A Concise, metathesis based approach to construction of the lepadiformine/cylindricine tricyclic framework

Article abstract of DOI:10.1016/j.tet.2010.06.027

A tandem dienyne metathesis based strategy has been developed for construction of the core tricyclic framework found in the lepadiformine and cylindricine alkaloids. 2-Pentenyl-2-ethynylpyrollidine acrylamide that serves as the starting material for the k

Full text of DOI:10.1016/j.tet.2010.06.027

Tetrahedron 66 (2010) 5955e5961
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A Concise, metathesis based approach to construction of the lepadiformine/
cylindricine tricyclic framework
*
Jiwen Zou, Dae Won Cho, Patrick S. Mariano
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2010
Received in revised form 8 June 2010
Accepted 9 June 2010
Available online 16 June 2010
A tandem dienyne metathesis based strategy has been developed for construction of the core tricyclic
framework found in the lepadiformine and cylindricine alkaloids. 2-Pentenyl-2-ethynylpyrollidine
acrylamide that serves as the starting material for the key ruthenium carbene catalyzed metathesis
process is prepared by using a concise route starting with
L-proline.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium carbene catalysis
Metathesis
Pyridinium salt photochemistry
1. Introduction
Lepadiformine A and the cylindricines attracted interest in the
synthetic community beginning shortly after their isolation in the
mid 1990s.5,6 The varied strategies that have been used to prepare
these targets rely on a broad array of modern synthetic methodol-
ogies. Recently, synthetic approaches to lepadiformine A and the
cylindricines have been thoroughly reviewed by Weinreb.7
The results of our earlier studies in the area of pyridinium salt
photochemistry8,9 provide the foundation for a new, photochemical
strategy to construct the tricyclic skeleton of the lepadiformines and
cylindricines. At the beginning of studies in this area, we envisaged
that the spirocyclic N-butenamidocyclopentene 2 could be accessed
by employing a route that involves documented sequential photo-
cyclization-aziridine ring opening,9 starting with the cyclopenta-
fused pyridinium perchlorate 1 (Scheme 1). Furthermore, we
hypothesized that ring rearrangement metathesis of the spirocyclic
The lepadiformines are structurally interesting alkaloids isolated
from the marine organisms clavelina lepadiformis and clavelina
moluccensis by Biard and his co-workers.1e3 Members of this family
share a common tricyclic-amine skeleton but differ in the nature of
substituents at the C-2 and C-13 positions. Lepadiformine A, the first
member of this family that was isolated and characterized,1,2 pos-
sesses a C-2 n-hexyl and C-13 hydroxymethyl moiety. In contrast,
n-butyl and hydroxymethyl groups are located at the respective C-2
and C-13 centers in lepadiformine B, and lepadiformine C contains
a C-2 n-butyl group but lacks substitution at C-13.3 Interestingly,
these alkaloids have tricyclic structures and substituent patterns that
closely resemble those found in members of the cylindricine alkaloid
family (e.g., cylindricine B).4 One of themajordifferencesbetweenthe
lepadiformines and cylindricines are the configurations at the side
chain bearing C-2 and C-13 carbons and the quaternary C-10 carbon.
R1O
R1O
R1O
hv
AcN
AcO
N
N
Ph
OH
H
H
10
13
O
2
2
N
N
1
Ru=C
HOH2C
R1
R2
nC6H13
lepadiformines
cylindricine B
N
N
A (R1 = CH2OH, R2 = nC6H13
B (R1 = CH2OH, R2 = nC4H9)
C (R1 = H, R2 = nC4H9)
)
R1O
R1O
R2
O
3
lepadiformines
and
cylindricines
* Corresponding author. Tel.: þ1 505 277 6390; fax: þ1 505 277 6202; e-mail
Scheme 1.
address: mariano@unm.edu (P.S. Mariano).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.027

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J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
butenamide 2 would produce the indolizidine 3,10 which contains
a properly positioned four-carbon side chain needed for construc-
tion of the final six-membered ring in the tricyclic framework that
constitutes the backbone of the target alkaloids.
2-butenylpyrrolidine butenamide 17 could be prepared in enan-
tiomerically pure forms by using short routes starting with either
or -proline. Moreover, we anticipated that treatment of 15 and/or
D
-
L
17 with a Grubbs’ ruthenium carbene catalyst could promote
dienyne metathesis17e19 to produce the respective tricyclic dien-
amides 16 and 18 (Scheme 4). This expectation was based on the
results of earlier work by Choi and Grubbs,20 which showed that
the substituted cyclohexyl ester 19 undergoes highly efficient
conversion (100%) to the tricyclic-lactone 20 when treated with the
second generation Grubbs catalyst (Scheme 5). In addition, dienyne
metathesis has been employed in novel approaches to the synthesis
of securine21 and members of the erythrina alkaloid family.22e24
In order to test this approach, the model spirocyclic amide 5
(Scheme 2) was prepared in racemic form by using either a photo-
chemical route, starting with pyridinium salt 4,9 or a metathesis
based method11,12 beginning with
L-proline (Scheme 2). Treatment
of an ethylene saturated CH2Cl2 solution of 8 with the second
generation Grubbs’ ruthenium catalyst13,14 did promote tandem
ring openingering closing metathesis15,16 to produce the indolizi-
dine 9 in modest yield.
O
Ph
PhCH=CHCH2COCl
6 N HCl
ClO4- +N
N
AcN
AcO
HN
HO
HO
TEA, CH2Cl2
(65%)
5
4
6
Grubbs
O
O
2nd gener.
Ru=C
Ph
Ph
DBU, DMF
(69%)
MsCl, pyrid.
(94%)
N
N
N
MsO
ethylene CH2Cl2
(50%)
O
8
7
9
1. TMSI
2. PhCH=CHCH2COCl
TEA, CH2Cl2
(50%)
Grubbs, 2nd generation
Ph3PCH3Br
BocN
L-proline
nBuLi
THF
N
N
CHO
CH=CH2
CH2Cl2, ethylene
(100%)
Boc
Boc
((100%)
12
11
10
Scheme 2.
At this point, potentially more efficient strategies for construc-
tion of the tricyclic core structures of the lepadiformine and cylin-
dricine alkaloids became apparent. For example, we recognized that
an alternate approach existed for the preparation of indolizidine 9
involving early introduction of the butenoyl-amide side chain. This
expectation proved to be correct as demonstrated by the high
yielding (80%) conversion of the pyrrolidine triene 14, generated
from the known11 Boc-protected pyrrolidine 11, to indolizidine 9
promoted by treatment with the second generation Grubbs’ catalyst
in the presence of ethylene (Scheme 3). It should be noted that the
mechanistic pathway for this process must involve ruthenium
alkylidene formation involving either the styryl or vinyl double
bond. Alternative routes via formation and cyclization of the side
chain butenyl derived ruthenium alkylidene would lead to forma-
tion of highly strained five- or eight-membered rings.
Grubbs'
2nd gener.
N
O
CH2Cl2, refl.
(100%)
N
O
O
15
16
N
N
O
Ph
17
18
Scheme 4.
Grubbs'
nd generation
Ru=C
O
2
Ph
N
1. HCl
11
9
O
Grubbs' 2nd
H
2. PhCH=CHCH2COCl
(45%)
CH2Cl2, CH2=CH2
(80%)
O
O
O
CH2Cl2, refl.
(100%)
14
20
19
Scheme 3.
Scheme 5.
The final iteration in the development of a highly concise
strategy for construction of the lepadiformine/cylindricine tricyclic
skeleton came from the belated recognition that the 2-ethynyl-2-
pentenylpyrrolidine acrylamide 15 and/or the analogous 2-ethynyl-
The feasibility of these metathesis based strategies was tested in
the context of applications to the preparation of the tricyclic dien-
amides 16 and 18. Following the methodology prescribed by

J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
5957
Seebach25 and others,26e28
L
-proline was sequentially transformed
Moreover, no identifiable products could be isolated from the
complex mixtures that are produced in these processes.
to the (S)-2-pentenyl derivative 22 via alkylation of the known25
bicyclic-oxazolidinone 21 (Scheme 6). By using methodology de-
veloped by Bestmann,29 aldehyde 27 was converted to correspond-
ing Boc-protected 2-pentenyl-2-ethynyl pyrrolidine 28. Finally,
deprotection of 28 followed by acrylamide formation gave the key
dienyne 15.
Borrowing from the mechanistic reasoning provided by Choi and
Grubbs,20 the conversion of 15 to 16 likely involves preferential ad-
dition of the initially formed, pentenyl double bond derived ruthe-
nium alkylidene 34 to the acetylene moiety rather than the
acrylamide group. This process provides an intermediate ruth-
enocyclobutene 35, which undergoes sequential electrocyclic ring
opening to form the rutheno-vinylcyclohexene 36 and RCM with the
acrylamide alkene moiety to form 16 (Scheme 8). Although any ex-
planation for the lack of dienyne metathesis reactivity of 17 is
speculative at this point, it should be noted that the success of this
process requires that initial ruthenium alkylidene formation take
place at the styryl group (Scheme 9). In another route involving ru-
thenium alkylidene formation at the butenyl double bond, cycliza-
tionwould produce strained five- andeight-membered ring systems.
O
O
H
N
lithium diethylamide
SiO
CO H
O
O
N
NH
HMPA, THF
5-bromo-1-pentene
(50%)
aq. MeOH
(95%)
tBu
tBu
23
22
21
Boc O
LiBH
CH I
CO CH
NBoc
CO H
NBoc
CH OH
NBoc
Me NOH
MeCN
DBU
C H
Et O
(90%)
(94%)
(80%)
26
24
25
Ru
Ru
pyrid-SO
CH COCN PO(OMe)
Ru
15
16
CHO
NBoc
N
N
O
N
DMSO
CH Cl
(100%)
O
K CO , MeOH
(80%)
O
Ru=C
NBoc
27
28
34
36
35
Scheme 8.
1. TMSOTf, CH Cl
2. CH =CHCOCl
TEA, CH Cl
(50%)
Ru
N
O
Ru
18
17
15
N
O
N
O
N
Scheme 6.
Ru
O
Scheme 9.
The butenamide 17 was prepared via a sequence that begins
with the known26 carboxylic acid 29 (Scheme 7). Conversion of this
substance to aldehyde 32 followed by installation of the alkyne
moiety provides the protected pyrrolidine derivative 33, which is
transformed to 17 by deprotection and amide formation.
In the anticipated manner, the pentenyl-acrylamide 15 un-
dergoes clean dienyne metathesis to generate the tricyclic dien-
amide 16 (Scheme 4). The best conditions for performing this
process involve refluxing CH2Cl2 and the Grubbs second generation
ruthenium catalyst. In this way, 15 is transformed to the tricyclic
dienamide 16 in yields as high as 100%. Surprisingly, conducting the
ring closing metathesis (RCM) process on an ethylene saturated
solution of 15 under otherwise identical conditions leads to for-
mation of a complex product mixture. In contrast, treatment of the
butenyl-butenamide 17 under a variety of reaction conditions (e. g.,
room temperature-to-refluxing CH2Cl2, with and without ethylene)
failed to promote formation of the tricyclic dienamide 18.
In addition to an early incorporation of a hydroxymethyl group
that would be ultimately positioned at C-13 in the tricyclic skele-
tons of the targets,30 completion of either a lepadiformine or
cylindricine synthesis by using dienyne metathesis based routes
requires methodology for stereocontrolled reduction of the C-5,C-
6-double bond in dienamide 16 (or a hydroxymethyl analog) and
the installation of a requisite alkyl chain at C-2. The former issue
was briefly explored. Inspection of energy-minimized structures of
16 gives little indication that a preference exists between confor-
mations 16a and 16b (Scheme 10). In conformer 16a, the pyrroli-
dine ring is positioned to block Pd-complexation from the
the -alkene moiety while in 16b the -face of the alkene group is
more accessible. We believed that, in accordance with this pre-
diction, treatment of 16 with Pd/H2 would result in the formation of
a mixture of tricyclic lactams 37 and 38, having the C-5 C-10
b-face of
g,
d
b
Pyridine:SO3
LiBH4
CH3I/DBU
21
CO2Me
CH2OH
NBoc
31
CO2H
NBoc
29
Benzene
(80%)
Et2O
(90%)
DMSO/CH2Cl2
(75%)
NBoc
30
1. TMSOTf, CH2Cl2
(MeO)2POC(N2)COCH3
CHO
NBoc
2. PhCH=CHCH2COCl
TEA, CH2Cl2
K2CO3
(65%)
N
NBoc
Ph
(50%)
O
32
33
17
Scheme 7.

5958
J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
relative stereochemistry found in the respective lepadiformine and
cylindricine alkaloids. However, in a manner, that is, contradictory
to this expectation, catalytic hydrogenation of 16 affords the tri-
cyclic lactam 38 exclusively, as shown by X-ray crystallographic
analysis of the derived thiolactam 41 (see Supplementary data). In
addition, 41 was converted to the known31,32 tricyclic amine 39
through a pathway involving formation and LiAlH4 reduction of the
thioiminium salt 40.
126.2, 127.4, 128.4, 132.7, 136.8, 172.7. The modestly unstable nature
of 6 prevented the attainment of HRMS data.
To a solution of amido-alcohol 6 (0.5 g, 1.8 mmol) and pyridine
(1 mL) in dry methylene chloride (20 mL) at 0 ꢀC was added
methanesulfonyl chloride (0.67 g, 3.5 mmol). The mixture was
stirred overnight at room temperature, diluted with methylene
chloride and saturated aq sodium bicarbonate, separated, dried,
and concentrated in vacuo to afford a residue, which was subjected
to column chromatography (10% acetone/hexane) on silica gel to
provide 7 (0.60 g, 94%). 1H NMR 1.49 (m, 2H), 1.86 (m, 2H), 2.03 (m,
4H), 2.38 (m, 1H), 2.93 (m, 4H), 3.25 (m, 2H), 3.62 (m, 2H), 4.66 (m,
1H), 6.43 (m, 2H), 7.20e7.40 (m, 5H); 13C NMR 22.0, 22.8, 32.8, 34.7,
38.6, 40.6, 41.5, 49.2, 71.1, 86.7, 123.4, 126.2, 127.3, 128.4, 132.7, 137.1,
170.2; HRMS (ES) m/z 364.1583, calcd for C19H26NO4S 364.1569.
N
N
O
O
16a
16b
H2, Pd/C
MeOH
(81%)
2.1.2. Compound 8 from 7. A solution of 7 (0.4 g,1.1 mmol) and DBU
(5 mL) in DMF (10 mL) was stirred at 120 ꢀC for 12 h, cooled, and
diluted with ethyl acetate, washed with saturated aq sodium chlo-
ride, dried, and concentrated in vacuo to give a residue, which was
subjected to column chromatography (10% acetone/hexane) on silica
gel to provide 8 (0.2 g, 69%). 1H NMR 1.1e1.5 (m, 3H),1.7e2.0 (m, 4H),
2.2e2.8 (m, 2H), 3.2e3.6 (m, 3H), 5.52 (d, 0.5H), 5.71 (d, 0.5H), 5.84(d,
0.5H), 5.90 (m, 0.5H), 7.1e7.5 (m, 6H); 13C NMR, 13.0, 23.5, 31.8, 34.6,
37.8, 40.1, 48.2, 123.5, 124.1, 125.3, 127.2, 128.4, 131.5, 132.4, 133.8,
137.1, 168.5; HRMS (ES) m/z 294.1864, calcd for C20H24NO 294.1858.
H
N
N
O
H
O
37
38
Lawesson's
Reagent
(77%)
LiAlH4
CH3OTf
2.1.3. Compound 11. To a solution of methyltriphenylphosphonium
bromide (13 g, 0.037 mol) in dry THF (150 mL) was added n-
butyllithium (15 mL, 2.5 M in hexane, 0.037 mol) at 0 ꢀC. The
mixture was stirred at 0 ꢀC for 1 h and a solution of the known34
aldehyde 10 (8.0 g, 0.031 mol) in dry THF (30 mL) was added at
0 ꢀC. The mixture was stirred overnight at room temperature,
concentrated in vacuo, giving a residue, which was dissolved in
ethyl acetate, washed with water, dried, and concentrated in vacuo
to give a residue, which was subjected to column chromatography
(10% acetone/hexane) on silica gel to afford 11 (7.8 g, 100%). 1H NMR
1.37 (s, 9H), 1.60e2.20 (m, 8H), 3.27 (m, 1H), 3.48 and 3.60 (m, 1H),
4.88 (m, 4H), 5.70e6.00 (m, 2H); 13C NMR, 20.8, 28.0, 28.6, 36.0,
37.2, 48.6, 66.0, 79.2, 111.0, 114.2, 138.4, 142.2, 154.3; HRMS (ES) m/z
274.1774, calcd for C15H25NO2Na 274.1783.
N
+
N
N
TfO-
SCH3
S
41
39
40
Scheme 10.
The study described above has led to the development of an
efficient approach for construction of the tricyclic structural core
shared by members of the lepadiformine and cylindricine alkaloid
families. The key tricyclic dienamide 16 (or a hydroxymethyl ana-
log), generated by using a highly efficient dienyne metathesis
process, contains an array of functionality that could prove bene-
ficial in synthesis of specific target in these natural product families.
2. Experimental
2.1. General
2.1.4. Compound 12. An ethylene gas purged solution of 11 (2.0 g,
8 mmol) in dry methylene chloride (50 mL) containing 10% mol
Grubbs II generation catalyst was stirred at reflux for 24 h, cooled,
and concentrated in vacuo to give a residue, which was subjected to
column chromatography (10% acetone/hexane) on silica gel to af-
ford 12 (1.8 g, 100%). 1H NMR 1.39 (s, 9H), 1.78 (m, 5H), 2.10e2.70
(m, 3H), 3.25e3.60 (m, 2H), 5.40e5.90 (m, 2H); 13C NMR, 22.1, 28.0,
30.8, 34.5, 35.3, 38.9, 40.4, 47.3, 73.9, 78.5, 128.9, 136.1, 154.1; HRMS
(ES) m/z 246.1467, calcd for C13H21NO2Na 246.1470.
All reagents were obtained from commercial sources and used
without further purification. All compounds were isolated as oils
and shown to be >90% pure by 1H and/or 13C NMR analysis, unless
otherwise noted. 1H and 13C NMR spectra were recorded by using
CDCl3 solutions and with residual CHCl3 was used as a reference.
2.1.1. Compound 7. A solution of the known33 amido-ester 5 (1.0 g,
4.5 mmol) in 6 N HCl (20 mL) was stirred at 100 ꢀC for 3 h, cooled,
and concentrated in vacuo to afford the spirocyclic aminoalcohol.
Dry methylene chloride, triethylamine, and trans-styrylacetyl
chloride (made from trans-styrylacetic acid (0.87 g, 5.4 mmol) and
thionyl chloride (20 mL) at reflux for 3 h) were added sequentially
and the resulting mixture was stirred overnight at room tempera-
ture, diluted with methyl chloride and water, washed with satu-
rated aq sodium bicarbonate, dried, and concentrated in vacuo to
yield a residue, which was subjected to column chromatography
(30% acetone/hexane) on silica gel to provide the modestly unstable
amido-alcohol 6 (0.83 g, 65%). 1H NMR 1.45 (m, 2H),1.73 (m, 1H),
2.03 (m, 4H), 1.91 (m, 6H), 2.72 (m, 1H), 3.26 (m, 2H), 3.58 (m, 2H),
3.76 (m, 1H), 4.67 (m, 1H), 6.34 (m, 1H), 6.45 (m, 1H), 7.10e7.50 (m,
5H); 13C NMR 21.1, 23.1, 34.5, 35.3, 40.3, 41.2, 49.4, 74.3, 81.7, 122.5,
2.1.5. Compound 8 from 12. To a solution of 12 (1.0 g, 4.5 mmol) in
drymethylene chloride(50 mL)wasadded trimethylsiyl iodide(1.8 g,
9.0 mmol) at 0 ꢀC. The mixture was stirred for 3 h at room tempera-
ture, quenched byaddition of methanol, concentrated in vacuo giving
a residue, which was dissolved in dry methylene chloride (50 mL).
Triethylamine (2.4 mL, 18 mmol) and trans-styrylacetyl chloride
(made from trans-styrylacetic acid (1.0 g, 6.2 mmol) and thionyl
chloride (15 mL) at reflux for 3 h) were added sequentially. The
mixturewas stirred overnight at room temperature and concentrated
to give a residue, which was subjected to column chromatography
(10% acetone/hexane) on silica gel to provide 8 (0.6 g, 50%).
2.1.6. Conversion of 8 to 9. An ethylene gas purged solution of 9
(0.2 g, 0.8 mmol) in dry methylene chloride (20 mL) containing 10%
mol Grubbs II generation catalyst was stirred at reflux for 24 h,

J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
5959
cooled, and concentrated in vacuo to give a residue, which was
subjected to column chromatography (25% acetone/hexane) on
silica gel to afford 9 (70 mg, 50%). 1H NMR 1.48 (m,1H), 1.71 (m, 2H),
1.93 (m, 5H), 2.87 (q, J¼18.00 Hz, 2H), 3.32 (m, 1H), 3.92 (m, 1H),
4.94 (q, J¼13.00 Hz, 1H), 5.79 (m, 3H); 13C NMR, 19.8, 28.2, 32.7,
36.4, 37.6, 43.1, 66.4, 114.8, 121.9, 129.3,137.7,167.0; HRMS (ES) m/z
192.1390, calcd for C12H18NO 192.1388.
a clear solution formed. (Boc)2O (3.9 g, 0.018 mol) was then added
and stirring was continued for 2 d. On the third day, another
0.82 equiv of (Boc)2O (1.8 g, 0.009 mol) was added, and the mixture
was stirred for 2 d. The acetonitrile was removed in vacuo, and the
residue was partitioned between ethyl acetate and water. The
aqueous layer was acidified with 1 N HCl aqueous solution to pH
2e3 and extracted with ethyl acetate. The extracts were dried and
concentrated in vacuo to give the Boc-derivative 24 as white crys-
2.1.7. Compound 14. A solution of the known11 pyrrolidine de-
rivative 13 (2 g, 8 mmol) in HCl/ethyl acetate (3 N, 50 mL) was stir-
red for 3 h at room temperature, concentrated in vacuo giving
a residue that was dissolved in dry methylene chloride (50 mL). A
solution of the residue made by sequentially adding triethylamine
(2 mL) and trans-styrylacetyl chloride (made from trans-styrylacetic
acid (1.6 g, 10 mmol) and thionyl chloride (20 mL) at reflux for 3 h)
was stirred overnight at room temperature and concentrated in
vacuo to give a residue, which was subjected to column chroma-
tography (10% acetone/hexane) on silica gel to provide 14 (1.1 g,
45%). 1H NMR 1.84e2.25 (m, 8H), 3.23 (m, 2H), 3.47 (m,1H), 3.66 (m,
1H), 4.99 (m, 4H), 5.81 (m, 1H), 6.12 (m, 1H), 6.41 (m, 2H), 7.20e7.40
(m, 5H); 13C NMR, 22.2, 28.7, 35.4, 35.7, 40.6, 49.2, 68.5, 111.9, 114.3,
123.3, 126.2, 127.2, 128.4, 132.6, 136.4, 138.5, 140.5, 142.0, 168.8;
HRMS (ES) m/z 318.1827, calcd for C20H25NONa 318.1834.
tals (2.9 g, 94%), mp 92e93 ꢀC. [
a
]
D
23 ꢁ50.40 (c 30.0, MeOH). 1H NMR
1.20e1.40 (m, 2H), 1.40e1.70 (d, 9H), 1.70e2.00 (m, 4H), 2.00e2.40
(m, 4H), 2.60e2.90 (s, 1H), 3.30e3.90 (m, 2H), 4.90e5.20 (m, 2H),
5.70e6.00 (m, 1H); 13C NMR, 22.7, 23.4, 28.4, 33.5, 33.8, 35.1, 49.3,
70.5, 82.06, 115.1, 138.0, 157.1, 174.9, 180.6; HRMS (ES) m/z calcd for
C15H25NO4 (MþNa) 306.1681, found 306.1677.
Following the procedure described by Ono,35 the proline de-
rivative 24 (6.0 g, 21 mmol) was dissolved in benzene. DBU (4.0 g,
26 mmol) was added followed by a solution of methyl iodide
(4.0 mL, 64 mmol) in benzene. Awhite precipitate appeared after ca.
10 min. The mixture was stirred at reflux overnight and concen-
trated in vacuo to give a residue, which was washed with water and
extracted with ethyl acetate. The organic layer was dried and con-
centrated to give a residue, which was subjected to column chro-
matography (10% acetone/hexane) on silica gel to afford the
corresponding ester 25 as a clear liquid (5.4 g, 80%). [
a
]
23 þ13.80 (c
D
2.1.8. Conversion of 14 to 9. An ethylene gas purged solution of 14
(1.0 g, 3.4 mmol) in dry methylene chloride (50 mL) containing 10%
mol Grubbs II generation catalyst, was stirred at reflux for 24 h,
cooled, and concentrated in vacuo to give a residue, which was
subjected to column chromatography (25% acetone/hexane) on
silica gel to afford 9 (0.52 g, 80%).
2.2, MeOH); 98% ee (determined by HPLC analysis). 1H NMR
1.30e1.50 (d, 11H), 1.75e2.20 (m, 9H), 3.30e3.45 (m, 1H), 3.70 (s,
3H), 4.90e5.10 (m, 2H), 5.70e5.90 (m,1H); 13C NMR, 22.8, 28.3, 33.9,
34.6, 37.5, 48.5, 52.0, 67.4, 79.9, 114.9, 138.5, 153.8, 175.6; HRMS (ES)
m/z calcd for C16H27NO4 (Mþ1) 320.1838, found 320.1831.
To a solution of the ester 25 (10 g, 34 mmol) in dry ethyl ether
(200 mL) was added a solution of lithium borohydride (35 mL,
70 mmol, 2 M in THF) at 0 ꢀC. The mixture was stirred overnight at
room temperature and quenched by the addition of satd sodium
bicarbonate. The organic layer was separated, dried, and concen-
trated in vacuo to afford a residue, which was subjected to column
chromatography (50% acetone/hexane) on silica gel to provide the
2.1.9. Compound 23. To a solution of LEDA (made from diethyl-
amine (16 mL, 0.154 mol) in THF (700 mL) and n-butyllithium
(60 mL, 0.15 mol, 2.5 M in hexane)) at ꢁ78 ꢀC was added a solution
of the known25 oxazolidinone 21 (23 g, 0.126 mol) in dry THF
(50 mL). The mixture was stirred at ꢁ78 ꢀC for 20 min and then
HMPA (26 mL, 0.173 mol) was added. After an additional 30 min,
a solution of 5-bromo-1-pentene (23 g, 0.16 mol) in THF (50 mL)
was added. The resulting mixture was stirred overnight at room
temperature, concentrated in vacuo to afford a residue, which was
dissolved in dichloromethane (400 mL), washed with water. The
organic layer was dried and concentrated in vacuo to give a residue,
which was purified by short path distillation (bp 90e120 ꢀC,
corresponding alcohol 26 (8.2 g, 90%) as an oil. [
a
]
23 þ6.80 (c 0.90,
D
MeOH). 1H NMR 1.40e1.70 (m, 13H), 1.70e2.20 (m, 8H), 3.30e3.40
(m, 2H), 3.63 (s, 2H), 4.90e5.05 (m, 2H), 5.20e5.50 (s, 1H),
5.70e5.90 (m, 1H); 13C NMR, 22.1, 23.8, 28.5, 32.0, 34.1, 48.8, 67.6,
69.4, 80.0, 114.5, 138.8, 156.2; HRMS (ES) m/z calcd for C15H27NO3
(MþNa) 292.1889, found 292.1886.
To a solution of the alcohol 26 (6.0 g, 22 mmol) in dry methylene
chloride (100 mL) at 0 ꢀC under nitrogen was added triethylamine
(7 mL) and 40 mL of the sulfur trioxide pyridine complex (12 g) in
dimethyl sulfoxide. The mixture was stirred overnight at room
temperature, quenched by the addition of satd sodium chloride.
The organic layer was separated, washed with water, dried, and
concentrated in vacuo to give a residue, which was subjected to
column chromatography (20% acetone/hexane) on silica gel to
0.2 mmHg) to provide the pentenylated product 22 as a clear oil
23
(15.6 g, 50%). [
a
]
D
ꢁ13.20 (c 2.1, MeOH). 1H NMR 0.87 (s, 9H),
1.40e1.90 (m, 6H), 2.00e2.15 (m, 3H), 2.80e2.90 (m,1H), 2.90e3.05
(m, 1H), 4.10e4.20 (s, 1H), 4.90e5.00 (m, 2H), 5.70e5.85 (m, 1H);
13C NMR, 23.0, 24.2, 24.7, 33.7, 35.63, 36.3, 57.4, 71.7, 104.9, 114.7,
138.3, 178.5; HRMS (ES) m/z calcd for C15H25NO2 (Mþ1) 252.1964,
found 252.1960.
The pentenylated oxazolidinone 22 (7.6 g, 0.03 mol) was dis-
solved in 100 mL of MeOH/H2O (6:1). Silica gel (7.6 g,
200e400 mesh) was added to the solution and the resulting sus-
pension was stirred at room temperature for 48 h. The reaction
mixture was filtered and the filtrate was evaporated in vacuo to give
a white solid, which was triturated with ethyl ether to give 23 as
provide 27 (6 g, 100%) as an oil. [
a
]
23 þ2.60 (c 0.6, MeOH). 1H NMR
D
1.20e1.50 (d, 9H), 1.70e2.20 (m, 8H), 3.20e3.70 (m, 2H), 4.90e5.30
(m, 5H), 5.70e5.90 (m, 1H), 9.30e9.50 (d, 1H); 13C NMR, 22.9, 28.2,
32.1, 34.0, 70.9, 80.9, 115.1, 138.2, 153.5, 199.9; HRMS (ES) m/z calcd
for C15H25NO3 (MþNa) 290.1732, found 290.1739.
a white solid (5.3 g, 95%), mp 300 ꢀC (dec). [
a
]
23 ꢁ6.40 (c 1.1, MeOH).
2.1.11. Compound 28. To a solution of CH3COCN2PO(OMe)2 (6.0,
31 mmol) in methanol (30 mL) at room temperature under nitrogen
was added potassium carbonate (8.0 g, 58 mmol). After stirring for
10 min, a solution of 27 (6.0 g, 22 mmol) in methanol (5 mL) was
added to the mixture, which was then stirred overnight at room
temperature. Filtration gave a filtrate, which was concentrated in
vacuo to give a residue, which was subjected to column chromatog-
raphy (20% acetone/hexane) on silica gel to provide 28 (4.7 g, 80%) as
D
1H NMR (D2O) 1.30e1.50 (m, 2H), 1.75e1.85 (m, 1H), 1.90e2.20 (m,
7H), 2.30e2.50 (m, 1H), 3.35e3.50 (m, 2H), 5.05e5.20 (m, 2H);
5.80e5.97 (m, 1H); 13C NMR, 15.9, 16.6, 25.6, 27.8, 28.4, 38.7, 67.56,
108.0, 131.3, 169.2; HRMS (ES) m/z calcd for C10H17NO2 (Mþ1)
184.1338, found 184.1337.
2.1.10. Compound 27. The substituted -proline 23 (2.0 g, 11 mmol)
L
and Me4NOH (2.2 g, 0.012 mol) were dissolved in 50 mL of dry
acetonitrile. The mixture was stirred at room temperature until
an oil. [
a
]
23 ꢁ9.20 (c 0.8, MeOH). 1H NMR 1.47 (s, 9H), 1.50e1.60 (m,
D
1H), 1.60e1.90 (m, 2H), 1.90e2.40 (m, 7H), 3.20e3.35 (m, 1H),

5960
J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
3.50e3.80 (m, 1H); 4.80e5.10 (m, 2H), 5.70e5.90 (m, 1H); 13C NMR,
22.5, 28.5, 33.7, 38.6, 40.7, 47.9, 59.5, 69.3, 79.8, 86.8,114.7,138.5,154.2;
HRMS (ES) m/z calcd for C16H25NO2 (Mþ1) 286.1783, found 286.1792.
nitrogen was added potassium carbonate (8.0 g, 58 mmol) resulting
in a pale yellow solution. After stirring for 10 min, a solution of 32
(6.0 g, 24 mmol) in methanol (5 mL) was added to the mixture,
which was then stirred overnight at room temperature. The mix-
ture was filtered and the filtrate was concentrated in vacuo to give
a residue, which was subjected to column chromatography (20%
acetone/hexane) on silica gel to provide 33 (3.8 g, 65%) as an oil. 1H
NMR 1.47 (s, 9H), 1.70e2.10 (m, 5H), 2.10e2.40 (m, 3H), 3.20e3.40
(m, 1H), 1.90e2.00 (m, 1H), 2.00e2.10 (m, 1H), 2.70e2.85 (m, 1H),
3.10e3.25 (m, 1H), 3.50e3.80 (m, 1H), 4.80e5.10 (m, 2H), 5.70e5.90
(m, 1H); 13C NMR 22.5, 29.1, 38.3, 40.6, 47.9, 60.0, 69.6, 114.6, 138.0,
154.6; HRMS (ES) m/z calcd for C15H23NO2 (MþNa) 272.1626, found
272.1618.
2.1.12. Compound 15. To a solution of 28 (6.0 g, 22.8 mmol) in dry
dichloromethane (10 mL) at room temperature under nitrogen was
added TMSOTf (10.0 g, 45 mmol). After stirring for 30 min, the
mixture was concentrated in vacuo to afford a pale yellow residue
to which dichloromethane was added. After cooling the solution to
0 ꢀC, dry triethylamine (7 mL) and then acryloyl chloride (5 mL,
62 mmol) were added. The resulting mixture was stirred overnight
at room temperature, washed with 1 N HCl followed by water,
dried, and concentrated in vacuo to give a residue, which was
subjected to column chromatography (20% acetone/hexane) on
silica gel to provide 15 as a liquid (2.3 g, 50%). [
a
]
23 ꢁ88.20 (c 24.0,
2.1.17. Compound 17. To a solution of compound 33 (6.0 g,
D
MeOH). 1H NMR 1.30e1.40 (m, 1H), 1.60e1.90 (m, 3H), 1.90e2.20
(m, 6H), 2.30e2.40 (m, 1H), 2.40e2.45 (m, 1H), 3.55e3.65 (m, 1H),
3.75e3.95 (m, 1H), 4.90e5.10 (m, 2H), 5.65e5.70 (m, 1H),
5.70e5.90 (m, 1H), 6.30e6.40 (m, 1.6H), 6.90e7.05 (m, 0.4H); 13C
NMR, 22.0, 23.6, 24.2, 33.6, 37.0, 39.6, 40.4, 41.7, 48.0, 61.0, 70.2,
72.9, 85.6, 114.7, 126.7, 127.9, 129.5, 138.5, 163.6; HRMS (ES) m/z
calcd for C13H17NO (Mþ1) 218.1545, found 218.1561.
24 mmol) in dry dichloromethane (10 mL) at room temperature
under nitrogen was added TMSOTf (5.0 g, 22 mmol). After stirring
for 30 min, the mixture was concentrated in vacuo to afford a pale
yellow residue, to which dichloromethane was added and cooled
in ice-water bath. Dry triethylamine, trans-styrylacetyl chloride
(made from trans-styrylacetic acid (1.6 g, 10 mmol) and thionyl
chloride (20 mL)) were added. The resulting mixture was stirred
overnight at room temperature, washed with 1 N HCl aqueous
solution followed by water, dried, and concentrated in vacuo to
give a residue, which was subjected to column chromatography
(20% acetone/hexane) on silica gel to provide 17 as a liquid (3.5 g,
50%). 1H NMR 1.80e2.20 (m, 5H), 2.20e2.40 (m, 2H), 2.50e2.70
(m, 1H), 3.20e3.25 (m, 2H), 3.40e3.55 (m, 1H), 3.65e3.75 (m, 1H),
4.85e5.15 (m, 2H), 5.70e5.90 (m, 1H), 6.35e6.55 (m, 2H),
7.20e7.55 (m, 5H); 13C NMR, 23.6, 29.4, 36.7, 39.6, 40.4, 48.5, 60.8,
70.5, 85.5, 114.7, 123.0, 126.2, 127.3, 128.5, 132.6, 138.0, 169.0;
HRMS (ES) m/z calcd for C20H23NO (Mþ1) 294.1858, found
294.1864.
2.1.13. Compound 30. By following the procedure described by
Ono,35 the known26 acid 29 (3.0 g, 11 mmol) was dissolved in ben-
zene. DBU (1.7 g, 11 mmol) was added followed by a solution of
methyl iodide (2 mL, 32 mmol) in benzene. A white precipitate
appeared after ca. 10 min. The mixture was stirred at reflux over-
night and concentrated in vacuo to give a residue, which was
washed with water and extracted with ethyl acetate. The organic
layers were dried and concentrated in vacuo to give a residue, which
was subjected to column chromatography (10% acetone/hexane) on
silica gel to afford 30 as a clear liquid (2.5 g, 80%). 1H NMR 1.30e1.50
(d, 9H), 1.70e2.10 (m, 6H), 2.15e2.40 (m, 1H), 3.30e3.45 (m, 1H),
3.69 (s, 3H), 4.80e5.10 (m, 2H), 5.70e5.90 (m, 1H); 13C NMR, 22.7,
28.3, 33.3, 37.4, 48.5, 52.0, 67.3, 79.9,114.5,138.2,153.7,175.3; HRMS
(ES) m/z calcd for C15H25NO4 (MþNa) 306.1681, found 306.1678.
2.1.18. Conversion of 15 to 16. A solution of 15 (0.5 g, 2.3 mmol) in
dry methylene chloride (500 mL) containing 10% mol Grubbs II
generation catalyst was stirred at reflux for 5 h, cooled, and con-
centrated in vacuo to give a residue, which was subjected to column
chromatography (10% acetone/hexane) on silica gel to afford 16
2.1.14. Compound 31. To a solution of 30 (10 g, 35 mmol) in dry
ethyl ether (400 mL) was added a solution of lithium borohydride
(35 mL, 70 mmol, 2 M in THF) at 0 ꢀC. The mixture was stirred for
8 h at room temperature and quenched with satd sodium bi-
carbonate and separated. The organic layer was dried and con-
centrated in vacuo to afford a residue, which was subjected to
column chromatography (50% acetone/hexane) on silica gel to
provide 31 (8.1 g, 90%) as an oil. 1H NMR 1.40 (s, 9H), 1.60e2.00 (m,
6H), 2.10e2.20 (m, 1H), 3.25e3.40 (m, 1H), 3.50e3.60 (m, 1H),
4.80e5.00 (m, 2H), 5.20e5.35 (m, 1H), 5.70e5.85 (m, 1H); 13C NMR,
21.9, 28.3, 31.7, 33.9, 48.6, 67.3, 68.9, 79.8, 114.2, 138.4, 155.9; HRMS
(FAB) m/z calcd for C14H26NO3 (Mþ1) 256.1913, found 256.1901.
(0.44 g, 100%) as an oil. [
a
]
23 ꢁ5.60 (c 1.1, MeOH). 1H NMR 1.40e1.60
D
(m, 2H), 1.70e1.90 (m, 4H), 1.90e2.10 (m, 2H), 2.20e2.40 (m, 2H),
3.00e3.20 (m, 1H), 4.30e3.45 (m, 1H), 5.65e5.75 (m, 1H),
5.80e5.90 (m, 1H), 5.55e5.65 (m, 1H); 13C NMR, 17.8, 20.0, 23.8,
30.1, 33.0, 42.0, 63.7, 119.7, 131.7, 135.1, 138.3, 165.6; HRMS (ES) m/z
calcd for C12H15NO (Mþ1) 190.1232, found 190.1237.
2.1.19. Conversion of 16 to 38. A solution of 16 (0.30 g,1.6 mmol) and
Pd/C (10%, 30 mg) in MeOH (100 mL) under a hydrogen atmosphere
was stirred for 5 h. The filtrate obtained by filtration was concen-
trated in vacuo giving a residue, which was subjected to column
chromatography (50% acetone/hexane) on silica gel to afford 38
2.1.15. Compound 32. To a solution of 31 (6.0, 23 mmol) in dry
methylene chloride (100 mL) at 0 ꢀC under nitrogen was added
triethylamine (7 mL) and 40 mL of the sulfur trioxide pyridine
complex (12 g) in dimethyl sulfoxide. The mixture was stirred
overnight at room temperature, quenched with satd sodium chlo-
ride, washed with water, dried, and concentrated in vacuo to give
a residue, which was subjected to column chromatography (20%
acetone/hexane) on silica gel to provide 32 (4.5 g, 75%) as an oil. 1H
NMR 1.30e1.50(d, 9H), 1.70e2.20 (m, 8H), 3.40e3.70 (m, 2H),
4.90e5.10 (m, 2H), 5.70e5.85 (m, 1H), 9.30e9.50 (d, 1H); 13C NMR,
22.8, 28.1, 31.9, 33.8, 48.1, 70.6, 80.9, 114.7, 137.8, 153.4, 199.5; HRMS
(ES) m/z calcd for C14H23NO3 (MþNa) 276.1576, found 276.1579.
(0.25 g, 81%) as an oil. [
a
]
23 ꢁ4.60 (c 0.58, MeOH).1H NMR 1.30e2.00
D
(m, 12H), 2.10e2.20 (m, 1H), 2.30e2.40 (m, 2H), 2.45e2.55 (m, 1H),
3.40e3.50 (m,1H), 3.75e3.85 (m,1H); 13C NMR,19.6, 20.1, 22.7, 23.4,
28.8, 29.9, 30.8, 35.9, 40.1, 43.8, 64.0,168.7; HRMS (FAB) m/z calcd for
C12H19NO (Mþ1) 194.1545, found 194.1550.
2.1.20. Conversion of 38 to 41. A solution of Lawesson’s reagent
(2.1 g, 5.2 mmol) and 38 (0.5 g, 2.6 mmol) in toluene (50 mL) was
stirred at reflux for 4 h, cooled, and concentrated in vacuo to give
a
residue, which was subjected to column chromatography
(dichloromethane to 20% acetone/hexane) on silica gel to afford 41
23
as a white solid (0.42 g, 77%), mp 86e88 ꢀC. [
a
]
D
ꢁ4.20 (c 0.65,
MeOH). 1H NMR 1.30e1.80 (m, 12H), 1.90e2.20 (m, 3H), 2.45e2.55
(m, 1H), 2.90e3.05 (m, 1H), 3.15e3.25 (m, 1H), 3.75e3.85 (m, 1H),
4.15e4.25 (m, 1H); 13C NMR, 19.4, 22.3, 23.2, 28.8, 29.1, 35.4, 39.3,
2.1.16. Compound 33. To a solution of CH3COCN2PO(OEt)2 (6.0 g,
31 mmol) in methanol (50 mL) at room temperature under

J. Zou et al. / Tetrahedron 66 (2010) 5955e5961
5961
40.0, 52.1, 67.7, 195.4; HRMS (ES) m/z calcd for C12H19NS (Mþ1)
for this article can be found in the online version, at 10.1016/j.
tet.2010.06.027.
210.1316, found 210.1316.
2.1.21. Conversion of 41 to 40. To solution of 41 (450 mg,
2.2 mmol) in anhydrous ethyl ether (5 mL) was added methyl
triflate (0.36 mL, 3.2 mmol), and the mixture was stirred for
30 min at room temperature. The solution was extracted with
Et2O and 1 N HCl and the resulting aqueous layer was extracted
again with CH2Cl2 and satd NaHCO3. The organic layer was dried
with Na2SO4, filtrated, and then concentrated in vacuo to give
a residue, which was subjected to column chromatography
(CH2Cl2/MeOH¼20:1) to afford S-methyl-thioiminium salt 40
(380 mg, 80%). 1H NMR 1.30e1.56 (m, 4H), 1.65e1.89 (m, 6H),
2.00e2.04 (m, 1H), 2.14e2.25 (m, 3H), 2.45e2.53 (m, 1H),
3.05e3.18 (m, 2H), 3.70 (t, 1H, J¼10.50 Hz), 3.92e3.98 (m, 1H); 13C
NMR 15.3, 18.8, 20.0, 20.1, 23.1, 28.1, 29.1, 30.5, 33.5, 36.4, 52.3,
73.2, 187.5; HRMS (ES) m/z calcd for C13H22NSþ (M) 224.1473,
found 224.1472.
References and notes
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5466.
2.1.22. Conversion of 40 to 39. To solution of LiAlH4 (1.0 M in THF,
0.76 ml, 0.76 mmol) in anhydrous ethyl ether (10 mL) was added 40
(170 mg, 0.76 mmol), and the mixture was stirred for 3 h at room
temperature. The solution was diluted with 1 N HCl and extracted
with Et2O. The resulting aqueous layer was extracted again with
CH2Cl2 and satd NaHCO3, dried with Na2SO4, filtered, and concen-
trated in vacuo to give a clear liquid 39 (106 mg, 78%). 1H NMR
1.25e1.40 (m, 4H), 1.50e1.63 (m, 4H), 1.68e1.88 (m, 9H), 2.83e2.90
(m, 3H), 3.04e3.10 (m, 1H); 13C NMR 20.1, 20.4, 22.0, 24.1, 25.1, 29.4,
29.7, 30.3, 35.2, 36.8, 43.9, 48.9; HRMS (ES) m/z calcd for C12H22
(Mþ1) 180.1752, found 180.1750.
N
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Financial support for this research provided by the National
Science Foundation (CHE-0348858) is gratefully acknowledged.
Also, PSM thanks Dojindo Molecular Technologies Inc. and the late
President Keiyu Ueno for their very generous, early support of his
research program.
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Supplementary data
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2401.
This material can be found on the online version. Contained in
this are 1H and 13C NMR spectra of all previously unidentified
compounds, and X-ray crystallographic data. Supplementary data