Asymmetric synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from (4s)-4-ethyl-4-[2-(hydroxycarbonyl)ethyl]-2-butyrolactone

Article abstract of DOI:10.1021/jo010751z

The key chiral nonracemic 4,4-disubstituted 2-butyrolactone carboxylic acid, (S)-4, is readily accessible via an efficient and stereospecific dirhodium(II) tetraacetate catalyzed tertiary C-H insertion reaction of the diazomalonate (S)-5. The coupling of the acid (S)-4 with tryptamine produces the amide (S)-3, which is then transformed into the aldehyde 23 and hydroxy-lactam 24. Acid-mediated Pictet-Spengler cyclization of 23 and 24 produces the tetracyclic indole lactams (1S,-12bS)-25a and (1S,12bR)-25b. Compounds 25a and 25b are converted, via the lactam alcohols 30a and 30b, to (-)-eburnamonine (1a) and (+)-epi-eburnamonine (1b).

Full text of DOI:10.1021/jo010751z

J . Org. Chem. 2001, 66, 8935-8943
8935
Asym m etr ic Syn th esis of (-)-Ebu r n a m on in e a n d
(+)-epi-Ebu r n a m on in e fr om
(4S)-4-Eth yl-4-[2-(h yd r oxyca r bon yl)eth yl]-2-bu tyr ola cton e
Andrew G. H. Wee* and Qing Yu
Department of Chemistry and Biochemistry, University of Regina,
Regina, Saskatchewan, S4S 0A2, Canada
Andrew.Wee@uregina.ca
Received J uly 25, 2001
The key chiral nonracemic 4,4-disubstituted 2-butyrolactone carboxylic acid, (S)-4, is readily
accessible via an efficient and stereospecific dirhodium(II) tetraacetate catalyzed tertiary C-H
insertion reaction of the diazomalonate (S)-5. The coupling of the acid (S)-4 with tryptamine produces
the amide (S)-3, which is then transformed into the aldehyde 23 and hydroxy-lactam 24. Acid-
mediated Pictet-Spengler cyclization of 23 and 24 produces the tetracyclic indole lactams (1S,-
12bS)-25a and (1S,12bR)-25b. Compounds 25a and 25b are converted, via the lactam alcohols
30a and 30b, to (-)-eburnamonine (1a ) and (+)-epi-eburnamonine (1b).
In tr od u ction
extensively explored. To our knowledge, only one example
of the use of a 4,4-disubstituted 5-hydroxy-2-butyrolac-
tone for the synthesis of a natural product has been
reported.3 We recently described4 a method, based on the
dirhodium(II)-carbenoid-mediated intramolecular ter-
tiary C-H insertion reaction of â-branched diazoma-
lonates, for the synthesis of 4,4-disubstituted 2-butyro-
lactones. Subsequently, we reported5 the preparation of
an appropriately functionalized 4,4-disubtituted 2-buty-
rolactone and demonstrated its utility as a synthetic
intermediate for the synthesis of quebrachamine. Herein,
we detail6 the results of our studies on the preparation
of the chiral nonracemic 2-butyrolactone carboxylic acid
4 and its use in the enantioselective synthesis of (-)-
eburnamonine (1a ), a peripheral and cerebral vaso-
dilator,7,8a and its C-3 epimer, (+)-epi-eburnamonine (1b).
The strategy adopted here for the synthesis of 1a and
1b is conceptually different from the ones that have been
reported in the recent literature.8 Two principal ap-
proaches have been developed: the first approach utilized
appropriately functionalized ∆1- and ∆2-piperidine deriva-
tives8b(ii),c,d as key intermediates and the second approach
used 3,3-disubstituted 2-butyrolactones.8b(i),e-h
Natural products that feature one or more quaternary
centers in their molecular architecture have always
served as challenging targets to synthetic organic chem-
ists. The strategies devised to tackle the synthesis of
these molecules must invariably also address the con-
struction of the quaternary center(s). Indeed, the con-
struction of quaternary centers has been the topic of
sustained investigations1 over the years, and more re-
cently newer approaches addressing the enantioselective
construction of quaternary centers have emerged.2
We have been interested in the use of 4,4-disubstituted
2-butyrolactones as intermediates in alkaloid synthesis.
Interestingly, a survey of the literature revealed that
neither the synthesis of these molecules nor their use as
intermediates in natural product synthesis has been
(1) Reviews: (a) Corey, E. J .; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388. (b) Fuji, K. Chem. Rev. 1993, 93, 2037. (c) Martin,
S. F. Tetrahedron 1980, 36, 419.
(2) Metal catalyzed methods: (a) Pearson, A. J .; Dorange, I. B. J .
Org. Chem. 2001, 66, 3140. (b) Nakamura, M.; Inoue, T.; Sato, A.;
Nakamura, E. Org. Lett. 2000, 2, 2193. (c) Ashimori, A.; Bachand, B.;
Overman. L. E.; Poon, D. J . J . Am. Chem. Soc. 1998, 120, 6477. Chiral
auxiliary based methods: (d) Christoffers, J .; Mann, A. Angew. Chem.,
Int. Ed. 2000, 39, 2752. (e) Watson, D. J .; Meyers, A. I. Tetrahedron
Lett. 2000, 41, 1519. (f) Yamashita, Y.; Odashima, K.; Koga, K.
Tetrahedron Lett. 1999, 40, 2803. (g) Pigge, F. C.; Fang, S.; Rath, N.
P. Tetrahedron Lett. 1999, 40, 2251. (h) Schwarz, J . B.; Meyers, A. I.
J . Org. Chem. 1998, 63, 1619. (i) Dalko. P. I.; Langlois, Y. Chem.
Commun. 1998, 331. Nucleophilic substitution: (j) Spino. C.; Beaulieu,
C. Angew. Chem., Int. Ed. 2000, 39, 1930. (k) Nishimura, N.; Mit-
sunobu, O. Tetrahedron Lett. 2000, 41, 2945. (l) Evans, P.; Kennedy,
L. J . Org. Lett. 2000, 2, 2213. (m) Ishibashi, N.; Miyazawa, M.;
Miyashita, M. Tetrahedron Lett. 1998, 39, 3775. Rearrangement
reactions: (n) Nishimura, N.; Mitsunobu, O. Tetrahedron Lett. 2000,
41, 2945. (o) Evans, P.; Kennedy, L. J . Org. Lett. 2000, 2, 2213. (p)
Ishibashi, N.; Miyazawa, M.; Miyashita, M. Tetrahedron Lett. 1998,
39, 3775. Cycloaddition: (q) Winkler, J . D.; Doherty, E. M. Tetrahedron
Lett. 1998, 39, 2253. (r) Roush, W. R.; Barda, D. A. J . Am. Chem. Soc.
1997, 119, 7402. (s) McN Seiburth, S.; Siegel, B. J . Chem. Soc., Chem.
Commun. 1996, 2244. Enzymic methods: (t) Fadel, A.; Arzel, P.
Tetrahedron: Asymmetry 1997, 8, 283. (u) Shutani, S.; Okada, H.;
Nakameta, K.; Yamamoto, T.; Sekino, F. Heterocycles 1996, 43, 1031.
Carbene-based: (v) Kosuka, T.; Bando, T.; Shishido, K. Chem. Com-
mun. 1997, 1167. (w) Temme, O.; Taj, S.-A.; Andersson, P. G. J . Org.
Chem. 1998, 63, 6007. Other (racemic): (x) Ghosh, A. K.; Kawahama,
R.; Wink, D. Tetrahedron Lett. 2000, 41, 8425.
(3) Wenkert, E.; Halls, T. D. J .; Kwart, L. D.; Magnosson, G.;
Showalter, H. D. H. Tetrahedron 1981, 37, 4017.
(4) Wee, A. G. H.; Yu, Q. J . Org. Chem. 1997, 62, 3324.
(5) Wee, A. G. H.; Yu, Q. Tetrahedron 1998, 54, 13435.
(6) Preliminary communication: Wee, A. G. H.; Yu, Q. Tetrahedron
Lett. 2000, 41, 587.
(7) (a) Merck Index, 11th ed.; Budavari, S., Ed.; Merck and Co.:
Rahway, NJ , 1989; no. 3464. (b) Czibula, L.; Nemes, A.; Visky, G.;
Farkas, M.; Szombathelyi, Z.; Karpati, E.; Sohar, P.; Kessel, M.; Kreidl,
J . Liebigs Ann. Chem. 1993, 221.
(8) (a) Review: Lounasmaa, M.; Tolvanen, A. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1992; Vol. 42, p 1. (b)
For a comprehensive listing of references to early synthesis, see: (i)
Node, M.; Nagasawa, H.; Fuji, K. J . Org. Chem. 1990, 55, 517. (ii)
Kaufman, M. D.; Grieco, P. A. J . Org. Chem. 1994, 59, 7197. (c) Greiner,
P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. 1990, 55, 3068.
(d) Wenkert, E.; Hudlicky, T. J . Org. Chem. 1988, 53, 1953. (e) Schultz,
A.; Pettus, L. J . Org. Chem. 1997, 62, 6855. (f) Meyers, A. I.; Romine,
J .; Robichaud, A. J . Heterocycles 1990, 30, 339. (g) Ihara, M.; Yasui,
K.; Taniguchi, N.; Fukumoto, K. Heterocycles 1990, 31, 1017. (h)
Takano, S.; Yonaga, M.; Morimoto, M.; Ogasawara, K. J . Chem. Soc.,
Perkin Trans. 1 1985, 305. (i) Ghosh, A. K.; Kawahama, R. J . Org.
Chem. 2000, 65, 5433.
10.1021/jo010751z CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/30/2001

8936 J . Org. Chem., Vol. 66, No. 26, 2001
Wee and Yu
Ch a r t 1. Retr osyn th etic An a lysis of
Sch em e 1a
Ebu r n a m on in e (1a ) a n d epi-Ebu r n a m on in e (1b)
The retrosynthetic analysis for the pentacyclic indole
alkaloids eburnamonine (1a ) and epi-eburnamonine (1b)
is shown in Chart 1. These compounds differ only in the
stereochemistry at the D/E ring junction. Therefore, both
of these compounds can be accessed from a common
precursor; that is, the hydroxy-lactam aldehyde 2. Com-
pound 2 can be derived from the 2-butyrolactone amide
3, which in turn, is accessible from the chiral nonracemic
2-butyrolactone carboxylic acid 4. Compound 4 is pre-
pared via Rh(II)-catalyzed tertiary C-H insertion reac-
tion of the chiral nonracemic diazo compound 5.
a
(i) Bu2BOTf, Et3N, CH2Cl2, 0 °C; MeCHO, -78 °C, 52%; (ii)
PhOC(dS)Cl, DMAP, CH2Cl2, 92%; (iii) Bu3SnH, AIBN, PhMe, 75
°C, 76%; (iv) NaN(SiMe3)2, THF, -78 °C; CH2dCHCH2Br, -40
°C, 88%; (v) LiOH‚H2O, H2O2, 3:1 v/v THF-H2O; 1.5 M NaHSO3,
100%; (vi) LiAlH4, Et2O, 0 °C to room temperature; aq NaOH, 50%;
(vii) MeO2CCH2CO2H, DCC, DMAP, CH2Cl2, 86%; (viii) di-
siamylborane, THF, 0 °C; 30% H2O2, NaOH, 74%; (ix) TBDPS-
Cl, pyridine, 0 °C, 89%; (x) MsN3, Et3N, MeCN, 88%.
Resu lts a n d Discu ssion
P r ep a r a tion of (S)-Dia zom a lon a te (5). The study
began with the synthesis of (S)-2-ethyl-4-penten-1-ol (11),
which was required for the preparation of the malonate
ester 12 (Scheme 1). Two routes, a and b, for the
synthesis of 11 were investigated. The first route (a)
entailed an asymmetric aldol reaction coupled with the
removal of the hydroxyl group in the aldol product to
complete the installation of the ethyl side-chain. Thus,
aldol reaction of the readily prepared N-(4-pentenoyl)-
oxazolidinone (6a ),9 via its dibutylboron enolate,10 with
freshly distilled acetaldehyde gave the aldol product 7.
Compound 7 was obtained as a mixture of two very
closely moving stereoisomers that were epimeric only at
the carbinol center. No attempt was made to separate
the two diastereomers because the carbinol center was
inconsequential to the synthesis of 9 since the hydroxyl
group in 7 will be deoxygenated11 in the next step. The
secondary alcohol 7 was then converted to the phenyl
thionocarbonate12 8, which was then subjected to free-
radical reduction using Bu3SnH to yield compound 9. The
overall yield for this three-step sequence to form 9 was
36%. It is interesting to note that under the free-radical
conditions used for the conversion 8 f 9, the intramo-
lecular cyclization of the secondary carbon-centered free
radical onto the terminal double bond to form a cyclobu-
tane derivative was not detected, although the process
corresponded to a favored 4-exo-trig cyclization.13 The
absence of such a competing cyclization reaction may be
due to the well-known14 propensity of a (cyclobutyl)-
methyl free radical-type intermediate to undergo rapid
ring opening to form the more stable 1-pentenyl system.
Although route a provided access to alcohol 11, the low
overall yield of 9 prompted us to investigate route b. This
route afforded a higher yield of 9, which also turned out
to be the more direct and preferred route. Therefore,
allylation of the sodium enolate10 derivative of the
known15 N-butanoyloxazolidinone 6b with allyl bromide
produced the allylated oxazolidinone 9 in 88% yield. The
1H and 13C NMR spectra as well as the specific optical
rotations of compound 9 obtained via routes a and b were
the same.
The removal of the oxazolidinone chiral auxiliary from
9 was not trivial. We found that the usual methods for
the removal of the auxiliary group, such as by reduction
with lithium aluminum hydride15 (LiAlH4), led to a
mixture of the desired alcohol 11 (and the chiral auxil-
(13) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(14) (a) Review: Beckwith, A. L. J . Tetrahedron 1981, 37, 3073. (b)
Ingold, K. U.; Maillard, B.; Walton, J . C. J . Chem. Soc., Perkin Trans
2 1981, 970 and references cited.
(15) Evans, D. A.; Polniaszek, R. P.; Devries, K. M.; Guinn, D. E.;
Mathre, D. J . J . Am. Chem. Soc. 1991, 113, 7613.
(9) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J . Am. Chem. Soc.
1985, 107, 4368.
(10) Review: Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(11) Review: Hartwig, W. Tetrahedron 1983, 39, 2609.
(12) Robins, M. J .; Wilson, J . S. J . Am. Chem. Soc. 1981, 103, 932.

Asymmetric Synthesis of (-)-Eburnamonine
J . Org. Chem., Vol. 66, No. 26, 2001 8937
Sch em e 2a
iary), the carbinol 15, and the N-methyl amino alcohol
16. The relative proportion of 11:15:16 was, not surpris-
ingly, found to depend on the reaction temperature. For
example, compound 15 was obtained as the major byprod-
uct when the reduction was conducted at -78 °C,
whereas at -5 °C both 15 and 16 were formed. These
results suggested that the oxazolidinone carbonyl moiety
in compound 9 was sterically more accessible than the
carbonyl moiety of the 4-pentenoyl unit; presumably the
ethyl group at the R-tertiary carbon shielded the carbonyl
moiety of the pentenoyl unit from attack by the LiAlH4
reagent.
Due to the difficulties encountered in the optimization
of reaction conditions for the direct removal of the
oxazolidinone auxiliary, we decided to adopt a two-step
procedure for the conversion of 9 to the primary alcohol
11 (Scheme 1). This entailed the hydrolysis of 9 under
Evans conditions (LiOH, H2O2)16 which led to a quantita-
tive yield of the carboxylic acid 10. The chiral (4R,5S)-
4-methyl-5-phenyl-2-oxazolidinone auxiliary was recov-
ered in 95% yield. Subsequent reduction of 10 with
LiAlH4 in diethyl ether gave a 50% yield of the volatile
primary alcohol 11.
The absolute configuration of 11 was confirmed via its
conversion to the 4-methoxybenzyl ether derivative 17
and comparison of the specific optical rotation of 17 with
that of the known17a dextrorotatory (R)-enantiomer.
Compound 17 {[R]D -2.8 (c, 1.8, CHCl3), 89% ee17b} was
levorotaory and possessed an optical rotation that was
of the same magnitude as the R-enantiomer {[R]D +1.9
(c, 2.01, CHCl3)}.
a
(i) 2 mol % Rh2(OAc)4, CH2Cl2, reflux, 87%; (ii) 10:1 v/v
DMSO-H2O, NaCl, 110 °C, 84%; (iii) Bu4NF, THF, 93%; (iv) CrO3,
H2SO4, H2O, 95%; (v) tryptamine (Tryp), DCC, DMAP, CH2Cl2,
67%; (vi) LiBH4, 5:1 v/v THF-MeOH, rt, 92%; (vii) TBDPS-Cl,
imidazole, DMF, 92%; (viii) Py‚SO3, DMSO, Et3N, rt, 95%; (ix)
CF3CO2H, CH2Cl2, -42 °C (see text also), 95%.
With the primary alcohol in hand, the next stage was
to prepare the diazomalonate 5. Esterification of 11 with
R-(methoxycarbonyl)acetic acid mediated by DCC18 pro-
duced the malonate ester 12 in 86% yield. Hydrobora-
tion-oxidation of the terminal double bond using di-
siamylborane19 followed by alkaline hydrogen peroxide
proceeded regioselectively and chemoselectively to fur-
nish a good yield (81%) of the primary alcohol 13. After
protection of the hydroxyl group as the tert-butyldiphe-
nylsilyl (TBDPS) ether, 14, the malonyl unit was diazo-
tized (MsN3,20 Et3N) to obtain the diazomalonate 5.
treated with 2 mol % of Rh2(OAc)4, which proceeded
efficiently and with high regioselectivity to provide a 1:1
diastereomeric mixture of the 4,4-disubstituted 2-buty-
rolactone 18 in 87% yield (Scheme 2). A small amount
(8.5%) of the 2-oxetanone product,5 which was produced
via a competitive Rh(II)-carbenoid insertion into the
C-H bond adjacent to the ester oxygen, was also isolated.
Trace amounts (0.9%) of products derived from the
interception of the Rh(II)-carbenoid intermediate by
water5 was also obtained. Subsequent decarboxylation22
of 18 in aqueous DMSO containing NaCl proceeded
smoothly to give the 2-butyrolactone 19 in 84%. The
fluoride anion mediated desilylation of 19 proceeded
efficiently to yield the primary alcohol 20, which was
subjected to J ones oxidation to give the carboxylic acid 4
in 95% yield.
The carboxylic acid 4 was then coupled to tryptamine
(Tryp), mediated by DCC,18 to give the amide 3. The next
step required the adjustment of the oxidation level at the
C-2 and C-5 positions of the 2-butyrolactone moiety in
3, and this was best achieved via the corresponding diol
21. We first investigated a two-step reduction protocol:
the lactone moiety was first treated with DIBAL-H to
P r ep a r a tion of (S)-γ-La cton e Ca r boxylic Acid (4)
a n d Con str u ction of th e Tetr a cyclic In d ole La cta m
(25). In our earlier work, we found5 that Rh2(OAc)4 was
the best catalyst for effecting tertiary C-H insertion in
malonate esters. Furthermore, dirhodium(II)-carbenoid
insertion into configurationally defined tertiary carbon
stereocenters has been found to be stereospecific and to
occur with retention of configuration.21 With these facts
in mind, we were confident that the transformation 5 f
18 could be realized. Therefore, the diazomalonate 5 was
(16) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(17) (a) Evans, D. A.; Reiger, D. L.; J ones, T. K.; Kaldor, S. W. J .
Am. Chem. Soc. 1990, 55, 6260. (b) The enantioselectivity of the
reaction was determined by conversion of the primary alcohol 13 to
the corresponding primary benzoate (PhC(O)Cl, cat. DMAP, pyridine).
HPLC analysis using a Chiralcel OD column (1.2 mL/min, 97:3
hexane: 2-propanol, λ ) 254 nm, see Supporting Information) gave
an ee of 89%.
(18) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522.
(19) Brown, H. C.; Kulkarni, S. U.; Rao, C. G.; Patil, V. Tetrahedron
1986, 42, 5515.
(21) (a) Taber, D. F.; Petty, E. H.; Raman, K. J . Am. Chem. Soc.
1985, 107, 196. (b) Stereospecific insertion with retention of configu-
ration has also been found for copper-carbenoid tertiary C-H insertion
reaction: see, Ledon, H.; Linstrumelle, G.; J ulia, S. Tetrahedron Lett.
1973, 25. (c) The stereochemistry of the newly formed quaternary
centre in 19 was confirmed by its transformation to the known lactam
alcohols 30a and 30b.
(20) Taber, D. F.; Ruckle, R. E., J r.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077.
(22) Review: Krapcho, A. P. Synthesis 1982, 805 and 893.

8938 J . Org. Chem., Vol. 66, No. 26, 2001
Wee and Yu
obtain the lactol intermediate, which was further reduced
with NaBH4 to produce the diol 21. This route, however,
was found to be inefficient, and only a 36% yield (over
two steps) of the 21 was obtained. After further investi-
gations, it was found that the reduction of 3 using excess
LiBH4 in THF-MeOH8e led to an excellent yield (92%)
of the diol 21.
rate of oxidation (reaction time was 22 h), but the yield
of the aldehyde 23 was increased to around 43% and no
starting alcohol 22 was detected. Also, under these mild
oxidation conditions, we were surprised to obtain the
unusable glutarimide 26 (14%), which was formed from
further oxidation of the hydroxy-lactam 24. Although the
yield of 23 was slightly improved, it was deemed unac-
ceptable in the context of our projected synthesis of the
vinca alkaloids 1a and 1b.
Therefore the oxidation of 22 using pyridine-SO3 (Py‚
SO3) complex in DMSO25 was investigated. We were
pleased to find that when alcohol 22 was treated with
Py‚SO3 (7 equiv) in DMSO containing Et3N,25a the alde-
hyde 23 and the hydroxy-lactam 24 were formed in a
combined yield of 95%, and in a ratio of 1:1.7. The
glutarimide 26 was not produced under these conditions.
The 1H NMR spectrum of the hydroxy-lactam 24
revealed that it was a 1:1 mixture of C-6 epimers. This
ratio was based on the integration of the H-6 doublets
centered at δ 4.37 and δ 4.72, respectively.
The differentiation of the two primary alcohol units in
21 was addressed. We were certain that the regioselective
protection of the less-hindered nonneopentylic primary
alcohol could be readily achieved. However, this operation
proved not to be trivial. We initially explored the selective
formation of the mono-benzoate and mono-tert-butyldim-
ethylsilyl ether, under various reaction conditions. For
example, when the diol 21 was treated with 1 mol equiv
of benzoyl chloride in dry pyridine no benzoate (mono
and/or di) product was obtained. Interestingly, when the
benzoylation was conducted in the presence of a catalytic
amount (10 mol %) of N,N-diisopropylethylamine (Hunig’s
base) and using a mixture of pyridine and chloroform (1:5
v/v) as solvent, equal amounts of the mono- (21 R1 ) Bz,
R2 ) H) and dibenzoates (21 R1 ) R2 ) Bz) were obtained,
and a very small amount (<2%) of starting diol 21 was
also recovered. To achieve efficient monoprotection of 21
and to obtain a good yield of the desired monoprotected
product, we investigated the reaction of 21 with the
bulkier tert-butyldimethylsilyl chloride. However, under
the improved reaction conditions (pyridine/CHCl3, cata-
lytic amounts of Hunig’s base) alluded to above, no
silylation occurred, and only unreacted diol 21 was
recovered. On the other hand, silylation of the diol 21 in
a mixture of imidazole and DMF23 afforded a 1.7:1 ratio
of the mono- (21, R1 ) TBDMS, R2 ) H) to bis- (21, R1 )
R2 ) TBDMS) silyl ethers. It was eventually found that
the best method consisted of the use of the sterically more
demanding TBDPS-chloride in imidazole/DMF;23 under
these conditions the mono-silyl ether 22 was obtained as
the predominant product (mono:bis; 14:1) and in a high
yield of 93%. It is useful to note that no silyl ether product
was formed when the silylation was conducted in either
pyridine or pyridine/CHCl3 containing a catalytic amount
of Hunig’s base.
With the hydroxyl groups differentiated, the oxidation
of the neopentylic primary alcohol moiety in 22 to the
aldehyde 23 was investigated. Several oxidation methods
were considered, and on the basis of literature reports8e,24
on the mildness of the tetrapropylammonium perruth-
enate (TPAP)-catalyzed oxidation reaction conditions
toward the indole nucleus, we treated the alcohol 22 with
5 mol % of TPAP in the presence of N-methylmorpholine
N-oxide (NMMO, 1.5 mol equiv; powdered 4A molecular
sieves). The oxidation reaction was slow and after 24 h
was incomplete as judged by TLC; the desired aldehyde
23 was obtained in only 34% yield and starting alcohol
22 (14%) was recovered.
Ley and co-workers have reported24 that the TPAP
oxidations can be accelerated by the use of acetonitrile
as cosolvent. Employing the same initial conditions (5 mol
% TPAP, 1.5 equiv of NMMO) as before, the alcohol 22
was oxidized in a mixture of CH2Cl2 and acetonitrile (10:1
v/v). There was, however, no enhancement in the overall
The stage was set for the Pictet-Spengler26 cyclization
of the aldehyde 23 and hydroxy-lactam 24 to form the
tetracyclic compounds 25. In preliminary studies, we
have found that the cyclization of the pure hydroxy-
lactam 24 under thermal conditions (toluene, 110 °C)
gave a modest 56% yield of the tetracycles 25. On the
other hand, the cyclization of the pure aldehyde 23 under
the same conditions did not afford the products 25. These
initial results indicated that the cyclization proceeded via
the more reactive hydroxy lactam 24. Thus, for the
efficient conversion of the mixture of the aldehyde 23 and
hydroxy-lactam 24 to 25, it was reasoned that the use of
an acidic medium would be beneficial because it would
favor formation of the acyl iminium intermediate from
the hydroxy-lactam 24 as well as promote the ring-chain
tautomerism of the aldehyde 23 in favor of the hydroxy-
lactam 24.
This line of reasoning was confirmed by the smooth
cyclization of the mixture of 23 and 24 in refluxing glacial
acetic acid8b to give a diastereomeric mixture of two
tetracyclic indoles 25a and 25b, which were readily
separated by chromatography. The ratio of 25a :25b,
based on isolated yields, was 1:2.
In an effort to delineate cyclization reaction conditions
that would favor the formation of more of the R-epimer
25a , we examined the Pictet-Spengler cyclization of the
mixture of 23 and 24 under two other acidic conditions.
The first employed Nafion-H27 (50 mol %), as a hetero-
geneous acid catalyst, in refluxing toluene. This also
yielded a 1:2 ratio of 25a and 25b. The second set of
conditions we examined was modeled after the cyclization
conditions developed by Schultz and Pettus.8e This en-
tailed conducting the cyclization in a mixture of trifluo-
roacetic acid (5 equiv) in dichloromethane at -42 °C.
This, however, led to a 1:3 ratio of the tetracyclic indoles
25a and 25b.
Further efforts to acquire more of the R-epimer 25a
led us to investigate the feasibilty of the BF3-mediated
equilibration of the â-epimer 25b. We were encouraged
by the work of Fuji and co-workers who demonstrated8b(i)
(25) (a) Parikh, J . R.; Doering, W. E. J . Am. Chem. Soc. 1967, 89,
5507. (b) Review on DMSO mediated reactions: Tidwell, T. T. Org.
React. 1990, 39, 297.
(26) (a) Review: Cox, E. D.; Cook, J . M. Chem. Rev. 1995, 95, 1797.
(b) Yu, P.; Cook, J . M. J . Org. Chem. 1998, 63, 9160 and references
therein.
(23) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(24) (a) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639. (b) Griffith, W. P.; Ley, S. P. Aldrichchimica Acta
1990, 23, 13.

Asymmetric Synthesis of (-)-Eburnamonine
J . Org. Chem., Vol. 66, No. 26, 2001 8939
Sch em e 3a
ascribed to π-π interaction between the C-1 â-vinyl
substituent and the indole moiety of the acyl iminium
ion intermediate. This, in turn, helped to deliver the
indole unit to the â-face of the iminium unit. Returning
to the formation of 25a and 25b, the diastereoselectivity
of the cyclization can be understood if the key bond
formation step in the presumed acyl iminium ion inter-
mediate involved the more stable reactive conformer 29B.
a
(i) Me3SiCl, MeOH, 0 °C: 30a (96%), 30b (97%); (ii) LiAlH4,
THF, 20 min, reflux: 31a (30%), 31b (84%); (iii) For 1a : Py‚SO3,
DMSO, Et3N, rt; then TPAP, NMMO, CH2Cl2, 4A MS, 33%; For
1b: TPAP, NMMO, CH2Cl2, 4A MS, 55%.
that the treatment of the pure alcohol 30b (see Scheme
3) with of BF3 etherate at 35-40 °C for 10 h yielded a
1:1 equilibrium ratio of 30a :30b. With compound 25b, it
was reasoned that under Fuji’s reaction conditions fluo-
ride anion-mediated desilylation (25b f 30b) as well as
epimerization of the C-12b stereocenter could be effected
in one operation. However, it should be noted that we do
not know the exact order by which these two processes
occur. Thus, when a solution of pure â-epimer 25b in neat
BF3‚etherate was heated at 40 °C for 10 h a 91% yield of
the mixture of 30a and 30b was obtained. Disappoint-
ingly, the ratio of 30a :30b was found to be 1:4. Prolonged
heating28 did not result in any increase in the amount of
the R-epimer 30a .
The preference for the formation of the â-epimer 25b
over the R-epimer 25a was intriguing. Literature reports
on similar Pictet-Spengler cyclization reactions indicated
that the cyclization normally resulted in the formation
of the C-12b R and â epimers in almost equal amounts
(ratio of R:â ) 1∼1.3:1).8b(i),29a The absence of diastereo-
control during the cyclization was attributed to a lack of
stereochemical differentiation of the π-face of the imi-
nium moiety because of the similar steric size of the C-1
geminal substituents. Recent studies,8e,29b however, have
also suggested that the nature of the geminal substitu-
ents at the quaternary carbon center adjacent to the
carbocation site may play a subtle but important role in
governing the diastereoselectivity of the reaction. For
example, Schultz and Pettus8e reported that the Pictet-
Spengler cyclization of the aldehyde 27 (eq 1) proceeded
with high diastereoselectivity to give an 18:1 ratio of 28a :
28b . The high diastereoselectivity of the reaction was
Conformer 29A is less preferred because it is destabilized
by an unfavorable A1,2 interaction30 between the pseu-
doequatorial, bulky tert-butyldiphenylsilyloxyethyl group
and the iminium C-H unit. Approach of the indole
moiety to the conformer 29B would occur from the less-
hindered Si-face of the iminium moiety leading to the
formation of 25b. The composite results from the acid-
mediated cyclization reaction of 23/24 and from the BF3-
mediated equilibration reaction of 25b are in accord with
this line of reasoning. That is, product 25b was a
kinetically and thermodynamically favored product under
the reaction conditions studied.
The structure of each of the diastereomers 25a and 25b
1
were fully characterized by H and 13C NMR spectros-
copy, including COSY-45, HETCOR, and HMQC. The
characteristic 1H and 13C resonances for the 25a and 25b
are collected in Table 1.
1
In the H NMR spectra, it was found that the H-12b,
NH, and the C-2′ methylene hydrogens in the silyloxy-
ethyl moiety in 25a are shielded relative to those in 25b,
with the exception of the C-3 methylene hydrogens (2H-
3). The latter set of hydrogens resonated at lower field
in 25a compared to the same set in 25b.
Interestingly, the 13C NMR spectra of 25a and 25b
showed that there was no significant difference in the
chemical shifts of the C-3 and C-12b resonances between
25a and 25b. However, the C-2′ signal in the silyloxy-
ethyl moiety and the C-1 quaternary carbon resonance
in 25a appeared at lower chemical shifts (shielded) when
compared to the C-2′ and C-1 signals in the 25b.
The structure of compound 25a 31a was confirmed by
its conversion to the primary alcohol 30a (vide infra), and
(27) Registered trademark of Dupont Co. (a) Review: Olah, G. A.;
Iyer, P. S.; Prakash, G. S. K. Synthesis 1986, 573. (b) Wee, A. G. H.;
Liu, B.-S. Tetrahedron 1994, 50, 609.
(28) We found that on extended heating, a small amount of an
unidentified polar compound was beginning to form as shown by TLC
analysis.
(29) (a) Wenkert, E.; Hudlicky, T. J . Org. Chem. 1988, 53, 1953. (b)
See also ref 8c. This study reported that the cyclization gave a 5.7:1
ratio of the C-12b â-epimer:R-epimer. The steric size of the CO2Et group
is relatively smaller than the ethyl group (A values are -1.1∼1.2 kcal/
mol and -1.75 kcal/mol, respectively; see Smith, M. B.; March, J .
Advanced Organic Chemistry, 5th ed.; Wiley-Interscience: New York,
2001; p 174). It is concievable that the â-CO2Et at the quaternary
carbon center might be involved in the stabilization of the carbocation
center via interaction of one of the lone-pairs of electrons on the ester
carbonyl oxygen with the vacant p-orbital of the carbocation. This
would result in the shielding of the â-face of the iminium moiety.
1
comparison of its H NMR spectrum with that reported
in the literature.8e The syn relative stereochemistry of
the silyoxyethyl substituent at the quaternary center (C-
1) and the C-12b hydrogen in compound 25b was
ascertained by NOE measurements.31b
(30) J ohnson, F. Chem. Rev. 1968, 68, 375.

8940 J . Org. Chem., Vol. 66, No. 26, 2001
Wee and Yu
Ta ble 1. Selected 1H a n d 13C Reson a n ces for 25a
a n d 25b
reospecific Rh(II)-carbenoid-mediated tertiary C-H in-
sertion reaction with retention of configuration, from the
diazo compound 5. Conversion of 19 to the carboxylic acid
4 followed by coupling with tryptamine gave 3. Readjust-
ment of the oxidation level of the C-2 and C-5 carbons of
the lactone moiety in 3 led to the aldehyde 23/hydroxy-
lactam 24. Acyl iminium-based Pictet-Spengler cycliza-
tion of 23/24 gave the tetracylic indoles 25a and 25b,
which served as advanced intermediates for the total
synthesis of the alkaloids (-)-eburnamonine (1a ) and (+)-
epi-eburnamonine (1b), respectively, as well as for the
formal synthesis of (-)-aspidospermidine 32. Further
studies on the use of 4,4-disubstituted 2-butyrolactones
in natural product synthesis is in progress.
1H
25a
25b
13C
25a 25b
2H-3
m, 2.43-2.55 m, 2.38-2.49 C-3
29.1 29.1
60.9 60.9
H-12b
CH2CH2OSi “t”, 3.59
NH s, 7.82
s, 4.75 s, 5.18 C-12b
m, 3.90-4.06 CH2CH2OSi 59.8 60.5
s, 9.38 C-1 38.9 39.3
Assem bly of Ebu r n a m on in e (1a ) a n d epi-Ebu r -
n a m on in e (1b). Each of the two epimers 25a and 25b
served as the key intermediate in the synthesis of the
vinca alkaloids (-)-eburnamonine (1a ) and (+)-epi-ebur-
namonine (1b), respectively. The synthesis of 1b, as
shown in Scheme 3, was first investigated.
The TBDPS protecting group in 25b was removed
using methanol-Me3SiCl to afford the known8b(i) lactam
alcohol 30b in high yield. The reduction of 30b using
LiAlH4 to the amino alcohol 31b was not straightforward.
In previous studies5 we have found that such reductions
required a reaction time of at least 15 h. However, the
use of the same reaction time (15 h) for this reduction
step (30b f 31b) was found to be detrimental to the yield
of the desired product; only 40% of the known8b(i) amino
alcohol 31b was obtained, and no starting 30b was
recovered. After careful monitoring (TLC) of the reduction
reaction, we were pleased to find that when the reaction
time was shortened to 20 min, an 84% yield of 31b was
realized. Subsequent oxidation of 31b using TPAP/
NMMO8e gave a 55% yield of (+)-epi-eburnamonine (1b),
whose spectral data and optical rotation were in accord
with published data.7b
For the synthesis of (-)-eburnamonine (1a ) (Scheme
3), the silyl ether 25a was desilylated (methanolic-Me3-
SiCl) to give the lactam alcohol8b(i),e 30a . The lactam
carbonyl in 30a was treated briefly (30 min) with LiAlH4
to afford a modest yield (30%) of 31a .8b(i),e No starting
material was recovered. It is not clear to us at this time
why there is a marked decrease in the efficiency of the
LiAlH4 reduction of 30a compared to 30b.
Exp er im en ta l Section
Melting points are uncorrected and were measured on a
Kofler hot-stage melting point apparatus. Only diagnostic
absorptions in the infrared spectrum are reported. 1H (200
MHz) and 13C (50.3 MHz) NMR spectra were recorded in
CDCl3, unless otherwise stated. Tetramethylsilane (δH ) 0.00)
and the CDCl3 resonance (δC ) 77.0) were used as references.
Proton assignments were made using double irradiation
experiments and confirmed, where necessary, by COSY-45
experiments. 13C assignments were made using DEPT-135,
HETCOR, and HMQC experiments. Elemental analyses and
high-resolution mass spectral analysis (EI, 70 eV) and chemi-
cal ionization mass spectral analyses were performed at the
Chemistry Department, University of Saskatchewan, Canada.
Tetrahydrofuran and diethyl ether were dried by distillation
from sodium/benzophenone ketyl. Dichloromethane and tri-
ethylamine were dried by distillation from CaH2. Flash chro-
matography32 was used for the purification of reaction prod-
ucts. All air and moisture sensitive reactions were conducted
under a static pressure of argon, and reaction progress was
monitored by thin-layer chromatography on Merck silica gel
60F254 precoated (0.25 mm) on aluminum backed sheets.
Dirhodium(II) tetraacetate and Nafion-H were purchased from
Strem Chemicals Inc., MA, and Aldrich Chemical Co., WI,
respectively.
(2S)-[5-(ter t-Bu t yld ip h en ylsilyloxy)-2-et h ylp en t yl]-r-
d ia zo-r-(m eth oxyca r bon yl)a ceta te (5). Compound (S)-14
(4.3 g, 9.1 mmol) was dissolved in dry MeCN (30 mL), and the
solution was cooled to 0 °C. Mesyl azide (1.3 mL, 14 mmol)
was added followed by dry Et3N (2.5 mL, 18 mmol). The
mixture was stirred at 0 °C for 30 min and then at room
temperature for 10 h. The mixture was diluted with CH2Cl2
and washed with 10% aqueous NaOH and water. The aqueous
layer was reextracted with more CH2Cl2. The combined organic
layers were dried, filtered, and evaporated. Chromatographic
purification (7:1 and then 2:1 v/v PE: Et2O) of the crude
product gave 5.9 g (88%) of the diazo product 5 as a viscous
oil. [R]D +3.3 (c 1.5, CHCl3). IR υmax (neat): 2135, 1761, 1737,
Next, the amino alcohol 31a was oxidized with Py‚SO3/
DMSO/Et3N24a to obtain the corresponding aldehyde
which, without further purification, was subjected to
further oxidation using TPAP/NMMO8e to afford a 33%
yield of (-)-eburnamonine (1a ). The 1H and 13C NMR
data as well as specific optical rotation of 1a were in
accord with the published data.8b(i),e
In view of the fact that both 30a and 30b have been
converted to (-)-aspidospermidine (32),8b(i),e the present
work also constitutes a formal synthesis of this alkaloid.
1
1695 cm-1. H NMR: δ 0.89 (t, 3H, J ) 7.2 Hz), 1.05 (s, 9H),
Con clu sion s
1.27-1.70 (m, 7H), 3.64 (t, 2H, J ) 6.0 Hz), 3.83 (s, 3H), 4.15
(d, 2H, J ) 5.8 Hz), 7.30-7.40 (m, 6H), 7.60-7.75 (m, 4H).
13C NMR: δ 10.9, 19.2, 23.6, 26.7, 26.8, 29.6, 38.6, 52.5, 63.9,
67.7, 127.6, 129.5, 133.9, 135.5, 160.9, 161.6. Anal. Calcd for
A new approach toward the enantioselective synthesis
of vinca alkaloids as exemplified by eburnamonine and
epi-eburnamonine is presented. The approach featured
the use of a chiral nonracemic 4,4-disubstituted 2-buty-
rolactone 19, which was readily prepared, via a ste-
C
27H36N2O5Si: C, 65.29; H,7.31; N, 5.64. Found: C, 65.34; H,
7.29; N, 5.54.
(4S)-4-[3-(ter t-Bu tyld ip h en ylsilyloxyp r op yl)-4-eth yl-3-
(m eth oxyca r bon yl)d ih yd r o-2(3H)-fu r a n on e(18).Thethree-
necked round-bottom flask was fitted with a reflux condenser
and a pressure-equalizing addition funnel. The whole ap-
paratus was flame dried under a stream of Ar before use. Rh2-
(OAc)4 (0.105 g, 0.24 mmol) was placed in the reaction flask,
and dry CH2Cl2 (400 mL) was added, under Ar. The suspension
was heated to reflux. A solution of the diazo compound 5 (5.92
g, 12 mmol) in dry CH2Cl2 (400 mL) was added dropwise over
(31) (a) NOE measurements were not done for compound 25a
because a solution of 25a in CDCl3 was found to have decomposed upon
extended storage. We do not know the exact length of time of storage
because the experiments were conducted at the Prairie Regional NMR
center in Winnipeg, Manitoba. We have, however, observed that a clear
solution of 25a in CDCl3 turned light brown when left standing on
the bench overnight (∼18 h). TLC analysis of the solution showed that
a polar material, which does not correspond to the primary alcohol
30a , was formed. No further attempts were made to characterize this
unknown material. (b) See Supporting Information, Figure S1, for
details.
(32) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Asymmetric Synthesis of (-)-Eburnamonine
J . Org. Chem., Vol. 66, No. 26, 2001 8941
a period of 6 h. After addition was complete, the reaction
mixture was refluxed for an additional 14 h, then cooled to
room temperature, and the mixture was filtered through a
Celite pad. The filtrate was evaporated, and the crude mixture
was purified by chromatography (2:1 v/v PE-Et2O) to yield
the desired oily γ-lactone 18 (4.90 g, 87%), two diastereomeric
â-lactones (0.48 g, 8.5%), and some water insertion products
(0.048 g, 0.8%). γ-Lactone 18: obtained as a 1:1 mixture of
diastereomers based on the integration of the ester methoxy
temperature. The precipitate was removed by filtration, and
the residue was washed with CH2Cl2. The filtrate was washed
with 5% HCl, water, saturated NaHCO3, and brine, dried, and
concentrated. Chromatographic purification (1:1 and 1:2 v/v
PE:EtOAc) of the crude oil yielded the amide 3 (0.090 g, 67%
yield). [R]24 -2.9 (c 0.9, CHCl3) IR υmax (neat): 3314, 1770,
D
1
1650 cm-1. H NMR: δ 0.83 (t, 3H, J ) 7.7 Hz), 1.40 (q, 2H,
J ) 7.7 Hz), 1.67-1.78 (m, 2H), 1.93-2.05 (m, 2H), 2.20 (s,
2H), 2.94 (t, 2H, J ) 6.6 Hz), 3.56 (dt, 2H, J ) 6.8, 6.3 Hz),
3.88 (d, 1H, J ) 8.4 Hz), 3.94 (d, 1H, J ) 8.4 Hz), 5.93 (bt, 1H,
J ) 5.7 Hz), 6.95-7.6 (m, 5H), 8.68 (bs, 1H). 13C NMR: δ 8.5,
25.2, 29.3, 31.3, 31.6, 39.4, 40.0, 42.4, 76.7, 111.5, 112.6, 118.6,
119.4, 122.1, 122.3, 127.4, 136.5, 172.1, 177.3. HRMS Calcd
for C19H24N2O3: 328.1787. Found: 328.1787.
singlets. [R]23 -4.7 (c 1.6, CHCl3). IR υmax (neat): 1787, 1737
D
cm-1. H NMR: δ 0.90 and 0.91 (t, 3H, J ) 7.2 Hz), 1.04 (s,
1
9H), 1.31-1.70 (m, 6H), 3.27 and 3.28 (s, 1H), 3.55-3.70 (m,
2H), 3.71 and 3.76 (s, 3H), 4.03 and 4.07 (d, 1H, J ) 8.6 Hz),
4.19 (d, 1H, J ) 8.6 Hz), 7.35-7.45 (m, 6H), 7.60-7.70 (m,
4H). Anal. Calcd for C27H36O5Si: C, 69.20; H, 7.74. Found: C,
69.00; H, 7.92. â-Lactones [2.8:1 ratio of “â-lactone 1” (0.35 g):
“â-lactone 2” (0.12 g)]. “â-Lactone 1”: IR υmax (neat): 3071,
(4S)-N-[2-(In dole-3-yl)-eth yl)]-4-eth yl-4-h ydr oxym eth yl-
6-h yd r oxyh exa m id e (21). To a solution of amide 3 (0.054 g,
0.16 mmol) in THF (1 mL)-MeOH (0.2 mL) at 0 °C was added
LiBH4 solution (0.4 mL, 0.8 mmol, 2 M in THF). The mixture
was stirred at room temperature for 48 h, cooled to 0 °C, and
quenched with saturated NH4Cl solution (0.5 mL). The aque-
ous layer was extracted with CH2Cl2, and the combined organic
layers were dried, filtered, and evaporated to leave a viscous
oil. Chromatographic purification of the oil (20:1 v/v CH2Cl2:
1
1836, 1754 cm-1. H NMR: δ 0.93 (t, 3H, J ) 7.4 Hz), 1.05 (s,
9H), 1.25-1.80 (m, 7H), 3.65 (t, 2H, J ) 5.7 Hz), 3.80 (s, 3H),
4.12 (1H, d, J ) 4.6 Hz), 4.64 (dd, 1H, J ) 9.1, 4.6 Hz), 7.30-
7.48 (m, 6H), 7.62-7.75 (m, 4H). “â-Lactone 2”: IR υmax
(neat): 3072, 1835, 1746 cm-1. 1H NMR: δ 0.92 (t, 3H, J )
7.4 Hz), 1.07 (s, 9H), 1.25-1.80 (m, 7H), 3.67 (t, 2H, J ) 5.7
Hz), 3.83 (s, 3H), 4.15 (d, 1H, J ) 4.6 Hz), 4.64 (dd, 1H, J )
8.6, 4.6 Hz), 7.34-7.48 (m, 6H), 7.60-7.75 (m, 4H).
MeOH) gave the diol 21 (0.05 g, 92% yield). [R]24 +1.3 (c 2.0,
D
MeOH). IR υmax (film): 3328, 1633 cm-1. H NMR: δ 0.77 (t,
1
(4S )-4-[3-(t er t -Bu t yld ip h e n ylsilyloxyp r op yl)-4-e t h -
yld ih yd r o-2(3H)-fu r a n on e (19). γ-Lactone 18 (0.72 g, 1.53
mmol) was dissolved in DMSO (2 mL) containing NaCl (90
mg, 1.53 mmol). Water (60 µL, 3.1 mmol) was added, and the
mixture was heated at 110 °C for 12 h. The mixture was cooled
to room temperature, and water (2 mL) was added. The
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine and then dried. The filtered
solution was evaporated, and the crude product was purified
by chromatography (4:1 and then 2:1 v/v PE: Et2O) to give (S)-
19 (0.53 g, 84%) as a colorless liquid. [R]D -3.3 (c 1.5, CHCl3).
3H, J ) 7.7 Hz), 1.16 (q, 2H, J ) 7.4 Hz), 1.32-1.55 (m, 3H),
1.68-1.86 (m, 1H), 2.06 (t, 2H, J ) 6.9 Hz), 2.97 (t, 2H, J )
6.3 Hz), 3.27 (bs, 2H), 3.53-3.74 (m, 5H), 4.48 (bs, 1H), 5.81
(bt, 1H, J ) 5.6 Hz), 7.0-7.66 (m, 5H), 8.35 (bs, 1H). 13C
NMR: δ 7.3, 25.1, 26.8, 27.4, 30.2, 38.8, 39.8, 58.2, 67.1, 111.3,
112.4, 118.6, 119.5, 122.2, 127.3, 136.4, 174.2.
(4S)-N-[2-(3-In d olyl)eth yl)]-4-eth yl-4-h yd r oxym eth yl-
6-ter t-bu tyld ip h en ylsiloxyh exa m id e (22). To a solution of
diol 21 (0.23 g, 0.69 mmol) in DMF (5 mL) was added tert-
butyldiphenylsilyl chloride (0.21 g, 0.76 mmol) followed by
addition of imidazole (0.12 g, 1.7 mmol). The mixture was
stirred at -20 °C for 4 h and then 12 h at room temperature.
The reaction was quenched with saturated NaCl and extracted
with CH2Cl2. The organic layer was washed with brine, dried,
filtered, and concentrated. Chromatographic separation (1:1
v/v PE: Et2O and 1:1 PE:EtOAc) gave monosilyl ether 22 (0.36
IR υmax (neat): 1778 cm-1 1H NMR: δ 0.87 (t, 3H, J ) 7.2
.
Hz), 1.05 (s, 9H), 1.42-1.58 (m, 6H), 2.31(s, 2H), 3.65 (t, 2H,
J ) 5.1 Hz), 3.96 (d, 1H, J ) 8.6 Hz), 4.03 (d, 1H, J ) 8.6 Hz),
7.35-7.40 (m, 6H), 7.60-7.70 (m, 4H). 13C NMR: δ 8.4, 19.2,
26.8, 27.3, 29.0, 32.2, 40.0, 42.5, 63.7, 77.1, 127.7, 129.7, 133.7,
135.5, 177.1. Anal. Calcd for C25H34O3Si: C, 73.13; H, 8.35.
Found: C, 73.08; H, 8.49.
g, 92% yield) as a thick oil. [R]24 -6.9° (c 0.4, CHCl3). IR υmax
D
1
(film): 3414, 3304, 3048, 1650 cm-1. H NMR: δ 0.75 (t, 3H,
(4S)-4-E t h yl-4-(3-h yd r oxyp r op yl)d ih yd r o-2(3H )-fu r a -
n on e (20). Compound 19 (0.40 g, 1 mmol) was dissolved in
THF (5 mL), and the solution was cooled to 0 °C. Bu4NF (0.51
mL, 0.51 mmol, 1 M in THF) was added dropwise, and the
mixture was stirred at room temperature for 40 min. Water
(1 mL) was added, THF was evaporated, and the residual oil
was chromatographed (1:1 v/v PE: EtOAc) to give 0.16 g (93%)
J ) 7.4 Hz), 1.04 (s, 9H), 1.11-1.31 (m, 2H), 1.39-1.60 (m,
4H), 1.87-2.12 (m, 2H), 2.95 (t, 2H, J ) 6.9 Hz), 3.29 (s, 2H),
3.50-3.75 (m, 5H), 5.53 (bt, 1H, J ) 5.6 Hz), 7.0 (d, 1H, J )
2.2 Hz), 7.06-7.25 (m, 2H), 7.30-7.50 (m, 7H), 7.50-7.70 (m,
5H), 8.10 (bs, 1H, NH). 13C NMR: δ 7.3, 18.9, 25.2, 26.0, 26.7,
28.8, 30.3, 36.5, 39.4 (39.7), 60.2, 66.7, 111.2, 112.7, 114.9,
118.6, 119.3, 122.0, 127.3, 129.8, 133.0, 135.5, 136.3, 173.7.
HRMS Calcd for C35H46N2O3Si: 570.3278. Found: 570.3274.
A small amount of bis-silyl ether 21 (R1 ) R2 ) TBDPS)
(0.038 g, 6% yield) was also isolated. [R}24D -2.6 (c 1.9, CHCl3).
of 20 as a viscous oil. [R]24 -4.5 (c 1.7, CHCl3) IR υmax (neat):
D
1
3600-3125, 1770 cm-1. H NMR: δ 0.88 (t, 3H, J ) 7.7 Hz),
1.40-1.60 (m, 6H), 1.60-1.88 (br hump, 1H), 2.35(s, 2H), 3.66
(br s, 2H), 4.03 (s, 2H). 13C NMR: δ 8.4, 27.2, 29.0, 32.2, 39.8,
42.5, 62.6, 77.0, 177.1. Anal. Calcd for C9H11O3: C, 62.77; H,
9.36. Found: C, 62.57; H, 9.16.
1
IR υmax (neat): 3428, 3294, 3070, 1658 cm-1. H NMR: δ 0.67
(t, 3H, J ) 7.4 Hz), 1.00 (s, 9H), 1.03 (s, 9H), 1.15-1.30 (m,
2H), 1.38-1.60 (m, 4H), 1.64-1.77 (m, 2H), 2.87 (t, 2H, J )
6.9 Hz), 3.26 (s, 2H), 3.46 (q, 2H, J ) 6.9 Hz), 3.63 (t, 2H, J )
7.4 Hz), 5.02 (bt, 1H, J ) 5.7 Hz), 6.83 (d, 1H, J ) 2.3 Hz),
7.04-7.22 (m, 2H), 7.24-7.43 (m, 7H), 7.52-7.67 (m, 5H), 7.79
(bs, 1H). 13C NMR: δ 7.5, 19.1, 19.4, 25.3, 26.5, 26.9, 27.0,
29.9, 30.9, 36.2, 39.4, 60.2, 67.3, 111.3, 113.0, 118.7, 119.5,
122.0, 127.3, 129.6, 133.7, 134.0, 135.6, 135.8, 136.4, 173.2.
HRMS Calcd for C51H64N2O3Si2: 808.4456. Found: 808.4459.
(4S)-N-[2-(3-In dolyl)eth yl)]-4-eth yl-4-(2-ter t-bu tyldiph e-
n ylsiloxyeth yl)-5-oxop en ta m id e (23) a n d (5S)-N-[2-(3-
In dolyl)eth yl)]-5-eth yl-5-(2-ter t-bu tyldiph en ylsiloxyeth yl)-
6-h yd r oxy-δ-la cta m (24). Monosilyl ether 22 (0.24 g, 0.42
mmol) was dissolved in DMSO (5 mL) at room temperature,
and dry Et3N (1.1 mL, 7.4 mmol) was added followed by
addition of Py‚SO3 complex (0.48 g, 3.0 mmol) in DMSO (2
mL). The mixture was stirred at room temperature for 60 h,
and then 1 M NaOH (5 mL) was added. The mixture was
stirred for another 15 min and then was extracted with EtOAc.
The combined organic layers were washed with brine, dried,
filtered, and concentrated. Chromatographic separation (1:1
(4S )-4-E t h yl-4-[2-(h yd r oxyca r b on yl)e t h yl]d ih yd r o-
2(3H)-fu r a n on e (4). J ones reagent was added dropwise to a
solution of 20 (0.62 g, 3.6 mmol) in acetone (40 mL) at 0 °C
until the orange color of the oxidant persisted. A few drops of
2-propanol was added and then followed by water (1 mL). The
mixture was evaporated, and the resulting mixture was mixed
with saturated NaCl. The mixture was extracted with EtOAc.
The organic layers were washed with brine, dried, filtered, and
evaporated to give a 4 (0.66 g, 98%) as a colorless oil. [R]24
D
-7.1 (c 1.4, CHCl3) IR υmax (neat): 3500-2500, 1770, 1710
cm-1. 1H NMR: δ 0.90 (t, 3H, J ) 7.4 Hz), 1.52 (q, 2H, J ) 7.4
Hz), 1.78-1.88 (m, 2H), 2.20-2.39 (m, 4H), 4.00 (d, 1H, J )
9.2 Hz), 4.06 (d, 1H, J ) 9.2 Hz). 13C NMR: δ 8.4, 28.8, 29.1,
30.6, 39.6, 42.4, 76.5, 176.5, 178.4. Anal. Calcd for C9H14O4:
C, 58.05; H, 7.58. Found: C, 58.17; H, 7.59.
Am id e 3. The carboxylic acid 4 (0.076 g, 0.41 mmol) was
dissolved in CH2Cl2 (10 mL) at 0 °C, and DCC (0.10 g, 0.5
mmol) was added. After for 1 h, tryptamine (0.080 g, 0.5 mmol)
was added, and the mixture was stirred for 15 h at room

8942 J . Org. Chem., Vol. 66, No. 26, 2001
Wee and Yu
v/v PE:Et2O and then 1:1 v/v PE:EtOAc) gave 23 (0.083 g, 35%
yield) and 24 (0.14 g, 60% yield). Compound 23: IR υmax
pound 25a (0.020 g, 0.036 mmol) was dissolved in dry MeOH
(1 mL), and the solution was cooled to 0 °C. Trimethylsilyl
chloride (0.016 g, 0.14 mmol) was added dropwise to the
methanolic solution at 0 °C. The mixture was stirred at 0 °C
for 1 h and then at room temperature for 2 h. Methanol was
evaporated, the residue was treated with NaHCO3, and the
mixture was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried, filtered, and evaporated
to leave a solid residue. Chromatographic purification (8:1 and
4:1 v/v CH2Cl2: acetone) gave pure 30a (10.8 mg, 96% yield).
1
(neat): 3402, 3296, 3052, 2710, 1721, 1653 cm-1. H NMR: δ
0.73 (t, 3H, J ) 7.4 Hz), 1.02 (s, 9H), 1.50 (q, 1H, J ) 7.4 Hz),
1.51 (q, 1H, J ) 7.7 Hz), 1.63-1.90 (m, 6H), 2.93 (t, 2H, J )
6.6 Hz), 3.47-3.64 (m, 4H), 5.35 (m, 1H), 6.97 (d, 1H, J ) 2.2
Hz), 7.07-7.24 (m, 2H), 7.29-7.45 (m, 7H), 7.55-7.68 (m, 5H),
8.02 (bs, 1H), 9.42 (s, 1H). 13C NMR: δ 7.6, 19.1, 23.7, 25.3,
26.7, 26.9, 30.7, 35.0, 39.7, 50.5, 59.7, 111.3, 112.9, 115.6, 118.7,
119.5, 122.1, 122.3, 127.8, 129.8, 133.4, 135.6, 136.4, 172.2,
205.7. HRMS Calcd for
568.3121.
C
35H44N2O3Si: 568.3121. Found:
mp 285-286 °C (dec) (lit.8b(i) mp 263-265 °C). [R]24 -192.3
D
(c 0.13, MeOH) {lit.8b(i) [R]24 -195.5 (c 0.16, MeOH)}. IR υmax
D
1
Compound 24: [R}24 +13.9 (c 0.9, CHCl3) IR υmax (film):
(KBr): 3272, 3054, 1604 cm-1. H NMR (DMSO-d6): 1.07 (t,
D
3420, 3300, 3050, 1625 cm-1. H NMR (1:1 Mixture of diaster-
3H, J ) 7.4 Hz), 1.30-1.64 (m, 2H), 1.65-2.12 (m, 3H), 2.30-
2.43 (m, 2H), 2.49-2.90 (m, 3H), 3.11-3.50 (m, 3H), 4.18 (t,
1H, J ) 5.2 Hz), 4.83 (s, 1H), 4.86-5.02 (m, 1H), 6.91-7.12
(m, 2H), 7.34-7.51 (m, 2H), 10.23 (bs, 1H).
(1S,12bR)-1-Eth yl-1-(2-h yd r oxyeth yl)-4-oxo-2,3,6,7,12,-
12b-h exa h yd r o-1H-in d olo[2,3-a ]qu in olizin e (30b). Com-
pound 25b (0.050 g, 0.091 mmol) was dissolved dry MeOH (2.5
mL), and the solution was treated with trimethylsilyl chloride
(0.04 g, 0.35 mmol) at 0 °C. The reaction mixture was then
1
eomers, ratio was based on integration of H-6 doublets at δ
4.37 and δ 4.72): δ 0.63, 0.68 (t, 3H, J ) 7.4 Hz), 1.05, 1.08 (s,
9H), 1.16-2.07 (m, 6H), 2.18-2.50 (m, 2H), 2.76 (d, 0.5H, J )
5.7 Hz), 3.00-3.20 (m, 2H), 3.46-3.73 (m, 3H), 3.77-4.09 (m,
1H), 4.37 (d, 0.5H, J ) 3.4 Hz), 4.56 (d, 0.5H, J ) 5.7 Hz),
4.72 (d, 0.5H, J ) 2.9 Hz), 6.98-7.23 (m, 3H), 7.30-7.55 (m,
7H), 7.60-7.78 (m, 5H), 7.95 and 8.02 (bs, 1H). HRMS Calcd
for C35H44N2O3Si: 568.3121. Found: 568.3118.
(3S)-N-[2-(3-In dolyl)eth yl)]-3-eth yl-3-(2-ter t-bu tyldiph e-
n ylsiloxyeth yl)glu ta r im id e (26). IR υmax (film): 3420, 3074,
processed according to the procedure as described for 25a to
8b(i)
obtain pure 30b (0.27 g, 97%). mp 110-113 °C. [lit.
mp
1722, 1660 cm-1. H NMR: δ 0.78 (t, 3H), 1.03 (s, 9H), 1.5-
107-108 °C]. [R]24 +111 (c 0.54, MeOH). {[lit.8b(i) [R]D +88.3
1
D
2.09 (m, 6H), 2.63 (t, 2H, J ) 6.9 Hz), 2.91 (t, 2H, J ) 8.0 Hz),
3.53-3.77 (m, 2H), 4.02 (t, 2H), 7.00 (d, 1H, J ) 3.0 Hz), 7.09-
7.22 (m, 2H), 7.23-7.32 (m, 1H), 7.33-7.50 (m, 6H), 7.53-
7.78 (m, 5H), 7.83 (bs, 1H).
(c 0.13, MeOH), lit. [R]D +98.7 (c 0.2, MeOH)}. IR υmax (film):
1
3337, 3052, 1630 cm-1. H NMR: δ 0.70 (t, 3H, J ) 7.8 Hz),
0.80-1.03 (m, 1H), 1.37-1.65 (m, 2H), 1.70-2.10 (m, 2H),
2.11-2.33 (m, 1H), 2.42-2.58 (m, 2H), 2.59-2.80 (m, 3H), 3.12
(s, 1H), 3.95-4.19 (m, 2H), 5.03-5.23 (m, 2H), 7.03-7.22 (m,
2H), 7.36 (d, 1H, J ) 7.2 Hz), 7.48 (d, 1H, J ) 7.2 Hz), 9.74 (s,
1H). 13C NMR: δ 7.1, 21.2, 24.1, 26.9, 29.2, 37.8, 39.4, 41.1,
58.1, 61.1, 111.2, 112.5, 117.9, 119.2, 121.6, 126.6, 131.9, 136.1,
170.5.
(1S,12bS)-1-Eth yl-1-(2-ter t-bu tyldiph en ylsilyloxyeth yl)-
4-oxo-2,3,6,7,12,12b-h exa h yd r o-1H-in d olo[2,3-a ]qu in oliz-
in e (25a ) a n d (1S,12bR)-1-Eth yl-1-(2-ter t-bu tyld ip h en yl-
s i ly lo x y e t h y l)-4-o x o -2,3,6,7,12,12b -h e x a h y d r o -1H -
in d olo[2,3-a ]qu in olizin e (25b). A mixture of aldehyde 23
and hydroxy-lactam 24 (0.073 g, 0.13 mmol) was dissolved in
dry CH2Cl2 (10 mL) at -42 °C, and trifluoroacetic acid (0.065
mL, 0.78 mmol) was added dropwise. The mixture was stirred
at -42 °C and then allowed to warm slowly to room temper-
ature for 16 h. The reaction was quenched with saturated
NaHCO3 and extracted with CH2Cl2. The organic layer was
dried and concentrated. Chromatographic purification (1:1 v/v
PE: EtOAc) gave the oily 25a (18.7 mg) and 25b (49.4 mg)
epi-Ebu r n a m on in e (1b). The lactam alcohol 30b (33 mg,
0.11 mmol) was dissolved in dry THF (15 mL). Lithium
aluminum hydride (40 mg, 1.10 mmol) was added, and the
mixture was refluxed for 20 min. The mixture was cooled to 0
°C and 10% aqueous KOH (50 µL) was added. The mixture
was stirred for 30 min and then was filtered through a Celite
pad. The residue was washed with CH2Cl2. The combined CH2-
Cl2 filtrates were dried, filtered, and evaporated. The residue
was purified by chromatography (6:1 and then 2:1 v/v PE-
EtOAc) to give the amino alcohol 31b (26.5 mg, 84%). mp 169-
and in a combined yield of 95%. Lactam 25a : [R]24 -50 (c
D
0.2, CHCl3) IR υmax (film): 3487, 3052, 1632 cm-1
.
1H NMR:
δ 0.98 (s, 9H), 1.12 (t, 3H, J ) 7.4 Hz), 1.20-1.37 (m, 1H),
1.66-1.98 (m, 5H), 2.43-2.55 (m, 2H), 2.63-2.83 (m, 3H), 3.59
(t, 2H, J ) 6.9 Hz), 4.76 (s, 1H), 5.10-5.22 (m, 1H), 7.09-7.23
(m, 2H), 7.24-7.46 (m, 8H), 7.48-7.58 (m, 4H), 7.82 (bs, 1H).
13C NMR: δ 8.3, 19.0, 21.1, 24.0, 26.8, 27.8, 29.1, 30.4, 33.9,
39.9, 41.0, 59.8, 60.9, 110.9, 113.4, 118.3, 119.8, 122.3, 126.5,
127.7, 129.7, 130.9, 133.3, 135.5, 136.1, 169.9.
172 °C (lit. mp 173.5-175 °C). [R]24 +72.4 (c 0.38, CHCl3).
D
IR υmax (film): 3475, 3450-3100, 2750, 1619, 1500 cm-1
.
1H
NMR: δ 0.69 (t, 3H, J ) 7.4 Hz), 0.98-1.17 (m, 1H), 1.45-
1.60 (m, 3H), 1.68-1.95 (m, 3H), 2.02-2.28 (m, 2H), 2.30-
2.50 (m, 1H), 2.55-2.70 (m, 2H), 2.85-3.08 (m, 2H), 3.50 (s,
1H), 3.95-4.20 (m, 2H), 7.00-7.20 (m, 2H), 7.30-7.35 (m, 1H),
7.45-7.50 (m, 1H), 9.20 (br s, 1H).
Lactam 25b: [R]24D + 85 (c 0.5, CHCl3) IR υmax (film): 3347,
The amino alcohol 31b (7.6 mg, 0.025 mmol) and NMMO
(6 mg, 0.05 mmol) were dissolved in dry CH2Cl2 (2 mL)
containing powdered 4A molecular sieves (13 mg). TPAP (1
mg, 0.003 mmol) was added, and the mixture was stirred at
room temperature overnight. The mixture was filtered through
Celite, and the residue was washed twice with CH2Cl2. The
combined CH2Cl2 filtrates were washed with 10% Na2SO3 (5
mL) and brine, and then dried, filtered, and evaporated. The
residue was purified by chromatography (1:1 v/v CH2Cl2-
acetone and then 10:1 v/v CH2Cl2-MeOH) to afford 4.1 mg
1
3052, 1644 cm-1. H NMR: δ 0.68 (t, 3H, J ) 7.4 Hz), 0.80-
1.12 (m, 1H), 1.02 (s, 9H), 1.38-1.60 (m, 2H), 1.65-1.86 (m,
2H), 2.26-2.50 (m, 3H), 2.65-2.90 (m, 3H), 4.01 (bt, 2H, J )
4.0 Hz), 5.11-5.23 (m, 2H), 7.06-7.22 (m, 2H), 7.37-7.58 (m,
8H), 7.63-7.77 (m, 4H), 9.04 (bs, 1H). 13C NMR: δ 7.0, 19.1,
21.3, 24.0, 26.8, 26.9, 29.1, 38.4, 39.4, 41.0, 60.5, 60.9, 111.2,
112.9, 118.0, 119.3, 121.7, 126.7, 128.1, 130.2, 130.4, 131.6,
132.2, 132.3, 135.5, 135.7, 136.0, 170.0. HRMS Calcd for
C
35H42N2O2Si: 550.3016. Found: 550.3018.
E q u ilib r a t ion of La ct a m (25b ) Usin g BF 3‚E t h er a t e.
(55%) of 1b. mp 145-146 °C (Lit.7b mp 145-146 °C). [R]24
D
Pure 25b (50 mg, 0.09 mmol) was dissolved in freshly distilled
BF3‚etherate (1.3 mL). The mixture was heated at 40 °C for
10 h. The reaction mixture was then cooled to 0 °C in an ice-
water bath, and ice cold aqueous NaHCO3 (8 mL) was added.
The mixture was stirred briefly and then extracted with CH2-
Cl2. The combined organic layers were dried, filtered, and
evaporated. Purification by column chromatography (8:1 and
4:1 v/v CH2Cl2: acetone) afforded compound 30b (21 mg) and
compound 30a (5 mg), and in a combined yield of 91%.
+158 (c 0.19, CHCl3). [lit.7b [R]D +168 (c 1.0, CHCl3)]. IR υmax
(film): 3053, 2802, 2746, 1708 cm-1 1H NMR: δ 0.69-1.00
.
(m, 4H), 1.10-1.25 (m, 1H), 1.58-1.65 (m, 1H), 1.75-2.05 (m,
3H), 2.25-3.00 (m, 6H), 3.05-3.18 (m, 3H), 7.28-7.30 (m, 2H),
7.38-7.45 (m, 1H), 8.30-8.38 (m, 1H). HRMS calcd for
C
C
19H22N2O (M+): 294.1732, Found: 294.1719; HRMS calcd for
19H21N2O (M - 1): 293.1654, Found: 293.1652.
Ebu r n a m on in e (1a ). A solution of the lactam alcohol 30a
(24.5 mg, 0.078 mmol) in dry THF (15 mL) was treated with
lithium aluminum hydride (29.4 mg, 0.78 mmol) for 30 min
following the procedure as outlined for the reduction of
compound 30b. The crude product was purified by chroma-
tography (1:1 v/v PE-EtOAc) to give the amino alcohol 31a
1
Compounds 30a and 30b showed identical H NMR spectral
data as detailed below for 30a and 30b.
(1S,12bS)-1-Eth yl-1-(2-h yd r oxyeth yl)-4-oxo-2,3,6,7,12,-
12b-h exa h yd r o-1H-in d olo[2,3-a ]qu in olizin e (30a ). Com-

Asymmetric Synthesis of (-)-Eburnamonine
J . Org. Chem., Vol. 66, No. 26, 2001 8943
(6.8 mg, 30%). mp 186-189 °C (lit.8b(i) mp 166-168 °C; lit.8e
2.60 (m, 1H), 2.57 (d, 1H, J ) 13.7 Hz), 2.70 (d, 1H, J ) 13.7
Hz), 2.80-3.00 (m, 1H), 3.20-3.40 (m, 1H), 4.00 (br s, 1H),
7.28-7.50 (m, 3H), 8.33-8.40 (m, 1H). HRMS calcd for
C19H22N2O (M+): 294.1732, Found: 294.1735; HRMS calcd for
C19H21N2O (M-1): 293.1654, Found: 293.1661.
mp 167-168 °C). [R]24 -125 (c 0.12, CHCl3) {lit.8b(i) [R]D -98
D
(c 1.0, CHCl3)}. 1H NMR: δ 1.05 (t, 3H, J ) 7.3 Hz), 1.25-
1.32 (m, 1H), 1.50-1.80 (m, 6H), 1.95-2.10 (m, 1H), 2.30-
2.47 (m, 1H), 2.55-2.75 (m, 2H), 2.90-3.10 (m, 3H), 3.30 (br
s, 1H), 3.35-3.45 (m, 1H), 3.50-3.75 (m, 2H), 7.00-7.10 (m,
2H), 7.20-7.28 (m, 1H), 7.35-7.40 (m, 1H), 7.80 (br s, 1H).
Compound 31a (6 mg, 0.02 mmol) was dissolved in dry
DMSO (0.2 mL) containing Py‚SO3 complex (23 mg, 0.14 mmol)
and dry Et3N (0.05 mL). The mixture was stirred at room
temperature for 20 h. Then 1 M aqueous NaOH (1 mL) was
added, and the mixture was stirred for another 15 min. The
mixture was extracted with EtOAc. The combined organic
layers were washed with brine and then dried, filtered, and
evaporated. The crude aldehyde (6 mg) and NMMO (3 mg)
were dissolved in dry CH2Cl2 (2 mL). Then powdered 4A
molecular sieves (13 mg) was added followed by TPAP (1 mg).
The mixture was stirred at room temperature for 3 h and then
filtered through Celite. The residue was washed twice with
CH2Cl2, and the combined CH2Cl2 filtrates were washed with
10% Na2SO3 (5 mL) and brine and then dried, filtered, and
evaporated. The residue was purified by chromatography (1:1
v/v PE-EtOAc) to give 1a (2 mg, 33%). mp 166-168 °C (lit.8b(i)
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council, Canada, and the
University of Regina for financial support of our pro-
gram. We also thank Professor A. G. Schultz, Rensselaer
Polytechnic Institute, NY, for providing the 1H NMR
spectrum of 30a for comparison. Dr. K. Marat, Prairie
Regional 500 MHz NMR center, Manitoba, and Mr. Ken
Thoms, University of Saskatchewan, are thanked for
performing 500 MHz NMR (NOE, HMQC on 25b) and
mass spectral analyses, respectively.
Su p p or tin g In for m a tion Ava ila ble: Preparation, spec-
tral and analytical data of compounds 7-17, NOE results for
compound 25b, HPLC chromatogram of benzoate derivative
1
of alcohol 13, and H NMR spectra of 1a and 1b. This material
mp 171-172 °C). [R]24 -77 (c 0.13, CHCl3). (Lit.8b(i) [R]D -88
D
is available free of charge via the Internet at http://pubs.acs.org.
(c 0.09, CHCl3). 1H NMR: δ 0.93 (t, 3H, J ) 7.3 Hz), 1.01-
1.15 (m, 1H), 1.35-1.80 (m, 6H), 1.95-2.15 (m, 1H), 2.38-
J O010751Z