A concise synthetic method towards (-)-swainsonine and its 8-epimer by using palladium-catalyzed asymmetric hydroamination of alkoxyallene as the key strategy

Article abstract of DOI:10.1016/j.tet.2015.05.034

Abstract A concise and flexible formal synthesis of (-)-swainsonine and the 8-epimer is reported. The synthesis features sequential Pd-catalyzed asymmetric hydroamination of alkoxyallene and the Ru-catalyzed ring-closing-metathesis as the key strategy, which generates cyclic allylic N,O-acetal as the pivotal intermediate. Notably, this reaction could be performed on a multigram-scale. In addition, both the natural product and its 8-epimer could be obtained with comparable synthetic efficiency.

Full text of DOI:10.1016/j.tet.2015.05.034

Tetrahedron xxx (2015) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise synthetic method towards (ꢀ)-swainsonine and its
8-epimer by using palladium-catalyzed asymmetric hydroamination
of alkoxyallene as the key strategy
*
Wontaeck Lim, Young Ho Rhee
Department of Chemistry, Pohang University of Science and Technology (POSTECH), Hyoja-dong San 31, Pohang, Kyungbook 790-784, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and flexible formal synthesis of (ꢀ)-swainsonine and the 8-epimer is reported. The synthesis
features sequential Pd-catalyzed asymmetric hydroamination of alkoxyallene and the Ru-catalyzed ring-
closing-metathesis as the key strategy, which generates cyclic allylic N,O-acetal as the pivotal in-
termediate. Notably, this reaction could be performed on a multigram-scale. In addition, both the natural
product and its 8-epimer could be obtained with comparable synthetic efficiency.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 15 March 2015
Received in revised form 8 May 2015
Accepted 11 May 2015
Available online xxx
Keywords:
Pi-allyl complex
Hydroamination
Asymmetric synthesis
(ꢀ)-Swainsonine
N,O-Acetal
1. Introduction
Among them (ꢀ)-swainsonine 1 was first isolated from the fungus
Rhizoctonia leguminicola in 1973.2 Since then, it has also been found
Over the past decades, polyhydroxylated indolizidine alkaloids
from several plants and fungi.
have drawn considerable attention from the field of synthetic or-
(ꢀ)-Swainsonine is known to be a potent inhibitor of the lyso-
ganic chemistry because of their unique biological activities.1
A
somal a
-mannosidase and mannosidase II.3 It also has anticancer,4
series of these indolizidine alkaloids including (ꢀ)-swainsonine,
(þ)-castanospermine, (ꢀ)-lentiginosine, (ꢀ)-uniflorine-A, and
(ꢀ)-steviamine are commonly found in plants and fungi (Fig. 1).
antimetastatic,5 immunoregulating6 and anti-HIV activities.7
Moreover, (ꢀ)-swainsonine has potential uses as an adjuvant for
protection from anti-cancer drug and chemotherapeutic toxicity.8
Due to these promising activities, numerous synthetic methods
toward swainsonine and its analogs have been reported.9 In fact,
(ꢀ)-swainsonine was one of the most popular targets in synthetic
organic community, for more than 40 synthetic methods have been
reported until now.10 Due to the presence of various hydroxyl and
amine functional groups, most syntheses of (ꢀ)-swainsonine utilize
abundant commercially available carbohydrate chiral pools as the
starting material. These methods usually rely on extensive pro-
tective group strategy, and thus require lengthy synthetic se-
quences (12e18 steps). Recently, asymmetric syntheses starting
from achiral starting materials have gained significant interest.
These new methods have unique advantage in that the absolute
and relative stereochemistry of the natural product can be easily
altered.
Fig. 1. Examples of polyhydroxylated indolizidine alkaloids.
In this article, we wish to report a highly concise and flexible
formal asymmetric synthesis of (ꢀ)-swainsonine and its 8-epimer.
The absolute stereochemistry of the natural product was introduced
by the enantioselective palladium-catalyzed hydroamination of
* Corresponding author. Tel.: þ82 054 279 2171; fax: þ82 054 279 3399; e-mail
address: yhrhee@postech.ac.kr (Y.H. Rhee).
http://dx.doi.org/10.1016/j.tet.2015.05.034
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

2
W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
alkoxyallene, which was recently developed by us.11 The synthetic
method uses minimal protective groups. In addition, the 8-epimer of
the natural product could be obtained with comparable efficiency to
the natural product.
tosyl amine 4 with n-pentyloxyallene 5 (2 equiv)11c at 40 ꢁC for 16 h
employing Pd2(dba)3 precatalyst (1 mol %) and (R,R)-DACH-naph-
thyl-Trost ligand 6 (2 mol %) produced the acyclic allylic acetal 7 in
>99% yield over >99% ee. Remarkably, the reaction on a multigram
scale showed a comparable result to our previous study in a re-
producible manner. Ring-closing-metathesis reaction of
7
2. Result and discussion
employing the first Grubbs catalyst provided the cyclic N,O-acetal 8
in near-quantitative yield.14,15 The subsequent Os-catalyzed dihy-
droxylation reaction gave 9 with desired absolute configuration in
high yield and selectivity, as shown previously.11c Thus, the key
sequential metal-catalyzed reaction proved to work well on
a multigram scale. More than 4 g of intermediate 9 was easily ob-
tained in 94% yield (over three steps) with >99% ee.
Our retrosynthetic analysis is depicted in Scheme 1. We envi-
sioned that the target compounds could be easily accessed from the
corresponding lactam precursors 1 and 2. The piperidine moiety in
1 and 2 could be formed from the lactone intermediate 3a (and 3b),
which would be easily prepared the alcohol A (and A0). These al-
cohols could be obtained by the stereocontrolled addition of the
propiolate moiety to the aldehyde B. We then envisaged that B
possessing all cis-substituents may be efficiently synthesized from
the N,O-acetal intermediate C,12 which could be accessed by the
sequential metal-catalyzed reactions from the allylic amine 4 and
the alkoxyallene D.
Scheme 2. Synthesis of hydroxylated pyrrolidine 9.
We then investigated the stereodivergent formation of the al-
cohols 13a/13b (Scheme 3). First, diol 9 was converted into the bis-
benzyl ether 10 in 96% yield with no particular event by treatment
with NaH and benzyl bromide in the presence of catalytic Bu4NI.
The subsequent Lewis acid-mediated synthesis of the cyanide 11
from 10 also proceeded smoothly in near-quantitative yield by the
use of BF3OEt2 (4 equiv) and TMSCN (3 equiv). Analysis of the 1H
NMR of the crude product showed over 10:1 stereoselectivity,
which is comparable to that observed with the bis-silyl ether in our
previous study.11c At this point, the stereochemistry of 11 was
tentatively assigned to be cis. (The stereochemical analysis was
confirmed by the synthesis of compound 14. Please see below).
Reduction of 11 to aldehyde 12 was somewhat troublesome, due to
the poor stability of 12.16 Under the optimized condition, 11 was
reacted with DiBAL-H (1.1 equiv) at ꢀ78 ꢁC. The resulting imine-
$aluminum complex was then carefully treated with 1N HCl solu-
tion at 0 ꢁC to give the aldehyde 12 inw88% yield after short-pad
chromatography, which was immediately used for the next step.17
As shown in Scheme 3, the stereodivergent formation of the alco-
hol 13a/13b from the aldehyde 12 showed fruitful outcome. The
reaction with no additive at ꢀ100 ꢁC gave a mixture of di-
astereomeric alcohols in overall 91% yield with moderate (4:1)
selectivity towards 13a (The stereochemistry of the major com-
pound was confirmed by the synthesis of the natural product.
Please see below). The use of MgBr2 (2 equiv) that are known to
induce chelation-controlled addition significantly improved the
diastereoselectivity (over 10:1) with slight increase of the yield. In
the light of this result, we reasoned that the use of additive that
prevents formation of the chelate would reverse the selectivity.
Indeed, the use of HMPA additive produced the diastereomeric 13b
(with 1:8 selectivity) as the major product in overall 94% yield.
Scheme 1. Retrosynthetic analysis of (ꢀ)-swainsonine.
A key task in the proposed method is to control the stereo-
chemical outcome of the propiolate addition to render a flexible
synthetic pathway that can give access to both (ꢀ)-swainsonine
and (ꢀ)-8-epi-swainsonine. In our previous study, the nature of the
protective group proved to be of critical importance in achieving
high cis-selectivity in the Lewis acid-mediated CeC bond formation
from the N,O-acetal intermediate D.11c,13 We decided to use the bis-
benzyl ether (OP¼OCH2Ph) because the benzyl moiety can be easily
removed under the hydrogenation condition for the formation of
the lactone 3a (and 3b) from B.
At the outset of the study, we sought to find a reliable synthetic
route that potentially allows for large-scale preparation of the tar-
get compound. Thus, we decided to investigate first the synthesis of
the key intermediate 9 on a multi-gram scale based upon our
previous report.11c As described in Scheme 2, the reaction of allyl
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
3
Scheme 5. Synthesis of lactam 1 and 2.
without harming various functional groups that are present in the
starting material. In this case, migration of the lactone moiety to the
lactam also occurred to provide a desired indolizidine compound 2
in 65% yield. Using the same protocol, the epimeric lactam 1 was
obtained in 71% yield from 3b. Based upon the known procedure for
the synthesis of 2 and its conversion into (ꢀ)-8-epi-swainsonine,
the above result represents a formal total synthesis of (ꢀ)-8-epi-
swainsonine.21 Our final task was to convert the compound 1 into
the known dimethylacetal analog 14, which was previously used
for the total synthesis of (ꢀ)-swainsonine. This transformation was
successfully accomplished in 88% yield by the reaction of 1 with
dimethoxypropane in the presence of catalytic p-TsOH. Thus, this
result represents a formal synthesis of (ꢀ)-swainsonine. In addi-
tion, the spectral data of compound 14 are in full accordance with
the literature value,22 thus unambiguously verifying the structural
Scheme 3. Synthesis of alcohol 13a and 13b.
The above result on the stereodivergent addition reaction can be
reasonably explained by the models shown in Scheme 4.18,19 In the
presence of HMPA, which prevents the chelation-controlled addi-
tion, E seems to be the reactive conformer in which the formyl
group moves away from the polar eOBn group. In this case, the
nucleophile should approach the aldehyde from the re-face, which
leads to the formation of diastereomer 13b. In the presence of
MgBr2, intermediate F is formed invoking chelation between the
formyl and OBn group. The subsequent addition reaction should
generate 13a as the major product.
Scheme 4. Rationlization of this selectivity in the synthesis of 13a and 13b.
With the both diastereomeric alcohols 13a and 13b in hand, we
moved to the final stage of the synthesis (Scheme 5). Debenzylation
of 13a and 13b with concomitant hydrogenation proceeded well
with Pd(OH)2/C under 10 atm of H2 atmosphere in the presence of
HCl. The resulting saturated ester slowly cyclized to furnish the
alcohol 3a and 3b in 85% and 88% yield, respectively. Initial efforts
towards the removal of the p-toluenesulfonyl group in 13a
employing Tomooka protocol20 (KPPh2 then HCl) showed extensive
decomposition of the starting material. To our delight, using clas-
sical dissolving-metal method (Na/NH3) smoothly proceeded
assignment suggested for the alcohol 13a and 13b. It should be fi-
nally pointed out that the lactam 1 and 2 could be obtained in 11
steps over 23e27% yield from commercially available starting ma-
terial n-pentanol (6 steps from known intermediate 9 in 37e41%
yield).
3. Conclusions
In conclusion, we have accomplished a concise formal synthesis
of (ꢀ)-swainsonine. The signature step features Pd-catalyzed
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

4
W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
asymmetric hydroalkoxylation of alkoxyallene, which can be per-
formed on a multi-gram scale. Noteworthy is the flexible nature of
the synthesis that gives access to both (ꢀ)-swainsonine and its 8-
epimer with comparable synthetic efficiency. Synthesis of other
nitrogen heterocycle natural products using the cyclic N,O-acetal 9
(and its piperidine analog) as the key building block are actively
ongoing in our laboratory.
4.3. (2R,3S,4R)- 3,4-Bis(Benzyloxy)-1-tosylpyrrolidine-2-
carbonitrile (11) and (2S,3S,4R)-3,4-bis(benzyloxy)-1-
tosylpyrrolidine-2-carbonitrile (110)
To a cold solution of compound 10 (6.99 g, 13 mmol) in CH3CN
(100 ml) at ꢀ40 ꢁC was added a solution of trimethylsilyl cyanide
(5.16 g, 6.51 ml, 52 mmol) and BF3ꢃOEt2(5.54 g, 4.82 ml,
39 mmol) in CH3CN (160 ml), respectively. The resulting solution
was stirred for 1 h at ꢀ40 ꢁC, and then warmed up to room
temperature. The reaction was monitored by TLC. When the re-
action was completed, the solution was quenched by satd
NaHCO3 (100 ml). The reaction solution was concentrated under
reduced pressure and aqueous residue was extracted with CH2Cl2
(3ꢄ30 ml). The organic layers were combined and dried over
anhydrous Na2SO4 and then concentrated under reduced pres-
sure. The residual oil was purified by flash column chromatog-
raphy (hexane/EtOAc¼80:20) to give the product mixture 11
(major isomer, 5.40 g, 11.7 mmol, 90%) and 110 (minor isomer,
541 mg, 1.17 mmol, 9%).
4. Experimental section
4.1. General information
Air and moisture sensitive reactions were carried out in oven-
dried glassware sealed with rubber septa under a positive pres-
sure of nitrogen. Similarly all solvents were dried and distilled
according to the standard methods before use, then were trans-
ferred via syringe. Reactions were stirred using Teflon-coated
magnetic stir bars. Pd2(dba)3 was purchased from Aldrich Chem-
ical. The Grubbs’ catalysts and chiral Trost ligands were purchased
form Strem Chemical Inc, and stored in glove box. Reactions were
monitored by thin-layer chromatography carried out on 0.25 mm E.
Merck silica gel plates (60F-254) using UV light as a visualizing
agent and acidic p-anisaldehyde and heat as developing agent.
Flash chromatography was carried out on Merck 60 silica gel
(230e400 mesh). 1H and 13C NMR spectra were recorded on Bruker
(300 MHz, 500 MHz) spectrometer. 1H NMR spectra were refer-
enced to CDCl3 (7.26 ppm), and reported as follows; chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
aps¼apparent singlet, apd¼apparent of doublet, apt¼apparent
triplet, m¼multiplet, br¼broad). Chemical shifts of the 13C NMR
spectra were measured relative to CDCl3 (77.23 ppm). Infrared
spectra were recorded on a Shimadzu IR-470 spectrometer. Specific
rotation data were measured on JASCO P-1020 Polarimeter. HPLC
was performed with an Agilent Technologies 1220 infinity LC sys-
tem. Melting points were measured on Electrothermal 9100. Mass
spectral data were obtained from the Korea Basic Science Institute
(Daegu) on a Jeol JMS 700 high resolution mass spectrometer (EI
and FAB).
For (2R,3 S,4R)- 3,4-bis(benzyloxy)-1-tosylpyrrolidine-2-
carbonitrile (11); Rf 0.34 (Hexane:EtOAc¼70:30); ½a D20
ꢀ4.18 (c
ꢂ
5.12, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d
7.76 (d, J¼8.31 Hz, 2H),
7.31 (m, 12H), 4.71 (m, 4H), 4.57 (d, J¼12.19 Hz, 1H), 4.05 (dt,
J¼2.21 Hz, 4.11 Hz, 1H), 3.96 (dd, J¼3.75 Hz, 7.10 Hz, 1H), 3.47 (dd,
J¼4.38 Hz, 10.73 Hz, 1H), 3.39 (dd, J¼2.13 Hz, 10.74 Hz, 1H), 2.43 (s,
3H); 13C NMR (75 MHz, CDCl3)
d 144.7, 137.6, 136.5, 134.5, 130.2,
128.9, 128.6, 128.6, 128.2, 127.9, 127.8, 127.7, 115.3, 78.7, 76.0, 73.4,
72.5, 50.7, 49.5.; IR (NaCl)
n 2876, 1597, 1497, 1455, 1352, 1212, 1165,
1045, 816, 739 cmꢀ1; HRMS (FABþ) calcd for C26H27N2O4Sþ
(MþH)þ 463.1692, found 463.1688.
For
(2S,3S,4R)-3,4-bis(benzyloxy)-1-tosylpyrrolidine-2-
carbonitrile (110); Rf 0.40 (Hexane:EtOAc¼70:30); ½a 2D0
þ30.348 (c
ꢂ
1.12, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d
7.72 (d, J¼8.26 Hz, 2H),
7.28 (m, 12H), 4.52 (m, 2H), 4.40 (m, 2H), 4.33 (d, J¼4.72 Hz, 1H),
4.17 (m, 1H), 4.04 (m, 1H), 3.54 (dd, J¼5.09 Hz, 10.32 Hz, 1H), 3.45
(dd, J¼5.41 Hz, 10.33 Hz, 1H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
144.7, 137.0, 136.4, 133.5, 130.1, 128.8, 128.7, 128.6, 128.4, 128.0,
128.0, 127.9, 81.1, 77.5, 77.2, 77.0, 75.8, 73.0, 72.3; IR (NaCl)
n 2924,
1597, 1497, 1455, 1354, 1215, 1167, 1091, 1028, 815, 740, 699 cmꢀ1
;
4.2. (2S,3R,4R)-3,4-Bis(benzyloxy)-2-(pentyloxy)-1-
tosylpyrrolidine (10)
HRMS (FABþ) calcd for C26H27N2O4Sþ (MþH)þ 463.1692, found
463.1690.
To a cold (0 ꢁC) slurry of NaH (1.5 g, 37.5 mmol, 60 w% in mineral
oil) in THF (50 ml) was added a solution of diol (6.61 g, 15 mmol) in
THF (100 ml) and stirred for 1 h at 0 ꢁC. The solution of BnBr (10.2 g,
7.13 ml, 60 mmol) in THF (50 ml) and TBAI (554 mg, 1.5 mmol) was
added and the reaction temperature was increased to reflux con-
dition. After 12 h, the reaction was quenched with satd NH4Cl sol
(10 ml) and H2O (150 ml) and the THF was removed under reduced
pressure. The resulting aqueous solution was extracted with
CH2Cl2 (150 ml) twice. Combined organic layer was dried with
Na2SO4 and solvent was removed. The obtained crude oil was pu-
rified by flash column chromatography eluted with (hexane/
EtOAc¼80:20) to give the product 10 as white solid. Rf 0.55
4.4. (2S,3S,4R)-3,4-Bis(Benzyloxy)-1-tosylpyrrolidine-2-
carbaldehyde (12)
To a cold solution of 11 (230 mg, 0.5 mmol) in CH2Cl2 (5 ml) at
ꢀ78 ꢁC was dropwisely added a solution of DIBAL-H (85 mg, 0.4 ml,
0.55 mmol, 1.5 M solution in toluene). The resulting solution was
stirred for 1 h at ꢀ78 ꢁC (monitored by TLC). Solution of aq 0.5 N HCl
(1 ml) and H2O (4 ml) was added and the solution was stirred for
1 h at 0 ꢁC. The precipitate was filtered and filtrate was extracted
with CH2Cl2 (3ꢄ10 ml). The organic layers were combined, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residual oil was purified by flash column chromatography
(hexane/EtOAc¼80:20) to give the desired aldehyde 12 (204 mg,
(Hexane:EtOAc¼70:30); mp: 60e62 ꢁC; ½a D20
þ15.592 (c 1.00,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d
7.69 (d, J¼8.3 Hz, 2H),
7.37e7.20 (m, 8H), 7.19e7.04 (m, 4H), 5.02 (s, 1H), 4.54e4.35 (m,
4H), 4.31 (ddd, J¼8.9, 7.4, 3.7 Hz, 1H), 3.90e3.72 (m, 2H), 3.65 (dd,
J¼8.4, 7.4 Hz, 1H), 3.49 (dt, J¼9.6, 6.5 Hz, 1H), 3.16 (t, J¼8.8 Hz, 1H),
2.28 (s, 3H), 1.61e1.47 (m, 2H), 1.40e1.20 (m, 4H), 0.91 (t, J¼6.8 Hz,
0.44 mmol, 88% yield). Rf 0.40 (Hexane:EtOAc¼70:30); ½a D20
ꢂ
ꢀ33.193 (c 1.03, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 9.63 (dd,
J¼0.71 Hz, 2.75 Hz, 1H), 7.68 (m, 2H), 7.30 (m, 12H), 4.60 (m, 4H),
4.01 (m, 2H), 3.84 (dd, J¼3.20 Hz, 7.46 Hz, 1H), 3.71 (dd, J¼3.38 Hz,
10.75 Hz, 1H), 3.31 (dd, J¼4.59 Hz, 10.73 Hz, 1H), 2.43 (s, 3H); 13C
3H). 13C NMR (75 MHz, CDCl3)
d 143.57, 137.75, 137.66, 135.08,
129.52, 128.62, 128.43, 128.10, 127.93, 127.86, 127.69, 91.69, 79.46,
77.50, 72.58, 72.04, 68.51, 48.67, 29.30, 28.46, 22.66, 21.67, 14.27. IR
NMR (75 MHz, CDCl3) d 199.7, 144.4, 137.5, 137.1, 134.4, 130.2, 128.7,
128.2, 128.2, 128.0, 127.9, 127.6, 81.2, 76.5, 73.0, 72.5, 65.8, 50.7,
21.8.; IR (NaCl) 2869, 1732, 1597, 1496, 1454, 1349, 1213, 1164,
(NaCl)
1168, 1098, 1063, 1029, 1002 cmꢀ1
30H37NO5S (Mþ) 523.2392, found 523.2389.
n
3089, 3065, 2953, 2871, 1650, 1598, 1497, 1455, 1351, 1209,
n
;
HRMS (EIþ) calcd for
1093, 1048, 1027, 816, 738 cmꢀ1
C
;
HRMS (FABþ) calcd for
C
26H28NO5Sþ (MþH)þ 466.1688, found 466.1685.
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
5
4.5. (S)-Ethyl 4-((2R,3S,4R)-3,4-bis(benzyloxy)-1-
4.7. Large scale preparation of (R)-ethyl 4-((2R,3 S,4R)-3,4-
tosylpyrrolidin-2-yl)-4-hydroxybut-2-ynoate (13a)
bis(benzyloxy)-1-tosylpyrrolidin-2-yl)-4-hydroxybut-2-ynoate
(13b)
To a cold solution of diisopropylamine (152 mg, 0.21 ml,
1.5 mmol) in THF (2 ml) was added n-BuLi (102 mg, 0.94 ml,
1.5 mmol, 1.6 M solution in hexane) at ꢀ78 ꢁC and the resulting
solution was stirred for 30 min at 25 ꢁC. The temperature was de-
creased to ꢀ100 ꢁC and ethyl propiolate (147 mg, 0.15 ml, 1.5 mmol)
in THF (1 ml) was added to the reaction mixture via syringe, and the
solution was stirred for 30 min. To the resulting solution was added
a solution of 12 (233 mg, 0.5 mmol) in THF (2 ml) and finally MgBr2
(184 mg,1 mmol) in THF (2 ml). The resulting solution was stirred at
ꢀ100 ꢁC for 1 h. The reaction mixture was quenched by aq NH4Cl
solution (10 ml) and THF was removed under reduced pressure. The
aqueous layer was extracted with CH2Cl2 (3ꢄ10 ml). The organic
layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residual oil was purified by flash column
chromatography (hexane/EtOAc¼80:20) to give the desired prod-
uct 13a (248 mg, 0.44 mmol) and 13b (24 mg, 0.04 mmol) in 96%
yield.
To a cold solution of 11 (5.56 g, 12 mmol) in CH2Cl2 (100 ml) at
ꢀ78 ꢁC was added a solution of DIBAL-H (2.05 g, 9.6 ml, 14.4 mmol,
1.5 M solution in toluene). The reaction solution was stirred for 1 h
at ꢀ78 ꢁC (monitored by TLC) and hydrolyzed by aq 0.5N HCl so-
lution (24 ml) and H2O (80 ml) for 1 h at 0 ꢁC. The precipitate was
filtered and filtrate was extracted with CH2Cl2 and water. The or-
ganic layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residual oil of 12 was filtered through
a pad of silica eluted with EtOAc 80% in Hexane. The solvent was
removed under reduced pressure, and the crude oil employed next
reaction without further purification.
To a cold solution of diisopropylamine (3.64 g, 5.04 ml,
36 mmol) was added n-BuLi (2.31 g, 22.5 ml, 36 mmol, 1.6 M so-
lution in hexane) at ꢀ78 ꢁC and stirred for 30 min at 25 ꢁC. The
temperature was decreased to ꢀ100 ꢁC and ethyl propiolate (3.53 g,
3.65 ml, 36 mmol) was added to the reaction mixture. After 30 min,
hexamethylphosphoramide (6.45 g, 6.26 ml, 36 mmol) was added
to this solution, and the resulting solution was stirred for 30 min.
To this solution was added the solution of crude 12 generated
above in THF (50 ml) slowly at ꢀ100 ꢁC and the resulting solution
was stirred for 1 h. The reaction mixture was quenched by aq NH4Cl
solution (100 ml) and THF was removed under reduced pressure.
The mixed residue was extracted with CH2Cl2 (100 mlꢄ3). The or-
ganic layers were combined, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residual oil was purified
by flash column chromatography (hexane/EtOAc¼80: 20) to give
the desired product 13a (549 mg, 0.97 mmol) and 13b (4.39 g,
7.78 mmol) in 73% yield over two step.
For 13a; Rf 0.40 (Hexane:EtOAc¼70:30); ½a D20
ꢀ21.580 (c 2.52,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.71 (m, 2H), 7.30 (m, 12H),
4.95 (dd, J¼4.36 Hz, 6.97 Hz, 1H), 4.63 (m, 4H), 4.20 (m, 2H), 4.10 (d,
J¼4.34 Hz, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.55 (m, 3H), 2.42 (s, 3H),
1.28 (t, J¼7.07 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d; 153.5, 141.6,
137.5, 137.2, 134.1, 130.2, 128.8, 128.6, 128.3, 128.1, 128.0, 127.8, 86.5,
78.4, 76.6, 74.0, 72.7, 64.3, 62.2, 62.0, 51.2, 21.8, 14.2; IR (NaCl)
n
3447, 3032, 2926, 2240, 1709, 1597, 1497, 1455, 1344, 1250, 1160,
1090, 1026, 941 cmꢀ1; HRMS (FABþ) calcd for C31H34NO7Sþ
(MþH)þ 564.2056, found 564.2060.
For 13b; Rf 0.31 (Hexane:EtOAc¼70:30); ½a D20
ꢀ45.841 (c 6.25,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d
7.70 (d, J¼8.18 Hz, 2H), 7.31
(m,12H), 4.98 (dd, J¼3.58 Hz,10.75 Hz,1H), 4.80 (d, J¼10.43 Hz,1H),
4.64 (d, J¼10.44 Hz, 1H), 4.55 (q, J¼12.01 Hz, 2H), 4.23 (m, 4H), 4.02
(dd, J¼3.66 Hz, 6.31 Hz, 1H), 3.59 (m, 2H), 3.44 (m, 1H), 2.42 (s, 3H),
4.8. (S)-5-((2S,3S,4R)-3,4-Dihydroxy-1-tosylpyrrolidin-2-yl)di-
hydrofuran-2(3H)-one (3b)
1.30 (t, J¼7.14 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 153.5, 144.3,
137.0, 136.9,134.5,130.1, 130.1,128.7,128.6,128.5,128.3,127.8,127.5,
To a stainless steel autoclave equipped with a stirring bar, the
catalyst Pd(OH)2/C (130 mg, 10 w%) and 13b (1.30 g, 2.31 mmol) in
MeOH and aqueous 1N HCl (20 ml, 1: one ratio by volume) were
placed. The autoclave was evacuated and filled with a hydrogen gas
three times (hydrogen was introduced until pressure gauge indicates
10 atm). The reaction temperature was increased to 120 ꢁC and the
resulting solution was stirred for 24 h. When the reaction was com-
pleted, an reaction mixture was neutralized with aq 1N NaOH solu-
tion until pH seven was reached. The reaction mixture was extracted
with CH2Cl2 (3ꢄ50 ml). The organic layers were combined, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residual oil was purified by flash column chromatography (hexane/
EtOAc¼20:80) to give the desired diol 3b (690 mg, 2.03 mmol, 88%
86.4, 79.7, 77.6, 76.5, 74.7, 72.6; IR (NaCl)
n 3473, 3064, 3032, 2983,
2938, 2874, 2234, 1709, 1497, 1455, 1402, 1249, 1159, 1092, 1026,
913 cmꢀ1; HRMS (FABþ) calcd for C31H34NO7Sþ (MþH)þ 564.2056,
found 564.2054.
4.6. (R)-Ethyl 4-((2R,3S,4R)-3,4-bis(benzyloxy)-1-
tosylpyrrolidin-2-yl)-4-hydroxybut-2-ynoate (13b)
To a cold solution of diisopropylamine (152 mg, 0.21 ml,
1.5 mmol) in THF (2 ml) was added n-BuLi (102 mg, 0.94 ml,
1.5 mmol, 1.6 M solution in hexane) at ꢀ78 ꢁC and the resulting
solution was stirred for 30 min at 25 ꢁC. The temperature was
decreased to ꢀ100 ꢁC and ethyl propiolate (147 mg, 0.15 ml,
1.5 mmol) in THF (1 ml) was added to the reaction mixture. After
30 min, hexamethylphosphoramide was added to generate
(269 mg, 0.26 ml, 1.5 mmol) pale red solution. To this solution was
added a solution of 12 (233 mg, 0.5 mmol) in THF (2 ml), and the
resulting solution was stirred for 1 h. The reaction mixture was
quenched by aq NH4Cl solution (10 ml) and THF was removed
under reduced pressure. The mixed residue was extracted with
CH2Cl2 (3ꢄ10 ml). The combined organic layers were washed with
water (3ꢄ10 ml), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residual oil was purified by flash
column chromatography (hexane/EtOAc¼80:20) to give the de-
sired product 13a (28 mg, 0.05 mmol) and 13b (237 mg,
0.42 mmol) in 94% yield.
yield). Rf 0.32 (Hexane:EtOAc¼40:60); ½a D20
ꢀ112.15 (c 0.55, CH2Cl2);
ꢂ
1H NMR (300 MHz, CDCl3)
d
7.71 (d, J¼8.28 Hz, 2H), 7.35 (d, J¼8.00 Hz,
2H), 4.99(m,1H), 3.96(dd, J¼5.11 Hz, 6.74 Hz,1H), 3.87(dd, J¼5.33 Hz,
8.48 Hz, 1H), 3.71 (dd, J¼5.50 Hz, 5.46 Hz, 1H), 3.55 (dd, J¼6.10 Hz,
12.29 Hz,1H), 3.34 (m,1H), 2.75 (br s, 2H), 2.58 (m, 3H), 2.44 (m, 4H);
13C NMR (75 MHz, CDCl3)
d 177.3,144.8,134.1,130.5,130.4,127.8,127.5,
79.8, 72.3, 70.4, 63.6, 52.9, 28.2, 25.5, 21.8; IR (NaCl)
n 3487, 3446,
3005, 2944, 2938, 1764, 1344, 1162, 667, 575 cmꢀ1; HRMS (FABþ)
calcd for C15H20NO6Sþ (MþH)þ 342.1011, found 342.1012.
4.9. (1S,2R,8R,8aR)-1,2,8-Trihydroxyhexahydroindolizin-
5(1H)-one (1)
To a deep blue solution of sodium (300 mg) in liq. NH3 (45 mL) at
ꢀ78 ꢁC was added compound 3b (66 mg, 0.2 mmol) in THF (5 mL)
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

6
W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
and the solution was stirred at ꢀ78 ꢁC for 90 min. The reaction was
quenched by addition of solid NH4Cl (200 mg). The solvent was
neutralized with aq 1N HCl solution until the pH reached seven and
the solvent was removed under reduced pressure. The resulting
crude product was dissolved in H2O and applied to ion-exchange
chromatography (Dowex 50WX8-100, Hþ form, 100e200 mesh)
eluting with H2O (100 ml) and 5% aq ammonium hydroxide solu-
tion (100 ml). Removal of water in vacuo provided 1 (27 mg,
4.12. (1S,2R,8S,8aR)-1,2,8-Trihydroxyhexahydroindolizin-
5(1H)-one (2)
To a deep blue solution of Na (400 mg) in liq. NH3 (55 ml) at
ꢀ78 ꢁC was added compound 3a (67 mg, 0.2 mmol) in THF (5 mL)
and the solution was stirred at ꢀ78 ꢁC for 90 min. The reaction was
quenched by addition of solid NH4Cl (200 mg). The solvent was
neutralized with aq 1N HCl solution until the pH reached seven and
the solvent was removed under reduced pressure. The resulting
crude product was dissolved in H2O and applied to ion-exchange
chromatography (Dowex 50WX8-100, Hþ form, 100e200 mesh)
eluting with H2O (100 ml) and 5% aq ammonium hydroxide solu-
tion (100 ml). Removal of water in vacuo provided 2 (25 mg,
0.14 mmol, 71% yield). Rf 0.25 (CHCl3:MeOH¼80:20); ½a D20
ꢀ24.755
ꢂ
(c 1.01, MeOH); 1H NMR (300 MHz, D2O)
d 4.44 (m, 1H), 4.26 (m,
1H), 4.00 (m, 1H), 3.72 (m, 1H), 3.53 (m, 1H), 3.19 (m, 1H), 2.43 (m,
2H), 2.09 (m, 1H), 1.87 (m, 1H); 13C NMR (75 MHz, D2O)
177.3,
3343, 2919,
d
144.8, 134.1, 130.5, 130.4, 127.8, 127.5, 79.8; IR (NaCl)
n
2850, 1570, 1456, 1418, 1033, 469 cmꢀ1; HRMS (FABþ) calcd for
0.13 mmol, 65% yield). Rf 0.27 (CHCl3:MeOH¼80:20); ½a D20
ꢀ0.807
ꢂ
C8H13NO4Naþ (MþNa)þ 210.0742, found 210.0740.
(c 2.60, MeOH); 1H NMR (300 MHz, D2O)
d
4.51 (td, J¼2.06 Hz,
3.87 Hz,1H), 4.47 (t, J¼3.93 Hz,1H), 4.35 (dt, J¼3.92 Hz, 7.87 Hz,1H),
3.78 (d, J¼1.62 Hz, 1H), 3.71 (dd, J¼7.65 Hz, 11.91 Hz, 1H), 3.36 (dd,
J¼7.32 Hz, 10.93 Hz, 1H), 2.42 (m, 2H), 1.94 (m, 2H); 13C NMR
4.10. (1R,2R,8R,8aS)-1,2,8,8a-Tetrahydroxyhexahy-
droindolizin-5(1H)-one (14)
(75 MHz, D2O)
(NaCl)
d 172.3, 73.2, 69.0, 63.8, 61.3, 48.3, 26.6, 25.5; IR
n
3355, 2919, 2849, 1609, 1470, 1412, 1327, 1115, 1033,
810 cmꢀ1; HRMS (FABþ) calcd for C8H14NO4Sþ (MþH)þ 188.0923,
To a solution of 1 (6 mg, 0.03 mmol) in acetone (1 ml) was added
dimethoxypropane (0.040 ml, 0.3 mmol) and p-toluenesulfonic
acid (3 mg, 0.017 mmol). The reaction solution was stirred for 3 h at
room temperature. When the reaction was complete, the reaction
solution was extracted with CH2Cl2 and water. The organic layers
were combined, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residual oil was purified by flash
column chromatography (hexane/EtOAc¼70: 30) to give the de-
sired product 14 (5 mg, 0.026 mmol, 88% yield). Rf 0.36
found 188.0923.
Acknowledgements
This research was supported by the National Research Founda-
tion of Korea (Nano-Material Technology Development Program
and NRF-2013R1A2A2A01068684).
(Hexane:EtOAc¼70:30); 1H NMR (300 MHz, CDCl3)
d 4.81 (t,
Supplementary data
J¼5.4 Hz, 1H), 4.75 (t, J¼5.3 Hz, 1H), 4.15 (m, 2H), 3.33 (dd, J¼8.1 Hz,
4.3 Hz, 1H), 3.13 (dd, J¼13.7 Hz, 5.0 Hz, 1H), 2.48 (m, 2H), 2.13 (m,
1H), 1.87 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3)
Supplementary data (Supplementary data (Electronic Supple-
mentary Data available: 1H and 13C NMR spectra of the new com-
pounds)) related to this article can be found at http://dx.doi.org/
10.1016/j.tet.2015.05.034.
d
168.3, 122.2, 79.8, 66.1, 65.6, 50.6, 29.7, 29.69, 26.3, 24.6; IR (NaCl)
3290, 2919, 1609, 1412, 1115 cmꢀ1. Spectral data are in full agree-
ment with the literature data.22
References and notes
1. (a) Shaheen, P.; Stadler, W.; Elson, P.; Knox, J.; Winquist, E.; Bukowski, R. Invest.
New Drugs 2005, 23, 577; (b) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin.
Cancer Res. 1997, 3, 1077; (c) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W.
Clin. Cancer Res. 1995, 1, 935.
4.11. (S)-5-((2S,3S,4R)-3,4-Dihydroxy-1-tosylpyrrolidin-2-yl)
dihydrofuran-2(3H)-one (3a)
2. Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem. Soc. 1973, 95, 2055.
To a stainless steel autoclave equipped with a stirring bar, the
catalyst Pd(OH)2/C (100 mg, 10 w%) and 13a (1.0 g, 1.77 mmol) in
MeOH and aqueous 1N HCl (10 ml, 1: one ratio by volume) were
placed. The autoclave was evacuated and filled with a hydrogen gas
three times (hydrogen was introduced until pressure gauge in-
dicates 10 atm). The reaction temperature was increased to 120 ꢁC
and the solution was stirred for 24 h. When the reaction was
completed, an acidic reaction solvent was neutralized with aq 1 N
NaOH solution until the pH reached 7. The reaction mixture was
extracted with CH2Cl2 (3ꢄ30 ml). The organic layers were com-
bined, dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The residual oil was purified by flash column
chromatography (hexane/EtOAc¼20:80) to give the desired diol 3a
(514 mg, 1.51 mmol, 85% yield). Rf 0.34 (Hexane:EtOAc¼40:60);
ꢀ
ꢀ
ꢀ
3. (a) Bastida, A.; Fernandez-Mayoralas, A.; Gomez Arrayas, R.; Iradier, F.; Carre-
tero, J. C.; García-Junceda, E. Chem.dEur. J. 2001, 7, 2390; (b) Liao, Y.-F.; Lal, A.;
Moremen, K. W. J. Biol. Chem. 1996, 271, 28348; (c) Tulsiani, D. R.; Harris, T. M.;
Touster, O. J. Biol. Chem. 1982, 257, 7936.
4. (a) Galustian, C.; Foulds, S.; Dye, J. F.; Guillou, P. J. Immunopharmacology 1994,
27, 165; (b) Dennis, J. W.; Koch, K.; Yousefi, S.; VanderElst, I. Cancer Res. 1990, 50,
1867; (c) Bowlin, T. L.; McKown, B. J.; Kang, M. S.; Sunkara, P. S. Cancer Res. 1989,
49, 4109.
5. (a) Bowen, D.; Adir, J.; White, S. L.; Bowen, C. D.; Matsumoto, K.; Olden, K.
Anticancer Res. 1993, 13, 841; (b) Myc, A.; Kunicka, J. E.; Melamed, M. R.; Dar-
zynkiewicz, Z. Cancer Res. 1989, 49, 2879; (c) Humphries, M. J.; Matsumoto, K.;
White, S. L.; Molyneux, R. J.; Olden, K. Cancer Res. 1988, 48, 1410.
6. (a) White, S. L.; Schweitzer, K.; Humphries, M. J.; Olden, K. Biochem. Biophys.
Res. Commun. 1988, 150, 615; (b) Kino, T.; Inamura, N.; Nakahara, K.; Kiyoto, S.;
Goto, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 936.
7. Borges de Melo, E.; da Silveira Gomes, A.; Carvalho, I. Tetrahedron 2006, 62,
10277.
8. (a) Hamaguchi, J.; Nakagawa, H.; Takahashi, M.; Kudo, T.; Kamiyama, N.; Sun, B.;
Oshima, T.; Sato, Y.; Deguchi, K.; Todo, S.; Nishimura, S.-I. Mol. Cancer 2007, 6,
58; (b) Oredipe, O. A.; Furbert-Harris, P. M.; Laniyan, I.; Griffin, W. M.; Sridhar, R.
Int. Immunopharmacol. 2003, 3, 1537; (c) Klein, J. L. D.; Roberts, J. D.; George, M.
D.; Kurtzberg, J.; Breton, P.; Chermann, J. C.; Olden, K. Br. J. Cancer 1999, 80, 87.
9. (a) Bhat, C.; Tilve, S. G. RSC Adv. 2014, 4, 5405; (b) Wardrop, D. J.; Waidyar-
achchi, S. L. Nat. Prod. Rep. 2010, 27, 1431; (c) Stocker, B. L.; Dangerfield, E. M.;
Win-Mason, A. L.; Haslett, G. W.; Timmer, M. S. M. Eur. J. Org. Chem. 2010, 2010,
1615; (d) Pyne, S. G. Curr. Org. Synth. 2008, 2, 39; (e) Michael, J. P. Nat. Prod. Rep.
2008, 25, 139; (f) El Nemr, A. Tetrahedron 2000, 56, 8579.
½
a 2D0
ꢂ
ꢀ21.580 (c 2.52, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.69 (d,
J¼8.29 Hz, 2H), 7.34 (d, J¼8.01 Hz, 2H), 4.98 (ddd, J¼1.91 Hz,
6.29 Hz, 7.82 Hz, 1H), 3.97 (dd, J¼1.96 Hz, 8.01 Hz, 1H), 3.84 (m, 2H),
3.59 (m, 1H), 3.34 (m, 1H), 3.23 (m, 1H), 3.03 (m, 1H), 2.76 (m, 2H),
2.56 (m, 1H), 2.45 (s, 3H), 2.38 (m, 1H); 13C NMR (75 MHz, CDCl3)
d
176.5, 144.9, 134.1, 130.4, 127.5, 77.0, 70.9, 69.6, 63.8, 55.2, 28.1,
24.1, 21.8; IR (NaCl)
n 3492, 2919, 2849, 1761, 1343, 1162, 668, 576,
549 cmꢀ1; HRMS (FABþ) calcd for C15H20NO6Sþ (MþH)þ 342.1011,
10. For selected recent examples, see: (a) Li, Q. R.; Dong, G. R.; Park, S. J.; Hong, Y.
found 342.1010.
R.; Kim, I. S.; Jung, Y. H. Eur. J. Org. Chem. 2013, 2013, 4427; (b) Dhand, V.;
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034

W. Lim, Y.H. Rhee / Tetrahedron xxx (2015) 1e7
7
Draper, J. A.; Moore, J.; Britton, R. Org. Lett. 2013, 15, 1914; (c) Archibald, G.; Lin,
C. P.; Boyd, P.; Barker, D.; Caprio, V. J. Org. Chem. 2012, 77, 7968; (d) Wardrop, D.
J.; Bowen, E. G. Org. Lett. 2011, 13, 2376; (e) Louvel, J.; Chemla, F.; Demont, E.;
Ferreira, F.; Perez-Luna, A. Org. Lett. 2011, 13, 6452; (f) Tian, Y. S.; Joo, J. E.; Kong,
B. S.; Pham, V. T.; Lee, K. Y.; Ham, W. H. J. Org. Chem. 2009, 74, 3962; (g) Bates,
R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706; (h) Kwon, H. Y.; Park, C. M.; Lee, S.
B.; Youn, J. H.; Kang, S. H. Chem.dEur. J. 2008, 14, 1023; (i) Guo, H. B.; O’Doherty,
G. A. Org. Lett. 2006, 8, 1609; (j) Ceccon, J.; Greene, A. E.; Poisson, J. F. Org. Lett.
2006, 8, 4739; (k) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097.
11. (a) Kim, H.; Rhee, Y. H. Synlett 2012, 2875; (b) Kim, H.; Rhee, Y. H. J. Am. Chem.
Soc. 2012, 134, 4011; (c) Kim, H.; Lim, W.; Im, D.; Kim, D.-G.; Rhee, Y. H. Angew.
Chem., Int. Ed. 2012, 51, 12055.
(c) Hilf, S.; Grubbs, R. H.; Kilbinger, A. F. M. J. Am. Chem. Soc. 2008, 130, 11040;
(d) Caskey, S. R.; Stewart, M. H.; Kivela, J. E.; Sootsman, J. R.; Johnson, M. J. A.;
Kampf, J. W. J. Am. Chem. Soc. 2005, 127, 16750.
16. For example, the aldehyde 12 was slowly transformed to the trans-epimer
during the column chromatography.
17. On a large-scale reaction, the crude aldehyde was used without column chro-
matography, due to the decomposition and the epimerization mentioned
above. In this case, the alcohol 13a could be obtained on 4.4 g scale in 73% yield
over two steps. For the detailed information, see the Experimental section.
18. (a) Dressel, M.; Restorp, P.; Somfai, P. Chem.dEur. J. 2008, 14, 3072; (b) Dono-
hoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.; Linney, I. D.
Org. Lett. 2008, 10, 3615; (c) Donohoe, T. J.; Cheeseman, M. D.; O’Riordan, T. J. C.;
Kershaw, J. A. Org. Biomol. Chem. 2008, 6, 3896; (d) Murray, A. J.; Parsons, P. J.
Synlett 2006, 1443; (e) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem.
2005, 70, 7297; (f) Donohoe, T. J.; Sintim, H. O. Org. Lett. 2004, 6, 2003; (g) Ikota,
N.; Hanaki, A. Chem. Pharm. Bull. 1990, 38, 2712.
12. (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am.
Chem. Soc. 2005, 127, 10879; (b) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am.
Chem. Soc. 2003, 125, 14149; (c) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco,
S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
13. Kang, S.; Kim, D.-g.; Rhee, Y. H. Chem.dEur. J. 2014, 20, 16391.
19. Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc. 2006, 128, 2920.
20. Yoshida, S.; Igawa, K.; Tomooka, K. J. Am. Chem. Soc. 2012, 134, 19358.
21. Fleet, G. W. J.; Peach, J. M.; Smith, P. W.; Austin, G. N.; Baird, P. D.; Watkin, D. J.
Tetrahedron 1987, 43, 3095.
14. We also investigated one-pot reaction of Pd-catalyzed hydroamination and
RCM for 8. However, this reaction showed no conversion. Presumably, excess
amount of the alkoxyallene inhibited the RCM reaction.
15. (a) Nagarkar, A. A.; Kilbinger, A. F. M. Chem. Sci. 2014, 5, 4687; (b) Lummiss, J. A.
M.; McClennan, W. L.; McDonald, R.; Fogg, D. E. Organometallics 2014, 33, 6738;
22. Shi, G.-F.; Li, J.-Q.; Jiang, X.-P.; Cheng, Y. Tetrahedron 2008, 64, 5005.
Please cite this article in press as: Lim, W.; Rhee, Y. H., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.034