Total synthesis of (+)-astrophylline

Article abstract of DOI:10.1021/jo026803h

The first total synthesis of (+)-astrophylline (2) has been achieved, starting from readily available enantiomerically pure (+)-(1R,4S)-4-hydroxycyclopent-2-enyl acetate (11). A novel ruthenium-catalyzed ring-closing ring-opening ring-closing metathesis of carbocyclic olefins of general type 5 was the key step, providing the stereochemically well-defined bis-piperidyl skeleton of the target molecule. A [2,3]-Wittig-Still rearrangement of 9 was also employed as the critical transformation in the stereocontrolled generation of the 1,2-trans configuration of the cyclopentene intermediate 6c. Our early synthetic efforts toward 1,2-trans cyclopentene derivatives of type 6, as well as the synthetic pathway to an optimized 13-step total synthesis of 2 (12% overall yield), are reported.

Full text of DOI:10.1021/jo026803h

Tota l Syn th esis of (+)-Astr op h yllin e
Marco Schaudt and Siegfried Blechert*
Institut fu¨r Chemie, Technische Universita¨t Berlin, Strasse des 17, J uni 135, D-10623 Berlin, Germany
blechert@chem.tu-berlin.de
Received December 4, 2002
The first total synthesis of (+)-astrophylline (2) has been achieved, starting from readily available
enantiomerically pure (+)-(1R,4S)-4-hydroxycyclopent-2-enyl acetate (11). A novel ruthenium-
catalyzed ring-closing ring-opening ring-closing metathesis of carbocyclic olefins of general type 5
was the key step, providing the stereochemically well-defined bis-piperidyl skeleton of the target
molecule. A [2,3]-Wittig-Still rearrangement of 9 was also employed as the critical transformation
in the stereocontrolled generation of the 1,2-trans configuration of the cyclopentene intermediate
6c. Our early synthetic efforts toward 1,2-trans cyclopentene derivatives of type 6, as well as the
synthetic pathway to an optimized 13-step total synthesis of 2 (12% overall yield), are reported.
In tr od u ction
Several new alkaloids1,2 were isolated in the end of the
sixties from Astrocasia phyllanthoides, a shrub belonging
to the Euphorbiaceae family and native to Central
America. Structure 1 was proposed1 for the predominant
alkaloid, astrocasine, based largely on spectral data (IR,
UV, NMR, MS) and partial degradation studies. Later,2
the isolation of 2 by Lloyd in 1965 from the same plant
and its characterization as cis-1-(2R,3′S)-[2,3′]bipiperidi-
nyl-1′-yl-3-phenyl-propenone provided strong support for
structure 1. Astrophylline 2 was also the first natural
cis-cinnamoyl alkaloid reported in the literature.
The key structural features of 2 include a cinnamoyl-
protected amine in the presence of a second piperidine
substructure, which makes the use of a carefully con-
ceived orthogonal protecting group strategy essential.
The unusual carbon skeleton of 2 represents a synthetic
challenge, due to the presence of unsymmetrically bridged
piperidine heterocycles, and a well-defined absolute
configuration of the two neighboring stereogenic centers.
At the start of this work, there were no general synthetic
methods known for the preparation of non-C2-symmetric
bridged bicyclic piperidines such as 2. Herein we report
the first total synthesis of 2, including our initial en-
deavors toward key precursors of type 6.
F IGURE 1.
selective synthesis of the bis-pyrrolidine alkaloid. We
envisaged that this type of transformation would also be
feasible for the stereocontrolled construction of the
heterocyclic skeleton of 2.
It was envisaged that the natural product would be
available from 3 after deprotection and subsequent
Z-selective Lindlar reduction6 (Scheme 1). Amide 3 could
be derived from 4 after simple functional group inter-
conversion operations. From previous studies in our
laboratories,3,5f,7 it was foreseen that 4 could be obtained
(4) For recent reviews, see: (a) Hoveyda, A. H.; Schrock, R. R. Chem.
Eur. J . 2001, 7, 945. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. (c) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140-3172;
Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (d) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413-4450. (e) Armstrong, S. J . Chem. Soc.,
Perkin Trans. 1 1998, 317-388. (f) Fu¨rstner, A. Top. Organomet. Chem.
1998, 1, 37-72. (g) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109,
2124-2144; Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056.
(5) For further examples of tandem ring rearrangement (RCM-ROM-
RCM) metathesis reactions, see: (a) Zuercher, W. J .; Hashimoto, M.;
Grubbs, R. H. J . Am. Chem. Soc. 1996, 118, 6634-6640. (b) Burke, S.
D.; Quinn, K J .; Chen, V. J . J . Org. Chem. 1998, 63, 8626-8627. (c)
Zuercher, W. J .; Scholl, M.; Grubbs, R. H. J . Org. Chem. 1998, 63,
4291-4298. (d) Weatherhead, G. S.; Ford, J . G.; Alexanian, E. J .;
Schrock, R. R.; Hoveyda, A. H. J . Am. Chem. Soc. 2000, 122, 1828-
1829. (e) Choi, T.-L.; Grubbs, R. H. Chem. Commun. 2001, 2648-2649.
(f) Stapper, C.; Blechert, S. Eur. J . Org. Chem. 2002, 16, 2855-2858.
(6) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 448. (b) Scho¨pf, C.;
Merkel, W. Liebigs Ann. Chem. 1967, 701, 180-197.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. Our approach was based
on previous work on the total synthesis of (+)-dihydro-
cuscohygrine, accomplished in our group.3 Taking ad-
vantage of the powerful olefin metathesis reaction4 as a
tool for the formation of carbon-carbon bonds under mild
conditions, a tandem ring rearrangement metathesis
(RRM) reaction3,5 served as the key step for the stereo-
(7) (a) Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179. (b)
Voigtmann, U.; Blechert, S. Org. Lett. 2000, 2, 3971-3974. (c) Stragies,
R.; Blechert, S. J . Am. Chem. Soc. 2000, 122, 9584-9591. (d) Bus-
chmann, N.; Ru¨ckert, A.; Blechert, S. J . Org. Chem. 2002, 67, 4325-
4329. (e) Ovaa, H.; Stapper, C.; van der Marel, G. A.; Overkleeft, H.
S.; van Boom, J . H.; Blechert, S. Tetrahedron 2002, 37, 7503-7518.
(1) Lloyd, H. A. Tetrahedron Lett. 1965, 22, 1761-1767.
(2) Lloyd, H. A. Tetrahedron Lett. 1965, 50, 4537-4540.
(3) Stapper, C.; Blechert, S. J . Org. Chem. 2002, 67, 6456-6460.
10.1021/jo026803h CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/07/2003
J . Org. Chem. 2003, 68, 2913-2920
2913

Schaudt and Blechert
SCHEME 1. Retr osyn th etic An a lyses of Astr op h yllin e 2
SCHEME 2. Syn th esis of Alcoh ol 6b via SN2′
after a ring-rearrangement metathesis reaction of key
intermediate 5, which involves the formation of two new
carbon-carbon bonds in one step. Since it was expected
that the stereochemical information associated with 5
would be transferred to 4 and thus to the natural product,
the synthetic challenge is reduced to the preparation of
enantiopure 5 from simple starting materials. Thus,
amide 6 (R ) H) could give 5 after displacement of the
hydroxy functionality with a suitably protected allyl-
amine. It was postulated that trans-1,2-disubstituted 6
could be prepared from 7 or 9 via either an SN2′-anti
addition of zinc cyanocuprate 8 to cis-1,4-disubstituted
chloride 78 or a [2,3]-Wittig-Still9 rearrangement of
stannane 9.10 This is highly desirable, as both 7 and 9
can be obtained from either epoxide 10 or enantiopure
acetate 11, both of which are trivial to prepare in
multigram quantities.
Ad d ition a
Syn th esis of 6. Monoepoxide 10,11 which could be
prepared easily from cyclopentadiene, was considered to
be a suitable racemic starting material to examine the
nucleophilic attack of the O-protected hydroxymethylcu-
prate 8 on cyclopentene derivatives of type 7. The effi-
ciency of η3-allyl-Pd(0) substitutions with N-allyl sul-
fonamides to open epoxide 10 has been demonstrated.5a,12
The tosyl group was chosen to protect the amine nitrogen,
as other standard protecting groups (Ns, Cbz, Boc) were
found to be problematic later in the synthesis. Thus Ts-
protected allylamine 12 was prepared by using the
a
Reagents and conditions: (a) (i) 12, Pd2(dba)3‚CHCl3 (2 mol
%), dppe (8 mol %), BSA, THF, 0 °C, 30 min; (ii) 10, 0 °C to room
temperature, 21 h (60%). (b) 13, SOCl2, 0 °C, 5 min (87%). (c) (i)
MTBE, KOtBu (4.0 equiv), tBuLi (4.4 equiv), -70 to -20 °C, 3 h;
(ii) ZnCl (4.5 equiv), THF, -60 °C, 2 h; (iii) CuCN (1.1 equiv), LiCl
(2.3 equiv), then 7, -75 °C to room temperature, 12 h (57%). (d)
(i) 6a , TFA, CH2Cl2, 0 °C to room temperature, 14 h; (ii) KOH,
MeOH/water, rt (79%).
literature procedure.13 Pd(0)-catalyzed allylic amination
of 10 with 12 proceeded smoothly to provide alcohol 13
in reasonable yield (Scheme 2). Subsequent chlorination
of the hydroxy functionality with thionyl chloride afforded
7 in a 5:1 diastereomeric mixture. The minor trans-
chloride was separated by column chromatography. The
halogen-leaving group is essential, as the corresponding
triflates and mesylates were too unstable to be conve-
niently handled, whereas acetate was found to be unre-
(8) (a) Corey, E. J .; Eckrich, T. M. Tetrahedron Lett. 1983, 24, 3165.
(b) Singer, R. D.; Knochel, P. Chem. Rev. 1993, 93, 2117-2188. (c)
Ernst, M.; Helmchen, G. Synthesis 2002, 14, 1953-1955.
(9) (a) Still, W. C.; Mitra, A. J . Am. Chem. Soc. 1978, 100, 1927. (b)
Bruckner, R.; Priepke, H. Angew. Chem., Int. Ed. 1988, 27, 278.
(10) For further examples of [2,3]-Wittig-Still rearrangements,
see: (a) Ovaa, H.; Lastdrager, H. B.; Codee, J . D. C.; van der Marel,
G. A.; Overkleeft, H. S.; van Boom, J . H. J . Chem. Soc., Perkin Trans.
1 2002, 21, 2370-2377. (b) Riether, D.; Mulzer, J . Org. Lett. 2000, 2,
3139-3141.
(11) Gerdil, R.; Liu, H.; Bernardineli, G. Helv. Chim. Acta 1999,
418-434.
(12) Shi, Y.; Trost, B. M. J . Am. Chem. Soc. 1993, 115, 9421-9438.
(13) Takeakin, N.; Ichiya, N.; Yoshiki, O.; Okiko, M. Tetrahedron
2000, 34, 6199-6208.
2914 J . Org. Chem., Vol. 68, No. 7, 2003

Total Synthesis of (+)-Astrophylline
SCHEME 3. Syn th esis of Alcoh ol 6c via a
active in the organometallic addition step. We were now
in a position to examine the feasibility of the SN2′
reaction. After considerable experimentation, optimized
conditions involved treatment of 7 with 8 (prepared in
situ from MTBE)8c at low temperature followed by
stirring overnight at room temperature, to give trans-
1,2-disubstituted tert-butyl ether 6a (>98% de, deter-
mined by 1H NMR spectroscopy), which was subsequently
hydrolyzed (via the TFA-ester) to give the required
alcohol 6b in 45% yield over two steps (Scheme 2). In
this transformation, the use of the tosyl moiety is critical,
as both nosyl and carbamate-based protecting groups
underwent reaction with 8.
[2,3]-Wittig-Still Rea r r a n gem en ta
The possible benefits of the use of a [2,3]-Wittig-Still10
sigmatropic rearrangement for the synthesis of 6 were
considered. The advantage of this reaction is that it can
offer greater protecting group flexibility compared with
the SN2′ process outlined previously. For example, car-
bamate-protecting groups (which were incompatible with
the SN2′ reaction), such as the tert-butyloxycarbonyl (Boc)
group should be inert under the basic rearrangement
conditions. The Boc-moiety would be the ideal choice for
the protection group PG1 (see Scheme 1), as preliminary
experiments indicated that it was compatible in terms
of cleavage conditions with the functionality present in
the latter stages of the synthesis,14 and in this regard
was expected to be superior to the tosyl group.
a
Reagents and conditions: (a) (i) 11, allylamine, Et3N, THF,
rt, 1 h; (ii) Pd(Ph3P)4 (5 mol %), rt, 14 h; (iii) (Boc)2O, MeOH, 65
°C, 14 h (67%). (b) (i) 14, Ph3P, benzoic acid, DIAD, THF, 0 °C to
room temperature, 2 h; (ii) 5% NaOH/MeOH, rt, 2 h (66%). (c) 15,
KH, dibenzo-18-crown-6, Bu3SnCH2I, 0 °C to room temperature,
3 h (92%). (d) 9, n-BuLi (1.1 equiv), THF, -78 °C to room
temperature, 12 h (69%).
Although the synthetic route to 9 could conceivably
start from 10, due to concerns about the practicality of
performing asymmetric Pd(0) allylic substitution reac-
tions on large scale, it was decided to evaluate the
feasibility of acetate 11 as a starting material, which
could be prepared easily on a 50-g scale from cyclopen-
tadiene.15 The Boc-protected amine 14 was obtained in
good overall yield after a η3-allyl-Pd(0) substitution with
allylamine in the presence of catalytic amounts of Pd-
(Ph3P)4 followed by the addition of Boc2O to the filtered
reaction mixture (Scheme 3). To provide the correct
absolute product stereochemistry the configuration at C4
in 14 had to be inverted. Thus, a Mitsunobu reaction with
benzoic acid was successful, affording the desired trans-
1,4-disubstituted alcohol 15 in 66% yield over these two
steps after hydrolysis of the intermediate ester. Next,
attention was focused on the installation of the hy-
droxymethyl substituent via the [2.3]-Wittig-Still rear-
rangement. Reaction of 15 with tributyl-iodomethylstan-
nane16 yielded the precursor 9 in excellent yield. Our first
attempts to transmetalate 9 with n-BuLi at -78 °C
resulted in a [2.3]-sigmatropic rearrangement in unsat-
isfactory yield. Further experimentation led to an opti-
mized multigram scale protocol (see Experimental Sec-
tion), which furnished the key building block 6c in good
yield.
We had now arrived at a point where two routes were
available for the synthesis of suitably protected enan-
tiopure 6. Of the two, the Wittig-Still route (Scheme 3)
held numerous advantages over the organocuprate meth-
odology (Scheme 2): it is a stereoselective synthesis,
affording the product as one enantiomer, it is compatible
with large-scale operations (the synthesis of 8 is tedious
and functions best on small scale), and it allows the
desirable Boc-protection group to be used (vide supra).
Thus this was the route of choice for the straightforward
synthesis of 2.
Syn th esis of 3. At this stage of the synthesis our
attention was focused on the necessary orthogonal pro-
tecting group strategy to provide the monoprotected
target alkaloid 2. Our initial retrosynthetic analysis
(Scheme 1) identified diene 4 as a late-stage intermedi-
ate. This molecule requires two different protecting
groups, as N1′ must be acylated in the presence of a
protected N1 to complete the synthesis. Since PG1 is fixed
as the Boc group, it was tempting to install a benzyloxy-
carbonyl (Cbz) group at N1′ (i.e. as PG2), which would
be cleaved under the conditions required to hydrogenate
both olefin moieties in 4. Thus, we set about the replace-
ment of the hydroxy moiety with a protected N-allyla-
mide. Facile conversion of 6c to the corresponding
mesylate followed by substitution with sodium azide gave
16. Subsequent Staudinger reduction17 performed under
standard conditions gave the amine in good conversion;
however, due to chromatographic complications it was
decided to attempt a one-pot reduction/protection proce-
dure. The crude reaction mixture from the Staudinger
reduction was cooled to room temperature and treated
with a slight excess of benzyl chloroformate in the
presence of K2CO3. After 3 h the Cbz-protected amine 17
(14) As an analogue of 3, we synthesized Boc-piperidine and mixed
it with 1 equiv of 3-phenylpropinoyl-piperidine. The mixture was
dissolved in methylene chloride and treated with TFA. After 1 h the
Boc-group was cleaved, while the triple bond had not reacted, as
indicated by TLC and a NMR analysis of the crude mixture. After
subsequent hydrogenation with Lindlar catalyst in methanol for 12 h
at room temperature and conventional workup, the NMR spectra of
the reaction residue showed the unchanged TFA salt of piperidine,
together with stereoselective formation of the cis-cinammoyl protected
piperidine in high yield.
(15) (a) Liu, W.; Ghosh, A. K. J . Org. Chem. 1997, 62, 7908-7909.
(b) J ohnson, C. R.; Bis, S. J . Tetrahedron Lett. 1992, 48, 7287-7290.
(16) Seyferth, D.; Andrews, S. B. J . Organomet. Chem. 1971, 30,
151-166.
(17) Staudinger, H.; Meyer, J . Helv. Chim. Acta 1919, 2, 635-646.
J . Org. Chem, Vol. 68, No. 7, 2003 2915

Schaudt and Blechert
SCHEME 4. F ir st Gen er a tion Syn th esis of
In ter m ed ia te 3a
SCHEME 5. Im p r oved Syn th esis of In ter m ed ia te 3
a n d F in a l Step s to 2a
a
Reagents and conditions: (a) 6c, 18, Ph3P, DIAD, 0 °C to room
temperature, 3.5 h (95%). (b) 5b, (IHMes)(Cy3P)Cl2RudCHPh (1
mol %), CH2Cl2, 40 °C, 2 h (82%). (c) 4b, PhSH, K2CO3, DMF, 70
°C, 1 h (80%). (d) (i) 19, H2, Pd/C, EtOH, rt, 15 h; (ii) phenyl-
propynoyl chloride, K2CO3, THF, rt, 2h (79%). (e) (i) 3, TFA,
CH2Cl2, 0 °C, 1 h; (ii) Lindlar catalyst, H2, MeOH, rt, 16 h (85%).
a
Reagents and conditions: (a) (i) 6c, methanesulfonyl chloride,
Et3N, CH2Cl2, 0 °C, 10 min; (ii) NaN3, DMF, 60 °C, 14 h (82%).
(b) (i) 16, Ph3P, THF, 60 °C, 13 h; (ii) benzyl chloroformate, K2CO3,
rt, 3 h (80%). (c) 17, NaH, allyl bromide, DMF, 0 °C to room
temperature, 30 min (86%). (d) 5a , (IHMes)(Cy3P)Cl2RudCHPh
(1 mol %), CH2Cl2, 40 °C, 3 h (80%). (e) (i) 4a , H2, Pd/C, EtOH, rt,
14 h; (ii) phenyl-propynoyl chloride, K2CO3, THF, rt, 1 h (77%).
protecting group, which has been found to be problematic
in metathesis reactions, previously7c gave no difficulties
in this metathesis rearrangement. Deprotection of the
Ns-group with thiophenol led to the amine 19, and a
subsequent hydrogenation-acylation sequence provided
intermediate 3 in good yield. Again it is noteworthy that
this order of reaction is critical, as attempted hydrogena-
tion of the olefins with the nosyl moiety still bound
results in efficient reduction of the nitro functionality to
give a less easily removable aniline derivative. Overall,
this route to 3 from 6c is three steps shorter than the
original synthetic pathway, and affords the product in
improved yield (49%).
The final steps of the total synthesis entailed the
cleavage of the Boc-group and subsequent cis-selective
Lindlar hydrogenation of the triple bond with catalyst
(85% yield over two steps) afforded the natural product
2 after purification. Spectral and analytical data for 2
were comparable with those reported in the literature
(see ref 2). It is remarkable that the cis-cinammoyl group
could only be prepared from the TFA salt of 3 (after
deprotection). If after deprotection of 3 the free-piperidine
is isolated and hydrogenated, complete reduction of the
triple bond to the corresponding saturated derivative is
observed.
could be isolated in 80% yield (two steps). To prepare the
metathesis precursor 5a , a simple allylation with allyl
bromide was carried out (Scheme 4).
The next step involved tandem metathesis of 5a
promoted by commercial available ruthenium alkylidene
catalyst (IHMes)(Cy3P)Cl2RudCHPh18 (1 mol %) in boil-
ing CH2Cl2. After 3 h the reaction was complete (as
determined by TLC) and column chromatography of the
crude material gave bis-piperidine 4a in good yield, with
complete transfer of the stereochemical information from
1
the starting material to the product (determined by H
NMR spectroscopy). Given the success of the one-pot
reduction/acylation strategy utilized to prepare 17, we
were encouraged to attempt the synthesis of 3 from 4a
without isolating the deprotected amine. Gratifyingly,
subjection of compound 4a to hydrogenation conditions
in the presence of catalytic Pd/C until TLC indicated
complete consumption of the starting material, followed
by removal of the heterogeneous catalyst by filtration,
solvent exchange, and addition of potassium carbonate
and phenyl-propynoyl chloride, gave amide 3 in 77% yield
as a white solid after purification (Scheme 4).
Con clu sion
Op tim ized Syn th esis of 2. Although the conversion
of 6c to Cbz-protected 5a and from there on to 3 was
successful, we were dissatisfied with the overall yield (6c
f 3) of 35%. We postulated that direct transformation
of 6c to Ns-protected 5b (Scheme 5) followed by cleavage
of the protecting group at a later stage of the synthesis
may prove more efficient in terms of yield and atom-
economy. The action of diisopropyl azodicarboxylate and
triphenylphosphine on diene 6c in the presence of N-allyl-
nosylamide (18)13 afforded 5b in high yield (95%, Scheme
5). Tandem metathesis of 5b, under identical conditions
to those used to convert 5a , provided the bicyclic 4b in
good yield (82%). It is interesting to note that the nosyl
We have accomplished a highly efficient stereoselective
synthesis of cis-cinnamoyl alkaloid (+)-astrophylline 2 in
13 steps and 12% overall yield. Starting from the common
enantiomeric pure acetate 11, two powerful key rear-
rangements have been used to construct the bis-piperi-
dine skeleton of the natural product. Access to the trans-
1,2-disubstituted chiral cyclopentene intermediate 6c
could be obtained by taking advantage of a selective
stereocenter-forming [2.3]-Wittig-Still rearrangement.
The preparation of the target skeleton could be achieved
by tandem olefin metathesis, where the chiral informa-
tion from the readily prepared carbocycle 5b is completely
transferred to both product heterocycles in a facile and
highly efficient carbon-carbon bond-forming transforma-
tion, furnishing a product, which can be transformed into
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
2916 J . Org. Chem., Vol. 68, No. 7, 2003

Total Synthesis of (+)-Astrophylline
(dddd, J ) 17, 10, 6, 6 Hz, 1H), 5.91 (m, 1H), 7.32 (d, J ) 8
Hz, 2H), 7.72 (d, J ) 8 Hz, 2H); 13C NMR (125.8 MHz, CDCl3)
δC 21.5 (CH3), 38.5 (CH2), 46.3 (CH2), 61.0 (CH), 62.9 (CH),
117.4 (CH2), 127.1 (CH), 129.7 (CH), 133.8 (CH), 135.0 (CH),
135.5 (CH), 137.2 (Cq), 143.5 (Cq); IR (neat, cm-1) ν˜ 2924, 1336,
1158, 1091; LRMS (EI) m/z (%) 311 ([M+], 12), 276 (100), 155
(16), 91 (37); HRMS calcd for C15H18ClNO2S [M+] 311.0747,
found 311.0743. Anal. Calcd for C15H18ClNO2S: C, 57.78; H,
5.82; N, 4.47. Found: C, 57.76; H, 5.78; N 4.59.
the natural product by using standard functional group
manipulations.
Exp er im en ta l Section
Gen er a l. Each reaction with air- and moisture-sensitive
components was performed under a N2 atmosphere; metathesis
reactions were carried out in a glovebox. Tetrahydrofuran was
distilled from sodium/benzophenone, and dichloromethane was
distilled from calcium hydride. 1H NMR (500 MHz) and 13C
NMR spectra (125.8 MHz) were recorded in the solvent
indicated. NMR chemical shifts are expressed in ppm upfield,
relative to the internal solvent peak. Mass spectra were
obtained at an ionizing potential of 70 eV. IR spectra were
measured by attenuated total reflectance (ATR). Optical
rotations were determined on a polarimeter as solutions in a
10 cm unit cell at 589 nm ([c] ) g/100 mL). Rf values indicated
refer to TLC on 0.2 mm analytical plates coated with silica
gel. MTBE ) methyl tert-butyl ether. Those chemicals which
were purchased were used without further purification. Cy-
clopentadiene monoepoxide (10),11 Ts- and Ns-protected allyl-
amides (12 and 18),12 and tributyl-iodmethyl-stannane16 were
prepared according to the published procedures.
tr a n s-N-Allyl-N-(2-ter t-bu toxym eth yl-cyclopen t-3-en yl)-
4-m eth yl-ben zen esu lfon a m id e (6a ). To a suspension of
KOtBu (256 mg, 2.28 mmol, 4.0 equiv) in MTBE (2.9 mL) was
added tBuLi (1.7 M/pentane, 1.46 mL, 2.51 mmol, 4.4 equiv)
dropwise at -70 °C. The resulting mixture was stirred for
several minutes at -70 °C until its color changed to yellow.
The reaction was allowed to warm to -20 °C (3 h). Subse-
quently the solution was cooled to -60 °C and treated with a
0.5 M solution of ZnCl2 in THF (347 mg of ZnCl2/5.1 mL of
THF, 2.52 mmol, 4.5 equiv). After being stirred at -60 °C for
2 h, a solution of CuCN (56 mg, 0.62 mmol, 1.1 equiv) and
LiCl (60 mg, 1.43 mmol, 2.3 equiv) in THF (2.0 mL) was
introduced. Then the mixture was cooled to -75 °C and treated
with a solution of chloride 7 (175 mg, 0.56 mmol, 1.0 equiv) in
THF (0.5 mL). The reaction mixture was allowed to warm to
room temperature and stirred for 12 h. Saturated aq NH4Cl
(10 mL) was then added, and the resulting mixture was
extracted with MTBE (2 × 20 mL). The combined organic
phases were dried over NaSO4 and the solvents were removed
under reduced pressure. Purification of the residue by flash
chromatography (hexane/ethyl acetate 8:1) gave compound 6a
(116 mg, 57%) as a colorless oil. Rf 0.87 (hexane/ethyl acetate
cis-N-Allyl-N-(4-h yd r oxy-cyclop en t -2-en yl)-4-m et h yl-
ben zen esu lfon a m id e (13). To a stirring solution of Pd2(dba)3‚
CHCl3 (297 mg, 0.32 mmol, 2 mol %) in THF (10 mL, 0.03 M)
was added (diphenylphosphino)ethane (510 mg, 1.28 mmol, 8
mol %). To this reaction mixture was added N-allyl-tosylamide
12 (3.38 g, 16.00 mmol, 1.0 equiv) in THF (16 mL, 1 M). The
resulting mixture was cooled to 0 °C and treated with N,O-
bis(trimethylsilyl)acetamide (4.87 g, 24.00 mmol, 1.5 equiv).
The mixture was allowed to stir for 30 min, after which time
cyclopentadiene monoxide 10 (3.93 g, 24.00 mmol, 1.5 equiv)
was added dropwise over a period of 6 h. The temperature was
kept at 0 °C for an additional hour, after which it was allowed
to warm to room temperature and stirred for 14 h. The solvent
was removed under reduced pressure. The remaining residue
was redissolved in MTBE (50 mL) and hydrolyzed with 4 N
aqueous HCl (25 mL) until complete disappearance of the
initial reaction product, TMS-protected alcohol, was observed
by TLC (Rf 0.9, hexane/ethyl acetate 1:2). The organic phase
was separated, and the aqueous phase was extracted with
MTBE (2 × 50 mL). The organic phases were combined and
dried over MgSO4 and the solvent was removed under reduced
pressure. The free alcohol 13 (2.81 g, 60%) was isolated by
flash chromatography (hexane/ethyl acetate 2:1) as a pale
yellow oil. Rf 0.58 (hexane/ethyl acetate 1:1). 1H NMR (500
MHz, CDCl3) δ 1.43 (dt, J ) 15, 4 Hz, 1H), 1.88 (d, J ) 6 Hz,
1H), 2.54 (dt, J ) 15, 8 Hz, 1H), 3.72 (dddd, J ) 14, 6, 6, 2 Hz,
2H), 4.64 (m, 1H), 4.84 (m, 1H), 5.13 (dd, J ) 10, 1 Hz, 1H),
5.21 (dd, J ) 17, 1 Hz, 1H), 5.59 (ddd, J ) 6, 2, 1 Hz, 1H),
5.85 (dddd, J ) 17, 10, 6, 6 Hz, 1H), 5.92 (ddd, J ) 6, 2, 2 Hz,
1H), 7.29 (d, J ) 8 Hz, 2H), 7.71 (d, J ) 8 Hz, 2H); 13C NMR
(125.8 MHz, CDCl3) δC 21.5 (CH3), 38.4 (CH2), 46.7 (CH2), 62.2
(CH), 74.7 (CH), 117.2 (CH2), 127.2 (CH), 129.7 (CH), 133.1
(CH), 136.0 (CH), 136.9 (CH), 137.5 (Cq), 143.3 (Cq); IR (neat,
cm-1) ν˜ 3511, 2978, 1333, 1157, 1090; LRMS (EI) m/z (%) 293
([M+], 1), 276 (5), 237 (52), 210 (69), 155 (57), 138 (100), 91
1
3:1). H NMR (500 MHz, CDCl3) δ 1.14 (s, 9H), 2.14 (m, 1H),
2.42 (s, 3H), 2.41-2.50 (m, 1H), 2.78 (m, 1H), 3.11 (dd, J ) 8,
8 Hz, 1H), 3.22 (dd, J ) 8, 6 Hz, 1H), 3.63 (m, 1H), 3.81 (m,
1H), 4.34 (ddd, J ) 9, 5, 5 Hz, 1H), 5.07 (br d, J ) 10 Hz, 1H),
5.18 (br d, J ) 17 Hz), 5.65 (m, 2H), 5.89 (dddd, J ) 17, 10, 6,
6 Hz, 1H), 7.27 (d, J ) 8 Hz, 2H), 7.76 (d, J ) 8 Hz, 2H); 13C
NMR (125.8 MHz, CDCl3) δC 21.4 (CH3), 27.4 (CH3), 36.6 (CH2),
46.7 (CH2), 50.8 (CH), 59.4 (CH), 63.5 (CH2), 72.7 (Cq), 116.7
(CH2), 127.4 (CH), 129.5 (CH), 129.8 (CH), 131.8 (CH), 135.8
(CH), 138.0 (Cq), 143.0 (Cq); IR (neat, cm-1) ν˜ 2973, 1340, 1158,
1091; LRMS (EI) m/z (%) 363 ([M+], <1), 289 (40), 276 (75),
208 (71), 155 (62), 91 (100), 57 (77); HRMS calcd for C20H29
-
NO3S [M+] 363.1868, found 363.1868.
tr a n s-N-Allyl-N-(2-h yd r oxym et h yl-cyclop en t -3-en yl)-
4-m eth yl-ben zen esu lfon a m id e (6b). To a solution of ether
6a (200 mg, 0.55 mmol) in CH2Cl2 (2 mL, 0.3 M) was added
trifluoroacetic acid (0.4 mL) dropwise at 0 °C. The solution
was stirred for 14 h at room temperature, then concentrated
to dryness; the residue was redissolved in a mixture of MeOH
and water (1 mL/2 mL) and treated with KOH (40 mg, 0.95
mmol, 1.7 equiv); and the solution was stirred at room
temperature until complete disappearance of the initial reac-
tion product (trifluoroacetic acid ester) was observed by TLC
(Rf 0.74, hexane/ethyl acetate 3:1). The reaction mixture was
diluted with saturated aqueous NH4Cl (2 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were
dried over Na2SO4, and the solvents were removed under
reduced pressure. The alcohol 6b (268 mg, 79%) was obtained
by flash chromatography (hexane/ethyl acetate 3:1) as a
(93); HRMS calcd for
C
15H19NO3S [M+] 293.1086, found
293.1088. Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N,
4.77. Found: C, 61.65; H, 6.18; N 4.78.
1
colorless oil. Rf 0.26 (hexane/ethyl acetate 3:1). H NMR (500
cis-N-Allyl-N-(4-ch lor o-cyclopen t-2-en yl)-4-m eth yl-ben -
zen esu lfon a m id e (7). To a solution of alcohol 13 (1.32 g, 3.50
mmol) in CH2Cl2 (10 mL) was added thionyl chloride (0.57 mL,
7.20 mmol, 1.6 equiv) dropwise at 0 °C. After 5 min of stirring
the mixture was concentrated in vacuo and the residue purified
by flash chromatography (hexane/ethyl acetate 4:1) to yield
chloride 7 (1.22 g, 87%) as a colorless oil. Rf 0.73 (hexane/ethyl
MHz, CDCl3) δ 2.18 (m, 1H), 2.39-2.47 (m, 4H), 3.13 (m, 1H),
3.64 (m, 1H), 3.89 (m, 1H), 4.14 (dd, J ) 11, 6 Hz, 1H), 4.39
(ddd, J ) 9, 5, 5 Hz, 1H), 4.45 (dd, J ) 11, 5 Hz, 1H), 5.12 (br
d, J ) 10 Hz, 1H), 5.19 (br d, J ) 17 Hz), 5.56 (m, 1H), 5.76
(m, 1H), 5.89 (dddd, J ) 17, 10, 6, 6 Hz, 1H), 7.30 (d, J ) 8
Hz, 2H), 7.71 (d, J ) 8 Hz, 2H); 13C NMR (125.8 MHz, CDCl3)
δC 21.5 (CH3), 35.7 (CH2), 46.7 (CH2), 49.2 (CH), 59.1 (CH),
68.3 (CH2), 117.2 (CH2), 127.2 (CH), 128.8 (CH), 129.7 (CH),
1
acetate 2:1). H NMR (500 MHz, CDCl3) δ 1.74 (dt, J ) 15, 4
Hz, 1H), 2.43 (s, 3H), 2.78 (dt, J ) 15, 8 Hz, 1H), 3.64 (m,
1H), 3.80 (m, 1H), 4.64 (m, 1H), 4.78 (m, 1H), 5.13 (dd, J )
10, 1 Hz, 1H), 5.23 (dd, J ) 17, 1 Hz, 1H), 5.66 (m, 1H), 5.86
132.0 (CH), 135.5 (CH), 137.5 (Cq), 143.5 (Cq); IR (neat, cm-1
)
ν˜ 3528, 2924, 1334, 1155, 1091; LRMS (EI) m/z (%) 307 ([M+],
J . Org. Chem, Vol. 68, No. 7, 2003 2917

Schaudt and Blechert
<1), 276 (90), 222 (29), 152 (94), 91 (100), 68 (34); HRMS calcd
3.60 (m, 2H), 3.62 (d, J ) 10 Hz, 1H), 3.68 (d, J ) 10 Hz, 1H),
4.44 (m, 1H), 5.06 (m, 2H), 5.34 (m, 1H), 5.77 (m, 1H), 5.85
(m, 1H), 6.01 (m, 1H); 13C NMR (125.8 MHz, CDCl3, rotameric
mixture) δC 7.5 (CH2), 13.6 (CH3), 27.1 (CH2), 28.3 (CH3), 29.0
(CH2), 35.1 (CH2), 45.6 (CH2), 58.7 (CH2), 61.2 (CH), 79.5 (Cq),
87.0 (CH), 115.1 (CH2), 134.3 (CH), 135.8 (CH), 155.3 (Cq); IR
(neat, cm-1) ν˜ 2926, 1695, 1401, 1172, 1141, 1049; LRMS (EI)
m/z (%) 487 ([M+ - C4H8], 21), 291 (71), 177 (44), 57 (100);
HRMS calcd for C22H41NO3Sn [M+ - C4H8] 487.2108, found
487.2110. Anal. Calcd for C26H49NO3Sn: C, 57.58; H, 9.11; N,
2.58. Found: C, 57.52; H, 9.04; N 2.50.
for C16H21NO3S [M+] 307.1242, found 307.1247.
Allyl-((1R,4S)-4-h yd r oxy-cyclop en t -2-en yl)-ca r b a m ic
Acid ter t-Bu tyl Ester (14). To a mixture of acetate 11 (10.00
g, 70.3 mmol) and allylamine (13.20 mL, 175.8 mmol, 2.5
equiv) in THF (280 mL, 0.25 M) was added triethylamine
(29.40 mL, 210.9 mmol, 3.0 equiv), and the solution was stirred
for 1 h at room temperature. Then Pd(Ph3P)4 (4.05 g, 3.5 mmol,
5 mol %) was introduced in eight portions over 80 min, and
the mixture was stirred for 13 h at room temperature. The
solution was concentrated in vacuo, dissolved in methanol (175
mL), and filtered through a small pad of silica. The filtrate
was treated with di-tert-butyl dicarbonate (16.94 g, 77.4 mmol,
1.1 equiv) and stirred for 14 h at 65 °C. The solvent was
removed under reduced pressure, and the alcohol 14 (11.27 g,
67%) was obtained by flash chromatography (hexane/ethyl
Allyl-((1R,2R)-2-h yd r oxym eth yl-cyclop en t-3-en yl)-ca r -
ba m ic Acid ter t-Bu tyl Ester (6c). Stannane 9 (10.0 g, 18.40
mmol) was dissolved in THF (260 mL, 0.07 M) and the solution
was cooled to -78 °C. n-BuLi (1.6 M in hexane, 12.65 mL,
20.24 mmol, 1.1 equiv) was added dropwise via the cold wall
of the flask. The solution was allowed to warm to room
temperature and was stirred for 12 h. The solution was poured
onto saturated aqueous NH4Cl (100 mL) and extracted with
ethyl acetate (4 × 100 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Purification of
the residue by flash chromatography (hexane/ethyl acetate
4:1-2:1) provided alcohol 6c (3.20 g, 69%) as a colorless oil.
acetate 2:1) as a colorless oil. Rf 0.57 (hexane/ethyl acetate
1
1:1). [R]20 +247° (c 0.83, EtOH); H NMR (500 MHz, CDCl3)
D
δ 1.44 (s, 9H), 1.63 (m, 1H), 2.48 (br s, 1H), 2.68 (dt, J ) 15,
8 Hz, 1H), 3.77 (m, 2H), 4.65 (m, 1H), 5.09-5.15 (m, 2H), 5.43
(m, 1H), 5.77-5.86 (m, 2H), 5.97 (m, 1H); 13C NMR (125.8
MHz, CDCl3) δC 28.3 (CH3), 39.0 (CH2), 48.2 (CH2), 60.9 (CH),
74.8 (CH), 79.8 (Cq), 115.4 (CH2), 133.3 (CH), 135.4 (CH), 136.1
(CH), 155.1 (Cq); IR (neat, cm-1) ν˜ 3424, 2976, 1690, 1668, 1404,
1168, 1142; LRMS (EI) m/z (%) 239 ([M+], <1), 183 (38), 165
(54), 120 (27), 57 (100); HRMS calcd for C13H21NO3 [M+]
239.1521, found 239.1522. Anal. Calcd for C13H21NO3: C,
65.25; H, 8.84; N, 5.85. Found: C, 64.89; H, 8.83; N 5.84.
Rf 0.53 (hexane/ethyl acetate 1:1). [R]20 -76° (c 0.50, EtOH);
D
1H NMR (500 MHz, CDCl3, rotameric mixture) δ 1.46 (s, 9H),
2.48 (m, 1H), 2.62 (m, 1H), 2.86 (m, 1H), 3.31 (br s, 1H), 3.45
(m, 1H), 3.53-3.71 (m, 2H), 3.82 (ddt, J ) 16, 5, 1 Hz, 1H),
4.52 (m, 1H), 5.07 (br d, J ) 10 Hz, 1H), 5.18 (br d, J ) 17 Hz,
1H), 5.59 (m, 1H), 5.75 (m, 1H), 5.85 (dddd, J ) 17, 10, 6, 6
Hz, 1H); 13C NMR (125.8 MHz, CDCl3, rotameric mixture) δC
28.4 (CH3), 35.8 (CH2), 46.2 (CH2), 54.7 (CH), 58.4 (CH), 65.0
(CH2), 80.3 (Cq), 115.4 (CH2), 130.3 (CH), 130.5 (CH), 135.4
(CH), 155.2 (Cq); IR (neat, cm-1) ν˜ 3438, 2976, 1690, 1669, 1366,
1166, 1140; LRMS (EI) m/z (%) 197 ([M+ - C4H8], 41), 179
Allyl-((1R,4R)-4-h yd r oxy-cyclop en t -2-en yl)-ca r b a m ic
Acid ter t-Bu tyl Ester (15). To a solution of alcohol 14 (8.52
g, 35.6 mmol) in THF (225 mL, 0.16 M) was added triphen-
ylphosphine (18.70 g, 71.2 mmol, 2.0 equiv) and benzoic acid
(6.53 g, 53.4 mmol, 1.5 equiv). The mixture was cooled to 0 °C
and diisopropyl azodicarboxylate (12.8 mL, 60.5 mmol, 1.7
equiv) was introduced dropwise over 1 h. After being stirred
for 2 h at room temperature, the solvent was removed in vacuo,
and the residue dissolved in ethyl acetate (50 mL). Then the
mixture was filtered over a small pad of silica, the filtrate was
concentrated under reduced pressure, and the crude benzoate
was then hydrolyzed by addition of 40 mL of 5% NaOH/
methanol. The reaction mixture was stirred for 2 h at room
temperature, then the solvent was removed in vacuo and the
residue was purified by flash chromatography (hexane/ethyl
acetate 2:1-1:1) to give the alcohol 15 (5.62 g, 66%) as a
(37), 122 (50), 57 (100); HRMS calcd for C10H15NO3 [M+
C4H8] 197.1052, found 197.1055. Anal. Calcd for C14H23NO3:
C, 66.37; H, 9.15; N, 5.53. Found: C, 66.02; H, 9.10; N 5.57.
-
Allyl-((1R,2S)-2-azidom eth yl-cyclopen t-3-en yl)-car bam -
ic Acid ter t-Bu tyl Ester (28). To a solution of alcohol 6c (280
mg, 1.11 mmol) and triethylamine (0.45 mL, 6.60 mmol, 6
equiv) in CH2Cl2 (10 mL, 0.1 M) at 0 °C was slowly added
methanesulfonyl chloride (0.16 mL, 2.20 mmol, 2 equiv). After
being stirred for 10 min, the mixture was diluted with water
(5 mL) and the layers were separated. The organic layer was
washed with water (5 mL) and brine (5 mL), dried over Na2-
SO4, and concentrated under reduced pressure to afford the
crude mesylate (368 mg, 100%). The product was used in the
next step without further purification. To a solution of the
mesylate in DMF (4 mL, 0.3 M) was added, in one portion,
NaN3 (430 mg, 6.6 mmol, 6 equiv). The resulting mixture was
stirred at 60 °C for 14 h and then diluted with water (4 mL).
The layers were separated and the aqueous layer was ex-
tracted with MTBE (3 × 10 mL). The combined extracts were
washed with brine (20 mL), dried over Na2SO4, and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (hexane/ethyl acetate 6:1) gave azide 16 (253 mg,
colorless oil. Rf 0.25 (hexane/ethyl acetate 2:1). [R]20 +157°
D
(c 0.84, EtOH); 1H NMR (500 MHz, CDCl3, rotameric mixture)
δ 1.45 (s, 9H), 2.06 (m, 2H), 3.56 (m, 2H), 4.95 (m, 1H), 5.03-
5.09 (m, 2H), 5.43 (m, 1H), 5.78 (m, 1H), 5.86 (m, 1H), 5.98
(m, 1H); 13C NMR (125.8 MHz, CDCl3, rotameric mixture) δC
28.3 (CH3), 39.0 (CH2), 45.6 (CH2), 61.1 (CH), 75.8 (CH), 79.8
(Cq), 115.3 (CH2), 128.2 (CH), 129.8 (CH), 135.6 (CH), 155.4
(Cq); IR (neat, cm-1) ν˜ 3416, 2976, 1690, 1669, 1403, 1170, 1141;
LRMS (EI) m/z (%) 239 ([M+], <1), 183 (22), 165 (6), 120 (11),
57 (100); HRMS calcd for C13H21NO3 [M+] 239.1521, found
239.1520. Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N,
5.85. Found: C, 65.10; H, 8.87; N 5.72.
82%) as a colorless oil. Rf 0.84 (hexane/ethyl acetate 3:1). [R]20
D
Allyl-((1R,4R)-4-tr ibu tylsta n n a n ylm eth oxy-cyclop en t-
2-en yl)-ca r ba m ic Acid ter t-Bu tyl Ester (9). To a solution
of alcohol 15 (5.0 g, 20.9 mmol) in THF (60 mL, 0.35 M) was
added KH (1.94 g, 45.9 mmol, 2.2 equiv) and dibenzo-18-
crown-6 (71 mg, 0.2 mmol, 0.5 mol %) at 0 °C. Bu3SnCH2I
(10.81 g, 25.07 mmol, 1.2 equiv) was added, then the solution
was allowed to warm to room temperature and stirred for 3
h. After addition of saturated aqueous NH4Cl (40 mL) the
mixture was extracted with ethyl acetate (3 × 50 mL) and the
combined organic phases were dried over Na2SO4 and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (hexane/ethyl acetate 40:1) provided stannane 9
1
-104° (c 0.74, EtOH); H NMR (500 MHz, CDCl3, rotameric
mixture) δ 1.45 (s, 9H), 2.45 (m, 1H), 2.61 (m, 1H), 2.96 (m,
1H), 3.30 (m, 1H), 3.42 (m, 1H), 3.68-3.87 (m, 2H), 4.09-4.46
(m, 1H), 5.05-5.14 (m, 2H), 5.61 (m, 1H), 5.74-5.87 (m, 2H);
13C NMR (125.8 MHz, CDCl3, rotameric mixture) δC 28.3 (CH3),
36.3 (CH2), 47.5 (CH2), 49.7 (CH), 54.4 (CH2), 59.0 (CH), 79.8
(Cq), 115.6 (CH2), 130.4 (CH), 131.2 (CH), 135.3 (CH), 155.2
(Cq); IR (neat, cm-1) ν˜ 2977, 2097, 1690, 1691, 1366, 1165;
LRMS (EI) m/z (%) 278 ([M+], < 1), 179 (35), 136 (73), 57 (100);
HRMS calcd for C14H22N4O2 [M+] 278.1743, found 278.1752.
Anal. Calcd for C14H22N4O2: C, 60.41; H, 7.97; N, 20.13.
Found: C, 60.15; H, 7.89; N, 20.20.
(10.42 g, 92%) as a colorless oil. Rf 0.62 (hexane/ethyl acetate
1
4:1). [R]20 +125° (c 0.85, EtOH); H NMR (500 MHz, CDCl3,
Allyl-[(1R,2S)-2-(ben zyloxyca r bon yla m in o-m eth yl)-cy-
clop en t-3-en yl]-ca r ba m ic Acid ter t-Bu tyl Ester (17). To
a solution of azide 16 (160 mg, 0.57 mmol) in THF (8 mL, 0.07
D
rotameric mixture) δ 0.89 (m, 15H), 1.29 (tq, J ) 7, 7 Hz, 6H),
1.45 (s, 9H), 1.49 (m, 6H), 1.85 (m, 1H), 2.13 (m, 1H), 3.48-
2918 J . Org. Chem., Vol. 68, No. 7, 2003

Total Synthesis of (+)-Astrophylline
M) was added triphenylphosphine (181 mg, 0.68 mmol, 1.2
equiv) and the mixture was stirred for 13 h at 60 °C. Then
the reaction mixture was cooled to room temperature and
treated with K2CO3 (236 mg, 1.71 mmol, 3.0 equiv) and benzyl
chloroformate (0.1 mL, 0.69 mmol, 1.2 equiv). After being
stirred for 3 h, the resulting mixture was diluted with water
(10 mL) and stirred for 1 h at room temperature. Ethyl acetate
(15 mL) was added, the solution was washed with saturated
aqueous potassium carbonate (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated in vacuo. Purification of the
residue by flash chromatography (hexane/ethyl acetate 7:1)
gave dicarbamate 17 (176 mg, 80%) as a colorless oil. Rf 0.53
(hexane/ethyl acetate 3:1). [R]20D -63° (c 0.51, EtOH); 1H NMR
(500 MHz, CDCl3, rotameric mixture) δ 1.43 (s, 9H), 2.42 (m,
1H), 2.57 (m, 1H), 2.73-2.98 (m, 2H), 3.47-3.79 (m, 3H), 4.55
(m, 1H), 5.03-5.15 (m, 4H), 5.57 (m, 1H), 5.71-5.83 (m, 2H),
7.27-7.39 (m, 5H); 13C NMR (125.8 MHz, CDCl3, rotameric
mixture) δC 28.2 (CH3), 35.8 (CH2), 44.0 (CH2), 46.2 (CH2), 49.9
(CH), 58.9 (CH), 66.2 (CH2), 80.0 (Cq), 115.3 (CH2), 127.8 (CH),
128.2 (CH), 128.3 (CH), 130.5 (CH), 130.9 (CH), 135.3 (CH),
136.7 (Cq), 155.9 (Cq), 156.5 (Cq); IR (neat, cm-1) ν˜ 3336, 2976,
2129, 1723, 1691, 1366, 1249, 1165; LRMS (EI) m/z (%) 368
([M+], < 1), 229 (22), 122 (64), 91 (100), 57 (62); HRMS calcd
for C22H30N2O4 [M+] 386.2206, found 386.2210. Anal. Calcd for
C23H30N2O4 [M+] 398.2207, found 398.2216. Anal. Calcd for
23H30N2O4: C, 69.32; H, 7.59; N, 7.03. Found: C, 69.18; H,
7.47; N 7.30.
C
(2R,3′S)-1′-(3-P h en yl-p r op -2-yn oyl)-[2,3′]bip ip er id in yl-
1-ca r boxylic Acid ter t-Bu tyl Ester (3). A solution of bipi-
peridine 4a (55 mg, 0.138 mmol) in ethanol (1.4 mL, 0.1 M)
containing palladium on charcoal (14 mg, 10 mol %) was
hydrogenated at room temperature for 14 h. The catalyst was
removed by filtration over Celite and the solution concentrated
in vacuo to give the crude amine as a colorless oil. This was
redissolved in THF (0.7 mL, 0.2 M) and treated with potassium
carbonate (57 mg, 0.414 mmol, 3.0 equiv) and phenyl-propy-
noyl chloride (27 mg, 0.166 mmol, 1.2 equiv), and the solution
was stirred for 1 h at room temperature. Then the mixture
was diluted with water (1 mL) and allowed to stir for 1 h. Ethyl
acetate (5 mL) was added, the layers were separated and the
organic layer was washed with saturated aqueous potassium
carbonate (3 mL) and brine (3 mL), dried over Na2SO4, and
concentrated in vacuo. Purification of the residue by flash
chromatography (hexane/ethyl acetate 3:1) gave 3 (41 mg, 77%)
as a white solid. Rf 0.37 (hexane/ethyl acetate 3:1). Mp 50-51
1
°C; [R]20 +124° (c 0.79, EtOH); H NMR (500 MHz, (CD3)2-
D
SO, 100 °C, not fully coalesced) δ 1.19-1.60 (m, 16H), 1.71-
2.07 (m, 4H), 2.52-2.91 (m, 3H), 3.91 (m, 2H), 4.26 (m, 2H),
7.37-7.57 (m, 5H); 13C NMR (125.8 MHz, CDCl3, rotameric
mixture) δC 19.0 (CH2), 19.1 (CH2), 25.2 (CH2), 28.4 (CH3), 28.7
(CH2), 29.0 (CH2), 34.0 (CH), 35.5 (CH), 42.0 (CH2), 47.8 (CH2),
50.3 (CH2), 79.5 (Cq), 81.5 (Cq), 90.1 (Cq), 120.7 (Cq), [128.4/
128.5] (CH), [129.8/130.0] (CH), 132.3 (CH), 152.8 (Cq), 155.0
(Cq); IR (neat, cm-1) ν˜ 2933, 2212, 1684, 1630, 1416, 1168;
LRMS (EI) m/z (%) 396 ([M+], < 1), 295 (15), 212 (100), 129
C
22H30N2O4: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.35; H,
7.87; N 7.24.
Allyl-{(1R,2S)-2-[allyl-(ben zyloxycar bon ylam in o)-m eth -
yl]-cyclopen t-3-en yl}-car bam ic Acid ter t-Bu tyl Ester (5a).
To a stirred solution of 17 (95 mg, 0.25 mmol) in DMF (2.5
mL, 0.1 M) at 0 °C was added NaH (60%, 59 mg, 1.5 mmol, 6
equiv). After the evolution of H2 had ceased, allyl bromide (0.08
mL, 0.74 mmol, 3 equiv) was added. After being stirred for 30
min at room temperature, the mixture was quenched with
water (3 mL). The aqueous layer was extracted with MTBE
(2 × 10 mL), and the combined extracts were washed with
brine (5 mL) and dried over Na2SO4. Removal of the solvents
left an oil that was purified by flash chromatography (hexane/
ethyl acetate 6:1), affording triene 5a (92 mg, 86%) as a
(52), 84 (80), 57 (26); HRMS calcd for
C
24H32N2O3 [M+]
396.2413, found 396.2411. Anal. Calcd for C24H32N2O3: C,
72.70; H, 8.13; N, 7.06. Found: C, 72.62; H, 8.23; N 7.15.
Allyl-((1R,2S)-2-{[allyl-(4-n itr o-ben zen esu lfon yl)-am in o]-
m eth yl}-cyclop en t-3-en yl)-ca r ba m ic Acid ter t-Bu tyl Es-
ter (5b). To a solution of alcohol 6c (3.00 g, 11.8 mmol) in
THF (80 mL, 0.15 M) was added triphenylphosphine (7.77 g,
29.6 mmol, 2.5 equiv) and N-allyl-p-nosylamide 18 (3.72 g, 15.4
mmol, 1.3 equiv). The mixture was cooled to 0 °C and
diisopropyl azodicarboxylate (4.80 mL, 23.7 mmol, 2.0 equiv)
was introduced dropwise over 30 min. After the solution was
stirred for 3 h at room temperature, the solvent was removed
in vacuo, and the residue was purified by flash chromatogra-
phy (hexane/ethyl acetate 6:1) to provide triene 5b (5.37 g,
colorless oil. Rf 0.80 (hexane/ethyl acetate 3:1). [R]20 -55° (c
D
1
0.85, EtOH); H NMR (500 MHz, CDCl3, rotameric mixture)
δ 1.43 (s, 9H), 2.36 (m, 1H), 2.58 (m, 1H), 3.00-3.40 (m, 3H),
3.53-4.04 (m, 4H), 4.42 (m, 1H), 4.98-5.18 (m, 6H), 5.60 (m,
1H), 5.65-5.86 (m, 3H), 7.25-7.37 (m, 5H); 13C NMR (125.8
MHz, CDCl3, rotameric mixture) δC 28.2 (CH3), 36.5 (CH2), 48.7
(CH), 50.1 (CH2), 50.3 (CH2), 50.6 (CH2), 59.3 (CH), 67.1 (CH2),
79.7 (Cq), 115.2 (CH2), 116.5 (CH2), [127.7, 127.8] (CH), 128.3
(CH), 129.9 (CH), 131.4 (CH), 133.3 (CH), 133.6 (CH), 135.4
(CH), 136.6 (Cq), 155.2 (Cq), 156.0 (Cq); IR (neat, cm-1) ν˜ 2976,
1692, 1365, 1238, 1165, 916; LRMS (EI) m/z (%) 426 ([M+], <
1), 269 (25), 160 (37), 122 (54), 91 (100), 57 (53); HRMS calcd
for C25H34N2O4 [M+] 426.2519, found 426.2521. Anal. Calcd for
95%) as a colorless oil. Rf 0.67 (hexane/ethyl acetate 3:1). [R]20
D
-99° (c 0.53, EtOH); 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H),
2.43 (br dd, J ) 17, 5 Hz, 1H), 2.62 (m, 1H), 3.07-3.26 (m,
3H), 3.66-3.95 (m, 4H), 4.30 (m, 1H), 5.07-5.18 (m, 4H), 5.50
(ddt, J ) 17, 10, 7 Hz, 1H), 5.65 (m, 1H), 5.75 (m, 1H), 5.82
(dddd, J ) 17, 11, 6 Hz, 6 Hz, 1H), 7.98 (d, J ) 8 Hz, 2H), 8.35
(d, J ) 8 Hz, 2H); 13C NMR (125.8 MHz, CDCl3, rotameric
mixture) δC 28.3 (CH3), 36.3 (CH2), 47.7 (CH2), 48.4 (CH), 50.3
(CH2), 59.4 (CH), 79.8 (Cq), 115.7 (CH2), 119.9 (CH2), 124.3
(CH), 128.4 (CH), 130.8 (CH), 131.8 (CH), 135.3 (CH), 145.7
(Cq), 149.9 (Cq), 155.2 (Cq); IR (neat, cm-1) ν˜ 2977, 1686, 1531,
1350, 1164, 931, 774; LRMS (EI) m/z (%) 376 ([M - C5H9O2]+,
5), 268 (4), 182 (16), 126 (100), 82 (85), 57 (80); HRMS calcd
for C18H22N3O4S [M - C5H9O2]+ 376.1331, found 376.1337.
Anal. Calcd for C23H31N3O6S: C, 57.84; H, 6.54; N, 8.80.
Found: C, 57.69; H, 6.52; N 8.86.
C
25H34N2O4: C, 70.39; H, 8.03; N, 6.57. Found: C, 70.27; H,
7.96; N 6.45.
(2R,3′S)-3,6,3′,6′-Tet r a h yd r o-2H ,2′H -[2,3′]b ip yr id in yl-
1,1′-d ica r boxylic Acid 1′-Ben zyl Ester 1-ter t-Bu tyl Ester
(4a ). Triene 5a (167 mg, 0.39 mmol) and (IHMes)(Cy3P)Cl2-
RudCHPh (4 mg, 1 mol %) were heated at reflux temperature
in dry CH2Cl2 (4 mL, 0.1 M) for 3 h. The solution was then
concentrated in vacuo, and the residue was purified by flash
chromatography (hexane/ethyl acetate 6:1), affording bipip-
eridine 4a (124 mg, 80%) as a colorless semisolid. Rf 0.62
(hexane/ethyl acetate 3:1). [R]20D +56° (c 0.63, EtOH); 1H NMR
(500 MHz, CDCl3, rotameric mixture) δ 1.44 (s, 9H), 2.18 (m,
1H), 2.34 (m, 1H), 2.55 (m, 1H), 2.85-3.53 (m, 2H), 3.52-4.42
(m, 5H), 5.03-5.30 (m, 2H), 5.55-5.84 (m, 4H), 7.27-7.37 (m,
5H); 13C NMR (125.8 MHz, CDCl3, rotameric mixture) δC 25.6
(CH2), 28.4 (CH3), 35.4 (CH), 39.6 (CH2), 43.6 (CH2), 43.9 (CH2),
49.2 (CH), 67.0 (CH2), 79.8 (Cq), 122.5 (CH), 124.0 (CH), 125.0
(CH), 125.7 (CH), 126.9 (CH), [127.8, 127.9] (CH), 128.4 (CH),
136.7 (Cq), 154.8 (Cq), 155.4 (Cq); IR (neat, cm-1) ν˜ 2957, 1691,
1410, 1232, 1168, 1111; LRMS (EI) m/z (%) 398 ([M+], < 1),
298 (1), 182 (34), 126 (100), 91 (83), 57 (39); HRMS calcd for
(2R,3′S)-1′-(4-Nitr o-ben zen esu lfon yl)-3,6,1′,2′,3′,6′-h exa -
h yd r o-2H-[2,3′]bip yr id in yl-1-ca r boxylic Acid ter t-Bu tyl
Ester (4b). Triene 5b (5.00 g, 10.47 mmol) and (IHMes)-
(Cy3P)Cl2RudCHPh (89 mg, 1 mol %) were heated at reflux
temperature in dry CH2Cl2 (100 mL, 0.1 M) for 2 h. The
solution was then concentrated in vacuo, and the residue was
purified by flash chromatography (hexane/ethyl acetate 6:1),
affording bipiperidine 4b (3.86 g, 82%) as a white solid. Rf 0.47
(hexane/ethyl acetate 3:1). Mp 158-159 °C; [R]20D +67° (c 0.18,
EtOH); 1H NMR (500 MHz, (CD3)2SO, 100 °C, not fully
coalesced) δ 1.44 (s, 9H), 2.18 (m, 1H), 2.27 (m, 1H), 2.49 (m,
J . Org. Chem, Vol. 68, No. 7, 2003 2919

Schaudt and Blechert
1H), 2.99 (dd, J ) 12, 8 Hz, 1H), 3.34 (dd, J ) 12, 5 Hz, 1H),
3.47 (m, 1H), 3.50 (m, 1H), 3.63 (dddd, J ) 17, 2, 2, 2 Hz, 1H),
3.76 (m, 1H), 4.08 (m, 1H), 4.23 (m, 1H), 5.68-5.81 (m, 4H),
8.0 (d, J ) 8 Hz, 2H), 8.35 (d, J ) 8 Hz, 2H); 13C NMR (125.8
MHz, CDCl3, rotameric mixture) δC [25.6/25.8] (CH2), 28.3
(CH3), [35.1/35.8] (CH), [39.6/40.8] (CH2), 44.8 (CH2), 45.4
(CH2), [49.1/50.6] (CH), 80.0 (Cq), 122.4 (CH), 123.4 (CH), 124.2
(CH), 127.0 (CH), 128.7 (CH), 142.4 (Cq), 150.1 (Cq), 154.8 (Cq);
IR (neat, cm-1) ν˜ 2965, 1686, 1530, 1350, 1168, 1109; LRMS
(EI) m/z (%) 449 ([M+], < 1), 376 (5), 182 (16), 126 (98), 82
(98), 57 (100); HRMS calcd for C21H27N3O6S [M+] 449.1621,
found 449.1616. Anal. Calcd for C21H27N3O6S: C, 56.11; H,
6.05; N, 9.35. Found: C, 55.92; H, 6.12; N 9.30.
solution was stirred for 2 h at room temperature. Then the
mixture was diluted with water (10 mL) and allowed to stir
for 1 h. Ethyl acetate (20 mL) was added, the layers were
separated, and the organic layer was washed with saturated
aqueous potassium carbonate (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated in vacuo. Purification of the
residue by flash chromatography (hexane/ethyl acetate 3:1)
gave 3 (801 mg, 79%) as a white solid. The spectroscopic data
were identical with those obtained starting from 4a (Scheme
4).
cis-1-(2R,3′S)-[2,3′]Bip ip er id in yl-1′-yl-3-p h en yl-p r op e-
n on e [(+)-Astr op h yllin e] (2). Compound 3 (150 mg, 0.39
mmol) was dissolved in CH2Cl2 (1.5 mL, 0.26 M), the solution
was cooled to 0 °C, and trifluoroacetic acid (0.6 mL, 4 mL/g)
was added dropwise. The reaction mixture was stirred for 1 h
at 0 °C and concentrated to dryness in vacuo. The crude TFA
salt was dissolved in methanol (1 mL) containing Pd/BaSO4
(80 mg, 20 mol %) and chinoline, and the salt was hydroge-
nated at room temperature for 16 h. The catalyst was removed
by filtration over Celite and the solution was concentrated in
vacuo. The residue was dissolved in CH2Cl2 (3 mL) and treated
with aq potassium hydroxide solution (10%, 3 mL) for 15 min.
The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were concentrated in vacuo and the residue was purified by
flash chromatography (MTBE/5% Et2N) yielding astrophylline
(2R,3′S)-3,6,1′,2′,3′,6′-Hexa h yd r o-2H-[2,3′]bip yr id in yl-1-
ca r boxylic Acid ter t-Bu tyl Ester (19). Bipiperidine 4b (1.50
g, 3.34 mmol) and K2CO3 (1.85 g, 13.36 mmol, 4 equiv) were
suspended in DMF (30 mL, 0.12 M). PhSH (0.41 mL, 4.00
mmol, 1.2 equiv) was added and the suspension was stirred
at 70 °C for 1 h. The mixture was poured onto water (15 mL)
and extracted with MTBE (15 mL). The aqueous phase was
saturated with NaCl and further extracted with MTBE (2 ×
15 mL). The combined organic phases were washed with brine
(15 mL), dried over NaSO4, and concentrated in vacuo.
Purification of the residue by filtration over silica (CH2Cl2/
methanol 1:0-1:1) furnished amine 19 (703 mg, 80%) as a pale
1
yellow oil. H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.17 (br
dd, J ) 17,4 Hz, 1H), 2.29 (m, 2H), 2.68 (br dd, J ) 13, 4, 1H),
2.84 (m, 1H), 3.27-3.46 (m, 3H), 3.90 (br s, 1H), 4.13 (m, 1H),
4.27 (m, 1H), 5.48-5.81 (m, 4H); 13C NMR (125.8 MHz, CDCl3,
rotameric mixture) δC 25.6 (CH2), 28.3 (CH3), 33.6 (CH), [39.7/
40.7] (CH2), [44.1/44.2] (CH2), 44.6 (CH2), [49.4/50.9] (CH), 79.9
(Cq), [122.4/122.7] (CH), [123.2/123.9] (CH), 127.1 (CH), [127.8/
128.3] (CH), 155.5 (Cq); IR (neat, cm-1) ν˜ 3335, 2974, 1689,
1409, 1172, 1110; LRMS (EI) m/z (%) 264 ([M+], 3), 126 (59),
82 (100), 57 (69); HRMS calcd for C15H24N2O2 [M+] 264.1838,
found 264.1833.
2 (99 mg, 85%) as a viscous oil. Rf 0.59 (MTBE/5% Et2N). [R]20
D
+27° (c 0.35, EtOH) (lit. [R]20 +23° (c unspecified, EtOH));
D
1H NMR (500 MHz, (CD3)2SO, 100 °C, not fully coalesced) δ
1.11-1.38 (m, 6H), 1.43-1.64 (m, 3H), 1.67-1.79 (m, 2H), 2.24
(m, 1H), 2.44-2.53 (m, 1H), 2.64-2.85 (m, 3H), 3.88-4.22 (m,
2H), 6.09 (d, J ) 12 Hz, 1H), 6.60 (d, J ) 12 Hz, 1H), 7.23-
7.44 (m, 5H); 13C NMR (125.8 MHz, CDCl3, rotameric mixture)
δC [24.6/24.9] (CH2), 26.4 (CH2), [26.9/27.1] (CH2), 27.7 (CH2),
[29.7/30.1] (CH2), [40.9/42.2] (CH), [42.0/44.1] (CH2), 47.3
(CH2), 49.8 (CH2), [58.5/58.9] (CH), [123.5/123.9] (CH), 128.4
(CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), [132.7/133.2] (CH),
[135.7/135.9] (Cq), 167.4 (Cq); IR (neat, cm-1) ν˜ 3315, 2928,
1634, 1614, 1557, 1439, 1260; LRMS (EI) m/z (%) 298 ([M+],
12), 214 (9), 131 (21), 103 (15), 84 (100); HRMS calcd for
(2R,3′S)-1′-(3-P h en yl-p r op -2-yn oyl)-[2,3′]bip ip er id in yl-
1-ca r boxylic Acid ter t-Bu tyl Ester (3). A solution of amine
19 (700 mg, 2.65 mmol) in ethanol (25 mL, 0.1 M) containing
palladium on charcoal (270 mg, 10 mol %) was hydrogenated
at room temperature for 15 h. The catalyst was removed by
filtration over Celite, and the solution concentrated in vacuo
to give the crude product (710 mg, 100%) as a colorless oil.
This was redissolved in THF (13 mL, 0.2 M) and treated with
potassium carbonate (1.13 g, 7.95 mmol, 3.0 equiv) and phenyl-
propynoyl chloride (522 mg, 3.18 mmol, 1.2 equiv), and the
C
C
19H26N2O [M+] 298.2045, found 298.2043. Anal. Calcd for
19H26N2O: C, 76.47; H, 8.78; N, 9.39. Found: C, 76.55; H,
8.87; N 9.42.
J O026803H
2920 J . Org. Chem., Vol. 68, No. 7, 2003