A short synthesis of (+)-narciclasine via a strategy derived from stereocontrolled epoxide formation and SnCl4-catalyzed arene-epoxide coupling

Article abstract of DOI:10.1021/jo020155k

A facile construction of the typical framework of narcissus alkaloids has been realized by virtue of the development of a practical route involving stereocontrolled epoxide formation and SnCl₄-catalyzed arene-epoxide coupling. To achieve this goal, it proved to be necessary to devise a strategy that would enable chemical transformations to install an epoxy moiety in a congested environment. The successful preparation of a hindered epoxide from O-isopropylidene-protected 4-aminocyclohexenol required three steps consisting principally of controlled bromohydration and base-promoted closure and N-alkylation. It was found that a catalytic amount of SnCl₄ not only maintained the catalytic cycle but also effected clean arylation to form a fused BC ring system. Several tactics that ultimately proved to be unsatisfactory are also discussed in an effort to set important boundary limits on arene-epoxide coupling. The requisite enantiopure 4-aminocyclohexenol was available via an asymmetric cycloaddition of diene to camphor-based chloronitroso. The total synthesis of (+)-narciclasine was realized in nine steps with an overall yield of 19%.

Full text of DOI:10.1021/jo020155k

A Sh or t Syn th esis of (+)-Na r cicla sin e via a Str a tegy Der ived fr om
Ster eocon tr olled Ep oxid e F or m a tion a n d Sn Cl4-Ca ta lyzed
Ar en e-Ep oxid e Cou p lin g
Shanmugham Elango and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan, ROC
thyan@mail.nchu.edu.tw
Received March 7, 2002
A facile construction of the typical framework of narcissus alkaloids has been realized by virtue of
the development of a practical route involving stereocontrolled epoxide formation and SnCl4-
catalyzed arene-epoxide coupling. To achieve this goal, it proved to be necessary to devise a strategy
that would enable chemical transformations to install an epoxy moiety in a congested environment.
The successful preparation of a hindered epoxide from O-isopropylidene-protected 4-aminocyclo-
hexenol required three steps consisting principally of controlled bromohydration and base-promoted
closure and N-alkylation. It was found that a catalytic amount of SnCl4 not only maintained the
catalytic cycle but also effected clean arylation to form a fused BC ring system. Several tactics
that ultimately proved to be unsatisfactory are also discussed in an effort to set important boundary
limits on arene-epoxide coupling. The requisite enantiopure 4-aminocyclohexenol was available
via an asymmetric cycloaddition of diene to camphor-based chloronitroso. The total synthesis of
(+)-narciclasine was realized in nine steps with an overall yield of 19%.
In tr od u ction
synthesis include introduction of the aryl group and
stereocontrolled construction of the fused BC ring system.
Recently, because the majority of the stereochemical
interrelationships and pendent functional groups in these
alkaloids share a striking similarity, a synthetic conver-
sion of narciclasine 1 to pancratistatin 3 has been
disclosed by Pettit.5 To explore some of the important
structure-activity relationships, the related cis-epimer
of saturated narcissus alkaloid has also garnered atten-
tion from the synthetic community. During the prepara-
tion of this manuscript, Hudlicky reported the total
synthesis of epi-7-deoxypancratistatin via aza-Payne
rearrangement and Me2AlCl-assisted intramolecular cy-
clization.6 We describe herein a short synthesis of (+)-
narciclasine2c,3,7 from the readily available chiral O-iso-
propylidene-protected 4-aminocyclohexenol 11 by a route
involving stereocontrolled installation of the bromohydrin
There has been considerable interest in recent years
in the development of new methodology suitable for the
synthesis of narcissus alkaloids such as (+)-narciclasine
1, (+)-lycoricidine 2, (+)-pancratistatin 3, and (+)-deoxy-
pancratistatin 4 because of the reputed biological activity
and low natural abundance of these compounds. In this
regard, the literature provides numerous strategies such
as asymmetric syntheses based upon nitroso cycloaddi-
tions from chiral diene derived from whole-cell oxidation
of bromobenzene with Pseudomonas putida 39/D,1a Pd-
catalyzed desymmetrization of the symmetric dicarbo-
nate,1b Pd-catalyzed desymmetrization of the prochiral
cyclohexanone,1c intramolecular coupling of arene to the
allyl triflate1d and carbamate,1e radical cyclization of the
oxime ether,2 aryl enamide photocyclization,3 and Pd-
catalyzed Heck cyclization.4 The principal hurdles to
(2) (a) Keck, G. E.; McHardy, S. F.; Murry, J . A. J . Am. Chem. Soc.
1995, 117, 7289. (b) Keck, G. E.; Wage, T. T. J . Org. Chem. 1996, 61,
8366. (c) Keck, G. E.; Wager, T. T.; Rodriquez, J . F. D. J . Am. Chem.
Soc. 1999, 121, 5176.
(3) (a) Rigby, J . H.; Mateo, M. E. J . Am. Chem. Soc. 1997, 119,
12655. (b) Rigby, J . H.; Maharoof, U. S. M.; Mateo, M. E. J . Am. Chem.
Soc. 2000, 122, 6624.
(4) (a) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991,
32, 4525. (b) Hudlicky, T.; Olivo, H. F. J . Am. Chem. Soc. 1992, 114,
9694. (c) Chida, N.; Ohtsuka, M.; Ogawa, S. J . Org. Chem. 1993, 58,
4441. (d) McIntosh, M. C.; Weinreb, S. M. J . Org. Chem. 1993, 58,
4823. (e) Hudlicky, T.; Olivo, H. F.; Mckibben, B. J . Am. Chem. Soc.
1994, 116, 5108.
(1) (a) Tian, X.; Hudlicky, T.; Konigsberger, K. J . Am. Chem. Soc.
1995, 117, 3643. (b) Trost, B. M.; Pulley, S. R. J . Am. Chem. Soc. 1995,
117, 10143. (c) Magnus, P.; Sebhat, I. K. J . Am. Chem. Soc. 1998, 120,
5341. (d) Doyle, T. J .; Hendrix, M.; VanDerveer, D.; J avanmard, S.;
Haseltine, J . Tetrahedron 1997, 53, 11153. (e) Gonzalez, D.; Martinot,
T.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3077.
(5) Pettit, G. R.; Melody, N.; Herald, D. L. J . Org. Chem. 2001, 66,
2583.
(6) Uwe, R.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2002, 4, 115.
(7) (a) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett.
1999, 40, 3077. (b) For the isolation of narciclasine, see: Piozzi, F.;
Modelli, R.; Fuganti, C.; Ceriotti, G. Tetrahedron 1968, 24, 1119.
10.1021/jo020155k CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/07/2002
6954
J . Org. Chem. 2002, 67, 6954-6959

Short Synthesis of (+)-Narciclasine
CHART 1
SCHEME 1
unit, base-promoted epoxide formation, and SnCl4-
catalyzed arene-epoxide coupling (Chart 1).7
Resu lts a n d Discu cssion
Camphor-based chiral controller molecules have previ-
ously been shown to exhibit high asymmetric induction
in aldol addition and cycloaddition reactions.8a-c We
envisioned employing the previously reported chiral
chloronitroso 98d as a practical nitroso synthon.9 Chloro-
nitroso 9 was readily prepared from the ketopinic acid
via a three-step protocol: (a) esterification (SOCl2/
MeOH), (b) formation of oxime (HONH2‚HCl/MeOH/
NaOAc), and (c) oxidation (t-BuO-Cl/CH2Cl2). The overall
isolated yield of 9 from ketopinic acid was 88%. The
requisite enantiopure O-isopropylidene-protected 4-ami-
nocyclohexenol 11 was prepared in one-pot by cycload-
dition of 9 to diene 510 (CH2Cl2, 0 °C, 12 h) followed by
treatment with water and Al-Hg (CH3CN, 0 to 25 °C, 2
h) (Scheme 1).11 While hydrolysis of the cycloaddition
adduct led to the desired oxazine hydrochloride 10, keto
ester 8 could be recovered in 93% yield by hexane
extraction of the aqueous reaction mixture. The enan-
tiomeric purity (>99%) of bicyclic oxazine was determined
fonamide 12 in hand, the stage was set for diastereocon-
trolled introduction of the epoxy unit in order to permit
intramolecular coupling of an aryl ring to the epoxide.
Experience had shown that all attempts to effect Lewis
acid-promoted arene-epoxide coupling of 7 failed to
1
by H NMR of its D-camphor-10-sulfonyl derivative and
also by comparing the achiral oxazine with our adduct
10 in HPLC (Chiracel OD; 95% hexane/isopropyl alcohol;
flow rate 1 mL/min; UV 254 nm). Only a single peak (tR
) 19.2 min) was observed for the chiral oxazine 10.
Because of the sensitivity of 11, it was generally used
directly in the next step without purification. Subsequent
protection of the amino and hydroxyl moieties with
p-nitrobenzenesulfonyl chloride (Ns-Cl) and TBS-Cl de-
livered the silylated sulfonamide 12 in 78% isolated yield.
Ster eocon tr olled Ep oxid e F or m a tion a n d Ar en e-
Ep oxid e Cou p lin g. With enantiopure unsaturated sul-
provide the desired fused ring system (eq 1).12 They either
decomposed, failed to react, or produced halohydrins,
through an epoxide ring-opening process. Apparently, in
these instances, the cyclization process cannot compete
with ring opening. It was felt that the acetonide moiety
might repel the arene ring, thereby preventing cycliza-
tion. Attention was then centered upon intramolecular
arylation of epoxides 14, where the epoxy unit and
acetonide ring are syn to each other (Scheme 2). In the
absence of a potent directing group for peracids,13 the
more hindered epoxide can usually be prepared by
bromohydrin formation and base-promoted closure.14
Generation of bromohydrin 13 was not anticipated to
present complications and did not. Thus, exposure of 12
(8) (a) For
a review concerning camphor derivatives as chiral
auxiliaries, see: Oppolzer, Z. Tetrahedron 1987, 43, 1969-2004. (b)
Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J . Am.
Chem. Soc. 1993, 115, 2613. (c) Lin, C.-C.; Wang, Y.-C.; Hsu, J .-L.;
Chiang, C.-C.; Su, D.-W.; Yan, T.-H. J . Org. Chem. 1997, 62, 3806. (d)
Extensive studies have revealed that camphor-based chloronitroso 9
has shown exceptionally high stereoselection in cycloadditions. Elango,
S.; Wang, Y.-C.; Cheng, C.-L.; Yan, T.-H. Tetrahedron Lett. 2002, 43,
3757.
(9) For chloronitroso dienophiles derived from steroid, D-manno-
furanose, D-xylofuranose, L-xylose, and D-xylose, see: (a) Iida, H.;
Watanabe, Y.; Kibayashi, C. Tetrahedron, Lett. 1984, 31, 5091. (b)
Schurrle, K.; Beier, B.; Piepersberg, W. J . Chem. Soc., Perkin Trans.
1 1991, 2407. (c) Braun, H.; Felber, H.; Kresze, G.; Schmidtchen, F.
P.; Prewo, R.; Vasella, A. Liebigs Ann. Chem. 1993, 261, and earlier
references therein. (d) Adrian, H.; Bailey, P. D.; Rees, D. C.; Wightman,
R. H. J . Chem. Soc., Chem. Commun. 1998, 2251. (e) Faitg, T.; Soulie,
J .; Lallemand J .-Y.; Ricard, L. Tetrahedron: Asymmetry 1999, 2165.
(f) Hall, A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.; Wightman, R. H.
J . Chem. Soc., Perkin Trans. 1 2000, 329.
(12) Yan, T.-H.; Wang, Y.-C. Unpublished observations.
(13) Stereoselective preparation of epoxides can be achieved by the
aid of the structure of the substrates, especially in the cyclic systems.
The presence of a hydroxyl group close to the olefinic bond strongly
determines the epoxide stereochemistry. For studies of the directive
effect of the hydroxyl group, see: (a) Henbest, H. B. Proc. Chem. Soc.
1963, 159. (b) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J .
Chem. Soc., B 1970, 1374. (c) Prat, D.; Delpech, B.; Lett, R. Tetrahedron
Lett. 1986, 27, 711.
(10) Su¨tbeyaz, Y.; Secen, H.; BalcI, M. J . Chem. Soc., Chem.
Commun. 1988, 1330.
(11) For additional examples of preparation of conduramine syn-
thons, see refs 4 and 9b.
(14) Hanselaer, R.; Samson, R.; Vandewalle, M. Tetrahedron 1978,
34, 2393.
J . Org. Chem, Vol. 67, No. 20, 2002 6955

Elango and Yan
SCHEME 2. Ster eocon tr olled Ep oxid e F or m a tion a n d Ar en e-Ep oxid e Cou p lin g
to NBS in aqueous acetone at room temperature gave
rise to bromohydrins 13 as a 1:1 mixture of two regio-
isomers. The resulting mixture was used as such for the
epoxide formation. Epoxides 14 could be prepared in one
step from 13 through base-promoted epoxide formation
and N-piperonylation. Thus, reaction of bromohydrin 13
with the requisite piperonyl bromides 615,16 in the pres-
ence of K2CO3 at 60 °C for 4 h led to clean internal SN2
reaction and N-alkylation to give the desired epoxides
14 in 91-95% isolated yields. With epoxides 14 in hand,
the stage was set to establish the feasibility of Lewis acid
as a catalyst to effect intramolecular arene-epoxide
coupling. After an extensive survey of Lewis acids such
as BF3‚OEt2, TiCl4, AlCl3, and MgBr2, we were dis-
appointed to discover that none of catalysts led to
acceptable levels of arene-epoxide coupling. Surpris-
ingly, a catalytic amount of SnCl4 (10-20 mol %) not only
maintained the catalytic cycle but also effected clean
intramolecular arylation of 14 to form the fused BC ring
system. Thus, exposure of 14a to SnCl4 in dry CH2Cl2 at
room temperature for 10 min followed by addition of Ac2O
provided after chromatography on silica gel the desired
tetracyclic ester 15a in 93% yield. The assignment of the
cis-fused ring stereochemistry of 15a follows by compari-
son to the known compounds pancratistatin 3 and
deoxypancratistatin 4. The 1H NMR absorptions for
benzylic proton (H-C-10b) in 3 (δ 2.96, br d, J ) 11.5-
12.9 Hz) and 4 (δ 2.98, d, J ) 9.8-12.0 Hz) are diagnostic
of the trans-fused BC ring system.1-3,5 The corresponding
methoxy substituent, we were not surprised to discover
a poor selectivity (intra- and intermolecular coupling) in
this cyclization. A 1:1 mixture of 15b and dimer (not
1
shown) was obtained as judged by H NMR spectrum.
All attempts to enhance the relative proportion of the
desired ester 15b in this cyclization were to no avail.
(+)-Na r cicla sin e. The ready accessibility to tetracyclic
intermediate 15a by the preceding protocol set the stage
for completion of the synthesis (Scheme 3). Thus, expo-
sure of 15a to 2 equiv of mercaptoacetic acid in the
presence of LiOH (5 equiv) at room temperature in DMF
for 1 h led to clean removal of the nosyl (p-nitrobenze-
nesulfonyl) moiety to liberate the free amine 16 (78%
isolated yield),17 which upon treatment with Boc2 followed
by addition of RuCl3 and aqueous NaIO4 to effect benzylic
oxidation provided the solid imide 17 in 67% yield. The
imide 17 possessing the typical framework of pancrat-
istatin is lacking the stereochemistry only at the benzylic
position (C-10b). There remained the task of eliminating
acetic acid from 17 to obtain the unsaturated alkaloid.
Dreiding models of 17 indicate the acetoxy and benzylic
hydrogen (H-C-10b) attached to a cis-fused bicyclic
framework (BC ring system) are not syn-periplanar in
its ground-state geometry. For this reason, base-pro-
moted syn-elimination most likely would require some
degree of heating. Thus, exposure of 17 with DBU at 70
°C led to clean syn-elimination to give 18 in 97% yield.
Subsequent exposure of the elimination product 18 to
formic acid at 60 °C followed by solvent removal and
immediate treatment with a solution of LiAlH4 in THF
resulted in efficient deprotection of all the protecting
groups to give the target molecule 1, which was identical
in all aspects to the literature report.2c,3,18 The total
synthesis of narciclasine 1 was thus realized in nine steps
with an overall yield of 19%.
absorptions for 15a (δ 3.05, t, J
) 6.4 Hz, J
) 6.4
ab
ac
Hz) establish the cis-fused ring stereochemistry as de-
picted, which, in turn, confirms our tentative assignment
of the stereochemistry of the initial bromohydrin products
13. We next investigated the arene-epoxide coupling of
14b. Due to well-documented para-directing effect of the
Con clu sion s
(15) (a) Piperonyl bromide 6a was prepared in three steps from the
corresponding 2-hydroxy-3,4-methylenedioxybenzaldehyde:16a (i) ClCO-
NEt2 (1 equiv), K2CO3 (3 equiv), CH3CN, 85 °C, 2 h. (ii) NaBH4 (2
equiv), MeOH, from 0 to 25 °C. (iii) HBr (48 wt % in H2O), CH2Cl2, 25
°C, 86% yield (three steps). (b) Reaction of 2-methoxy-3,4-methylene-
dioxybenzyl alcohol16b with HBr (48 wt % in H2O) in CH2Cl2 at 25 °C
afforded the corresponding piperonyl bromide 6b in 96% yield.
(16) (a) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Tetrahedron 1995,
51, 8585. (b) Takaba, K.; Komori, K.; Kunitomo, J .-I.; Ishida, T.
Heterocycles 1996, 43, 1777.
In summary, asymmetric chloronitroso cycloaddition,
application of the stereocontrolled epoxide formation, and
(17) Hamada, T.; Nishida, A.; Yonemitsu, O. J . Am. Chem. Soc.
1986, 108, 140.
(18) (a) Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968,
16, 1860. (b) Piozzi, F.; Modelli, R.; Fuganti, C.; Ceriotti, G. Tetrahedron
1968, 24, 1119.
6956 J . Org. Chem., Vol. 67, No. 20, 2002

Short Synthesis of (+)-Narciclasine
SCHEME 3
Anal. Calcd for C9H15NO3: C, 49.22; H, 6.20; N, 3.59. Found:
C, 49.31; H, 6.16; N, 3.62.
implementation of a SnCl4-catalyzed intramolecular ary-
lation led efficiently to the tetracyclic ester. (+)-Narci-
clasine was available in nine steps by this route. Tetra-
cyclic sulfonamide 15 might also serve as a synthetic
intermediate toward pancratistatin 3 and its epimer. The
conversion of tetracyclic intermediate 15 to pancratistatin
3 requires inversion at C-10b (benzylic carbon). Now,
efforts are directed toward inverting the stereochemistry
of C-10b.
(1S,2S,3S,6R)-3-((t-Bu t yld im et h ylsilyl)oxy)-1,2-O-iso-
p r o p y lid e n e -6-(N -(p -n it r o b e n ze n e s u lfo n y l)a m in o )-
cycloh exen e-1,2-d iol (12). To a solution of 11 (1.85 g, 10.0
mmol) and NEt3 (4.2 mL, 30 mmol) in CH3CN (20 mL) was
added p-nitrobenzenesulfonyl chloride (2.3 g, 10 mmol). After
the mixture was stirred at 25 °C for 8 h, a solution of DBU
(2.3 mL, 15 mmol) and TBS-Cl (1.69 g, 11 mmol) in CH3CN
(10 mL) was added and the mixture was stirred further for a
period of 9 h. The reaction was quenched with aqueous
NaHCO3, and CH3CN was removed under vacuum. The
aqueous solution was extracted with CH2Cl2 (40 mL × 3). The
combined organic extracts were washed with dilute HCl and
brine, dried (MgSO4), concentrated in vacuo, and purified by
flash chromatography (silica gel, 20% EtOAc/hexane) to give
3.78 g (78%) of 12 as a white solid: mp 78-79 °C; IR (neat)
3280, 3106,1607 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J
) 8.8 Hz, 2 H), 8.02 (d, J ) 8.8 Hz, 2 H), 6.06 (dd, J ) 9.6, 5.2
Hz, 1 H), 5.88 (d, J ) 10.4 Hz, 1 H), 5.83 (dd, J ) 9.6, 5.6 Hz,
1 H), 4.38 (dd, J ) 7.2, 2.8 Hz, 1 H), 4.31 (dt, J ) 7.2, 2.8, 1.6
Hz, 1 H), 4.16 (dd, J ) 4.8, 1.6 Hz, 1 H), 3.95-3.93 (m, 1 H),
1.23 (s, 6 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.09 (s, 3 H); 13C NMR
(75.5 MHz, CDCl3) δ 150.01, 147.27, 133.15, 130.30, 128.18,
124.30, 108.62, 78.21, 77.30, 66.18, 50.12, 26.09, 25.71, 24.32,
17.93, -4.80, -4.92; high-resolution MS (FAB+) m/e calcd for
Exp er im en ta l Section
Gen er a l. Reactions were generally conducted under a
positive pressure of dry nitrogen within oven-dried glassware.
THF and ether were distilled from sodium/benzophenone ketyl
prior to use. Methylene chloride and acetonitrile were distilled
from CaH2 prior to use. Flash chromatography was done on
E. Merck silica gel 60 (230-400 mesh). Melting points (Pyrex
capillary) are uncorrected. Concentrations for rotation data are
given as g/100 mL of solvent.
(1S,2R,3S,6R)-6-Am in o-1,2-O-isop r op ylid en e-4-cyclo-
h exen e-1,2,3-tr iol (11). To a solution of chloronitroso ester
9 (5.4 g, 20.0 mmol) in CH2Cl2 (40 mL) in a round-bottom flask
covered with aluminum foil at 0 °C was added cyclohexadiene
acetonide 5 (3.1 g, 20.0 mmol) in CH2Cl2 (10 mL), and the
mixture was stirred for 12 h at the same temperature. Then,
the solvent was removed in vacuo to yield a solid residue that
was dissolved in water (60 mL) and stirred at room temper-
ature for 30 min. This aqueous solution was thoroughly
washed with hexane and directly treated with Al-Hg (3.1 g)
and CH3CN (230 mL). [From the hexane solution was recov-
ered pure camphor ester in 85-90% yield.] After stirring at
room temperature for 1.5 h, the reaction mixture was filtered
over a Celite pad and washed the residue with CH3CN (30
mL × 2). The filtrate was completely concentrated in vacuo to
afford the amino alcohol 11, which was generally found to be
pure by 1H NMR spectroscopy. If necessary, the crude product
is redissolved in CH3CN, dried with K3CO3, and evaporated
in vacuo to afford 2.36 g (85% yield) of 11 as a colorless oil:
C
21H32N2O7SSi 485.1699. found 485.1704; [R]25D -23.0° (c 0.8,
CH2Cl2). Anal. Calcd for C21H32N2O7SSi: C, 52.04; H, 6.65; N,
5.78. Found: C, 51.97; H, 6.56; N, 5.92.
(1S,2S,3S,4S,5S,6S)-5-Br om o-3-((t-bu tyld im eth ylsilyl)-
oxy)-1,2-O-isop r op ylid en e-6-(N-(p -n it r ob en zen esu lfon -
yl)am in o)cycloh exan e-1,2,4-tr iol an d (1S,2S,3R,4S,5R,6R)-
4 -B r o m o -3 -((t -b u t y l d i m e t h y l s i l y l )o x y )-1 ,2 -O -i s o -
p r op ylid en e-6-(N-(p-n itr oben zen esu lfon yl)a m in o)cyclo-
h exa n e-1,2,5-tr iol (13). To a solution of 12 (4.84 g, 10.0 mmol)
in acetone (10 mL) and water (40 mL) was added NBS (2.67
g, 15 mmol). After stirring at 25 °C for 10 h, the reaction
mixture was diluted with CH2Cl2 (150 mL), washed with
water, dried (MgSO4), concentrated in vacuo, and purified by
flash chromatography (silica gel, 17% EtOAc/hexane) to give
5.71 g (98%) of 13 as a sticky solid (two regioisomers, found
IR (neat) 3354, 2986, 1602, 1055 cm-1 1H NMR (400 MHz,
;
1
CDCl3) δ 6.15 (dd, J ) 9.6, 4.4 Hz, 1 H, HCdCH), 5.94 (dd, J
) 9.6, 4.4 Hz, 1 H, HCdCH), 4.41 (dd, J ) 7.6, 3.6 Hz, 1 H,
HC-OH), 4.16-4.13 (m, 2 H, O-CH-CH-O), 3.57 (t, J ) 4.0
Hz, 1 H, HC-N), 2.24-2.15 (bs, 3 H, OH, NH2), 1.40 (s, 3 H,
H3C-C-CH3), 1.33 (s, 3 H, H3C-C-CH3); 13C NMR (75.5
MHz, CDCl3) δ 133.01, 131.58, 108.70, 79.76, 79.72, 68.45,
by 400 MHz H NMR to be in a 3:2 ratio). Major isomer: mp
82-83 °C; IR (neat) 3528, 3277 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 8.32 (d, J ) 8.8 Hz, 2 H), 8.06 (d, J ) 8.8 Hz, 2 H),
6.20 (d, J ) 10.4 Hz, 1 H), 4.43 (dd, J ) 6.8, 3.2 Hz, 1 H), 4.31
(dd, J ) 6.4, 3.6 Hz, 1 H), 4.20 (dd, J ) 7.6, 3.6 Hz, 1 H), 4.05
(t, J ) 2.4 Hz, 1 H), 3.85 (dd, J ) 8.0, 2.4 Hz, 1 H), 3.76 (dt,
J ) 10.4, 3.2 Hz, 1 H), 1.42 (s, 3 H), 1.29 (s, 3 H), 0.93 (s, 9 H),
0.17 (s, 6 H); 13C NMR (75.5 MHz, CDCl3) δ 150.08, 146.14,
56.62, 26.58, 24.37; [R]25 +11.2° (c 0.75, CH2Cl2); high-
D
resolution MS m/e calcd for C9H15NO3 185.2234, found 185.2235.
J . Org. Chem, Vol. 67, No. 20, 2002 6957

Elango and Yan
128.76, 124.09, 109.74, 78.43, 77.31, 76.10, 73.96, 56.99, 52.97,
(1R,2R,3S,4R,4a R,10bS)-1-Acetoxy-2-((t-bu tyld im eth yl-
silyl)oxy)-7-(o-ca r b a m oyloxyp ip e r on yl)-3,4-(isop r op -
yliden edioxy)-8,9-(m eth ylen edioxy)-1,1a ,2,3,4,4a ,5,6-octa -
h yd r op h en a n th r id in e (16). To a solution of 15a (0.6 g, 0.76
mmol) in DMF (4.0 mL) was added LiOH (0.07 g, 3 mmol)
followed by mercaptoacetic acid (0.11 mL, 1.52 mmol). After
stirring at 25 °C for 1 h, the solution was diluted with ether
(30 mL) and washed with aqueous NaHCO3 followed by brine.
The ether layer was dried, concentrated, and purified by flash
chromatography (silica gel, 25% EtOAc/hexane) to afford 0.36
g (78%) of 16 as a white solid: mp 114-115 °C; IR (neat) 3330,
1728 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.50 (s, 1 H), 5.93 (d,
J ) 1.6 Hz, 1 H), 5.89 (d, J ) 1.6 Hz, 1 H), 5.13 (t, J ) 9.6 Hz,
1 H), 4.15-4.08 (m, 2 H), 4.06 (d, J ) 16.0 Hz, 1 H), 3.91 (d,
J ) 16.0 Hz, 1 H), 3.80 (dd, J ) 9.2, 6.4 Hz, 1 H), 3.46 (dd, J
) 1.6, 1.2 Hz, 1 H), 3.42-3.27 (m, 4 H), 2.81 (dd, J ) 10.4, 3.2
Hz, 1 H), 1.95 (s, 3 H), 1.73 (br s, i H), 1.53 (s, 3 H), 1.21 (t, J
) 7.2 Hz, 3 H), 1.16 (t, J ) 7.2 Hz, 3 H), 0.81 (s, 9 H), 0.12 (s,
3 H), 0.04 (s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 169.54,
152.45, 146.96, 138.34, 130.96, 127.32, 122.13, 108.61, 107.26,
101.65, 80.20, 78.20, 76.15, 74.43, 53.44, 43.81, 42.47, 42.05,
39.32, 28.18, 26.22, 25.66, 21.37, 17.93, 14.15, 13.34, -4.20,
26.46, 25.64, 23.93, 17.93, -5.02, -5.23; [R]25 -10.7° (c 1.5,
D
CH2Cl2). Minor isomer: mp 99-100 °C; IR (neat) 3508, 3280
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.33 (d, J ) 8.8 Hz, 2 H),
8.10 (d, J ) 8.8 Hz, 2 H), 5.68 (d, J ) 8.8 Hz, 1 H), 4.25-4.20
(m, 2 H), 4.18 (dd, J ) 9.2, 1.2 Hz, 1 H), 4.15-4.11 (m, 1 H),
3.80 (dd, J ) 8.8, 6.8 Hz, 1 H), 3.62 (dq, J ) 6.4, 1.6 Hz, 1 H),
1.41 (s, 3 H), 1.28 (s, 3 H), 0.90 (s, 9 H), 0.19 (s, 3 H), 0.15 (s,
3 H); 13C NMR (75.5 MHz, CDCl3) δ 149.97, 146.79, 128.55,
124.04, 110.19, 77.30, 72.96, 72.36, 59.96, 56.26, 27.31, 25.76,
25.64, 25.29, 18.02, -4.66, -4.74; [R]25 -50.7° (c 2.2, CH2-
D
Cl2); high-resolution MS (FAB+) m/e calcd for C21H33BrN2O8-
SSi 581.0988, found 581.0984.
(1S,2S,3S,4R,5R,6S)-3-((t-Bu tyld im eth ylsilyl)oxy)-6-(N-
(o-ca r ba m oyloxyp ip er on yl)-N-(p-n itr oben zen esu lfon yl)-
a m in o)-4,5-ep oxy-1,2-O-isop r op ylid en ecycloh exa n e-1,2-
d iol (14a ). To a solution of 13 (1.16 g, 2.0 mmol) and 6a (0.66
g, 2.0 mmol) in CH3CN (15 mL) was added K2CO3 (2.8 g, 20.0
mmol). The reaction mixture was heated at 60 °C for 4 h,
allowed to cooled to room temaerature, and then concentrated
in vacuo. The residue was taken in CH2Cl2 and washed with
water, dilute HCl, and brine. The organic layer was dried,
concentrated, and purified by flash chromatography (silica gel,
25% EtOAc/hexane) to give 1.32 g (88%) of 14a as a white
-4.86; [R]25 +38.2° (c 1.9, CH2Cl2); high-resolution MS m/e
D
calcd for C30H46N2O9Si 607.3051, found 607.3054. Anal. Calcd
for C30H46N2O9Si: C, 59.38; H, 7.64; N, 4.62. Found: C, 59.22;
H, 7.69; N, 4.44.
solid: mp 92-93 °C; IR (neat) 3105, 1725, 1531, 1473 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J ) 8.8 Hz, 2 H), 8.01
(d, J ) 8.8 Hz, 2 H), 6.95 (d, J ) 8.4 Hz, 1 H), 6.60 (d, J ) 8.4
Hz, 1 H), 5.97 (d, J ) 1.6 Hz, 1 H), 5.96 (d, J ) 1.6 Hz, 1 H),
4.48 (s, 2 H), 4.40 (t, J ) 8.8 Hz, 1 H), 4.10 (dd, J ) 8.0, 6.8
Hz, 1 H), 3.69-3.64 (m, 2 H), 3.43-3.29 (m, 4 H), 3.11 (t, J )
4.4 Hz, 1 H), 3.01 (dd, J ) 4.4, 3.2 Hz, 1 H), 1.24 (s, 3 H), 1.22
(t, J ) 7.6 Hz, 3 H), 1.16 (t, J ) 7.2 Hz, 3 H), 1.14 (s, 3 H),
0.85 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 152.54, 149.82, 149.05, 146.29, 139.52, 133.07, 128.72,
123.87, 122.84, 122.75, 109.71, 105.90, 102.20, 79.99, 74.07,
72.78, 61.91, 56.61, 53.46, 44.81, 42.55, 42.16, 26.77, 25.68,
(1R,2R,3S,4R,4a R,10bS)-1-Acetoxy-5-(t-bu toxyca r bon -
yl)-2-((t -b u t yld im e t h ylsilyl)oxy)-7-(o-ca r b a m oyloxy-
piperonyl)-3,4-(isopropylidenedioxy)-8,9-(methylenedioxy)-
1,1a ,2,3,4,4a -p en ta h yd r op h en a n th r id on e (17). A solution
of 16 (0.3 g, 0.5 mmol) and di-tert-butyl dicarbonate (0.12 g,
0.5 mmol) in CH3CN (9 mL) was stirred at 25 °C until the
starting amine disappeared on TLC (ca. 4 h). To this vigorously
stirred solution was added CCl4 (9 mL) followed by an aqueous
solution of NaIO4 (0.45 g in 13.5 mL H2O) and RuCl3 (20 mg,
0.10 mmol). After being stirred for 3 h, the reaction mixture
was diluted with CH2Cl2 (30 mL), and the aqueous phase was
extracted with CH2Cl2 (15 mL × 3) and EtOAc (15 mL × 3).
The combined organic extracts were dried and concentrated
in vacuo. The residue was diluted with ether (20 mL), filtered
through a Celite pad, concentrated, and purified by flash
chromatography (silica gel, 15%, 25%, and 33% EtOAc/hexane)
to afford 0.24 g (67%) of 17 as a white solid: mp 100-101 °C;
IR (neat) 1728 (broad), 1633 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.01 (s, 1 H), 6.04 (d, J ) 0.8 Hz, 1 H), 6.02 (d, J ) 0.8 Hz,
1 H), 5.34 (dd, J ) 7.6, 3.2 Hz, 1 H), 4.83 (dd, J ) 9.2, 5.6 Hz,
1 H), 4.25 (dd, J ) 8.8, 7.2 Hz, 1 H), 4.00 (t, J ) 7.6 Hz, 1 H),
3.83 (t, J ) 7.2 Hz, 1 H), 3.46 (q, J ) 6.8 Hz, 2 H), 3.42-3.29
(m, 2 H), 2.10 (s, 3 H), 1.52 (s, 9 H), 1.46 (s, 3 H), 1.24 (t, J )
7.6 Hz, 1 H), 1.23 (s, 3 H), 1.18 (t, J ) 6.8 Hz, 1 H), 0.84 (s, 9
H), 0.09 (s, 3 H), 0.08 (s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ
170.03, 159.19, 152.84, 152.68, 152.23, 140.33, 135.27, 133.02,
117.81, 109.71, 103.55, 102.73, 83.19, 77.70, 75.29, 74.79,
72.89, 53.05, 42.26, 41.99, 41.91, 27.88, 27.26, 25.65, 25.14,
24.18, 18.05, 14.12, 13.25, -4.82, -4.99; [R]25 -6.4° (c 4.0,
D
CH2Cl2); high-resolution MS m/e calcd for C34H47N3O12
SSi 750.2728, found 750.2736. Anal. Calcd for C34H47N3O12
-
-
SSi: C, 54.45; H, 6.32; N, 5.60. Found: C, 54.60; H, 6.54; N,
5.76.
(1R,2R,3S,4R,4aR,10bS)-1-Acetoxy-2-((t-butyldimethylsilyl)-
o x y )-7-(o-c a r b a m o y lo x y p ip e r o n y l)-3,4-(is o p r o p y li-
denedioxy)-8,9-(methylenedioxy)-5-(p-nitrobenzenesulfonyl)-
1,1a ,2,3,4,4a ,6-h ep ta h yd r op h en a n th r id in e (15a ). To a so-
lution of epoxide 14a (0.75 g, 1.0 mmol) in CH2Cl2 (50 mL)
was added SnCl4 (1.0 M in CH2Cl2, 0.2 mL). After the reaction
mixture was stirred at 25 °C for 20 min, K2CO3 (1.73 g, 12.5
mmol) was added followed by the addition of a solution of
DMAP (0.11 g, 0.9 mmol), pyridine (7.5 mmol), and acetic
anhydride (0.8 mL, 8.5 mmol) in CH2Cl2. Stirring was contin-
ued for 6 h, and the reaction mixture was diluted with water
(20 mL). The organic layer was washed with dilute HCl and
brine. Concentration and purification by flash chromatography
(silica gel, 17% EtOAc/hexane) to afford 0.77 g (98%) of 15a
21.22, 17.98, 13.85, 13.17, -4.47, -4.92; [R]25 -11.9° (c 1.9,
D
as a white solid: mp 110-111 °C; IR (neat) 3112, 1729 cm-1
;
CHCl3); high-resolution MS (FAB+) m/e calcd for C35H52N2O12
-
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J ) 8.8 Hz, 2 H), 7.96
(d, J ) 8.8 Hz, 2 H), 6.50 (s, 1 H), 5.90 (dd, J ) 4.0, 1.6 Hz, 2
H), 5.03 (dd, J ) 8.4, 6.4 Hz, 1 H), 4.80 (d, J ) 17.2 Hz, 1 H),
4.35 (t, J ) 8.4 Hz, 1 H), 4.27 (dd, J ) 8.4, 6.4 Hz, 1 H), 4.16
(d, J ) 17.2 Hz, 1 H), 4.01-3.93 (m, 2 H), 3.43 (q, J ) 7.2 Hz,
1 H), 3.37 (q, J ) 7.2 Hz, 1 H), 3.05 (t, J ) 6.4 Hz, 1 H), 2.03
(s, 3 H), 1.46 (s, 3 H), 1.26 (t, J ) 7.2 Hz, 3 H), 1.23 (s, 3 H),
1.19 (t, J ) 7.2 Hz, 3 H), 0.81 (s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3
H); 13C NMR (75.5 MHz, CDCl3) δ 169.47, 152.10, 149.88,
148.65, 145.27, 138.30, 130.65, 128.80, 126.52, 123.81, 118.84,
109.78, 105.13, 102.06, 78.18, 74.44, 72.83, 72.18, 52.89, 42.70,
42.20, 40.23, 39.15, 27.45, 25.58, 25.18, 21.30, 17.89, 14.25,
Si 721.3368, found 721.3371. Anal. Calcd for C35H52N2O12Si:
C, 58.31; H, 7.27; N, 3.89. Found: C, 58.38; H, 6.98; N, 3.83.
(2S ,3S ,4R ,4a R )-5-(t -Bu t oxyca r b on yl)-2-((t -b u t yld i-
m et h ylsilyl)oxy)-7-(o-ca r b a m oyloxyp ip er on yl)-3,4-(iso-
p r o p y li d e n e d i o x y )-8,9-(m e t h y le n e d i o x y )-2,3,4,4a -
tetr a h yd r op h en a n th r id on e (18). To a solution of 17 (0.22
g, 0.3 mmol) in benzene (3 mL) was added DBU (0.45 mL, 3
mmol). After being heated at 70 °C for 40 h, the reaction
mixture was cooled, diluted with ether (15 mL), and washed
with aqueous NaHCO3 followed by brine. Drying, solvent
evaporation, and silica gel chromatography (elution with 15%
EtOAc/hexane) gave 0.19 g (96%) of 18 as a white solid: mp
202-203 °C; IR (neat) 1730 (broad), 1674 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.90 (s, 1 H), 6.17 (t, J ) 2.8 Hz, 1 H), 6.05 (d,
J ) 1.2 Hz, 1 H), 6.04 (d, J ) 1.2 Hz, 1 H), 4.76 (dt, J ) 8.0,
2.4 Hz, 1 H), 4.36 (dt, J ) 5.6, 2.4 Hz, 1 H), 4.05 (t, J ) 8.0
13.31, -4.41, -4.90; [R]25 -26.9° (c 2.1, CH2Cl2); high-
D
resolution MS (FAB+) m/e calcd for C36H49N3O13SSi 792.2834,
found 792.2831. Anal. Calcd for C36H49N3O13SSi: C, 54.60; H,
6.24; N, 5.30. Found: C, 54.54; H, 6.42; N, 5.50.
6958 J . Org. Chem., Vol. 67, No. 20, 2002

Short Synthesis of (+)-Narciclasine
Hz, 1 H), 3.96 (dd, J ) 8.0, 6.4 Hz, 1 H), 3.61-3.25 (m, 4 H),
1.51 (s, 9 H), 1.45 (s, 3 H), 1.27 (t, J ) 7.6 Hz, 1 H), 1.26 (s, 3
H), 1.19 (t, J ) 7.2 Hz, 1 H), 0.92 (s, 9 H), 0.13 (s, 3 H), 0.12
(s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 160.10, 153.52, 153.06,
152.53, 141.56, 134.79, 129.72, 128.38, 127.43, 115.14, 111.44,
102.80, 98.88, 83.14, 79.81, 79.76, 73.68, 57.56, 42.20, 41.99,
27.71, 26.91, 25.86, 25.03, 18.19, 13.69, 13.12, -4.50, -5.02;
product was extracted with EtOAc (5 × 15 mL). Drying,
solvent evaporation, and silica gel chromatography (elution
with 15% EtOAc/hexane) gave 0.06 g (65%) of 1 as a white
solid: mp 246 °C dec (lit.2c 216 °C dec; lit.3b 248 °C dec; lit.11a
217-221 °C; lit.11b 250-251 °C dec); 1H NMR (400 MHz,
DMSO-d6) δ 13.25 (s, 1H), 7.90 (s, 1 H), 6.85 (s, 1 H), 6.14 (t,
J ) 2.8 Hz, 1 H), 6.074 and 6.070 (2s, 2 H), 5.26-5.16 (m, 2
H), 5.04 (br s, 1 H), 4.18 (d, J ) 8.4 Hz, 1 H), 4.01 (br s, 1 H),
3.78 (d, J ) 8.0 Hz, 1 H), 3.69 (s, 1 H); 13C NMR (75.5 MHz,
CDCl3) δ 168.97, 152.38, 144.85, 133.46, 132.16, 129.28, 124.78,
105.58, 102.11, 95.86, 72.40, 69.17, 68.85, 52.92; [R]25D +126.5°
(c 0.5, MeOH) [lit.2c +112° (c 0.57, MeOH); lit.3b +141.8°; lit.11a
+142.8° (c 0.7, MeOH); lit.11b +145° (c 1.5, EtOH)].
[R]25 +1.3° (c 3.1, CHCl3); high-resolution MS (FAB+) m/e
D
calcd for C33H48N2O10Si 661.3078, found 661.3083. Anal. Calcd
for C33H48N2O10Si: C, 59.98; H, 7.32; N, 4.24. Found: C, 60.19;
H, 7.18; N, 4.27.
(+)-Na r cicla sin e 1. To a solution of 18 (0.10 g, 0.15 mmol)
in THF was added 60% HCOOH (8 mL) at 25 °C, and the
mixture was heated at 60 °C for 45 min. After solvent
evaporation, the residue was dissolved in dry THF (20 mL)
and a solution of LiAlH4 (1.0 M in THF, 0.75 mL) was
introduced dropwise. After the reaction mixture was stirred
at room temperature for 12 h, the reaction was quenched with
aqueous Na2SO4 solution and acidified with dilute HCl. The
Ack n ow led gm en t. Support from the National Sci-
ence Council of the Republic of China (NSC 90-2113-
M-005-017) is gratefully acknowledged.
J O020155K
J . Org. Chem, Vol. 67, No. 20, 2002 6959