Enantioselective allyltitanations and metathesis reactions. Application to the synthesis of piperidine alkaloids (+)-sedamine and (-)-prosophylline

Article abstract of DOI:10.1021/jo010653d

An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20% from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%, starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation reactions and ring-closing or cross-metathesis reactions.

Full text of DOI:10.1021/jo010653d

1982
J . Org. Chem. 2002, 67, 1982-1992
En a n tioselective Allyltita n a tion s a n d Meta th esis Rea ction s.
Ap p lica tion to th e Syn th esis of P ip er id in e Alk a loid s (+)-Sed a m in e
a n d (-)-P r osop h yllin e
J anine Cossy,* Catherine Willis, Ve´ronique Bellosta, and Samir BouzBouz
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received J une 26, 2001
An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is
reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20%
from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%,
starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation
reactions and ring-closing or cross-metathesis reactions.
In tr od u ction
Piperidine alkaloids constitute a large family of com-
pounds, many of which exhibit a wide range of physi-
ological activities. As a result of this aspect, intense
activity has been devoted to the isolation and structure
determination of bases of this class and to the develop-
ment of general methodologies and routes for their
synthesis.1 In this context, during the past few years,
several methods were developed for the synthesis of
2-substituted piperidine alkaloids, as well as for the
synthesis of 2,6-disubstituted piperidine alkaloids.2
Sedamine was the first alkaloid isolated from Sedum
acre3 and was obtained later from a number of Sedum
species.4 Both levorotatory (-)-sedamine and the dex-
trorotatory enantiomer were found in all of the Sedum
species mentioned above. Numerous syntheses of sedamine
have been reported either in racemic form5 or as a single
enantiomer.6 (-)-Prosophylline is a prosopis alkaloid that
contains a 2,6-disubstituted-3-piperidinol skeleton. This
alkaloid was isolated from the leaves of Prosopis afri-
cana7 and possesses noteworthy antibiotic and anesthetic
properties.8 Surprisingly, only one synthesis of racemic
prosophylline9 and two enantioselective synthesis of (-)-
prosophylline10 have been reported to date.
F igu r e 1.
displacement of an activated alcohol moiety (e.g., tosylate,
mesylate or triflate) by an amine is certainly one of the
most useful and reliable methods.11 Furthermore, during
the past 10 years, the ring-closing metathesis reaction
(RCM) has been developed into a powerful method for
the preparation of both carbo- and heterocyclic ring
systems.12 Furthermore, piperidine rings can be very ef-
ficiently constructed from allylbutenylamines.12g How-
ever, these two approaches require that the stereochem-
istry has already been established in previous steps using
either chiral pool-derived cyclization precursors or ste-
(6) (a) Beyerman, H. C.; Eveleens, W.; Muller, Y. M. F. Recl. Trav.
Chim. Pays-Bas 1956, 75, 63. (b) Beyerman, H. C.; Eenshuistra, J .;
Eveleens, W.; Zweistra, A. Recl. Trav. Chim. Pays-Bas 1959, 78, 43.
(c) Scho¨pf, C.; Dummer, G.; Wu¨st, W. Liebigs Ann. Chem. 1959, 626,
134. (d) Wakabayashi, T.; Watanabe, K.; Kato, Y.; Saito, M. Chem.
Lett. 1977, 223. (e) Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J . Chem.
Soc., Chem. Commun. 1985, 633. (f) Pyne, S. G.; Bloem, P.; Chapman,
S. L.; Dixon, C. E.; Griffith, R. J . Org. Chem. 1990, 55, 1086. (g)
Kiguchi, T.; Nakazono, Y.; Kotera, S.; Ninomiya, I.; Naito, T. Hetero-
cycles 1990, 31, 1525. (h) Comins, D. L.; Hong, H. J . Org. Chem. 1993,
58, 5035. (i) Poerwono, H.; Higashiyama, K.; Takahashi, H. Heterocycles
1998, 47, 262. (j) Yu, C. Y.; Meth-Cohn, O. Tetrahedron Lett. 1999,
40, 6665. (k) Compe`re, D.; Marazano, C.; Das, B. C. J . Org. Chem.
1999, 64, 4528.
Among the different methods that allow the formation
of a piperidine ring,11 the intramolecular nucleophilic
(1) Strunz, G. M.; Findlay, J . A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26, pp 89-174.
(2) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 31.
(3) (a) Marion, L.; Lavigne, R.; Lemay, L. Can. J . Chem. 1951, 29,
347. (b) Franck, B. Chem. Ber. 1958, 91, 2803.
(4) (a) Logar, S.; Mesicek, M.; Perpar, M.; Seles, E. Farm. Vestn.
1974, 21; Chem. Abstr. 1975, 82, 82916h. (b) Krasnov, E. A.; Petrova,
L. V.; Bekker, E. F. Khim. Prir. Soedin. 1977, 585; Chem. Abstr. 1977,
87, 164249k.
(5) (a) Tufariello, J . J .; Ali, S. A. Tetrahedron Lett. 1978, 47, 4647.
(b) Shono, T.; Matsumura, Y.; Tsubaka, K. J . Am. Chem. Soc. 1981,
103, 1172. (c) Tirel, P. J .; Vaultier, M.; Carrie´, R. Tetrahedron Lett.
1989, 30, 1947. (d) Pilli, R. A.; Dias, L. C. Synth. Commun. 1991, 21,
2213. (e) Ozawa, N.; Nakajima, S.; Zzoya, K.; Hamaguchi, F.; Na-
gasaka, T. Heterocycles 1991, 32, 889. (f) Driessens, F.; Hootele´, C.
Can. J . Chem. 1991, 69, 211. (g) Ghiaci, M.; Adibi, M. Org. Prep.
Proced. Int. 1996, 38, 474.
(7) (a) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J .; Khuong-Huu,
Q.; Goutarel, R. Bull. Soc. Chim. Fr. 1966, 2945. (b) Khuong-Huu, Q.;
Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc. Chim. Belg. 1972, 81,
443.
(8) (a) Bourinet, P.; Quevauviller, A. Compt. Rend. Soc. Biol. 1968,
162, 1138; Chem. Abstr. 70, 95233k. (b) Bourinet, P.; Quevauviller, A.
Ann. Pharm. Fr. 1968, 26, 787; Chem. Abstr. 71, 29012g.
(9) Natsume, M.; Ogawa, M. Heterocycles 1981, 16, 973.
(10) (a) Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869. (b) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J .
Org. Chem. 1999, 64, 4914.
(11) For reviews see: (a) Wang, C. L. J .; Wuonola, M. A. Org. Prep.
Proced. Int. 1992, 24, 585. (b) Lashat, S.; Dickner, T. Synthesis 2000,
1781.
10.1021/jo010653d CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/22/2002

Synthesis of (+)-Sedamine and (-)-Prosophylline
J . Org. Chem., Vol. 67, No. 7, 2002 1983
Sch em e 1
ported procedure,14 homoallylic alcohol (+)-1 was pro-
duced in 90% yield with an enantiomeric excess of 93%.15
Protection of this product as the p-methoxybenzyl ether
(t-BuOK, PMB-Br, THF, 96% yield) followed by oxidative
cleavage of the double bond by using NaIO4/OsO4, in
THF/H2O (1/1), led to the unstable aldehyde 3, which was
immediatly treated with the (R,R)-I complex in ether at
-78 °C, to give the alcohol (+)-4 with a diastereomeric
ratio of 96:4 (75% yield for the two steps). The next step
of the synthesis was the transformation of the homoallylic
alcohol (+)-4 to the corresponding amine 6. For this
purpose, a two-step sequence was used. The first step
was a Mitsunobu reaction. When alcohol (+)-4 was
treated by Zn(N3)2‚2pyr (0.6 equiv)16 in the presence of
diethyl azodicarboxylate (DEAD) and triphenylphos-
phine, the expected azide 5 was not formed and the
starting material was recovered. On the contrary, when
(+)-4 was treated with diphenylphosphoryl azide (DP-
PA)17 in the presence of DEAD and PPh3 in THF at 0 °C
and the temperature was raised immediatly to room
temperature, the azide (+)-5 was isolated in 40% yield.
The yield of (+)-5 was increased to 82% when the
temperature was increased from 0 °C to room tempera-
ture over 12 h. When the reduction of azide (+)-5 to
amine 6 was achieved by using PPh3/H2O or PPh3/NH4-
OH in THF, the amine 6 could not be extracted from the
aqueous phase. On the contrary, the reduction of azide
(+)-5 with LiAlH4 in THF proceeded in 94% yield, and
the homoallylic amine 6 was isolated and converted
directly to carbamate (+)-7 (Boc2O, dioxane) with a
diastereomeric ratio of 97.5:2.5 (85% yield). Compound
(+)-7 was then alkylated with allyl bromide in the
presence of KHMDS to produce (+)-8 in 91% yield.
Treatment of (+)-8 with the Grubbs’ catalyst G118 (Scheme
3) in benzene furnished the 3,4-dehydropiperidine (+)-9
in 94% yield. After catalytic hydrogenation of the double
bond of (+)-9 in EtOAc over PtO2, the p-methoxybenzyl
group was removed with 1.1 equiv of DDQ in a mixture
of CH2Cl2/H2O (18/1, rt, 15 min). Under these conditions,
the alcohol (+)-11 was obtained in 75% yield and 15% of
the starting material (+)-10 was recovered. These two
Sch em e 2. Retr osyn th etic Sch em e
reoselective C-N bond formation such as a Mitsunobu
reaction on alcohols of the appropriate configuration.
Recently, we have shown that enantioselective allylti-
tanation reactions of aldehydes by the (R,R)-I or (S,S)-I
complex (Scheme 1), followed by a Mitsunobu reaction,
appear to be methods of choice for obtaining amines and/
or 1,3-amino alcohols of high enantiomeric excess. The
considerable potential of these reactions has been applied
to the synthesis of (+)-sedamine.13 Herein, we would like
to give a full account of this work and also to report the
synthesis of (-)-prosophylline.
Syn th esis of (+)-Sed a m in e. We recently reported
that the addition of enantioenriched allyltitanium com-
plexes I can convert protected 3-hydroxy aldehydes to
monoprotected 1,3-diols with high selectivity. This meth-
odology was applied to the synthesis of enantiopure
piperidines such as (+)-sedamine in combination with a
Mitsunobu reaction and a ring closing metathesis reac-
tion of diene A according to the retrosynthetic scheme
(Scheme 2).
When benzaldehyde was treated with the (S,S)-I
allyltitanium complex (Scheme 3) according to the re-
(12) (a) Schrock, R. R.; Murdzek, J . S.; Bazar, G. C.; Robbins, J .;
DiMare, M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3575. (b)
Nguyen, S. T.; J ohnson, L. K.; Grubbs, R. H. J . Am. Chem. Soc. 1992,
114, 3974. (c) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115,
3875. (d) Fu, G. C.; Nguyen, S. T.; Grubbs R. H. J . Am. Chem. Soc.
1993, 115, 9856. (e) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. (f) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012 and references therein. (g)
Phillips, A. J .; Abell., A. D. Aldrichimica Acta 1999, 32, 75.
(13) Cossy, J .; Willis, C.; Bellosta, V.; Bouzbouz, S. Synlett 2000,
1461.
(14) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit,
P.; Swarzenbach, F. J . Am. Chem. Soc. 1992, 114, 2321.
(15) The enantiomeric excess was determined by HPLC; column,
Chiralpak AD2; eluent, 3% isopropyl alcohol in n-hexane.
(16) Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
(17) Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1992, 48, 7251.
(18) Miller, S. J .; Blackwell, M. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606.

1984 J . Org. Chem., Vol. 67, No. 7, 2002
Sch em e 3. Syn th esis of (+)-Sed a m in ea
Cossy et al.
a
Reagents and conditions: (a) (S,S)-I, Et2O, -78 °C, 90%; (b) t-BuOK, PMB-Br, THF, 96%; (c) OsO4/NaIO4, THF/H2O; (d) (R,R)-I,
Et2O, -78 °C, 75% for the two steps; (e) DEAD, PPh3, DPPA, THF, 0 °C to rt, 82%; (f) LiAlH4, Et2O, 94%; (g) Boc2O, dioxane, 85%; (h)
allylbromide, KHMDS, THF/DMF = 3/1, 91%; (i) G1, C6H6, 94%; (j) H2, PtO2, AcOEt, 94%; (k) DDQ, CH2Cl2/H2O = 18/1, 75%; (l) LiAlH4,
THF, reflux, 78%.
Sch em e 4
compounds could be separated easily. We note that when
1.5 equiv of DDQ was used, (+)-10 was entirely consumed
and a chromatographically separable mixture of alcohol
(+)-11 (80%) and ketone 11′ 5d (10%) was formed (Scheme
4). After reduction of the Boc group of (+)-11 with LiAlH4
in refluxing THF for 6 h, (+)-sedamine was obtained after
crystallization in 78% yield with a diastereoselectivity
of 98%. The properties were identical to those reported
in the literature.6
The replacement of the p-methoxybenzyl protecting
group by a benzyl group would shorten the synthesis of
(+)-sedamine provided that reduction of the dehydropi-
peridine and hydrogenolysis of the benzyl group could
be achieved in a one-pot reaction. Accordingly, the
benzylic ether 12 was also prepared and hydrogenated,
but contrary to expectation compound 13 was obtained
instead of 11, with either Pd/C or Pd(OH)2 as catalyst
(Scheme 4). Nonetheless the synthesis of (+)-sedamine
was still efficient as this compound was obtained with
high diastereoselectivity (98%) in 12 steps in an overall
yield of 20%.
Syn th esis of (-)-P r osop h yllin e. The enantioselec-
tive allyltitanation of aldehydes with (R,R)-I and (S,S)-I
was also used to synthesize (-)-prosophylline. The con-
struction of the piperidine ring of prosophylline was
envisaged to arise by intramolecular nucleophilic dis-
placement of a mesylate by an amine. The stereogenic
centers at C-6 and C-3 could be controlled through

Synthesis of (+)-Sedamine and (-)-Prosophylline
J . Org. Chem., Vol. 67, No. 7, 2002 1985
Sch em e 5. Retr osyn th etic Sch em e
enantioselective allyltitanations of aldehydes, and the
stereogenic center at C-2 could come from D-glyceralde-
hyde acetonide. Furthermore the ketonic side chain could
be built up by using a cross-metathesis reaction between
the substituted piperidine B and the unsaturated enone
28 (Scheme 5).
next step of the synthesis was the formation of the
piperidine ring. For this purpose, a two-step sequence
was used. First, reduction of the azide (+)-25 to the amine
(+)-26, with PPh3 in aqueous THF at 50 °C for 12 h, was
achieved in 89% yield. Treatment of amine (+)-26 with
Et3N in refluxing methanol furnished the desired pip-
eridine (-)-27 in 88% yield. It is worth noting that the
transformation of the azido compound (+)-25 to amine
(+)-27 in a one-pot procedure by addition of PPh3 in THF
followed by the addition of aqueous Et3N afforded pip-
eridine (-)-27 in lower yield (37%).
When D-glyceraldehyde acetonide 1419 was treated with
the allyltitanium complex (S,S)-I,14 homoallylic alcohol
(+)-15 (dr ) 98:2) was isolated in 86% yield.14 Protection
of (+)-15 as the benzyl derivative (+)-16 was achieved
in the presence of t-BuOK and benzyl bromide in THF
(91%). Compound (+)-16 was then transformed to the
unstable aldehyde 18 in a two step-sequence. Olefin (+)-
16 was hydroborated (BH3‚THF, THF; NaOH, H2O2) and
transformed to the primary alcohol (+)-17 in 83% yield.
After Swern oxidation of (+)-17, aldehyde 18 was im-
mediately treated with the allyltitanium complex (R,R)-I
at -78 °C in ether to give the homoallylic alcohol (+)-19
in a 98:2 diastereomeric ratio (yield 81%). The next
step of the synthesis was the transformation of the
homoallylic alcohol (+)-19 to the azide by a Mitsunobu
reaction. When homoallylic alcohol (+)-19 was treated
with DPPA in the presence of PPh3 and DEAD in THF
at 0 °C and the temperature was raised to room temper-
ature over 12 h, according to the procedure used for the
synthesis of (+)-sedamine, the azide 20 was formed,
but it could not be separated from DPPA. However,
after the azide was reduced by LiAlH4 (ether, 0 °C) amine
(+)-21 was obtained in 41% overall yield for the two
steps. With the aim of obtaining the precursor of the
piperidine ring of prosophylline, compound (+)-21 was
treated with acid in order to deprotect the diol. How-
ever, 22 could not be obtained when CSA in MeOH or
an acidic resin in a mixture of MeOH/H2O were used
(Scheme 6).
As a possible method that would introduce the ketonic
side chain at C-6, we examined the cross-metathesis
reaction20 between the substituted piperidine (-)-27 and
the unsaturated ketone 28.21 Unfortunately when a
mixture of (-)-27 and unsaturated ketone 28 were
22
treated with the “new generation” Grubbs’ catalyst G2
(10 mol %), the desired coupling product 29 was not
obtained and the starting material was recovered (Scheme
8). However, when piperidine (-)-27 was transformed to
its benzylcarbamate (+)-30 (CbzCl, Na2CO3, CH2Cl2/H2O,
quantitative yield) and treated with the Grubbs’ catalyst
G2 in the presence of the unsaturated ketone 28, the
desired coupling product (+)-31 was isolated in 58%
yield after 4 h in refluxing CH2Cl2. The synthesis of (-)-
prosophylline was completed by hydrogenation of the
olefin and deprotection of the hydroxyl and amino groups.
When compound (+)-31 was hydrogenated over Pd/C,
reduction of the double bond was achieved, as well as
the deprotection of the piperidine nitrogen and the
secondary alcohol. The resulting hydroxylated amine (-)-
32 was then treated with tetrabutylammonium fluoride
in THF to afford (-)-prosophylline in 54% yield. The
spectral and physical data were in accordance with the
literature data.9 (-)-Prosophylline was obtained by the
above route in 15 steps with a diastereomeric ratio of 98:2
and with an overall yield of 9.2%.
In an alternative route, the impure azide acetal 20 was
treated with AcOH/H2O (80/20) and transformed to the
corresponding diol (-)-23 in 76% yield (two steps).
Protection of the primary alcohol of (-)-23 as the tert-
butyldiphenylsilyl ether (TBDPSCl, imidazole, CH2Cl2)
afforded (-)-24 in 96% yield. Treatment with methane-
sulfonyl chloride in the presence of DMAP and pyridine
gave the mesylate (+)-25 in 98% yield (Scheme 7). The
(20) For cross-metathesis reactions see: Chatterjee, A. K.; Morgan,
J . P.; Scholl, M.; Grubbs, R. H. J . Am. Chem. Soc. 2000, 122, 3783
and references therein.
(21) Compound 28 was prepared from ethyl vinyl ketone by 1,4-
addition of the Grignard reagent prepared from 6-bromo-1-hexene in
the presence of CuBr‚Me2S, in THF.
(22) Scholl, M.; Ding, S.; Woo Lee, C.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(19) Schmid, C. R.; Bryant, J . D. Org. Synth. 1995, 72, 6.

1986 J . Org. Chem., Vol. 67, No. 7, 2002
Cossy et al.
Sch em e 6a
a
Reagents and conditions: (a) (S,S)-I, Et2O, -78 °C, 86%; (b) t-BuOK, BnBr, THF, 91%; (c) (i) BH3‚THF, (ii) H2O2, NaOH, H2O, 83%;
(d) DMSO, (COCl)2, Et3N, CH2Cl2, quantitative yield; (e) (R,R)-I, Et2O, -78 °C, 81%; (f) PPh3, DEAD, DPPA, THF, 0 °C to rt; (g) LiAlH4,
Et2O, 0 °C, 41% for the two steps; (h) CSA/MeOH or H+ resin, MeOH/H2O.
Sch em e 7a
a
Reagents and conditions: (a) AcOH/H2O, 80/20, 76% for the two steps; (b) TBDPSCl, imidazole, CH2Cl2, 96%; (c) MsCl, DMAP, pyridine,
98%; (d) PPh3, THF/H2O, 89%; (e) Et3N, MeOH, reflux, 88%.
distilled from sodium/benzophenone ketyl immediately before
use. Benzene, dichloromethane, DMF and triethylamine were
distilled from calcium hydride under argon. Benzaldehyde and
allyl bromide were distilled prior to use. Moisture-sensitive
reactions were conducted in oven- or flame-dried glassware
under an argon atmosphere. Flash chromatography was
carried out on Kieselgel 60 (230-400 mesh, Merck) and
analytical thin-layer chromatography was performed on Merck
precoated silica gel (60 F254). Melting points are uncorrected.
Microanalyses were performed at the Service de Microanalyse
de l’Universite´ Pierre et Marie Curie in Paris. Mass spectra
were obtained by GC/MS with electron impact ionization by
using a 5971 Hewlett-Packard instrument at 70 eV; only
The application of the enantioselective allyltitanation
methodology to the synthesis of (+)-sedamine and (-)-
prosophylline was efficient, as these compounds could be
obtained in relatively few steps with high diastereose-
lectivity. As both the (R,R)-I and (S,S)-I allyltitanium
complexes are available, (-)-sedamine and (+)-proso-
phylline could also be prepared by these routes.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise specified, materi-
als were purchased from commercial suppliers and used
without further purification. THF and diethyl ether were

Synthesis of (+)-Sedamine and (-)-Prosophylline
J . Org. Chem., Vol. 67, No. 7, 2002 1987
Sch em e 8a
a
Reagents and conditions: (a) CbzCl, Na2CO3, CH2Cl2/H2O, quantitative yield; (b) 28, G2, CH2Cl2, reflux, 58%; (c) H2, Pd/C 10%,
MeOH/HCl, 50/1, 60%; (d) TBAF, THF 90%.
selected ions are reported. HRMS and CIMS were performed
at the Laboratoire de Spectrochimie de l’Ecole Normale
Supe´rieure in Paris. 1H and 13C spectra were respectively
recorded on a Bruker AC 300 spectrometer at 300 and 75 MHz.
Unless otherwise specified, spectra were recorded in CDCl3
as solvent; chemical shifts (δ) were expressed in ppm and
coupling constant (J ) in hertz. IR spectra were recorded as neat
films (NaCl cell) and KBr pellets or CHBr3 solutions for solids
on a Perkin-Elmer 298. Optical rotations were determined
operating at the sodium D line. HPLC analyses were conducted
using Chiralpak AD2 column. Cyclopentadienyl[(4S,trans)-2,2-
dimethyl-R,R,R′,R′-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-
O,O′]titanium chloride was prepared following the reported
procedure.14
[R]20D ) +47.9 (c 5.0, C6H6)}; IR (neat) 3360, 1640, 1595 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.40-7.26 (m, 5H), 5.83 (m, 1H),
5.22-5.13 (m, 2H), 4.74 (m, 1H), 2.57-2.50 (m, 2H), 2.22 (d,
1H, J ) 3.3 Hz); 13C NMR (75.5 MHz) δ (ppm) 143.7 (s), 134.3
(d), 128.3 (d), 127.4 (d), 125.7 (d), 118.2 (t), 73.2 (d), 43.7 (t);
MS (EI, 70 eV) m/z 148 (M, 1), 129 (1), 128 (2), 115 (1), 108
(8), 107 (100), 105 (8), 91 (2), 79 (58), 77 (33), 51 (7).
1-Meth oxy-4-{[((1R)-1-p h en ylbu t-3-en yl)oxy]m eth yl}-
ben zen e (+)-2. To a solution of (+)-1 (1.20 g, 8.1 mmol, 1
equiv) in THF (10 mL) at 0 °C was added t-BuOK (1.27 g, 11.4
mmol, 1.4 equiv). The mixture was stirred for 5 min, and
p-methoxybenzyl bromide (2.00 g, 9.7 mmol, 1.2 equiv) was
added dropwise. After 4 h at room temperature, the reaction
was quenched by addition of a 20% aqueous NH4Cl solution
(50 mL). After extraction of the aqueous phase with EtOAc (3
× 85 mL), the combined organic phases were washed with
water (45 mL) and brine (45 mL), dried over MgSO4 and
concentrated in vacuo. The crude residue was purified on silica
gel (Et2O/petroleum ether, 2/98 to 5/95) to afford (+)-2 as a
yellow oil (2.10 g, 7.8 mmol, 96%): Rf ) 0.57 (Et2O/petroleum
(1R)-1-P h en ylbu t-3-en -1-ol14 (+)-1. Allylmagnesium chlo-
ride (5.19 mL, 2 M in THF, 10.4 mmol, 1.1 equiv) was added
at 0 °C to a mixture of cyclopentadienyl[(4S,trans)-2,2-dim-
ethyl-R,R,R′,R′-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-
O,O′]titanium chloride (7.51 g, 12.3 mmol, 1.3 equiv) in
anhydrous Et2O (150 mL). The orange mixture was stirred for
2 h at 0 °C and cooled to -78 °C. To this mixture was added
dropwise a solution of benzaldehyde (0.96 mL, 1.0 g, 9.4 mmol,
1 equiv) in Et2O (12 mL). After 3 h at -78 °C, the reaction
was quenched by addition of a 45% aqueous NH4F solution
(50 mL). The mixture was stirred overnight at room temper-
ature and then filtered through Celite. The organic phase was
washed with brine (300 mL), dried over MgSO4 and concen-
trated in vacuo. The crude residue was diluted with pentane
(150 mL) and filtered to afford (4S,trans)-2,2-dime´thyl-R,R,R′,R′-
tetraphenyl-1,3-dioxolane-4,5-dimethanol ((S,S)-taddol) (4.98
g, 10.7 mmol, 87%). The organic layer was concentrated in
vacuo, and the crude residue was purified on silica gel (CH2-
Cl2/hexanes/Et2O, 4/4/1) to afford (+)-1 (1.26 g, 8.5 mmol, 90%)
as a yellow oil (93% ee, determined by chiral HPLC, column
Chiralpak AD2, n-hexane/i-PrOH, 97/3, (+)-1 96.6%, tR ) 14.10
min; (-)-1 3.4%, tR ) 14.70 min). Physical and spectral data
were identical to those previously reported:14 Rf ) 0.53 (CH2-
ether, 1/9); [R]20 ) +67.3 (c 1.0, C6H6); IR (neat) 1640, 1610,
D
1585 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.47-7.35 (m, 5H),
7.32-7.25 (m, 2H), 6.97-6.89 (m, 2H), 5.85 (m, 1H), 5.14-
5.04 (m, 2H), 4.48 (d syst AB, 1H, J ) 11.4 Hz), 4.41 (dd, 1H,
J ) 7.7, J ) 5.9 Hz), 4.27 (d syst AB, 1H, J ) 11.4 Hz), 3.85
(s, 3H), 2.69 (m, 1H), 2.49 (m, 1H); 13C NMR (75.5 MHz) δ
(ppm) 159.0 (s), 141.9 (s), 134.9 (d), 130.5 (s), 129.2 (d), 128.3
(d), 127.5 (d), 126.8 (d), 116.7 (t), 113.7 (d), 80.7 (d), 69.9 (t),
55.2 (q), 42.6 (t); MS (EI, 70 eV) m/z 268 (M, 1), 227 (1), 162
(1), 150 (1), 135 (1), 131 (1), 129 (1), 122 (10), 121 (100), 115
(1), 105 (2), 91 (4), 77 (6), 65 (1), 51 (1). Anal. Calcd for
C
18H20O2: C, 80.57; H, 7.51. Found: C, 80.55; H, 7.56.
(3R)-3-[(4-Meth oxyben zyl)oxy]-3-p h en ylp r op a n a l 3. To
a solution of (+)-2 (2.10 g, 7.8 mmol, 1 equiv) in THF/H2O (1/
1) (60 mL) was added OsO4 (0.50 mL, 4% aqueous solution,
0.078 mmol, 0.01 equiv). The black solution was stirred for 5
min at room temperature, and NaIO4 (6.70 g, 31.3 mmol, 4
equiv) was added by small portions over 2 h. After additional
Cl2/hexanes/Et2O, 4/4/1); [R]20 ) +51.5 (c 1.0, C6H6) {lit.14
D

1988 J . Org. Chem., Vol. 67, No. 7, 2002
Cossy et al.
stirring for 2 h, the reaction was quenched by addition of a
saturated aqueous solution of Na2S2O3 (72 mL). After 30 min,
Et2O (115 mL) and brine (72 mL) were added to the reaction
mixture. The aqueous phase was extracted with Et2O (3 × 120
mL), and the combined organic phases were dried over MgSO4
and concentrated in vacuo. The crude product (2.17 g) was used
for the next step without further purification: Rf ) 0.45 (Et2O/
petroleum ether, 1/2); IR (neat) 1725, 1610 cm-1; 1H NMR (300
MHz) δ (ppm) 9.77 (dd, 1H, J ) 2.6, J ) 1.5 Hz), 7.46-7.34
(m, 5H), 7.26-7.18 (m, 2H), 6.93-6.85 (m, 2H), 4.91 (dd, 1H,
J ) 9.2, J ) 4.0 Hz), 4.44 (d syst AB, 1H, J ) 11.0 Hz), 4.25
(d syst AB, 1H, J ) 11.0 Hz), 3.81 (s, 3H), 2.97 (ddd, 1H, J )
16.5, J ) 9.2, J ) 2.6 Hz), 2.64 (ddd, 1H, J ) 16.5, J ) 4.0, J
) 1.5 Hz); 13C NMR (75.5 MHz) δ (ppm) 200.5 (d), 159.2 (s),
140.5 (s), 129.8 (s), 129.4 (d), 128.7 (d), 128.1 (d), 126.5 (d),
113.7 (d), 75.7 (d), 70.1 (t), 55.1 (q), 51.5 (t); MS (EI, 70 eV)
m/z 270 (M, 4), 197 (1), 163 (1), 138 (21), 137 (77), 132 (16),
131 (26), 122 (14), 121 (100), 109 (17), 105 (19), 103 (15), 92
(11), 77 (26), 65 (4), 51 (8).
(8), 77 (13); HRMS (IC+, CH4) calcd for C20H24N3O2 (MH+) m/z
338.1869, found 338.1904.
(1R,3R)-1-[(4-Meth oxyben zyl)oxy]-1-p h en ylh ex-5-en -3-
a m in e 6. A suspension of LiAlH4 (0.54 g, 14.3 mmol, 3 equiv)
in anhydrous Et2O (37 mL) was stirred for 5 min at 0 °C, and
a solution of (+)-5 (1.60 g, 4.75 mmol, 1 equiv) in Et2O (37
mL) was then added dropwise. The mixture was stirred for 1
h at 0 °C and for 1 h at room temperature. Water (0.56 mL),
a 15% aqueous NaOH solution (0.56 mL), and water (1.12 mL)
were successively added, and the resulting mixture was then
diluted with EtOAc (120 mL) and water (25 mL). The aqueous
phase was extracted with EtOAc (3 × 110 mL), and the
combined organic phases were dried over MgSO4 and concen-
trated in vacuo. The crude product (1.39 g, 4.5 mmol, 94%)
was used in the next step without further purification: Rf )
1
0.07 (EtOAc); IR (neat) 3370, 1640, 1610 cm-1; H NMR (300
MHz) δ (ppm) 7.43-7.28 (m, 5H), 7.26-7.19 (m, 2H), 6.93-
6.85 (m, 2H), 5.73 (m, 1H), 5.15-4.96 (m, 2H), 4.48 (dd, 1H, J
) 8.6, J ) 5.3 Hz), 4.39 (d syst AB, 1H, J ) 11.2 Hz), 4.17 (d
syst AB, 1H, J ) 11.2 Hz), 3.81 (s, 3H), 2.90 (m, 1H), 2.17 (m,
1H), 2.05-1.62 (m, 5H); 13C NMR (75.5 MHz) δ (ppm) 159.0
(s), 142.2 (s), 135.3 (d), 132.9 (s), 129.3 (d), 128.4 (d), 127.4
(d), 126.7, (d), 117.4 (t), 113.7 (d), 79.9 (d), 69.8 (t), 55.1 (q),
48.7 (d), 45.9 (t), 42.5 (t); MS (EI, 70 eV) m/z 312 (M + 1, 1),
270 (1), 227 (2), 192 (1), 177 (8), 175 (7), 160 (14), 134 (12),
121 (100), 117 (13), 104 (10), 91 (5), 72 (11), 63 (1), 51 (1).
ter t-Bu t yl (1R)-1-{(2R)-2-[(4-Met h oxyb en zyl)oxy]-2-
p h en yleth yl}bu t-3-en ylca r ba m a te (+)-7. To a solution of
6 (1.39 g, 4.5 mmol, 1 equiv) in dioxane (11 mL), cooled at 0
°C, was added dropwise a solution of Boc2O (1.56 g, 7.15 mmol,
1.6 equiv) in dioxane (9 mL). The mixture was stirred for 19
h at room temperature and was then diluted with water (26
mL) and Et2O (75 mL). The aqueous phase was extracted with
Et2O (2 × 80 mL). The combined organic phases were washed
with brine (73 mL), dried over MgSO4 and concentrated in
vacuo. The crude residue was purified on silica gel (EtOAc/
pentane, 5/95 to 20/80) to afford (+)-7 (1.56 g, 3.8 mmol, 85%)
(1R,3S)-1-[(4-Meth oxyben zyl)oxy]-1-p h en ylh ex-5-en -3-
ol (+)-4. Allylmagnesium chloride (4.30 mL, 2 M in THF, 8.6
mmol, 1.1 equiv) was added at 0 °C to a mixture of cyclopenta-
dienyl[(4R,trans)-2,2-dimethyl-R,R,R′,R′-tetraphenyl-1,3-dioxolane-
4,5-dimethanolato-O,O′]titanium chloride (6.23 g, 10.2 mmol,
1.3 equiv) in anhydrous Et2O (125 mL). The orange mixture
was stirred for 2 h at 0 °C and cooled to -78 °C, and a solution
of 3 (2.17 g of crude) in Et2O (27 mL) was then added dropwise
to this mixture. After 3 h at -78 °C, the reaction was quenched
by addition of a 45% aqueous NH4F solution (45 mL). The
mixture was stirred overnight at room temperature and was
then filtered through Celite. The organic phase was washed
with brine (320 mL), dried over MgSO4 and concentrated in
vacuo. The crude residue was diluted with pentane (120 mL)
and filtered to afford (R,R)-taddol (3.18 g, 6.8 mmol, 67%). The
filtrate was concentrated in vacuo, and the crude residue was
purified on silica gel (CH2Cl2/hexanes/Et2O, 4/4/1) to afford
(+)-4 as a yellow oil (1.82 g, 5.8 mmol, 75% from (+)-2), with
1
a diastereomeric ratio of 96:4 (determined by H NMR): Rf )
as yellow crystals: Rf ) 0.17 (EtOAc/pentane, 0.5/9.5); [R]20
D
0.48 (CH2Cl2/hexane/Et2O, 4/4/1); [R]20D ) +80.0 (c 1.1, C6H6);
IR (neat) 3440, 1640, 1610 cm-1; 1H NMR (300 MHz) δ (ppm)
7.41-7.28 (m, 5H), 7.27-7.21 (m, 2H), 6.92-6.85 (m, 2H), 5.81
(m, 1H), 5.13-5.01 (m, 2H), 4.70 (dd, 1H, J ) 9.2, J ) 3.3
Hz), 4.45 (d syst AB, 1H, J ) 11.2 Hz), 4.23 (d syst AB, 1H, J
) 11.2 Hz), 3.97 (m, 1H), 3.80 (s, 3H), 2.61 (d, 1H, J ) 4.4
Hz), 2.27-2.19 (m, 2H), 1.96 (ddd, 1H, J ) 14.5, J ) 9.2, J )
2.6 Hz), 1.76 (ddd, 1H, J ) 14.5, J ) 8.8, J ) 3.3 Hz); 13C
NMR (75.5 MHz) δ (ppm) 159.2 (s), 142.0 (s), 134.8 (d), 130.1
(s), 129.4 (d), 128.5 (d), 127.5 (d), 126.4 (d), 117.4 (t), 113.8
(d), 78.0 (d), 70.2 (t), 67.5 (d), 55.1 (q), 44.5 (t), 41.8 (t); MS
(EI, 70 eV) m/z 312 (M, 1), 294 (1), 270 (1), 227 (1), 197 (1),
176 (1), 158 (2), 137 (56), 121 (100), 117 (7), 105 (9), 91 (5), 77
(7), 65 (1). Anal. Calcd for C20H24O3: C, 76.89; H, 7.74.
Found: C, 76.69; H, 7.94.
) +34.7 (c 1.1, C6H6); mp ) 87-89 °C; IR (neat) 3410, 3360,
1700, 1640, 1610, 1585 cm-1 1H NMR (300 MHz) δ (ppm)
;
7.44-7.28 (m, 5H), 7.27-7.20 (m, 2H), 6.92-6.84 (m, 2H), 5.71
(m, 1H), 5.12-4.96 (m, 2H), 4.93 (m, 1H), 4.40 (dd, 1H, J )
7.7, J ) 5.1 Hz), 4.34 (d syst AB, 1H, J ) 11.0 Hz), 4.17 (d
syst AB, 1H, J ) 11.0 Hz), 3.80 (s, 3H), 3.72 (m, 1H), 2.30-
2.13 (m, 2H), 2.02-1.88 (m, 1H), 1.85-1.72 (m, 1H), 1.47 (s,
9H); 13C NMR (75.5 MHz) δ (ppm) 159.1 (s), 155.3 (s), 142.0
(s), 134.2 (d), 130.2 (s), 129.5 (d), 128.5 (d), 127.7 (d), 126.6
(d), 117.6 (t), 113.7 (d), 79.2 (d), 78.8 (s), 70.0 (t), 55.1 (q), 48.6
(d), 42.4 (t), 39.6 (t), 28.3 (q); MS (EI, 70 eV) m/z 339 (MH+
-
tBuO, 1), 277 (1), 221 (7), 204 (7), 178 (4), 160 (16), 137 (43),
121 (100), 105 (7), 91 (5), 77 (7), 59 (6); HRMS (IC+, CH4) calcd
for C25H34NO4 (MH+) m/z 412.2488, found 412.2495.
ter t-Bu tyl Allyl-(1R)-1-{(2R)-2-[(4-m eth oxyben zyl)oxy]-
2-p h en yleth yl}bu t-3-en ylca r ba m a te (+)-8. A solution of
(+)-7 (1.53 g, 3.7 mmol, 1 equiv) in a mixture of THF/DMF
(3/1) (29.3 mL) was cooled at 0 °C, and KHMDS (7.88 mL, 0.5M
in toluene, 3.9 mmol, 1.06 equiv) was added dropwise. The
mixture was stirred for 30 min at 0 °C, and freshly distilled
allyl bromide (0.35 mL, 0.49 g, 4.1 mmol, 1.1 equiv) was added
dropwise. After 2 h at room temperature, the reaction was
quenched by addition of an aqueous 1 M HCl solution (14.4
mL). The reaction mixture was diluted with EtOAc (86 mL),
and the aqueous phase was extracted with EtOAc (3 × 120
mL). The combined organic phases were washed with water
(120 mL) and brine (120 mL), dried over MgSO4, and concen-
trated in vacuo. The crude residue was purified on silica gel
(Et2O/petroleum ether, 5/95 to 15/85) to afford (+)-8 (1.52 g,
3.4 mmol, 91%) as a pale yellow oil: Rf ) 0.43 (Et2O/petroleum
1-{[((1R,3R)-3-Azid o-1-p h en ylh ex-5-en yl)oxy]m eth yl}-
4-m eth oxyben zen e (+)-5. To a solution of (+)-4 (1.82 g, 5.8
mmol, 1 equiv) in anhydrous THF (70 mL), cooled at 0 °C, was
added PPh3 (1.68 g, 6.4 mmol, 1.1 equiv). The mixture was
stirred for 5 min at 0 °C, and then DEAD (1.01 mL, 1.12 g,
6.4 mmol, 1.1 equiv) and DPPA (1.38 mL, 1.77 g, 6.4 mmol,
1.1 equiv) were added dropwise. The mixture was allowed to
warm slowly at room temperature with stirring for 12 h, and
the solution was concentrated in vacuo. The crude residue was
purified on silica gel (EtOAc/petroleum ether, 5/95) to afford
(+)-5 (1.62 g, 4.8 mmol, 82%): Rf ) 0.92 (EtOAc/petroleum
ether, 1/4); [R]20 ) +13.2 (c 1.0, C6H6); IR (neat) 2100, 1640,
D
1610 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.49-7.31 (m, 5H),
7.31-7.20 (m, 2H), 6.96-6.87 (m, 2H), 5.77 (m, 1H), 5.19-
5.05 (m, 2H), 4.49 (dd, 1H, J ) 7.2, J ) 7.2 Hz), 4.41 (d syst
AB, 1H, J ) 11.2 Hz), 4.21 (d syst AB, 1H, J ) 11.2 Hz), 3.83
(s, 3H), 3.31 (m, 1H), 2.39-2.06 (m, 3H), 1.86 (m, 1H); 13C NMR
(75.5 MHz) δ (ppm) 159.1 (s), 141.2 (s), 133.4 (d), 130.1 (s),
129.3 (d), 128.6 (d), 127.7 (d), 127.1 (d), 118.3 (t), 113.7 (d),
78.0 (d), 69.9 (t), 58.7 (d), 55.2 (q), 41.9 (t), 38.4 (t); MS (EI, 70
eV) m/z 310 (1), 309 (M - N2, 1), 268 (1), 218 (1), 202 (1), 170
(3), 162 (5), 137 (18), 135 (7), 132 (65), 121 (100), 104 (23), 91
ether, 2/8); [R]20 ) +32.0 (c 1.0, C6H6); IR (neat) 1690, 1640,
D
1
1610, 1585 cm-1; H NMR(300 MHz) δ (ppm) 7.44-7.29 (m,
5H), 7.26-7.17 (m, 2H), 6.92-6.84 (m, 2H), 5.82 (m, 1H), 5.61
(m, 1H), 5.21-4.91 (m, 4H), 4.34 (d syst AB, 1H, J ) 11.2 Hz),
4.29 (dd, 1H, J ) 7.2, J ) 7.2 Hz), 4.13 (d syst AB, 1H, J )
11.2 Hz), 3.81 (s, 3H), 3.92-3.69 (m, 2H), 3.64 (m, 1H), 2.32-
2.02 (m, 3H), 1.87 (m, 1H), 1.44 (s, 9H); 13C NMR (75.5 MHz)

Synthesis of (+)-Sedamine and (-)-Prosophylline
J . Org. Chem., Vol. 67, No. 7, 2002 1989
(rotamers) δ (ppm) 159.0 (s), 155.4 (s), 141.9-141.6 (s), 136.1
(d), 135.7 (d), 135.3 (d), 130.4 (s), 129.3 (d), 128.3 (d), 127.7
(d), 127.1 (d), 116.8-116.6 (t), 116.0-115.6 (t), 113.6 (d), 79.4-
79.1 (s), 78.3 (d), 69.7 (t), 55.1 (q), 53.3-52.8 (d), 46.5 (t), 41.5-
41.2 (t), 38.2-37.5 (t), 28.3 (q); MS (EI, 70 eV) m/z 352 (1),
332 (1), 310 (MH+-allyl-Boc, 7), 274 (1), 261 (9), 232 (5), 218
(14), 204 (4), 188 (2), 174 (5), 160 (16), 156 (15), 137 (4), 121
(100), 112 (20), 104 (3), 91 (4), 57 (11); HRMS (IC+, CH4) calcd
for C28H38NO4 (MH+) m/z 452.2801, found 452.2805.
19.0 (t); MS (EI, 70 eV) m/z 305 (M, 1), 249 (4), 230 (4), 202
(32), 186 (5), 184 (7), 128 (100), 120 (4), 105 (23), 84 (80), 79
(6), 57 (41). Anal. Calcd for C18H27NO3: C, 70.79; H, 8.91; N,
4.59. Found: C, 70.66; H, 9.07; N, 4.55.
(2R)-2-((2R)-2-Hyd r oxy-2-p h en yleth yl)-1-m eth ylp ip er i-
d in e (+)-Sed a m in e. To a mixture of LiAlH4 (0.17 g, 4.35
mmol, 5.2 equiv) in THF (11 mL) was added dropwise a
solution of (+)-11 (0.26 g, 0.84 mmol, 1 equiv) in THF (11 mL).
After 6 h under reflux, the reaction mixture was quenched by
addition of H2O (0.17 mL), followed by the addition of a 15%
aqueous NaOH solution (0.17 mL) and water (0.34 mL). The
mixture was filtered through Celite, and the filtrate was dried
over MgSO4 and concentrated in vacuo. The crude residue was
purified on silica gel (CH2Cl2/MeOH, 12/1 to 0/1) to afford (+)-
sedamine (0.15 g, 0.68 mol, 78%). The product was crystallized
in pentane at 0 °C to afford white crystals; their spectral and
physical data were in accordance with the literature data:6 Rf
ter t-Bu t yl (2R)-2-{(2R)-2-[(4-Met h oxyb en zyl)oxy]-2-
p h en ylet h yl}-1,2,3,6-t et r a h yd r op yr id in e-1-ca r b oxyla t e
(+)-9. To a solution of (+)-8 (1.52 g, 3.4 mmol, 1 equiv) in
anhydrous benzene (37 mL) was added a solution of G1 (0.14
g, 0.2 mmol, 0.05 equiv) in benzene (3.5 mL) over 4 h at room
temperature. The mixture was stirred for 12 h at room
temperature and was then concentrated in vacuo. The crude
residue was purified on silica gel (Et2O/petroleum ether, 1/9
to 3/7) to afford (+)-9 (1.34 g, 3.2 mmol, 94%): Rf ) 0.51 (Et2O/
) 0.07 (CH2Cl2/Et2O, 30/1); [R]20 ) +87.0 (c 1.1, EtOH) {lit.6i
D
petroleum ether, 3/7); [R]20 ) +27.1 (c 1.0, C6H6); IR (neat)
[R]20D ) +88.4 (c 1.1, EtOH)}; mp ) 54-56 °C {lit.6i mp ) 59-
D
1
1700, 1610, 1585 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.43-
61 °C}; IR (KBr) 3533, 3467, 1604 cm-1; H NMR (300 MHz)
7.28 (m, 5H), 7.27-7.19 (m, 2H), 6.92-6.85 (m, 2H), 5.73-
5.53 (m, 2H), 4.61 (br s, 1H), 4.35 (d syst AB, 1H, J ) 11.4
Hz), 4.35-4.21 (m, 2H), 4.18 (d syst AB, 1H, J ) 11.4 Hz),
3.82 (s, 3H), 3.54 (br m, 1H), 2.32 (m, 1H), 2.16 (m, 1H), 1.88-
1.63 (m, 2H), 1.47 (s, 9H); 13C NMR (75.5 MHz) δ (ppm) 158.9
(s), 154.7 (s), 142.3 (br s), 130.5 (s), 129.2 (d), 128.3 (d), 127.5
(d), 126.8 (d), 123.6 (d), 122.6 (d), 113.6 (d), 79.3 (s), 78.7 (d),
69.7 (t), 55.1 (q), 45.8-45.1 (br d), 40.4 (t), 39.9 (t), 28.32 (q),
28.3 (t); MS (EI, 70 eV) m/z 322 (M - Boc, 1), 302 (2), 287 (2),
231 (50), 202 (13), 184 (9), 170 (2), 158 (2), 137 (15), 127 (22),
126 (44), 121 (100), 105 (8), 91 (6), 82 (60), 57 (27). Anal. Calcd
for C26H33NO4: C, 73.73; H, 7.85; N, 3.31. Found: C, 73.72;
H, 7.99; N, 3.19.
δ (ppm) 7.45-7.21 (m, 5H), 6.47 (br s, 1H), 4.92 (dd, 1H, J )
10.7, J ) 2.6 Hz), 3.10 (m, 1H), 2.89 (m, 1H), 2.57 (m, 1H),
2.51 (s, 3H), 2.14 (m, 1H), 1.85-1.22 (m, 7H); 13C NMR (75.5
MHz) δ (ppm) 145.5 (s), 128.1 (d), 126.9 (d), 125.4 (d), 74.7
(d), 60.8 (d), 51.0 (t), 39.8 (q), 39.6 (t), 25.5 (t), 22.2 (t), 20.3
(t); MS (EI, 70 eV) m/z 219 (M, 2), 198 (1), 176 (1), 144 (1),
128 (1), 120 (1), 112 (2), 105 (2), 98 (100), 91 (2), 84 (1), 79 (4),
77 (5), 70 (8), 55 (1). Anal. Calcd for C14H21NO: C, 76.67; H,
9.65; N, 6.39. Found: C, 76.65; H, 9.71; N, 6.26.
2-[2-(Ben zyloxy)-2-ph en yleth yl]-1-(ter t-bu toxycar bon yl)-
1,2,3,6-tetr a h yd r op yr id in e 12. Compound 12 was synthe-
sized with an analogous strategy as for (+)-9: Rf ) 0.35
(pentane/EtOAc, 95/5); IR (neat) 3330, 1740, 1690 cm-1 1H
;
ter t-Bu t yl (2R)-2-{(2R)-2-[(4-Met h oxyb en zyl)oxy]-2-
p h en yleth yl}p ip er id in e-1-ca r boxyla te (+)-10. To a solu-
tion of (+)-9 (1.34 g, 3.2 mmol, 1 equiv) in EtOAc (64 mL) was
added PtO2 (0.04 g, 0.2 mmol, 0.05 equiv). After 1 h under H2
(1 atm), the mixture was filtered through Celite and concen-
trated in vacuo. The crude residue was purified on silica gel
(Et2O/petroleum ether, 1/9 to 3/7) to afford (+)-10 (1.62 g, 3.0
mmol, 94%) as a yellow oil: Rf ) 0.51 (Et2O/petroleum ether,
NMR (300 MHz) (2 diastereomers) δ (ppm) 7.49-7.25 (m,
10H), 5.80-5.52 (m, 2H), 5.05-4.10 (m, 3H), 4.44 (d syst AB,
1H, J ) 11.8 Hz), 4.27 (d syst AB, 1H, J ) 11.8 Hz), 3.77-
3.38 (m, 1H), 2.64-1.72 (m, 4H), 1.60-1.40 (m, 9H); 13C NMR
(75.5 MHz) (2 diastereomers) δ (ppm) 155.4 (s), 143.0 (br s),
139.1 (s), 129.2 (d), 129.1 (d), 128.3 (d), 128.0 (d), 127.5 (d),
127.1 (d), 124.3 (br d), 123.7 (br d), 123.4 (br d), 80.0 (s), 79.5
(br d), 71.9 (br t), 71.3 (br t), 70.9 (br t), 46.9 (br d), 46.0 (br
d), 41.2 (t), 40.7 (t), 39.9 (t), 30.3 (t), 30.1 (t), 29.1 (q); MS (EI,
70 eV) m/z 320 (M - tBuO, 1), 292 (8), 213 (17), 229 (47), 202
(17), 184 (15), 172 (6), 158 (5), 140 (1), 126 (43), 104 (19), 91
(100), 82 (69), 77 (7), 65 (6), 57 (40).
3/7); [R]20 ) +68.6 (c 1.2, C6H6); IR (neat) 1685, 1610, 1585
D
1
cm-1; H NMR (300 MHz) δ (ppm) 7.41-7.27 (m, 5H), 7.26-
7.20 (m, 2H), 6.90-6.84 (m, 2H), 4.34 (d syst AB, 1H, J ) 11.0
Hz), 4.45-4.26 (m, 2H), 4.16 (d syst AB, 1H, J ) 11.0 Hz),
3.98 (m, 1H), 3.81 (s, 3H), 2.85 (m, 1H), 2.23 (m, 1H), 1.84 (m,
1H), 1.65-1.30 (m, 6H), 1.46 (s, 9H); 13C NMR (75.5 MHz) δ
(ppm) 158.9 (s), 154.9 (s), 142.3 (s), 130.6 (s), 129.2 (d), 128.3
(d), 127.5 (d), 126.9 (d), 113.6 (d), 79.0 (s), 78.7 (d), 69.7 (t),
55.1 (q), 47.7 (d), 39.0 (t), 38.5 (t), 28.3 (q), 27.9 (t), 25.5 (t),
18.9 (t); MS (EI, 70 eV) m/z 324 (M - Boc, 1), 289 (3), 233
(33), 206 (2), 204 (5), 189 (5), 186 (4), 184 (3), 172 (3), 160 (3),
137 (8), 128 (100), 121 (63), 104 (4), 84 (81), 77 (6), 57 (17);
HRMS (IC+, CH4) calcd for C26H36NO4 (MH+) m/z 426.2644,
found 426.2643.
1-(t er t -Bu t oxyca r b on yl)-2-(2-p h e n ylm e t h yl)p ip e r i-
d in e 13. Meth od A. To a solution of 12 (0.09 g, 0.24 mmol, 1
equiv) in a mixture of EtOAc and MeOH (4/1) (2 mL) was
added 20% Pd(OH)2 (0.01 g, 0.02 mmol, 0.07 equiv). After 1 h
under H2 (1 atm) at room temperature, the reaction mixture
was filtered through Celite and concentrated in vacuo to afford
13 (0.06 g, 0.22 mmol, 94%). Meth od B. To a solution of 12
(0.10 g, 0.26 mmol, 1 equiv) in EtOAc (5 mL) was added 10%
Pd/C (0.02 g, 0.02 mmol, 0.07 equiv). After 1 h under H2 (1
atm) at room temperature, the reaction mixture was filtered
through Celite and concentrated in vacuo to afford 13 (0.08 g,
0.29 mmol, quantitative yield): Rf ) 0.55 (pentane/EtOAc, 95/
ter t-Bu tyl (2R)-2-((2R)-2-Hyd r oxy-2-p h en yleth yl)p ip -
er id in e-1-ca r boxyla te (+)-11. To a solution of (+)-10 (1.12
g, 2.6 mmol, 1 equiv) in a mixture of CH2Cl2 and H2O (18/1)
(43.3 mL) was added DDQ (0.66 g, 2.9 mmol, 1.1 equiv). After
15 min, the reaction mixture was quenched with an aqueous
saturated NaHCO3 solution (3.5 mL). The mixture was diluted
with water (25 mL) and CH2Cl2 (40 mL), and the aqueous layer
was extracted with CH2Cl2 (3 × 100 mL). The combined
organic phases were washed with water (100 mL) and brine
(100 mL), dried over MgSO4 and concentrated in vacuo. The
crude residue was purified on silica gel (CH2Cl2/Et2O, 30/1 to
30/10) to afford (+)-11 as a white solid (0.61 g, 2.0 mmol, 75%)
and (+)-10 (0.17 g, 0.39 mmol, 15%). (+)-11: Rf ) 0.09 (CH2-
5); IR (neat) 1690 cm-1 1H NMR (300 MHz) δ (ppm) 7.35-
;
7.15 (m, 5H), 4.32 (br m, 1H), 4.04 (m, 1H), 2.82 (m, 1H), 2.71-
2.47 (m, 2H), 2.03 (m, 1H), 1.82-1.52 (m, 7H), 1.47 (s, 9H);
13C NMR (75.5 MHz) δ (ppm) 155.1 (s), 142.1 (s), 128.3 (d),
128.2 (d), 125.6 (d), 79.0 (s), 50.2 (d), 38.7 (br t), 32.7 (t), 31.8
(t), 28.4 (t), 28.4 (q), 25.5 (t), 18.9 (t); MS (EI, 70 eV) m/z 289
(M, 1), 233 (17), 216 (4), 188 (2), 184 (8), 160 (1), 144 (1), 128
(100), 117 (3), 112 (2), 105 (3), 91 (16), 84 (52), 77 (2), 65 (2),
57 (25).
(1R)-1-((4R)-2,2-Dim eth yl-1,3-d ioxola n -4-yl)bu t-3-en -1-
ol14 (+)-15. Allylmagnesium chloride (5.0 mL, 2 M in Et2O,
10.0 mmol, 1.1 equiv) was added at 0 °C to a mixture of
cyclopentadienyl[(4S,trans)-2,2-dimethyl-R,R,R′,R′-tetraphenyl-
1,3-dioxolane-4,5-dimethanolato-O,O′]titanium chloride (7.27
g, 11.9 mmol, 1.3 equiv) in anhydrous Et2O (145 mL). After 2
h at 0 °C, the orange reaction mixture was cooled to -78 °C,
and a solution of 14 (1.19 g, 9.1 mmol, 1 equiv) in Et2O (12
mL) was added dropwise. After 4 h at -78 °C, the reaction
Cl2/Et2O, 30/1); [R]20 ) +121.1 (c 1.2, C6H6); mp ) 59-61 °C;
D
IR (neat) 3390, 1670 cm-1; 1H NMR (300 MHz) δ (ppm) 7.41-
7.21 (m, 5H), 4.75 (br m, 1H), 4.40 (br m, 1H), 4.04-3.73 (br
m, 2H), 2.78 (br m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.71-1.51
(6H), 1.46 (s, 9H); 13C NMR (75.5 MHz) δ (ppm) 155.4 (br s),
144.6 (br s), 128.2 (d), 127.1 (d), 125.6 (d), 79.6 (s), 72.5 (d),
48.4 (br d), 40.2 (br t), 39.3 (br t), 29.1 (br t), 28.3 (q), 25.3 (t),

1990 J . Org. Chem., Vol. 67, No. 7, 2002
Cossy et al.
was quenched by addition of a 45% aqueous NH4F solution
(48 mL). The mixture was stirred overnight at room temper-
ature and then filtered through Celite (Et2O, 500 mL). The
organic phase was washed with brine (350 mL), dried over
MgSO4 and concentrated in vacuo. The crude residue was
diluted in pentane (150 mL) and filtered to afford (S,S)-taddol
(4.04 g, 8.7 mmol, 73%). The organic layer was concentrated
in vacuo and the crude residue was purified on silica gel
(pentane/Et2O, 8/2 to 1/1) to afford (+)-15 (1.35 g, 7.85 mmol,
86%). The spectral and physical data are in accordance with
1.81-1.47 (m, 4H), 1.45 (s, 3H), 1.38 (s, 3H); 13C NMR (75.5
MHz) δ (ppm) 138.4 (s), 128.2 (d), 127.9 (d), 127.5 (d), 109.3
(s), 79.4 (d), 78.2 (d), 72.7 (t), 65.8 (t), 62.4 (t), 28.6 (t), 27.0 (t),
26.4 (q), 25.3 (q); MS (EI, 70 eV) m/z 281 (M+1, 1), 265 (M -
Me, 2), 179 (8), 160 (2), 157 (2), 134 (2), 107 (2), 101 (18), 91
(100), 79 (2), 71 (22), 65 (5), 59 (3); HRMS (CI+, CH4) calcd for
C16H25O4 (MH+) m/z 281.1753, found 281.1745.
(4R)-4-(Ben zyloxy)-4-((4R)-2,2-d im et h yl-1,3-d ioxola n -
4-yl)bu ta n a l 18. To a solution of oxalyl chloride (0.99 mL,
1.44 g, 11.4 mmol, 2.2 equiv) in CH2Cl2 (79 mL) at -78 °C
was added dropwise DMSO (1.03 mL, 1.13 g, 14.5 mmol, 2.8
equiv). After 30 min at -78 °C, a solution of (+)-17 (1.45 g,
5.2 mmol, 1 equiv) in CH2Cl2 (19 mL) was added. After 20 min
at -78 °C, Et3N (3.5 mL) was added, and the mixture was
stirred for 15 min at -78 °C and 10 min at 0 °C. The mixture
was then diluted with pentane (20 mL) and brine (20 mL).
The aqueous phase was extracted with pentane (3 × 235 mL),
and the combined organic phases were dried over MgSO4 and
concentrated in vacuo. The crude residue was diluted in
pentane, filtered on paper, and concentrated in vacuo to afford
18 (1.44 g, 5.2 mmol, quantitative yield) as a yellow oil: Rf )
the literature data:14 Rf ) 0.76 (pentane/Et2O, 1/2); [R]20
)
D
+14.2 (c 1.0, CHCl3) {lit.23 [R]20 ) +12.7 (c 1.5, CHCl3)}; IR
D
(neat) 3430, 1640, 1210 cm-1; 1H NMR (300 MHz) δ (ppm) 5.85
(m, 1H), 5.18-5.06 (m, 2H), 4.06-3.93 (m, 2H), 3.73 (m, 1H),
3.58 (m, 1H), 2.39 (br s, 1H), 2.26-2.18 (m, 2H), 1.42 (s, 3H),
1.35 (s, 3H); 13C NMR (75.5 MHz) δ (ppm) 133.9 (d), 117.7 (t),
109.2 (s), 78.3 (d), 71.4 (d), 65.9 (t), 38.1 (t), 26.4 (q), 25.2 (q);
MS (EI, 70 eV) m/z 157 (M - Me, 74), 131 (14), 115 (4), 103
(2), 101 (100), 97 (12), 83 (9), 79 (9), 73 (23), 72 (11), 67 (4), 61
(11), 59 (43), 55 (23). Anal. Calcd for C9H16O3: C, 62.77; H,
9.36. Found: C, 62.86; H, 9.43.
0.86 (Et2O/petroleum ether, 9/1); IR (neat) 1720, 1210 cm-1
;
(4R)-4-[(1R)-1(Ben zyloxy)bu t-3-en yl]-2,2-d im eth yl-1,3-
d ioxola n e (+)-16. To a solution of (+)-15 (1.33 g, 7.7 mmol,
1 equiv) in THF (10 mL) at 0 °C was added t-BuOK (1.21 g,
10.8 mmol, 1.4 equiv). After 5 min at 0 °C, benzyl bromide
(1.10 mL, 1.59 g, 9.3 mmol, 1.2 equiv) was added dropwise.
The mixture was stirred for 2.5 h at room temperature, and
then the reaction was quenched by addition of a 20% aqueous
NH4Cl solution (57 mL). The aqueous phase was extracted
with EtOAc (3 × 115 mL), the organic layer was washed with
water (85 mL) and brine (85 mL), dried over MgSO4 and
concentrated in vacuo. The crude residue was purified on silica
gel (Et2O/petroleum ether, 5/95 to 20/80) to afford (+)-16 (1.84
1H NMR (300 MHz) δ (ppm) 9.67 (t, 1H, J ) 1.5 Hz), 7.40-
7.22 (m, 5H), 4.76 (d syst AB, 1H, J ) 11.8 Hz), 4.55 (d syst
AB, 1H, J ) 11.8 Hz), 4.20 (ddd, 1H, J ) 7.4, J ) 6.6, J ) 6.2
Hz), 4.00 (dd, 1H, J ) 8.1, J ) 6.6 Hz), 3.73 (dd, J ) 8.1, J )
7.4 Hz), 3.46 (m, 1H), 2.64-2.40 (m, 2H), 1.85-1.61 (m, 2H),
1.45 (s, 3H), 1.37 (s, 3H); 13C NMR (75.5 MHz) δ (ppm) 201.7
(d), 138.2 (s), 128.2 (d), 128.0 (d), 127.6 (d), 109.3 (s), 78.4 (d),
78.2 (d), 72.7 (t), 65.7 (t), 39.8 (t), 26.4 (q), 25.2 (q), 23.1 (t);
MS (EI, 70 eV) m/z 278 (M, 1), 263 (M - Me, 3), 245 (1), 220
(1), 202 (2), 177 (20), 157 (1), 134 (5), 129 (1), 116 (1), 107 (2),
101 (27), 91 (100), 83 (3), 73 (6), 65 (7), 59 (4).
g, 7.0 mmol, 91%): Rf ) 0.77 (Et2O/petroleum ether, 2/1); [R]20
(4R,7R)-7-(Ben zyloxy)-7-((4R)-2,2-dim eth yl-1,3-dioxolan -
4-yl)h ep t-1-en -4-ol (+)-19. Allylmagnesium chloride (2.84
mL, 2 M in THF, 5.7 mmol, 1.1 equiv) was added at 0 °C to a
mixture of cyclopentadienyl[(4R,trans)-2,2-dimethyl-R,R,R′,R′-
tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O′]titanium chlo-
ride (4.12 g, 6.7 mmol, 1.3 equiv) in anhydrous diethyl ether
(88 mL). After 2 h at 0 °C, the orange reaction mixture was
cooled to -78 °C, and a solution of 18 (1.44 g, 5.2 mmol, 1
equiv) in Et2O (19 mL) was added dropwise. The mixture was
stirred 3 h at -78 °C, and the reaction was quenched by
addition of a 45% aqueous NH4F solution (30 mL). The mixture
was stirred overnight at room temperature and filtered
through Celite (Et2O, 290 mL), and the filtrate was washed
with brine (250 mL), dried over MgSO4 and concentrated in
vacuo. The crude residue was diluted with pentane (100 mL)
and filtered to afford (R,R)-taddol (2.79 g, 6.0 mmol, 89%). The
filtrate was concentrated in vacuo, and the crude residue was
purified on silica gel (Et2O/petroleum ether, 2/8 to 7/3 to afford
(+)-19 (1.348 g, 4.2 mmol, 81%): Rf ) 0.31 (Et2O/petroleum
ether, 6/4); [R]20D ) +48.1 (c 1.1, CHCl3); IR (neat) 3440, 1640,
D
) +13.9 (c 1.1, CHCl3); IR (neat) 1640, 1210 cm-1; H NMR
1
(300 MHz) δ (ppm) 7.45-7.25 (m, 5H), 5.91 (m, 1H), 5.19-
5.06 (m, 2H), 4.75 (d syst AB, 1H, J ) 11.8 Hz), 4.69 (d syst
AB, 1H, J ) 11.8 Hz), 4.24 (ddd, 1H, J ) 7.4, J ) 6.6, J ) 6.2
Hz), 4.01 (dd, 1H, J ) 8.1, J ) 6.6 Hz), 3.73 (dd, 1H, J ) 8.1,
J ) 7.4 Hz), 3.53 (m, 1H), 2.41-2.18 (m, 2H), 1.46 (s, 3H),
1.40 (s, 3H); 13C NMR (75.5 MHz) δ (ppm) 138.5 (s), 134.4 (d),
128.2 (d), 127.7 (d), 127.4 (d), 117.1 (t), 109.2 (s), 79.2 (d), 77.8
(d), 72.4 (t), 65.7 (t), 35.2 (t), 26.4 (q), 25.3 (q); MS (EI, 70 eV)
m/z 262 (1), 247 (5), 221 (6), 204 (4), 163 (15), 161 (6), 145 (3),
134 (2), 117 (4), 115 (2), 105 (2), 101 (19), 91 (100), 79 (2), 77
(2), 65 (6), 59 (3). Anal. Calcd for C16H22O3: C, 73.25; H, 8.45.
Found: C, 73.32; H, 8.54.
(4R)-4-(Ben zyloxy)-4-((4R)-2,2-d im et h yl-1,3-d ioxola n -
4-yl)bu ta n -1-ol (+)-17. To a solution of (+)-16 (1.63 g, 6.21
mmol, 1 equiv) in THF (15 mL) at 0 °C was added dropwise
BH3 (6.21 mL, 1 M in THF, 6.21 mmol, 1 equiv). After 2 h at
room temperature, the reaction mixture was cooled to 0 °C,
and water (0.7 mL), 3 M aqueous NaOH (2.2 mL) and 30%
aqueous H2O2 (1.5 mL) were successively added. The mixture
was stirred for 2.3 h at room temperature and was then diluted
with water (62 mL). The pH was adjusted to 6-7 with 10%
aqueous HCl. The aqueous phase was extracted with ether (3
× 240 mL), and the combined organic phases were washed
with a saturated aqueous NaHCO3 solution (155 mL) and brine
(155 mL), dried over MgSO4 and concentrated in vacuo. The
crude residue was purified on silica gel (Et2O/petroleum ether,
40/60 to 70/30) to afford (+)-17 (1.45 g, 5.2 mmol, 83%). The
spectral and physical data are in accordance with the literature
1215 cm-1 1H NMR (300 MHz) δ (ppm) 7.44-7.23 (m, 5H),
;
5.79 (m, 1H), 5.13 (m, 1H), 5.08 (m, 1H), 4.79 (d syst AB, 1H,
J ) 11.8 Hz), 4.63 (d syst AB, 1H, J ) 11.8 Hz), 4.23 (ddd,
1H, J ) 7.7, J ) 6.6, J ) 6.3 Hz), 3.99 (dd, 1H, J ) 8.1, J )
6.6 Hz), 3.69 (dd, 1H, J ) 8.1, J ) 7.7 Hz), 3.54 (m, 1H), 3.46
(m, 1H), 2.30-2.05 (m, 3H), 1.62-1.49 (m, 4H), 1.45 (s, 3H),
1.38 (s, 3H); 13C NMR (75.5 MHz) δ (ppm) 138.5 (s), 134.7 (d),
128.2 (d), 128.0 (d), 127.5 (d), 117.7 (t), 109.2 (s), 79.1 (d), 78.3
(d), 72.6 (t), 70.1 (d), 65.8 (t), 41.9 (t), 32.2 (t), 26.5 (q), 26.4
(t), 25.3 (q); MS (EI, 70 eV) m/z 305 (M - Me, 1), 279 (7), 262
(1), 203 (1), 183 (2), 171 (3), 157 (1), 141 (2), 129 (2), 117 (3),
111 (20), 101 (13), 91 (100), 83 (2), 73 (4), 65 (4). Anal. Calcd
for C19H28O4: C, 71.22; H, 8.81. Found: C, 71.04; H, 8.99.
(4R)-4-[(1R,4S)-4-Azid o-1-(ben zyloxy)h ep t-6-en yl]-2,2-
d im eth yl-1,3-d ioxola n e 20. To a solution of (+)-19 (1.348 g,
4.2 mmol, 1 equiv) in THF (50 mL) at 0 °C, was added PPh3
(1.21 g, 4.6 mmol, 1.1 equiv). DEAD (0.73 mL, 0.81 g, 4.6 mmol,
1.1 equiv) and DPPA (1.0 mL, 1.27 g, 4.6 mmol, 1.1 equiv) were
added dropwise, and the mixture was allowed to warm slowly
to room temperature with stirring for 12 h. The solution was
concentrated in vacuo, and the crude residue was purified on
silica gel (Et2O/petroleum ether, 2/8 to 1/1) to afford a mixture
data:24 Rf ) 0.64 (Et2O/petroleum ether, 95/5); [R]20 ) +41.2
D
(c 2.0, CHCl3) {lit.24 [R]20 ) -42.5 (c 1.1, CHCl3) for (-)-17};
D
IR (neat) 3405, 1210 cm-1; 1H NMR (300 MHz) δ (ppm) 7.41-
7.23 (m, 5H), 4.81 (d syst AB, 1H, J ) 11.8 Hz), 4.63 (d syst
AB, 1H, J ) 11.8 Hz), 4.24 (ddd, 1H, J ) 7.4, J ) 6.6, J ) 6.2
Hz), 4.00 (dd, 1H, J ) 8.1, J ) 6.6 Hz), 3.69 (dd, 1H, J ) 8.1,
J ) 7.4 Hz), 3.62-3.54 (m, 2H), 3.48 (m, 1H), 2.11 (br s, 1H),
(23) Mulzer, J .; Angermann, A. Mu¨nch, W. Liebigs Ann. Chem. 1986,
825.
(24) Miyazaki, H.; Nakamura, N.; Ito, T.; Sada, T., Oshima, T.;
Koike, H. Chem. Pharm. Bull. 1989, 37, 2391.

Synthesis of (+)-Sedamine and (-)-Prosophylline
J . Org. Chem., Vol. 67, No. 7, 2002 1991
of 20 and DPPA (1.749 g): Rf ) 0.84 (Et2O/petroleum ether,
6/4); 1H NMR (300 MHz) δ (ppm) 7.48-7.20 (m, 5H), 5.80 (m,
1H), 5.22-5.09 (m, 2H), 4.80 (d syst AB, 1H, J ) 11.8 Hz),
4.62 (d syst AB, 1H, J ) 11.8 Hz), 4.24 (ddd, 1H, J ) 7.4, J )
6.6, J ) 6.2 Hz), 4.02 (dd, 1H, J ) 8.5, J ) 6.6 Hz), 3.74 (dd,
1H, J ) 8.5, J ) 7.4 Hz), 3.46 (m, 1H), 3.31 (m, 1H), 2.30 (m,
1H), 1.86-1.50 (m, 4H), 1.48 (s, 3H), 1.40 (s, 3H); 13C NMR
(75.5 MHz) δ (ppm) 138.4 (s), 133.6 (d), 128.2 (d), 127.9 (d),
127.6 (d), 118.1 (t), 109.3 (s), 79.4 (d), 78.1 (d), 72.8 (t), 65.7
(t), 62.3 (d), 38.7 (t), 30.1 (t), 27.2 (t), 26.4 (q), 25.2 (q); MS
(EI, 70 eV) m/z 330 (M - Me, 1), 318 (4), 276 (1), 216 (5), 176
(3), 170 (3), 131 (4), 110 (2), 101 (18), 91 (100), 77 (2), 67 (2),
59 (2), 55 (2); HRMS (CI+, CH4) calcd for C19H28N3O3 (MH+)
m/z 346.2131, found 346.2137.
(m, 4H), 7.26-7.04 (m, 11H), 5.60 (m, 1H), 5.03-4.91 (m, 2H),
4.41 (d syst AB, 1H, J ) 11.4 Hz), 4.36 (d syst AB, 1H, J )
11.4 Hz), 3.83-3.78 (m, 2H), 3.73 (m, 1H), 3.55 (m, 1H) 2.92
(m, 1H), 2.40 (d, 1H, J ) 5.9 Hz), 2.09-1.87 (m, 2H), 1.76 (m,
1H), 1.55-1.25 (m, 3H) 1.14 (s, 9H); 13C NMR (75.5 MHz, C6D6)
δ (ppm) 139.5 (s), 136.5 (d), 136.4 (d), 134.6 (d), 134.2 (s), 130.6
(d), 129.1 (d), 128.7 (d), 128.2 (d), 118.6 (t), 79.3 (d), 73.8 (d),
73.1 (t), 65.7 (t), 62.8 (d), 39.4 (t), 30.6 (t), 27.6 (q), 27.5 (t),
19.9 (s); MS (EI, 70 eV) m/z 441 (2), 420 (1), 390 (4), 333 (18),
309 (3), 289 (3), 273 (9), 267 (8), 259 (4), 253 (4), 207 (4), 199
(22), 177 (14), 163 (6), 135 (10), 121 (98), 105 (5), 91 (100), 69
(7); HRMS (CI+, CH4) calcd for C32H42NSiO3 (MH+ - N2) m/z
516.2934, found 516.2936.
(4S,7R,8R)-4-Azid o-7-(ben zyloxy)-9-[(ter t-b u t yld ip h e-
n ylsilyl)oxy]-8-[(m eth ylsu lfon yl)oxy]n on -1-en e (+)-25. To
a solution of (-)-24 (1.46 g, 2.7 mmol, 1 equiv) and DMAP (49
mg, 0.4 mmol, 0.15 eq) in pyridine (5.3 mL) at 0 °C was added
dropwise MsCl (0.31 mL, 0.43 g, 4.0 mmol, 1.5 equiv). After
1.5 h at 0 °C and 1 h at room temperature, the reaction
mixture was diluted with Et2O (42 mL) and washed with water
(42 mL), an aqueous saturated solution of CuSO4 (42 mL) and
water (17.5 mL). The organic phase was dried over MgSO4 and
concentrated in vacuo. The crude residue was purified by flash
chromatography on silica gel (Et2O/petroleum ether, 2/8) to
give (+)-25 (1.63 g, 2.6 mmol, 98%) as a viscous oil: Rf ) 0.55
(4S,7R)-7-(Ben zyloxy)-7-((4R)-2,2-dim eth yl-1,3-dioxolan -
4-yl)h ep t-1-en -4-a m in e (+)-21. To a mixture of LiAlH4 (0.08
g, 2.0 mmol, 3 equiv) in Et2O (5 mL) at 0 °C was added
dropwise a solution of 20 (0.23 g of crude) in Et2O (5 mL). After
1 h at 0 °C and 1 h at room temperature, the reaction was
quenched by addition of water (0.16 mL), followed by the
addition of a 15% aqueous NaOH solution (0.16 mL) and water
(0.32 mL). The mixture was diluted with EtOAc (15 mL) and
water (15 mL). The aqueous layer was extracted with EtOAc
(3 × 15 mL), and the combined organic phases were dried over
MgSO4 and concentrated in vacuo. The crude residue was
purified on silica gel (CH2Cl2/MeOH, 98/2 to 0/1) to afford (+)-
21 (0.09 g, 0.27 mmol, 41% from (+)-19): Rf ) 0.02 (CH2Cl2/
(Et2O/petroleum ether, 4/6); [R]20 ) +1.5 (c 1.1, CHCl3); IR
D
(neat) 2100, 1640, 1585, 1350, 1175 cm-1; 1H NMR (300 MHz)
δ (ppm) 7.76-7.68 (m, 4H), 7.53-7.29 (m, 12H), 5.79 (m, 1H),
5.22-5.10 (m, 2H), 4.77 (m, 1H), 4.63 (d syst AB, 1H, J ) 11.4
Hz), 4.57 (d syst AB, 1H, J ) 11.4 Hz), 4.02 (dd, 1H, J ) 11.8,
J ) 3.3 Hz), 3.94 (dd, 1H, J ) 11.8, J ) 6.2 Hz), 3.81 (m, 1H),
3.29 (m, 1H), 3.03 (s, 3H), 2.33-2.25 (m, 2H), 1.84 (m, 1H),
1.70-1.27 (m, 3H), 1.13 (s, 9H); 13C NMR (75.5 MHz) δ (ppm)
137.9 (s), 135.9 (d), 135.8 (d), 133.9 (d), 133.0 (s), 132.8 (s),
130.4 (d), 130.3 (d), 128.8 (d), 128.5 (d), 128.3 (d), 128.2 (d),
118.7 (t), 84.0 (d), 77.8 (d), 73.3 (t), 63.1 (t), 62.3 (d), 39.0 (t),
38.7 (q), 30.0 (t), 27.1 (q), 26.6 (t), 19.5 (s); MS (CI+, CH4) m/z
622 (M + 1, 9), 594 (69), 552 (14), 526 (18), 498 (100), 486
(15), 420 (31), 390 (14), 330 (12), 315 (10), 257 (7), 179 (9), 107
(15); HRMS (CI+, CH4) calcd for C33H44NSSiO5 (MH+ - N2)
m/z 594.2709, found 594.2708.
MeOH, 95/5); [R]20 ) +27.6 (c 1.5, CHCl3); IR (neat) 3350,
D
1
1640, 1210 cm-1; H NMR (300 MHz) δ (ppm) 7.39-7.23 (m,
5H), 5.75 (m, 1H), 5.14-5.01 (m, 2H), 4.77 (d syst AB, 1H, J
) 11.6 Hz), 4.60 (d syst AB, 1H, J ) 11.6 Hz), 4.21 (ddd, 1H,
J ) 7.3, J ) 6.6, J ) 6.3 Hz), 3.99 (dd, 1H, J ) 8.1, J ) 6.6
Hz), 3.69 (dd, 1H, J ) 8.1, J ) 7.3 Hz), 3.42 (m, 1H), 2.73 (m,
1H), 2.21 (m, 1H), 2.10-1.45 (m, 7H), 1.44 (s, 3H), 1.37 (s, 3H);
13C NMR (75.5 MHz) δ (ppm) 138.5 (s), 135.3 (d), 128.2 (d),
127.9 (d), 127.5 (d), 117.4 (t), 109.2 (s), 79.8 (d), 78.2 (d), 72.8
(t), 65.8 (t), 50.5 (d), 42.2 (t), 33.3 (t), 27.3 (t), 26.4 (q), 25.2
(q); MS (EI, 70 eV) m/z 320 (M + 1, 1), 304 (M - Me, 6), 278
(30), 228 (2), 220 (28), 218 (14), 196 (3), 172 (4), 153 (3), 110
(19), 101 (6), 91 (100), 70 (14), 65 (5), 56 (6).
(2R,3R,6S)-6-Azido-3-(ben zyloxy)-n on -8-en e-1,2-diol (-)-
23. A solution of the crude 20 (1.749 g) in AcOH/H2O (4/1) (10
mL) was stirred 7 h at room temperature. The reaction mixture
was then concentrated in vacuo, diluted with EtOAc (200 mL)
and washed with water (10 mL). The organic phase was dried
over MgSO4 and concentrated in vacuo. The crude residue was
purified on silica gel (Et2O/petroleum ether, 5/5 to 1/0) to
provide (-)-23 (0.976 g, 3.20 mmol, 76% from (+)-19) as a
viscous oil: Rf ) 0.1 (Et2O/petroleum ether, 6/4); [R]20D ) -40.1
(c 1.0, CHCl3); IR (neat) 3390, 2100, 1640 cm-1; 1H NMR (300
MHz) δ (ppm) 7.44-7.25 (m, 5H), 5.80 (m, 1H), 5.22-5.10 (m,
2H), 4.63 (d syst AB, 1H, J ) 11.4 Hz), 4.52 (d syst AB, 1H, J
) 11.4 Hz), 3.77-3.55 (m, 3H), 3.49 (m, 1H), 3.33 (m, 1H),
3.09 (br s, 1H), 2.89 (br s, 1H), 2.36-2.26 (m, 2H), 1.85 (m,
1H), 1.71-1.46 (m, 3H); 13C NMR (75.5 MHz) δ (ppm) 137.7
(s), 133.5 (d), 128.5 (d), 127.9 (d), 118.3 (t), 79.0 (d), 72.7 (d),
72.3 (t), 63.7 (t), 62.1 (d), 38.6 (t), 29.2 (t), 26.4 (t); MS (CI+,
CH4) m/z 306 (M+1, 50), 278 (100), 260 (35), 245 (13), 216 (16),
209 (27), 198 (10), 170 (46), 152 (19), 131 (49), 119 (26), 106
(14); HRMS (CI+, CH4) calcd for C16H24NO3 (MH+-N2) m/z
278.1756, found 278.1759.
(2R,3R,6S)-6-Azid o-3-(b en zyloxy)-1-[(ter t-b u t yld ip h e-
n ylsilyl)oxy]n on -8-en -2-ol (-)-24. To a solution of (-)-23
(0.860 g, 2.8 mmol, 1 equiv) and imidazole (0.25 g, 3.7 mmol,
1.3 equiv) in CH2Cl2 (3.5 mL) at 0 °C was added dopwise
TBDPSCl (0.73 mL, 0.775 g, 2.8 mmol, 1 equiv). The reaction
mixture was stirred overnight at room temperature and
quenched with a saturated aqueous NaHCO3 solution (4.2 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 21 mL),
and the combined organic phases were dried over MgSO4 and
concentrated in vacuo. The crude residue was purified on silica
gel (Et2O/petroleum ether, 5/95 to 3/7) to give (-)-24 (1.47 g,
2.7 mmol, 96%) as a colorless oil: Rf ) 0.78 (Et2O/petroleum
ether, 6/4); [R]20D ) -11.3 (c 1.1, CHCl3); IR (neat) 3430, 2080,
1635, 1585 cm-1; 1H NMR (300 MHz, C6D6) δ (ppm) 7.81-7.68
(4S,7R,8R)-7-(Ben zyloxy)-9-[(ter t-bu tyld ip h en ylsilyl)-
oxy]-8-[(m eth ylsu lfon yl)oxy]n on -1-en -4-a m in e (+)-26. A
solution of (+)-25 (1.624 g, 2.62 mmol, 1 equiv) and PPh3 (0.76
g, 2.9 mmol, 1.1 equiv) in THF/H2O (9/1) (33 mL) was stirred
for 12 h at 50 °C under Ar. The reaction mixture was then
diluted with Et2O (75 mL) and acidified with an aqueous 5%
HCl solution (66 mL). The aqueous phase was extracted with
Et2O (3 × 75 mL). The combined organic phases were dried
over MgSO4 and concentrated in vacuo. The crude residue was
purified on silica gel (CH2Cl2/MeOH/EtOAc, 90/5/5) to give (+)-
26 (1.38 g, 2.33 mmol, 89%) as a very viscous oil: Rf ) 0.30
(CH2Cl2/MeOH/EtOAc, 8/1/1); [R]20 ) +10.5 (c 1.0, CHCl3);
D
IR (neat) 3030, 1640, 1590, 1355, 1175 cm-1
;
1H NMR (300
MHz) δ (ppm) 7.72-7.63 (m, 4H), 7.52-7.21 (m, 11H), 5.75
(m, 1H), 5.14-4.99 (m, 2H), 4.77 (m, 1H), 4.58 (s, 2H), 3.98
(dd, 1H, J ) 11.8, J ) 3.7 Hz), 3.92 (dd, 1H, J ) 11.8, J ) 6.2
Hz), 3.74 (m, 1H), 3.01 (s, 3H), 2.69 (m, 1H), 2.18 (m, 1H),
1.95 (m, 1H), 1.77 (m, 1H), 1.58-1.17 (m, 5H), 1.09 (s, 9H);
13C NMR (75.5 MHz) δ (ppm) 137.6 (s), 135.5 (d), 135.3 (d),
134.3 (d), 132.6 (s), 132.4 (s), 129.9 (d), 128.3 (d), 128.0 (d),
127.9 (d), 127.8 (d), 118.1 (t), 83.5 (t), 77.6 (t), 72.7 (t), 62.7 (t),
50.7 (d), 40.9 (t), 38.3 (q), 31.7 (t), 26.7 (q), 26.1 (t), 19.0 (s);
MS (EI, 70 eV) m/z 498 (1), 458 (44), 442 (23), 380 (26), 310
(3), 272 (5), 230 (100), 199 (26), 197 (14), 183 (7), 152 (7), 135
(24), 110 (19), 91 (99), 67 (9); HRMS (CI+, CH4) calcd for C33H46
-
NSSiO5 (MH+) m/z 596.2866, found 596.2864.
(2S ,3R ,6S )-6-Ally l-3-(b e n z y lo x y )-2-{[(t er t -b u t y l-
d ip h en ylsilyl)oxy]m eth yl}p ip er id in e (-)-27. A mixture of
(+)-26 (1.30 g, 2.2 mmol, 1 equiv) and Et3N (0.76 mL, 0.55 g,
5.5 mmol, 2.5 equiv) in MeOH (30 mL) was refluxed (75-80
°C) during 8 h. The solution was then concentrated in vacuo
and the crude residue was purified on silica gel (EtOAc/
hexanes, 1/10 to 2/10) to afford (-)-27 (0.962 g, 1.9 mmol, 88%)
as a colorless oil: Rf ) 0.40 (EtOAc/petroleum ether, 2/8); [R]20
D

1992 J . Org. Chem., Vol. 67, No. 7, 2002
Cossy et al.
1
) -37.4 (c 1.0, CHCl3); IR (neat) 3330, 1640, 1585 cm-1; H
NMR (300 MHz) δ (ppm) 7.74-7.66 (m, 4H), 7.50-7.35 (m,
6H), 7.27-7.19 (m, 3H), 7.17-7.09 (m, 2H), 5.85 (m, 1H), 5.26-
5.09 (m, 2H), 4.55 (d syst AB, 1H, J ) 11.4 Hz), 4.30 (d syst
AB, 1H, J ) 11.4 Hz), 4.13 (dd, 1H, J ) 9.6, J ) 3.0 Hz), 3.65
(dd, 1H, J ) 9.6, J ) 8.8 Hz), 3.15 (ddd, 1H, J ) 9.9, J ) 9.2,
J ) 4.7 Hz), 2.80 (ddd, 1H, J ) 9.2, J ) 8.8, J ) 3.0 Hz), 2.64
(m, 1H), 2.34-2.06 (m, 3H), 1.77 (m, 1H), 1.47-1.12 (m, 3H),
1.08 (s, 9H); 13C NMR (75.5 MHz) δ (ppm) 138.4 (s), 135.5 (d),
135.4 (d), 133.5 (s), 133.4 (s), 129.5 (d), 128.1 (d), 127.5 (d),
127.4 (d), 127.3 (d), 117.4 (t), 76.3 (d), 70.4 (t), 65.3 (t), 62.4
(d), 54.6 (d), 40.8 (t), 31.2 (t), 30.0 (t), 26.7 (q), 19.2 (s); MS
(EI, 70 eV) m/z 499 (M, 1), 484 (1), 458 (67), 442 (34), 380 (29),
334 (4), 310 (4), 292 (1), 272 (4), 230 (100), 211 (2), 199 (26),
197 (13), 135 (19), 110 (11), 91 (72); HRMS (CI+, CH4) calcd
for C32H42NSiO2 (MH+) m/z 500.2985, found 500.2990.
C6D5CD3, 363 K) δ (ppm) 208.8 (s), 157.3 (s), 140.5 (s), 138.4
(s), 136.9 (d), 135.2 (s), 134.0 (d), 133.9 (d), 130.9 (d), 130.0
(d), 129.7 (d), 129.4 (d), 129.3 (d), 129.1 (d), 129.0 (d), 128.6
(d), 73.0 (d), 71.5 (t), 68.1 (t), 66.1 (t), 57.7 (d), 51.8 (d), 43.0
(t), 39.8 (t), 36.5 (t), 33.6 (t), 30.5 (t), 30.3 (t), 30.1 (t), 28.2 (q),
25.0 (t), 22.2 (t), 21.6 (t), 20.6 (s), 8.7 (q); MS (CI+, NH3) m/z
791 (M + NH3+, 1), 761 (1), 747 (1), 627 (10), 458 (100), 368
(5), 274 (37), 200 (37), 106 (51). Anal. Calcd for C49H63NSiO5:
C, 76.03; H, 8.20; N, 1.81. Found: C, 75.71; H, 8.42; N, 1.76.
12-((2R,5R,6S)-6-{[(ter t-Bu tyldiph en ylsilyl)oxy]m eth yl}-
p ip er id in -2-yl)-5-h yd r oxyd od eca n -3-on e (-)-32. To a solu-
tion of (+)-31 (0.36 g, 0.47 mmol, 1 equiv) in MeOH/HCl (50/
1, 8 mL) was added 10% Pd on carbon (50 mg, 0.05 mmol, 0.1
equiv). After 20 h under H2 (1 atm) at room temperature, the
reaction mixture was filtered through Celite and extracted
with EtOAc (200 mL). The organic phase was washed with a
saturated aqueous NaHCO3 solution (3 × 50 mL), dried over
MgSO4 and concentrated in vacuo. The crude residue was
purified on silica gel (EtOAc/petroleum ether, 3/10 to 6/10) to
give (-)-32 (0.155 g, 0.28 mmol, 60%): Rf ) 0.15 (EtOAc/
(2S,3R,6S)-6-Allyl-3-(ben zyloxy)-1-[(ben zyloxy)ca r bo-
n y l ] -2 -{[ ( t e r t -b u t y l d i p h e n y l s i l y l ) o x y ] m e t h y l }-
p ip er id in e (+)-30. To a solution of (-)-27 (0.680 g, 1.4 mmol,
1 equiv) in CH2Cl2 (40 mL) was added dropwise a solution of
Na2CO3 (0.30 g, 2.9 mmol, 2.1 equiv) in water (7.8 mL), and
the mixture was cooled at 0 °C. Benzyl chloroformate (0.31
mL, 0.37 g, 2.2 mmol, 1.6 equiv) was added dropwise to this
solution, and the mixture was stirred overnight at room
temperature. The reaction mixture was diluted with CH2Cl2
(50 mL) and water (12 mL), and the aqueous phase was
extracted with CH2Cl2 (3 × 120 mL). The combined organic
phases were washed with water (120 mL), dried over MgSO4
and concentrated in vacuo. The crude residue was purified on
silica gel (EtOAc/petroleum ether, 5/100 to 10/100) to afford
(+)-30 (0.860 g, 1.4 mmol, quantitative yield): Rf ) 0.68
petroleum ether, 4/6); [R]20 ) -1.5 (c 1.1, CHCl3); IR (neat)
D
3405, 1710, 1585 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.71-
7.58 (m, 4H), 7.45-7.28 (m, 6H), 3.95 (dd, 1H, J ) 9.6, J )
5.5 Hz), 3.71 (dd, 1H, J ) 9.6, J ) 6.6 Hz), 3.38 (m, 1H), 2.64
(m, 1H), 2.48-2.23 (m, 6H), 2.01 (m, 1H), 1.69 (m, 1H), 1.54
(m, 2H), 1.42-1.14 (m, 16H), 1.10 (m, 1H), 1.05 (s, 9H), 1.03
(t, 3H, J ) 7.4 Hz); 13C NMR (75.5 MHz) δ (ppm) 211.8 (s),
135.4 (d), 132.9 (s), 132.8 (s), 129.7 (d), 127.6 (d), 71.0 (d), 66.9
(t), 62.8 (d), 55.5 (d), 42.2 (t), 36.4 (t), 35.7 (t), 33.6 (t), 31.1 (t),
29.5 (t), 29.4 (t), 29.3 (t), 29.2 (t), 29.1 (t), 26.7 (q), 26.0 (t),
23.8 (t), 19.0 (s), 7.7 (q); MS (CI, CH4) m/z 552 (MH+, 56),
538 (65), 524 (37), 460 (17), 446 (11), 368 (5), 296 (16), 282
(27), 239 (37), 199 (58), 179 (100); HRMS (CI+, CH4) calcd for
(EtOAc/petroleum ether, 2/8); [R]20 ) +8.3 (c 1.1, CHCl3); IR
D
(neat) 1660, 1640 cm-1
;
1H NMR (300 MHz) δ (ppm) 7.75-
7.54 (m, 4H), 7.54-7.22 (m, 16H), 5.67 (m, 1H), 5.27-5.02 (m,
2H), 5.00-4.45 (m, 5H), 4.25 (m, 1H), 3.85 (m, 1H), 3.71 (m,
1H), 3.55 (m, 1H), 2.25-1.15 (m, 6H), 1.06 (s, 9H); 13C NMR
(75.5 MHz) δ (ppm) (rotamers) 156.1 (s), 138.5 (s), 136.9 (s),
135.5 (d), 132.9 (s), 129.7 (d), 128.3 (d), 128.2 (d), 127.6 (d),
127.3 (d), 116.8 (t), 70.7 (d), 70.0 (t), 66.8 (t), 63.9-63.5 (t),
55.9-55.5 (d), 49.6 (d), 39.5-39.0 (t), 26.7 (q), 20.1 (t), 19.2
(s), 19.1 (t); MS (EI, 70 eV) m/z 458 (63), 442 (31), 408 (2), 380
(30), 334 (12), 272 (4), 230 (100), 207 (20), 199 (25), 197 (12),
183 (9), 135 (21), 110 (14), 91 (89), 67 (9). Anal. Calcd for
C
34H54NSiO3 (MH+) m/z 552.3873, found 552.3868.
(-)-P r osop h yllin e. To a solution of (-)-32 (155 mg, 0.28
mmol, 1 equiv) in THF (15 mL) was added TBAF (0.56 mL, 1
M in THF, 0.56 mmol, 2 equiv), and after 20 h at room
temperature, the reaction mixture was concentrated in vacuo.
The crude residue was purified on silica gel (MeOH/CH2Cl2,
5/100 to 20/100) to afford (-)-prosophylline (79 mg, 0.25 mmol,
90%) as white crystals. Spectral and physical data are in
accordance with the literature data:7,10 Rf ) 0.09 (CH2Cl2/
MeOH, 10/2); [R]20D ) -17.6 (c 1.5, MeOH) {lit.10 [R]20D ) -13.4
(c 1.5, MeOH)}; mp ) 77-79 °C {lit.10 mp ) 75-76 °C}; IR
(neat) 3300-3200, 1710 cm-1; 1H NMR (300 MHz) δ (ppm) 3.81
(m, 1H), 3.70 (m, 1H), 3.65-3.27 (m, 4H), 2.58-2.45 (m, 2H),
2.45-2.30 (m, 4H), 2.01 (m, 1H), 1.74 (m, 1H), 1.62-1.46 (m,
2H), 1.45-1.10 (m, 3H), 1.25 (s, 13H), 1.03 (t, 3H, J ) 7.4 Hz);
13C NMR (75.5 MHz) δ (ppm) 212.0 (s), 69.5 (d), 63.5 (t), 63.2
(d), 56.0 (d), 42.2 (t), 36.1 (t), 35.7 (t), 33.5 (t), 30.6 (t), 29.6 (t),
29.5 (t), 29.3 (t), 29.2 (t), 29.1 (t), 26.0 (t), 23.7 (t), 7.7 (q); MS
(CI+, CH4) m/z 314 (MH+, 76), 300 (100), 286 (60), 272 (14),
266 (3), 222 (4), 208 (19), 194 (12), 180 (6), 141 (8), 122 (24),
104 (14); HRMS (CI+, CH4) calcd for C18H36NO3 (MH+) m/z
314.2695, found 314.2693.
C
40H47NSiO4: C, 75.79; H, 7.47; N, 2.21. Found: C, 75.64; H,
7.46; N, 2.15.
12-((2S,5R,6S)-5-(Ben zyloxy)-1-[(ben zyloxy)ca r bon yl]-
6-{[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl}p ip er id in -2-yl)-
d od ec-10-en -3-on e (+)-31. To a mixture of G2 (58 mg, 0.07
mmol, 0.05 equiv) in CH2Cl2 (9 mL) was added dropwise at
room temperature a solution of (+)-30 (0.860 g, 1.36 mmol, 1
equiv) and 28 (0.46 g, 2.72 mmol, 2 equiv) in CH2Cl2 (3 mL).
The solution was stirred under Ar for 4 h at 50 °C and
concentrated in vacuo. The crude residue was purified on silica
gel (Et2O/petroleum ether, 2/10 to 3/10) to afford (+)-31 (0.61
g, 0.79 mmol, 58%) as a colorless oil: Rf ) 0.25 (Et2O/petroleum
ether, 3/7); [R]20 ) +8.9 (c 1.0, CHCl3); IR (neat) 1690, 1585
D
cm-1; 1H NMR (300 MHz, C6D5CD3, 363 K) δ (ppm) 7.76-7.63
(m, 4H), 7.28-6.98 (m, 16H), 5.32-5.19 (m, 2H), 5.11 (d syst
AB, 1H, J ) 12.7 Hz), 5.00 (d syst AB, 1H, J ) 12.7 Hz), 4.91
(m, 1H), 4.54 (d syst AB, 1H, J ) 12.1 Hz), 4.44 (d syst AB,
1H, J ) 12.1 Hz), 4.32 (m, 1H), 3.92-3.80 (m, 2H), 3.71 (m,
1H), 2.21-1.70 (m, 10H), 1.64-1.37 (m, 4H), 1.31-1.01 (m,
6H), 1.10 (s, 9H), 0.91 (t, 3H, J ) 7.4 Hz); 13C NMR (75.5 MHz,
Ack n ow led gm en t. C.W. thanks Rhodia for a grant.
We thank Delphine and Thierry J ouet for kindly
providing the picture of Sedum acre. A. Duprat is
thanked for his help in the realization of the cover
art.
J O010653D