Total synthesis of (-)-sessilifoliamide J

Article abstract of DOI:10.1021/jo3014484

An efficient synthesis of the Stemona alkaloid (-)-sessilifoliamide J (1) in 12 steps and 7.7% overall yield from the known building block 8 is presented. The synthesis features the Corey lactonization reaction and a highly diastereoselective α-methylation reaction to build the spirolactone moiety.

Full text of DOI:10.1021/jo3014484

Article
pubs.acs.org/joc
Total Synthesis of (−)-Sessilifoliamide J
Xue-Kui Liu,† Jian-Liang Ye,† Yuan-Ping Ruan,† Yu-Xiu Li,† and Pei-Qiang Huang*,†,‡
†Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: An efficient synthesis of the Stemona alkaloid
(−)-sessilifoliamide J (1) in 12 steps and 7.7% overall yield
from the known building block 8 is presented. The synthesis
features the Corey lactonization reaction and a highly
diastereoselective α-methylation reaction to build the spiro-
lactone moiety.
alkaloids, such as tuberostemospironine (2), croomine (3),
and dehydrocroomine (4).
INTRODUCTION
■
Over one hundred alkaloids have been isolated from plants of
genus Stemona (family Stemonaceae).1 The extracts of roots
and leaves of Stemonaceae plants have been used in China and
Japan for centuries as cough suppressants and domestic
insecticides.2 Recent studies showed that some of them possess
interesting bioactivities.3 The diverse and challenging structures
of Stemona alkaloids serve as attractive targets for synthetic
organic chemists, and in turn resulted in a number of elegant
total syntheses in either racemic or enantioselective manners.
Many novel and efficient synthetic strategies were thus
developed.4−12 Sessilifoliamide J (1) (Figure 1) is a Stemona
As a continuation of a program directed toward the total
synthesis of alkaloids,15 we have embarked recently on the total
synthesis of sessilifoliamide J (1).14 Our previous synthetic
efforts have led to the synthesis of 9-epi-sessilifoliamide J along
with sessilifoliamide J (1) as a minor diastereomer.14 However,
an efficient total synthesis of sessilifoliamide J (1) has not yet
been achieved. Toward this end, and in light of our previous
results,14 we devised an alternative approach starting from the
known chiron 8. We now report the successful implementation
of this new approach, which resulted in an efficient synthesis of
sessilifoliamide J (1).
RESULTS AND DISCUSSION
■
Our initial retrosynthetic analysis of sessilifoliamide J (1) is
outlined in Scheme 1. The retro-bis-lactonization16 disconnec-
tion implicates ketoaldehyde 5 as the key intermediate. The
Scheme 1. Retrosynthetic Analysis of (−)-Sessilifoliamide J
Figure 1. Structures of (−)-sessilifoliamide J (1) and some
tuberostemospironine group alkaloids.
alkaloid isolated in 2008 from the roots of Stemona sessilifolia
(Miq.) Miq. (Stemonaceae).13 Its structure and relative
stereochemistry was established by single crystal X-ray
crystallography analysis. The absolute configuration of the
natural product was determined very recently by our group as
3S,9S,9aS,11R,14S,16S.14
Structurally, sessilifoliamide J (1) contains a six-membered
piperidin-2-one ring, which is unique among the known
Stemona alkaloids; the C9 spiro α-methyl-γ-lactone moiety
also found in tuberostemospironine subclass of Stemona
Special Issue: Robert Ireland Memorial Issue
Received: July 13, 2012
© XXXX American Chemical Society
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subsequent retro-vinylogous Mannich reaction (VMR)17
disconnection has been well documented.18−20 The challenges
associated with the synthetic route based on this retrosynthetic
analysis include the unprecedented one-pot bis-lactonization
and the establishment of the four new chiral centers with
correct stereochemistries.
Scheme 3. Attempted Bis-lactonization Approach
Our investigation started with the construction of the
indolizidinone skeleton 6. Although the synthesis of this
compound has been reported previously by Hanessian18a and
Rassu/Casiraghi,18b respectively, starting from the N,O-acetal
7a,18 we devised a modified three-step approach to 6 involving
the use of Cbz-protected N,O-acetal 719 in a VMR (Scheme 2).
Scheme 2. Synthesis of the Indolizidinone Skeleton 6
Due to the configurational instability of the chiral aldehyde,
the crude ketoaldehyde 5 was promptly subjected to the SmI2-
mediated bis-lactonization. Although many SmI2-mediated
lactonization reactions between ketones and activated alkenes
have been reported,21 our attempts of various lactonization
conditions22 yielded neither the bis-lactonization of the
ketoaldehyde 5 to methyl methacrylate nor the monolactoniza-
tion of the aldehyde group apart from the reduced product 11.
We next tried the Reformatsky-type reaction23 by treating
ketoaldehyde 5 with organozinc reagent generated in situ from
zinc and methyl bromomethacrylate in THF at reflux.
Unfortunately, none of the desired product 12 was observed.
Instead, a rapid degradation of the starting ketoaldehyde in
refluxing THF was observed. At this stage, we decided to
abandon the initial plan of the one-pot bis-lactonization. A
stepwise installation of the two lactone rings in (−)-sessilifo-
liamide J (1) was anticipated.
Thus, compound 8, easily obtained from commercially available
(S)-pyroglutaminol 9 as described by Martin et al.,19 was
subjected to successive partial reduction with DIBAL-H and
CSA-catalyzed reaction with MeOH to afford the known N,O-
acetal 719 in 92% overall yield. The BF3·Et2O-catalyzed VMR18
between 7 and (trimethylsiloxy)furan (TMSOF) at −78 °C in
CH2Cl2 for 1 h produced an 85:15 ratio (determined by HPLC
on a crude) of threo-10 and its erythro diastereomer in 97%
yield (Scheme 2). According to our synthetic plan, both
diastereomers can be used for the synthesis of the target
molecule. Thus, under catalytic hydrogenation conditions (10%
Pd/C, H2 1 atm, 10 h), the diastereomeric mixture of 10 was
converted into the N-deprotected pyrrolidine-lactone. The
resulting lactone−pyrrolidine, without purification, was treated
with a catalytic amount of NaOMe at 0 °C for 2 h to afford
indolizidinone 6 as a diastereomeric mixture in 95% yield over
two steps.
We next proceeded to investigate the stepwise oxidation−
spiro-lactonization of alcohol 6 (Scheme 4). In contrast to the
Scheme 4. Stereoselective Installation of the Spiro-Lactone
Moiety
To prepare the ketoaldehyde 5 according to the planned bis-
lactonization, indolizidinone 6 was treated with 10 equiv of
Py·HF adduct in THF at room temperature for 24 h, which
gave the diol 11 in practically quantitative yield (Scheme 3).
The bis-oxidation of the diol 11 was attempted with several
methods including the Ley oxidation, Dess−Martin oxidation,
and Parikh−Doering oxidation. Even though the desired bis-
oxidation reaction took place under the above-mentioned
conditions, partial epimerization was observed. Only the Swern
oxidation at −78 °C afforded the desired ketoaldehyde 5 in a
75% yield. This ketoaldehyde turned out to be very susceptible
to epimerization, which could occur during the purification by
column chromatography on silica gel or when stored at 4 °C for
several hours.
bis-oxidation of diol 11, oxidation of the alcohol 6 under either
Ley or Dess−Martin oxidation conditions proceeded smoothly
to give the corresponding ketone. However, partial epimeriza-
tion at C8a was observed once again during the column
chromatography purification. This could be avoided by
subjecting the crude ketone directly to the SmI2-mediated
lactonization reaction with methyl methacrylate. In view of our
previous results,14 it was obvious that the conditions we used
previously for the spiro-lactonization at C8 would lead to 9-epi-
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sessilifoliamide J.24 To install the correct stereochemisry at C8
in sessilifoliamide J (1), we turned to the lactonization method
reported by Corey and Zheng.25 Indeed, the Ley oxidation−
Corey lactonization (10% SmI2, LiI, Zn−Hg, phenyl acrylate,
TMSOTf, THF, rt) of the alcohol 6 produced lactone 13
(Scheme 4) as a separable diastereomeric mixture in a ratio of
2:1 (13a:13b) in favor of the desired diastereomer 13a. Their
stereochemistries were deduced from that of compound 14.
Remarkably, the α-methylation (LiHMDS, THF, −78 °C, then
MeI) of lactone 13a gave almost exclusively the (8S,10R)-
diastereomer 14 in 72% yield. The relative stereochemistry of
compound 14 was determined by NOESY experiments. The
observed NOESY correlations (cf. Supporting Information for
Scheme 6. Synthesis of (−)-Sessilifoliamide J
the NOESY spectrum) between H7β ↔ H8a, H8a ↔ H1β
↔
CH2OTBDPS and those between H7α ↔ H9β ↔ 10-Me (Figure
2) allowed the unambiguous assignment of the stereochemistry
for compound 14.
Figure 2. Key correlations observed from the NOESY spectrum of
compound 14.
It is worth noting that although methylation is a valuable
tactic frequently used for the construction of the α-
methyllactone moiety of Stemona alkaloids,4,5e,f,8b it has not
been used for the α-methylation of the spirolactone to the best
of our knowledge. The stereochemical outcome of the highly
diastereoselective methylation of the enolate (A) generated
from the diastereomer 13a can be understood on the basis of
the conformation of the enolate A. The α-face (concave) of the
enolate, being blocked by the indolizidinone moiety, is highly
hindered. The approach of the electrophile (methyl iodide)
from the β-face (convex) predominates, giving rise to the
methylated product 14 with a R-configuration at the newly
formed stereogenic center.
diastereomeric lactones 17a and 17b in a 41:59 ratio
(determined by HPLC on a crude) with a combined yield of
90% from compound 15. The stereochemical assignment for
17a was confirmed by the ultimate transformation of 17a into
(−)-sessilifoliamide J, while that of 17b could be deduced from
17a. Hydrogenation6c [10% Pd/C, EtOH, H2 (1 atm), rt] of
the diastereomer 17a produced (−)-sessilifoliamide J (1) as the
sole diastereomer in 99% yield. The specific optical rotation
data [synthetic 1: [α]20 −72 (c 0.15, CHCl3); natural
sessilifoliamide J (1): [α]2D6 −73 (c 0.13, CHCl3);13 previous
D
synthesized compound: [α]20 −71 (c 0.15, CHCl3)14] and
D
spectroscopic data of our synthetic material are in agreement
with those reported previously.13
Scheme 5. Stereochemical Course of the Highly
Diastereoselective Methylation
CONCLUSIONS
■
In summary, we accomplished the first total synthesis of the
natural (−)-sessilifoliamide J (1) in 12 steps with an overall
yield of 7.7% starting from the known building block 8 (14
steps and 6.7% overall yield from commercially available 9).
Through this work, we demonstrated that the Corey
lactonization method is useful for the stereoselective con-
struction of the spiro-lactone moiety of the Stemona alkaloid,
and the subsequent lactone α-methylation can be achieved with
excellent diastereoselectivity.
The remaining task for our total synthesis of sessilifoliamide J
(1) was the construction of the second lactone ring. For this
purpose, compound 14 was desilylated (10 equiv Py·HF, THF,
rt) to give the corresponding compound 15 in 85% yield
(Scheme 6). The Swern oxidation of alcohol 15 proceeded
smoothly to produce aldehyde 16. However, epimerization of
16 occurred during its purification by column chromatography
on silica gel. This prompted us to attempt a tandem protocol.
While the tandem oxidation−SmI2-mediated lactonization was
unsuccessful, oxidation followed by organozinc reagent
addition23 led, without observable racemization, to the
EXPERIMENTAL SECTION
General Methods. Melting points were uncorrected. Infrared
spectra were measured using film KBr pellet techniques. H NMR
■
1
spectra were recorded in CDCl3 with tetramethylsilane as an internal
standard. Chemical shifts are expressed in δ (ppm) units downfield
from TMS. Silica gel (300−400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with ethyl acetate/
hexane. Ether and THF were distilled over sodium benzophenone
ketyl under N2. Dichloromethane was distilled over calcium hydride
C
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under N2. High-resolution mass spectra were obtained using
electrospray ionization using an ICR analyzer (ESI-MS).
Celite, and the retained solids were washed with MeOH (7 × 10 mL).
To the combined filtrates was added NaOMe (45 mg, 0.84 mmol) at 0
°C. After being stirred at 0 °C for 2 h, the reaction was concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with EtOAc to afford compound
6 (1.68 g, yield: 95%) as an inseparable diastereomeric mixture.
Compound 6: colorless oil; IR (film) νmax 3483, 3285, 3070, 3046,
2961, 2928, 2875, 2853, 1622, 1606, 1470, 1426, 1413, 1315, 1112,
Benzyl (2S,5R/S)-2-[(tert-Butyldiphenylsilyloxy)methyl]-5-
methoxypyrrolidine-1-carboxylate (7). To a solution of the
known chiron 819 (6.10 g, 12.5 mmol) in anhydride THF (125 mL)
was added dropwise a solution of DIBAL-H (1 M in hexane, 13.7 mL,
13.7 mmol) at −45 °C under N2. After being stirred at the same
temperature for 30 min, the reaction was quenched with a saturated
aqueous NH4Cl (5 mL) and a 1 M HCl (30 mL). The organic layer
was separated, and the aqueous layer was extracted with EtOAc (3 ×
30 mL). The combined organic layers were washed with brine (10
mL), dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was dissolved in MeOH (125 mL), and
camphorsulfonic acid (CSA, 360 mg, 1.3 mmol) was added at 0 °C.
After being stirred at 0 °C for 2 h, the reaction was concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel eluting with EtOAc/hexane (1:8) to afford the known
compound 719(5.80 g, yield: 92%) as an inseparable diastereomeric
mixture whose diastereomeric ratio was not determined due to the
rotamerism. Compound 7: colorless oil. Data of the diastereomeric
mixture: IR (film) νmax 3070, 3044, 2931, 2857, 1776, 1708, 1643,
1
1093, 1072 cm−1; H NMR (500 MHz, CDCl3) data of the major
diastereomer read from the spectrum of the mixture δ 1.05 (s, 9H),
1.72−1.81 (m, 1H), 1.85−2.10 (m, 5H), 2.20−2.35 (m, 1H), 2.46
(ddd, J = 18.8, 12.2, 7.1 Hz, 1H), 2.72 (br s, 1H), 3.60 (td, J = 8.4, 2.4
Hz, 1H), 3.75 (dd, J = 10.1, 2.4 Hz, 1H), 4.04 (br s, 1H), 4.07 (dd, J =
10.1, 4.2 Hz, 1H), 4.18−4.25 (m, 1H), 7.34−7.44 (m, 6H), 7.58−7.65
(m, 4H); 13C NMR (125 MHz, CDCl3) data of the major
diastereomer read from the spectrum of the mixture δ 19.4 (C),
24.5 (CH2), 26.3 (CH2), 26.7 (CH2), 26.9 (CH3), 28.2 (CH2), 58.2
(CH), 63.4 (CH), 63.7 (CH), 64.2 (CH2), 127.63 (CH), 127.65
(CH), 129.6 (CH), 129.7 (CH), 133.7 (C), 135.5 (CH), 135.6 (CH),
168.6 (CO); HRMS (ESI) calcd for [C25H33NO3Si + Na+] 446.2122,
found 446.2121.
1
1470, 1402, 1356, 1166, 1112 cm−1; H NMR (500 MHz, CDCl3) δ
(3S,8aS)-8-Hydroxy-3-(hydroxymethyl)hexahydroindolizin-
5(1H)-one (11). To a cooled solution (0 °C) of compound 6 (210
mg, 0.50 mmol) in anhydrous THF (5 mL) was added Py·HF (0.45
mL, 5.0 mmol) dropwise under N2. After being stirred at room
temperature for 24 h, the mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel eluting with EtOAc/MeOH (15:1) to afford compound 11 (92 mg,
yield: 99%) as an inseparable diastereomeric mixture. Compound 11:
white solid; IR (film) νmax 3485, 3415, 3280, 2960, 2928, 2874, 2853,
1620, 1600, 1470, 1425, 1112, 1093 cm−1; 1H NMR (500 MHz,
CDCl3) data of the major diastereomer read from the spectrum of the
mixture δ 1.60−1.94 (m, 4H), 2.01−2.15 (m, 2H), 2.37 (dd, J = 18.2,
7.0 Hz, 1H), 2.54 (ddd, J = 18.2, 12.4, 7.2 Hz, 1H), 3.46−3.56 (m,
2H), 3.65 (app d, J = 11.3 Hz, 1H), 4.06−4.21 (m, 2H), 5.65 and 5.94
(br 2s, 1H); 13C NMR (125 MHz, CDCl3) data of the major
diastereomer read from the spectrum of the mixture δ 26.0 (CH2),
26.2 (CH2), 26.3 (CH2), 27.9 (CH2), 61.9 (CH), 63.0 (CH), 63.5
(CH), 67.5 (CH2), 172.0 (CO); HRMS (ESI) calcd for [C9H15NO3 +
Na+] 208.0944, found 208.0946.
1.05 and 1.07 (2s, 9H), 1.74−1.88 (m, 1H), 1.90−2.08 (m, 1H),
2.10−2.30 (m, 2H), 3.18−3.46 (m, 3H), 3.50−4.15 (m, 3H), 4.94−
5.36 (m, 3H), 7.10−7.46 (m, 11H), 7.60−7.76 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 19.2 and 19.3 (C), 25.2 and 25.9 (CH2), 26.86
and 26.92 (CH3), 29.4 (CH2), 30.4 (CH2), 31.5 (CH2), 35.2 (CH2),
55.6 and 56.6 (CH3), 58.3 and 58.8 (CH), 63.6 and 64.1 (CH2), 66.8,
66.9, and 67.1 (CH2), 89.9 and 90.4 (CH), 127.6(CH), 127.7 (CH),
128.0 (CH), 128.1 (CH), 128.4 (CH), 128.5 (CH), 133.6 (C), 133.8
(C), 134.8 (C), 135.6 (CH), 136.4 (C), 154.9 (CO); HRMS (ESI)
calcd for [C30H37NO4Si + Na+] 526.2284, found 526.2284.
Benzyl (2S,5S)-2-[(tert-Butyldiphenylsilyloxy)methyl]-5-(5-
oxo-2,5-dihydrofuran-2-yl)pyrrolidine-1-carboxylate (10). To
a cooled solution (−78 °C) of compound 7 (2.178 g, 4.33 mmol) in
anhydrous CH2Cl2 (43 mL) was added dropwise (trimethylsiloxy)-
furan (TMSOF, 1.09 mL, 6.50 mmol) under N2. After being stirred at
−78 °C for 15 min, BF3·Et2O (0.32 mL, 2.60 mmol) was added
dropwise. After being stirred for an additional 1 h at the same
temperature, the reaction was quenched with a saturated aqueous
NaHCO3 (10 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with EtOAc/hexane (1:4) to
afford compound 10 (2.320 g, yield: 97%) as an inseparable
diastereomeric mixture in a ratio of 85:15 [determined by HPLC:
Shim-pack VP-ODS (150 × 4.6), CH3CN/H2O 75:25, 1.2 mL/min, λ
= 254 nm, t1 = 79.8 min (85.4%), t2 = 86.4 min (14.6%)]. Compound
10: colorless oil. Data of the diastereomeric mixture: IR (film) νmax
3070, 2957, 2930, 2857, 1759, 1698, 1405, 1354, 1157, 1112 cm−1; 1H
NMR (500 MHz, CDCl3) δ 1.019, 1.025, and 1.035 (3s, 9H), 1.43−
1.56 and 1.65−1.72 (m, 1H), 1.78−2.10 (m, 2H), 2.14−2.30 (m, 1H),
3.58−3.75 and 3.90−4.22 (m, 3H), 4.44 (dd, J = 8.6, 3.5 Hz, 0.8H)
and 4.89 (t, J = 1.8 Hz, 0.2H), 4.82 (d, J = 12.2 Hz, 0.6H) and 4.91−
5.21 (m, 1.4H), 5.30−5.80 (m, 1H), 5.92−6.18 (m, 1H), 7.00−7.70
(m, 16H); 13C NMR (125 MHz, CDCl3) δ 19.1 and 19.2 (C), 24.87
and 24.94 (CH2), 26.8 and 26.9 (CH3), 27.2 and 27.8 (CH2), 58.4 and
58.9 (CH), 59.6 and 60.2 (CH), 63.3, 64.3, and 64.5 (CH2), 67.1,
67.3, and 72.0 (CH2), 83.9 (CH), 121.0 and 122.4 (CH), 127.1 (CH),
127.8 (CH), 128.0 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH),
128.7 (CH), 129.75 (CH), 129.80 (CH), 129.83 (CH), 133.2 (C),
133.3 (C), 133.4 (C), 135.5 and 136.6 (CH), 136.1 (CH), 153.4
(CH), 153.7 (CH), 154.2 (CH), 154.7 (CH), 172.4 and 172.9 (CO);
HRMS (ESI) calcd for [C33H37NO5Si + Na+] 578.2333, found
578.2334.
(3S,8aS)-5,8-Dioxooctahydroindolizine-3-carbaldehyde (5).
To a cooled solution of (COCl)2 (0.40 mL, 4.20 mmol) in anhydrous
CH2Cl2 (7 mL) was added DMSO (0.35 mL, 4.90 mmol) in
anhydrous CH2Cl2 (2 mL) at −78 °C over 30 min. After being stirred
at −78 °C for another 30 min, to the resulting mixture was slowly
added diol 11 (130 mg, 0.70 mmol) in anhydrous CH2Cl2 (2 mL) at
−78 °C over 30 min. After being stirred at −78 °C for an additional 1
h, to the solution was slowly added TEA (1.17 mL, 8.40 mmol) at −78
°C over 30 min. After being stirred at the same temperature for 2 h,
the reaction was quenched with H2O (2 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 2
mL). The combined organic layers were washed with brine (1 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to afford crude ketoaldehyde 5 (96 mg, yield: 75%)
as a pale yellow oil: IR (film) νmax 2917, 2845, 2776, 1765, 1735, 1715,
1
1464, 1389, 1335, 1130, 1066 cm−1; H NMR (500 MHz, CDCl3) δ
1.94−2.01 (m, 1H), 2.00−2.21 (m, 2H), 2.23−2.30 (m, 1H), 2.54−
2.65 (m, 1H), 2.67−2.78 (m, 2H), 2.83−2.95 (m, 1H), 4.20 (t, J = 7.4
Hz, 1H), 4.66 (t, J = 7.0 Hz, 1H), 9.61 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 23.9 (CH2), 26.9 (CH2), 30.5 (CH2), 34.5 (CH2), 64.7
(CH), 65.1 (CH), 169.2 (CO), 197.7 (CHO), 205.8 (CO); HRMS
(ESI) calcd for [C9H11NO3 + Na+] 204.0631, found 204.0628.
Synthesis of Compounds 13a and 13b by Ley Oxidation−
Corey Lactonization Reaction (2S,3′S,8a′S)-3′-((tert-
Butyldiphenylsilyloxy)methyl)tetrahydro-1′H,3H-spiro[furan-
2,8′-indolizine]-5,5′(4H,8a′H)-dione (13a) (2R,3′S,8a′S)-3′-
((tert-Butyldiphenylsilyloxy)methyl)tetrahydro-1′H,3H-spiro-
[furan-2,8′-indolizine]-5,5′(4H,8a′H)-dione (13b). To a solution
of compound 6 (423 mg, 1.0 mmol) in CH2Cl2 (10 mL) were added 4
Å molecular sieves (423 mg), NMO (293 mg, 2.5 mmol), and TPAP
(3S,8aS)-3-((tert-Butyldiphenylsilyloxy)methyl)-8-hydroxy-
hexahydroindolizin-5(1H)-one (6). A suspension of 10% Pd on
carbon (232 mg) and 10 (2.32 g, 4.20 mmol) in MeOH (42 mL) was
stirred under H2 (1 atm) for 10 h. The mixture was filtered through
D
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(35 mg, 0.1 mmol). The resultant mixture was stirred at room
temperature for 30 min before being filtered through a thin silica gel
pad eluting with EtOAc/hexane (1:1). The solvent was removed under
reduced pressure. The crude ketone was used in the next step without
further purification. A suspension of LiI (700 mg, 5.20 mmol), the
crude ketone (1.0 mmol), and phenyl acrylate (0.166 mL, 1.2 mmol)
in THF (5 mL) was placed in a 5 mL gastight syringe which was
mounted on a syringe drive. A small aliquot of the solution (0.5 mL)
was added to a mixture of Zn−Hg (1 g, 15 mmol) and SmI2 (0.1 M,
1.0 mL, 0.1 mmol) in THF (15 mL) at room temperature. The rest of
the solution was added by the drive over 9 h. The reaction mixture
changed color gradually from dark blue to light blue. A small portion
of TMSOTf (10 μL, 0.06 mmol) was then added via a 100 μL gastight
micro syringe as soon as the color of the reaction mixture faded to
light blue. The reaction mixture became dark blue again in less than 2
min. When the color faded to light blue, a second aliquot of TMSOTf
(10 μL, 0.06 mmol) was added to restore the dark blue color.
TMSOTf was added portionwise as described above until the reaction
was judged completed by TLC monitoring. The total amount of
TMSOTf used was about 550 μL (3.0 mmol), and the total time of
reaction was about 9 h. The reaction mixture was concentrated in
vacuo to remove THF, treated with saturated aqueous NaHCO3 (10
mL) and extracted with Et2O (3 × 10 mL). The combined organic
layers were washed with brine (1 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel eluting with EtOAc/
hexane (2:1) to afford diastereomers 13a (194 mg, yield: 41%) and
13b (97 mg, yield: 20%).
1.05 (s, 9H), 1.31 (d, J = 7.1 Hz, 3H), 1.37−1.50 (m, 1H), 1.60 (dd, J
= 13.4, 10.8 Hz, 1H), 1.85 (ddd, J = 12.6, 6.3, 1.8 Hz, 1H), 1.99−2.13
(m, 3H), 2.20 (td, J = 12.6, 6.4 Hz, 1H), 2.32 (ddd, J = 18.2, 12.6, 6.2
Hz, 1H), 2.43−2.56 (m, 2H), 2.67−2.79 (m, 1H), 3.71 (dd, J = 10.1,
1.9 Hz, 1H), 3.81 (dd, J = 11.2, 4.8 Hz, 1H), 4.15 (dd, J = 10.1, 7.4 Hz,
1H), 4.15−4.20 (m, 1H), 7.34−7.44 (m, 6H), 7.58−7.62 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 16.7 (CH3), 19.3 (C), 24.4 (CH2), 26.9
(CH3), 27.3 (CH2), 28.7 (CH2), 34.6 (CH2), 35.0 (CH2), 35.3 (CH),
58.6 (CH), 63.4 (CH2), 64.9 (CH), 81.4 (C), 127.7 (CH), 129.8
(CH), 133.4 (C), 133.5 (C), 135.5 (CH), 135.6 (CH), 166.8 (CO),
178.0 (CO); HRMS (ESI) calcd for [C29H37NO4Si + Na+] 514.2384,
found 514.2388.
(2S,3′S,4R,8a′S)-3′-(Hydroxymethyl)-4-methyltetrahydro-
1′H,3H-spiro[furan-2,8′-indolizine]-5,5′(4H,8a′H)-dione (15).
To a cooled solution (0 °C) of compound 14 (41 mg, 0.08 mmol)
in anhydrous THF (1 mL) under N2 was added Py·HF (0.072 mL, 0.8
mmol) dropwise. After being stirred at room temperature for 24 h, the
mixture was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel eluting with EtOAc/
MeOH (15:1) to afford compound 15 (18 mg, yield: 85%) as a white
20
solid: mp 156−158 °C (MeOH); [α]D −23.4 (c 0.5, CHCl3); IR
(film) νmax: 3407, 2917, 2849, 1767, 1620, 1452, 1382, 1215, 1070
cm−1; 1H NMR (500 MHz, CDCl3) δ 1.34 (d, J = 7.2 Hz, 3H), 1.41−
1.51 (m, 2H), 1.66 (dd, J = 13.5, 10.8 Hz, 1H), 1.93 (ddd, J = 12.5,
6.2, 1.6 Hz, 1H), 1.99−2.06 (m, 1H), 2.13−2.22 (m, 1H), 2.33 (td, J =
12.6, 6.2 Hz, 1H), 2.44 (ddd, J = 18.4, 12.6, 6.6 Hz, 1H), 2.51 (dd, J =
13.6, 9.9 Hz, 1H), 2.68−2.80 (m, 2H), 3.60 (dd, J = 11.4, 7.5 Hz, 1H),
3.72 (br, 1H), 3.76 (td, J = 11.4, 4.8 Hz, 1H), 4.18 (app q, J = 7.8 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 16.6 (CH3), 25.9 (CH2), 26.8
(CH2), 28.6 (CH2), 34.2 (CH2), 35.0 (CH2), 35.2 (CH), 62.4 (CH),
64.6 (CH), 66.9 (CH2), 81.0 (C), 169.7 (CO), 177.6 (CO); HRMS
(ESI) calcd for [C13H19NO4 + Na+]: 276.1206; found: 276.1211.
Synthesis of Compounds 17a and 17b by Swern Oxidation−
organozinc Reagent Addition. (2S,3′S,4R,8a′S)-4-Methyl-3′-
((S)-4-methylene-5-oxotetrahydrofuran-2-yl)tetrahydro-
1′H,3H-spiro[furan-2,8′-indolizine]-5,5′(4H,8a′H)-dione (17a)
and (2S,3′S,4R,8a′S)-4-Methyl-3′-((R)-4-methylene-5-oxotetra-
hydrofuran-2-yl)tetrahydro-1′H,3H-spiro[furan-2,8′-indoli-
zine]-5,5′(4H,8a′H)-dione (17b). To a cooled solution of (COCl)2
(0.09 mL, 0.96 mmol) in anhydrous CH2Cl2 (1 mL) was slowly added
DMSO (0.09 mL, 1.28 mmol) in anhydrous CH2Cl2 (1 mL) at −78
°C over 30 min. After being stirred at −78 °C for another 30 min, to
the reaction was slowly added compound 15 (80 mg, 0.32 mmol) in
anhydrous CH2Cl2 (2 mL) at −78 °C over 30 min. After being stirred
at −78 °C for an additional 1 h, to the solution was slowly added TEA
(0.25 mL, 1.92 mmol) at −78 °C over 30 min. After being stirred at
the same temperature for 2 h, the reaction was quenched with H2O (2
mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 2 mL). The combined organic layers were
washed with brine (1 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford crude compound 16 as
a pale yellow solid, which was used in the next step without further
purification. To a stirred solution of aldehyde 16 (79 mg, 0.32 mmol)
in dry THF (3 mL) under N2 atmosphere, Zn (83 mg, 1.28 mmol)
was added. The solution was heated, and when reflux started, a
solution of ethyl 2-(bromomethyl)acrylate (0.077 mL, 0.64 mmol) in
dry THF (1 mL) was added. After 1 h, TLC analysis of the reaction
mixture revealed the disappearance of the starting aldehyde. The
reaction mixture was filtered through Celite and the solvent was
evaporated under vacuum. The remaining colorless oil was purified by
preparative HPLC on reversed phase [separated by HPLC: Shim-pack
VP-ODS (150 × 15), CH3CN/H2O 75:25, 20 mL/min, λ = 254 nm, t1
= 13.4 min (41.2%), t2 = 15.6 min (58.8%)] to afford compound 17a
(38 mg, yield: 37%) and compound 17b (54 mg, yield: 53%).
Compound 17a: white solid; mp 188−190 °C (MeOH); [α]20D −74.0
(c 0.5, CHCl3); IR (film) νmax 2918, 1768, 1654, 1443, 1413, 1290,
Compound 13a: colorless oil; [α]20 −33.8 (c 1.0, CHCl3); IR
D
(film) νmax 3070, 3046, 2930, 2856, 1777, 1656, 1643, 1427, 1413,
1113, 1068, 1018 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.06 (s, 9H),
1.41−1.53 (m, 1H), 1.88−2.04 (m, 3H), 2.05−2.21 (m, 4H), 2.33
(ddd, J = 18.5, 11.7, 6.8 Hz, 1H), 2.50−2.71 (m, 3H), 3.72 (dd, J =
10.2, 2.4 Hz, 1H), 3.86 (dd, J = 10.5, 5.2 Hz, 1H), 4.12 (dd, J = 10.2,
4.0 Hz, 1H), 4.18−4.26 (m, 1H), 7.34−7.44 (m, 6H), 7.58−7.61 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 19.3 (C), 24.5 (CH2), 25.6
(CH2), 26.8 (CH2), 26.9 (CH3), 28.6 (CH2), 28.8 (CH2), 33.2 (CH2),
58.7 (CH), 63.6 (CH2), 64.6 (CH), 83.7 (C), 127.7 (CH), 129.8
(CH), 133.3 (C), 133.4 (C), 135.5 (CH), 135.6 (CH), 166.8 (CO),
175.2 (CO); HRMS (ESI) calcd for [C28H35NO4Si + Na+] 500.2228,
found 500.2234.
Compound 13b: colorless oil; [α]20 −62.8 (c 1.0, CHCl3); IR
D
(film) νmax 3070, 3044, 2955, 2930, 2857, 1779, 1641, 1461, 1427,
1411, 1193, 1112, 1028 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.06 (s,
9H), 1.72 (m, 1H), 1.83 (m, 1H), 1.91−1.98 (m, 1H), 2.00−2.11 (m,
4H), 2.12−2.18 (m, 1H), 2.37 (dd, J = 17.3, 6.2 Hz, 1H), 2.48−2.72
(m, 3H), 3.66 (dd, J = 11.0, 5.4 Hz, 1H), 3.76 (dd, J = 10.2, 2.3 Hz,
1H), 4.16 (dd, J = 10.2, 3.9 Hz, 1H), 4.24−4.30 (m, 1H), 7.34−7.44
(m, 6H), 7.59−7.62 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.4
(C), 23.9 (CH2), 25.5 (CH2), 26.9 (CH3), 28.0 (CH2), 28.2 (CH2),
30.1 (CH2), 32.9 (CH2), 58.3 (CH), 64.3 (CH2), 65.8 (CH), 81.7
(C), 127.68 (CH), 127.70 (CH), 129.7 (CH), 129.8 (CH), 133.5 (C),
133.6 (C), 135.49 (CH), 135.53 (CH), 167.1 (CO), 175.6 (CO);
HRMS (ESI) calcd for [C28H35NO4Si + Na+] 500.2228, found
500.2228.
(2S,3″S,4R,8a′S)-3′-((tert-Butyldiphenylsilyloxy)methyl)-4-
methyltetrahydro-1′H,3H-spiro[furan-2,8′-indolizine]-
5,5′(4H,8a′H)-dione (14). To a solution of lactone 13a (400 mg,
0.84 mmol) in THF (8.5 mL) was added LiHMDS (0.872 mL, 0.924
mmol, 1.06 M in THF/ethylbenzene) at −78 °C under N2. After the
solution was stirred at −78 °C for 30 min, MeI (0.26 mL, 4.20 mmol)
was added and stirring continued for 1 h at −78 °C. The reaction was
quenched with saturated NH4Cl (0.5 mL), and the resulting mixture
was extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel eluting with EtOAc to afford compound 17 (296 mg,
yield: 72%) as a white solid: mp 78−81 °C (EtOAc); [α]20D −35.0 (c
0.9, CHCl3); IR (film) νmax 3075, 3041, 2917, 2849, 1777, 1657, 1642,
1
1254, 1116, 1019 cm−1; H NMR (500 MHz, CDCl3) δ 1.32 (d, J =
7.2 Hz, 3H), 1.44−1.54 (m, 1H), 1.63 (dd, J = 13.6, 10.1 Hz, 1H),
1.78−1.86 (m, 1H), 1.88 (ddd, J = 18.0, 6.4, 3.5 Hz, 1H), 2.06−2.16
(m, 2H), 2.20 (ddd, J = 18.0, 13.0, 6.5 Hz, 1H), 2.36 (ddd, J = 18.4,
1
1427, 1383, 1284, 1113, 1019 cm−1; H NMR (500 MHz, CDCl3) δ
E
dx.doi.org/10.1021/jo3014484 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
11.0, 6.4 Hz, 1H), 2.42 (dd, J = 13.6, 9.9 Hz, 1H), 2.61 (ddd, J = 18.4,
6.6, 3.6 Hz, 1H), 2.70−2.79 (m, 1H), 2.92 (ddt, J = 17.6, 8.4, 2.8 Hz,
1H), 3.05 (ddt, J = 17.6, 5.0, 2.6 Hz, 1H), 3.76 (dd, J = 10.1, 5.8 Hz,
1H), 4.56−4.62 (m, 1H), 4.94 (ddd, J = 8.4, 5.0, 3.0 Hz, 1H), 5.61 (t, J
= 2.6 Hz, 1H), 6.19 (t, J = 2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 16.8 (CH3), 24.5 (CH2), 27.3 (CH2), 28.6 (CH2), 29.8 (CH2), 33.6
(CH2), 35.2 (CH), 35.4 (CH2), 59.0 (CH), 65.5 (CH), 78.2 (CH),
81.1 (C), 121.8 (CH2), 134.0 (C), 168.7 (CO), 169.7 (CO), 177.5
(CO); HRMS (ESI) calcd for [C17H21NO5 + Na+]: 342.1312; found:
342.1316. Compound 17b: white solid; mp 209−211 °C (MeOH);
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D
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35.2 (CH), 60.0 (CH), 64.3 (CH), 75.2 (CH), 81.1 (C), 123.0 (CH2),
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D
D
CHCl3); lit.14 [α]20D −71 (c 0.15, CHCl3)]; IR (film) νmax 2964, 1773,
1637, 1450, 1407, 1384, 1263, 1096, 1018 cm−1; 1H NMR (500 MHz,
CDCl3) δ 1.27 (d, J = 7.1 Hz, 3H), 1.34 (d, J = 7.2 Hz, 3H), 1.51−1.56
(m, 1H), 1.65−1.72 (m, 2H), 1.78−1.87 (m, 1H), 1.92 (ddd, J = 13.0,
6.4, 3.8 Hz, 1H), 2.07−2.13 (m, 1H), 2.13−2.19 (m, 1H), 2.26 (ddd, J
= 13.0, 11.0, 6.4 Hz, 1H), 2.35 (ddd, J = 12.7, 8.6, 5.9 Hz, 1H), 2.41
(ddd, J = 18.3, 11.0, 6.4 Hz, 1H), 2.45 (dd, J = 13.6, 10.0 Hz, 1H),
2.63−2.69 (m, 1H), 2.70 (ddd, J = 18.3, 6.4, 3.9 Hz, 1H), 2.74−2.80
(m, 1H), 3.80 (dd, J = 10.3, 5.9 Hz, 1H), 4.60 (td, J = 7.7, 4.1 Hz, 1H),
4.86 (ddd, J = 10.2, 5.5, 4.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
14.9 (CH3), 16.9 (CH3), 24.3 (CH2), 27.3 (CH2), 28.7 (CH2), 32.4
(CH2), 33.7 (CH2), 35.2 (CH), 35.4 (CH2), 35.5 (CH), 57.7 (CH),
65.3 (CH), 78.5 (CH), 81.2 (C), 168.4 (CO), 177.6 (CO), 178.7
(CO); HRMS (ESI) calcd for [C17H23NO5 + Na+] 344.1474, found
344.1477.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds; NOESY
spectra of compound 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pqhuang@xmu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Basic Research Program (973
Program) of China (Grant No. 2010CB833200), the NSF of
China (20832005, 21072160), and the Fundamental Research
Funds for the Central Universities of China (Grant No.
201112G001) for financial support. We are grateful to Prof. Dr.
L.-F. Xie for valuable discussions.
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(23) Rauter, A. P.; Figueiredo, J.; Ismael, M.; Canda, T.; Font, J.;
Figueredo, M. Tetrahedron: Asymmetry 2001, 12, 1131−1146.
(24) Sessilifoliamide J and 9-epi-sessilifoliamide J were numbered
according to ref 13, which is different from the numbering for
compounds 6−17. As a consequence, C8 and C8a for the latter
compounds correspond to C9 and C9a in sessilifoliamide J and 9-epi-
sessilifoliamide J.
(25) Corey, E. J.; Zheng, G. Z. Tetrahedron Lett. 1997, 38, 2045−
2048.
G
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