Synthesis of chiral furopyrrolizidinones through a key tandem cope elimination/1,3-dipolar cycloaddition reaction of tricyclic lactones

Article abstract of DOI:10.1002/ejoc.201001515

Highly functionalized chiral furo-pyrrolizidinones containing contiguous quaternary centers were synthesized in moderate to good yields by treatment of various hexahydro-3,4-dioxa-8a-aza-as-indacen-2-ones with m-CPBA under basic conditions through a tande

Full text of DOI:10.1002/ejoc.201001515

FULL PAPER
DOI: 10.1002/ejoc.201001515
Synthesis of Chiral Furopyrrolizidinones through a Key Tandem Cope
Elimination/1,3-Dipolar Cycloaddition Reaction of Tricyclic Lactones
Yu-Jang Li,*[a] Hsiang-Yu Chuang,[a] Shang-Ming Yeh,[a] and Weng-Sang Huang[a]
Keywords: Synthetic methods / Heterocycles / Tandem reaction / Cycloaddition
Highly functionalized chiral furo-pyrrolizidinones containing
contiguous quaternary centers were synthesized in moderate
to good yields by treatment of various hexahydro-3,4-dioxa-
8a-aza-as-indacen-2-ones with m-CPBA under basic condi-
tions through a tandem Cope elimination/1,3-dipolar cyclo-
addition reaction sequence, followed by N–O cleavage and
lactam ring cyclization.
Introduction
We have recently reported on the synthesis of tri-
cyclic hexahydro-3,4-dioxa-8a-aza-as-indacen-2-ones
1
(Scheme 1) through [3,3]- or [1,3]-sigmatropic rearrange-
ments of γ-allyloxy vinylogous urethanes.[1] In our efforts
to explore new synthetic usages of these tricyclic lactones,
we envisioned that the tetracyclic compounds 5 might be
obtained by starting from compounds 1 through tandem
Cope elimination/1,3-dipolar cycloaddition reaction se-
quences.[2,3] Presumably, such a process would involve an
initial Cope elimination in a compound 2 to generate an
intermediate 3, consisting of an α,β-unsaturated lactone
component and a tethered N-hydroxypyrrolidine. After a
latent transformation of the initially formed N-hydroxypyr-
rolidine 3 into the cyclic nitrone 4, a sequential intramolec-
ular 1,3-dipolar cycloaddition of the cyclic nitrone to the
α,β-unsaturated moiety in a stereospecific fashion, dictated
by the existing chiral acetal tether, should furnish a tetra-
cyclic compound 5 containing a quaternary aza center and
a quaternary carbon center (Scheme 1). Although 1,3-di-
polar cycloadditions relating to cyclic nitrones have been
studied extensively,[4] nevertheless only one example of a
Cope elimination/intramolecular nitrone cycloaddition
strategy has been reported, by O’Neil et al.,[2a] involving the
reaction between a five-membered cyclic nitrone (generated
from TPAP/NMNO oxidation of N-hydroxypyrrolidine)
and a pre-existing simple alkene.
Scheme 1. Proposed pathway for the synthesis of furo-pyrrolizidi-
nones 6 starting form tricyclic compounds 1.
available for the synthesis of this type of molecule, and so
here we would like to report our studies directed towards
the synthesis of molecules of this type starting from 1.
Results and Discussion
We commenced our investigations with a search for ap-
propriate reaction conditions. Cope eliminations with the
aid of mCPBA to provide N-hydroxypyrrolidines of type 2
should be straightforward. For the oxidation of N-hydroxy-
pyrrolidines 2 into nitrones, there are various choices of rea-
gents, such as manganese dioxide, mercuric oxide, sodium
hypochlorite, or simply air.[7] To our great delight, when
compound 7a (Table 1) was treated with three equivalents
of m-CPBA along with three equivalents of potassium car-
bonate as a buffer in CH2Cl2 at ambient temperature for
12 h, the tetracyclic compound 8a was obtained as a single
diastereoisomer in 65% yield (Entry 1, Table 1). When com-
pounds 7b–e, with allyl, tert-butyldimethylsilyl ether, or
The N–O bond in a tetracyclic compound such as 5 can
be cleaved and then subsequently lactamized to provide a
furo[3,4-g]pyrrolizidinone such as 6.[5,6] To the best of our
knowledge, though, there are no general methodologies
[a] Department of Applied Chemistry, National Chiayi University,
300 University Road, Chiayi City 600, Taiwan
Fax: +886-5-2717901
E-mail: yjli@mail.ncyu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001515.
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Synthesis of Chiral Furopyrrolizidinones
benzyl substituents, were subjected to the same reaction cally from the α-face of the dipolarophile in an exo ap-
conditions, compounds 8b–e were obtained in reasonable proach as indicated in Scheme 1.
57–68% yields (Entries 2–5, Table 1). Under the same con-
To study the elimination process in this tandem reaction,
ditions, compounds 7f–h (with R2 = Me) and 7i–j (with R5 elimination reactions of 9 (labeled with exo deuterium, 81%
= Me or CH2CO2Et) were successfully transformable into D/H) and 12 (Scheme 2) were carefully scrutinized.[9] Al-
the tetracyclic compounds 8f–j in 60–70% yields (Entries 6– most exclusive formation of the tetracyclic 11 (81% D/H)
10, Table 1).
indicated that the tricyclic 9 had undergone a straightfor-
ward kinetically favored intramolecular syn elimination of
endo hydrogen. Nevertheless, the generation of 8i (same
product as the reaction product of 7i) from the tricyclic 12
(without an endo H) revealed that when no endo hydrogen
was available for syn elimination, anti elimination through
intermolecular exo hydrogen abstraction, presumably by
basic carbonate ion, can take place as an alternative route.
Table 1. Treatment of the tricyclic compounds 7a–n with mCPBA
in the presence of base.
Tricyclic compounds
R2–5
Prod.[a]
%
R1
Yield[b]
1
2
3
4
5
6
7
8
9
R2–5 = H
CH2CH2CH3
CH2CH=CH2
(CH2)3OTBS
Bn
7a 8a
7b 8b
7c 8c
7d 8d
65
68
57
62
58
70
70
68
60
60
65
68
57
63
R2–5 = H
R2–5 = H
R2–5 = H
R2–5 = H
CH2-3,4-(OMe)2Ph 7e 8e
R2 = Me, R3–5 = H
R2 = Me, R3–5 = H
R2 = Me, R3–5 = H
R2–4 = H, R5 = Me
CH2CH2CH3
CH2CH=CH2
(CH2)3OTBS
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
(CH2)3OTBS
CH2CH=CH2
CH2CH2CH3
7f 8f
7g 8g
7h 8h
7i 8i
7j 8j
7k 8k
7l 8l
7m 8m
7n 8n
10 R2–4 = H, R5 = CH2CO2Et
11 R2,4,5 = H, R3 = OTES
12 R2,4,5 = H, R3 = OTES
13 R2,3,5 = H, R4 = OTES
14 R2,3,5 = H, R4 = OPh
Scheme 2. Reactions of the tricyclic compounds 9 and 12 with
mCPBA in the presence of base.
Reductive cleavage of the N–O bonds of tetracyclic com-
pounds with activated zinc (activated with saturated aque-
ous NH4Cl)[10] resulted in one-pot reduction/lactamization
sequences providing the furo-pyrrolizidinone compounds
14a–g (Table 2) in 57–75% yields. The isomer ratios of β-
OH to α-OH in all the compounds 14a–g were determined
by 1H NMR integration. In addition, NOESY examination
of 14e indicated that R2 and R5 are syn to each other,
thereby confirming that the major isomer of 14e was a β-
[a] Reaction conditions: mCPBA (3 equiv.), K2CO3 (3 equiv.),
CH2Cl2, 25 °C, 12 h. [b] Isolated yields.
When the more complex tricyclic compounds 7k–n, with
latent functionality on their pyrrolidine rings, were sub-
jected to this tandem Cope elimination/1,3-dipolar cycload-
dition reaction sequence, the reactions also provided 8k–n
in satisfactory 57–68% yields (Entries 11–14, Table 1). The
stereochemistries of the products were as we had antici-
pated and were confirmed by the single-crystal X-ray analy- Table 2. Synthesis of the furo-pyrrolizidinones 14a–g through N–O
sis of compound 8n (Figure 1),[8] which suggests that the
bond cleavage.
chiral acetal-tethered nitrone dipole reacted stereospecifi-
Tetracyclic compounds
R2–5
Prod.[a] % Yield[b]
R1
(β-/α-OH)[c]
1
2
3
4
5
6
7
R2–5 = H
CH2CH2CH3 8a
CH2CH=CH2 8b
14a
14b
14c
14d
14e
14f
14g
75 (6:1)
72 (6:1)
57 (1:1)
62 (Ͼ19:1)
75 (7:1)
67 (8:1)
65 (15:1)
R2–5 = H
R2–5 = H
Bn
8d
R2 = Me, R3–5 = H
R2–4 = H, R5 = Me
CH2CH=CH2 8g
CH2CH=CH2 8i
R2,4,5 = H, R3 = OTES CH2CH=CH2 8k
R2,4,5 = H, R3 = OTES (CH2)3OTBS 8l
Figure 1. ORTEP view of the X-ray crystallographic structure of
8n (thermal ellipsoids shown at 50% probability).
[a] Reaction conditions: Zn powder, THF/H2O 4:1. [b] Isolated
yields. [c] Determined by H NMR integration.
1
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1933

Y.-J. Li, H.-Y. Chuang, S.-M. Yeh, W.-S. Huang
FULL PAPER
OH isomer. Although treatment of 8l with activated zinc
provided the expected furo-pyrrolizidinone 14g, the cleav-
age of the N–O bonds in 8c and 8h (Pearlman’s catalyst)
generated unexpected extra tetrahydropyran rings in the
products 15a and 15b (Scheme 3).[11] These tetrahydropyran
rings could conceivably have been formed by intramolecular
silyl transfer, followed by the formation of the oxonium ion
intermediates and intramolecular trapping of the hydroxy
moieties (Scheme 4). The stereochemistries of the three con-
tiguous quaternary centers in 15b were determined by sin-
gle-crystal X-ray analysis (Figure 2).[12]
Experimental Section
General: The starting materials 7b, 7d, 7e, and 7g were synthesized
by treatment of the corresponding 4-allyloxy keto esters or 4-aryl-
methoxy keto esters with prolinol (Ͼ99% ee purity), with the major
compounds each being obtained as a single diastereomer after flash
chromatography purification (de Ͼ 99%).[1] Compounds 7a and 7f
were obtained by hydrogenation (Pd/C, H2) of 7b and 7g. Com-
pounds 7i (R5 = Me) and 7j (R5 = CH2CO2Et) were synthesized
by diastereoselective alkylation of 7b with the corresponding alkyl-
ating reagents (de values greater than 99%). Compound 7k was
synthesized by treatment of trans-4-hydroxy-l-prolinol (Ͼ99% ee)
with the 4-allyloxy keto ester, followed by TES protection of the
alcohol (de Ͼ 99% after flash chromatography). Compound 7m
was prepared by treatment of trans-4-hydroxy-l-prolinol
(Ͼ99% ee) with the γ-allyloxy keto ester, followed by inversion of
the secondary alcohol and TES protection. Compound 7n was pre-
pared by treatment of trans-4-hydroxy-l-prolinol (Ͼ99% ee) with
the γ-allyloxy keto ester, followed by hydrogenation of the alkene
and inversion of the secondary alcohol with phenol. Compounds
7c, 7h, and 7l were obtained by alkene hydroboration of 7b, 7g,
and 7k and TBS protection of the resulting primary alcohols.
Scheme 3. Formation of 15a and 15b on hydrogenolysis of 8c and
8h.
General Procedure for the Synthesis of Compounds 8a–n: K2CO3
(191.2 mg, 1.38 mmol, 3 equiv.) and m-CPBA (311 mg, 1.38 mmol,
3 equiv.) were added at 0 °C to a tricyclic compound 7 (0.46 mmol)
in a 10 mL flask with CH2Cl2. The mixture was stirred for 10 min
at 0 °C and then allowed to warm to room temperature for an
additional 12 h. The reaction mixture was filtered and the filtrate
was concentrated to afford crude material. The crude material was
purified by flash chromatography (hexane/EtOAc 4:1) to provide
the products 8.
(2aS,6aR,8aS,8bR)-Hexahydro-8b-propyl-4H-1,3,8-trioxa-3a-aza-
dicyclopenta[a,gh]pentalen-2(2aH)-one (8a): Yield 71 mg, 65%. Col-
orless oil. Rf = 0.20 (hexane/EtOAc 3:1); [α]2D6 = +68.2 (c = 2.1,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.81 (s, 1 H,
OCHO), 4.28 (s, 1 H, OCHCO), 4.18 (d, J = 9.7 Hz, 1 H, ABq,
OCHHCN), 3.77 (d, J = 9.7 Hz, 1 H, ABq, OCHHCN), 3.54–3.47
(m, 1 H, NCHH), 2.94–2.84 (m, 1 H, NCHH), 2.24–2.08 (m, 2 H,
NCH2CHH, NCH2CH2CHH), 1.86–1.76 (m, 3 H, CCH2CH2CH3,
NCH2CHH), 1.63–1.57 (m, 2 H, CCH2CH2CH3), 1.46–1.35 (m, 1
H, NCH2CH2CHH), 1.04 (t, J = 7.2 Hz, 3 H, CCH2CH2-
CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.6 (C=O),
108.6 (CH), 86.2 (Cq), 81.6 (CH), 78.6 (CH2), 67.0 (Cq), 54.8
(CH2), 33.1 (CH2), 27.4 (CH2), 24.5 (CH2), 18.7 (CH2), 14.5
(CH3) ppm. MS-EI: m/z (%) = 239 (20) [M]+, 194 (3), 166 (20), 138
(16), 99 (100), 83 (38), 69 (20). HRMS-EI calcd. for C12H17NO4
239.1158; found 239.1153. C12H17NO4 (239.27): calcd. C 60.24, H
7.16, N 5.85; found C 60.35, H 7.28, N 5.62.
Scheme 4. Possible mechanism for the formation of the tetra-
hydropyran rings in 15a and 15b.
Figure 2. ORTEP view of the X-ray crystallographic structure of
(2aS,6aR,8aS,8bR)-Hexahydro-8b-propenyl-4H-1,3,8-trioxa-3a-
azadicyclopenta[a,gh]pentalen-2(2aH)-one (8b): Yield 74 mg, 68%.
Colorless oil. Rf = 0.20 (hexane/EtOAc 3:1); [α]2D6 = +32.4 (c = 2.3,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.81 (s, 1 H,
OCHO), 5.80–5.66 (m, 1 H, CH2CH=CH2), 5.33–5.27 (m, 2 H,
CH2CH=CH2), 4.34 (s, 1 H, OCHCO), 4.18 (d, J = 9.8 Hz, 1 H,
ABq, OCHHCN), 3.78 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN),
3.53–3.45 (m, 1 H, NCHHCH2), 2.96–2.86 (m, 1 H, NCHHCH2),
2.66–2.53 (m, 2 H, CH2CH2=CH), 2.29–2.06 (m, 2 H, NCH2CHH,
NCH2CH2CHH), 1.86–1.75 (m, 1 H, NCH2CHH), 1.64–1.54 (m,
1 H, NCH2CH2CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 173.3 (C=O), 131.1 (CH), 121.4 (CH2), 108.3 (CH), 86.2 (Cq),
81.1 (CH), 78.5 (CH2), 66.4 (Cq), 54.9 (CH2), 34.9 (CH2), 27.5
(CH2), 24.7 (CH2) ppm. MS-EI: m/z (%) = 237 (50) [M]+, 164 (30),
150 (30), 99 (100), 83, (42), 69 (24). HRMS-EI calcd. for
15b (thermal ellipsoids shown at 50% probability).
Conclusions
In conclusion, we have successfully obtained highly func-
tionalized furo-pyrrolizidinones from tricyclic hexahydro-
3,4-dioxa-8a-aza-as-indacen-2-ones through
Cope elimination/1,3-dipolar cycloaddition reaction se-
quence, subsequent N–O bond cleavage, and lactamization.
Further studies relating to this methodology, as well as syn-
thetic applications of furo-pyrrolizidinones to natural prod-
uct synthesis, are in progress in our laboratory.
a
tandem
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Synthesis of Chiral Furopyrrolizidinones
C12H15NO4 237.1001; found 237.0995. C12H15NO4 (237.25): calcd.
C 60.75, H 6.37, N 5.90; found C 60.46, H 6.32, N 5.74.
81 mg, 70%. Colorless oil. Rf = 0.22 (hexane/EtOAc 3:1); [α]2D6
=
1
+68.8 (c = 1.1, CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C): δ =
4.29 (s, 1 H, OCHCO), 4.12 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN),
3.72 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN), 3.52–3.44 (m, 1 H,
NCHH), 2.95–2.85 (m, 1 H, NCHH), 2.25–2.05 (m, 2 H,
NCH2CHH, NCH2CH2CHH), 1.88–1.75 (m, 3 H, CCH2CH2CH3,
NCH2CHH), 1.71–1.62 (m, 2 H, CCH2CH2CH3), 1.65 (s, 3 H,
CCH3), 1.52–1.39 (m, 1 H, NCH2CH2CHH), 1.02 (t, J = 7.1 Hz,
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 172.6
(C=O), 116.8 (Cq), 87.4 (Cq), 83.0 (CH), 77.6 (CH2), 68.2 (Cq),
54.7 (CH2), 32.2 (CH2), 29.6 (CH3), 25.0 (CH2), 22.4 (CH2), 18.6
(CH2), 14.8 (CH3) ppm. MS-EI: m/z (%) = 253 (16) [M]+, 289 (9),
180 (74), 166 (36), 152 (57), 139 (100), 138 (78). HRMS-EI calcd.
for C13H19NO4 253.1314; found 253.1316. C13H19NO4 (253.29):
calcd. C 61.64, H 7.56, N 5.53; found C 61.55, H 7.55, N 5.62.
(2aS,6aR,8aS,8bR)-Hexahydro-8b-(3-tert-butyldimethylsiloxy-
propyl)-4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-
one (8c): Yield 96 mg, 57%. Colorless oil. Rf = 0.22 (hexane/EtOAc
3:1); [α]2D6 = +34.7 (c = 2.3, CH2Cl2). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 5.79 (s, 1 H, OCHO), 4.30 (s, 1 H, OCHCO), 4.18 (d,
J = 9.8 Hz, 1 H, ABq, OCHHCN), 3.78 (d, J = 9.8 Hz, 1 H, ABq,
OCHHCN), 3.66 (dt, J = 5.7, 2.8 Hz, 2 H, SiOCH2), 3.50 (m, 1 H,
NCHH), 2.88 (m, 1 H, NCHH), 2.33–2.04 (m, 2 H, NCH2CHH,
NCH2CH2CHH), 1.95–1.90 (m, 2 H, CCH2CH2), 1.85–1.75 (1 H,
NCH2CHH), 1.63–1.52 (m, 3 H, CCH2, NCH2CH2CHH), 0.92 (s,
9 H, SiCMe3), 0.12 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 173.6 (C=O), 108.7 (CH), 86.2 (Cq), 81.8 (CH),
78.8 (CH2), 66.8 (Cq), 62.2 (CH2), 54.8 (CH2), 28.3 (CH2), 27.5
(CH2), 27.3 (CH2), 25.9 (3 ϫ CH3), 24.5 (CH2), 18.3 (Cq), –5.4
(2ϫCH3) ppm. MS-EI: m/z (%) = 369 (6) [M]+, 312 (30), 284 (30),
256 (57), 172 (40), 128 (53), 99 (30), 98 (100), 83 (29). HRMS-EI
calcd. for C18H31NO5Si 369.1972; found 369.1977. C18H31NO5Si
(369.53): calcd. C 58.51, H 8.46, N 3.79; found C 58.56, H 8.44, N
3.81.
(2aS,6aR,8aS,8bR)-Hexahydro-8a-methyl-8b-propenyl-4H-1,3,8-
trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8g): Yield
81 mg, 70%. Colorless oil. Rf = 0.22 (hexane/EtOAc 3:1); [α]2D6
=
1
+49.8 (c = 1.5, CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C): δ =
5.84–5.71 (m, 1 H, CH2 CH=CH2 ), 5.33–5.26 (m, 2 H,
CH2CH=CH2), 4.36 (s, 1 H, OCHCO), 4.15 (d, J = 9.8 Hz, 1 H,
ABq, OCHHCN), 3.75 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN),
3.51–3.43 (m, 1 H, NCHH), 2.96–2.86 (m, 1 H, NCHH), 2.69 (dt,
J = 6.4, 1.5 Hz, 2 H, CH2CH=CH2), 2.35–2.26 (m, 1 H,
NCH2CHH), 2.19–2.03 (m, 1 H, NCH2CH2CHH), 1.85–1.74 (m,
1 H, NCH2CHH), 1.69–1.62 (m, 1 H, NCH2CH2CHH), 1.66 (s, 3
H, CCH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 172.4
(C=O), 132.1 (CH), 120.7 (CH2), 116.6 (Cq), 87.5 (Cq), 82.7 (CH),
77.6 (CH2), 67.3 (Cq), 55.0 (CH2), 34.0 (CH2), 29.8 (CH3), 25.2
(CH2), 22.4 (CH2) ppm. MS-EI: m/z (%) = 251 (42) [M]+, 178 (70),
137 (71), 98 (56), 83 (100). HRMS-EI calcd. for C13H17NO4
251.1158; found 251.1152. C13H17NO4 (251.28): calcd. C 62.14, H
6.82, N 5.57; found C 62.32, H 6.90, N 5.31.
(2aS,6aR,8aS,8bR)-Hexahydro-8b-benzyl-4H-1,3,8-trioxa-3a-aza-
dicyclopenta[a,gh]pentalen-2(2aH)-one (8d): Yield 82 mg, 62%. Col-
orless oil. Rf = 0.28 (hexane/EtOAc 3:1); [α]3D0 = –0.8 (c = 1.1,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.39–7.19 (m, 5
H, ArH), 5.91 (s, 1 H, OCHO), 4.54 (s, 1 H, OCHCO), 4.22 (d, J
= 9.8 Hz, 1 H, ABq, OCHHCN), 3.84 (d, J = 9.8 Hz, ABq, 1 H,
OCHHCN), 3.53 (ddd, J = 14.5, 7.2, 3.4 Hz, 1 H, NCHH), 3.15
(d, J = 14.1 Hz, 1 H, ABq, ArCHH), 3.00 (d, J = 14.1 Hz, 1 H,
ABq, ArCHH), 3.00 (ddd, J = 14.5, 7.2, 2.8 Hz, 1 H, NCHH), 2.39
(ddd, J = 13.4, 8.9, 4.4 Hz, 1 H, NCH2CH2CHH), 2.21 (m, 1 H,
NCH2CHH), 1.83 (m, 1 H, NCH2CHH), 1.64 (ddd, J = 15.8, 13.4,
7.9 Hz, 1 H, NCH2CH2CHH) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 173.0 (C=O), 135.4 (C), 129.6 (2ϫCH), 129.3 (2ϫCH),
127.8 (CH), 107.6 (CH), 86.9 (Cq), 80.6 (CH), 78.3 (CH2), 67.5
(Cq), 54.9 (CH2), 36.0 (CH2), 28.2 (CH2), 25.0 (CH2) ppm. MS-EI:
m/z (%) = 287 (25) [M]+, 214 (18), 172 (42), 115 (58), 99 (100), 91
(72), 83 (37), 57 (23). HRMS-EI calcd. for C16H17NO4 287.1158;
found 287.1155. C16H17NO4 (287.31): calcd. C 66.89, H 5.96, N
4.88; found C 66.65, H 5.71, N 4.75.
(2aS,6aR,8aS,8bR)-Hexahydro-8b-(3-tert-butyldimethylsiloxy-
propyl)-8a-methyl-4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]-
pentalen-2(2aH)-one (8h): Yield 120 mg, 68%. Colorless oil. Rf =
0.25 (hexane/EtOAc 3:1); [α]2D6 = +36.5 (c = 1.2, CH2Cl2). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 4.33 (s, 1 H, OCHCO), 4.12 (d, J =
9.8 Hz, 1 H, ABq, OCHHCN), 3.72 (d, J = 9.8 Hz, 1 H, ABq,
OCHHCN), 3.65 (t, J = 5.7 Hz, 2 H, SiOCH2), 3.48 (ddd, J = 14.1,
7.0, 2.8 Hz, 1 H, NCHH), 2.94–2.84 (m, 1 H, NCHH), 2.36–2.28
(m, 1 H, NCH2CHH), 2.19–2.03 (m, 1 H, NCH2CH2CHH), 1.97–
1.91 (m, 2 H, SiOCH2CH2), 1.86–1.74 (m, 1 H, NCH2CHH), 1.72–
1.58 (m, 3 H, SiOCH2CH2CH2, NCH2CH2CHH), 1.65 (s, 3 H,
CCH3), 0.89 (s, 9 H, CCH3), 0.06 (s, 6 H, 2ϫCH3) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 172.6 (C=O), 116.8 (Cq), 87.4 (Cq),
83.1 (CH), 77.6 (CH2), 67.9 (Cq), 62.4 (CH2), 54.8 (CH2), 29.6
(CH3), 28.2 (CH2), 26.2 (CH2), 25.8 (3ϫCH3), 25.0 (CH2), 22.5
(CH2), 18.2 (Cq), –5.4 (2ϫCH3) ppm. MS-EI: m/z (%) = 383 (3)
[M]+, 326 (41), 310 (6), 114 (16), 98 (100). HRMS-EI calcd. for
C19H33NO5Si 383.2128; found 383.2135. C19H33NO5Si (383.55):
calcd. C 59.50, H 8.67, N 3.65; found C 59.38, H 8.55, N 3.62.
(2aS,6aR,8aS,8bR)-Hexahydro-8b-(3,4-dimethoxybenzyl)-4H-1,3,8-
trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8e): Yield
92 mg, 58%. Colorless oil. Rf = 0.28 (hexane/EtOAc 3:1); [α]3D0
=
1
+1.1 (c = 0.8, CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C): δ =
6.84 (d, J = 8.2 Hz, 1 H), 6.74 (dd, J = 8.2, 2.1 Hz, 1 H), 6.70 (d,
J = 2.1 Hz, 1 H), 5.94 (s, 1 H, OCHO), 4.54 (s, 1 H, OCHCO),
4.23 (d, J = 9.8 Hz, ABq, 1 H, OCHHCN), 3.87 (s, 6 H, 2ϫOCH3),
3.83 (d, J = 9.8 Hz, ABq, 1 H, OCHHCN), 3.53 (m, 1 H, NCHH),
3.09 (d, J = 14.2 Hz, 1 H, ABq, ArCHH), 2.99 (m, 1 H, NCHH),
2.94 (d, J = 14.2 Hz, 1 H, ABq, ArCHH), 2.37 (m, 1 H,
NCH2CH2CHH), 2.21 (m, 1 H, NCH2CHH), 1.84 (m, 1 H,
NCH2CHH), 1.63 (m, 1 H, NCH2CH2CHH) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 173.1 (C=O), 149.4 (C), 148.6 (C),
127.7 (C), 121.7 (CH), 112.6 (CH), 111.8 (CH), 107.7 (CH), 86.8
(Cq), 80.7 (CH), 78.3 (CH2), 67.6 (Cq), 56.0 (CH3), 55.9 (CH3),
54.9 (CH2), 35.6 (CH2), 28.1 (CH2), 24.9 (CH2) ppm. MS-EI: m/z
(%) = 347 (17) [M]+, 232 (100), 203 (19), 175 (13), 151 (28), 83
(11). HRMS-EI calcd. for C18H21NO6 347.1369; found 347.1366.
C18H21NO6 (347.36): calcd. C 62.24, H 6.09, N 4.03; found C
62.35, H 6.17, N 3.98.
(2aS,6aR,8aS,8bR)-Hexahydro-2a-methyl-8b-propenyl-4H-1,3,8-
trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8i): Yield
69 mg, 60%. Colorless oil. Rf = 0.20 (hexane/EtOAc 3:1); [α]2D6
=
1
+32.4 (c = 2.3, CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C): δ =
5.77 (s, 1 H, OCHO), 5.81–5.67 (m, 1 H, CH2CH=CH2), 5.35–5.27
(m, 2 H, CH2 CH=CH2 ), 4.14 (d, J = 9.7 Hz, 1 H, ABq,
OCHHCN), 3.73 (d, J = 9.7 Hz, 1 H, ABq, OCHHCN), 3.51–3.43
(m, 1 H, NCHH), 2.95–2.85 (m, 1 H, NCHH), 2.55 (dd, J = 14.7,
7.2 Hz, 1 H, CHHCH=CH2), 2.43 (dd, J = 14.7, 7.0 Hz, 1 H, CHH
CH=CH2), 2.28–2.09 (m, 2 H, NCH2CHH, NCH2CH2CHH),
(2aS,6aR,8aS,8bR)-Hexahydro-8a-methyl-8b-propyl-4H-1,3,8-
trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8f): Yield
Eur. J. Org. Chem. 2011, 1932–1939
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1935

Y.-J. Li, H.-Y. Chuang, S.-M. Yeh, W.-S. Huang
FULL PAPER
1 . 8 2 – 1 . 7 2 ( m , 1 H , N C H 2 C H H ) , 1 . 6 8 – 1 . 5 9 ( m , 1 H ,
NCH2CH2CHH), 1.37 (s, 3 H, CCH3) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 176.2 (C=O), 130.5 (CH), 121.1 (CH2), 108.5
(CH), 86.9 (Cq), 85.2 (Cq), 79.3 (CH2), 66.4 (Cq), 54.2 (CH2), 33.7
(C=O), 108.4 (CH), 85.4 (Cq), 82.2 (CH), 78.0 (CH2), 73.4 (CH2),
66.9 (Cq), 62.8 (CH), 62.0 (CH2), 38.1 (CH2), 28.8 (CH2), 27.3
(CH2), 25.9 (3ϫCH3), 18.3 (Cq), 6.7 (3ϫCH3), 4.6 (3ϫCH2), –6.2
(2ϫCH3) ppm. MS-EI: m/z (%) = 499 (3) [M]+, 484 (18), 442 (100),
(CH2), 27.2 (CH2), 24.4 (CH2), 15.0 (CH3) ppm. MS-EI: m/z (%) 414 (34), 384 (11), 356 (18), 228 (21), 183 (56), 115 (22), 96 (33),
= 251 (30) [M]+, 164 (11), 136 (31), 99 (100). HRMS-EI calcd. for
C13H17NO4 251.1158; found 251.1156. C13H17NO4 (251.28): calcd.
C 62.14, H 6.82, N 5.57; found C 62.08, H 6.70, N 5.61.
75 (94). HRMS-EI calcd. for C24H45NO6Si2 499.2785; found
499.2792. C24H45NO6Si2 (499.79): calcd. C 57.68, H 9.08, N 2.80;
found C 57.52, H 9.14, N 2.83.
(2aS,6aR,8aS,8bR)-Hexahydro-2a-(ethoxycarbonylmethyl)-8b- (2aS,5S,6aR,8aS,8bR)-Hexahydro-8b-propenyl-5-(triethylsiloxy)-
propenyl-4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-
one (8j): Yield 89 mg, 60%. Colorless oil. Rf = 0.22 (hexane/EtOAc
3:1); [α]2D6 = +123.4 (c = 2.1, CH2Cl2). 1H NMR (300 MHz, CDCl3,
4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8m):
Yield 96 mg, 57%. Colorless oil. Rf = 0.26 (hexane/EtOAc 3:1);
[α]2D6 = +32.1 (c = 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 5.90 (s, 1 H, OCHO), 5.74 (m, 1 H, CH2CH=CH2), 25 °C): δ = 5.80 (s, 1 H, OCHO), 5.73 (m, 1 H, CH2CH=CH2),
5.31–5.24 (m, 2 H, CH2CH=CH2), 4.17 (d, J = 9.7 Hz, 1 H, ABq,
OCHHCN), 4.16 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.74 (d, J =
9.7 Hz, 1 H, ABq, OCHHCN), 3.44 (m, 1 H, NCHH), 3.17 (d, J
5.29 (m, 2 H, CH2CH=CH2), 4.60 (m, 1 H, SiOCH), 4.35 (d, J =
10.4 Hz, 1 H, ABq, OCHHCN), 4.34 (s, 1 H, OCHCO), 3.89 (d, J
= 10.4 Hz, 1 H, ABq, OCHHCN), 3.52 (dd, J = 15.1, 5.4 Hz, 1 H,
= 18.1 Hz, 1 H, ABq, CHHCO), 2.91 (m, 1 H, NCHH), 2.70 (d, J NCHH), 3.16 (dd, J = 15.1, 2.8 Hz, 1 H, NCHH), 2.65–2.51 (m, 2
= 18.1 Hz, 1 H, ABq, CHHCO), 2.54 (m, 2 H, CH2CH2=CH), 2.25 H, CH2CH=CH2), 2.34 (dd, J = 13.3, 5.7 Hz, 1 H, NCCHH), 1.68
(m, 1 H, NCH2CHH), 2.11 (m, 1 H, NCH2CH2CHH), 1.79–1.63 (dd, J = 13.3, 2.1 Hz, 1 H, NCCHH), 0.93 [t, J = 7.9 Hz, 9 H,
(m, 2 H, NCH2CHH, NCH2CH2CHH), 1.26 (t, J = 7.2 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 175.1
(C=O), 169.4 (C=O), 130.5 (CH), 120.8 (CH2), 109.3 (CH), 87.2
(Cq), 85.5 (Cq), 79.6 (CH2), 66.6 (Cq), 61.7 (CH2), 54.1 (CH2),
Si(CH2CH3)3], 0.56 [q, J = 7.9 Hz, 6 H, Si(CH2CH3)3] ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 173.3 (C=O), 131.2 (CH),
121.3 (CH2), 107.8 (CH), 85.8 (Cq), 81.5 (CH), 78.3 (CH2), 73.3
(CH), 65.7 (Cq), 64.2 (CH2), 37.3 (CH2), 34.4 (CH2), 6.7 (3ϫCH3),
34.2 (CH2), 32.8 (CH2), 27.7 (CH2), 24.3 (CH2), 13.9 (CH3) ppm. 4.7 (3ϫCH2) ppm. MS-EI: m/z (%) = 367 (12) [M]+, 352 (10), 310
MS-EI: m/z (%) = 323 (45) [M]+, 278 (18), 164 (54), 136 (41), 114
(100), 99 (97), 83 (66), 67 (24). HRMS-EI calcd. for C16H21NO6
(100), 282 (32), 252 (30), 224 (15), 208 (25), 195 (28). HRMS-EI
calcd. for C18H29NO5Si 367.1815; found 367.1810. C18H29NO5Si
323.1369; found 323.1375. C16H21NO6 (323.34): calcd. C 59.43, H (367.51): calcd. C 58.83, H 7.95, N 3.81; found C 58.90, H 7.93, N
6.55, N 4.33; found C 59.61, H 6.45, N 4.18. 3.72.
(2aS,5R,6aR,8aS,8bR)-Hexahydro-8b-propenyl-5-(triethylsiloxy)- (2aS,5S,6aR,8aS,8bR)-Hexahydro-5-phenoxy-8b-propyl-4H-1,3,8-
4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8k):
Yield 110 mg, 65%. Colorless oil. Rf = 0.26 (hexane/EtOAc 3:1);
[α]2D6 = +82.2 (c = 0.8, CH2Cl2). 1H NMR (300 MHz, CDCl3,
2 5 °C ): δ = 5 . 78 (s, 1 H , O C HO ) , 5 . 7 8 – 5 . 6 8 ( m , 1 H ,
CH2CH=CH2), 5.32–5.26 (d, J = 16.9 Hz, 1 H, CH2CH=CHH),
trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (8n): Yield
96 mg, 63%. Colorless solid, m.p. 164–165 °C. Rf = 0.30 (hexane/
EtOAc 3:1); [α]2D6 = +44.5 (c = 0.1, CH2Cl2). H NMR (300 MHz,
1
CDCl3, 25 °C): δ = 7.32–7.29 (dd, J = 8.7, 7.3 Hz, 2 H, ArH), 7.00–
6.96 (dd, J = 7.3, 0.9 Hz, 1 H, ArH), 6.83–6.80 (dd, J = 8.7, 0.9 Hz,
5.29–5.26 (d, J = 10.1 Hz, 1 H, CH2CH=CHH), 4.49 (s, 1 H, 2 H, ArH), 5.81 (s, 1 H, OCHO), 5.14–5.10 (m, 1 H, SiOCH), 4.39
OCHCO), 4.42 (m, 1 H, SiOCH), 4.17 (d, J = 9.7 Hz, 1 H, ABq, (d, J = 10.3 Hz, 1 H, ABq, OCHHCN), 4.33 (s, 1 H, OCHCO),
OCHHCN), 3.78 (d, J = 9.7 Hz, 1 H, ABq, OCHHCN), 3.37 (dd, 3.89 (d, J = 10.3 Hz, 1 H, ABq, OCHHCN), 3.82–3.75 (dd, J =
J = 14.2, 6.5 Hz, 1 H, NCHH), 3.18 (dd, J = 14.2, 4.7 Hz, 1 H, 15.8, 5.9 Hz, 1 H, NCHH), 3.49–3.43 (dd, J = 15.8, 2.9 Hz, 1 H,
NCHH), 2.73 (dd, J = 14.4, 7.2 Hz, 1 H, CHHCH=CH2), 2.58 (dd, NCHH), 2.59–2.52 (dd, J = 14.1, 6.0 Hz, 1 H, NCCHH), 2.04–
J = 14.4, 7.0 Hz, 1 H, CHHCH=CH2), 2.30 (dd, J = 13.6, 6.0 Hz,
1.99 (d, J = 14.1 Hz, 1 H, NCCHH), 1.87–1.80 (m, 2 H,
1 H, NCCHH), 1.99 (dd, J = 13.6, 6.9 Hz, 1 H, NCCHH), 0.93 (t, CH3CH2CH2), 1.46–1.35 (m, 2 H, CH3CH2CH2), 1.06–1.01 (t, J =
J = 7.9 Hz, 9 H, 3ϫCH3), 0.59 (q, J = 7.9 Hz, 6 H, 3ϫCH2) ppm. 7.2 Hz, 3 H, CH3CH2CH2) ppm. 13C NMR (75 MHz, CDCl3,
13C NMR (75 MHz, CDCl3, 25 °C): δ = 172.8 (C=O), 131.4 (CH), 25 °C): δ = 173.2 (C=O), 156.6 (C), 129.7 (2ϫCH), 121.5 (2ϫCH),
121.2 (CH2), 108.2 (CH), 85.4 (Cq), 81.8 (CH), 78.0 (CH2), 73.3
(CH), 66.6 (Cq), 62.1 (CH2), 38.3 (CH2), 35.0 (CH2), 6.7 (3ϫCH3), (CH), 66.5 (Cq), 60.7 (CH2), 33.9 (CH2), 18.9 (CH2), 14.5
4.6 (3ϫCH2) ppm. MS-EI: m/z (%) = 367 (8) [M]+, 352 (15), 310 (CH2) ppm. MS-EI: m/z (%) = 331 (10) [M]+, 274 (100), 258 (60),
(100), 282 (41), 252 (33), 224 (18) (56), 208 (20), 195 (52). HRMS- 238 (71), 210 (30), 194 (25), 181 (20), 165 (31). HRMS-EI calcd.
115.3 (CH), 108.1 (CH), 85.9 (Cq), 82.1 (CH), 78.1 (CH2), 77.6
EI calcd. for C1 8 H2 9 NO5 Si 367.1815; found 367.1819.
C18H29NO5Si (367.51): calcd. C 58.83, H 7.95, N 3.81; found C
58.96, H 7.99, N 3.72.
for C18H21NO5 331.1420; found 331.1412. C18H21NO5 (331.36):
calcd. C 65.24, H 6.39, N 4.23; found C 65.09, H 6.57, N 4.14.
(2aS,6aR,8aS,8bR)-Hexahydro-2a-deuterio-8b-propenyl-4H-1,3,8-
(2aS,5R,6aR,8aS,8bR)-Hexahydro-8b-(3-tert-butyldimethylsiloxy- trioxa-3a-azadicyclopenta[a,gh]pentalen-2(2aH)-one (11): Yield
propyl)-5-(triethylsiloxy)-4H-1,3,8-trioxa-3a-azadicyclopenta[a,gh]-
pentalen-2(2aH)-one (8l): Yield 156 mg, 68%. Colorless oil. Rf =
0.28 (hexane/EtOAc 3:1); [α]2D6 = +35.6 (c = 0.1, CH2Cl2). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.77 (s, 1 H, OCHO), 4.45 (s, 1 H,
62 mg, 57%. Colorless oil, Rf = 0.20 (hexane/EtOAc 3:1); [α]2D6
+30.6 (c = 5.4, CH2Cl2). H NMR (300 MHz, CDCl3, 25 °C): δ =
5.78 (s, 1 H, OCHO), 5.76–5.64 (m, 1 H, CH2CH=CH2), 5.29 (m,
2 H, CH2CH=CH2), 4.14 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN),
=
1
OCHCO), 4.43 (m, 1 H, SiOCH), 4.17 (dd, J = 9.7 Hz, 1 H, ABq, 3.76 (d, J = 9.8 Hz, 1 H, ABq, OCHHCN), 3.53–3.45 (m, 1 H,
OCHHCN), 3.77 (d, J = 9.7 Hz, 1 H, ABq, OCHHCN), 3.71–3.63 NCHH), 2.96–2.86 (m, 1 H, NCHH), 2.67–2.53 (m, 2 H,
(m, 2 H, SiOCH2), 3.36 (ddd, J = 11.1, 11.1, 6.7 Hz, 1 H, NCHH),
CH2CH=CH2), 2.29–2.06 (m, 2 H, NCH2CHH, NCH2CH2CHH),
3.20 (m, 1 H, NCHH), 2.31 (m, 1 H, NCCHH), 2.04–1.92 (m, 2 1 . 8 6 – 1 . 7 5 ( m , 1 H , N C H 2 C H H ) , 1 . 6 4 – 1 . 5 4 ( m , 1 H ,
H), 1.60–1.51 (m, 3 H), 0.94 [t, J = 7.8 Hz, 9 H, Si(CH2CH3)3], NCH2CH2CHH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
0.90 (s, 9 H, SiCMe3), 0.58 [q, J = 7.8 Hz, 6 H, Si(CH2CH3)3], 0.06 173.3 (C=O), 131.1 (CH), 121.2 (CH2), 108.3 (CH), 86.1, 81.1 (19%
(s, 6 H, SiMe2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 173.1
C-H), 78.4 (CH2), 66.3 (Cq), 54.8 (CH2), 34.8 (CH2), 27.4 (CH2),
1936
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1932–1939

Synthesis of Chiral Furopyrrolizidinones
24.6 (CH2) ppm. MS-EI: m/z (%) = 238 (7) [M]+, 164 (74), 150
(45), 99 (100), 83 (30), 57 (23). HRMS-EI calcd. for C12H14DNO4
238.1064; found 238.1070.
OH compounds: 13C NMR (75 MHz, CDCl3, 25 °C): δ = 177.5
(C=O), 173.3 (C=O), 138.5 (C), 137.5 (C), 130.5 (2ϫCH), 130.4
(2ϫCH), 128.4 (2ϫCH), 127.9 (2ϫCH), 126.5 (CH), 125.9 (CH),
101.3 (CH), 100.9 (CH), 78.9 (CH2), 77.1 (CH2), 76.7 (Cq), 76.6
(Cq), 74.6 (CH), 72.0 (CH), 62.0 (Cq), 56.2 (Cq), 41.8 (N–CH2),
41.1 (N–CH2), 32.7 (CH2), 32.6 (CH2), 31.3 (CH2), 30.7 (CH2),
25.3 (CH2), 24.3 (CH2) ppm. MS-EI: m/z (%) = 289 (11) [M]+, 271
(9), 229 (100), 212 (20), 150 (30), 91 (42). HRMS-EI calcd. for
C16H19NO4 289.1314; found 289.1310. C16H19NO4 (289.33): calcd.
C 66.42, H 6.62, N 4.84; found C 66.40, H 6.58, N 4.77.
General Procedure for the Synthesis of Compounds 14a–g: Activated
zinc[10] (0.13 g, 2.0 mmol, 10 equiv.) was added to a tetracyclic com-
pound 8 (0.2 mmol) in a 10 mL flask with THF (2 mL) and deion-
ized water (0.5 mL). After the mixture had been stirred for 15 h at
room temperature, saturated aqueous NaHCO3 (1.5 mL) was
added to quench the reaction and the mixture was then extracted
with EtOAc (2 mLϫ3). Combined organic layers were dried with
anhydrous sodium sulfate and then purified by flash chromatog-
raphy (CH2Cl2/MeOH 50:1) to provide 14.
(3S,3aR,4S,8aR)-3a-Allyl-3,4-dihydroxy-3-methyl-tetrahydro-7H-
furo[3,4-g]pyrrolizin-5(3H)-one (14d): Yield 31 mg, 62%. Colorless
oil. Rf = 0.45 (CH2Cl2/MeOH 10:1); [α]2D6 = +57.5 (c = 1.4,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.86 (m, 1 H,
CH2CH=CH2), 5.20–5.07 (m, 2 H, CH2CH=CH2), 4.65 (s, 1 H,
OCHCO), 3.91 (d, J = 9.2 Hz, 1 H, ABq, OCHHCN), 3.84 (d, J
= 9.2 Hz, 1 H, ABq, OCHHCN), 3.48 (m, 1 H, NCHH), 3.10 (m,
1 H, NCHH), 2.56 (m, 2 H, CH2CH=CH2), 2.30 (m, 1 H,
NCH2CH2CHH), 2.10 (m, 1 H, NCH2CHH), 1.95–1.73 (m, 2 H,
NCH2CHH, NCH2CH2CHH), 1.60 (s, 3 H, CCH3) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 174.1 (C=O), 134.6 (CH),
118.5 (CH2), 106.4 (Cq), 77.9 (CH2), 76.2 (CH), 75.8 (Cq), 62.7
(Cq), 41.1 (N–CH2), 31.4 (CH2), 31.1 (CH2), 25.5 (CH2), 22.3
(CH3) ppm. MS-EI: m/z (%) = 253 (16) [M]+, 236 (20), 223 (18),
179 (27), 164 (100), 136 (12). HRMS-EI calcd. for C13H19NO4
253.1314; found 253.1318. C13H19NO4 (253.29): calcd. C 61.64, H
7.56, N 5.53; found C 61.61, H 7.73, N 5.61.
(3aR,4S,8aR)-3,4-Dihydroxy-3a-propyl-tetrahydro-7H-furo[3,4-g]-
pyrrolizin-5(3H)-one (14a): Yield 36 mg, 75%. Colorless oil. Rf =
0.41 (CH2Cl2/MeOH 10:1); [α]2D6 = +9.5 (c = 1.0, EtOH). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.50 (s, 1 H, OCHO), 4.58 (s, 1 H,
OCHCO), 3.93 (d, J = 9.7 Hz, 1 H, ABq, OCHHCN), 3.90 (d, J
= 9.7 Hz, 1 H, ABq, OCHHCN), 3.57 (m, 1 H, NCHH), 3.11 (m,
1 H, NCHH), 2.07 (m, 1 H, NCH2CH2CHH), 1.96 (m, 1 H,
NCH2 CHH), 1.81–1.40 (m, 6 H, CH2 CH2 , NCH2 CHH,
NCH2CH2CHH), 0.90 (t, J = 6.6 Hz, 3 H, CH2CH2CH3) ppm. 13
C
NMR (75 MHz, CDCl3, 25 °C): δ = 173.8 (C=O), 101.5 (CH), 77.2
(CH2), 76.0 (CH), 74.6 (Cq), 61.5 (Cq), 41.0 (N–CH2), 31.3 (CH2),
29.4 (CH2), 25.6 (CH2), 18.5 (CH2), 15.2 (CH3) ppm. MS-EI: m/z
(%) = 241 (2) [M]+, 224 (71), 181 (100), 164 (25), 152 (37), 124
(17). HRMS-EI calcd. for C12H19NO4 241.1314; found 241.1306.
C
12H19NO4 (241.28): calcd. C 59.73, H 7.94, N 5.81; found C
59.86, H 8.01, N 5.86.
(3aR,4S,8aR)-3a-Allyl-3,4-dihydroxy-4-methyl-tetrahydro-7H-
furo[3,4-g]pyrrolizin-5(3H)-one (14e): Yield 38 mg, 75%. Colorless
oil. Rf = 0.45 (CH2Cl2/MeOH 10:1); [α]2D6 = +24.6 (c = 2.0,
CH2Cl2). 1H NMR (300 MHz, CDCl, 25 °C): δ = 6.11 (m, 1 H,
CH2CH=CH2), 5.52 (s, 1 H, OCHO), 5.41–5.06 (m, 2 H,
CH2CH=CH2), 3.86 (s, 2 H, OCH2CN), 3.64 (m, 1 H, NCHH),
3.12 (m, 1 H, NCHH), 2.55 (dd, J = 14.1, 5.0 Hz, 1 H,
CHHCH=CH2), 2.42 (dd, J = 14.1, 7.6 Hz, 1 H, CHHCH=CH2),
2.11–2.09 (m, 2 H, NCH2CH2CHH, NCH2CHH), 2.00–1.76 (m, 2
H, NCH2CHH, NCH2CH2CHH), 1.48 (s, 3 H, CCH3) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 176.7 (C=O), 136.8 (CH),
117.7 (CH2), 100.6 (CH), 80.3 (Cq), 77.5 (Cq), 75.1 (CH2), 58.8
(Cq), 41.1 (N–CH2), 32.3 (CH2), 30.3 (CH2), 24.9 (CH2), 23.3
(CH3) ppm. MS-EI: m/z (%) = 253 (23) [M]+, 236 (31), 192 (39),
164 (70), 152 (100), 136 (34). HRMS-EI calcd. for C13H19NO4
253.1314; found 253.1320. C13H19NO4 (253.29): calcd. C 61.64, H
7.56, N 5.53; found C 61.74, H 7.52, N 5.38.
(3aR,4S,8aR)-3a-Allyl-3,4-dihydroxy-tetrahydro-7H-furo[3,4-g]-
pyrrolizin-5(3H)-one (14b): Yield 34 mg, 72%. Colorless oil, Rf =
0.41 (CH2Cl2/MeOH 10:1); [α]2D6 = +68.2 (c = 0.6, CH2Cl2). 1H
NMR (300 MHz, CDCl3 , 25 °C): δ = 6.06–5.93 (m, 1 H,
CH2CH=CH2), 5.48 (s, 1 H, OCHO), 5.25–5.08 (m, 2 H,
CH2CH=CH2), 4.62 (s, 1 H, OCHCO), 3.96 (d, J = 9.2 Hz, 1 H,
ABq, OCHHCN), 3.92 (d, J = 9.2 Hz, 1 H, ABq, OCHHCN),
3.63–3.54 (m, 1 H, NCHH), 3.15–3.07 (m, 1 H, NCHH), 2.96 (br.,
1 H, OH), 2.54–2.41 (m, 2 H, CH2CH=CH2), 2.16–2.05 (m, 2 H,
NCH2CHH, NCH2CH2CHH), 1.98–1.88 (m, 1 H, NCH2CHH),
1.81–1.71 (m, 1 H, NCH2CH2CHH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 173.5 (C=O), 135.2 (CH), 118.3 (CH2), 101.5
(CH), 77.6 (CH2), 76.8 (CH), 75.7 (Cq), 60.9 (Cq), 41.1 (N–CH2),
31.2 (CH2), 31.1 (CH2), 25.6 (CH2) ppm. HRMS-EI: MS-EI: m/z
(%) = 239 (19) [M]+, 222 (7), 179 (79), 162 (42), 150 (100), 138 (33),
94 (35). HRMS-EI calcd. for C12H17NO4 239.1158; found
239.1162. C12H17NO4 (239.27): calcd. C 60.24, H 7.16, N 5.85;
found C 60.44, H 7.26, N 5.74.
(3aR,4S,7R,8aR)-3a-Allyl-3,4-dihydroxy-7-(triethylsiloxy)-tetra-
hydro-7H-furo[3,4-g]pyrrolizin-5(3H)-one (15f): Yield 49 mg, 67%.
(3aR,4S,8aR)-3a-Benzyl-3,4-dihydroxy-tetrahydro-7H-furo[3,4-g]- Colorless oil. Rf = 0.47 (CH2Cl2/MeOH 10:1); [α]2D6 = +57.8 (c =
pyrrolizin-5(3H)-one (14c): Yield 33 mg, 57%. Colorless oil. β-OH
0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 6.20–6.01
(m, 1 H, CH2CH=CH2), 5.5 (s, 1 H, OCHO), 5.21–5.10 (m, 2 H,
compound: Rf = 0.48 (CH2Cl2/MeOH 10:1); [α]2D6 = –6.2 (c = 0.3,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.48 (d, J = CH2CH=CH2), 4.55 (s, 1 H, OCHCO), 4.49 (m, 1 H, SiOCH), 3.92
7.0 Hz, 1 H, ArH), 7.30–7.15 (m, 4 H, ArH), 5.60 (s, 1 H, OCHO), (d, J = 9.4 Hz, 1 H, ABq, OCHHCN), 3.87 (d, J = 9.4 Hz, 1 H,
4.56 (s, 1 H, OCHCO), 3.95 (d, J = 9.1 Hz, 1 H, ABq, OCHHCN), ABq, OCHHCN), 3.54–3.49 (dd, J = 11.7, 4.7 Hz, 1 H, NCHH),
3.90 (d, J = 9.1 Hz, 1 H, ABq, OCHHCN), 3.73 (m, 1 H, NCHH), 3.21–3.19 (dd, J = 11.7, 5.9 Hz, 1 H, NCHH), 3.06 (br. s, 1 H,
3.47 (d, J = 14.2 Hz, 1 H, ABq, ArCHH), 3.10 (m, 1 H, NCHH),
OH), 2.95 (br. s, 1 H, OH), 2.53–2.39 (m, 2 H, CH2CH=CH2),
2.56 (d, J = 14.2 Hz, 1 H, ABq, ArCHH), 2.11–1.72 (m, 4 H, 2.23–2.17 (dd, J = 13.2, 6.1 Hz, 1 H, NCH2CHCHH), 1.96–1.90
1
CH2CH2) ppm; α-OH compound. H NMR (300 MHz, CDCl3, (dd, J = 13.2, 5.6 Hz, 1 H, NCH2CHCHH), 0.94 [t, J = 7.9 Hz, 9
25 °C): δ = 7.40 (d, J = 8.2 Hz, 1 H, ArH), 7.30–7.15 (m, 4 H,
H, Si(CH2CH3)3], 0.59 [q, J = 7.9 Hz, 6 H, Si(CH2CH3)3] ppm. 13
C
ArH), 5.26 (s, 1 H, OCHO), 4.66 (s, 1 H, OCHCO), 4.08 (d, J = NMR (75 MHz, CDCl3, 25 °C): δ = 174.6 (C=O), 135.7 (CH),
9.5 Hz, 1 H, ABq, OCHHCN), 3.70 (d, J = 9.5 Hz, 1 H, ABq, 118.0 (CH2), 101.2 (CH), 77.2 (CH2), 76.1 (Cq), 74.3 (CH), 71.6
OCHHCN), 3.59 (m, 1 H, NCHH), 3.10 (m, 1 H, NCHH), 3.11 (CH), 61.3 (Cq), 50.1 (N–CH2), 40.8 (CH2), 31.7 (CH2), 6.7
(d, J = 14.5 Hz, 1 H, ABq, ArCHH), 2.90 (d, J = 14.5 Hz, 1 H,
ABq, ArCHH), 2.11–1.72 (m, 4 H, CH2CH2) ppm; β-OH and α- (100), 310 (17), 238 (10), 174 (21), 103 (51), 75 (56). HRMS-EI
(3ϫCH3), 4.6 (3ϫCH2) ppm. MS-EI: m/z (%) = 369 (4) [M]+, 340
Eur. J. Org. Chem. 2011, 1932–1939
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y.-J. Li, H.-Y. Chuang, S.-M. Yeh, W.-S. Huang
FULL PAPER
calcd. for C18H31NO5Si 369.1971; found 369.1967. C18H31NO5Si
(369.53): calcd. C 58.51, H 8.46, N 3.79; found C 58.35, H 8.36, N
3.71.
(15), 124 (60). HRMS-EI calcd. for C13H19NO4 253.1314; found
253.1323. C13H19NO4 (253.30): calcd. C 61.64, H 7.56, N 5.53;
found C 61.54, H 7.38, N 5.40.
(3aR,4S,7R,8aR)-[3-(tert-Butyldimethylsiloxy)propyl]-3,4-di-
hydroxy-7-(triethylsiloxy)-tetrahydro-7H-furo[3,4-g]pyrrolizin-
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of compounds 8a–n, 11,
5(3H)-one (14g): Yield 65 mg, 65 %. Colorless oil. Rf = 0.48 14a–g, 15a, and 15b. NOESY spectra of 14e and crystallographic
1
(CH2Cl2/MeOH 10:1); [α]2D6 = +21.4 (c = 0.1, CH2Cl2). H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.53 (s, 1 H, OCHO), 4.51, (s, 1 H,
OCHCO), 4.45–4.42 (m, 1 H, SiOCH), 3.98 (d, J = 9.6 Hz, 1 H,
ABq, OCHHCN), 3.88 (d, J = 9.6 Hz, 1 H, ABq, OCHHCN),
3.68–3.49 (m, 3 H, SiOCH2, NCHH), 3.20–3.14 (dd, J = 12.0,
6.3 Hz, 1 H, NCHH), 2.93 (br. s, 1 H, OH), 2.07 (dd, J = 13.3,
6.3 Hz, 1 H, NCH2CHCHH), 1.92 (dd, J = 13.3, 65.7 Hz, 1 H,
NCH2CHCHH), 1.62–1.51 (br., 4 H, CH2CH2), 0.96 (s, 9 H,
SiCMe3), 0.95 [t, J = 8.1 Hz, 9 H, Si(CH2CH3)3], 0.58 [q, J =
8.1 Hz, 6 H, Si(CH2CH3)3], 0.17 (s, 6 H, SiMe2) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 174.8 (C=O), 101.1 (CH), 76.1, 74.7,
71.6, 64.2, 62.3, 50.1 (N–CH2), 40.8 (CH2), 28.6 (CH2), 25.9
(3ϫCH3), 25.7 (CH2), 23.4 (CH2), 18.4 (Cq), 6.7 (3ϫCH3), 4.6
(3ϫCH2), –6.2 (2ϫCH3) ppm. MS-EI: m/z (%) = 501 (1) [M]+,
454 (32), 426 (100), 72 (100), 352 (15), 322 (12), 266 (10). HRMS-EI
calcd. for C24H47NO6Si2 501.2942; found 501.2948. C24H47NO6Si2
(501.80): calcd. C 57.44, H 9.44, N 2.79; found C 57.55, H 9.52, N
2.66.
data for compounds 8n and 15b.
Acknowledgments
We thank the National Science Council (Taiwan) (grant numbers
NSC-96-2113-M-415-002 and NSC-98-2119-M-415-001) for gener-
ous financial support. Partial support of the mass spectrometer fa-
cility provided by National Chung-Hsing University and the sup-
port of the X-ray facility by National Taiwan University are also
acknowledged.
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2009, 11, 4224–4227.
[2] For tandem reactions involving a Cope elimination as an initial
step, see: a) I. A. O’Neil, V. E. Ramos, G. L. Ellis, E. Cleator,
A. P. Chorlton, D. J. Tapolczay, S. B. Kalindjian, Tetrahedron
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Ramos, E. Cleator, S. B. Kalindjian, A. P. Chorlton, D. J. Ta-
polczay, Tetrahedron Lett. 2007, 48, 1683–1686.
Synthesis of Compounds 15a and 15b: The tetracyclic compound 8c
(0.084 mmol) was hydrogenated under H2 in the presence of
Pd(OH)2/C (20% w/w, 17.6 mg, 0.025 mmol) in MeOH (5 mL) for
12 h. The reaction mixture was filtered through a short path of
celite, washed with MeOH (5 mLϫ2), and then concentrated to
give the crude material. The crude material was purified by flash
chromatography (CH2Cl2/MeOH 100:1) to provide 15a.
[3] For tandem reactions involving a nitrone 1,3-dipolar cycload-
dition as a sequential step, see: a) O. Tamura, T. Okabe, T.
Yamaguchi, K. Gotanda, K. Noe, M. Sakamoto, Tetrahedron
1995, 51, 107–118; b) S. E. Denmark, A. Thorarensen, Chem.
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S. E. Wolkenberg, D. R. Soenen, M. M. Miller, S. Pollack, J.
Am. Chem. Soc. 2002, 124, 11292–11294; i) S. E. Denmark, J.
Cottell, in: The Chemistry of Heterocyclic Compounds: Syn-
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Pearson), Wiley-Interscience, New York, NY, 2002, p. 83–167;
j) S. E. Denmark, J. I. Montgomery, L. A. Kramps, J. Am.
Chem. Soc. 2006, 128, 11620–11630; k) S. E. Denmark, R. Y.
Baiazitov, S. T. Nguyen, Tetrahedron 2009, 65, 6535–6548, and
references cited therein.
[4] 1,3-Dipolar cycloaddition of cyclc nitrones, see: a) P. Merino,
in: Science of Synthesis (Ed.: A. Padwa), Thieme, Stuttgart,
Germany, 2004, vol. 27, chapter 13 (Nitrones and Analogues),
p. 511–580, and references cited therein; b) S. Stecko, K. Pas´-
niczek, M. Jurczak, Z. Urban´czyk-Lipkowska, M. Chmielew-
ski, Tetrahedron: Asymmetry 2006, 17, 68–78; c) F. Cardona,
A. Goti, A. Brandi, Eur. J. Org. Chem. 2007, 1551–1565; d) J.
Revuelta, S. Cicchi, A. Goti, A. Brandi, Synthesis 2007, 485–
504, and references cited therein e) S. Stecko, K. Pas´niczek,
C. Michel, A. Milet, S. Perez, M. Chmielewski, Tetrahedron:
Asymmetry 2008, 19, 1660–1669; f) S. Stecko, J. Frelek, M.
Chmielewski, Tetrahedron: Asymmetry 2009, 20, 1778–790.
[5] Synthesis of hexahydrofuro[3,4-g]pyrrolizin-1-one, see: M. Jou-
cla, J. Mortier, Tetrahedron Lett. 1987, 28, 2973–2974.
(5S,5aR,9aS,11aR)-Octahydro-5-hydroxy-9,10-dioxa-3a-azacyclo-
penta[a]benzo[e]pentalene-4-one (15a): Yield 16 mg, 81%. Colorless
oil. Rf = 0.45 (CH2Cl2/MeOH 10:1); [α]2D6 = +13.6 (c = 0.5,
CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 5.06 (s, 1 H,
OCHO), 4.52 (s, 1 H, CHO), 4.01 (d, J = 9.2 Hz, 1 H, ABq,
OCHHCN), 3.95 (d, J = 9.2 Hz, 1 H, ABq, OCHHCN), 3.97–3.93
(m, 1 H, OCHHCH2), 3.57–3.43 (m, 3 H, OCH2CH2, NCHH),
3.21–3.12 (m, 1 H, NCHH), 2.25–2.15 (m, 2 H), 2.01–1.92 (m, 2
H), 1.82–1.72 (m, 1 H), 1.60–1.51 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 173.0 (C=O), 103.8 (CH), 78.1 (CH2),
75.5 (Cq), 75.4 (CH), 64.5 (CH2), 56.6 (Cq), 40.3 (N–CH2), 32.5
(CH2), 25.6 (CH2), 21.7 (CH2), 20.1 (CH2) ppm. MS-EI: m/z (%)
= 239 (30) [M]+, 192 (33), 179 (92), 152 (100), 124 (32). HRMS-
EI calcd. for C12H17NO4 239.1158; found 239.1151. C12H17NO4
(239.27): calcd. C 60.24, H 7.16, N 5.85; found C 60.28, H 7.24, N
5.67.
(5S,5aR,9aS,11aR)-Octahydro-5-hydroxy-9a-methyl-9,10-dioxa-
3a-azacyclopenta[a]benzo[e]pentalene-4-one (15b): Yield 17 mg,
78%. Colorless crystal, m.p. 185–187 °C (decomp.). Rf = 0.48
1
(CH2Cl2/MeOH 10:1); [α]2D6 = +32.0 (c = 1.5, CH2Cl2). H NMR
(300 MHz, CDCl3, 25 °C): δ = 4.52 (s, 1 H, CHO), 3.96 (d, J =
9.1 Hz, 1 H, ABq, OCHHCN), 3.92 (d, J = 9.1 Hz, 1 H, ABq,
OCHHCN), 3.91–3.87 (m, 1 H, OCHHCH), 3.61 (dt, J = 12.3,
2.8 Hz, 1 H, OCHHCH2), 3.54–3.44 (m, 1 H, NCHH), 3.21–3.14
(m, 1 H, NCHH), 2.65 (br., 1 H, OH), 2.24–1.91 (m, 4 H,
NCH2CH2CH2), 1.78–1.61 (m, 4 H, OCH2CH2CH2), 1.58 (s, 3 H,
CCH3), 1.56–1.47 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 173.1 (C=O), 106.9 (Cq), 76.8 (CH2), 76.6 (Cq), 75.5
(CH), 63.2 (CH2), 58.5 (Cq), 40.0 (N–CH2), 34.3 (CH2), 25.4
(CH2), 21.4 (CH2), 19.6 (CH2), 16.8 (CH3) ppm. MS-EI: m/z (%)
= 253 (22) [M]+, 208 (100), 99 (60), 194 (7), 179 (20), 166 (18), 152
[6] For other types of furo-fused pyrrolizidine-related compounds,
see: a) F. Ghelfi, A. F. Parsons, D. Tommasini, A. Mucci, Eur.
J. Org. Chem. 2001, 1845–1852; b) J. M. Aurrecoechea, R.
Suero, E. de Torres, J. Org. Chem. 2006, 71, 8767–8778; c) I.
Kim, H.-K. Na, K. R. Kim, S. G. Kim, G. H. Lee, Synlett
2008, 2069–2071.
1938
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1932–1939

Synthesis of Chiral Furopyrrolizidinones
[7] a) J. T. Tufariello, G. F. Lee, J. Am. Chem. Soc. 1980, 102, 373–
374; b) S. A. Ali, S. M. A. Hashmi, M. N. Siddiqui, M. I. M.
Wazeer, Tetrahedron 1996, 52, 14917–14928; c) E. C. Davison,
I. T. Forbes, A. B. Holmes, J. A. Warner, Tetrahedron 1996, 52,
11601–11624; d) S. Cicchi, M. Corsi, A. Goti, J. Org. Chem.
1999, 64, 7243–7245; e) S. Cicchi, M. Marradi, A. Goti, A.
Brandi, Tetrahedron Lett. 2001, 42, 6503–6505.
[8] CCDC-723800 contains the supplementary crystallographic
data for 8n. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
isomerization of exo- to endo-methyl through a deprotonation/
kinetic protonation sequence.
F. A. J. Kerdesky, R. J. Ardesky, M. V. Lakshmikantham, M. P.
Cava, J. Am. Chem. Soc. 1981, 103, 1992–1996.
Reductive lactamization of 8c and 8h (Zn/H2O/THF) provided
variable ratios of mixtures of the desired tricyclic furo-pyrroliz-
idinones and tetracyclic compounds.
[10]
[11]
[12] CCDC-723799 contains the supplementary crystallographic
data for 15b. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[9] Tricyclic 9 (81% D-labeled) was synthesized by deprotonation
of 7b with LDA, followed by D2O quenching. Tricyclic 12 was
synthesized by methylation of the enolate of 7b, followed by
Received: November 11, 2010
Published Online: February 15, 2011
Eur. J. Org. Chem. 2011, 1932–1939
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1939