Applications of organosulfur chemistry to organic synthesis: Total synthesis of (+)-himbeline and (+)-himbacine

Article abstract of DOI:10.1021/jo970612a

Total syntheses of (+)-himbacine (1) and (+)-himbeline (2) are described. The synthesis involves the preparation of sulfone 38 and aldehyde 42 as single enantiomers followed by coupling of these compounds using a Julia-Lythgoe olefination. The preparation of sulfone 38 features an acid- promoted intramolecular Diels-Alder reaction of an α,β-unsaturated thioester while the synthesis of 42 features a Beak alkylation of piperidine 39.

Full text of DOI:10.1021/jo970612a

J . Org. Chem. 1997, 62, 5023-5033
5023
Ap p lica tion s of Or ga n osu lfu r Ch em istr y to Or ga n ic Syn th esis:
Tota l Syn th esis of (+)-Him belin e a n d (+)-Him ba cin e
David J . Hart,*,1 J ing Li, and Wen-Lian Wu
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210
Alan P. Kozikowski*,1
Georgetown University Medical Center, Drug Discovery Laboratory, Room EP11, Institute for Cognitive
and Computational Sciences, 3970 Reservoir Road, NW, Washington, D.C. 20007-2197
Received April 4, 1997X
Total syntheses of (+)-himbacine (1) and (+)-himbeline (2) are described. The synthesis involves
the preparation of sulfone 38 and aldehyde 42 as single enantiomers followed by coupling of these
compounds using a J ulia-Lythgoe olefination. The preparation of sulfone 38 features an acid-
promoted intramolecular Diels-Alder reaction of an R,â-unsaturated thioester while the synthesis
of 42 features a Beak alkylation of piperidine 39.
In tr od u ction
chemical efforts in the area, a total synthesis of himba-
cine was undertaken.9 It is notable that synthesis efforts
in other laboratories have also recently been reported.10
This paper presents the full details of total syntheses of
(+)-himbacine (1) and (+)-himbeline (2), accompanied by
observations made along the way.
The isolation of himbacine (1) from samples of bark of
Galbulimima baccata collected in North Queensland and
New Guinea was first reported in 1956.2 The structural
formula of himbacine was reported in 1961,3 and stereo-
chemical aspects of the structure were secured by X-ray
crystallography as reported in 1962.4 The structurally
related alkaloids himbeline (2) and himgravine (3), along
with other alkaloids, have also been isolated from Gal-
bulimima baccata.5,6 There was relatively little interest
in himbacine until it was reported that it is a potent
muscarinic antagonist that displays selectivity for the M2
receptor.7 Since blockage of presynaptic inhibitory mus-
carinic receptors leads to an elevation of synaptic levels
of acetylcholine, it was anticipated that appropriate
himbacine analogs might offset some of the losses in the
cholinergic system that occurs in Alzheimer’s disease.8
Thus, himbacine became a lead compound for identifying
possible new drug candidates for the treatment of Alzhe-
imer’s dementia. Initial SAR studies suggested that
while certain himbacine substructures retained antimus-
carinic activity, they failed to retain receptor selectivity.
For example, lactone 4 binds to the M1 and M2 receptor
subtypes with Kd values of 9.7 and 1.2 µM, respectively,
while analog 5 shows Kd values of 1.5 and 3.2 nM,
respectively. For comparison, himbacine binds to the M1
and M2 receptors with Kd values of 168 and 9 nM,
respectively.7 To lay the foundation for further medicinal
Our plan to address the eight stereogenic centers in
himbacine revolved around preparing perhydronaphtha-
lene and piperidine fragments and coupling them using
an appropriate olefination procedure. Our initial targets
for synthesis were aldehyde 6 and sulfone 7 (Chart 1),
which were to be coupled using the J ulia-Lythgoe
olefination protocol.
P r ep a r a tion of Ald eh yd e 6. An intramolecular
Diels-Alder approach was taken to the synthesis of
aldehyde 6. Ozonolysis of cycloheptene (8) using the
Schreiber protocol gave aldehyde 9 (Scheme 1).11 Treat-
ment of the crude aldehyde with (carbomethoxymeth-
ylidene)triphenylphosphorane in methanol provided un-
saturated ester 10 in 72% yield. This material was a 2:1
mixture of E and Z geometrical isomers, respectively,
based on integration of NMR signals due to the â-vinylic
hydrogens which appeared at δ 6.95 (dt, J ) 15, 7 Hz)
and 6.23 (dt, J ) 11, 7 Hz), respectively. Deprotonation
of 10 with lithium diisopropyamide in HMPT-THF,
followed by treatment of the resulting dienolate anion
with (S)-2-hydroxypropanal12 gave a 94% yield of â-hy-
droxy esters 11 as a mixture of geometrical and configu-
rational isomers.13 Following chemistry precedented in
the work of Kende and Wu, treatment of 11 with catalytic
p-toluenesulfonic acid in methanol gave crude â-hydroxy
lactone, which was converted to an 8:1 mixture of
butenolides 12 (78% from 10) upon treatment with
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) This paper is dedicated to the memory of Professor William G.
Dauben.
(2) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.;
Pinhey, J . T.; Ritchie, E.; Taylor, W. C. Aust. J . Chem. 1956, 9, 283.
(3) Pinhey, J . T.; Ritchie, E.; Taylor, W. C. Aust. J . Chem. 1961, 14,
106.
(4) Fridrichsons, J .; Mathieson, J . M. Acta Crystallogr. 1962, 15,
119.
(9) For a communication, see: Hart, D. J .; Wu, W.-L.; Kozikowski,
A. P. J . Am. Chem. Soc. 1995, 117, 9369.
(5) For a review see Ritchie, E.; Taylor, W. C. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, p 529.
(6) Galbulimima baccata is not a pine as stated in our earlier
communication.9 It belongs to the Magnoliales order and thus is
somewhat related to magnolias. We thank Professor Frank R. Stermitz
of Colorado State University for bringing this error to our attention.
(7) Kozikowski, A.; Fauq, A. H.; Miller, J . H.; McKinney, M. Bioorg.
Med. Chem. Lett. 1992, 2, 797. Malaska, M. J .; Fauq, A. H.; Kozikowski,
A. P.; Aagaard, P. J .; McKinney, M. Bioorg. Med. Chem. Lett. 1993, 3,
1247. Malaska, M. J .; Fauq, A. H.; Kozikowski, A. P.; Aagaard, P. J .;
McKinney, M. Bioorg. Med. Chem. Lett. 1995, 5, 61.
(8) Miller, J . H.; Aagaard, P. J .; Gibson, V. A.; McKinney, M. J .
Pharmacol. Exp. Ther. 1992, 263, 663.
(10) For approaches that are very similar to ours, see: De Baecke,
G.; De Clercq, P. J . Tetrahedron Lett. 1995, 36, 7515. Baldwin, J . E.;
Chesworth, R.; Parker, J . S.; Russell, A. T. Tetrahedron Lett. 1995,
36, 9551. For another total synthesis and a different approach, see:
Chackalamannil, S.; Davies, R. J .; Asberom, T.; Doller, D.; Leone, D.
J . Am. Chem. Soc. 1996, 118, 9812.
(11) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett. 1982,
23, 3867.
(12) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767.
(13) Hermann, J . L.; Kieczykowski, G.; Schlessinger, R. H. Tetra-
hedron Lett. 1973, 14, 2433.
S0022-3263(97)00612-9 CCC: $14.00 © 1997 American Chemical Society

5024 J . Org. Chem., Vol. 62, No. 15, 1997
Hart et al.
Ch a r t 1
Sch em e 1
methanesulfonyl chloride and triethylamine in dichlo-
romethane.14 The E:Z isomer ratio was improved to 32:1
by allowing a dichloromethane solution of 11 to sit on
the windowsill in the presence of iodine on a sunny day.15
We next turned to the construction of Diels-Alder
substrate 14 and other trienes that were eventually
studied. Hydrolysis of acetal 12 was accomplished using
Amberlyst-15 in aqueous acetone. The resulting crude
aldehyde 13 was subjected to Wadsworth-Horner-
Emmons olefination to provide 14 in 71% overall yield.16
Thioester substrate 15 was also prepared in 67% overall
yield from 12 using the appropriate stabilized phospho-
rane.17 Finally, crude 13 was allowed to react with the
appropriate arsenic ylide to afford unsaturated aldehyde
16 (76%).18 Luche reduction of 16 (NaBH4-CeCl3) gave
allylic alcohol 17 (96%)19 which was readily converted to
the corresponding tert-butyldimethylsilyl ether 18 (88%).20
The results of a series of intramolecular Diels-Alder
reactions are documented in Table 1. We first examined
the cycloaddition of unsaturated ester 14. This substrate
underwent cycloaddition when heated to 200 °C in
toluene to give a mixture of cycloadducts that were
inseparable by column chromatography (entry 1). Sig-
Ta ble 1. In tr a m olecu la r Cycloa d d ition s of Tr ien es
1
nals in the vinylic region of the H NMR spectrum of the
(14) Kende, A. S.; Toder, B. H. J . Org. Chem. 1982, 47, 163. Yao,
Z.-J .; Wu, Y.-L. Tetrahedron Lett. 1994, 35, 157.
(15) Corey, E. J .; Snider, B. B. J . Am. Chem. Soc. 1972, 94, 2549.
(16) Wadsworth, W. S., J r. Organic Reactions; Wiley: New York,
1977; Vol. 25, pp 73-254.
(17) Keck, G. E.; Boden, E. P.; Mabury, S. A. J . Org. Chem. 1985,
50, 709.
(18) Huang, Y.-Z., Shi, L.; Yang, J .; Cai, Z. J . Org. Chem. 1987, 52,
3558.
a
b
SiO2-Et2AlCl was used as an acid promoter. Isolated yield
of product mixture. c A minor isomer was detected in addition to
19 and 20.
(19) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.
(20) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(21) The appearance of a small signal at about δ 6.79 in the
cycloadditions of 19a and 19b suggested that a small amount of third
stereoisomer was formed in these cycloaddition reactions. This signal
did not appear in the Lewis acid promoted reactions.
mixture at δ 6.64 and 6.69 with relative intensities of
1:4 suggested that the cycloaddition had provided a
mixture of endo and exo cycloadducts derived from
addition anti to the butenolide methyl group. Although

Total Syntheses of (+)-Himbeline and (+)-Himbacine
J . Org. Chem., Vol. 62, No. 15, 1997 5025
Sch em e 2
it was initially not possible to assign stereochemistry to
each cycloadduct, evidence was eventually obtained to
support assignment of the δ 6.64 and 6.69 signals to the
endo-anti (19a ) and exo-anti (20a ) cycloadducts, respec-
tively. Since the endo-anti cycloadduct 19a was required
for the synthesis of himbacine, some other conditions
were examined. These studies showed that lowering the
reaction temperature to 110 °C gave approximately a 1:1
ratio of 19a and 20a (entry 2), but attempts to further
improve the endo-exo ratio using homogeneous Lewis
acid promotors resulted in no reaction or decomposition
products.22 It is possible that the lactone in 14 competes
with the unsaturated ester for the Lewis acid, causing
problems with this approach.
Sch em e 3
On the basis of the notion that we might be involved
with an inverse electron demand Diels-Alder, silyl ether
18 was selected as the next substrate for study. Unfor-
tunately, this substrate offered no improvement over
unsaturated ester 14. Once again, two major cycload-
ducts, whose vinylic protons appeared a δ 6.61 (minor)
and 6.65 (major), were obtained in a 1:4 ratio, respec-
tively (entry 4).21 This time, however, the major cycload-
duct was obtained in pure form by recrystallization of
the product mixture, and 2D-NMR spectroscopy clearly
established its structure as 20b. For example, COSY
spectra showed that H3a, H4, H4a, and H8a appeared at δ
2.7, 1.55, 1.9, and 2.4, respectively. In difference NOE
experiments, irradiation of H4a gave 8% and 7% enhance-
ments of the signals due to H8a and H3a, respectively,
suggesting a cis relationship between these hydrogens.
Furthermore, irradiation of the H3a, H4a, and H8a signals
failed to show an NOE at H4, consistent with a trans
relationship between H4 and other hydrogens on the
cyclohexene ring. Finally, irradiation of the lactone
methine at δ 4.2 showed a small NOE of 2% at H3a and
a larger NOE of 4% at H4, establishing the stereochemical
relationship between stereogenic centers in the lactone
and cyclohexene rings.
Based on knowledge that thioesters are more reactive
than esters as Diels-Alder dienophiles, we next exam-
ined unsaturated thioester 15.23 This change had little
effect on product ratios in the thermal cycloaddition
(entry 5). For example, warming 15 at 110 °C gave
nearly equal amounts of 19c (vinyl proton at δ 6.63) to
20c (vinyl proton at δ 6.68). Once again we examined
Lewis acid promotors. Although homogeneous Lewis
acids again met with failure, excellent results were
obtained using a heterogeneous promotor prepared by the
reaction of diethylaluminum chloride with silica gel
(entry 6).24 When treated with this promotor, thioester
15 gave a 75% yield of a mixture of cycloadducts 19c and
20c (20:1, respectively) from which the desired endo
isomer could be crystallized in 67% yield. Given this
result, we reinvestigated ester 14 as a substrate and
found that although it underwent cycloaddition upon
treatment with SiO2-Et2AlCl, the yield and endo-exo
ratios were inferior to those obtained with thioester 15
(entry 3). The precise reasons for the difference in
behavior of 14 and 15 are not known. The results,
however, are consistent with observations that Lewis
acids such as ethylaluminum dichloride and titanium
tetrachloride seem to activate unsaturated thioesters in
preference to unsaturated esters in competitive situa-
tions.23 In the case of 15, perhaps the Lewis acid
promotor complexes the thioester and not the lactone,
thus activating the dienophile without deactivating the
diene.
It turns out that use of a thioester in the critical Diels-
Alder reaction was beneficial in the next stage of the
synthesis (Scheme 2). Although treatment of 19c with
sodium borohydride under several different conditions
failed to accomplish reduction of the thioester without
disturbing the lactone, treatment of 19c with Raney
nickel in ethanol accomplished chemoselective reduction
of both the thioester and alkene in the presence of the
lactone to provide alcohol 21 (81%),25 whose structure was
confirmed by X-ray crystallography, along with buteno-
lide 22 (9%).26 Swern oxidation of 21 gave aldehyde 6
(70-90%) as a sensitive oil that was best used directly
in subsequent reactions.27
P r ep a r a tion of Su lfon e 7. The original plan called
for the coupling of aldehyde 6 with sulfone 7, whose
preparation is described in Scheme 3. (R)-Piperidine-2-
carboxylic acid (23) was resolved via its tartrate salt
using a published procedure.28 Treatment of 23 with
boron trifluoride etherate followed by borane-dimethyl
sulfide complex gave crude amino alcohol 24,29 which was
reacted with di-tert-butyl dicarbonate and sodium hy-
droxide to provide 25 in 88% overall yield.30 Treatment
of alcohol 25 with diphenyl disulfide and tri-n-butylphos-
phine in the presence of pyridine gave sulfide 26 (94%).31
(25) McIntosh, A. V., J r.; Meinzer, E. M.; Levin, R. H. J . Am. Chem.
Soc. 1948, 70, 2955.
(26) We thank Dr. J udith Gallucci of the Department of Chemistry
Crystallography Facility for determining the crystal structures of 21,
31, and 35.
(27) Mancuso, A. J .; Swern, E. Synthesis 1981, 165.
(28) Shiraiwa, T.; Shinjo, K.; Kurokawa, H. Bull. Chem. Soc. J pn.
1991, 64, 3251.
(29) Dickman, D. A.; Meyers, A. I.; Smith, G. A.; Gawley, R. E.
Organic Syntheses; Wiley: New York, 1990; Collect. Vol. 7, p 530.
(30) Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Natl. Acad. Sci.
U.S.A. 1972, 69, 730.
(22) An exhaustive list of Lewis acids was not tried, but it is notable
that diethylaluminum chloride (not supported on silica gel) failed to
afford cycloadducts.
(23) Wladislaw, B.; Marzorati, L.; Gruber. J . Phosphorus, Sulfur,
Silicon Relat. Elem. 1991, 59, 479. Chen, C.-Y.; Hart, D. J . J . Org.
Chem. 1993, 58, 3840. Byeon, C.-H. Ph.D. Thesis, The Ohio State
University, Columbus, OH, 1994.
(24) Cativiela, C.; Fraile, J . M.; Garcia, J . I.; Mayoral, J . A.; Pires,
E.; Royo, A. J .; Figueras, F.; de Menorval, L. C. Tetrahedron 1993, 49,
4073.
(31) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 16, 1409.

5026 J . Org. Chem., Vol. 62, No. 15, 1997
Hart et al.
Sch em e 4
Sch em e 5
lithium in DME followed by reaction with benzaldehyde
gave a mixture of four diastereomeric â-hydroxy sulfones
in a 9:1:1:1 ratio and 84% combined yield. It was possible
to separate all four diastereomers and determine the
stereochemistry of the major isomer (31) by X-ray crys-
tallography.26 It was more surprising to find that the
anion derived from 30 gave better stereoselectivity upon
reaction with cyclohexanecarbaldehyde and propanal.
The reaction with cyclohexanecarbaldehyde gave four
diastereomers (93%) in an 18:1:1:1 ratio, and the major
diastereomer was assigned structure 32 by analogy with
the benzaldehyde results and supported by similarities
in their 1H NMR spectra. The reaction of 30 with
heptanal similarly provided an 18:1:1:1 mixture of ad-
ducts (81%) with the major isomer assigned as structure
33.
Unfortunately, this diastereoselectivity appears to be
sensitive to sulfone structure. For example, metalation
of sulfone 34 followed by reaction with cyclohexanecar-
baldehyde gives a 59:27:7:7 mixture of diastereomers
with 35 as the major product (Scheme 5).26,37 Finally,
treatment of â-(dimethylamino)ethyl phenyl sulfone38
with n-butyllithium followed by cyclohexanecarbaldehyde
provides a 1:1 mixture of diastereomeric â-hyroxysul-
fones, an indication that the asymmetric induction
observed with sulfones 30 and 34 is due to the ring
stereogenic center.
Metalation of 26 in diethyl ether-TMEDA using a
cyclohexane solution of sec-butyllithium, followed by
treatment of the resulting carbanion with iodomethane,
gave 27 in 41% yield.32 Oxidation of 27 to sulfone 28 was
accomplished in 87% yield using m-chloroperoxybenzoic
acid. Treatment of 28 with trifluoroacetic acid, followed
by neutralization and Borch methylation of the resulting
amine, completed the synthesis of sulfone 7 (90%).33
Attem p ted Cou p lin g of Ald eh yd e 6 w ith Su lfon e
7. All attempts to couple aldehyde 6 with the anion
derived from metalation of sulfone 7 met with failure.34
This was a mild surprise since metalated â-amino sul-
fone-aldehyde couplings had been used during the
course of preparing several himbacine analogs.7a,b The
problem appeared to be that the aldehyde was too
hindered, and we speculate that either proton transfer
reactions and/or nucleophilic addition of the carbanion
to the lactone carbonyl group caused problems. No
tractable products were ever isolated from these reac-
tions, although it was demonstrated that metalation of
the sulfone was not the problem. For example, treatment
of 7 with n-butyllithium in tetrahydrofuran followed by
benzaldehyde gave a mixture of â-hydroxy sulfone ad-
ducts.
A Su ccessfu l Cou p lin g St r a t egy: Syn t h esis of
Him ba cin e. Due to lack of success in the coupling of 6
and 7, the approach was revised in a manner that
switched the polarity of the coupling partners. Thus, it
was hoped that the carbanion derived from metalation
of sulfone 38 would couple with aldehyde 42. The
synthesis of 38 is described in Scheme 6. Treatment of
alcohol 21 with p-toluenesulfonyl chloride and pyridine
provided the corresponding tosylate which was treated
with thiophenol and potassium tert-butoxide in DMSO
to afford sulfide 36 (94%). Anticipating that a lactone
and metalated sulfone would be incompatible, 36 was
treated with diisobutylaluminum hydride and the result-
ing lactol was converted to acetal 37 (94%) using boron
trifluoride etherate and methanol.39 Oxidation of 37 with
m-chloroperoxybenzoic acid completed the preparation of
38 (94%).
Although dissapointing, this approach was not without
some benefit as during attempts to find conditions to
effect the desired J ulia-Lythgoe olefination,35 some
useful solvent effects on carbonyl addition reactions of
metalated sulfones were discovered.36 In addition, some
interesting diastereoselectivities in coupling reactions of
the simpler â-amino sulfones 30 and 34 with aldehydes
were observed. Sulfone 30 was prepared from racemic
sulfide 26 as described in Scheme 4. Thus, oxidation of
the sulfide gave sulfone 29 (89%) which was converted
to 30 in 90% yield using standard conditions. On the
basis of our experience with sulfone 7, it was not
surprising to find that metalation of 30 with n-butyl-
(32) Beak, P.; Lee, W. K. J . Org. Chem. 1990, 55, 2578.
(33) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897.
The synthesis of aldehyde 42 is described in Scheme
7. Alcohol 25 was converted to silyl ether 39 in 96% yield
using standard conditions.20 Metalation and methylation
of 25 using the Beak protocol gave 40 in 71% yield.32
Deprotection of the alcohol using tetra-n-butylammonium
(34) On one occasion, treatment of the anion derived from sulfone
7 with aldehyde 6 followed by benzoyl chloride gave crude material,
which upon treatment with sodium amalgam clearly gave olefin I in
about 15% overall yield [1H NMR (CDCl3, 300 MHz) δ 0.75 (m, 1H),
1.0-1.3 (m, 6H), 1.38 (d, J ) 7 Hz, 3H), 1.6-1.8 (m, 4H), 1.9 (m, 1H),
2.10 (m, 1H), 2.25 (m, 1H), 2.6 (m, 1H), 4.65 (dq, J ) 12, 7 Hz, 1H),
5.1 (m, 2H), 5.5 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.0 (q), 26.0 (t),
26.3 (t), 31.1 (t), 31.9 (t), 33.5 (t), 39.8 (d), 41.0 (d), 42.1 (d), 46.9 (d),
48.6 (d), 76.7 (d), 116.7 (t), 139.7 (d), 178.1 (s)]. This material could
have resulted from sequential carbonyl addition, alcohol acylation, a
Grob fragmentation, and vinyl sulfone reduction.
(37) The preparation of sulfone 35 followed the same general path
used to prepare sulfone 30 (see Experimental Section), only (S)-2-
(hydroxymethyl)pyrrolidine was used as the starting material (J ing
Li, unpublished results).
(38) Metalation of â-(dimethylamino)ethyl phenyl sulfone (Barlow,
K. N.; Marshall, D. R.; Stirling, C. J . M. J . Chem. Soc., Perkin Trans.
2 1977, 1920) with n-BuLi followed by reaction of the resulting
carbanion with cyclohexanecarbaldehyde gave a 58:42 mixture of
diastereomeric â-hydroxy sulfones in 91% yield.
(39) Acetal 37 is a single isomer whose stereochemistry at the acetal
carbon was not proven, but is most likely as shown. We note that the
stereochemistry shown in the communication describing this research
is most likely in error.9
(35) J ulia, M.; Paris, J . M. Tetrahedron Lett. 1973, 14, 4833.
(36) Hart, D. J .; Wu, W.-L. Tetrahedron Lett. 1996, 37, 5283.

Total Syntheses of (+)-Himbeline and (+)-Himbacine
J . Org. Chem., Vol. 62, No. 15, 1997 5027
Sch em e 6
rotation) and a 1:1 mixture of the synthetic and natural
materials melted undepressed.44
Exp er im en ta l Section
7,7-Dim eth oxyh ep ta n a l (9). A solution of 7.0 g (71.3
mmol) of cycloheptene (8) in 250 mL of CH2Cl2 and 50 mL of
MeOH was cooled to -78 °C, and ozone (Welsbach ozone
generator) was bubbled through the mixture. When the
solution turned blue, ozone addition was stopped and argon
was passed through the mixture until the blue color was
discharged. The cold bath was removed, and 1.215 g (6.4
mmol) of p-TsOH monohydrate was added. The solution was
allowed to warm to rt over a 2.5-h period with stirring under
an atmosphere of argon. To the mixture was added 2.15 g
(25.6 mmol) of anhydrous sodium bicarbonate. The mixture
was stirred for 20 min, and 12 mL (163 mmol) of dimethyl
sulfide was added. After being stirred overnight, the mixture
was concentrated to approximately 50 mL in vacuo, 100 mL
of CH2Cl2 and 75 mL of water were added, and the aqueous
phase was extracted with two 100-mL portions of CH2Cl2. The
combined organic layers were washed with 100 mL of water.
The aqueous layer was extracted with 100 mL of CH2Cl2, and
the combined extracts were dried (Na2SO4) and concentrated
to give 12.5 g (97%) of crude aldehyde 9, suitable for use in
subsequent reactions without further purification: IR (neat)
2720, 1724 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.30-1.65 (m,
8H), 2.38 (dt, J ) 7.3, 1.6 Hz, 2H), 3.29 (s, 6H), 4.33 (t, J )
5.7 Hz, 1H), 9.74 (t, J ) 1.7 Hz, 1H); mass spectrum m/ e
(relative intensity) 174 (M+, 1), 173 (9), 141 (12).
Sch em e 7
Meth yl 9,9-Dim eth oxy-2-n on en oa te (10). To a solution
of 12.5 g (71.8 mmol) of crude aldehyde 9 in 200 mL of MeOH
was added 25.0 g (73.3 mmol) of (carbomethoxymethyliden-
e)triphenylphosphorane at 0 °C. The mixture was stirred at
0 °C for 5 h and then at rt for 2 h. The solvent was removed
in vacuo, and the residue was extracted with three 100-mL
portions of diethyl ether-hexane (1:1). The combined extracts
were concentrated and chromatographed over silica gel (eluted
with ethyl acetate-hexane, 1:9 plus 1% triethylamine) to give
11.93 g (72% from 8) of ester 10 as a 3:2 mixture of E and Z
1
isomers, respectively: IR (neat) 1725, 1657 cm-1; H NMR of
mixture (250 MHz, CDCl3) δ 1.35-1.61 (m, 8H), 2.19-2.80 (m,
2H), 3.31 (s, 6H), 3.73 (s, 3H), 4.35 (t, J ) 5.7 Hz, 1H), 5.70-
7.0 (m, 2H); exact mass calcd for C12H22O4 m/ e 230.1518, found
m/ e 230.1501.
fluoride gave 41 (93%), and oxidation using the Ley
procedure provided aldehyde 42 (86%).40
The synthesis was completed as outlined in Scheme 6.
Metalation of 38 in 1,2-dimethoxyethane followed by
addition of excess aldehyde 42 provided a diastereomeric
mixture of â-hydroxy sulfones in 67% yield along with
25% of recovered sulfone. Treatment of the mixture of
sulfones with sodium amalgam and disodium hydrogen
phosphate in methanol gave olefin 43 in 68% yield.41
Thus, the overall yield of this J ulia-Lythgoe coupling
was 45% (or 60% taking into account recovered 38).
Oxidation of 43 with J ones reagent provided 44 (95%),42
and removal of the nitrogen protecting group using
trifluoroacetic acid provided (+)-himbeline (2) in 92%
yield.43 Borch methylation of himbeline afforded (+)-
himbacine (1) in 70% yield. The synthetic alkaloid was
identical in all respects with a sample of the natural
product (TLC, 1H NMR, 13C NMR, IR, mp, optical
(S)-3-[(E)-7,7-Dim et h oxy-1-h ep t en yl]-5-m et h yl-2(5H )-
fu r a n on e (12). To a solution of 36.7 mL (55.0 mmol) of LDA
in THF and 9.5 mL (55.0 mmol) of HMPA in 150 mL of THF
at -78 °C was introduced via syringe 11.58 g (50.3 mmol) of
ester 10. The solution was stirred for 30 min, and then 8.70
g (55.0 mmol) of the tetrahydropyranyl ether of (S)-2-hydroxy-
propanal12 was added dropwise. The mixture was stirred at
-78 °C for 1 h , quenched with 200 mL of water, and then
extracted with three 100-mL portions of diethyl ether. The
combined extracts were washed with 100 mL of brine, dried
(Na2SO4), and concentrated in vacuo. Chromatagraphy of the
residue over silica gel (eluted with ethyl acetate-hexane, 1:3
plus 1% triethylamine) gave 18.3 g (94%) of â-hydroxy ester
11 as a colorless oil: IR (neat) 3444 (br), 1738 cm-1; 1H NMR
(250 MHz, CDCl3) δ 1.0-1.9 (m, 10H), 2.0-2.2 (m, 2H), 2.3-
3.2 (m, 4H), 4.33(t, J ) 5.7 Hz, 1H), 4.60-4.90 (m, 2H), 5.35-
5.70 (m, 2H); exact mass calcd for C20H36O7 m/ e 388.2462,
found m/ e 388.2471. This material was used directly in the
next reaction.
(40) Griffith, W. P.; Ley, S. V.; Whitcombe, F. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 39.
(41) For alternative methods for conducting this elimination which
were not tried, see: Keck, G. E.; Savin, K. A.; Weglarz, M. A. J . Org.
Chem. 1995, 60, 3194.
(42) Bowden, K.; Heilbron, I. M.; J ones, E. R. H.; Weedon, B. C. L.
J . Chem. Soc. 1946, 39.
A solution of 18.3 g (47.1 mmol) of 11 in 150 mL of MeOH
containing 1.20 g of p-TsOH was stirred at rt overnight. After
addition of 3.0 mL of triethylamine, the solvent was removed
by rotary evaporation to give 11.8 g of crude â-hydroxy
lactone: IR (neat) 3443, 1771 cm-1; exact mass calcd for
C
14H24O5 m/ e 272.1624, found m/ e 272.1614. This material
(43) Synthetic himbeline gave a melting point and specific rotation
in agreement with those reported for the natural product.2 Spectral
data were also in accord with the assigned structure.
(44) We thank Professor Viresh Rawal for kindly providing a sample
of the natural product.
was used in the following reaction without further purification.
The crude â-hydroxy lactone was dissolved in 150 mL of
CH2Cl2 and cooled to 0 °C, and 4.7 mL (6.87 g, 60.0 mmol) of
methanesulfonyl chloride and 16.8 mL (12.1 g, 120.0 mmol)

5028 J . Org. Chem., Vol. 62, No. 15, 1997
Hart et al.
of triethylamine were added successively. The reaction mix-
ture was stirred at 0 °C for 2 h and diluted with 250 mL of
CH2Cl2 and 150 mL of water. The aqueous layer was extracted
with an additional 100 mL of CH2Cl2. The combined extracts
were washed with 100 mL of brine, dried (Na2SO4), and
concentrated to dryness. Chromatography of the residue over
silica gel (eluted with ethyl acetate-hexane, 1:4 plus 1%
triethylamine) afforded 1.60 g of pure E-12 and 7.7 g of a
(2E,8E)-9-[(S)-2,5-Dih yd r o-5-m eth yl-2-oxo-3-fu r yl]-2,8-
n on a d ien a l (16). A mixture of 0.84 g (4.0 mmol) of crude
aldehyde 13 (prepared from 12 as described above), 2.06 g (4.8
mmol) of (formylmethyl)triphenylarsonium bromide,18 0.66 g
(4.8 mmol) of potassium carbonate, and 40 mL of THF-diethyl
ether (v/v ) 7:3, containing 0.2 mL of water) was stirred at rt
for 3 h. The solution was decanted, and the residue was
washed with diethyl ether. The combined solutions were
concentrated in vacuo, and the residue was chromatographed
over silica gel (eluted with EtOAc-hexane, 1:4) to give 0.71 g
(76% from acetal 12) of aldehyde 16 containing a small amount
of impurities. This material was suitable for use in the next
reaction: IR (neat) 2733, 1754, 1688, 1638 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.39 (d, J ) 7 Hz, 3H), 1.4-1.7 (m, 4H), 2.1-
2.5 (m, 4H), 5.02 (q, J ) 7 Hz, 1H), 6.06 (d, J ) 15 Hz, 1H),
6.10 (dd, J ) 15, 7.5 Hz, 1H), 6.76 (m, 2H), 7.03 (s, 1H), 9.50
(d, J ) 7.5 Hz, 1H).
mixture of E-12 and Z-12 (78% for two steps). E-12: [R]20
D
+30.3 (c 0.54, CHCl3); IR (neat) 1756, 1661 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.36 (d, J ) 6.7 Hz, 3H), 1.19-1.50 (m, 4H),
1.52-1.57 (m, 2H), 2.11 (q, J ) 7.0 Hz, 2H), 3.25 (s, 6H), 4.29
(t, J ) 5.7 Hz, 1H), 4.96 (q, J ) 6.7 Hz, 1H), 6.04 (d, J ) 15.4
Hz, 1H), 6.71 (dt, J ) 15.3, 7.0 Hz, 1H), 7.00 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 19.0 (q), 24.0 (t), 28.4 (t), 32.0 (t), 33.1 (t),
52.5 (q), 76.7 (d), 104.3 (d), 118.5 (d), 129.1 (s), 138.1 (d), 147.0
(d), 171.8 (s); exact mass calcd for C14H22O4 m/ e 254.1519,
found m/ e 254.1498.
(S )-3-[(1E ,7E )-9-H yd r oxy-1,7-n on a d ie n yl]-5-m e t h yl-
2(5H)-fu r a n on e (17). To a solution of 0.71 g (3.0 mmol) of
aldehyde 16 and 1.12 g (3.0 mmol) of cerium chloride hep-
tahydrate in 7.5 mL of MeOH was added 0.11 g (3.0 mmol) of
sodium borohydride over a 3-min period. The mixture was
stirred for 5 min, diluted with 30 mL of water, and extracted
with three 30-mL portions of diethyl ether. The combined
extracts were washed with 30 mL of brine, dried (Na2SO4),
and concentrated in vacuo. The residue was chromatographed
over silica gel (eluted with EtOAc-hexane, 1:3) to give 0.69 g
A solution of 4.30 g (16.9 mmol) of the mixture of E and Z
isomers in 150 mL of CH2Cl2 containing 0.20 g of iodine was
irradiated with sunlight for 10 h. After isomerization was
complete by TLC analysis (silica gel, ethyl acetate-hexane,
1:3), the mixture was washed with 50 mL of 10% aqueous
sodium thiosulfate, dried (Na2SO4), and concentrated in vacuo.
The residue was chromatographed over silica gel (eluted with
ethyl acetate-hexane, 1:4 plus 1% triethylamine) to give 3.56
g (83%) of pure E-12.
(96%) of alcohol 17 as a colorless oil: [R]20 +27.8 (c 0.2,
D
Eth yl (2E,8E)-9-[(S)-Dih yd r o-5-m eth yl-2-oxo-3-fu r yl]-
2,8-n on a d ien oa te (14). To a solution of 8.0 mL (12.0 mmol)
of 1.5 M LDA in cyclohexane, 40 mL of THF, and 5 mL of
HMPA was added 2.69 g (12.0 mmol) of triethyl phosphono-
acetate at 0 °C. The solution was stirred at 0 °C for 15 min,
and then 1.71 g (8.2 mmol) of crude aldehyde 13 (prepared
from 12 as described in the preparation of 15) was added. The
mixture was stirred at 0 °C for 30 min, diluted with 100 mL
of saturated aqueous ammonium chloride, and then extracted
with three 100-mL portions of diethyl ether. The combined
extracts were washed with 100 mL of brine, dried (Na2SO4),
and concentrated in vacuo. The residue was chromatographed
over silica gel (eluted with EtOAc-hexane, 1:10) to give 1.84
CHCl3); IR (neat) 3418, 1752 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.42 (d, J ) 7 Hz, 3H), 1.4-1.6 (m, 4H), 2.05 (m, 2H), 2.18
(m, 2H), 4.09 (m, 2H), 5.03 (dq, J ) 7, 1.6 Hz, 1H), 5.65 (m,
2H), 6.08 (d, J ) 16 Hz, 1H), 6.79 (dt, J ) 16, 7 Hz, 1H), 7.03
(d J ) 1.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 19.1 (q), 28.1
(t), 28.5 (t), 31.8 (t), 33.1 (t), 63.7 (t), 77.1 (d), 118.4 (d), 129.1
(d), 132.9 (d), 138.4 (d), 146.8 (d), the carbonyl and adjacent
olefinic carbon were not observed.
(S)-3-[(1E,7E)-9-(ter t-Bu t yld im et h ylsiloxy)-1,7-n on a -
d ien yl]-5-m eth yl-2(5H)-fu r a n on e (18). To a solution of 0.48
g (2.0 mmol) of alcohol 17 in 10 mL of dry DMF were added
0.375 g (2.6 mmol) of tert-butyldimethylsilyl chloride and 0.544
g (8.0 mmol) of imidazole. The mixture was stirred at rt
overnight, diluted with 30 mL of water, and then extracted
with three 30-mL portions of diethyl ether. The combined
extracts were washed with 30 mL of brine, dried (Na2SO4),
and concentrated in vacuo. The residue was chromatographed
over silica gel (eluted with EtOAc-hexane, 1:9) to give 0.62 g
g (83% from acetal 12) of ester 14 as a colorless oil: [R]20
D
+26.4 (c 0.50, CHCl3); IR (neat) 1756, 1715, 1652 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7 Hz, 3H), 1.38 (d, J )
7 Hz, 3H), 1.4-1.5 (m, 4H), 2.1-2.2 (m, 4H), 4.14 (q, J ) 7
Hz, 2H), 5.00 (q, J ) 6.8 Hz, 1H), 5.77 (d, J ) 15.6 Hz, 1H),
6.06 (d, J ) 15.3 Hz, 1H), 6.74 (dt, J ) 15.9, 7 Hz, 1H), 6.91
(dt, J ) 15.6, 7 Hz, 1H), 7.01 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.1 (q), 19.0 (q), 27.4 (t), 28.1 (t), 31.8 (t), 32.9 (t), 60.0 (t),
76.8 (d), 118.6 (d), 121.4 (d), 129.1 (s), 137.8 (d), 147.1 (d), 148.7
(d), 166.5 (s), 171.8 (s); exact mass calcd for C16H22O4 m/ e
278.1519, found m/ e 278.1517.
(88%) of slightly impure silyl ether 18 as a colorless oil: [R]20
D
+21.3 (c 0.57, CHCl3), IR (neat) 1759, 1662 cm-1; 1H NMR (300
MHz, CDCl3), δ 0.069 (s, 6H), 0.91 (s, 9H), 1.43 (d, J ) 7 Hz,
3H), 1.35-1.50 (m, 4H), 2.05 (m, 2H), 2.18 (m, 2H), 4.15-4.25
(m, 2H), 5.03 (dq, J ) 7, 2 Hz, 1H), 5.40-5.68 (m, 2H), 6.08
(d, J ) 15 Hz, 1H), 6.79 (dt, J ) 16, 7 Hz, 1H), 7.03 (d, J ) 2
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ -5.2 (q), 18.2 (s), 19.0
(q), 25.8 (q), 28.1 (t), 28.5 (t), 31.8 (t), 33.0 (t), 63.8 (t), 76.7
(d), 118.4 (d), 129.1 (s), 129.3 (d), 130.8 (d), 138.2 (d), 146.9
(d), 171.8 (s); exact mass calcd for C20H34O3Si m/ e 350.2305,
found m/ e 350.2258.
S-Eth yl (2E,8E)-9-[(S)-2,5-Dih yd r o-5-m eth yl-2-oxo-3-fu -
r yl]-2,8-n on a d ien eth ioa te (15). A solution of 3.30 g (13.0
mmol) of acetal 12 in 50 mL of acetone containing 0.5 g of
Amberlyst-15 and 0.8 mL of water was stirred at rt for 24 h.
The resin was removed by filtration, and the filtrate was
concentrated in vacuo to give 2.81 g of crude aldehyde 13,
which was used in the next step without further purification.
Eth yl (3S,3aR,4R,4aS,8aS)-1,3,3a,4,4a,5,6,7,8,8a-Decah y-
d r o-3-m et h yl-1-oxon a p h t h o[2,3-c]fu r a n -4-ca r b oxyla t e
(19a ) a n d Eth yl (3S,3a R,4S,4a R,8a S)-1,3,3a ,4,4a ,5,6,7,8,8a -
Deca h yd r o-3-m eth yl-1-oxon a p h th o[2,3-c]fu r a n -4-ca r box-
yla te (20a ). A. Th er m a l Rea ction . A solution of 1.67 g
(6.0 mmol) of triene 18 in 25 mL of toluene was heated in a
sealed tube (bath temperature 200 °C) under an argon
atmosphere for 27 h. The mixture was cooled to rt, and the
residue was chromatographed over silica gel (eluted with
EtOAc-hexane, 1:20 f 1:15 f 1:10) to give 1.29 g (77%) of a
1:4 mixture (by NMR) of 19a and 20a , respectively: 1H NMR
(300 MHz, CDCl3) δ 1.25 (t, J ) 7 Hz, CH3), 1.35 (d, J ) 7 Hz,
CH3CH), 6.64 (t, J ) 3 Hz, dCH for 19a ), 6.69 (t, J ) 3 Hz,
dCH for 20a ), 6.79 (t, J ) 3 Hz, dCH for third isomer), other
overlapping signals appeared at appropriate chemical shifts.
B. SiO2-Et2AlCl-P r om oted Rea ction . A mixture of 36 mg
(0.13 mmol) of triene 14 and 78 mg of SiO2-Et2AlCl in 2 mL
of dry toluene was stirred at 40 °C for 4 days and then cooled
to rt and concentrated in vacuo. The residue was subjected
A solution of the above aldehyde and 6.20 g (17.0 mmol) of
S-ethyl ((thiocarboxy)methylene)triphenylphosphorane17 in
150 mL of chloroform was heated at reflux for 2 h. The
solution was cooled to rt, 50 mg of 4-(dimethylamino)pyridine
was added, and the mixture was stirred at rt for another 2 h.
The solution was concentrated in vacuo, and the residue was
chromatographed over silica gel (eluted with ethyl acetate-
hexane, 1:4) to provide 2.55 g (67% from 12) of thioester 15 as
a colorless oil: [R]20 +26.5o (c 0.81, CHCl3); IR (neat) 1756,
D
1668, 1631 cm-1; 1H NMR (250 MHz, CDCl3) δ 1.2 (t, J ) 7.4
Hz, 3H), 1.38 (d, J ) 6.8 Hz, 3H), 1.39-1.51 (m, 4H), 2.11-
2.21 (m, 4H), 2.90 (q, J ) 7.4 Hz, 2H), 5.00 (q, J ) 6.8 Hz,
1H), 6.03 (d, J ) 15.5 Hz, 2H), 6.70-6.90 (two dt, 2H), 7.02 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 14.7 (q), 19.0 (q), 22.9 (t),
27.4 (t), 28.1 (t), 31.8 (t), 32.9 (t), 76.8 (d), 118.7 (d), 128.8 (d),
129.1 (s), 137.8 (d), 144.7 (d), 147.1 (d), 171.8 (s), 189.9 (s);
FAB mass for C16H22O3S m/ e (M+ + 1) 295.17 (100).

Total Syntheses of (+)-Himbeline and (+)-Himbacine
J . Org. Chem., Vol. 62, No. 15, 1997 5029
to preparative TLC (eluted with ethyl acetate-hexane, 1:25)
to provide 18 mg (50%) of recovered 14 and 11 mg (31%) of a
3:1 mixture (by NMR) of 19a and 20a , respectively. A small
signal due to a third isomer also appeared at δ 6.79.
calcd for C14H22O3 m/ e 238.1570, found m/ e 238.1572. Anal.
Calcd for C14H22O3: C, 70.54; H, 9.31. Found: C, 70.47; H,
9.28. The structure of 21 was confirmed by X-ray crystal-
lography.45 Alcohol 22: mp 164-165 °C; [R]20 -19.3 (c 0.44,
D
CHCl3); IR (neat) 3468, 1731, 1673 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.95-1.37 (m, 6H), 1.41 (d, J ) 6.7 Hz, 3H), 1.65-
2.0 (m, 5H), 2.08 (m, 1H), 2.15 (m, 1H), 2.30 (m, 1H), 3.66 (dd,
J ) 10.6, 6.3 Hz, 1H), 3.89 (dd, J ) 10.7, 3.4 Hz, 1H), 5.17 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 18.7 (q), 25.8 (t), 26.1 (t),
27.2 (t), 31.4 (t), 33.6 (t), 37.9 (d), 39.1 (d), 43.5 (d), 61.7 (t),
79.0 (d), 126.6 (s), 166.0 (s), 173.4 (s); exact mass calcd for
C14H20O3 m/ e 236.1413, found m/ e 236.1422. Anal. Calcd for
C14H20O3: C, 71.14; H, 8.54. Found: C, 71.11; H, 8.55.
ter t-Bu tyl (R)-2-(Hyd r oxym eth yl)-1-p ip er id in eca r box-
yla te (25). To a solution of 6.45 g (50 mmol) of (R)-2-
piperidinecarboxylic acid28 and 6.5 mL (53 mmol) of boron
trifluoride etherate in 30 mL of THF was added, under reflux,
25 mL (50 mmol) of 2.0 M borane-dimethyl sulfide complex
in THF over a 3-h period. The light brown solution was heated
under reflux for an additional 18 h and then cooled to rt. To
the residue was added 44 mL (176 mmol) of 4.0 M aqueous
NaOH. The mixture was refluxed for 4 h, cooled to rt, and
extracted with four 100-mL portions of chloroform. The
combined extracts were dried (K2CO3) and concentrated to give
5.88 g of crude 24 as a thick oil. This material was used
directly in the next step without further purification. To a
solution of 5.88 g of crude 24 in 300 mL of THF-water (1:1)
were added successively 10 mL of aqueous 6 N NaOH and 13.1
g (60 mmol) of di-tert-butyl dicarbonate in 60 mL of THF
through a dropping funnel. The mixture was stirred at rt
overnight and then extracted with two 150-mL portions of
EtOAc. The combined extracts were washed with 100 mL of
brine, dried (Na2SO4), and concentrated in vacuo. The residue
was chromatographed over silica gel (eluted with EtOAc-
hexane, 1:1) to give 9.5 g (88% from 2-piperidinecarboxylic
acid) of alcohol 25 as a white solid: mp 86-87 °C; [R]20D +35.9
(c 2.0, CHCl3); IR (neat) 3443, 1652 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.42 (s, 9H), 1.36-1.70 (m, 6H), 2.47 (br, 1H), 2.83
(t, J ) 12.2 Hz, 1H), 3.57 (m, 1H), 3.75 (m, 1H), 3.90 (br d, J
) 13.3 Hz, 1H), 4.25 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
19.4 (t), 25.0 (t), 25.1 (t), 28.3 (q), 39.8 (t), 52.3 (d), 61.3 (t),
79.6 (s), 156.1 (s); exact mass calcd for C11H21O3N m/ e
215.1522, found m/ e 215.1498. Anal. Calcd for C11H21O3N:
C, 61.37; H, 9.83. Found: C, 61.15; H, 9.90.
(3S ,3a R ,4R ,4a S ,8a S )-4-[(t er t -Bu t yld im e t h ylsiloxy)-
m eth yl]-3a,4,4a,5,6,7,8,8a-octah ydr o-3-m eth yln aph th o[2,3-
c]fu r a n -1(3H)-on e (19b) a n d (3S,3a R,4S,4a R,8a S)-4-[(ter t-
Bu tyldim eth ylsiloxy)m eth yl]-3a,4,4a,5,6,7,8,8a-octah ydr o-
3-m eth yln a p h th o[2,3-c]fu r a n -1(3H)-on e (20b). A solution
of 0.176 g (0.5 mmol) of triene 18 in 15 mL of toluene
containing 3 mg of hydroquinone was heated in a sealed tube
(bath temperature 210 °C) under an argon atmosphere for 18
h. The mixture was cooled to rt and concentrated in vacuo,
and the residue was chromatographed over silica gel (eluted
with EtOAc-hexane, 1:9) to give 0.144 g (82%) of a 4:1 mixture
(by NMR) of 20b and 19b, respectively. Recrystallization of
a sample from EtOAc-hexane provided 41 mg of pure exoad-
duct 20b as a white solid: mp 126-127 °C; [R]20 -36.1 (c
D
0.44, CHCl3); IR (neat) 1765, 1685 cm-1; H NMR (500 MHz,
1
CDCl3) δ 0.061 (s, 3H), 0.069 (s, 3H), 0.89 (s, 9H), 1.17-1.23
(m, 2H), 1.30-1.44 (m, 2H), 1.45-1.58 (m, 1H), 1.52 (d, J ) 6
Hz, 3H), 1.58-1.62 (m, 1H), 1.70 (m, 2H), 1.85 (m, 1H), 1.95
(m, 1H), 2.37 (m, 1H), 2.90 (tt, J ) 9, 3 Hz, 1H), 3.65 (dd, J )
10.5, 3 Hz, 1H), 3.77 (dd, J ) 10.5, 4 Hz, 1H), 4.24 (dq, J )
8.5, 6 Hz, 1H), 6.64 (t, J ) 3.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -5.7 (q), -5.6 (q), 18.0 (s), 21.5 (q), 21.8 (t), 25.6 (q),
25.8 (t), 26.9 (t), 29.5 (t), 34.8 (d), 37.7 (d), 38.2 (d), 46.3 (d),
60.5 (t), 81.0 (d), 129.8 (s), 139.7 (d), 170.0 (s); exact mass calcd
for C20H34O3Si m/ e 350.2305, found m/ e 350.2290. Anal.
Calcd for C20H34O3Si: C, 68.63; H, 9.78. Found: C, 68.39; H,
9.73.
S-Eth yl (3S,3a R,4R,4a S,8a S)-1,3,3a ,4,4a ,5,6,7,8,8a -Deca -
h yd r o-3-m et h yl-1-oxon a p h t h o[2,3-c]fu r a n -4-ca r b ot h io-
a te (19c). A mixture of 4.70 g (16.0 mmol) of triene 15 and
9.6 g of SiO2-Et2AlCl in 150 mL of dry toluene was stirred at
40 °C for 4 days and then cooled to rt and filtered through a
short column of silica gel. Concentration of the filtrate and
chromatography of the residue over silica gel (eluted with ethyl
acetate-hexane, 1:9) afforded 3.51 g (75%) of a 20:1 mixture
of two diastereomeric cycloadducts (by 1H NMR) and 0.46 g
(10%) of recovered 16. Recrystallization of the cycloadducts
from ethyl acetate-hexane gave 3.17 g (67%) of pure endo
adduct 19c as a white solid: mp 72-73 °C; [R]20 +2.7 (c 0.6,
D
CHCl3); IR (neat) 1770, 1682 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.04 (dq, J ) 8.4, 1.9 Hz, 1H), 1.28 (t, J ) 7.4 Hz, 3H), 1.37
(d, J ) 6.0 Hz, 3H), 1.20-1.50 (m, 4H), 1.70-1.95 (m, 4H),
2.06 (m, 1H), 2.80 (tt, J ) 9.5, 3.5 Hz, 1H), 2.90 (q, J ) 7.4
Hz, 2H), 2.96 (dd, J ) 11.1, 9.6 Hz, 1H), 4.40 (dq, J ) 9.1, 6.0
Hz, 1H), 6.63 (t, J ) 2.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.4 (q), 20.5 (q), 23.7 (t), 25.7 (t), 25.8 (t), 30.7 (t), 32.3 (t),
39.5 (d), 41.9 (d), 44.6 (d), 55.4 (d), 77.0 (d), 130.0 (s), 140.6
(d), 168.6 (s), 200.1 (s); exact mass calcd for C16H22O3S m/ e
294.1219, found m/ e 294.1286. Anal. Calcd for C16H22O3S:
C, 65.28; H, 7.54; S, 10.87. Found: C, 65.29; H, 7.49; S, 10.79.
(3S,3aR,4R,4aS,8aR,9aS)-Decah ydr o-4-(h ydr oxym eth yl)-
3-m eth yln a p h th o[2,3-c]fu r a n -1(3H)-on e (21) a n d (3S,4R,
4a S,8a R)-4,4a ,5,6,7,8,8a ,9-Octa h yd r o-4-(h yd r oxym eth yl)-
3-m eth yln a p h th o[2,3-c]fu r a n -1(3H)-on e (22). A suspen-
sion of approximately 40 g of active Raney nickel25 in 75 mL
of EtOH and 75 mL of diethyl ether was stirred for 15 min
followed by the addition of 2.35 g (8.0 mmol) of thioester 19c.
The mixture was stirred for 30 min at rt and then passed
through a short column of silica gel which was washed with
three 50-mL portions of EtOAc. The combined organic solu-
tions were concentrated in vacuo, and the residue was chro-
matographed over silica gel (eluted with EtOAc-hexane, 1:4)
to give 1.54 g (81%) of alcohol 21 as a white solid and 0.29 g
of a mixture of other products. Recrystallization of the mixture
from EtOAc-hexane afforded 22 as a white solid. Alcoh ol
ter t-Bu tyl (R)-2-[(P h en ylth io)m eth yl]-1-p ip er id in eca r -
boxyla te (26). A mixture of 21.5 g (100 mmol) of alcohol 25,
32.7 g (150 mmol) of diphenyl disulfide, and 31.2 g (150 mmol)
of 97% tri-n-butylphosphine in 24 mL (300 mmol) of dry
pyridine was stirred at rt for 24 h and then diluted with 500
mL of diethyl ether and 200 mL of water. The organic layer
was washed with 100 mL of dilute aqueous sodium bicarbonate
and 100 mL of brine, dried (K2CO3), and concentrated in vacuo.
The residue was chromatographed over silica gel (eluted with
EtOAc-hexane, 1:20) to give 28.9 g (94%) of sulfide 26 as a
white solid: mp 57-58 °C; [R]20D +13 (c 1.15, CHCl3); IR (neat)
1
3057, 1694, 1584 cm-1; H NMR (300 MHz, CDCl3) δ 1.40 (s,
9H), 1.35-1.63 (m, 5H), 1.94 (m, 1H), 2.75 (dt, J ) 14, 2 Hz,
1H), 3.03-3.17 (m, 2H), 4.03 (broad d, 1H), 4.38 (m, 1H), 7.14-
7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 18.6 (t), 25.1 (t),
26.3 (t), 28.3 (q), 33.3 (t), 38.9 (t), 49.5 (d), 79.4 (s), 125.8 (d),
128.8 (d), 129.0 (d), 136.2 (s), 154.7 (s); exact mass calcd for
C17H25O2NS m/ e 307.1608, found m/ e 307.1604. Anal. Calcd
for C17H25O2NS: C, 66.41; H, 8.20. Found: C, 66.27; H, 8.30.
ter t-Bu tyl (2S,6R)-2-Meth yl-6-[(p h en ylth io)m eth yl]-1-
p ip er id in eca r boxyla te (27). To a solution of 27.6 g (90
mmol) of sulfide 26 in 250 mL of diethyl ether at -78 °C was
added 15.7 g (135 mmol) of TMEDA followed by 97 mL (126
mmol) of 1.3 M s-BuLi in cyclohexane. The mixture was
stirred at -78 °C for 6 h, and then 25.4 g (180 mmol) of methyl
iodide was added dropwise. The mixture was slowly warmed
to rt overnight. The mixture was diluted with 300 mL of
21: mp 162-163.5 °C; [R]20 +53.9 (c 0.51, CHCl3); IR (neat)
D
3482, 1735 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.85-1.30 (m,
6H), 1.51 (d, J ) 5.9 Hz, 3H), 1.50-1.90 (m, 7H), 2.43 (m, 1H),
2.57 (dt, J ) 12.8, 6.7 Hz, 1H), 3.63-3.78 (m, 2H), 4.70 (dq, J
) 10.1, 5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 21.1 (q), 25.7
(t), 26.2 (t), 29.8 (t), 32.1 (t), 33.6 (t), 38.4 (d), 40.3 (d), 42.5
(d), 42.8 (d), 45.7 (d), 61.3 (t), 77.5 (d), 178.5 (s); exact mass
(45) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

5030 J . Org. Chem., Vol. 62, No. 15, 1997
Hart et al.
water, extracted with three 200-mL portions of diethyl ether,
dried (K2CO3), and concentrated in vacuo. The residue was
chromatographed over silica gel (eluted with EtOAc-hexane,
1:25) to give 11.8 g (41%) of sulfide 27 as a white solid: mp
monium hydroxide. The organic layer was washed with 300
mL of dilute aqueous ammonium hydroxide, dried (Na2SO4),
and concentrated in vacuo. The residue was chromatographed
over 100 g of silica gel (eluted with ethyl acetate-hexane, 1:4)
to give 16.1 g (89%) of sulfone 29 as a white solid: mp 98-99
°C; IR (neat) 3064, 1694, 1682, 1586, 1478 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.27 (s, 9H), 1.18-1.60 (m, 5H), 1.70 (m, 1H),
2.43 (m, 1H), 3.24 (m, 2H,), 3.74 (br, 1H), 4.68 (m, 1H), 7.39-
7.79 (m, 5H); 13C NMR (75 MHz, CHCl3) δ 18.6 (t), 24.7 (t),
28.0 (t), 28.1 (q), 39.1 (t), 46.0 (d), 55.5 (t), 79.7 (s), 127.6 (d),
129.1 (d), 133.5 (d), 139.7 (s), 153.9 (s); exact mass calcd for
C17H25O4NS m/ e 339.1506, found m/ e 339.1502.
56-57 °C; [R]20 +7.8 (c 1.0, CDCl3); IR (neat) 1682, 1584,
D
1
1391, 1372 cm-1; H NMR (300 MHz, CDCl3) δ 1.21 (d, J )
6.7 Hz, 3H), 1.44 (s, 9H), 1.5-1.75 (m, 3H), 1.75-1.86 (m, 2H),
2.03-2.11 (m, 1H), 2.89 (dd, J ) 13, 11 Hz, 1H), 3.34 (dd, J )
13, 3 Hz, 1H), 4.0 (m, 2H), 7.16-7.43 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 13.1 (t), 20.4 (q), 21.9 (t), 26.6 (t), 28.4 (q), 36.8
(t), 47.0 (d), 50.8 (d), 79.3 (s), 125.8 (d), 128.7 (d), 129.2 (d),
154.9 (s), an aromatic singlet was not detected; exact mass
calcd for C18H27O2NS m/ e 321.1764, found m/ e 321.1754. Anal.
Calcd for C18H27O2NS: C, 67.25; H, 8.47. Found: C, 67.02;
H, 8.47.
(()-(R*)-1-Meth yl-2-[(p h en ylsu lfon yl)m eth yl]-1-p ip er i-
d in e (30). A mixture of 16.1 g (47.5 mmol) of carbamate 29
and 15 mL of trifluoroacetic acid in 20 mL of CH2Cl2 was
stirred at room temperature for 15 h and then diluted with
200 mL of CH2Cl2 and 150 mL of 6 N aqueous NaOH. The
aqueous layer was extracted with 100 mL of CH2Cl2, and the
combined extracts were dried (K2CO3) and concentrated in
vacuo to give 12.4 g of crude amine. This material was used
in next step without further purification. To a stirred solution
of the crude amine and 25 mL of aqueous 37% formaldehyde
in 150 mL of acetonitrile was added 6.25 g (100 mmol) of
sodium cyanoborohydride. The mixture was stirred for 30 min,
and acetic acid was then added dropwise until the solution
tested neutral on wet pH paper. The solution was stirred for
an additional 1 h, and the solvents were evaporated in vacuo.
To the residue was added 100 mL of aqueous 2 N NaOH. The
resulting solution was extracted with three 100-mL portions
of chloroform. The combined extracts were washed with 50
mL of aqueous 1 N NaOH, dried (K2CO3), and concentrated
in vacuo. The residue was chromatographed over 50 g of
activity II alumina (eluted with EtOAc-hexane, 1:9 plus 1%
methanol) to give 10.7 g (90% from carbamate 29) of sulfone
ter t-Bu tyl (2S,6R)-2-Meth yl-6-[(ph en ylsu lfon yl)m eth yl]-
1-p ip er id in eca r boxyla te (28). To an ice-cooled and well-
stirred heterogeneous solution of 9.63 g (30 mmol) of sulfide
27 and 11.3 g (135 mmol) of sodium bicarbonate in 150 mL of
CH2Cl2 was added 19.0 g (66 mmol) of 60% m-chloroperoxy-
benzoic acid. The mixture was stirred at rt for 3 h and
quenched with 50 mL of dilute aqueous ammonium hydroxide.
The organic layer was washed with 50 mL of dilute aqueous
ammonium hydroxide, dried (K2CO3), and concentrated in
vacuo. The residue was chromatographed over silica gel
(eluted with EtOAc-hexane, 1:20) to give 9.2 g (87%) of sulfone
28 as a white solid: mp 104-105 °C; [R]20 +20.8 (c 1.74,
D
CHCl3); IR (neat) 1689, 1477, 1391, 1376 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.18 (d, J ) 7 Hz, 3H), 1.39 (s, 9H), 1.52-1.76
(m, 4H), 1.86 (m, 1H), 2.05 (m, 1H), 3.32 (dd, J ) 14, 10 Hz,
1H), 3.58 (dd, J ) 14, 3.5 Hz, 1H), 3.98 (m, 1H), 4.25 (m, 1H),
7.50-7.95 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.3 (t), 19.8
(q), 24.4 (t), 26.9 (t), 28.3 (q), 46.7 (d), 47.9 (d), 58.9 (t), 79.8
(s), 127.8 (d), 129.1 (d), 133.5 (d), 140.0 (s), 154.6 (s); exact
mass calcd for C18H27O4NS m/ e 353.1662, found m/ e 353.1681.
Anal. Calcd for C18H27O4NS: C, 61.16; H, 7.70. Found: C,
61.05; H, 7.69.
30 as a colorless thick oil: IR (neat) 3063, 1585, 1446 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.35 (m, 1H), 1.50 (m, 4H), 1.87
(m, 1H), 2.10 (m, 3H), 2.20 (m, 1H), 2.52 (m, 1H), 2.83 (m,
1H), 3.05 (dd, J ) 14.5, 7.8 Hz, 1H), 3.36 (dd, J ) 14.4, 2.2
Hz, 1H), 7.52-7.92 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 21.5
(t), 25.0 (t), 31.6 (t), 42.7 (q), 53.7 (t), 55.9 (t), 56.6 (d), 127.8
(d), 129.2 (d), 133.6 (d), 139.9 (s); exact mass calcd for
C13H19O2NS m/ e 253.1138, found m/ e 253.1133.
(2S,6R)-2-Meth yl-6-[(p h en ylsu lfon yl)m eth yl]-1-p ip er i-
d in e (7). A mixture of 6.35 g (18.0 mmol) of carbamate 28
and 5 mL of trifluoroacetic acid in 5 mL of CH2Cl2 was stirred
at rt for 2 h and then diluted with 200 mL of CH2Cl2 and 50
mL of 6 N aqueous NaOH. The aqueous layer was extracted
with 100 mL of CH2Cl2, and the combined extracts were dried
(K2CO3) and concentrated in vacuo to give 4.91 g of crude
amine. This material was used in the following reaction
without purification.
(()-(rR*,âR*,2R*)-1-Meth yl-r-ph en yl-â-(ph en ylsu lfon yl)-
2-p ip er id in eeth a n ol (31). To a solution of 0.253 g (1 mmol)
of sulfone 30 in 2.0 mL of DME, cooled in a dry ice-acetone
bath, was added 0.63 mL (1.0 mmol) of 1.6 M n-BuLi in
hexanes. The resulting red solution was stirred for 20 min,
and then 0.106 g (1.0 mmol) of benzaldehyde in 1.0 mL of DME
was added. The mixture was stirred for 30 min, quenched with
50 mL of saturated aqueous ammonium chloride, and then
extracted with three 50-mL portions of diethyl ether. The
combined extracts were washed with 30 mL of brine, dried
(Na2SO4), and concentrated in vacuo. The residue was chro-
matographed over 15 g of silica gel (eluted with EtOAc-
hexane, 1:9 f 1:6 f 1:4 f 1:2 with 1% MeOH) to give 20 mg
of a diastereomer of 31: mp 89-91 °C; IR (CCl4) 3500, 1548,
To a stirred solution of the crude amine and 5 mL of aqueous
37% formaldehyde in 80 mL of acetonitrile was added 2.0 g
(30 mmol) of sodium cyanoborohydride. A vigorous exothermic
reaction ensued. The mixture was stirred for 30 min while
glacial acetic acid was added dropwise to maintain a pH of 7.
Stirring was continued for an additional 1 h, and the solvents
were removed in vacuo. To the residue was added 60 mL of
aqueous 2 N NaOH, and the solution was extracted with three
100-mL portions of CH2Cl2. The combined extracts were
washed with 50 mL of 1 N aqueous sodium hydroxide, dried
(K2CO3), and concentrated in vacuo. The residue was chro-
matographed over silica gel (eluted with EtOAc-hexane, 9:1
plus 2.5% triethylamine) to give 4.32 g (90% from 28) of sulfone
7 as a white solid: mp 54.4-55.5 °C; [R]20D +1.7 (c 0.7, CHCl3);
1
1447 cm-1; H NMR (300 MHz, CDCl3) δ 1.20-1.70 (m, 3H),
1.80 (m, 1H), 2.00-2.30 (m, 3H), 2.19 (s, 3H), 2.80-2.95 (m,
2H), 4.03 (t, J ) 2.9 Hz, 1H), 5.50 (d, J ) 2.1 Hz, 1H), 7.07-
7.54 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 24.2 (t), 25.4 (t),
27.6 (t), 43.5 (q), 57.8 (t), 63.1 (d), 68.8 (d), 69.4 (d), 125.4 (d),
126.9 (d), 127.6 (d), 127.9 (d), 128.6 (d), 132.9 (d), 141.3 (s),
142.0 (s). This was followed by 27 mg of another diasteromer
IR (neat) 2933, 2776, 1446, 1378 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.93 (d, J ) 7 Hz, 3H), 1.20 (m, 1H), 1.35-1.65 (m,
3H), 1.76 (m, 2H), 2.12 (s, 3H), 2.15 (m, 1H), 3.17 (dd, J ) 14,
8 Hz, 1H), 3.29 (dd, J ) 14, 2.4 Hz, 1H), 3.45 (m, 1H), 7.52-
7.93 (m, 5H); 13C NMR (75 MHz, CHCl3) δ 19.2 (t), 20.1 (q),
29.2 (t), 33.4 (t), 38.9 (q), 51.4 (t), 51.9 (d), 55.3 (d), 127.8 (d),
129.1 (d) 133.5 (d), 139.9 (s); exact mass calcd for C14H21O2NS
1
of 31: mp 168-170 °C; IR (CCl4) 3150, 3066, 1449 cm-1; H
NMR (300 MHz, CDCl3) δ 1.20-1.75 (m, 3H), 1.85-2.30 (m,
3H), 2.43 (m, 1H), 2.53 (s, 3H), 3.05 (m, 1H), 3.33 (dt, J ) 10.4,
2.6 Hz, 1H), 4.12 (dd, J ) 10.4, 2.6 Hz, 1H), 5.39 (d, J ) 10.4
Hz, 1H), 6.97-7.33 (m, 10H), the hydroxyl proton was not
observed; 13C NMR (75 MHz, CDCl3) δ 23.6 (t), 25.6 (t), 26.7
(t), 44.1 (q), 57.9 (t), 63.9 (d), 65.8 (d), 72.8 (d), 126.9 (d), 128.0
(d), 128.2 (d), 128.36 (d), 128.43 (d), 132.1 (d), 140.0 (s), 141.0
(s). This was followed by yet another diasteromer of 31: mp
m/ e 267.1294, found m/ e 267.1291. Anal. Calcd for C14H21
-
O2NS: C, 62.89; H, 7.92. Found: C, 62.78; H, 7.92.
(()-ter t-Bu tyl (R*)-2-[(P h en ylsu lfon yl)m eth yl]-1-p ip -
er id in eca r boxyla te (29). To a well-stirred heterogeneous
solution of 16.3 g (53 mmol) of racemic sulfide 26 and 20.0 g
(239 mmmol) of sodium bicarbonate in 500 mL of CH2Cl2 cooled
in an ice bath was added 33.6 g (117 mmol) of 60% m-
chloroperoxybenzoic acid. The mixture was stirred at rt for 3
h and then quenched with 300 mL of dilute aqueous am-
1
120-122 °C; IR (CCl4) 3400, 2930, 1446 cm-1; H NMR (300
MHz, CDCl3) δ 1.25-1.68 (m, 3H), 1.70-1.90 (m, 2H), 2.10-
2.30 (m, 2H), 2.60 (s, 3H), 2.94 (m, 1H) 3.37 (dt, J ) 8.7, 1.8
Hz, 1H), 3.56 (dd, J ) 8.2, 1.9 Hz, 1H), 5.43 (d, J ) 8.2 Hz,

Total Syntheses of (+)-Himbeline and (+)-Himbacine
J . Org. Chem., Vol. 62, No. 15, 1997 5031
1H), 6.95 (br, 1H), 7.10-7.41 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 24.1 (t), 24.4 (t), 34.0 (t), 45.3 (q), 56.6 (t), 61.0 (d),
72.7 (d), 73.7 (d), 127.5 (d), 127.9 (d), 128.2 (d), 128.5 (d), 132.7
(d), 140.5 (s), 140.9 (s), one aromatic carbon was obscured. This
was finally followed by 242 mg of a mixture of 31 and starting
sulfone 30 from which was crystallized 217 mg of pure 31: mp
(eluted with EtOAc-hexane, 1:30) to give 0.95 g (95%) of a
tosylate suitable for use in the next reaction.
To a solution of 0.27 g (2.5 mmol) of thiophenol in 3 mL of
DMSO, stirred under argon at rt, was added 0.375 g (2.5 mmol)
of potassium tert-butoxide followed by a solution of 0.75 g of
the tosylate in 3 mL of DMSO. The reaction mixture was
stirred at rt for 1 h, whereupon it was diluted with 30 mL of
EtOAc and washed with 20 mL of water. The organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue
was chromatographed over silica gel (eluted with EtOAc-
hexane, 1:20) to give 0.59 g (94%) of sulfide 36 as a thick oil:
1
110-112 °C; IR (CCl4) 3200, 2938, 1448 cm-1; H NMR (300
MHz, CDCl3) δ 1.0 (m, 1H), 1.15-1.35 (m, 2H), 1.45 (m, 1H),
1.63 (m, 1H), 1.75-1.90 (m, 1H), 2.10-2.25 (m, 1H), 2.22 (s,
3H), 2.65 (m, 1H), 2.85 (ddd, J ) 12.4, 6.4, 3.6 Hz, 1H), 4.05
(t, J ) 5.7 Hz, 1H), 5.60 (d, J ) 5.2 Hz, 1H), 6.0 (br, 1H), 7.25-
7.84 (m, 10H); 13CNMR (75 MHz, CDCl3) δ 21.9 (t), 22.3 (t),
24.3 (t), 42.2 (q), 53.5 (t), 60.7 (d), 69.8 (d), 72.2 (d), 127.0 (d),
127.8 (d), 128.1 (d), 128.7 (d), 133.1 (d), 140.0 (s), 142.2 (s),
one aromatic carbon was obscured; exact mass calcd for
[R]20 +99.4 (c 1.1, CHCl3); IR (neat) 3057, 1770, 1582 cm-1
;
D
1H NMR (300 MHz, CDCl3) δ 0.80 (dq, J ) 11.1, 2.4 Hz, 1H),
0.99-1.26 (m, 6H), 1.52 (d, J ) 6.0 Hz, 3H), 1.64-1.78 (m,
5H), 2.02 (m, 1H), 2.57 (dt, J ) 12.8, 6.7 Hz, 1H), 2.60 (dd, J
) 13.0, 11.0 Hz, 1H), 2.65 (m, 1H), 3.33 (dd, J ) 13.0, 3.5 Hz,
1H), 4.65 (dq, J ) 10.2, 6.0 Hz, 1H), 7.20-7.30 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 22.0 (q), 25.7 (t), 26.3 (t), 30.1 (t),
32.1 (t), 33.7 (t), 34.9 (t), 40.7 (d), 40.9 (d), 41.5 (d), 42.5 (d),
44.8 (d), 76.7 (d), 126.2 (d), 129.0 (d), 129.1 (d), 136.4 (s), 177.9
(s); exact mass calcd for C20H26O2S m/ e 330.1655, found m/ e
330.1658.
C
20H24O3NS (M+-H) m/ e 358.1478, found m/ e 358.1449.
(()-(rR*,âR*,2R*)-r-Cycloh exyl-1-m eth yl-â-(p h en ylsu l-
fon yl)-2-p ip er id in e-eth a n ol (32). Treatment of 253 mg (1.0
mmol) of 30 with 112 mg (1.0 mmol) of cyclohexanecarbalde-
hyde as described for the preparation of 31 gave 49 mg (13%)
of a roughly equal mixture of three diastereomers of 32 (by
1H NMR) and 291 mg (80%) of 32 as a colorless oil: IR (neat)
3450, 3065, 1585, 1447 cm-1 1H NMR (300 MHz, CDCl3) δ
;
(1S,3S,3a S,4R,4a S,8sR,9a S)-Deca h yd r o-1-m et h oxy-3-
m eth yl-4-[(ph en ylth io)m eth yl]n aph th o[2,3-c]fu r an -1(3H)-
on e (37). To a solution of 0.56 g (1.7 mmol) of lactone 36 in
10 mL of diethyl ether stirred at -78 °C was added 5 mL (5.0
mmol) of a 1 M solution of diisobutylaluminum hydride in
hexane. The solution was stirred for 30 min, and then 2 mL
of MeOH and 20 mL of 5% aqueous HCl were carefully added.
The mixture was extracted with three 30-mL portions of
diethyl ether. The combined extracts were washed with 20
mL of brine, dried (Na2SO4), and cconcentrated to afford 0.543
g (96%) of crude lactol: IR (neat) 3397 cm-1; exact mass calcd
for C20H28O2S m/ e 332.1811, found m/ e 332.1801. This
material was used directly in the next step.
1.05-1.30 (m, 6H), 1.40 (m, 2H), 1.50-1.80 (m, 8H), 1.90-
2.15 (m, 2H), 2.12 (s, 3H), 2.70-2.90 (m, 2H), 3.70 (t, J ) 5.0
Hz, 1H), 3.99 (t, J ) 5.2 Hz, 1H), 7.55 (m, 2H), 7.65 (m, 1H),
7.95 (m, 2H), the OH was not observed; 13C NMR (75 MHz,
CDCl3) δ 22.8 (t), 23.0 (t), 25.7 (t), 25.9 (t), 26.1 (t), 26.2 (t),
27.2 (t), 30.4 (t), 40.4 (d), 43.0 (q), 54.8 (t), 62.1 (d), 68.3 (d),
73.8 (d), 128.5 (d), 128.6 (d), 133.1 (d), 142.3 (s); exact mass
calcd for C20H31O3NS m/ e 365.2026, found m/ e 365.1994.
(()-(rR*,âR*,2R*)-r-Hexyl-1-m eth yl-â-(ph en ylsu lfon yl)-
2-p ip er id in eeth a n ol (33). Treatment of 253 mg (1.0 mmol)
of 30 with 114 mg (1.0 mmol) of heptanal as described for the
preparation of 31 gave 52 mg of a nearly equal mixture of three
diastereomers of 33 (by 1H NMR), 16 mg (6%) of recovered
30, and 276 mg (75%) of 33 as a colorless oil: IR (neat) 3500,
To a stirred solution of 0.52 g (1.5 mmol) of the lactol in 12
mL of MeOH was added 0.2 mL of boron trifluoride etherate
at -20 °C. Dichloromethane (3 mL) was added to achieve a
homogeneous solution. The reaction was stirred from -20 °C
to rt for 2 h, quenched with a few drops of triethylamine, and
concentrated in vacuo. The residue was chromatographed over
silica gel (eluted with EtOAc-hexane, 1:25) to give 0.53 g
3064, 1585, 1462, 1446 cm-1 1H NMR (300 MHz, CDCl3) δ
;
0.87 (t, J ) 6.8 Hz, 3H), 1.05-1.70 (m, 13H), 1.82-2.10 (m,
3H), 2.50 (s, 3H), 2.45-2.55 (m, 1H), 3.01 (dt, J ) 11.4, 3.2
Hz, 1H), 3.47 (dt, J ) 10.5, 4.2 Hz, 1H), 3.57 (broad d, J )
10.8 Hz, 1H), 3.94 (dd, J ) 10.7, 2.9 Hz, 1H), 7.52-7.90 (m,
5H), the OH was not observed; 13C NMR (75 MHz,CDCl3) δ
13.9 (q), 18.9 (t), 20.5 (t), 21.5 (t), 22.5 (t), 26.4 (t), 29.1 (t),
31.7 (t), 32.7 (t), 40.5 (q), 49.0 (t), 57.2 (d), 65.3 (d), 71.8 (d),
128.1 (d), 129.1 (d), 133.5 (d), 140.0 (s); exact mass calcd for
(98%) of acetal 37: [R]20 +138.5 (c 0.73, CHCl3); IR (neat)
D
3057, 1583, 1480, 1375 cm-1
;
1H NMR (300 MHz, CDCl3) δ
0.80-1.10 (m, 5H), 1.15-1.30 (m, 2H), 1.41 (d, J ) 6.0 Hz,
3H), 1.50-1.80 (m, 5H), 2.03 (m, 1H), 2.14 (m, 1H), 2.59 (dd,
J ) 12.6, 11.0 Hz, 1H), 2.71 (m, 1H), 3.32 (dd, J ) 12.6, 3.3
Hz, 1H), 3.33 (s, 3H), 4.17 (dq, J ) 9.1, 6.0 Hz, 1H), 4.47 (s,
1H), 7.10-7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 24.96
(q), 25.85 (t), 26.5 (t), 30.1 (t), 33.3 (t), 34.0 (t), 35.1 (t), 40.7
(d), 41.3 (d), 41.5 (d), 44.4 (d), 46.4 (d), 53.8 (q), 75.2 (d), 108.2
(d), 125.5 (d), 128.5 (d), 128.8 (d), 137.3 (s); exact mass calcd
for C21H30O2S m/ e 346.1968, found m/ e 346.1956.
C
20H33O3NS m/ e 367.2183, found m/ e 367.2194.
(rS,âS,2S)-r-Cycloh exyl-1-m eth yl-â-(p h en ylsu lfon yl)-
2-p yr r olid in eeth a n ol (35). Treatment of 240 mg (1.0 mmol)
of 34 with 137 mg (1.2 mmol) of cyclohexanecarbaldehyde as
described for the preparation of 31 gave 267 mg (76%) of a
mixture of diastereomeric â-hydroxy sulfones from which 35
could be crystallized as a white solid using ethyl acetate-
(1S,3S,3a S,4R,4a S,8sR,9a S)-Deca h yd r o-1-m et h oxy-3-
m eth yl-4-[(p h en ylsu lfon yl)m eth yl]n a p h th o[2,3-c]fu r a n -
1(3H)-on e (38). To an ice-cooled suspension of 0.50 g (1.45
mmol) of sulfide and 0.61 g (7.25 mmol) of sodium bicarbonate
in 50 mL of CH2Cl2 was added slowly 1.0 g (3.48 mmol) of 60%
m-chloroperoxybenzoic acid. The suspension was stirred at
rt for 2 h, diluted with 50 mL of CH2Cl2, and washed with
100 mL of a saturated aqueous sodium bicarbonate. The
aqueous layer was extracted with 100 mL of CH2Cl2. The
combined extracts were washed with 50 mL of brine, dried
(Na2SO4), and concectrated in vacuo. The residue was chro-
matographed over silica gel (eluted with EtOAc-hexane, 1:9)
to provide 0.513 g (94%) of sulfone 38 as a white solid: mp
127-128 °C; [R]20D +100 (c 0.35, CHCl3); IR (neat) 2928, 1549,
hexane: mp 122-123 °C; [R]20 -25.5 (c 0.69, MeOH); IR
D
(neat) 3432 cm-1; H NMR (CDCl3, 300 MHz) δ 0.9-2.1 (m,
1
15H), 2.26 (s, 3H), 2.35 (dt, J ) 8, 6 Hz, 1H), 2.99 (m, 1H),
3.27 (m, 1H), 3.33 (t, J ) 3.5 Hz, 1H), 3.85 (dd, J ) 8, 3.5 Hz,
1H), 5.97 (s, 1H), 7.52 (dd, J ) 7, 2 Hz, 2H), 7.60 (tt, J ) 6, 2
Hz, 1H), 7.95 (dd, J ) 7, 2 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 24.0 (t), 25.7 (t), 25.8 (t), 26.2 (t), 28.6 (t), 29.7 (t), 31.1 (t),
39.9 (d), 42.2 (q), 57.7 (t), 64.0 (d), 67.8 (d), 74.1 (d), 128.5 (d),
128.6 (d), 133.1 (d), 142.0 (s); exact mass calcd for C19H29NO3S
m/ e 351.1870, found m/ e 351.1857. Anal. Calcd for C19H29
-
NO3S: C, 64.92; H, 8.32. Found: C, 64.94; H, 8.34.
(3S ,3a S ,4R ,4a S ,8s R ,9a S )-D e c a h y d r o -3-m e t h y l-4-
[(p h en ylth io)m eth yl]n a p h th o[2,3-c]fu r a n -1(3H)-on e (36).
A solution of 0.48 g (2.0 mmol) of alcohol 21 in 6 mL of pyridine
was cooled in an ice-water slurry and treated with 0.76 g (4.0
mmol) of p-toluenesulfonyl chloride. The mixture was stirred
at 0 °C for 2 h and then placed in a refrigerator overnight (4
°C). The mixture was diluted with 10 mL of 5% aqueous HCl
and extracted with two 15-mL portions of CH2Cl2. The
combined extracts were washed with 10 mL of saturated
sodium bicarbonate, dried (Na2SO4), and concentrated in
vacuo. The residue was chromatographed over silica gel
1
1446, 1377 cm-1; H NMR (300 MHz, CDCl3) δ 0.60 (dq, J )
11.5 Hz, 1H), 0.8-1.0 (m, 4H), 1.05-1.20 (m, 2H), 1.41 (d, J
) 6.1 Hz, 3H), 1.40-1.73 (m, 5H), 2.00-2.20 (m, 2H), 2.73 (dt,
J ) 8.9, 5.6 Hz, 1H), 2.96 (dd, J ) 14.7, 9.4 Hz, 1H), 3.24 (dd,
J ) 14.7, 1.8 Hz, 1H), 3.27 (s, 3H), 4.06 (dq, J ) 9.0, 6.1 Hz,
1H), 4.42 (s, 1H), 7.50-7.90 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 25.5 (q), 25.7 (t), 26.4 (t), 29.8 (t), 32.9 (t), 34.0 (t),
36.6 (d), 40.6 (d), 40.8 (d), 44.9 (d), 46.0 (d), 53.8 (q), 55.6 (t),
75.2 (d), 108.1 (d), 127.8 (d), 129.2 (d), 133.5 (d), 139.8 (s); exact

5032 J . Org. Chem., Vol. 62, No. 15, 1997
Hart et al.
mass calcd for C21H30O4S m/ e 378.1866, found m/ e 378.1847.
Anal. Calcd for C21H30O4S: C, 66.63; H, 7.99. Found: C,
66.70; H, 7.99.
25.3 (t), 28.1 (q), 29.2 (t), 47.3 (d), 59.1 (d), 81.2 (s), 156.1 (s),
196.3 (d); exact mass calcd for C11H20O2N (M+ - CHO) m/ e
198.1495, found m/ e 198.1475.
ter t-Bu tyl (R)-2-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-6-
m eth yl-1-p ip er id in eca r boxyla te (39). To a solution of 3.23
g (15 mmol) of alcohol 25 in 40 mL of DMF were added 2.94 g
(19.5 mmol) of tert-butyldimethylsilyl chloride and 4.08 g (60
mmol) of imidazole. The mixture was stirred at rt overnight,
diluted with 80 mL of water, and extracted with three 100-
mL portions of diethyl ether. The combined extracts were
washed with 100 mL of aqueous saturated sodium bicarbonate
and 100 mL of brine, dried (Na2SO4), and concentrated in
vacuo. The residue was chromatographed over silica gel
(eluted with EtOAc-hexane, 1:50) to give 4.73 g (96%) of silyl
ter t-Bu tyl (2R,6S)-2-[(E)-[2-(1S,3S,3aR,4R,4aS,8aR,9aS)-
Dod eca h yd r o-1-m eth oxy-3-m eth yln a p h th o[2,3-c]fu r a n -
4-yl]vin yl]-6-m eth yl-1-p ip er id in eca r boxyla te (43). To a
solution of 0.31 g (0.8 mmol) of sulfone 38 in 10 mL of DME
was added 0.5 mL (0.8 mmol) of n-BuLi in hexane dropwise.
The resulting yellow solution was stirred at -50 °C for 30 min,
and then 0.28 g (1.23 mmol) of aldehyde 42 in 2 mL of DME
was added slowly. The mixture was stirred at -60 °C for 2 h,
then quenched with 30 mL of water, and extracted with two
30 mL portions of diethyl ether. The combined extracts were
washed with 30 mL of brine, dried (Na2SO4), and concentrated
in vacuo. The residue was chromatographed over silica gel
(eluted with ethyl acetate-hexane, 1:9) to give 0.334 g (67%)
of a diastereomeric mixture of â-hydroxy sulfones as a white
solid and 0.078 g (25%) of recovered sulfone 38. The â-hydroxy
sulfone mixture was characterized as follows: IR (neat) 3372,
ether 39 as a colorless oil: [R]20 +34.9 (c 0.59, CHCl3); IR
D
(neat) 2931, 1694 cm-1; H NMR (300 MHz, CDCl3) δ 0.02 (s,
1
6H), 0.86 (s, 9H), 1.42 (s, 9H), 1.36-1.55 (m, 5H), 1.82 (d, J )
6.8 Hz, 1H), 2.71 (m, 1H), 3.56 (dd, J ) 9.8, 6.3 Hz, 1H), 3.66
(dd, J ) 9.4, 8.8 Hz, 1H), 3.95 (br, 1H), 4.13 (br, 1H); 13C NMR
(75 MHz, CDCl3) δ -5.52 (q), -5.46 (q), 18.1 (s), 19.0 (t), 24.3
(t), 25.2 (t), 25.8 (q), 28.4 (q), 39.9 (t), 51.5 (d), 60.7 (t), 79.0
(s), 155.1 (s); exact mass calcd for C13H26O3NSi (M - C4H9)
m/ e 272.1683, found m/ e 272.1672.
1
1682 cm-1; H NMR (300 MHz, CDCl3) δ 0.61 (m, 1H), 0.88
(m, 4H), 1.23 (two d, J ) 7.0 Hz, 6H), 1.39, 1.46 (s, 9H), 1.0-
1.70 (m, 13H), 1.80-2.20 (m, 2H), 2.50-2.70 (m, 1H), 3.30 (s,
3H), 3.50-3.85 (m, 1H), 4.20 (m, 1H), 4.40-4.50 (m, 1H), 4.62-
4.73 (m, 1H), 4.75-5.34 (m, 1H), 7.45-8.07 (m, 5H); exact mass
calcd for C32H48O6NS (M+ - OCH3) m/ e 574.3204, found m/ e
574.3242. Anal. Calcd for C33H51O7NS: C, 65.42; H, 8.49.
Found: C, 65.20; H, 8.45.
ter t-Bu tyl (2R,6S)-2-[(ter t-Bu tyldim eth ylsiloxy)m eth yl]-
6-m eth yl-1-p ip er id in eca r boxyla te (40). A solution of 4.60
g (14.0 mmol) of silyl ether 39 in 45 mL of diethyl ether was
cooled to -78 °C, and 2.1 g (18.2 mmol) of TMEDA was added,
followed by 14 mL (18.2 mmol) of s-BuLi in cyclohexane. The
pale yellow mixture was stirred at -78 °C for 6 h, and then
3.36 g (23.8 mmol) of methyl iodide was added. The mixture
was slowly warmed to rt with stirring overnight, then diluted
with 100 mL of water, and extracted with three 100-mL
portions of diethyl ether. The combined extracts were washed
with 100 mL of brine, dried (Na2SO4), and concentrated in
vacuo. The residue was chromatographed over silica gel
(eluted with EtOAc-hexane, 1:50) to provide 3.41 g (71%) of
A mixture of 0.37 g (0.61 mmol) of the â-hydroxy sulfones,
6.6 g of 6% sodium amalgam, and 1.2 g of disodium hydrogen
phosphate in 15 mL of methanol was stirred at room temper-
ature for 3 h, quenched with 20 mL of water, and then
extracted with two 30-mL portions of diethyl ether. The
combined extracts were dried (Na2SO4) and concentrated in
vacuo. Chromatography of the residue over silica gel (eluted
with ethyl acetate-hexane, 1:9) gave 0.186 g (68%) of olefin
43 as a white solid: mp 92-93 °C; [R]20D +90.5 (c 0.38, CHCl3);
IR (CCl4) 1690, 1390 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.6-
0.7 (m, 1H), 0.92 (m, 4H), 1.22 (d, J ) 6.7Hz, 3H), 1.27 (d, J
) 6.0 Hz, 3H), 1.15-1.25 (m, 3H), 1.42 (s, 9H), 1.40-1.80 (m,
8H), 1.84-2.08 (m, 3H), 2.17 (m, 2H), 3.29 (s, 3H), 3.96 (m,
1H), 4.16 (dq, J ) 8.6, 6.0 Hz, 1H), 4.40 (br, 1H), 4.46 (s, 1H),
5.20 (ddd, J ) 15.2, 9.9, 1.3 Hz, 1H), 5.46 (dd, J ) 15.2, 6.3
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 13.3 (t), 20.8 (q), 24.6
(q), 25.7 (q), 26.3 (t), 26.4 (t), 26.5 (t), 28.3 (q), 31.3 (t), 32.9
(t), 34.0 (t), 40.2 (d), 41.2 (d), 46.3 (d), 46.4 (d), 46.9 (d), 48.6
(d), 52.3 (d), 53.7 (q), 75.4 (d), 78.8 (s), 108.3 (d), 132.9 (d),
154.9 (s), one carbon was not observed; exact mass calcd for
C27H45O4N m/ e 447.3351, found m/ e 447.3347. Anal. Calcd
for C27H45O4N: C, 72.44; H, 10.13. Found: C, 72.38; H, 10.16.
ter t-Bu t yl (2R,6S)-2-[(E)-[2-(3S,3a R,4R,4a S,8a R,9a S)-
Dod eca h yd r o-3-m eth yl-1-oxon a p h th o[2,3-c]fu r a n -4-yl]vi-
n yl]-6-m eth yl-1-p ip er id in eca r boxyla te (44). To a solution
of 0.14 g (0.31 mmol) of acetal 43 in 5 mL of acetone was added
0.8 mL of J ones reagent (prepared from 1.03 g of CrO3, 3 mL
of water, and 0.87 g of sulfuric acid). The mixture was stirred
at rt for 30 min, diluted with 50 mL of diethyl ether, and
washed with 20 mL of water. The aqueous layer was extracted
with 20 mL of diethyl ether. The combined extracts were dried
(Na2SO4) and concentrated in vacuo. Chromatography of the
residue over silica gel (eluted with EtOAc-hexane, 1:9) gave
128 mg (95%) of lactone 44 as a thick oil: [R]20D +60.6 (c 0.55,
CHCl3); IR (neat) 1777, 1682 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.66 (m, 1H), 0.97 (m, 3H), 1.10-1.20 (m, 4H), 1.23 (d, J )
6.6 Hz, 3H), 1.40 (d, J ) 6.0 Hz, 3H), 1.43 (s, 9H), 1.45-1.80
(m, 8H), 1.80-2.10 (m, 3H), 2.20 (m, 1H), 2.60 (m, 1H), 3.98
(m, 1H), 4.42 (br, 1H), 4.61 (dq, J ) 10.2, 5.9 Hz, 1H), 5.21
(ddd, J ) 15.2, 10.0, 1.3 Hz, 1H), 5.52 (dd, J ) 15.2, 6.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 13.3 (t), 20.8 (q), 22.0 (q),
25.5 (t), 26.0 (t), 26.3 (t), 28.4 (q), 31.1 (t), 31.9 (t), 33.5 (t),
39.9 (d), 41.5 (d), 42.2 (d), 45.6 (d), 46.9 (d), 48.7 (d), 52.1 (d),
76.8 (d), 79.0 (s), 131.2 (d), 134.1 (d), 154.9 (s), 178.2 (s), one
carbon was not observed; exact mass calcd for C26H41O4N m/ e
431.3037, found m/ e 431.3040.
piperidine 40 as a colorless oil: [R]20 +38.6 (c 0.65, CHCl3);
D
1
IR (neat) 1692, 1388, 1364 cm-1; H NMR (300 MHz, CDCl3)
δ 0.002 (s, 6H), 0.83 (s, 9H), 1.17 (d, J ) 9.3, 4.3 Hz, 3H), 1.40
(s, 9H), 1.42-1.89 (m, 6H), 3.44 (t, J ) 9.5 Hz, 1H), 3.63 (dd,
J ) 9.3, 4.3 Hz, 1H), 3.74 (m, 1H), 3.93 (m, 1H); 13C NMR (75
MHz, CDCl3) δ -5.6 (q), -5.4 (q), 13.2 (t), 18.1 (s), 20.4 (q),
20.5 (t), 25.8 (q), 26.9 (t), 28.4 (q), 46.7 (d), 52.6 (d), 63.8 (t),
78.9 (s), 155.0 (s); exact mass calcd for C18H38O3NSi (M+ + 1)
m/ e 344.2623, found m/ e 344.2595.
ter t-Bu tyl (2R,6S)-2-(Hyd r oxym eth yl)-6-m eth yl-1-p ip -
er id in eca r boxyla te (41). A solution of 2.06 g (6.0 mmol) of
silyl ether 40 and 9.0 mL of tetra-n-butylammonium fluoride
in 20 mL of THF was stirred at 0 °C for 1 h and then at rt for
2 h. The mixture was diluted with 100 mL of diethyl ether,
washed with 40 mL of brine, dried (Na2SO4), and concentrated
in vacuo. The residue was chromatographed over silica gel
(eluted with EtOAc-hexane, 1:4) to give 1.28 g (93%) of alcohol
41 as a thick oil: [R]20 +45.4 (c 0.97, CHCl3); IR (neat) 3444
D
(br), 1694 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.18 (d, J ) 6.8
Hz, 3H), 1.45 (s, 9H), 1.39-1.75 (m, 6H), 3.61-3.75 (m, 3H),
3.98 (br, 1H), 4.19 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 15.8
(t), 18.4 (q), 25.2 (t), 27.9 (t), 28.3 (q), 48.3 (d), 54.1 (d), 66.1
(t), 79.8 (s), 156.3 (s); exact mass calcd for C11H19O3N (M+
CH4) m/ e 213.1366, found m/ e 213.1315.
-
ter t-Bu tyl (2R,6S)-2-F or m yl-6-m eth yl-1-p ip er id in eca r -
boxyla te (42). To a mixture of 4 g of 4 Å molecular sieves
and 0.404 g (3.5 mmol) of N-methylmorpholine N-oxide in 25
mL of CH2Cl2 was added 0.53 g (2.3 mmol) of alcohol 41. The
mixture was stirred for 10 min, 50 mg of tetra-n-propylam-
monium perruthenate (TPAP) was added, and the reaction was
stirred at rt overnight. The mixture was diluted with 200 mL
of CH2Cl2, washed with 50 mL of 10% aqueous sodium
thiosulfate and 50 mL of brine, and dried (Na2SO4). The
mixture was concentrated, and the residue was chromato-
graphed over silica gel (eluted with EtOAc-hexane, 1:9) to give
0.45 g (86%) of aldehyde 42 as a colorless oil: [R]20 +121.7 (c
D
0.96, CHCl3); IR (neat) 1732, 1682 cm-1; H NMR (300 MHz,
1
CDCl3) δ 1.11 (d, J ) 6.8 Hz, 3H), 1.44 (s, 9H), 1.45-1.74 (m,
6H), 3.62 (dt, J ) 12.3, 3.9 Hz, 1H), 4.25 (br, 1H), 9.27 (d, J )
3.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.2 (t), 16.4 (q),
(3S,3a R,4R,4a S,8a R,9a S)-Deca h yd r o-3-m eth yl-4-[(E)-2-
[(2R,6S)-6-m eth yl-2-piper idyl]vin yl]-3-m eth yln aph th o[2,3-
c]fu r a n -1(3H)-on e (Him belin e, 2). To a stirred solution of

Total Syntheses of (+)-Himbeline and (+)-Himbacine
J . Org. Chem., Vol. 62, No. 15, 1997 5033
0.13 g (0.38 mmol) of carbamate 44 in 2 mL of CH2Cl2 was
slowly added 1 mL of trifluoroacetic acid. The mixture was
stirred at rt for 30 min, quenched with 10 mL of 6 N aqueous
NaOH, and extracted with four 15-mL portions of CH2Cl2. The
combined extracts were dried (K2CO3) and concentrated in
vacuo. Chromatography over silica gel (eluted with EtOAc-
MeOH, 1:1) gave 92 mg (92%) of himbeline (2) as a white solid.
Further chromatography of a sample over activity II alumina
(eluted with EtOAc-hexane, 1:1) afforded salt free him-
beline: mp 97.5-98.5 °C (lit.2 mp 100 °C); [R]20D +17.1 [c 0.56,
CHCl3; lit.2 +19 (2.4% in CHCl3)]; IR (neat) 3325, 1778, 1629,
EtOAc-MeOH, 2:1) gave 71 mg of product as a semisolid,
which contained inorganic impurities. Chromatography over
a short column of activity II alumina (eluted with EtOAc-
hexane, 1:4) afforded 54 mg (70%) of pure himbacine (1) as a
white solid: mp 129-130 °C [lit.2 mp 132 °C; standard
sample,44 129-130 °C]; [R]20 +51.4 [c 1.01, CHCl3; lit.2 +63
D
(2.4% in CHCl3); standard sample,44 +51.4 (c 1.01, CHCl3)];
IR (neat) 2929, 2852, 1777, 1446, 1383 cm-1 1H NMR (300
;
MHz, CDCl3) δ 0.73 (m, 1H), 0.98 (d, J ) 6.5 Hz, 3H), 0.90-
1.10 (m, 3H), 1.10-1.30 (m, 3H), 1.38 (d, J ) 5.9 Hz, 3H),
1.30-1.46 (m, 2H), 1.50-1.55 (m, 2H), 1.60-1.75 (m, 6H), 1.86
(m, 1H), 2.10 (m, 1H), 2.20 (s, 3H), 2.18-2.25 (m, 1H), 2.60
(dt, J ) 12.7, 6.6 Hz, 1H), 2.80-2.85 (m, 1H), 2.98-3.05 (m,
1H), 4.61 (dq, J ) 7.3, 5.9 Hz, 1H), 5.24 (dd, J ) 15.2, 9.8 Hz,
1H), 5.56 (dd, J ) 15.2, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 13.9 (q), 18.8 (t), 22.1 (q), 26.0 (t), 26.3 (t), 31.3 (t), 31.9 (t),
32.4 (t), 33.1 (t), 33.5 (t), 39.8 (d), 41.0 (q), 41.4 (d), 42.1 (d),
45.6 (d), 49.0 (d), 53.3 (d), 61.2 (d), 76.6 (d), 133.3 (d), 133.4
(d), 178.1 (s); exact mass calcd for C22H35O2N m/ e 345.2669,
found m/ e 345.2667.
1
1452, 1381 cm-1; H NMR (300 MHz, CDCl3) δ 0.69 (m, 1H),
0.94-1.08 (m, 3H), 1.08 (d, J ) 6.5 Hz, 3H), 1.10-1.27 (m,
4H), 1.40 (d, J ) 6.0 Hz, 3H, CH3), 1.38-1.42 (m, 1H), 1.50-
1.80 (m, 8H), 1.84 (ddd, J ) 11.5, 6.3, 1.7 Hz, 1H), 2.09 (m,
1H), 2.23 (dt, J ) 10.1, 6.1 Hz, 1H), 2.60 (dt, J ) 12.9, 6.7 Hz,
1H), 3.09 (m, 1H), 3.52 (q, J ) 5.0 Hz, 1H), 4.63 (dq, J ) 10.2,
6.0 Hz, 1H), 5.24 (ddd, J ) 15.4, 9.9, 1.2 Hz, 1H), 5.69 (dd, J
) 15.3, 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 19.6 (t), 21.3
(q), 22.1 (q), 26.0 (t), 26.3 (t), 31.0 (t), 31.2 (t), 31.9 (t), 32.6 (t),
33.5 (t), 39.9 (d), 41.4 (d), 42.2 (d), 45.5 (d), 46.2 (d), 48.9 (d),
52.9 (d), 76.7 (d), 131.1 (d), 135.3 (d), 178.1 (s); exact mass
calcd for C21H33O2N m/ e 331.2513, found m/ e 331.2510.
(3S,3aR,4R,4aS,8aR,9aS)-4-[(E)-2-[(2R,6S)-1,6-Dim eth yl-
2-p ip er id yl]vin yl]d eca h yd r o-3-m eth yln a p h th o[2,3-c]fu -
r a n -1(3H)-on e (Him ba cin e, 1). To a stirred solution of 75
mg (0.227 mmol) of himbeline (2) and 0.2 mL of 37% aqueous
formaldehyde in 4 mL of acetonenitrile was added 30 mg of
sodium cyanoborohydride. The mixture was stirred for 20 min,
and then acetic acid was added dropwise until the solution
tested neutral. Stirring was continued for an additional 1 h,
the solvent was evaporated in vacuo, 10 mL of 2 N NaOH was
added, and the mixture was extracted with four 15-mL
portions of CH2Cl2. The combined extracts were dried (K2CO3)
and concentrated. Chromatography over silica gel (eluted with
Ack n ow led gm en t. We thank the NIH and Inter-
neuron Pharmaceuticals for financial support of this
research, Dr. Kurt Loening for help with nomenclature,
and the Campus Chemical Instrumentation Center at
the Ohio State University for technical support.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal and H and 13C NMR spectra for most new compounds (74
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O970612A