Application of the photocyclization reaction of 1,2-cyclopenta-fused pyridinium perchlorate to formal total syntheses of (-)-cephalotaxine

Article abstract of DOI:10.1016/j.tet.2006.05.045

Two strategies for the formal total synthesis of (-)-cephalotaxine, based on pyridinium salt photochemistry, are described. The routes begin with photocyclization reaction of 1,2-cyclopenta-fused pyridinium perchlorate. This process efficiently and regios

Full text of DOI:10.1016/j.tet.2006.05.045

Tetrahedron 62 (2006) 7266–7273
Application of the photocyclization reaction of 1,2-cyclopenta-
fused pyridinium perchlorate to formal total syntheses
of (L)-cephalotaxine
*
Zhiming Zhao and Patrick S. Mariano
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131, USA
Received 23 March 2006; revised 15 May 2006; accepted 18 May 2006
Available online 12 June 2006
Abstract—Two strategies for the formal total synthesis of (ꢀ)-cephalotaxine, based on pyridinium salt photochemistry, are described. The
routes begin with photocyclization reaction of 1,2-cyclopenta-fused pyridinium perchlorate. This process efficiently and regioselectively pro-
duces a tricyclic aziridine, which undergoes sequential aziridine ring opening and enzymatic desymmetrization to generate enantio-enriched
intermediates that contain the spirocyclic D,E-ring system found in cephalotaxine. These substances serve as precursors to late stage key
intermediates used by Mori, Tietze, and Yoshida in earlier syntheses of (ꢀ)-cephalotaxine.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
N
(ꢀ)-Cephalotaxine is the parent member of the harringto-
nine alkaloid family. These natural products occur in about
eight known species of the genus Cephalotaxus, evergreen
plum yews that are indigenous to Southeast Asia.1
(ꢀ)-Cephalotaxine was isolated from yew plants by Paudler
and his co-workers in 19632 and its structure was determined
in 1969.3 This natural product has become an interesting
synthetic target,4a–q not only because of its unique penta-
cyclic ring skeleton, containing a 1-azaspiro[4.4]-nonane
moiety fused to a benzazepine system, but also as a result
of the observed antileukemic and antitumor activities of
several of its C-3 2-alkylhydroxysuccinate derivatives,
including harringtonine 2, deoxyharringtonine 3, homo-
harringtonine 4, and isoharringtonine 5 (Scheme 1).5 The
cancer chemotherapeutic effectiveness of homoharring-
tonine 4 has been evaluated in phase II–III clinical trials,6
and this substance has been investigated in the treatment
of chloroquine-resistant malaria.7
H
RO
OMe
R=H, (-)-cephalotaxine (1)
HO
HO
R=
CO
CO
COOMe
HO
R=
H
HO
COOMe
harringtonine (2)
iso-harringtonine (5)
HO
CO
HO
CO
R=
HO
R=
COOMe
deoxyharringtonine (3)
COOMe
homoharringtonine (4)
Scheme 1.
exploratory study of the photochemistry of a 1,2-cyclo-
penta-fused pyridinium perchlorate 6 (Scheme 2).9 Specifi-
cally, we observed that irradiation of a basic aqueous
solution of this substance promotes a remarkably regioselec-
tive photocyclization reaction that results in efficient forma-
tion of a single tricyclic-allylic alcohol 8. The degree of
structural, functional, and stereochemical complexity intro-
duced in this ‘green’ chemical process is remarkable. More-
over, transformation of 8 to the corresponding spirocyclic
amido diester 9 by acid promoted, regiocontrolled aziridine
ring opening followed by enzymatic desymmetrization was
used to produce the enantiomerically pure monoalcohol 10
Extensive studies have been carried out in our laboratory
to both develop and demonstrate the preparative utility of
pyridinium salt photochemistry in sequences targeted at a
variety of biomedically interesting natural and nonnatural
products.8 Recently, we reported the results of an
Keywords: Pyridinium salt photochemistry; (ꢀ)-Cephalotaxine formal
synthesis.
* Corresponding author. Tel.: +1 505 277 6390; fax: +1 505 277 6202;
e-mail: mariano@unm.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.045

Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
7267
(Scheme 2) that contains a structurally interesting [4.4]-
spirocyclic framework.
13 to form the late stage intermediate 11 in Mori’s synthesis
of (ꢀ)-cephalotaxine. We visualized that these synthons
would arise by appropriate manipulation of the monoalcohol
14.
+
H2O
hv
N
H
N
H
N
2.2. One formal total synthesis of (L)-cephalotaxine
aq. KOH
+
3
5
3
5
OH
6
7
8
The sequence developed for formal total synthesis of
(ꢀ)-cephalotaxine that targets construction of the Mori spi-
rocyclic allylic alcohol 12 is initiated by the known photo-
cyclization reaction of the the cyclopenta-fused pyridinium
salt 6 (Scheme 4). Irradiation of an aqueous basic solution of
this substance gives tricyclic aziridine 8, which is directly
transformed to N-Boc-protected spirocyclic monoalcohol
15 by treatment with acetic acid, to promote regioselective
aziridine ring opening, followed by protection of the liber-
ated secondary amine through the action of Boc2O and
Et3N. This three-step sequence serves as an exceptionally
convenient method to access the racemic structurally and
functionally complex intermediate 15 in a 50% overall yield.
Acetylation of 15 with Ac2O and pyridine followed by de-
protection of the Boc group with TFAyields the meso amino-
diester 16 (81%, two steps). Importantly, this diester serves
as an active substrate for EEACE9 catalyzed hydrolysis
(pH¼6.9, 0.5 M NaH2PO4) that affords a modestly unstable
aminomonoalcohol intermediate 18, which without purifica-
tion is reacted with (3,4-dimethoxyphenyl)acetyl chloride
(17) to furnish amidomonoalcohol 19 in a 80% two-step
yield. The enantiomeric purity of 18 is determined by its
conversion to an N-Boc derivative followed by reaction
Ac
AcO
N
Ac
AcO
N
1. HOAc
EEACE
OH
OAc
2. Ac2O, Pyr.
9
10
Scheme 2.
The unique structural and stereochemical features of spiro-
cyclic amide 10 along with the efficiency of its construction
should make this substance and its relatives ideal synthons in
routes for the preparation of a number of natural product
targets. The aim of the effort described below was to demon-
strate how the photochemistry of 1,2-cyclopenta-fused pyri-
dinium perchlorate 6 can be readily adapted to routes that
rapidly generate two key intermediates in the syntheses of
(ꢀ)-cephalotaxine.
2. Results and discussion
2.1. Retrosynthetic analyses
Two retrosynthetic plans for formal total syntheses of
(ꢀ)-cephalotaxine, designed on the basis of pyridinium
salt photochemistry, are outlined in Scheme 3. A key inter-
mediate in both sequences is pentacyclic alkene 11, a sub-
stance used by Mori and Isono in the first nonracemic total
synthesis of this natural product.4i We envisaged that in
one approach 11 would be derive from the known spirocyclic
amido-allylic alcohol 12, which has already been converted
to 11 in the seminal synthesis of (ꢀ)-cephalotaxine reported
by Mori and Isono.4i We assumed that 12 would be easily
prepared from an aminomonoalcohol 14, formed by an
enzymatic hydrolytic desymmetrization process10 on
a meso-diester derived by application of the pyridinium
salt photocyclization/aziridine ring opening sequence
(Scheme 2).
+
ClO4
hv
aq. KOH
1. HOAc
2. Boc2O
N
H
N
Boc
AcO
N
OH
OH
50%, 3 steps
6
8
15
1. Ac2O
2. TFA
1. EEACE
H
AcO
N
H
AcO
N
2. 17
OAc
OH
(80%, 2 steps)
(76%, 2 steps)
18
16
O
MeO
CH2COCl
MeO
MeO
N
AcO
19
OH
MeO
In more recent approaches to the synthesis (ꢀ)-cephalo-
taxine, Tietze4j and Yoshida4l have utilized Heck coupling
reactions of haloarylethyl tethered spirocyclic intermediates
17
Scheme 4.
(-)-cephalotaxine
MeO
N
HO
MeO
O
O
Mori Intermediate (12)
ClO4
N
P
N
N
AcO
OH
H
14
6
N
O
Mori's Intermediate (11)
O
X
Yoshida Tietze Intermediate (13)
Scheme 3.

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Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
with both (R)- and (S)-Mosher acetyl chloride and 1H NMR
analysis of the derived esters.11 The % ee determined in this
manner are in the range of 80–90% ee depending on the
time/percent conversion of the enzymatic reaction.
this substance is reacted with the iodoarylethyl 4-nitrobenz-
enesulfonate 244i to generate the spirocyclic aminoalcohol
25. A brief exploration for optimal conditions resulted in
an optimized 40% yield for the three-step sequence. In order
to complete the synthesis of Yoshida spirocyclic alkene 13
all that is needed was dehydration of aminoalcohol 25. How-
ever, we found that this was a difficult task when we
observed that several typical time-tested methods (POCl3/
Py, Burgess salts, CS2/MeI, and MeOCOCOCl/Pyr) failed
to give satisfactory results.
The transformation of spirocyclic monoalcohol 19 to the
Mori intermediate 11, on first thought seemed simple since
all that is required is reductive removal of the unblocked
hydroxyl group. Among a number of radical reduction ap-
proaches explored for this purpose (e.g., O-phenoxythio-
carbonate reduction), Barton12 type oxalate reduction was
superior. Accordingly, treatment of 19 with methyl(chloro-
carbonyl)formate followed by free radical reduction of the
intermediate mixed oxalate ester by using AIBN/n-Bu3SnH
in refluxing toluene leads to the generation of the desired de-
hydroxylated product 20 in a 10% yield along with the rear-
ranged homoallylic alcohol 21 as the major product (65%).
As expected, treatment of 20 with lithium aluminum hydride
gives 12 (95%) (Scheme 5), which has physical and spectro-
scopic properties that match those reported by Mori and
Isono.4i In addition, 21 is also transformed to Mori inter-
mediate through a fivestep sequence (55% overall yield)
involving alcohol liberation and oxidation, a,b-unsaturated
enone formation, and reduction, and amide reduction
(Scheme 5).
1. H2, Pd/C
2. 6N HCl
Ac
AcO
N
1. MeOCOCOCl
OH 2. AIBN, n-Bu3SnH AcO
Ac N
(85%, 2 steps)
10
22
CH2CH2ONs
O
24
O
O
O
H
N
N
I
HO
HO
I
(40%, 3 steps)
23
25
Scheme 6.
As a result of low yields of the N-alkylation reaction of spi-
rocyclic amine 23 and dehydration reaction of alcohol 25,
the synthetic plan was modified by employing the amido-
alcohol 27 as an intermediate (Scheme 7). As anticipated,
23 derived by successive hydrogenation of 22 and amide hy-
drolysis, reacts with iodoarylacetyl chloride 26 to give spiro-
cyclic amidoalcohol 27 in a dramatically improved 80%
three-step yield. Formation of the tosylate derivative 28 by
reaction of 27 with p-TsCl and pyridine (85%) is followed
by smooth DBU13 catalyzed elimination to afford the unsat-
urated amide 29 in an 80% yield. Finally, low temperature
(ꢀ40 ꢁC) aluminum hydride reduction14 of 29 (60%) gives
13, the late stage intermediate in Yoshida’s formal synthesis
of (ꢀ)-cephalotaxine along with about 20% of a product (13,
X¼H) missing the iodide group. Importantly, the physical
and spectroscopic properties of 13, prepared by the current
methodology, match those reported by Yoshida and his
co-workers.4l
O
MeO
N
AcO
OH
MeO
O
19
1. MeOCOCOCl
2. AIBN, n-Bu3SnH
O
MeO
MeO
MeO
N
N
+
AcO
AcO
MeO
20 (10%)
21 (65%)
LiAlH4
1. NaOMe
2. Swern
3. DBU
MeO
MeO
4. Al(iPrO)3, iPrOH
5. LiAlH4
N
HO
12
(56%, 5 steps)
Scheme 5.
O
O
O
1. H2, Pd/C
DBU
N
Ac
AcO
N
2.3. Another formal total synthesis of (L)-cephalotaxine
(80%)
RO
2. 6N HCl
I
3. 26
The second approach developed for the synthesis of
(ꢀ)-cephalotaxine links with the iodoarylethyl spirocyclic
alkene 13, which served as a key intermediate in Yoshida
and his co-workers’ synthesis of this target. The sequence
begins with monoalcohol 109 (Scheme 6), a substance we
prepared earlier in nonracemic form by using a sequential-
photocyclization/aziridine ring opening/enzymatic desym-
metrization sequence (Scheme 2). Free radical reduction
(AIBN, n-Bu3SnH, toluene, reflux) of the mixed oxalate
arising by treatment of 10 with methyl(chlorocarbonyl)for-
mate gives the homoallylic ester 22 (90%). Hydrogenation of
22 with 10% Pd/C in ethanol generates the saturated amide,
which upon reaction in refluxing 6 N HCl affords the HCl
salt of spirocyclic aminoalcohol 23. Without purification,
22
27 (R = H)
(80%, 3 steps)
pTsCl
(85%)
28 (R = pTs)
O
AlH3
O
O
O
O
N
N
(60%)
I
29
X
13 (X = I)
CH2COCl
I
O
O
26
Scheme 7.

Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
7269
3. Conclusions
4.1.2. 1,4-Diacetoxy-6-azaspiro[4.4]non-2-ene (16). A
solution of Boc-protected amidomonoalcohol 15 (3.0 g,
0.01 mol) in CH2Cl2 (100 mL), DMAP (300 mg), Ac2O
(5 mL), and pyridine (10 mL) was stirred at room tem-
perature for 12 h, poured into satd NaHCO3 solution, and
extracted with CHCl3. The chloroform extracts were dried
and concentrated in vacuo to provide the crude diacetate,
which was subjected to column chromatography (silica gel,
30% acetone/hexane) to give pure diacetate (3.1 g, 90%). 1H
NMR (1:0.8 mixture of rotamers) 1.48 (s, 16.2H), 1.65–1.74
(m, 3.6H), 2.00 (t, J¼7.0 Hz, 2H), 2.10 (s, 10.8H), 2.14
(t, J¼7.0 Hz, 1.6H), 3.31 (t, J¼7.0 Hz, 2H), 3.40
(t, J¼7.0 Hz, 1.6H), 5.89 (s, 1.6H), 5.90 (s, 2H), 6.14 (s,
1.6H), 6.34 (s, 2H); 13C NMR (1:0.8 mixture of rotamers)
20.9 (4), 22.5, 23.1, 27.7, 28.4 (2), 29.1, 47.2, 47.6, 75.3,
76.2, 78.6 (2), 79.2 (2), 79.6, 80.6, 132.3 (2), 132.4 (2),
153.0, 153.6, 170.0 (4) ; HRMS (ES) m/z 362.1535
(M+Na), calcd for C17H25NO6Na 362.1580.
The results described above add further to the growing body
of observations that suggest that pyridinium salt photo-
chemistry can serve as an important methodology in syn-
thetic organic chemistry. Despite the well recognized
limitations (e.g., scale up) of photochemical reactions, the
ability to construct structurally, stereochemically, and func-
tionally complex substances by irradiation of pyridinium
salts stands as a unique feature of this chemistry that is
unmatched by any ground state processes. As with all inter-
esting excited state reactions of organic compounds, this
environmentally friendly process will become an important
component of the synthetic arsenal, especially if/when the
cost of photon production becomes low.
4. Experimental
4.1. General
A solution of the diacetate (1.5 g, 4.4 mmol) in CH2Cl2
(10 mL) and TFA (3.5 mL) was stirred overnight at room
temperature, diluted with satd aq NaHCO3, and extracted
with CHCl3. The extracts were dried and concentrated
in vacuo to provide a residue, which was subjected to column
chromatography (silica gel, 10% MeOH/ethyl acetate) to
All reactions were run under a nitrogen atmosphere. Unless
otherwise noted, all reagents were obtained from commer-
cial sources and used without further purification. All com-
pounds were isolated as oils and shown to be >90% pure
by 1H NMR/or 13C NMR, unless otherwise noted. 1H
NMR and 13C NMR spectra were recorded on CDCl3 solu-
tion unless otherwise specified and chemical shifts are
reported in parts per million (ppm) relative to residual
1
yield 16 (0.9 g, 85%). H NMR 1.71–1.80 (m, 4H), 2.10
(s, 6H), 2.98 (t, J¼6.8 Hz, 2H), 5.37 (s, 2H), 6.07 (s, 2H);
13C NMR 20.8 (2), 24.8, 26.8, 45.9, 74.6, 82.1 (2), 134.0
(2), 170.2 (2); HRMS (ES) m/z 240.1233 (M+1), calcd for
C12H18NO4 240.1236.
1
CHCl3 at 7.24 ppm (for H NMR at 250 or 500 MHz) and
77.0 ppm (for 13C NMR at 62.9 MHz). 13C NMR resonance
assignments were aided by the use of DEPT technique to
determine the number of attached hydrogens.
4.1.3. (1S,4R,5S)-N-(3,4-Dimethoxyphenylacetyl)-1-ace-
toxy-6-azaspiro[4.4]non-2-en-4-ol (19). A solution of
50 mg of sodium azide, 500 units of lypholized electric eel
acetyl cholinesterase (EEACE) and amine-diacetate 16
(4.0 g, 16.7 mmol) in 100 mL of 0.58 M sodium dihydrogen
phosphate buffer (pH¼6.9) at room temperature was gently
stirred for 0.5–1 h and extracted with CHCl3. The extracts
were dried and concentrated in vacuo to yield the recovered
16 (3.0 g). The aqueous layer was concentrated in vacuo to
provide a residue, which was dissolved in methanol and fil-
tered. The filtrate was concentrated in vacuo to yield the
monoalcohol 18, which was used without further purification
in the next step. 1H NMR (D2O) 1.96–2.06 (m, 3H), 2.26 (s,
3H), 2.18–2.21 (m, 1H), 3.32 (t, J¼6.5 Hz, 2H), 4.58 (s, 1H),
5.56 (s, 1H), 6.13 (d, J¼6.0 Hz, 1H), 6.28 (d, J¼5.5 Hz, 1H);
13C NMR (D2O) 20.1, 21.9, 25.1, 45.0, 76.5, 77.5, 78.9,
130.9, 136.9, 173.1; HRMS (ES) m/z 198.1127 (M+1), calcd
for C10H16NO3 198.1130. The % ee of the monoalcohol
(80–90%, depending on reaction time) was determined by
conversion to the N-Boc derivative, followed by reaction
with (R)- and (S)-Mosher acetyl chloride.
4.1.1. N-Boc-1-acetoxy-6-azaspiro[4.4]non-2-en-4-ol
(15). A solution of fused pyridinium salt 6 (2.14 g,
0.01 mol) in water (500 mL) containing KOH (0.60 g,
0.01 mol) was irradiated in a circular reactor with light emit-
˚
ted from 2537 A lamps for 24 h (70% conversion). Concen-
tration of the photolysate in vacuo provided a residue, which
was triturated with chloroform. Concentration of the tri-
turate in vacuo to yield the known9 bicyclic alcohol 8, which
was used without purification in the next step.
A solution of 8 in CH2Cl2 (100 mL) and HOAc (5 mL) was
stirred at room temperature for 12 h. Triethylamine (7 mL)
and di-tert-butyl dicarbonate (3.4 g, 15.6 mmol) were then
added and then the mixture was stirred for 12 h at room tem-
perature, diluted sequentially with 5% aq KHSO4 (10 mL)
and CHCl3 (200 mL), washed sequentially with 5% aq
KHSO4 and satd aq NaHCO3, dried, and concentrated
in vacuo to give a residue, which was subjected to column
chromatography (silica gel, 30% acetone/hexane) to provide
15 (1.04 g, 50%, three steps). 1H NMR (1:1 mixture of two
rotamers) 1.45 (s, 9H), 1.46 (s, 9H), 1.60–1.65 (m, 2H),
1.75–1.83 (m, 3H), 1.95–2.05 (m, 1H), 2.17 (s, 6H), 2.21–
2.36 (m, 2H), 3.30–3.54 (m, 5H), 3.71 (br s, 1H), 5.11 (s,
1H), 5.35 (s, 1H), 5.76 (s, 2H), 5.91 (d, J¼5.6 Hz, 2H),
6.13 (s, 1H), 6.32 (s, 1H); 13C NMR (1:1 mixture of two
rotamers) 20.2 (2), 21.9, 22.3, 26.0, 27.3, 27.6 (2), 46.9,
47.0, 75.5, 76.0, 77.6, 77.7, 77.8, 77.9, 78.9, 79.0, 129.7
(2), 135.3, 135.2, 152.7, 153.0, 169.9 (2); HRMS (ES) m/z
320.1452 (M+Na), calcd for C15H23NO5Na 320.1474.
To a solution of the crude monoalcohol in CH3CN (30 mL)
at ꢀ40 ꢁC were added sequentially Et3N (2 mL) and a solu-
tion of 3,4-dimethoxyphenylacetyl chloride (17) (0.7 g,
3.24 mmol) in CH3CN (10 mL). The mixture was stirred at
ꢀ40 ꢁC for 70 min, diluted with water, and extracted with
CHCl3. The extracts were dried and concentrated in vacuo
to yield a residue, which was subjected to column chromato-
graphy (silica gel, 33% acetone/hexane) to provide 19
1
(0.94 g, 80%); [a]2D3 +7.4 (c 0.41, CHCl3). H NMR 1.70–
1.81 (m, 1H), 1.85–1.92 (m, 2H), 2.07 (s, 3H), 2.17–2.22

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Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
(m, 1H), 3.40–3.44 (m, 1H), 3.47–3.52 (m, 1H), 3.56 and
3.61 (abq, J¼15.0 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 5.48
(d, J¼1.0 Hz, 1H), 5.79 (d, J¼6.0 Hz, 1H), 5.91 (dd,
J¼2.0, 6.3 Hz, 1H), 6.42 (d, J¼1.5 Hz, 1H), 6.77 (d,
J¼8.0 Hz, 1H), 6.80 (d, J¼8.0 Hz, 1H), 6.82 (s, 1H); 13C
NMR 20.9, 23.7, 26.5, 42.7, 48.5, 55.8 (2), 76.2, 78.5,
79.2, 111.1, 112.2, 121.1, 127.1, 130.6, 136.2, 147.7,
148.9, 170.3 (2); HRMS (ES) m/z 376.1757 (M+1), calcd
for C20H26NO6 376.1760.
4.1.5. (1S,5S)-N-[2-(3,4-Dimethoxyphenylethyl)]-6-aza-
spiro[4.4]non-2-en-1-ol (12) from 20. To a solution of 20
(0.10 g, 0.3 mmol) in THF (10 mL) was added LiAlH4
(1 mL, 1 M solution, 1 mmol). The mixture was stirred at
reflux for 3 h, cooled, sequentially diluted by addition of
a solution of 0.5 mL water in 10 mL THF followed by
0.6 mL 10% aq NaOH, and filtered. The filtrate was concen-
trated in vacuo to afford a residue, which was subjected to
column chromatography (silica gel, 10% CHCl3/MeOH) to
afford 12 (0.09 g, 95%), [a]2D3 +44.4 (c 0.03, CHCl3) [lit.4i
86.4 (c 1.02, CHCl3)] whose spectroscopic properties
matched with those previously reported.4i 1H NMR 1.56–
1.61 (m, 1H), 1.80–1.86 (m, 2H), 2.02 (d, J¼17.0 Hz, 1H),
2.23 (ddd, J¼8.0, 12.0, 12.0 Hz, 1H), 2.39 (d, J¼17.0 Hz,
1H), 2.40–2.45 (m, 1H), 2.64–2.74 (m, 4H), 3.11 (dd,
J¼3.5, 9.0 Hz, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 4.63 (s,
1H), 5.70 (dd, J¼2.0, 6.0 Hz, 1H), 5.82 (d, J¼5.5 Hz, 1H),
6.70 (s, 1H), 6.71 (d, J¼8.0 Hz, 1H), 6.75 (d, J¼8.0 Hz,
1H); 13C NMR 20.7, 32.4, 35.4, 36.5, 51.4, 51.8, 55.8,
55.8, 75.3, 78.0, 111.1, 112.0, 120.4, 132.2, 132.9, 133.0,
147.3, 148.7; HRMS (ES) m/z 304.1906 (M+1), calcd for
C18H26NO3 304.1913.
4.1.4. (1S,5S)-N-(3,4-Dimethoxyphenylacetyl)-1-acetoxy-
6-azaspiro[4.4]non-2-ene (20) and (4S,5S)-N-(3,4-di-
methoxyphenylacetyl)-5-acetoxy-6-azaspiro[4.4]non-1-
ene (21). To a solution of monoalcohol 19 (1.1 g, 2.9 mmol)
in CH2Cl2 (30 mL) containing DMAP (1.1 g, 9.0 mmol) at
0 ꢁC, was added methyl chlorooxoacetate (0.7 mL). The
mixture was stirred at room temperature for 4 h, diluted
with CHCl3 and water, and separated. The CHCl3 layer
was washed with aq NH4Cl, dried, and concentrated in vacuo
to afford the mixed oxalate ester, which was used without
1
further purification in the next step. H NMR 1.74–1.86
(m, 2H), 2.05 (t, J¼6.8 Hz, 2H), 2.09 (s, 3H), 3.42 (dd,
J¼2.0, 6.5 Hz, 2H), 3.63 (s, 2H), 3.86 (s, 3H), 3.88 (s,
3H), 3.91 (s, 3H), 5.96 (dd, J¼6.0, 12.3 Hz, 2H), 6.45 (s,
1H), 6.58 (s, 1H), 6.78 (d, J¼8.0 Hz, 1H), 6.81 (s, 1H),
6.82 (d, J¼8.0 Hz, 1H); 13C NMR 20.8, 23.7, 27.4, 42.5,
47.8, 53.5, 55.7 (2), 77.4, 78.0, 81.5, 111.1, 112.1, 121.2,
126.9, 130.8, 133.8, 147.7, 148.9, 156.9, 157.9, 169.9,
170.5; HRMS (ES) m/z 462.1765 (M+1), calcd for
C23H28NO9 462.1764.
4.1.6. Spirocyclic cyclopentenol 12 from 21. A solution of
21 (0.36 g, 1.0 mmol) and NaOMe (0.10 g, 19 mmol) in
MeOH (10 mL) was stirred at room temperature for 2 h,
diluted with water and extracted with CHCl3, The extracts
were washed with satd aq NaCl, dried and concentrated in
vacuo to yield the crude homoallylic alcohol (0.32 g).
[a]2D3 +99.4 (c 0.264, CHCl3); 1H NMR 1.68–1.72 (m, 1H),
1.78–1.81 (m, 1H), 1.91–2.17 (m, 2H), 2.53 (dd, J¼2.0,
19.3 Hz, 1H), 2.73 (dd, J¼5.5, 20.5 Hz, 1H), 3.53 (abq,
J¼7.5 Hz, 1H), 3.64 (abq, J¼18.0 Hz, 2H), 3.86 (s, 6H),
3.96–3.99 (m, 1H), 4.4 (d, J¼11.5 Hz, 1H), 5.60 (d,
J¼6.0 Hz, 1H), 5.82 (d, J¼5.5 Hz, 1H), 6.78 (d, J¼8.5 Hz,
1H), 6.81 (s, 1H), 6.81 (d, J¼8.0 Hz, 1H); 13C NMR 23.0,
36.6, 41.8, 42.4, 49.0, 55.7 (2), 77.8, 79.3, 111.1, 111.8,
121.0, 126.7, 128.0, 133.2, 147.8, 148.9, 173.1; HRMS
(ES) m/z 318.1702 (M+1), calcd for C18H24NO4 318.1705.
To a solution of the crude oxalate in toluene (10 mL) were
added AIBN (0.3 g, 1.8 mmol) and n-Bu3SnH (3 mL,
11.3 mmol). The mixture was stirred at 100 ꢁC for 2 h,
cooled to room temperature, diluted with CHCl3, washed
with satd aq NaHCO3, dried, and concentrated in vacuum
to afford a residue, which was subjected to column chroma-
tography (silica gel, 30% acetone/hexane) to afford 20
(0.11 g, 10%), 21 (0.68 g, 65%), and recovered starting
material 19 (0.3 g).
To a solution of oxalyl chloride (1 mL, 2 M solution,
2 mmol) and DMSO (0.31 g, 4 mmol) in CH2Cl2 (15 mL)
at ꢀ78 ꢁC was added a solution of the crude homoallylic
alcohol (0.32 g, 1 mmol) in CH2Cl2 (20 mL) slowly. The
mixture was stirred at ꢀ78 ꢁC for 2 h, and diluted with
Et3N (5 mL). After stirring for 1 h, the mixture was diluted
with satd aq NH4Cl, and extracted with CHCl3. The extracts
were washed with satd aq NaCl, dried, and concentrated
in vacuo to afford the crude unsaturated enone, which was
Compound 20: [a]2D3 +90.2 (c 0.1, CHCl3); 1H NMR 1.62 (dt,
J¼6.0, 13.0 Hz, 1H), 1.78 (dt, J¼7.0, 13.0 Hz, 2H), 2.20 (s,
3H), 2.22 (ddd, J¼7.5, 5.5, 4.5 Hz, 2H), 3.27 (dd, J¼1.5,
16.3 Hz, 1H), 3.42 (abq, J¼7.5 Hz, 1H), 3.51 (abq,
J¼6.0 Hz, 1H), 3.59 (abq, J¼15.0 Hz, 2H), 3.86 (s, 3H),
3.87 (s, 3H), 5.66 (dd, J¼1.5, 6.0 Hz, 1H), 5.95 (dd, J¼2.0,
6.5 Hz, 1H), 6.49 (s, 1H), 6.77 (d, J¼9.5 Hz, 1H), 6.80 (s,
1H), 6.82 (d, J¼9.5 Hz, 1H); 13C NMR 21.1, 23.7, 35.2,
42.8, 44.0, 48.3, 55.8, 72.7, 81.9, 111.1, 111.9, 121.1,
127.3, 129.2, 133.2, 147.7, 148.9, 169.6, 170.5; HRMS
(ES) m/z 360.1823 (M+1), calcd for C20H26NO5 360.1811.
1
used without purification in the next step. H NMR 1.75–
1.78 (m, 1H), 1.95–2.05 (m, 3H), 2.74 and 3.28 (abq,
J¼23.0 Hz, 2H), 3.51–3.52 (m, 2H), 3.53 (abq, J¼7.0 Hz,
2H), 3.81 (s, 3H), 3.85 (s, 3H), 5.85 (dt, J¼2.0, 7.0 Hz,
1H), 6.23 (dt, J¼2.0, 7.0 Hz, 1H), 6.68 (d, J¼7.5 Hz, 1H),
6.69 (s, 1H), 6.76 (d, J¼7.5 Hz, 1H); 13C NMR 24.6, 35.7,
41.0, 41.4, 48.1, 55.8 (2), 71.8, 111.2, 111.6, 120.9, 126.6,
129.8, 132.5, 147.8, 149.0, 168.9, 213.6; HRMS (ES) m/z
316.1553 (M+1), calcd for C18H22NO4 316.1549.
Compound 21: [a]2D3 +94.9 (c 0.28, CHCl3); 1H NMR 1.61–
1.65 (m, 1H), 1.81 (abq, J¼7.5 Hz, 2H), 2.06 (s, 3H), 2.21–
2.27 (m, 2H), 3.10 (dd, J¼8.0, 17.0 Hz, 1H), 3.44–3.47 (m,
1H), 3.50–3.57 (m, 1H), 3.57 (abq, J¼15.0 Hz, 2H), 3.85
(s, 3H), 3.87 (s, 3H), 5.52 (d, J¼4.0 Hz, 1H), 5.75–5.77
(m, 1H), 5.88–5.90 (m, 1H), 6.76 (d, J¼8.5 Hz, 1H), 6.80
(s, 1H), 6.81 (d, J¼8.5 Hz, 1H); 13C NMR 21.1, 23.7, 32.8,
38.1, 42.9, 48.1, 55.8, 76.7, 77.6, 111.1, 111.9, 121.1,
127.3, 128.1, 134.1, 147.7, 148.9, 169.6, 170.4; HRMS
(ES) m/z (M+1), 360.1810 calcd for C20H26NO5 360.1811.
A solution of the crude nonconjugated enone and DBU
(2.5 mL) in CH3CN (10 mL) was stirred at room tempera-
ture for 12 h, diluted with satd aq NaHCO3, and extracted
with CHCl3. The extracts were dried and concentrated

Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
7271
in vacuo to yield a residue, which was subjected to column
chromatography (silica gel, 1:1 acetone/hexane) to give
the crude conjugated enone as a colorless oil (0.19 g, 60%,
major rotamer 1.66 (dt, J¼8.5, 13.0 Hz, 1H), 1.88 (dd,
J¼7.5, 8.0 Hz, 1H), 2.04 (s, 3H), 2.06 (s, 3H), 2.21–2.30
(m, 3H), 3.05–3.09 (m, 1H), 3.47–3.53 (m, 2H), 5.55 (dt,
J¼6.0, 2.0 Hz, 1H), 5.75 (dt, J¼6.0, 2.5 Hz, 1H), 5.83 (dd,
J¼5.5, 8.0 Hz, 1H); 13C NMR (major rotamer) 20.9, 23.4,
23.9, 32.7, 37.7, 48.7, 76.0, 77.6, 127.5, 134.2, 168.9,
170.2; HRMS (ES) m/z 246.1106 (M+Na), calcd for
C12H17NO3Na 246.1105.
1
three steps). [a]2D3 ꢀ27.4 (c 0.13, CHCl3); H NMR 1.74–
1.76 (m, 1H), 1.97–2.00 (m, 2H), 2.08–2.17 (m, 1H), 2.54
and 3.13 (abq, J¼23.0 Hz, 2H), 3.50–3.53 (m, 1H), 3.55
(abq, J¼9.0 Hz, 2H), 3.59–3.65 (m, 1H), 3.85 (s, 3H), 3.90
(s, 3H), 6.27 (dt, J¼2.0, 6.0 Hz, 1H), 6.75 (d, J¼8.0 Hz,
1H), 6.80 (d, J¼8.0 Hz, 1H), 6.82 (s, 1H), 7.72 (m, 1H);
13C NMR 24.5, 38.0, 41.4, 42.1, 48.4, 55.7, 55.8, 68.4,
111.1, 111.7, 120.9, 126.7, 132.3, 147.7, 148.9, 159.2,
168.8, 206.9; HRMS (ES) m/z 316.1551 (M+1), calcd for
C18H22NO4 316.1549.
4.1.8. 2-Iodo-4,5-methylenedioxyphenylacetyl chloride
(26). To a solution of CrO3 (6 g, 0.06 mol) and concd
H2SO4 (4 mL) in 20 mL water was added 2-(3,4-methylene-
dioxy-6-iodophenyl)ethanol4c (6.0 g, 0.021 mol) in 80 mL
acetone and the mixture was stirred at room temperature
i
To a solution of the conjugated enone (0.15 g, 0.48 mmol) in
iPrOH (5 mL) was added Al(iPrO)3 (4.7 g, 18.3 mmol). The
solvent was removed by distillation at 80 ꢁC and the residue
was stirred at 130 ꢁC for 2 h, cooled, and poured into
100 mL of dilute HCl at 0 ꢁC. The mixture was stirred for
30 min and extracted with CHCl3. The extracts were dried
and concentrated in vacuo to yield the crude allylic alcohol,
for 5 h. Then 10 mL PrOH was added and the solution
was stirred for an additional 1 h and filtered through Celite.
The filtrate was concentrated in vacuo, diluted with 50 mL
3 N NaOH, washed with chloroform, and acidified to pH
1–2 by the addition of concd HCl. The formed solid was fil-
tered and dried to give 3.9 g (60%) of 2-(3,4-methylene-
dioxy-6-iodophenyl)acetic acid. 1H NMR (CD3COCD3)
3.75 (s, 2H), 6.04 (s, 2H), 6.97 (s, 1H), 7.29 (s, 1H); 13C
NMR 46.0, 89.4, 102.9, 111.7, 118.9, 132.8, 148.6, 149.5,
171.8.
1
which was used without purification in the next step. H
NMR 1.49–1.58 (m, 1H), 1.70–1.83 (m, 1H), 1.93 (dt,
J¼6.0, 12.5 Hz, 1H), 2.04 (d, J¼6.5 Hz, 1H), 2.12 (dd,
J¼2.0, 16.0 Hz, 1H), 2.46–2.51 (m, 1H), 3.23 (dd, J¼2.0,
16.0 Hz, 1H), 3.50 (t, J¼6.8 Hz, 2H), 3.57 (abq, J¼
18.0 Hz, 2H), 3.86 (s, 3H), 3.86 (s, 3H), 5.56 (br s, 1H),
5.67 (d, J¼6.0 Hz, 1H), 5.85 (d, J¼5.5 Hz, 1H), 6.76 (d,
J¼8.0 Hz, 1H), 6.80 (d, J¼8.0 Hz, 1H), 6.82 (s, 1H); 13C
NMR 23.7, 34.1, 43.0, 43.1, 48.9, 55.8 (2), 74.4, 78.9,
111.1, 111.9, 121.0, 127.3, 131.6, 133.0, 147.7, 148.9,
169.5; HRMS (ES) m/z 318.1707 (M+1), calcd for
C18H24NO4 318.1705.
A solution of (3,4-methylenedioxy-6-iodophenyl)acetic acid
(1.37 g, 0.0045 mol) in 10 mL SOCl2 containing two drops
of DMF was stirred at room temperature for 4 h and concen-
trated in vacuo to give the crude 2-(3,4-methylenedioxy-6-
iodophenyl)acetyl chloride (26) (1.46, 100%).
4.1.9. (1S,5R)-N-(2-Iodo-4,5-methylenedioxyphenylace-
tyl)-6-azaspiro[4.4]nonan-1-ol (27). A solution of 22
(2.23 g, 10 mmol) in EtOH (30 mL) containing 10% Pd/C
(2.0 g) and H2 (1 atm) was stirred under an atmosphere of
hydrogen at 25 ꢁC for 12 h, and filtered through a Celite
pad. The filtrate was concentrated in vacuo to yield a crude
amido-ester (2.24 g, ca. 100%, >95% purity), which was
To a solution of the crude allylic alcohol (0.1 g, 0.28 mmol)
in anhydrous THF (5 mL) was added LiAlH4 (1 mL,
1 mmol). The mixture was stirred at reflux for 1 h, cooled,
diluted with ether, and then slowly diluted with a solution
of 0.5 mL water in 10 mL THF followed by 0.6 mL 10%
aq NaOH, and filtered. The filtrate was concentrated in vacuo
to afford a residue, which was subjected to column chroma-
tography (silica gel, 10% CHCl3/MeOH) to afford 12
(0.09 g, 92%).
1
used without purification. [a]2D2 +48.4 (c 0.79, CHCl3). H
NMR 1.45–1.55 (m, 2H), 1.62–1.66 (m, 2H), 1.76–1.94
(m, 3H), 2.03 (s, 6H), 2.22–2.31 (m, 2H), 2.59–2.64 (m,
1H), 3.43 (dd, J¼16.0, 7.0 Hz, 2H), 5.88 (t, J¼7.5 Hz,
1H); 13C NMR 20.1, 21.1, 23.2, 24.5, 30.0, 34.4, 34.9,
49.2, 71.8, 76.5, 168.9, 170.3; HRMS (ES) m/z 248.1255
(M+Na), calcd for C12H19NO3Na 248.1263.
4.1.7. (4S,5S)-N-Acetyl-4-acetoxy-6-azaspiro[4.4]non-
1-ene (22). To a solution of the known9 alcohol 10 (2.4 g,
10 mmol, 80% ee) in CH2Cl2 (50 mL) containing DMAP
(2.5 g, 20 mmol) was added methyl chlorooxoacetate
(2 mL) at 0 ꢁC. The reaction mixture was stirred at 25 ꢁC
for 2 h, diluted with chloroform and water, and separated.
The combined organic layers were washed with satd aq
NH4Cl, dried, and concentrated in vacuo giving the oxalate
ester, which was used without further purification.
A solution of amido-ester (2.24 g, 10 mmol) in 6 N HCl
(20 mL) was stirred at 100 ꢁC for 3 h, cooled, and concen-
trated in vacuo to afford the spirocyclic aminoalcohol 23
as its HCl salt (1.69 g, 95%, >95% purity), which was
1
used without purification. H NMR (D2O) 1.53–1.69 (m,
2H), 1.75–1.95 (m, 4H), 1.97–2.10 (m, 4H), 3.32 (m, 2H),
4.04 (2d, J¼5.0 Hz, 1H); 13C NMR (D2O) 22.3, 26.0,
34.5, 36.0, 36.5, 48.0, 78.0, 78.3.
A solution of the crude oxalate, AIBN (0.6 g, 3.6 mmol), and
n-Bu3SnH (12 mL, 45 mmol) in 20 mL toluene was stirred at
100 ꢁC for 1 h, cooled, diluted with chloroform, and washed
with satd aq NaHCO3. The organic layer was dried and con-
centrated in vacuo to afford the residue, which was subjected
to silica gel column chromatography (30% acetone/hexane)
to afford the unsaturated amido-ester 22 [1.34 g, 85% based
on recovered 0.64 g (25%) starting material]. [a]2D2 +111.6
To a solution of aminoalcohol 23 (0.89 g, 5 mmol) and Et3N
(10 mL) in CH3CN (30 mL) at ꢀ40 ꢁC was slowly added
a solution of 2-(3,4-methylenedioxy-6-iodophenyl)acetyl
chloride (26) (1.46 g, 4.5 mmol) in CH3CN (10 mL). The
mixture was stirred at ꢀ40 ꢁC for 70 min, diluted with water,
and extracted with chloroform. The combined extracts were
dried and concentrated in vacuo to give a residue, which
was subjected to silica gel column chromatography (33%
1
(c 0.7, CHCl3); H NMR (4:1 mixture of two rotamers)

7272
Z. Zhao, P. S. Mariano / Tetrahedron 62 (2006) 7266–7273
1
acetone/hexane) to provide arylacetamide 27 (1.54 g, 80%
[a]2D2 ꢀ32.0 (c 0.08, CHCl3). H NMR 1.49–1.66 (m, 1H),
1
based on 26). [a]2D2 +14.2 (c 0.65, CHCl3). H NMR 1.45–
1.75–1.96 (m, 5H), 2.30 (m, 2H), 2.38–2.49 (m, 2H),
2.78–2.84 (m, 3H), 2.97–3.01 (m, 1H), 5.56–5.57 (m,
J¼1 Hz, 1H), 5.80–5.81 (m, 1H), 5.93 (s, 2H), 6.74 (s,
1H), 7.20 (s, 1H); 13C NMR 21.4, 29.7, 31.5, 38.2, 40.9,
50.0, 51.3, 77.7, 87.8, 101.4, 109.6, 118.5, 132.1, 134.7,
136.8, 146.7, 148.4; HRMS (ES) 398.0610 (M+1), calcd
for C17H21NO2I 398.0617.
1.51 (m, 2H), 1.77–1.80 (m, 1H), 1.89–1.94 (m, 6H),
2.69–2.76 (m, 1H), 3.63–3.64 (m, 1H), 3.70 (abq,
J¼16.5 Hz, 2H), 3.77 (dt, J¼10.0, 5.0 Hz, 1H), 4.44 (dd,
J¼3.5, 10.5 Hz, 1H), 5.94 (d, J¼1.5 Hz, 2H), 6.80 (s, 1H),
7.23 (s, 1H); 13C NMR 21.2, 23.1, 34.5, 35.3, 41.2, 47.5,
49.4, 74.2, 81.7, 89.0, 101.5, 110.3, 118.3, 131.5, 147.3,
148.4, 171.4; HRMS (ES) 430.0507 (M+1), calcd for
C17H21NO4I 430.0515.
Acknowledgements
4.1.10. (1S,5R)-N-(2-Iodo-4,5-methylenedioxyphenylace-
tyl)-6-azaspiro[4.4]nonan-1-yl-p-toluenesulfonate (28).
To a solution of amidoalcohol 27 (0.75 g, 1.75 mmol) and
pyridine (1 mL) in CH2Cl2 (10 mL) at 0 ꢁC was added p-
toluenesulfonyl chloride (0.67 g, 3.5 mmol). The mixture
was stirred at 0 ꢁC for 4 h and at 25 ꢁC for 12 h, diluted with
15% aq NaOH, and extracted with chloroform. The extracts
were washed with satd aq NaCl, dried, and concentrated in
vacuo to yield a residue, which was subjected to silica gel
column chromatography (30% acetone/hexane) to give the
tosylate 28 (0.71 g, 85% based on recovered 0.11 g starting
material). [a]2D2 +16.4 (c 0.37, CHCl3). 1H NMR 1.29–1.39
(m, 1H), 1.46–1.50 (m, 1H), 1.63–1.65 (m, 1H), 1.86–2.06
(m, 4H), 2.12–2.21 (m, 2H), 2.43 (s, 3H), 2.87–2.90 (m,
1H), 3.59–3.65 (m, 2H), 3.68 (abq, J¼16.5 Hz, 2H), 4.52
(t, J¼7.0 Hz, 1H), 5.93 (d, J¼8.0 Hz, 2H), 6.83 (s, 1H),
7.22 (s, 1H), 7.30 (d, J¼8.0 Hz, 2H), 7.76 (d, J¼8.5 Hz,
2H); 13C NMR 21.5, 21.7, 22.7, 32.5, 34.4, 41.6, 47.8,
49.2, 71.2, 88.0, 89.0, 101.5, 110.7, 118.1, 127.5 (2), 129.6
(2), 132.3, 134.5, 144.3, 147.2, 148.4, 168.7; HRMS (ES)
584.0592 (M+1), calcd for C24H27NO6I 584.0604.
Support for this work provided by the National Science
Foundation (CHE-0506758) and Dojindo Molecular Tech-
nologies Inc., is gratefully appreciated.
Supplementary data
Within this section are (1) the general experimental section,
and (2) H and 13C NMR spectra of 12, 13, 15, 16, 18–23,
1
27–29, (S)-Mosher ester derivative of N-Boc-13, and (R)-
Mosher ester derivative of N-Boc-13. Supplementary data
associated with this article can be found, in the online
version at doi:10.1016/j.tet.2006.05.045.
References and notes
1. For a review see: Jalil Miah, M. A.; Hudlicky, T.; Reed, J. W.
The Alkaloids; Brossi, A., Ed.; Academic: New York, NY,
1998; Vol. 51, p 199.
4.1.11. (5S)-N-(2-Iodo-4,5-methylenedioxyphenylacetyl)-
6-azaspiro[4.4]non-1-ene (29). A solution of tosylate 28
(0.59 g, 1 mmol) and DBU (5 mL) in DMF (10 mL) was
stirred at 120 ꢁC for 12 h, cooled, diluted with EtOAc,
washed with satd aq NaCl, and concentrated in vacuo, giving
a residue, which was subjected to silica gel column chroma-
tography (20% acetone/hexane) to give amidoalkene 29
(0.25 g, 80% based on recovered 0.15 g starting material).
2. Paudler, W. m.; Kerley, G. I.; Mckay, J. J. Org. Chem. 1963, 28,
2194.
3. Powell, R. G.; Weisleder, D.; Smith, C. R., Jr.; Wolff, I. A.
Tetrahedron Lett. 1969, 4081.
4. (a) Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972, 94,
7172; (b) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc.
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J. Am. Chem. Soc. 1975, 97, 2507; (d) Yasuda, S.; Yamada,
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Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112,
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1990, 1436; (g) Kuehne, M. E.; Bornmann, W. E.; Parsons,
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J. Org. Chem. 1996, 61, 7335; (i) Isono, N.; Mori, M. J. Org.
Chem. 1995, 60, 115; (j) Tietze, L. F.; Schirok, H. J. Am.
Chem. Soc. 1999, 121, 10264; (k) Nagasaka, T.; Sato, H.;
Saeki, S. Tetrahedron: Asymmetry 1997, 8, 191; (l) Suga, S.;
Watanabe, M.; Yoshida, J. J. Am. Chem. Soc. 2002, 124,
14824; (m) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T.
Org. Lett. 2002, 4, 885; (n) Li, W. D.; Wang, Y. Q. Org. Lett.
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1
[a]2D2 ꢀ57.6 (c 0.18, CHCl3). H NMR (2.5:1 mixture of
two rotamers) major rotamer 1.75–1.79 (m, 1H), 1.83–1.95
(m, 4H), 2.25–2.32 (m, 1H), 2.39–2.45 (m, 1H), 2.60–2.69
(m, 1H), 3.51–3.65 (m, 4H), 5.54 (t, J¼3.0 Hz, 1H), 5.81
(t, J¼3.0 Hz, 1H), 5.92 (d, J¼5.5 Hz, 2H), 6.77 (s, 1H),
7.21 (s, 1H); 13C NMR (major rotamer) 23.6, 31.7, 34.5,
39.7, 47.6, 48.4, 76.0, 88.9, 101.5, 110.6, 118.2, 131.5,
132.3, 133.7, 147.2, 148.4, 167.8; HRMS (ES) 412.0404
(M+1), calcd for C17H19NO3I 412.0410.
4.1.12. (5S)-N-[2-(2-Iodo-4,5-methylenedioxyphenyl-
ethyl)]-6-azaspiro[4.4]non-1-ene (13). To a solution of
amidoalkene 29 (0.041 g, 0.1 mmol) in THF (3 mL) at
ꢀ40 ꢁC was added a solution of AlH3 in THF (0.2 mL,
0.67 M, 0.134 mmol). The solution was stirred at ꢀ40 ꢁC
for 15 min, diluted with satd aq Na2SO4, and filtered. The fil-
trate was dried and concentrated in vacuo, giving a residue,
which was subjected to silica gel column chromatography
(EtOAc then 10:1 EtOAc/MeOH containing 1% Et3N) to
yield aminoalkene 13 (24 mg, 60%) whose spectroscopic
properties (except for its optical rotation, which was not
reported in Ref. 4l) matched with those reported earlier.4l
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