scheme 2. The
cyclopentanone 11 was transformed to a pair of nitro
cyclopentane 13 diastereoisomers through oxime 12 in
74% yield (two steps). m-CPBA was used for the oxidation
of oxime 12 instead of 90% hydrogen peroxide to avert a
potential explosion danger,12 although the yield might be
lower. The nitro cyclopentane 13 is a good donor for
Michael addition and did add successfully to methyl
acrylate. It is interesting that the nitroester 14 is
produced as a single diastereoisomer in high yield.13 The
Results and Discussion
The cyclopentene 4 (Scheme 1) was treated with
N-bromosuccinimide (NBS) in water and then with
aqeous NaOH at 2-10 °C to afford the epoxide 5 in 65%
yield.8 The epoxide 5 was opened with sodium malonic
ester to give the trans-diester,9 which was decarboxlated
in the presence of LiCl and water in DMSO at 140 °C to
give (() 6 in 82% yield.10 Selective acylation of (() 6
under the control of Lipase PS in vinyl acetate produced
(6) (a) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3542. (b) Trauner, D.; Danishefsky, S. J. Tetrahedron
lett. 1999, 40, 6513.(c) Trauner, D.; Churchill, D. G.; Danishefsky, S.
J. Helv. Chim. Acta 2000, 83, 2344. (d) Carson, M. W.; Kim, G.;
Hentemann, M. F.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4450. (e) Carson, M. W.; Kim, G.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4453.
(7) Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 12079-12084
(11) Hashimoto, S.; Miyazaki, Y.; Ikegami, S. Synth. Commun. 1992,
22, 2717.
(12) (a) Iffland, D. C.; Criner, G. X. J. Am. Chem. Soc. 1953, 75,
4047. (b) Barners, M. W. J. Org. Chem. 1976, 41, 733. (c) Corey, E. J.;
Estreicher, H. Tetrahedron Lett. 1980, 21, 1117. (d) Waters, T. R.;
Zajac, W. W.; Woods, J. M. J. Org. Chem. 1991, 56, 316. (e) Marchand,
A. P.; Sharma, R.; Zope, U. R. J. Org. Chem. 1993, 58, 759.
(8) Goodman, L.; Benitez, A.; Baker, B. R. J. Am. Chem. Soc. 1958,
80, 1680.
(9) Grigsby, W. E.; Hind, J.; Chanley, J.; Westheimer, F. H. J. Am.
Chem. Soc. 1942, 64, 2606.
(10) Krapcho, A. P. Synthesis 1982, 805.
J. Org. Chem, Vol. 70, No. 13, 2005 4955

Zhang et al.
SCHEME 2a
SCHEME 3a
a Reaction conditions: (a) Raney-Ni, MeOH, 5 atm H2; (b) Ni2B,
NH2NH2‚H2O, EtOH, refux, 2 h, 72%; (c) NaBH4, MeOH, 0 °C to
room temperature, 96%; (d) TiCl3, NaOAc, MeOH, H2O, rt, 1.5 h,
79%.
a Reaction conditions: (a) NH2OH•HCl, K2CO3, MeOH, rt, 4 h,
97%; (b) m-CPBA, Na2HPO4, crushed urea, MeCN, 80 °C, 76%;
(c) methyl acrylate, Triton B, t-BuOH, THF, rt, 48 h, 95%; (d)
NaBH4, dioxane/H2O 1:1, rt, 24 h, 84%; (e) MsCl, Et3N, DMAP,
CH2Cl2, 0 °C to room temperature, 2 h; (f) NaI, NaHCO3, acetone,
rt, 24 h, 77% over two steps; (g) 17, 1.5 eq. t-BuLi, 3 eq. HMPA,
-78 °C, 40 min, 99%; (h) MeI, CaCO3, MeCN/H2O 4:1, rt, 24 h,
91%.
FIGURE 3. Stereoselectivity of cyclic nitrone 23 reduction
with NaBH4.
shown in Scheme 3, TBS was also partially cleaved, and
two benzyl deprotected products 20 and 21 were obtained.
To avoid these deprotection problems, 19 was reduced
using freshly prepared Ni2B as the catalyst and hydra-
zine hydrate as the hydrogen donor in EtOH,16 but
surprisingly only spiro-2,3,4,5-tetrahydropyridine N-ox-
ide 23 was produced instead of the expected spiropiperi-
dine 22. This may be because the intramolecular con-
densation to cyclonitrone 23 occurred more quickly than
reduction of the nitro group. Although we optimized the
reaction conditions, compound 23 was still the only
product.
stereochemistry of the newly formed quarternary carbon
in 14 has tentatively been assigned and its structure is
depicted in Scheme 2, in view of the likelihood of the
acrylate approaching from the less hindered side of 13.
This stereochemical assignment was later confirmed by
NOE and by X-ray crystallography. Reduction of the
nitroester 14 with NaBH4 to give the nitro alcohol 15 in
84% yield, followed by mesylation and iodination, led to
the iodide 17 (77% over two steps). Metalation of the
dithiane 1714 with t-BuLi and alkylation with the iodide
16 afforded 18 in high yield,15 but when n-BuLi was used
as a base, the reaction was reluctant to proceed. Removal
of the dithiolane by exposure of 18 to MeI and CaCO3 in
MeCN/H2O (4:1) gave the ketone 19 that is the critical
precursor for the piperidine ring cyclization.
To form the piperidine ring by intramolecular conden-
sation of δ-aminoketone, the tertiary nitro group in 19
has to be reduced to an amino group. When 19 was
hydrogenated in the presence of Pd/C, the nitro group
was intact, but both the benzyl and TBS groups were
cleaved. Although Raney-Ni could reduce the nitro group
and gave the desired spiropiperidine core structure as
Reduction of the cyclic nitrone 23 with NaBH4 in
MeOH gave the desired diastereoisomer 24 exclusively.17
We think the excellent selectivity was mainly attributed
to hydride attack from the less hindered face as shown
in Figure 3. Therefore, although compound 19 was not
directly reduced to product 22, compounds 23 and 24
could be obtained in high yield, and the reaction condi-
tions (for the reduction of 23) are mild and very simple.
18
The hydroxyl group in 24 was reduced with TiCl3 to
afford the desired product 25. Notably, in this case, the
TBS and benzyl protecting groups were not attacked.
(13) Gardiner, J. M.; Bryce, M. R.; Bates, P. A.; Hursthouse, M. B.
J. Org. Chem. 1990, 55, 1261.
(16) (a) Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986, 51, 4294.
(b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 764.
(17) (a) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J.
M.; Tata, J. R. J. Am. Chem. Soc. 2001, 123, 3239. (b) Overman, L. E.;
Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983, 105, 5373.
(18) Yamada, K.; Kishikawa, K.; Yamamoto, M. J. Org. Chem. 1987,
52, 2327.
(14) Tarnchompoo, B.; Thebtaranonth, Y. Tetrahedron Lett. 1984,
25, 5567.
(15) Smith, A. B., III; Condon, S. M.; Mccauley, J. A.; Leazer, J. L.,
Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119,
947.
4956 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of Azaspirocyclic Core of Alkaloids
SCHEME 4a
Since intermediate 3 has already been transformed
into pinnaic acid6d,e and compound 27 can be transformed
to halichlorine,5q,6a the formal synthesis of pinnaic acid
and halichlorine is complete.
Summary
In conclusion, we have presented herein an efficient
and highly stereoselective synthesis of an azaspirocyclic
core, which contains four stereogenic carbons consistent
with the structure of natural halichlorine and pinnaic
acid. Mild conditions, excellent stereoselectivity, and high
yields in construction of four stereogenic carbons are
featured in this synthesis. A formal synthesis of hali-
chlorine and pinnaic acid was completed.
Experimental Section
Cyclopentene oxide (5) and (()-(trans-2-hydroxy-cyclopen-
tyl)-acetic acid methyl ester (() 6 were prepared according to
the previously described procedure.8-11
a Reaction conditions: (a) (CF3CO)2O, (iPr)2NEt, CH2ClCH2Cl,
0 °C, 40 min, 84%; (b) HF‚Py, THF, rt, 24 h, 88%; (c) p-iodobenzoic
acid, DCC, DMAP, CH2Cl2, rt, 71%.
(1R, 2S)-(trans-2-Hydroxy-cyclopentyl)-1-acetic Acid
Methyl Ester (+6).11 A solution of (() 6 (35.0 g, 221 mmol)
in vinyl acetate (41 mL, 442 mmol) was incubated with Lipase
PS (1.8 g, 0.05 mass eq.) at room temperature with stirring
for 48 h. Filtration and evaporation in vacuo furnished the
crude product, which was purified by column chromatography
(silica gel, EtOAc/Hexanes 1:3) to give the acetate 7 (21.3 g,
48%) and the alcohol (+) 6 (15 g, 43%, 99.5% ee, analytical
sample was converted to benzoate and determined by HPLC
on Chiralcel OD column, eluent: Vhexane:Vi-PrOH 10:1) as
colorless oil.
SCHEME 5a
[R]20D + 43.5 (c 1.12, MeOH); Rf 0.66 (EtOAc/Hexanes 1:3);
1H NMR (300 MHz, CDCl3) δ 3.84 (q, J ) 6.3 Hz, 1H), 3.69 (s,
3H), 3.32 (s, 1H), 2.44 (d, J ) 2.5 Hz, 1H), 2.42 (s, 1H), 2.08
(dd, J ) 7.5, 15.8 Hz, 1H), 2.01-1.91 (m, 2H), 1.77-1.55 (m,
3H), 1.22 (ddd, J ) 8.1, 12.5, 16.5 Hz, 1H).
(4R, 8S)-Hexahydro-cyclopenta[b]furan-2-one (8). The
alcohol (+) 6 (5.6 g, 35.3 mmol), Et3N (9.8 mL, 70.6 mmol),
and DMAP (100 mg) were dissolved in CH2Cl2 (60 mL) at 0
°C, and methanesulfonyl chloride (4.2 mL, 52.9 mmol) was
added dropwise with stirring. The reaction mixture was stirred
at 0 °C for 1 h, allowed to warm to room temperature, and
poured into 5% aqueous NaHCO3. Extraction with CH2Cl2 and
removal of solvent gave the crude mesylate, which was then
directly dissolved in THF (180 mL) at 0 °C without further
purification, and then 5% aqueous sodium hydroxide (90 mL)
was added dropwise. After stirring for 24 h at 0 °C, concen-
trated hydrochloric acid was added to acidify to pH ) 3, the
organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo, and the crude product
was purified by column chromatography (silica gel, EtOAc/
Hexanes 2:5) to give the bicyclolactone 8 (3.9 g, 89%) as
colorless oil.
a Reaction conditions: (a) PCC, Celite, CH2Cl2, rt, 93%; (b)
triethyl-2-phosphonopropionate, NaH, THF, 0 °C to room temper-
ature, 90%; (c) TMSI, CH2Cl2, rt, 83%; (d) BBr3, CH2Cl2, -78 °C,
91%.
The stereochemistry of 27 was established by single-
crystal X-ray structure analysis of its p-iodo-benzoate 28
(its ORTEP drawing of the X-ray structure is shown in
the Supporting Information), which was prepared by
N-acylation with trifluoroacetic anhydride, deprotection
of the TBS group, and transformation to derivative 28
(Scheme 4).19
With substrate 27 in hand, we extended its upper side
chain by olefination. The (E)-C2-C3 double bond could
be easily constructed by a Horner-Wadworth-Emmons
reaction, and the yield reached 90%. Subsequent removal
of the benzyl group using TMSI in CH2Cl2 at room
temperature resulted in an undesired product in high
yield, which was proven to be a seven-membered semi-
ketal, 31 (1HNMR, IR, 19FNMR). Its easy formation could
be attributed to the high elecrophilicity of the trifluoro-
acetyl group. By using BBr3 in CH2Cl2 at -78 °C instead
of TMSI, the desired compound 3 was obtained smoothly
(Scheme 5).
[R]20D + 59.7 (c 1.28, MeOH); Rf 0.64 (EtOAc/Hexanes 1:2);
IR (film) νmax 2961, 2872, 1773, 1177, 984 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.01 (t, J ) 5.3 Hz, 1H), 2.92-2.82 (m, 1H),
2.79, (d, J ) 10.3 Hz, 1H), 2.29 (d, J ) 17.5 Hz, 1H), 2.07-
2.02 (m, 1H), 1.90-1.66 (m, 4H), 1.58-1.51 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 177.7, 86.3, 37.8, 35.9, 33.4, 33.3, 23.3; MS
(EI) m/z 126 (M+, 12.94%), 98 (49.59), 97 (58.75), 80 (42.07),
67 (100), 54 (68.47); HRMS (EI) calcd for C7H10O2 (M+)
126.0681, found 126.0677.
(3R, 4R, 8S)-3-Methyl-hexahydro-cyclopenta[b]furan-
2-one (9). To a solution of lithium diisopropylamide, prepared
from a solution of diisopropylamine(4.9 mL, 35.1 mmol) in 120
mL of THF and n-BuLi (1.6 M in hexanes, 20 mL, 32.4 mmol)
at -78 °C, was added a solution of lactone 8 (3.4 g, 27 mmol)
in THF (10 mL). After stirring for an additional 30 min at -78
°C, MeI (1.8 mL, 28.4 mmol) was added. The reaction mixture
(19) Caldwell, C. G.; Rupprecht, K. M.; bondy, S. S.; Davis, A. A. J.
Org. Chem. 1990, 55, 2355.
J. Org. Chem, Vol. 70, No. 13, 2005 4957

Zhang et al.
was stirred at -78 °C for 6 h, quenched with water, and
acidified with concentrated hydrochloric acid to pH ) 3-4; the
organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined extracts were dried (Na2-
SO4), concentrated, and purified by flash chromatography
(silica gel, EtOAc/Hexanes 2:5) to afford 9 (2.9 g, 77%) as
colorless oil.
column chromatography (silica gel, EtOAc/Hexanes 2:5) to give
oxime 12 (3.7 g, 97%) as colorless oil.
[R]20 + 53.6 (c 1.41, CHCl3); Rf 0.67 (EtOAc/Hexanes 2:5);
D
1
IR (film) νmax 3313, 2960, 1454, 1092, 914, 736, 698 cm-1; H
NMR (300 MHz, CDCl3) δ 9.28 (br, 1H), 7.34-7.23 (m, 5H),
4.52 (d, J ) 11.9 Hz, 1H), 4.46 (d, J ) 12.2 Hz, 1H), 3.39 (qd,
J ) 7.5, 9.3 Hz, 2H), 2.79-2.61 (m, 2H), 2.39-2.21 (m, 2H),
1.86-1.71 (m, 2H), 1.59-1.45 (m, 2H), 0.86 (d, J ) 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 169.8, 140.6, 130.3, 129.5,
129.4, 76.2, 74.8, 46.6, 35.6, 29.8, 28.2, 24.5, 14.6; MS (EI) m/z
247 (M+, 3.19%), 230 (5.69), 189 (9.85), 156 (16.83), 126 (26.69),
99 (83.51), 91 (100), 67 (10.55); Anal. Calcd for C15H21NO2
(247.16): C, 72.84; H, 8.56; N, 5.66. Found: C, 72.77; H, 8.66;
N, 5.46.
(1R, 1′R)-1-(2′-Benzyloxy-1′-methyl-ethyl)-2-nitro-cy-
clopentane (13). A mixture of oxime 12 (3.7 g, 14.9 mmol),
anhydrous dibasic sodium phosphate (17.7 g, 124.6 mmol),
crushed urea (4.8 g, 81.5 mmol), and dry MeCN (200 mL) was
refluxed for 0.5 h under Ar. Portions of m-CPBA (70-75%,
6.7 g, 28.1 mmol) were then added at intervals of 15 min. After
refluxing for 2 h, the reaction mixture was cooled to room
temperature, filtered, and concentrated to a solid residue,
which was then dissolved in CH2Cl2 (150 mL). The CH2Cl2
solution was washed with saturated aqueous NaHCO3, aque-
ous Na2S2O3 and water, and dried (Na2SO4). After removal of
the solvent in vacuo, the residue was purified by flash
chromatography (silica gel, EtOAc/Hexanes 1:10) to afford 13
(3 g, 76%) as yellow oil.
[R]20 ) +68.6 (c ) 1.64, in MeOH); Rf ) 0.69 (EtOAc/
D
Hexanes 2:5); IR (film) νmax 2964, 2874, 1767, 1191, 984 cm-1
;
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ ) 4.98 (t, J ) 5.5
Hz, 1H), 2.53 (ddd, J ) 3.5, 7.3, 11.1 Hz, 1H), 2.36 (qd, J )
4.1, 7.8 Hz, 1H), 2.04-1.99 (m, 1H), 1.87-1.57 (m, 5H), 1.32
(d, J ) 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ ) 180.8,
84.3, 46.7, 42.4, 33.4, 32.7, 23.4, 17.4; MS (ESI): m/z (%): 141.1
[M + H] +; HRMS (ESI) calcd for C8H12O2Na 163.0730, found
+
163.0736 [M + Na]
.
(1S, 2R, 1′R)-2-(2′-Benzyloxy-1′-methyl-ethyl)-1-cyclo-
pentanol (10). To a stirred cold slurry of lithium aluminum
hydride (1.0 g, 26.3 mmol) in THF (100 mL) was added a
solution of lactone 9 (3.0 g, 21.4 mmol) in THF (10 mL). The
mixture was refluxed for 4 h, quenched with saturated aqueous
ammonium chloride solution (5 mL) under cooling, and con-
centrated. The residue was diluted with water (15 mL) and
extracted with EtOAc, dried (Na2SO4), concentrated to afford
crude alcohol, which was dissolved in THF (50 mL) at 0 °C
without purification, and sodium hydride (60%, 1.1 g, 26.2
mmol) was added. After stirring 30 min, benzyl bromide (2.9
mL, 24.1 mmol) was added dropwise. The resulting solution
was stirred at room temperature for 10 h, quenched with
saturated aqueous ammonium chloride solution (5 mL), ex-
tracted with ethyl acetate, dried (Na2SO4), concentrated, and
purified by flash chromatography (silica gel, EtOAc/Hexanes
1:5) to afford 10 (4 g, 80%) as colorless oil.
Rf 0.68 (EtOAc/Hexanes 1:10); IR (film) νmax 2964, 2876,
1546, 1454, 1373, 1098, 738, 699 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.36-7.24 (m, 5H), 4.93 (t, J ) 5.5 Hz, 0.13H), 4.80
(ddd, J ) 1.8, 4.3, 8.5 Hz, 0.87H), 4.49 (s, 0.3H), 4.42 (s, 1.7H),
3.34 (dd, J ) 2.7, 9.2 Hz, 2H), 2.64 (dq, J ) 7.5, 9.9 Hz, 1H),
2.20 (dq, J ) 4.3, 17.2 Hz, 1H), 2.12-1.61 (m, 5H), 1.38-1.27
(m, 1H), 1.01 (d, J ) 6.8 Hz, 0.4H), 0.96 (d, J ) 6.8 Hz, 2.6H);
13C NMR (75 MHz, CDCl3) δ 138.4, 128.5, 128.4, 127.8, 127.7,
127.6, 89.8, 89.5, 74.4, 73.9, 73.2, 73.1, 49.1, 49.0, 36.5, 34.2,
33.4, 32.1, 29.2, 28.1, 24.3, 22,5, 16.9, 14.7; MS (ESI) 264.2
(M+ + H); Anal. Calcd for C15H21NO3 (263.15): C, 68.42; H,
8.04; N, 5.32. Found: C, 68.47, H, 7.85; N, 5.38.
[R]20 + 13.8 (c 1.22, CHCl3); Rf 0.60 (EtOAc/Hexanes 1:5);
D
IR (film) νmax 3448, 2958, 1454, 1093, 737, 698 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 4.53 (s, 2H), 4.24 (s,
1H), 3.44 (dd, J ) 3.1, 9.0 Hz, 1H), 3.37 (t, J ) 9.0 Hz, 1H),
3.17 (s, 1H), 1.92-1.71 (m, 5H), 1.54-1.38 (m, 3H), 0.91 (d, J
) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 137.8, 128.5, 127.8,
127.7, 77.0, 73.7, 73.5, 53.3, 34.5, 33.9, 28.7, 21.9, 17.3; MS
(EI) m/z 234 (M+, 0.14%), 133 (0.13), 125 (19.81), 110 (16.64),
91 (100), 67 (27.83); Anal. Calcd for C15H22O2 (234.16): C,
76.88; H, 9.46. Found: C, 76.71; H, 9.35.
(1R, 2S, 1′R)-1-(2′-benzyloxy-1′-methyl-ethyl)-2-Nitro-
2-(2′′-methoxycarbonyl-ethyl)- cyclopentane (14). Methyl
acrylate (1.1 mL, 12.2 mmol) and Triton B (40% in MeOH, 0.6
mL) were added to a solution of 13 (3 g, 11.4 mmol) in dry
THF (25 mL) and t-BuOH (50 mL), and the mixture was
stirred under Ar atmosphere at room temperature for 48 h.
The solution was evaporated to a residue, which was subjected
to column chromatography (silica gel, EtOAc/Hexanes 1:5) to
give nitroester 14 (3.8 g, 95%) as colorless oil.
(2R, 1′R)-2-(2′-Benzyloxy-1′-methyl-ethyl)-cyclopen-
tanone (11). The alcohol 10 (4 g, 17.1 mmol) in CH2Cl2 (15
mL) was added to a mixture of PCC (8 g, 37.2 mmol) and Celite
(8 g) in CH2Cl2 (150 mL). After stirring at room temperature
for 4 h, the mixture was diluted with hexanes (100 mL) and
filtered through a short silica gel column. The filtrate was
concentrated and purified by flash chromatography (silica gel,
EtOAc/Hexanes 1:5) to afford cyclopentanone 11 (3.6 g, 90%)
as colorless oil.
[R]20D + 115.6 (c 1.10, CHCl3); Rf 0.71 (EtOAc/Hexanes 1:5);
IR (film) νmax 2962, 2876, 1735, 1098, 737, 698 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 4.53 (d, J ) 12.4 Hz,
1H), 4.46 (d, J ) 11.9 Hz, 1H), 3.40 (dd, J ) 6.0, 9.3 Hz, 1H),
3.35 (dd, J ) 7.8, 9.3 Hz, 1H), 2.47-2.26 (m, 3H), 2.05-1.94
(m, 3H), 1.73-1.60 (m, 2H), 0.78 (d, J ) 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 221.0, 138.6, 128.4, 127.6, 127.5, 73.8, 72.8,
50.9, 39.0, 32.3, 24.2, 20.7, 12.9; MS (EI) m/z 232 (M+, 2.76%),
190 (5.25), 174 (5.76), 141 (9.18), 91 (100), 84 (26.96), 55
(27.75); Anal. Calcd for C15H20O2 (232.15): C, 77.55; H, 8.68.
Found: C, 77.43; H, 8.49.
[R]20 + 27.6 (c 0.98, CHCl3); Rf 0.44 (EtOAc/Hexanes 1:5);
D
IR (film) νmax 2952, 2877, 1740, 1532, 738, 699 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.34-7.27 (m, 5H), 4.52 (d, J ) 11.9 Hz,
1H), 4.44 (d, J ) 12.0 Hz, 1H), 3.66 (s, 3H), 3.40 (dd, J ) 5.0,
9.4 Hz, 1H), 3.24 (dd, J ) 6.8, 9.3 Hz, 1H), 2.85-2.75 (m, 1H),
2.52 (ddd, J ) 5.7, 9.1, 14.4 Hz, 1H), 2.35 (t, J ) 8.0 Hz, 2H),
2.20 (ddd, J ) 4.2, 7.3, 11.7 Hz, 1H), 2.11-1.60 (m, 7H), 0.75
(d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.9, 138.4,
128.4, 127.6, 127.5, 99.2, 74.6, 72.9, 51.8, 51.7, 35.7, 32.8, 32.1,
29.9, 26.2, 22.1, 13.7; MS (ESI) 372.3 (M+ + Na); Anal. Calcd
for C19H27NO5 (349.19): C, 65.35; H, 7.79; N, 4.01. Found: C,
65.42; H, 7.65; N, 3.91.
(1R, 2S, 1′R)-1-(2′-Benzyloxy-1′-methyl-ethyl)-2-(3′′-hy-
droxypropyl)-2-nitro-cyclopentane (15). To a stirred solu-
tion of the nitroester 14 (299 mg, 0.86 mmol) in dioxane-water
(1:1, 10 mL) was added NaBH4 (0.46 g, 12 mmol) in small
portions, and stirring was continued for 24 h at room temper-
ature. The mixture was acidified with HCl (18%) under ice
cooling and extracted with ether. The combined ether extracts
were concentrated to a residue, which was treated with a
solution of NaOH (100 mg) in EtOH/H2O (10 mL/3 mL). The
mixture was heated to reflux for 2 h. After removal of the
solvents, water was added and the mixture was extracted with
(2R, 1′R)-2-(2′-Benzyloxy-1′-methyl-ethyl)-cyclopen-
tanone oxime (12). To a solution of cyclopentanone 11 (3.57
g, 15.4 mmol) in MeOH (50 mL) at room temperature was
added hydroxylamine hydrochloride (1.6 g, 23.1 mmol) and K2-
CO3 (3.2 g, 23.1 mmol). The resulting mixture was stirred at
room temperature for 4 h, diluted with water, and extracted
with EtOAc. The extracts were dried (Na2SO4) and concen-
trated in vacuo to give a residue, which was subjected to
4958 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of Azaspirocyclic Core of Alkaloids
EtOAc. The organic phase was washed with water and brine
and then dried (Na2SO4), concentrated, and purified by flash
chromatography (silica gel, EtOAc/Hexanes 1:2) to afford nitro
alcohol 15 (230 mg, 84%) as colorless oil.
H2O (4:1, 150 mL) at room temperature was added MeI (25
mL, 394.5 mmol) and CaCO3 (2.63 g, 26.3 mmol). The resulting
mixture was stirred at room temperature for 24 h. The organic
phase was separated, the aqueous phase was extracted with
EtOAc, and the combined extracts were dried (Na2SO4) and
concentrated in vacuo to give a residue, which was subjected
to column chromatography (silica gel, EtOAc/Hexanes 1:5) to
give 19 (1.06 g, 91%) as a colorless oil.
[R]20 + 36.2 (c 1.26, CHCl3); Rf 0.38 (EtOAc/Hexanes 1:2);
D
IR (film) νmax 3395, 2958, 2875, 1530, 1097, 738, 699 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 4.51 (d, J ) 12.1
Hz, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 3.64-3.54 (m, 2H), 3.39
(dd, J ) 5.0, 9.3 Hz, 1H), 3.24 (dd, J ) 7.2, 9.2 Hz, 1H), 2.61-
2.42 (m, 2H), 2.20 (ddd, J ) 3.9, 7.5, 11.7 Hz, 1H), 2.08-1.98
(m, 3H), 1.91-1.81 (m, 1H), 1.77-1.45 (m, 6H), 0.74 (d, J )
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.3, 128.3, 127.5,
127.4 99.8, 74.7, 72.7, 62.3, 51.3, 35.5, 33.9, 31.7, 28.0, 25.7,
22.0, 13.4; MS (ESI) 344.2 (M+ + Na); Anal. Calcd for C18H27-
NO4 (321.19): C, 67.26; H, 8.47; N, 4.36. Found. C, 67.05; H,
8.41; N, 4.29.
[R]20 + 23.9 (c 0.91, CHCl3); Rf 0.53 (EtOAc/Hexanes 1:5);
D
IR (film) νmax 2955, 2856, 1716, 1532, 1096, 836 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.46 (d, J ) 12.3 Hz,
1H), 4.41 (d, J ) 11.9 Hz, 1H), 3.82 (t, J ) 6.3 Hz, 2H), 3.33
(dd, J ) 5.0, 9.2 Hz, 1H), 3.19 (dd, J ) 7.1, 9.5 Hz, 1H), 2.54-
2.30 (m, 6H), 2.10 (ddd, J ) 3.6, 7.4, 11.7 Hz, 1H), 2.00-1.89
(m, 3H), 1.70-1.47 (m, 6H), 0.83 (s, 9H), 0.68 (d, J ) 6.9 Hz,
3H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 209.2, 138.5,
128.4, 127.6, 127.5, 99.9, 74.8, 72.8, 58.9, 51.5, 45.6, 43.5, 37.1,
35.5, 31.9, 25.9, 25.8, 22.1, 18.8, 18.3, 13.5, -5.4; MS (ESI)
514.2 (M+ + Na); Anal. Calcd for C27H45NO5Si (491.31): C,
65.95; H, 9.22; N, 2.85. Found: C, 66.01; H, 8.85; N, 2.75.
(1R, 2S, 1′R)-1-(2′-Benzyloxy-1′-methyl-ethyl)-2-(3′′-io-
dopropyl)-2-nitro-cyclopentane (16). The above nitro al-
cohol 15 (1 g, 3.12 mmol) and Et3N (0.8 mL, 5.7 mmol) and
DMAP (50 mg) were dissolved in CH2Cl2 (60 mL) at 0 °C, and
methanesulfonyl chloride (0.4 mL, 5.16 mmol) was added
dropwise with stirring. The reaction mixture was stirred at 0
°C for 1 h, allowed to warm to room temperature, and poured
into a solution of 5% aqueous NaHCO3. The methanesulfonate
ester was isolated by extraction with CH2Cl2 and the solvent
was removed. The crude mesylate was then stirred with
sodium iodide (4.2 g, 28 mmol) and NaHCO3 (500 mg, 6 mmol)
in acetone (50 mL) for 24 h at room temperature. After the
solvent was removed in vacuo, the residue was redissolved in
water and extracted with ethyl acetate. The combined organic
phase was dried (Na2SO4), concentrated, and purified by flash
chromatography (silica gel, EtOAc/Hexanes 1:10) to give iodide
16 (1.03 g, 77%) as yellow oil.
(1R, 5S, 7R, 1′R)-1-(2′-tert-butyldimethylsilanyloxy -1′-
methyl-ethyl)-7-(2′′-benzyloxy-1′′-methyl-ethyl)-6-aza-5-
spiro[4.5]dec-6-ene-6-oxide (23). Ni2B catalyst was prepared
according to literature.16 To a solution of 19 (400 mg, 0.81
mmol) in ethanol (16 mL) was added Ni2B (207 mg, 1.62
mmol), and the mixture was heated at 80 °C and then NH2-
NH2‚H2O (85%, 1.5 mL) was added and stirred at 80 °C for 2
h. The catalyst was filtered off and the filtrate was then
concentrated and purified by flash chromatography (silica gel,
EtOAc/Hexanes 1:2) to give 23 (270 mg, 72%) as a colorless
oil.
[R]20 - 68.3 (c 0.95, CHCl3); Rf 0.42 (EtOAc/Hexanes 1:2);
D
IR (film) νmax 3046, 3030, 2954, 2858, 1455, 1255, 1088, 837,
[R]20D + 32.5 (c 1.02, CHCl3); Rf 0.69 (EtOAc/Hexanes 1:10);
IR (film) νmax 2960, 2874, 1530, 1096, 737 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.39-7.26 (m, 5H), 4.55 (d, J ) 12.1 Hz, 1H),
4.47 (d, J ) 11.7 Hz, 1H), 3.44 (dd, J ) 5.0, 9.4 Hz, 1H), 3.28-
3.19 (m, 2H), 3.10 (q, J ) 7.5 Hz, 1H), 2.60-2.47 (m, 2H), 2.20
(ddd, J ) 4.1, 7.3, 11.8 Hz, 1H), 2.06-1.96 (m, 2H), 1.91-1.59
(m, 7H), 0.75 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 138.6, 128.6, 127.8, 127.7, 99.6, 74.8, 73.1, 51.7, 38.9, 36.0,
32.2, 29.0, 26.2, 22.2, 13.9, 6.2; MS (ESI) 453.9 (M+ + Na);
HRMS (ESI) calcd for C18H26INO3Na (M+ + Na) 454.0849,
found 454.0846.
777 cm-1 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 5H),
;
4.50 (d, J ) 11.9 Hz, 1H), 4.43 (d, J ) 12.4 Hz, 1H), 3.95 (dt,
J ) 6.1, 9.9 Hz, 1H), 3.80 (dt, J ) 5.5, 9.8 Hz, 1H), 3.37 (dd,
J ) 4.4, 9.1 Hz, 1H), 3.26 (dd, J ) 4.5, 9.3 Hz, 1H), 2.64-2.38
(m, 5H), 2.25 (ddd, J ) 5.7, 10.6, 19.1 Hz, 1H), 2.01-1.45 (m,
9H), 1.42 (m, 1H), 1.04 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H), 0.04
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 147.9, 138.4, 128.1, 127.5,
127.3, 76.5, 74.4, 72.8, 58.7, 53.4, 40.1, 37.7, 36.1, 33.9, 32.2,
31.2, 25.8, 24.3, 18.0, 17.3, 17.2, -5.5, -5.6; MS (ESI) 460.3
(M+ + H); HRMS (ESI) calcd for C27H45NO3SiNa (M+ + Na)
482.3061, found 482.3062.
(1R, 2S, 1′R)-1-(2′-benzyloxy-1′-methyl-ethyl)-2-nitro-
2-(6′′-tert-butyldimethylsilanyloxy-4′′-[1,3] dithian-hexyl)-
cyclopentane (18). To a solution of dithiane 1714 (1 g, 3.6
mmol) in 100 mL of THF at -78 °C was added t-BuLi (2.4
mL, 3.6 mmol) and HMPA (1.25 mL, 7.2 mmol). After stirring
for an additional 20 min at -78 °C, iodide 15 (1.03 g, 2.4 mmol)
in THF (10 mL) was added dropwise. The reaction mixture
was stirred at -78 °C for 40 min, quenched with saturated
aqueous ammonium chloride solution (5 mL), and extracted
with EtOAc and dried (Na2SO4), concentrated, and purified
by flash chromatography (silica gel, EtOAc/Hexanes 1:10) to
give 18 (1.37 g, 99%) as a colorless oil.
(1R, 5S, 7R, 1′R)-1-(2′-tert-butyldimethylsilanyloxy-1′-
methyl-ethyl)-7-(2′′- benzyloxy-1′′-methyl-ethyl)-6-hydroxy-
6-aza-5-spiro[4.5]decane (24). To nitrone 23 (285 mg, 0.62
mmol) in MeOH (10 mL), NaBH4 (152 mg, 4 mmol) was added
at 0 °C and stirred overnight. The solution was evaporated
and the residue was diluted with water and extracted with
EtOAc. The extracts was washed with water and brine and
dried (Na2SO4), concentrated, and purified by flash chroma-
tography (silica gel, EtOAc/Hexanes 1:10) to afford 23 (275 mg,
96%) as a colorless oil.
[R]20D - 24.7 (c 1.05, CHCl3); Rf 0.41 (EtOAc/Hexanes 1:10);
IR (film) νmax 3416, 2931, 2859, 1255, 1092, 836, 777 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 5.63 (br, 1H),
4.54 (d, J ) 12.2 Hz, 1H), 4.47 (d, J ) 12.2 Hz, 1H), 3.75 (ddd,
J ) 4.3, 7.6, 10.3 Hz, 1H), 3.66 (d, J ) 5.4 Hz, 3H), 2.68 (ddd,
J ) 2.9, 5.8, 8.8 Hz, 1H), 2.11 (dd, J ) 11.4, 20.0 Hz, 2H),
1.87-1.25 (m, 14H), 1.02 (d, J ) 6.9 Hz, 3H), 0.87 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 140.8,
129.9, 129.4, 129.0, 76.9, 74.7, 72.2, 61.8, 61.7, 55.7, 40.9, 38.8,
36.2, 34.2, 33.1, 29.9, 27.7, 25.9, 23.6, 20.0, 19.5, -3.6, -3.8;
MS (ESI) 462.4 (M+ + 1); HRMS (ESI) calcd for C27H48NO3Si
(M+ + H) 462.3398, found 462.3377.
(1R, 5S, 7R, 1′R)-1-(2′-tert-butyldimethylsilanyloxy-1′-
methyl-ethyl)-7-(2′′-benzyloxy-1′′-methyl-ethyl)-6-aza-5-
spiro[4.5]decane (25). 24 (1.2 g, 2.6 mmol) was dissolved in
MeOH (16 mL), and sodium acetate (3.2 g, 39.0 mmol) and
water (9.6 mL) were added. The mixture was stirred under
Ar atmosphere for 10 min, and TiCl3 (30% in 2 N HCl, 4 mL,
[R]20 + 18.5 (c 1.03, CHCl3); Rf 0.74 (EtOAc/Hexanes 1:5);
D
IR (film) νmax 2953, 2856, 1532, 1095, 837, 777 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.29-7.19 (m, 5H), 4.46 (d, J ) 12.2 Hz,
1H), 4.40 (d, J ) 12.2 Hz, 1H), 3.70 (t, J ) 7.2 Hz, 2H), 3.33
(dd, J ) 5.4, 9.3 Hz, 1H), 3.17 (dd, J ) 7.0, 9.6 Hz, 1H), 2.76-
2.69 (m, 4H), 2.50 (ddd, J ) 5.4, 9.2, 14.4 Hz, 1H), 2.34 (dd, J
) 10.6, 13.6 Hz, 1H), 2.09-2.03 (m, 3H), 1.98-1.36 (m, 13H),
0.82 (s, 9H), 0.66 (d, J ) 6.9 Hz, 3H), 0.01 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 138.6, 128.5, 127.7, 127.6, 100.1, 74.8, 72.9,
59.8, 51.8, 51.7, 40.8, 39.6, 38.1, 35.7, 32.1, 26.24, 26.17, 26.1,
25.4, 22.2, 20.1, 18.5, 13.7, -5.1; MS (ESI) 604.1 (M+ + Na);
Anal. Calcd for C30H51NO4S2Si (581.30): C, 61.92; H, 8.83; N,
2.41. Found: C, 61.64; H, 8.70; N, 2.25.
(1R, 2S, 1′R)-1-(2′-benzyloxy-1′-methyl-ethyl)-2-nitro-
2-(6′′-tert-butyldimethylsilanyloxy-4′′-oxo-hexyl)-cyclo-
pentane (19). To a solution of 18 (1.37 g, 2.36 mmol) in MeCN/
J. Org. Chem, Vol. 70, No. 13, 2005 4959

Zhang et al.
10.3 mmol) was added dropwise. After stirring for 1.5 h at room
temperature, the suspension was poured into a solid mixture
of Na2SO4 and Na2CO3 containing water; when the black solid
turned to white, the solid was filtered and washed with EtOAc.
The filtrate was then concentrated and purified by flash
chromatography (silica gel, MeOH/CHCl3 1:10) to afford 25
(910 mg, 79%) as a yellow oil.
and the reaction mixture was stirred at room temperature
overnight and then stirred for 1 h with water (2 mL) and
filtered. The precipitate was washed with ether. The combined
organic phase was concentrated and purified by flash chro-
matography (silica gel, EtOAc/ Hexanes 1:10) to give 28 (110
mg, 71%) as a white solid.
Mp 153.9 ( 0.5 °C; [R]20 - 26.2 (c 0.82, CHCl3); Rf 0.73
D
[R]20 -29.4 (c 1.14, CHCl3); Rf 0.50 (MeOH/CHCl3 1:20);
(EtOAc/Hexanes 1:5); IR (KBr) νmax 1715, 686, 1196, 1275,
D
IR (film) νmax 3342, 2931, 2858, 1255, 1095, 836, 776 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 4.50 (d, J ) 1.2
Hz, 2H), 3.66 (q, J ) 5.9 Hz, 2H), 3.51 (dd, J ) 5.9, 9.0 Hz,
1H), 3.33 (t, J ) 8.1 Hz, 1H), 2.76-2.73 (m, 1H), 2.05 (m, 1H),
1.77-1.22 (m, 16H), 0.96 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H),
0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6,
129.6, 128.9, 128.7, 77.9, 77.5, 74.1, 64.4, 62.3, 53.2, 50.5, 41.8,
38.0, 37.3, 34.5, 33.5, 28.7, 27.4, 24.2, 23.9, 19.7, 17.5, -3.93,
-3.95; MS (ESI) 446.3 (M+ + H); HRMS (ESI) calcd for C27H48-
NO2Si (M+ + H) 446.3449, found 446.3445.
1
1134 cm-1; H NMR (300 MHz, CDCl3) δ 7.83 (d, J ) 8.6 Hz,
2H), 7.70 (d, J ) 9.0 Hz, 2H), 7.34-7.25 (m, 5H), 4.54 (d, J )
11.9 Hz, 1H), 4.26 (d, J ) 12.1 Hz, 1H), 4.20 (t, J ) 5.8 Hz,
1H), 4.17 (dd, J ) 4.4, 9.2 Hz, 1H), 4.06 (d, J ) 11.3 Hz, 1H),
3.34 (d, J ) 3.8 Hz, 2H), 2.23 (dd, J ) 6.3, 13.0 Hz, 1H), 2.16
(dd, J ) 7.9, 13.0 Hz, 1H), 2.00 (dd, J ) 8.8, 14.2 Hz, 2H),
1.91-1.52 (m, 11H), 1.39-1.30 (m, 1H), 0.96 (d, J ) 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 159.1 (q, JF,CdO ) 34
Hz), 140.0, 139.2, 132.3, 130.7, 129.7, 129.4, 129.0, 120.4 (q,
JF,C ) 287 Hz), 102.3, 77.0, 74.6, 70.5, 63.6, 56.0, 52.6 (d, JF,C
) 3 Hz), 37.2, 35.2, 35.1, 34.7, 32.1, 25.9, 24.3, 18.1, 15.3; MS
(ESI) 680.1 (M+ + Na); Anal. Calcd for C30H35F3INO4
(657.16): C, 54.80; H, 5.37; N, 2.13. Found: C, 54.85; H, 5.36;
N, 2.11.
(1R, 5S, 7R, 1′R)-1-(2′-tert-butyldimethylsilanyloxy-1′-
methyl-ethyl)-7-(2′′-benzyloxy-1′′-methyl-ethyl)-6-trifluo-
roacetyl-6-aza-5-spiro[4.5] decane (26). The secondary
amine 25 (770 mg, 1.73 mmol) and diisopropylethylamine (6.2
mL, 34.6 mmol) were dissolved in CH2ClCH2Cl (30 mL) at 0
°C, and trifluoro acetic anhydride (4.8 mL, 34.6 mmol) was
added dropwise with stirring. The reaction mixture was stirred
at 0 °C for 40 min, quenched with saturated aqueous NaHCO3,
and diluted with CH2Cl2 (150 mL); the organic phase was
washed with brine and dried (Na2SO4), concentrated, and
purified by flash chromatography (silica gel, EtOAc/Hexanes
1:10) to afford 26 (790 mg, 84%) as a colorless oil.
(1′R, 5′S, 7′R, 1′′R)-4-{1′-[2′′-benzyloxy-1′′-methyl-ethyl]-
6′-trifluoroacetyl-6′-aza-5′-spiro [4.5]dec-7′-yl}-2-methyl-
but-2E-enoic Acid Ethyl Ester (30). The alcohol 27 (140 mg,
0.33 mmol) in CH2Cl2 (18 mL) was added to a mixture of PCC
(355 mg, 1.65 mmol) and Celite (500 mg). After stirring at room
temperature for 2 h, the mixture was diluted with hexanes
(50 mL) and filtered through a short silica gel column. The
filtrate was concentrated and purified by flash chromatography
(silica gel, EtOAc/Hexanes 1:2) to afford aldehyde 29 (130 mg,
93%) as a colorless oil. To sodium hydride (60%, 25 mg, 0.61
mmol) was added triethyl-2-phosphonopropionate (183 mg,
0.76 mmol) in THF (5 mL) at 0 °C. After stirring for 30 min,
aldehyde 29 (130 mg, 0.30 mmol) in THF (2 mL) was added.
After 20 min, the mixture was warmed to room temperature
and reacted for 1 h and saturated ammonium chloride was
added to the solution and extracted with ethyl acetate. The
extract was washed with water and brine, and dried (Na2SO4),
concentrated, and purified by flash chromatography (silica gel,
EtOAc/Hexanes 1:10) to afford 30 (141 mg, 90%) as a colorless
oil.
[R]20D - 21.6 (c 0.95, CHCl3); Rf 0.70 (EtOAc/Hexanes 2:10);
IR (film) νmax 1712, 1690, 1652, 1260, 1200, 1139 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.35-7.32 (m, 5H), 6.54 (t, J ) 7.2 Hz,
1H), 4.48 (q, J ) 12.6 Hz, 2H), 4.22 (q, J ) 7.1 Hz, 2H), 3.92
(d, J ) 9.3 Hz, 1H), 3.40-3.32 (t, J ) 4.8 Hz, 2H), 2.59-2.37
(m, 2H), 2.25-2.05 (m, 3H), 1.86-1.57 (m, 14H), 1.28 (t, J )
7.2 Hz, 3H), 0.96 (d, J ) 6.3 Hz, 3H); 19F NMR(200 MHz,
CDCl3): δ -69.02; 13C NMR (75 MHz, CDCl3) δ 167.7, 162.4,
157.4 (q, JF,CdO ) 34 Hz), 138.6, 136.6, 130.2, 128.3, 127.6,
117.0 (q, JF,C ) 287 Hz), 75.8, 73.2, 69.2, 60.7, 54.6, 53.1 (t,
JF,C ) 3.5 Hz), 35.6, 34.8, 34.3, 33.4, 30.6, 24.5, 23.3, 16.7, 14.3,
14.1, 12.7; MS (ESI) 532.3 (M+ + Na); HRMS (ESI) calcd for
C28H38F3NO4Na (M+ + Na) 532.2645, found 532.2647.
[R]20D - 36.0 (c 1.10, CHCl3); Rf 0.64 (EtOAc/Hexanes 1:10);
IR (film) νmax 2954, 2859, 1687, 1199, 1143, 1100, 836, 777
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.30-7.29 (m, 5H), 4.49
(d, J ) 12.0 Hz, 1H), 4.38 (d, J ) 12.1 Hz, 1H), 4.04 (d, J )
13.3 Hz, 1H), 3.50 (ddd, J ) 5.7, 10.5, 19.7 Hz, 2H), 3.35 (dd,
J ) 4.0, 8.9 Hz, 1H), 3.29 (dd, J ) 5.6, 8.9 Hz, 1H), 2.18 (dd,
J ) 6.5, 12.9 Hz, 1H), 2.10 (dd, J ) 7.6, 12.9 Hz, 1H), 1.90-
1.45 (m, 13H), 1.31-1.22 (m, 1H), 0.91 (d, J ) 6.6 Hz, 3H),
0.85 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 158.0 (q, JF,CdO )34 Hz), 139.4, 128.9, 128.4, 128.1,
117.6 (q, JF,C ) 287 Hz), 76.1, 73.6, 69.6, 60.9, 55.1, 52.3 (d,
JF,C ) 3 Hz), 38.1, 36.4, 34.8, 33.9, 31.5, 26.4, 25.2, 23.7, 18.8,
17.5, 14.7, -4.9, -5.0; MS (ESI) 542.3 (M+ + H); HRMS (ESI)
calcd for C29H46F3NO3SiNa (M+ + Na) 564.3091, found 564.3097.
(1R, 5S, 7R, 1′R)-1-(2′-hydroxy-1′-methyl-ethyl)-7-(2′′-
benzyloxy-1′′-methyl-ethyl)-6-trifluoroacetyl-6-aza-5-
spiro [4.5]decane (27). To a solution of 26 (780 mg, 1.44
mmol) in THF (10 mL) was added HF‚Py (1 M, 1.8 mL, 1.8
mmol). The mixture was stirred for 24 h at room temperature
and diluted with EtOAc (200 mL). The organic layer was
washed with brine and dried (Na2SO4), concentrated, and
purified by flash chromatography (silica gel, EtOAc/Hexanes
1:2) to afford 27 (540 mg, 88%) as a syrup.
[R]20 - 29.9 (c 1.07, CHCl3); Rf 0.50 (EtOAc/Hexanes 1:2);
D
IR (film) νmax 3460, 2947, 2872, 1686, 1194, 1142 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 4.53 (d, J ) 12.1 Hz,
1H), 4.44 (d, J ) 12.0 Hz, 1H), 4.03-3.99 (m, 1H), 3.53 (dt, J
) 5.8, 11.7 Hz, 2H), 3.37 (dd, J ) 4.1, 8.6 Hz, 1H), 3.31 (dd, J
) 5.7, 8.6 Hz, 1H), 2.24-2.15 (m, 2H), 1.98 (m, 1H), 1.88-
1.49 (m, 12H), 1.34(m, 1H), 1.18 (m, 1H), 0.96 (d, J ) 6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ157.9 (q, JF,CdO ) 34 Hz),
139.4, 128.9, 128.5, 128.1, 117.5 (q, JF,C ) 287 Hz), 76.3, 73.6,
69.7, 60.8, 55.2, 52.0 (q, JF,C ) 3 Hz), 38.4, 36.3, 34.7, 33.9,
31.3, 25.1, 24.1, 17.3, 14.6; MS (ESI) 428.1 (M+ + H); HRMS
(ESI) calcd for C23H32F3NO3Na (M+ + Na) 450.2226, found
450.2226.
(11R, 1′S, 5′R, 6′R)-4-(6′-Methyl-9′-hydroxy-9′-trifluoro-
methyl-8′-oxa-10′-aza-1′-tricyclo[8.4. 0.01′, 5′]tetradec-11′-
yl)-2-methyl-but-2E-enoic Acid Ethyl Ester (31). TMSI
(0.53 mL, 2.60 mmol) was added dropwise to a solution of 30
(1.02 g, 2.00 mmol) in CH2Cl2 (20 mL) at room temperature.
After 40 min, MeOH (0.8 mL) was added to the orange-red
solution. The mixture was diluted with EtOAc and washed
with saturated Na2S2O3, saturated NaHCO3, and brine and
dried over Na2SO4, filtered, concentrated, and purified by flash
chromatography (silica gel, EtOAc/Hexanes 2:5) to give 31 (700
mg, 83%) as a yellow oil.
(1R, 5S, 7R, 1′R)-1-(2′-p-iodobenzoyloxy-1′-methyl-eth-
yl)-7-(2′′-benzyloxy-1′′-methyl -ethyl)-6-trifluoroacetyl-6-
aza-5-spiro[4.5]decane (28). p-iodobenzoic acid (200 mg, 0.80
mmol) and DMAP (50 mg) were added to a solution of alcohol
27 (100 mg, 0.22 mmol) in CH2Cl2 (8 mL), DCC (250 mg, 1.20
mmol) in two portions was added within a 15-min interval,
[R]20D + 26.8 (c 0.35, CHCl3) Rf 0.32 (EtOAc/hexanes 2:10);
IR (film) νmax 3311, 2954, 2869, 1709, 1651, 1553, 1182 cm-1
;
1H NMR (300 MHz, CDCl3) δ 6.69 (t, J ) 7.1 Hz, 1H), 6.44 (d,
J ) 8.7 Hz, 1H), 4.19 (q, J ) 7.2 Hz, 2H), 4.07 (m, 1H), 3.87
(dd, J ) 8.7, 6.6 Hz, 1H), 3.21 (t, J ) 8.7 Hz, 1H), 2.45 (q, J )
7.2 Hz, 2H), 2.34 (t, J ) 7.5 Hz, 1H), 1.85 (s, 3H), 1.82-1.41
4960 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of Azaspirocyclic Core of Alkaloids
(m, 13H), 1.27 (t, J ) 7.2 Hz, 3H), 1.02 (d, J ) 6.9 Hz, 3H);19F
NMR(200 MHz, CDCl3) δ -76.25; MS (ESI) 442.2 (M+ + Na);
HRMS (ESI) calcd for C21H32F3NO4Na (M+ + Na) 442.2175,
found 442.2162.
1H), 2.59 (m, 1H), 2.20 (m, 3H), 1.91-1.61 (m, 15H), 1.30 (t, J
) 7.1 Hz, 3H), 0.95 (d, J ) 6.2 Hz, 3H); 19F NMR(200 MHz,
CDCl3) δ -69.02; 13C NMR (75 MHz, CDCl3) δ 167.4, 157.1 (q,
JF,CdO ) 34 Hz), 136.0, 130.1, 116.6 (q, JF,C ) 287 Hz), 68.8,
67.6, 60.5, 53.7, 52.9 (dd, JF,C ) 3.9, 6.8 Hz), 35.3, 35.1, 34.5,
34.1, 30.4, 24.2, 22.9, 15.9, 13.9, 13.8, 12.4; IR (film) νmax 3518,
2953, 2873, 1711, 1691, 1652, 1263, 1201, 1138 cm-1; MS (ESI)
442.2 (M+ + Na); HRMS (ESI) calcd for C21H32F3NO4Na (M+
+ Na) 442.2176, found 442.2177.
(1′R, 5′S, 7′R, 1”R)-4-[7′-(2′′-hydroxy-1′′-methyl-ethyl)-
6′-trifluoroacetyl-6′-aza-5′-spiro[4.5] dec-1′-yl]-2-methyl-
but-2E-enoic Acid Ethyl Ester (3). A solution of BBr3 (0.36
mL, 2 M in CH2Cl2, 0.72 mmol) was added rapidly via syringe
to a stirred solution of the ester 30 (183 mg, 0.36 mmol) in
CH2Cl2 (15 mL) at -78 °C. After 20 min, saturated NaHCO3
and Na2S2O3 were added sequentially to stirred solution. The
organic layer was washed with saturated NaHCO3 and water,
dried over Na2SO4, filtered, concentrated, and purified by flash
chromatography (silica gel, EtOAc/Hexanes 2:5) to give 3 (138
mg, 91%) as a colorless oil.
Acknowledgment. We thank the National Natural
Sciences Foundation for support of this research.
Supporting Information Available: 1H NMR and 13C
NMR spectra and data of single-crystal X-ray structure
analysis of p-iodo-benzoate 28. This material is available free
of charge via the Internet at http://pubs.acs.org.
[R]20 - 7.2 (c 1.01, CHCl3); Rf 0.29 (EtOAc/Hexanes 2:5);
D
1H NMR (300 MHz, CDCl3) δ 6.61 (t, J ) 7.5 Hz, 1H), 4.20 (q,
J ) 7.1 Hz, 2H), 4.02 (d, J ) 11.0 Hz, 1H), 3.65 (dd, J ) 10.2,
3.1 Hz, 1H), 3.51 (dd, J ) 10.4, 5.1 Hz, 1H), 2.88-2.76 (m,
JO047882V
J. Org. Chem, Vol. 70, No. 13, 2005 4961