Total synthesis of dumsin. 1. Retrosynthetic strategy and the elaboration of key intermediates from (-)-bornyl acetate

Article abstract of DOI:10.1021/jo0301346

An intramolecular anionic oxy-Cope rearrangement (44 → 46) serves as the key step in a synthetic approach to the insect antifeedant dumsin. Initial investigations clarified the manner in which (-)-bornyl acetate may be transformed into the exo-norbornenol

Full text of DOI:10.1021/jo0301346

Tota l Syn th esis of Du m sin . 1. Retr osyn th etic Str a tegy a n d th e
Ela bor a tion of Key In ter m ed ia tes fr om (-)-Bor n yl Aceta te
Leo A. Paquette* and Fang-Tsao Hong
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 18, 2003
An intramolecular anionic oxy-Cope rearrangement (44 f 46) serves as the key step in a synthetic
approach to the insect antifeedant dumsin. Initial investigations clarified the manner in which
(-)-bornyl acetate may be transformed into the exo-norbornenol 44. Two routes were developed to
advance beyond 46. The first involved acetal 51 as a matrix that was expected to allow the
elaboration of rings D and E. The second plan deferred oxidation of the cyclopentene ring in 46 to
a later stage of molecular construction. The latter experiments formed the basis of a protocol that
led to the successful acquisition of keto aldehydes typified by 108 and 114.
Numerous plants native to the African and Asian
continents contain limonoid triterpenes as their principal
biologically active ingredient.1 Many of these sources
have historically been extensively utilized as traditional
medicines and valued for their ability to cure or alleviate
a variety of symptoms including fever, tuberculosis,
hemorrhoids, and snake bite.2 More recently, the evolu-
tionary diversification of limonoids has become regarded
as profitable for further investigation. Indeed, promising
antifungal, anticancer, and insect antifeedant activities
continue to be uncovered. Some of the more recently
characterized members of this class are represented by
1-9 (Chart 1).2-9
with a view to producing effective probes, identifying
structure-activity relationships, and enhancing biologi-
cal activity.12-19 To us, the lineage of dumsin (2) and its
eye-catching molecular intricacy were sufficient to engage
our curiosity and attention. The Kubo group was suc-
cessful in isolating 2 from the bitter root bark of the East
African plant known in Swahili as “Msinduzi”.9 The
natives valued its extracts for alleviating stomach aches
and warding off the symptoms of the common cold. More
recent screening efforts have shown dumsin to possess
remarkably potent insect antifeedant properties. On the
basis of detailed spectroscopic analysis and a single-
crystal X-ray determination performed by Clardy,9 2 was
identified to be a tetranortriterpenoid housing a highly
oxygenated central core compactly accommodating four
quaternary carbon atoms and nine additional stereogenic
centers. The absolute configuration was also defined to
be as shown. Also noteworthy is the presence of a
hemiacetal of an R-diketone embedded in the western
ABC sector.
Two lines of synthetic effort have been explored in this
area. The first is, of course, the de novo assembly of these
complex structures, remarkably few examples of which
have appeared in the literature.10,11 More often, attention
has been focused on simplified or degraded limonoids
(1) Champagne, D. E.; Koul, O.; Isman, M. B.; Scudder, G. G. E.;
Towers, G. H. N. Phytochemistry 1992, 31, 377.
(2) Rajab, M. S.; Rugutt, J . K.; Fronczek, F. R.; Fischer, N. H. J .
Nat. Prod. 1997, 60, 822.
(3) Ahmad, J .; Wizarat, K.; Shamsuddin, K. M.; Zaman, A.; Connolly,
J . D. Phytochemistry 1984, 23, 1269.
(4) Zhou, J .-B.; Minami, Y.; Yagi, F.; Tadera, K.; Nakatani, M.
Heterocycles 1997, 45, 1781.
Syn th etic Str a tegy. Since no chemistry has been
recorded for 2, our preoccupation with its construction,
colloquially referred to in these laboratories as “The
Dumsinthesis”, was forced to proceed without any prior
insight into its chemical idiosyncrasies. One point of
(5) Gargez, F. R.; Garces, W. S.; Tsutumi, M. T.; Roque, N. F.
Phytochemistry 1997, 45, 141.
(6) Zheng, S.; Meng, J .; Shen, X.; Wang, D.; Fu, H.; Wang, Q. Planta
Med. 1997, 63, 379.
(7) Zhou, J . B.; Minami, Y.; Yagi, F.; Yadera, K.; Nakatani, M.
Phytochemistry 1997, 46, 911.
(8) Huang, R. C.; Minami, Y.; Yagi, F.; Nakamura, Y.; Nakayama,
N.; Tadera, K.; Nakatani, M. Heterocycles 1996, 43, 1477.
(9) Kubo, I.; Hanke, F.-J .; Asaka, Y.; Matsumoto, T.; He, C.-H.;
Clardy, J . Tetrahedron 1990, 46, 1515.
(12) Fernandez-Mateos, A.; Blanco, J . A. de la Fuente, J . Org. Chem.
1990, 55, 1349.
(13) Fernandez-Mateos, A.; Coca, G. P.; Alonso, J . J . P.; Gonzalez,
R. R.; Hernandez, C. T. Synlett 1996, 1134.
(14) Fernandez-Mateos, A.; Barba, M. L. J . Org. Chem. 1995, 60,
3580.
(15) Fernandez-Mateos, A.; Coca, G. P.; Hernandez, C. T. J . Org.
Chem. 1996, 61, 9097.
(10) (a) Corey, E. J .; Hahl, R. W. Tetrahedron Lett. 1989, 30, 3023.
(b) Money, T.; Richardson, S. R.; Wong, M. K. C. J . Chem. Soc., Chem.
Commun. 1996, 667.
(11) (a) Durand-Reville, T.; Gobbi, L. B.; Gray, B. L.; Ley, S. V.; Scott,
J . S. Org. Lett. 2002, 4, 3847. (b) Ley, S. V.; Gutteridge, C. E.; Pape,
A. R.; Spilliing, C. D.; Zumbrunn, C. Synlett 1999, 1295. (c) Denholm,
A. A.; J ennens, L.; Ley, S. V.; Wood, A. Tetrahedron 1995, 51, 6591.
(d) Koot, W. J .; Ley, S. V. Tetrahedron 1995, 51, 2077 and relevant
references therein.
(16) Fernandez-Mateos, A.; Coca, G. P.; Gonzalez, R. R.; Hernandez,
C. T. Tetrahedron 1996, 52, 4817.
(17) Fernandez-Mateos, A.; Barba, M. L.; Coca, G. P.; Gonzalez, R.
R.; Hernandez, C. T. Synlett 1995, 409.
(18) Fernandez-Mateos, A.; Barba, A. L.; Coca, G. P.; Gonzalez, R.
R.; Hernandez, C. T. Synthesis 1997, 1381.
(19) Fernandez-Mateos, A.; Barba, A. L.; de la Neva, E. M.; Coca,
G. P.; Alonso, J . P.; Silvo, A. R.; Gonzalez, R. R. Tetrahedron 1997, 53,
14131.
10.1021/jo0301346 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003
J . Org. Chem. 2003, 68, 6905-6918
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Paquette and Hong
CHART 1
SCHEME 1
SCHEME 2
first routing was via ketal 12, an intermediate considered
to have substantial potential as a consequence of its high
conformational rigidity and functional group constitution.
The alternative sequence was to be channeled through
13, a compound anticipated to be readily available and
whose oxidation within the cyclopentene ring was pro-
jected to set the proper level of oxygenation required of
the target. The likely prospect that 12 could materialize
as one of the oxidatively cleaved end-products of 13 did
not escape our notice.
One of the more interesting underlying opportunities
that would allow us to take advantage of this strategy
was considered to be the facile charged-accelerated
operation of an oxy-Cope rearrangement within a suit-
ably substituted norbornene exemplified by 14 (Scheme
2). The ring strain resident in 14 was certain to represent
a contributory factor to an enhanced rate for the [3,3]
sigmatropic shift. Furthermore, it would be particularly
advantageous to have access to 14 from a readily avail-
able, chiral nonracemic, and inexpensive commodity such
as (-)-bornyl acetate (15). By judicious selection of this
terpenoid ester, one introduces absolute configuration
directly relatable to that resident in dumsin (2) from the
very outset of the undertaking.
concern was the projected sensitivity of the oxygenated
A/B ring system. Although it seemed appropriate to delay
its installation as long as possible, we remained con-
cerned as to whether the concept of intramolecular
condensation of a silyl-protected cyanohydrin anion20
with a lactone carbonyl as envisioned for 10 f 2 (Scheme
1) could in fact be exploited. Accordingly, this step was
initially modeled with a structurally simpler prototype.21
Two approaches to 11 were also initially scrutinized. The
(20) For a review of intramolecular alkylation reactions of anions
of protected cyanohydrins, see: Albright, J . D. Tetrahedron 1983, 39,
3207.
Efficien t Ster eocon tr olled Syn th esis of th e ABC
Su bu n it. Although examples of ring closures based on
(21) Hong, F.-T.; Paquette, L. A. Tetrahedron Lett. 1994, 35, 9135.
6906 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
SCHEME 3
F IGURE 1. Computer-generated perspective drawing of the
final X-ray model of 21.
SCHEME 4
the nucleophilic addition of a protected cyanohydrin to a
ketone22 or aldehyde group have been documented in the
context of natural products synthesis,23 no reports of
analogous cyclization onto a lactone carbonyl had been
reported. To ensure the feasibility of this step and hence
our entire tactical design, the previously described lac-
tone 1624 was deprotonated with LDA and alkylated with
2-(2-bromoethyl)-1,3-dioxolane. The angular side chain
was thereby introduced to give 17 in 77% yield (Scheme
3), but only when standard conditions25 were avoided and
use was made of HMPA as cosolvent. This adjustment
was necessary in order to accommodate the limited
solubility of the lithium salt of 16 in THF alone. Depro-
tection of the acetal and Lewis acid-promoted conversion
of aldehyde 18 to the TBS-cyanohydrin26 set the stage
for the key cyclization step. Following dropwise treatment
of a cold (-78 °C) THF solution of 19 with 1.1 equiv of
potassium hexamethyldisilazide, 20 was indeed produced
in a highly diastereoselective manner. Only the R-cyano-
substituted tricyclic hemiacetal was detected. Corrobora-
tion of the stereochemical assignment, initially based on
the assumption that the larger substituent would be
positioned on the less crowded exo surface, was achieved
by X-ray crystallographic analysis of 21 (Figure 1).21,27
Arrival at 22 was accomplished by stirring an ethereal
solution of 21 with 1 N sodium hydroxide solution at room
temperature for 30 min. This simple procedure delivered
the colorless crystalline dumsin ABC prototype in quan-
titative yield. Advantageously, if the last three steps in
Scheme 3 are performed without the isolation of inter-
mediates, the overall yield of this conversion is increased
to a satisfying 61% level.
Eva lu a tion of En a n tiod efin ed Oxy-Cop e Rea r -
r a n gem en ts. The remote oxidation of (-)-15 followed by
a protecting group exchange has been reported by Money
and by Ward to be a reliable means for generating ketone
23.28 The organocerate species generated by transmeta-
lation of 3-benzyloxy-1-propyllithium with anhydrous
cerium trichloride29 added to 23 in an efficient manner
(Scheme 4). Endo attack was assumed to prevail as
commonly observed with camphor derivatives. When
attempts to effect the dehydration of 24 invariably led
to the undesired exo-methylene derivatives typified by
25-27, our attention was redirected to elaboration of
functionalized norbornenes instead. To this end, 23 was
transformed into triflate 28 by trapping of the enolate
anion with Comins’ reagent (Scheme 5). The correspond-
ing vinyl stannane 29, bromide 30, and iodide 31 could
subsequently be formed without difficulty in conventional
fashion.31 These attractive intermediates did not react
universally as originally anticipated. However, palladium-
catalyzed reaction of 28 with other vinylic and allylic
stannanes proceeded smoothly to afford 32, 34, and 35,
(22) Kraus, G. A.; Wan, Z. Tetrahedron Lett. 1997, 38, 6509.
(23) (a) Stork, G.; Manabe, K.; Liu, L. J . Am. Chem. Soc. 1998, 120,
1337. (b) Takahashi, T.; Iwamoto, H.; Nagashima, K.; Okabe, T.; Doi,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1319. (c) Takahashi, T.;
Satoshi, T.; Sakamoto, Y.; Yamada, H. J . Org. Chem. 1997, 62, 1912.
(d) Kato, A.; Higo, A.; Wu, X.; Takeshita, H. Heterocycles 1997, 46,
123. (e) Williams, D. R.; Coleman, P. J .; Henry, S. S. J . Am. Chem.
Soc. 1993, 115, 11654.
(24) Wolinsky, J .; Senyek, M. J . Org. Chem. 1968, 33, 3950.
(25) Clive, D. L. J .; Postema M. H. D. J . Chem. Soc., Chem. Commun.
1993, 429.
(26) Rawal, V. H.; Rao, J . A.; Cava, M. P. Tetrahedron Lett. 1985,
26, 4275.
(28) (a) Allen, M. S.; Darby, N.; Salisbury, P.; Sigurdson, E. R.;
Money, T. Can. J . Chem. 1978, 56, 733. (b) Ward, D. E.; Gai, Y. Can.
J . Chem. 1992, 70, 2627.
(29) Dimitrov, V.; Simova, S.; Kostova, K. Tetrahedron 1996, 52,
1699.
(27) We thank Prof. Robin Rogers (University of Alabama) for this
determination.
(30) Comins, D. L.; Dehghani, A. J . Org. Chem. 1995, 60, 794.
(31) Ritter, K. Synthesis 1993, 735.
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Paquette and Hong
SCHEME 5
SCHEME 6
SCHEME 7
from which the terminal carbinols 33 and 36 were
regioselectively crafted.
To set the stage for demonstrating the feasibility of the
oxy-Cope isomerization, the functionalized alkenyllithi-
um 3832 was coupled to 37 at -78 °C. During subsequent
warming to room temperature, the lithium alkoxide so
formed underwent spontaneous electronic reorganization
to furnish 39 after acidification (Scheme 6). Carbinol 40
proved to be isolable by quenching the same reaction
mixture with saturated NH4Cl in the cold. The rear-
rangement reaction could then be independently per-
formed by subjecting 40 to a basic environment about 0
°C. The stereochemical features of 39 were ascertained
by detailed NOE analysis (see the Experimental Section).
To incorporate a side chain that would ultimately
evolve into the A ring of dumsin, it becomes necessary
to position a three-carbon unit in the norbornenone as
reflected in 43. The precise location of this R group brings
added steric compression to the oxy-Cope rearrangement
since C-C bond formation necessarily must occur at that
site. The allyl derivative and the terminally oxygenated
equivalent (OMOM) were both examined (Scheme 7).
These options conveniently allowed for selective cleavage
of the tetrahydropyranyl ether (as 41 f 42) with pyri-
dinium tosylate in methanol followed by perruthenate
oxidation.33 As before, 43a and 43b could be converted
smoothly into 45 and 46, respectively. This structural
isomerization could be interrupted at the stage of carbinol
44, but this alternative was not routinely practiced.
Gen er a tion of Tr icyclic Aceta ls a n d Elu cid a tion
of Th eir Rea ctivity. Having learned how to assemble
46 in an expedient manner, we now were positioned to
examine various oxidative protocols aimed at transform-
ing its cyclopentene ring into a properly substituted
tetrahydrofuran. According to plan, the initial focus was
on tricyclic acetals such as 12. Ozonolysis of 46 under
pyridine-modulated conditions34 provided not the keto
(32) Generated by lithium-halogen exchange of the predescribed
bromide: Corey, E. J .; Kania, R. S. J . Am. Chem. Soc. 1996, 118, 1228.
(33) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
6908 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
SCHEME 8
SCHEME 10
was a stereoselective tandem bicycloacetalization process
that formally includes MOM deprotection and several
ensuing steps on the way to generating 51 in one pot. A
synopsis of the possible sequence of chemical events is
provided in Scheme 10. X-ray diffraction analysis of 51
(Figure 2)36 indicated clearly that the -CH2OTBDPS
substituent is projected axially from the cyclohexanone
ring and provides confirmation of the fact that 47 was
produced by way of a fully stereocontrolled oxy-Cope
reaction. Close stoichiometric control of the proportion
of trifluoroacetic anhydride is highly desirable in order
to preclude any visible signs of conversion to 52. This
lactone was the only insoluble product when a significant
excess of the oxidant was employed.
SCHEME 9
Attention is also drawn to the outcome of heating 47
with a catalytic quantity of p-toluenesulfonic acid in
benzene. These conditions led efficiently to the free keto
aldehyde 53 (92%) with only minimal epimerization R to
the ketone carbonyl (2% of 54). The premixing of 51 with
acetic acid at 0 °C followed by the introduction of TBAF
gave rise to 56 (Scheme 11). This carbinol was subjected
to photoinduced oxidative cyclization by irradiation with
a tungsten lamp at 45 °C in the presence of iodosobenzene
diacetate and iodine.37 Abstraction by the photogenerated
oxo radical of a proximate hydrogen atom generates a
C-centered radical amenable to intra- or intermolecular
interception.38 In the present circumstance, the ortho
ester 57 was isolated in 52% yield.
It was our hope to exploit the arrival at 56 and
57 by means of one or another hydrolytic reaction,
precedent for which was available.39 Should the conver-
sion of 57 to 58 occur uneventfully, we would find
ourselves ready for construction of the CD rings of
dumsin. However, the production of this dihydroxy keto
lactone did not materialize. The cyclic compound 57
aldehyde but its hydrated form 47 (Scheme 8). NOE
measurements on 47 demonstrated that, at least in
solution, the two hydroxy groups are oriented syn to each
other in a way that allows a double-anomeric effect and
intramolecular hydrogen bonding to operate. As a con-
sequence, 47 is formed exclusively relative to the other
possible diastereomers. Although 46 could be reduced
cleanly to â-alcohol 49, and access to 48-55 was as
readily achieved, none of these proved to be targets of
opportunity for more extensive scrutiny (Scheme 9).
A noteworthy observation was made during the oxida-
tion of 47 with trifluoroperacetic acid.35 Thereby initiated
(35) Cooper, M. S.; Heaney, H.; Newbold, A. J .; Sanderson, W. R.
Synlett 1990, 533.
(36) We thank Dr. J udith Gallucci (Ohio State University) for this
determination.
(37) Martin, A.; Salazar, J . A.; Suarez, E. J . Org. Chem. 1996, 61,
3999.
(38) (a) Spitz, U. P.; Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2220. (b) Paquette, L. A.; Meister, P. G.; Friedrich, D.; Sauer, D.
R. J . Am. Chem. Soc. 1993, 115, 49. (c) Paquette, L. A.; Sun, L.-Q.;
Friedrich, D.; Savage, P. B. Tetrahedron Lett. 1997, 38, 195. (d) Togo,
H.; Muraki, T.; Hoshina, Y.; Yamabuchi, K.; Yokoyama, M. J . Chem.
Soc., Perkin Trans. 1 1997, 787. (e) Hatakeyama, S.; Kawamura, M.;
Takano, S. J . Am. Chem. Soc. 1994, 116, 4081.
(39) (a) Nicolaou, K. C.; Sorensen, E. J . Classics in Organic
Synthesis; VCH: Weinheim, 1996. (b) White, J . D.; Shin, H.; Kim, T.-
S.; Cutshall, N. S. J . Am. Chem. Soc. 1997, 119, 2414.
(34) Haag, T.; Luu, B.; Tetru, C. J . Chem. Soc., Perkin Trans. 1 1988,
2353.
J . Org. Chem, Vol. 68, No. 18, 2003 6909

Paquette and Hong
F IGURE 2. Computer-generated perspective drawing of the final X-ray model of 51.
SCHEME 11
SCHEME 12
unmasking later in the synthesis could prove feasible.
The perruthenate oxidation of 56 was sluggish but gave
aldehyde 61 cleanly in 78% yield (Scheme 12). The first
chain extension option to be explored consisted of ap-
plication of the Wadsworth-Emmons protocol to furnish
62, followed by acetalization and reduction with Dibal-
H. As expected, the carbomethoxy group emerged as a
primary alcohol, which was transformed by SN2 chem-
istry into nitrile 65. While the reduction of these steps
to practice proceeded with reasonable efficiency, the
elaboration of diol 66 and more advanced intermediates
appears to have the enthalpic advantage, the proclivity
for existing in cyclic forms being also noted in the
quantitative conversion of 56 into 59 with 5% HCl in
aqueous acetone and the unoptimized intramolecular
closure to generate 60 in the presence of trimethyl
orthoformate.
Notwithstanding, the predescribed results lent cre-
dence to the working hypothesis that the acetal moiety
in 51 would prove to be a robust protecting group for the
primary alcohol and lactal functional groups, and that
6910 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
SCHEME 13
F IGURE 3. Computer-generated perspective drawing of the
final X-ray model of 76.
The stereochemical assignments to aldol products 76
and 77 were elucidated by NOE methods applied to 76
and 79 (see the Experimental Section), and the relative
stereochemistry of 76 was confirmed by X-ray crystal-
lographic evidence (Figure 3).36 The ORTEP diagram
clearly shows that the newly formed cyclohexanol ring
adopts a chair conformation housing a bulky axially
disposed OTBS group. We consider it remarkable that
diastereomers 80a and 80b in which the bulky siloxy
substituent occupies an equatorial position were not
formed at detectable levels.
was characterized by low yields at every step. An
alternative mode of construction of the dumsin D ring
was consequently explored.
4-Butenylmagnesium bromide proved to be an accept-
able elongation element to couple with aldehyde 70. At
-78 °C, the R-alcohol 71 proved to be the predominant
product (R/â ) 10:1, Scheme 13). Protection of the
secondary alcohol as the TBS ether 72 followed by a
hydrolysis-oxidation sequence led to the unsaturated
ketone 74. Ozonolysis was successful in delivering keto
aldehyde 75a , thereby setting the stage for cycloaldoliza-
tion chemistry. The use of potassium carbonate in
methanol at room temperature generated predominantly
the thermodynamic aldol product 76, whereas the kinetic
isomer 77 dominated when the cyclization was performed
with sodium methoxide in methanol at approximately
-10 °C for 120 h. When 77 was heated with sodium
hydroxide in aqueous methanol, conversion to 76 was
observed.
The dilemma that we now faced could arise by virtue
of severe steric repulsion between the equatorial protect-
ing group and the adjacent tetrahydropyran ring. On this
basis, it was considered appropriate to orient the siloxy
group axially as in 81 or to drastically reduce the size of
the oxygenated carbon by placing a ketone carbonyl at
that site (see 82). We opted to examine the latter
alternative.
The discovery that the oxidation of 71, when performed
with pyridinium chlorochromate, resulted in formation
of the rearranged aldehyde 83 was only a temporary
setback (Scheme 14). Alternate use of the Dess-Martin
J . Org. Chem, Vol. 68, No. 18, 2003 6911

Paquette and Hong
SCHEME 14
SCHEME 15
SCHEME 16
periodinane40 gave rise to 84. The latter on reduction with
Dibal-H simply reinstated the R-hydroxyl as in 85. On
the other hand, hydrolytic removal of the acetate, oxida-
tion to diketone 87, and ozonolysis resulted in the
efficient formation of 88. While this was a key advance,
we were disappointed to find that subsequent aldolization
gave rise to a mixture of 89/90 or only 90 depending upon
conditions. As before, the relative stereochemistry of 90
was elucidated by NOE experiments. Having encountered
this obstacle, we departed from this plan and returned
to probe the prospects held by ketones of the generic
family 13.
Im p lem en ta tion of th e Alter n a tive P la n Ba sed on
46. The feasibility of involving 46 was next accorded
prime consideration. This readily accessible intermediate
was quickly noted to be base-sensitive. For example,
epimerization could not be skirted during desilylation
with TBAF. Although this complication could be circum-
vented through the utilization of buffers, it proved more
advisable to engage 46 in ketalization as the initial
maneuver (Scheme 15). Standard oxidation of 92 with a
catalytic amount of perruthenate salt in the presence of
NMO as the co-oxidant followed by nucleophilic side-
chain elongation of aldehyde 93 furnished 94 in quite
respectable yield. This secondary alcohol was expedi-
tiously silylated with TBSOTf in advance of acid-
catalyzed intramolecular aldol cyclization. The use of 2%
HCl in THF at room temperature (72 h) gave rise to the
desired products 96a and 96b in a 7:1 ratio.
The crossover in stereoselectivity observed for the
4-butenylmagnesium bromide addition to 70 leading to
71 and for the conversion of 93 to 94 prompted examina-
tion of the analogous Grignard coupling to 70 (Scheme
16). In so doing, we discovered that 98 was formed
exclusively (70% isolated) in line with earlier observa-
tions. These findings are explainable in terms of the
Cram model. Should steric constraints cause orientation
of the carbonyl oxygen away from these regions, the
(40) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
6912 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
SCHEME 17
SCHEME 18
illustrated conformations are likely to be adopted. Nu-
cleophilic attack by the organometallic species from the
less hindered direction (as denoted by the arrows)
eventuates in the involvement of opposite faces of the
carbonyl π cloud.
Before carrying the silyl ethers 97a and 97b forward,
we were prompted to examine the consequences of the
exposure of these intermediates to ozonolysis conditions.
For this purpose, keto alcohol 96a was reduced to 100 in
diastereocontrolled fashion and protected as the ac-
etonide 101 (Scheme 17). The conformational rigidity
imposed on 101 as a consequence of the presence of the
dioxane ring was of advantage to stereochemical assign-
ment by means of NOE studies. Unlike the behavior of
46, which leads to 47 on oxidative cleavage, 101 reacts
more sluggishly to generate a labile ozonide amenable
to clean conversion to keto aldehyde 102.
The successful screening of the 96a f 102 conversion
prompted a detailed analysis of the response of the three
substrates compiled in Scheme 18 to the identical oxida-
tive cleavage conditions. Although a product of the same
type as 102 made its appearance in each of the examples,
the over-oxidized R-hydroxy keto aldehydes 111, 113, and
115 unexpectedly materialized as the major products. No
improvement was realized by modifying the ozonolysis
solvent from polar (CH3OH, CH2Cl2, etc.) to nonpolar
(pentane). Ultimately, a more broadly based investigation
turned up the fact that ruthenium tetraoxide at room
temperature41 smoothly transformed 104 into 110 with-
out detectable contamination from the over-oxidized
product (Scheme 19). Prolonged reaction times have been
shown not to generate the corresponding keto acid.
Furthermore, there exists no need for prior reduction of
the ketone carbonyl group as reflected in the rather
efficient conversion of 97b to 116 without visible signs
of 117.
precursor to dumsin, viz. 119 or a closely related struc-
ture (Scheme 20). In principle, two sequential oxidations
would allow us to access this advanced intermediate and
allow in-depth investigation of E-ring incorporation.
While the exact order of these two steps is not likely of
direct importance, the regioselectivity of the Baeyer-
Villiger oxidative insertion is most crucial. With these
guidelines in mind, extensive investigation was made of
a broad spectrum of intermediates, the oxidation levels
in which were varied in order to uncover an optimal
substrate/functional group interrelationship if such ex-
isted.
However, all trials have so far failed to yield positive
results. The principal complicating factor behind these
difficult experiments is the substantive steric congestion
in the â-region of these compounds. Reagents cannot
perform their normal, anticipated function because of an
With these observations in hand, only two steps were
believed to separate us from a presumed key lactone
(41) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
J . Org. Chem, Vol. 68, No. 18, 2003 6913

Paquette and Hong
layers were washed with brine, dried, and concentrated under
reduced pressure to afford 1.53 g of viscous product. Purifica-
tion of this residue by flash chromatography (ethyl acetate/
hexanes, 1:5) provided 17 as a colorless waxy solid (1.24 g,
SCHEME 19
1
77%): IR (neat, cm-1) 2937, 1757, 1145; H NMR (300 MHz,
CDCl3) δ 4.87-4.84 (m, 1 H), 3.96-3.81 (m, 4 H), 2.14 (d, J )
2.7 Hz, 1 H), 1.82-1.47 (series of m, 12 H), 1.46 (s, 3 H), 1.40
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 180.5, 104.2, 85.0, 69.5,
45.0, 44.6, 30.9, 30.4, 29.1, 28.9, 25.8, 21.2, 20.6, 20.1; MS m/z
(M+) calcd 268.1674, obsd 268.1669. Anal. Calcd for C15H24O4:
C, 67.12; H, 9.02. Found: C, 66.57; H, 9.03.
(()-(3a R*,7a R*)-7a -(2-F or m ylet h yl)h exa h yd r o-3,3-d i-
m eth ylp h th a lid e (18). To a stirred solution of 17 (2.15 g, 8.04
mmol) in wet acetone (270 mL, 20% water) was added a
catalytic amount of TsOH (4.02 g), and the resulting mixture
was stirred at room temperature for 72 h or heated to reflux
for 7 h. The solvent was volatilized under reduced pressure,
and the residue was partitioned between water and ether (100
mL of each). The separated aqueous phase was extracted with
ether (100 mL × 3), and the combined organic phases were
washed with brine, dried, and evaporated to give 18 (1.75 g,
1
97%) as a colorless oil: IR (neat, cm-1) 1755, 1722, 1266; H
NMR (300 MHz, CDCl3) δ 9.79 (s, 1 H), 2.59 (m, 2 H), 2.15 (d,
J ) 2.9 Hz, 1 H), 2.14-1.85 (series of m, 2 H), 1.77-1.48 (series
of m, 8 H), 1.46 (s, 3 H), 1.40 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 201.2, 180.2, 85.2, 45.8, 44.5, 39.4, 30.5, 30.1, 26.6,
25.7, 21.1, 20.4, 19.8; MS m/z (M+) calcd 224.1412, obsd
224.1395.
SCHEME 20
(()-(3a R*,7a R*)-7a -[3-(ter t-Bu tyld im eth ylsiloxy)-3-cy-
a n op r op yl]h exa h yd r o-3,3-d im eth ylp h th a lid e (19). To a
solution of 18 (1.30 g, 5.8 mmol) in anhydrous acetonitrile (29
mL) was added sequentially potassium cyanide (1.51 g, 20.2
mmol), anhydrous zinc iodide (29 mg, 0.09 mmol), and tert-
butyldimethylsilyl chloride (1.044 g, 20.2 mmol) at room
temperature. The mixture was stirred for 24 h and evaporated
under reduced pressure to afford a residue which was redis-
solved in ether (25 mL). The undissolved material was removed
by filtration and rinsed with more ether (15 mL). The filtrate
was washed with water, dried, and concentrated in vacuo.
Isolation of the mixture of diastereomers 19 as a colorless oil
(1.76 g, 83%) was accomplished by column chromatography
(silica gel, ethyl acetate/hexanes, 1:6): IR (neat, cm-1) 1759,
1
1263, 1114; H NMR (300 MHz, CDCl3) δ 4.44 (m, 1 H), 2.08
(d, J ) 5.9 Hz, 2 H), 1.98-1.49 (series of m, 11 H), 1.46 (s, 3
H), 1.41 (s, 3 H), 0.89 (s, 9 H), 0.15 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 180.0, 178.9, 119.6, 85.1, 62.0, 61.7, 45.5, 44.8, 44.7,
31.4, 30.5, 30.4, 29.8, 29.5, 25.7, 25.5, 21.1, 20.5, 19.8, 18.0,
17.9, -5.3, -5.4; MS m/z (M+) calcd 365.2386, obsd 365.2356.
Anal. Calcd for C20H35NO3Si: C, 65.71; H, 9.66. Found: C,
65.8; H, 9.68.
inability to become covalently linked to the substrate in
question. This deterrent mandates that very special
tactics be fruitfully applied in order to achieve the
targeted goal. Undertakings of this type are currently in
progress.
(()-(3aR*,3aS*,5aR*,9aR*)-3-(ter t-Bu tyldim eth ylsiloxy)-
d eca h yd r o-3a -h yd r oxy-5,5-d im eth ylcyclop en t[c]isoben -
zofu r a n -3-ca r bon itr ile (20). To a stirred solution of TBS-
cyanohydrin 19 (30.2 mg, 0.083 mmol) in THF (1 mL) was
added KHMDS (0.5 M in toluene, 0.19 mL) dropwise at -78
°C. After 10 min of stirring, water (1 mL) was introduced in
one portion and the whole system was allowed to warm to room
temperature. The resulting solution was diluted with ether (1
mL), and the aqueous phase was extracted with ether (1 mL
× 3). The organic solutions were dried, filtered, and concen-
trated to yield a pale yellow residue which was subjected to
flash chromatography (ethyl acetate/hexanes, 1:5) to afford 20
(18.7 mg, 62%) as a colorless wax: IR (neat, cm-1) 3591, 3453,
Exp er im en ta l Section
(()-(3a R*,7a R*)-7a -[2-(1,3-Dioxola n -2-yl)eth yl]h exa h y-
d r o-3,3-d im eth ylp h th a lid e (17). To a stirred solution of
diisopropylamine (1.0 mL, 6.6 mmol) in THF (10 mL) was
added n-butyllithium (4.2 mL, 1.6 M in hexanes, 6.6 mmol) at
0 °C. Stirring was continued for 15 min, and the temperature
was lowered to -78 °C, and then 2 mL of HMPA was added.
This reaction mixture was added dropwise to a solution of
lactone 1624 (1.01 g, 6.0 mmol) in a mixed solvent system
consisting of THF (10 mL) and HMPA (2 mL). The resulting
yellow solution was stirred at -78 °C for 1 h followed by the
addition of 2-(2-bromoethyl)-1,3-dioxolane (1.187 g, 6.6 mmol)
in THF (10 mL). The mixture was allowed to warm to room
temperature, stirred for another 30 min, and quenched with
saturated NH4Cl solution. The separated aqueous layer was
extracted with ether (50 mL × 3), and the combined organic
1
2257; H NMR (300 MHz, CDCl3) δ 2.61 (s, 1 H), 2.12 (m, 1
H), 1.89 (m, 2 H), 2.28 (m, 4 H), 1.46 (series of m, 6 H), 1.28
(s, 3 H), 1.24 (s, 3 H), 0.92 (s, 9 H), 0.24 (s, 3 H), 0.22 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 120.5, 111.9, 86.6, 81.4, 55.7, 51.6,
36.4, 35.4, 29.6, 29.0, 25.8, 25.7, 21.8, 20.7, 19.7, 18.2, -3.3,
-3.5; MS m/z (M+ + 1) calcd 366.2646, obsd 366.2632.
(()-(3a R*,3a S*,5a R*,9a R*)-Deca h yd r o-3-3a -d ih yd r oxy-
5,5-d im et h ylcyclop en t [c]isob en zofu r a n -3-ca r b on it r ile
(21). To a solution of 20 (18.7 mg, 0.051 mmol) in dry THF (1
6914 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
mL) was added a solution of TBAF (1.0 M in THF, 56 µL) and
stirred for 30 min at room temperature. After a water quench
(1 mL) and dilution with ether (1 mL), the separated aqueous
layer was extracted with ether (1 mL × 3), and the combined
organic layers were washed with brine, dried, and concentrated
under reduced pressure to afford a viscous product. Purifica-
tion of this residue by flash chromatography (ethyl acetate/
hexanes, 1:5) provided pure 21 (8.8 mg, 77%) as a colorless
crystalline solid: mp 112-114 °C (from ethyl acetate-hex-
reduced pressure to give a yellow oil which was subjected to
flash chromatographic purification (ethyl acetate/hexanes,
1:40) to yield 35 (98 mg, 89%) as a colorless oil: IR (neat, cm-1
)
1642, 1137, 1117; 1H NMR (300 MHz, CDCl3) δ 5.89-5.77 (m,
1H), 5.23 (d, J ) 14.0 Hz, 1 H), 5.10 (dd, J ) 3.3, 1.6 Hz, 1 H),
5.03 (m, 1 H), 4.56 (m, 1 H), 4.27 (dd, J ) 7.0, 2.8 Hz, 0.5 H),
4.06 (dd, J ) 7.0, 2.8 Hz, 0.5 H), 3.92-3.80 (m, 1 H), 3.47 (m,
1 H), 2.87 (m, 2 H), 2.25 (m, 1 H), 2.11 (dd, J ) 11.1, 3.7 Hz,
1 H), 1.81-1.41 (m, 6 H), 1.33 (m, 1 H), 1.09 (s, 3 H), 0.82 (s,
3 H), 0.81 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 147.1, 146.2,
136.03, 136.01, 129.6, 128.8, 115.5, 115.4, 101.0, 96.0, 86.1,
81.8, 62.9, 61.9, 57.4, 57.3, 57.0, 56.8, 54.48, 54.46, 35.7, 35.1,
33.8, 31.10, 31.07, 25.6, 25.5, 20.04, 20.00, 19.40, 19.37, 19.26,
11.50, 11.48; MS m/z (M+) calcd 276.2090, obsd 276.2085.
1
anes); IR (neat, cm-1) 3418, 1256, 1225; H NMR (300 MHz,
CDCl3) δ 3.48 (d, J ) 1.6 Hz, 1 H), 2.67 (s, 1 H), 2.00-1.98
(series of m, 2 H), 1.90-1.65 (series of m, 5 H), 1.63 (s, 1 H),
1.62-1.35 (series of m, 5 H), 1.32 (s, 3 H), 1.30 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 119.8, 112.9, 87.7, 76.9, 54.4, 52.9,
37.9, 52.9, 30.3, 28.8, 25.2, 21.9, 20.7, 20.0; MS m/z (M+) calcd
251.1521, obsd 251.1524.
(1R,4S,5R)-4,7,7-Tr im eth yl-5-[(tetr a h yd r o-2H-p yr a n -2-
yl)oxy]bicyclo[2.2.1]h ep t-2-en e-2-p r op a n ol (36). A solution
of 2,3-dimethyl-2-butene (42 mL, 1.0 M in THF) was treated
with BH3-THF complex (42 mL, 1.0 M in THF) at 0 °C, and
the solution was stirred for 1.5 h prior to the addition of a
solution of 35 (11.50 g, 0.042 mol) at the same temperature.
The resulting mixture was stirred for another 2 h, treated with
15% NaOH solution (42 mL) followed by H2O2 (aq, 30%, 42
mL) at 0 °C, and allowed to warm to room temperature during
1.5 h. The mixture was extracted with ether (40 mL × 3), and
the combined organic layers were dried and evaporated to
leave a colorless oil, which was purified by flash chromatog-
raphy (ethyl acetate/hexanes, 1:4) to give colorless oily 36 (as
two separable diastereomeric alcohols 36a and 36b, 1:1, 10.70
g, 87%).
(()-(3a R *,5a S *,9a S *)-Oct a h yd r o-3a -h yd r oxy-5,5-d i-
m eth ylcyclop en t[c]isoben zofu r a n -3(3a H)-on e (22). A so-
lution of 21 (6.4 mg, 0.026 mmol) in ether (0.5 mL) was treated
with 1 N aqueous NaOH solution (0.04 mL), stirred vigorously
at room temperature for 30 min, and diluted with brine (1 mL).
The separated organic layer was dried and concentrated under
reduced pressure to furnish 22 (3.9 mg, 100%) as a colorless
crystalline solid: mp 72-75 °C (from ethyl acetate/hexanes);
IR (neat, cm-1) 3432, 1755; 1H NMR (300 MHz, CDCl3) δ 3.39
(s, 1 H), 2.67 (m, 1 H), 2.28 (ddd, J ) 18.0, 8.1, 3.4 Hz, 1 H),
2.05 (ddd, J ) 18.0, 8.1, 3.4 Hz, 1 H), 1.89 (m, 2 H), 1.75-1.46
(series of m, 6 H), 1.39-1.37 (m, 2 H), 1.34 (s, 3 H), 1.28 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 212.0, 104.3, 87.0, 53.6, 50.8,
32.5, 32.0, 30.0, 29.3, 26.1, 22.3, 21.4, 19.8; MS m/z (M+) calcd
224.1412, obsd 224.1381. Anal. Calcd for C13H20O3: C, 69.60;
H, 8.99. Found: C, 69.57; H, 9.10.
1
For 36a : IR (neat, cm-1) 3461, 1137, 1062; H NMR (300
MHz, CDCl3) δ 5.23 (s, 1H), 4.59 (m, 1 H), 4.07 (dd, J ) 7.5,
2.6 Hz, 1 H), 3.82 (m, 1 H), 3.69 (t, J ) 6.1 Hz, 2 H), 3.45 (m,
1 H), 2.33 (ddd, J ) 12.6, 7.5, 3.9 Hz, 1 H), 2.19 (m, 2 H), 2.08
(d, J ) 3.5 Hz, 1 H), 1.80-1.59 (series of m, 5 H), 1.48 (m, 4
H), 1.10 (dd, J ) 12.1, 2.8 Hz, 1 H), 1.02 (s, 3 H), 0.79 (s, 3 H),
0.77 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 148.5, 128.4, 101.0,
86.0, 63.2, 62.9, 57.2, 57.1, 55.2, 35.8, 31.0, 30.0, 27.0, 25.5,
20.0, 19.9, 19.3, 11.6; MS m/z (M+) calcd 294.2159, obsd
294.2188.
(1S,4S,5R)-4,7,7-Tr im eth yl-5-(tetr a h yd r o-2H-p yr a n -2-
yl)oxy]b icyclo[2.2.1]h ep t -2-en -2-ol Tr iflu or om et h a n e-
su lfon a te (28). To a stirred solution of 23 (8.4 g, 0.034 moL)
in anhydrous THF (180 mL) was added slowly via addition
funnel a solution of KHMDS (0.5 M in toluene, 100 mL, 0.05
mol) at 0 °C during 40 min. The resulting brown solution was
stirred at the same temperature for another 1 h, allowed to
warm to room temperature overnight, treated slowly with
N-(5-chloro-2-pyridyl)triflimide (17.5 g, 0.044 mol) in THF (120
mL) at 0 °C during 45 min, and allowed to gradually warm to
room temperature during 4 h. The mixture was diluted with
water (50 mL) and ether (100 mL), and the separated organic
layer was washed with 5% NaOH solution and brine and then
dried. The filtrate was concentrated under reduced pressure,
and the residue was purified by flash chromatography (ethyl
acetate/hexanes, 1:40) to provide 28 (9.96 g, 78%) as a colorless
oil containing two inseparable acetals; IR (neat, cm-1) 1460,
1
For 36b: IR (neat, cm-1) 3406, 1060, 1036; H NMR (300
MHz, CDCl3) δ 5.27 (d, J ) 0.8 Hz, 1 H), 4.53 (t, J ) 3.4 Hz,
1 H), 4.25 (dd, J ) 7.1, 2.5 Hz, 1 H), 3.87 (m, 1 H), 3.65 (t, J
) 6.1 Hz, 2 H), 3.48 (m, 1 H), 2.25-2.14 (m, 3 H), 2.10 (d, J )
3.8 Hz, 1 H), 1.84 (br s, 1 H), 1.82-1.67 (series of m, 3 H),
1.65-1.42 (series of m, 5 H), 1.07 (s, 3 H), 0.90 (dd, J ) 12.2,
2.5 Hz, 1 H), 0.80 (s, 3 H), 0.76 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 147.9, 128.9, 96.0, 81.8, 63.2, 61.8, 57.3, 56.6, 55.2,
33.8, 30.9, 29.9, 27.2, 25.6, 20.0, 19.3, 19.2, 11.5; MS m/z (M+)
calcd 294.2159, obsd 294.2192.
1
1399; H NMR (300 MHz, CDCl3) δ 5.38 (d, J ) 1.0 Hz, 1 H,
Tetr ah ydr o-2-[[(1S,2R,4R)-5-[3-[(m eth oxym eth oxy)pr o-
p yl-1,7,7-t r im et h ylb icyclo[2.2.1]h ep t -5-en -2-yl]oxy]-2H -
p yr a n (41). A stirred solution of 36 (3.7 g, 1.3 mmol) in CH2Cl2
(40 mL) was cooled to 0 °C, treated with diisopropylethylamine
(11.0 mL, 0.06 mol) and dropwise with chloromethyl methyl
ether (2.9 mL, 0.04 mol), allowed to warm to room temperature
overnight, diluted with CH2Cl2 (20 mL), and washed with brine
(15 mL). The separated organic phase was dried and concen-
trated to yield a brown residue that was subjected to flash
chromatography (ethyl acetate/hexanes, 1:20 with 1% of tri-
ethylamine) to provide 41 (3.87 g of a mixture of two isomers,
minor isomer), 5.34 (d, J ) 0.5 Hz, 1 H, major isomer), 4.65
(t, J ) 3.4 Hz, 1 H, minor isomer), 4.56 (t, J ) 3.2 Hz, 1 H,
major isomer), 4.33 (dd, J ) 7.0, 2.4 Hz, 1 H, minor isomer),
4.11 (dd, J ) 7.5, 2.6 Hz, 1 H, major isomer), 3.82 and 3.52
(two sets of m, 2 H), 2.51-2.31 (two sets of m, 2 H), 1.78-1.30
(series of m, 7 H), 1.18, 1.11 and 0.81 (three sets of s, 9 H,
major isomer), 0.97, 0.96, and 0.82 (three sets of s, 9 H, minor
isomer); 13C NMR (75 MHz, CDCl3) δ 154.7, 154.0, 121.3, 120.6,
100.7, 95.9, 84.9, 80.8, 62.4, 61.9, 57.9, 57.8, 57.5, 57.4, 53.3,
53.2, 35.8, 33.7, 30.8, 30.7, 25.5, 25.4, 19.5, 19.4, 19.3, 19.1,
18.9, 18.8, 11.4; MS m/z (M+) calcd 384.1216, obsd 384.1249.
1
91%) as a colorless oil: IR (neat, cm-1) 1442, 1384, 1118; H
2-[[(1S,2R,4R)-5-Allyl-1,7,7-tr im eth ylbicyclo[2.2.1]h ep t-
5-en -2-yl]oxy]tetr ah ydr o-2H-pyr an (35). Flame-dried lithium
chloride (86 mg, 2 mmol) was added to dry DMF (10 mL),
followed by 28 (153 mg, 0.4 mmol), allyltributylstannane (134
mg, 0.4 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The
bright yellow solution was heated at 100 °C until the formation
of a black precipitate was complete (2 h). After being cooled
to room temperature, the mixture was poured into a mixture
of ether (15 mL) and saturated KF solution (20 mL) and stirred
vigorously for at least 20 min. The organic layer was washed
with brine and dried. The filtrate was concentrated under
NMR (300 MHz, CDCl3) δ 5.22 (s, 1 H, minor isomer), 5.18 (s,
1 H, major isomer), 4.62 (s, 2 H, major isomer), 4.61 (s, 2 H,
minor isomer), 4.60-4.53 (m, 1 H), 4.25 (dd, J ) 7.0, 2.4 Hz,
1 H, minor isomer), 4.06 (dd, J ) 7.6, 2.6 Hz, 1 H, major
isomer), 3.91-3.79 (m, 1 H), 3.60-3.38 (m, 4 H), 3.36 (s, 3 H,
major isomer), 3.35 (s, 3 H, minor isomer), 2.23 (ddd, J ) 12.0,
7.6, 3.8 Hz, 1 H), 2.24-2.07 (m, 4 H), 1.83-1.42 (series of m,
7 H), 1.09 (dd, J ) 12.1, 2.5 Hz, 1 H, major isomer), 1.08 (s, 3
H, minor isomer), 1.00 (s, 3 H, major isomer), 0.86 (dd, J )
12.1, 2.5 Hz, 1 H, minor isomer), 0.81 (s, 3 H, minor isomer),
0.79 (s, 3 H, major isomer), 0.77 (s, 3 H); 13C NMR (75 MHz,
J . Org. Chem, Vol. 68, No. 18, 2003 6915

Paquette and Hong
CDCl3) δ 148.4, 147.5, 128.9, 128.2, 100.9, 96.4, 96.0, 86.0, 81.8,
67.6, 67.5, 62.8, 61.9, 57.2, 57.0, 56.7, 55.1, 55.0, 35.8, 33.9,
31.1, 27.8, 26.8, 25.7, 25.5, 20.1, 20.0, 19.4, 19.3, 11.6, 11.5;
MS m/z (M+) calcd 338.2457, obsd 338.2464.
For 46: IR (neat, cm-1) 1714, 1112; 1H NMR (300 MHz,
CDCl3) δ 7.67-7.63 (m, 4 H), 7.45-7.37 (m, 6 H), 5.15 (d, J )
1.1 Hz, 1 H), 4.58 (s, 2 H), 3.64 (dd, J ) 10.4, 5.3 Hz, 1 H),
3.56 (dd, J ) 16.6, 6.2 Hz, 1 H), 3.43 (m, 2 H), 3.39 (s, 3 H),
2.60 (dd, J ) 7.1, 5.5 Hz, 1 H), 2.30 (dd, J ) 11.6, 7.6 Hz, 2
H), 2.18 (dd, J ) 11.9, 6.2 Hz, 1 H), 2.07 (t, J ) 7.3 Hz, 1 H),
1.56 (d, J ) 1.3 Hz, 3 H), 1.51 (m, 4 H), 1.12 (d, J ) 7.1 Hz, 3
H), 1.09 (s, 3 H), 1.03 (s, 9 H), 0.85 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 216.2, 145.6, 135.64, 135.56, 135.1, 133.37, 133.36,
129.7, 127.9, 127.67, 127.65, 96.4, 68.3, 62.3, 55.1, 51.8, 51.7,
48.3, 46.1, 42.6, 40.6, 38.8, 30.7, 26.8, 25.2, 22.5, 19.1, 12.6,
12.4.; MS m/z (M+ - C4H9) calcd 505.2774, obsd 505.2738;
(1S ,2R ,4R )-5-[3-[(Me t h o x y m e t h o x y )p r o p y l]-1,7,7-
tr im eth ylbicyclo[2.2.1]h ep t-5-en -2-ol (42b). A mixture of
41 (3.87 g, 0.011 mol) and p-toluenesulfonic acid (0.11 g, 0.58
mmol) in methanol (150 mL) was stirred at room temperature
for 1 h, and the resulting pale yellow solution was diluted with
saturated sodium bicarbonate solution (50 mL) and extracted
with ether (75 mL × 3). The combined organic layers were
washed with brine, dried, and concentrated under reduced
pressure. The crude product (3.21 g) was purified by flash
chromatography (ethyl acetate/hexanes, 1:2 with 1% triethy-
lamine) to afford deprotected alcohol 42b (ca. 3.0 g, 100%) as
a colorless oil: IR (neat, cm-1) 3450, 1148, 1113; 1H NMR (300
MHz, CDCl3) δ 5.23 (s, 1 H), 4.59 (s, 2 H), 4.08 (br m, 1 H),
3.54 (t, J ) 6.4 Hz, 2 H), 3.34 (s, 3 H), 2.39 (ddd, J ) 12.7, 7.7,
3.6 Hz, 1 H), 2.20 (ddd, J ) 7.7, 7.7, 1.3 Hz, 2 H), 2.11 (d, J )
3.6 Hz, 1 H), 1.84-1.67 (m, 2 H), 1.03 (s, 3 H), 0.80 (s, 3 H),
0.77 (m, 1 H), 0.75 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 152.9,
126.0, 96.3, 78.9, 67.6, 58.2, 57.7, 55.2, 55.1, 37.9, 27.3, 27.1,
20.3, 19.0, 10.8; MS m/z (M+) calcd 254.1882, obsd 254.1873.
[R]24 -5.4 (c 0.50, CHCl3). Anal. Calcd for C35H52O4Si: C,
D
74.69; H, 8.96. Found: C, 74.76; H, 8.94.
1
For 44b: IR (neat, cm-1) 3475, 1112, 1039; H NMR (300
MHz, CDCl3) δ 7.70-7.66 (m, 4 H), 7.43-7.36 (m, 6 H), 5.44
(t, J ) 6.8 Hz, 1 H), 5.06 (d, J ) 1.1 Hz, 1 H), 4.60 (s, 2 H),
4.24 (dd, J ) 5.9, 1.1 Hz, 1 H), 3.50 (t, J ) 6.4 Hz, 2 H), 3.34
(s, 3 H), 2.13-2.00 (series of m, 4 H), 1.79-1.60 (series of m,
4 H), 1.41 (s, 3 H), 1.14 (s, 3 H), 1.04 (s, 9 H), 1.02 (s, 3 H),
0.91 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 147.2, 140.8, 135.6,
134.0, 131.2, 129.6, 127.6, 126.1, 96.4, 86.3, 67.6, 61.6, 60.8,
59.9, 55.1, 54.2, 38.4, 27.2, 26.9, 26.8, 22.3, 21.5,19.1, 15.4, 8.83;
MS m/z (M+) calcd 562.3478, obsd 562.3479; [R]24 +36.2 (c
D
(1S ,4R )-5-[3-(M e t h o x y m e t h o x y )p r o p y l]-1,7,7-t r i -
m et h ylbicyclo[2.2.1]h ep t -5-en -2-on e (43b ). A solution of
42b (3.0 g, 0.01 mol) in CH2Cl2 (50 mL) was charged with
powdered 4 Å molecular sieves (ca. 2.0 g) and 4-methylmor-
pholine N-oxide (2.08 g, 0.018 mol). The resulting suspension
was slightly cooled in a water bath, treated with tetrapropy-
lammonium perruthenate (TPAP, 0.21 g, 0.59 mmol) slowly
at room temperature (slightly exothermic), stirred for 2 h until
the starting material was completely consumed (TLC analysis),
and passed through a short pad of Florisil and Celite (1:1).
The filter cake was washed several times with CH2Cl2. The
combined filtrates were concentrated to give a green-yellowish
oil which was purified by flash chromatography (ethyl acetate/
hexanes, 1:5 with 1% of trithylamine) to afford 43b (2.68 g,
90%) as a colorless liquid: IR (neat, cm-1) 1746, 1112, 1040;
1H NMR (300 MHz, C6D6) δ 4.86 (s, 1 H), 4.46 (s, 2 H), 3.35 (t,
J ) 1.7 Hz, 2 H), 3.17 (s, 3 H), 2.00-1.88 (m, 4 H), 1.66-1.49
0.63, CHCl3). Anal. Calcd for C35H50O4Si: C, 74.69; H, 8.96.
Found: C, 74.63; H, 8.89.
(4a S,6a R,9R,10S,10a S)-10-[(ter t-Bu tyld ip h en ylsiloxy)-
m eth yl]h exa h yd r o-6,6,9-tr im eth yl-1H,4a H-p yr a n o[2,3-c]-
isoben zofu r a n -8(6H)-on e (51) a n d (1S,2R,5a R,7a S,11a S)-
1-[(ter t-Bu t yld ip h en ylsiloxy)m et h yl]h exa h yd r o-2,6,6-
tr im eth yl-7a H,9H-p yr a n o[2′,3′,2,3]fu r o[3,4]oxep in -4(5H)-
on e (52). To a stirred suspension of 47 (61 mg, 0.1 mmol) and
freshly grounded urea-hydrogen peroxide powder (47 mg, 0.5
mmol) in anhydrous CH2Cl2 (2 mL) was added dropwise freshly
distilled trifluoroacetic anhydride (56 µL, 0.4 mmol) at 0 °C,
and the resulting slurry was stirred at this temperature for 2
h prior to being neutralized with saturated sodium bicarbonate
solution. The separated aqueous phase was extracted with
CH2Cl2 (5 mL × 2), and the combined organic layers were
washed with brine, dried, concentrated under reduced pres-
sure, and subjected to flash chromatography (ethyl acetate/
hexanes, 1:5) to provide 51 (31 mg, 62%) as a colorless solid
and 52 (1.2 mg, 2%) as a colorless oil.
For 51: mp 134-135 °C (from ethyl acetate/hexanes); IR
(neat, cm-1) 1715, 1112, 1062; 1H NMR (300 MHz, C6D6) δ
7.87-7.72 (m, 4 H), 7.28-7.17 (m, 6 H), 5.72 (s, 1 H), 4.10
(dd, J ) 11.4, 2.1 Hz, 1 H), 4.00 (m, 1 H), 3.61 (dd, J ) 11.4,
3.6 Hz, 1 H), 2.97 (dd, J ) 17.3, 4.3 Hz, 1 H), 2.10 (dd, J )
17.3, 5.3 Hz, 1 H), 1.88 (q, J ) 6.5 Hz, 1 H), 1.64 (td, J ) 13.5,
4.2 Hz, 1 H), 1.53 (q, J ) 2.7 Hz, 1 H), 1.39 (dd, J ) 14.2, 5.2
Hz, 1 H), 1.28 (m, 2 H), 1.24 (s, 3 H), 1.15 (s, 9 H), 1.11 (s, 3
H), 0.98 (d, J ) 6.8 Hz, 3 H), 0.95 (m, 2 H); 13C NMR (75
MHz, C6D6) d 210.6, 136.4, 136.0, 132.7, 132.5, 130.0, 129.8,
128.2, 128.1, 99.3, 76.4, 60.0, 59.5, 49.8, 45.8, 43.3, 41.7, 39.7,
32.8, 31.8, 26.9, 25.3, 21.3, 19.1, 11.6; FAB MS m/z (M+) calcd
506.29, obsd 506.33; [R]24 D -69.4 (c 1.00, CHCl3). Anal. Calcd
for C31H42O4Si: C, 73.48; H, 8.36. Found: C, 73.52; H, 8.33.
(series of m, 3 H), 0.98 (s, 3 H), 0.83 (s, 3 H), 0.63 (s, 3 H); 13
C
NMR (75 MHz, C6D6) δ 213.5, 156.2, 124.7, 96.5, 67.3, 65.4,
58.9, 54.8, 52.2, 35.9, 27.9, 26.9, 19.4, 19.2, 7.5; MS m/z (M+)
calcd 252.1725, obsd 252.1724; [R]24 +594.1 (c 0.41, CHCl3).
D
Anal. Calcd for C15H24O3: C, 71.38; H, 9.59. Found: C, 71.48;
H, 9.66.
(3a R,6R,7S,7a R)-7-[(ter t-Bu tyld ip h en ylsiloxy)m eth yl]-
3,3a ,4,6,7,7a -h exa h yd r o-7a -[3-(m eth oxym eth oxy)p r op yl]-
2,3,6,6-tetr a m eth yl-5H-in d en -5-on e (46) a n d (1S,2R,4R)-
2-[(E)-3-(ter t-Bu tyld ip h en ylsiloxy)-1-m eth yl-1-p r op en yl]-
5 -[ 3 -( m e t h o x y m e t h o x y ) p r o p y l ] -1 ,7 ,7 -t r i m e t h y l -
bicyclo[2.2.1]-h ep t-5-en -2-ol (44b). A flame-dried 25 mL
round-bottomed flask was charged with (E)-2-bromo-4-(tert-
butyldimethylsilyloxy)-2-butene (0.59 g, 1.53 mmol) in THF
(6 mL), cooled to -78 °C, and treated dropwise with a solution
of tert -butyllithium (1.8 mL, 1.7 M in pentane, 3.06 mmol)
dropwise. After 15 min, the resulting homogeneous yellow
solution was added a solution of 43b (0.17 g, 0.77 mmol) in
THF (3 mL) slowly, and the reaction mixture was allowed to
warm to room temperature overnight, recooled to -78 °C, and
finally quenched with 2 mL of saturated NH4Cl solution. After
returning to room temperature, the mixture was diluted with
brine and ether (5 mL of each), and the aqueous layer was
extracted with ether (10 mL × 2). The combined organic layers
were dried, and the filtrate was concentrated to give a pale
yellow oil that was purified by flash chromatography (ethyl
acetate/hexanes, 1:20 then 1:10) to afford 46 (0.318 g, 78%) as
a colorless oil accompanied by trace amounts of 44b (e 5%),
which was isolated as the exclusive product when the reaction
was performed at -78 °C for 2 h and quenched at the same
temperature.
For 52: IR (neat, cm-1) 1732, 1112, 1068; 1H NMR (300
MHz, C6D6) δ 7.85-7.75 (m, 4 H), 7.23-7.17 (m, 6 H), 4.78 (s,
6916 J . Org. Chem., Vol. 68, No. 18, 2003

Total Synthesis of Dumsin
1 H), 4.17 (d, J ) 5.2 Hz, 2 H), 3.17-3.06 (m, 2 H), 2.90 (td, J
) 11.0, 2.6 Hz, 1 H), 2.33 (dd, J ) 15.9, 4.2 Hz, 1 H), 2.16 (dd,
J ) 15.8, 5.2 Hz, 1 H), 1.91 (t, J ) 4.7 Hz, 1 H), 1.64 (t, J )
5.1 Hz, 1H), 1.35 (d, J ) 6.6 Hz, 3 H), 1.32 (s, 3 H), 1.30-1.18
(m, 4 H), 1.20 (s, 3 H), 1.16 (s, 9 H); 13C NMR (75 MHz, C6D6)
δ 171.7, 135.9, 135.8, 133.5, 133.4, 129.84, 129.80, 127.89,
127.85, 102.9, 84.6, 71.7, 63.3, 60.7, 56.1, 48.5, 45.7, 33.7, 33.0,
30.6, 26.8, 25.2, 21.6, 21.0, 19.0; FAB MS m/z (M+) calcd
522.28, obsd 522.43.
18.0, 15.4, 12.3, -1.4, -3.9, -4.4; FAB MS m/z (M+) calcd
624.42, obsd 624.39; [R]24 +116.6 (c 0.35, CHCl3).
D
(3a R,5a R,6S,9S,9a R,9bR)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,3a ,4,5a ,6,7,8,9,9a ,9b -d eca h yd r o-9b -[3-(m et h oxym et h -
oxy)propyl]-2,3,3,5a-tetra-methyl-6-[[2-(trimethylsilyl)ethoxy]
m eth oxy]-5H-ben z[e]in d en -5-on e (97b). A solution of 96b
(16 mg, 0.032 mmol) in CH2Cl2 (0.5 mL) was treated with
diisopropylethylamine (0.3 mL, excess), SEMCl (0.12 mL, 20
equiv), and a catalytic amount of tetrabutylammonium iodide
as described above to provide 97b (20 mg, quantitative) as a
pale yellow oil: IR (neat, cm-1) 1710, 1026; 1H NMR (300 MHz,
CDCl3) δ 5.59 (d, J ) 1.3 Hz, 1 H), 4.63 (s, 2 H), 4.53 (d, J )
6.8 Hz, 1 H), 4.48 (d, J ) 6.8 Hz, 1 H), 4.35 (d, J ) 1.3 Hz, 1
H), 3.73 (s, 1 H), 3.64-3.40 (series of m, 4 H), 3.37 (s, 3 H),
2.42 (br s, 1 H), 2.35 (br s, 1 H), 2.28 (dd, J ) 7.0, 3.1 Hz, 1
H), 1.93-1.53 (series of m, 9 H), 1.51 (d, J ) 1.3 Hz, 3 H),
1.32 (m, 1 H), 1.26 (s, 3 H), 1.05 (s, 3 H), 0.99-0.85 (m, 2 H),
0.93 (s, 9 H), 0.84 (s, 3 H), 0.14 (s, 3 H), 0.11 (s, 3 H), 0.01 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 219.6, 142.5, 132.5, 96.5,
94.3, 81.8, 68.4, 68.3, 65.0, 55.2, 51.2, 50.8, 50.4, 48.6, 42.0,
40.8, 37.8, 31.6, 29.4, 26.0, 24.9, 21.9, 21.2, 20.7, 18.0, 17.9,
12.3, -1.4, -3.7, -4.4; MS m/z (M+ - C3H5O) calcd 567.3902,
(3a R,5a R,6R,9S,9a R,9bR)-9-(ter t-Bu tyld im eth ylsiloxy)-
3,3a ,4,5a ,6,7,8,9,9a ,9b-d eca h yd r o-6-h yd r oxy-9b-[3-(m eth -
oxym et h oxy)p r op yl]-2,3,3, 5a -t et r a m et h yl-5H -b en z[e]-
in d en -5-on e (96a ) a n d (3a R,5a R,6S,9S,9a R,9bR)-9-(ter t-
Bu tyld im eth ylsiloxy)-3,3a ,4,5a ,6,7,8,9,9a ,9b-d eca h yd r o-
6-h y d r o xy-9b -[3-(m e t h ox ym e t h o x y )p r o p y l]-2,3,3,5a -
tetr a m eth yl-5H-ben z[e]in d en -5-on e (96b). A solution 95
(20 mg, 0.045 mmol) in THF (10 mL) was treated with 0.1 mL
of 2 N aqueous HCl solution, stirred for 72 h at 20-25 °C,
diluted with water and ethyl acetate (2 mL of each), and
extracted with ethyl acetate (4 mL × 3). The combined organic
layers were washed with water, saturated sodium bicarbonate
solution, and brine, dried, and concentrated. The residue was
purified by flash chromatography (ethyl acetate/hexanes, 1:3)
to furnish 96a (12 mg, 71%) and 96b (ca. 1 mg, 7%), both as
colorless oils.
obsd 567.3895; [R]24 +117.0 (c 0.50, CHCl3). Anal. Calcd for
D
C
34H64O6Si2: C, 65.34; H, 10.33. Found: C, 65.43; H, 10.27.
(3a R,5S,5a S,6R,9S,9a R,9b R)-9-(ter t-Bu t yld im et h ylsi-
lo x y )-3a ,4,5,5a ,6,7,8,9,9a ,9b -d e c a h y d r o -9b -[3-(m e t h -
oxym eth oxy)p r op yl]-2,3,3,5a -tetr a m eth yl-6-[[2-(tr im eth -
ylsilyl)eth oxy]m eth oxy]-3H-ben z[e]in d en -5-ol (103) a n d
(3a R ,5R ,5a S ,6R ,9S ,9a R ,9b R )-9-(t er t -B u t y ld im e t h y l-
siloxy)-3a,4,5,5a,6,7,8,9,9a,9b-decahydro-9b-[3-(methoxymeth-
oxy)propyl]-2,3,3,5a-tetramethyl-6-[[2-(trimethylsilyl)ethoxy]-
m eth oxy]-3H-ben z[e]in d en -5-ol (105). To a stirred solution
of 97a (24 mg, 0.038 mmol) in THF (1 mL) was added
DIBAL-H solution (1.0 M in hexanes, 0.5 mL, excess) at -78
°C. After being stirred at this temperature for 1 h, the reaction
mixture was carefully quenched with saturated sodium sulfate
solution until a solid precipitate formed, was allowed to warm
to room temperature, and was filtered. The filter cake was
washed several times with ethyl acetat,e and the combined
filtrates were concentrated to give a colorless residue that was
subjected to flash chromatographic purification (ethyl acetate/
hexanes, 1:5) to yield 103 (14 mg, 58 %) and 105 (3.5 mg, 15%),
both as colorless oils.
1
For 96a : IR (neat, cm-1) 3483, 1686, 1253; H NMR (300
MHz, CDCl3) δ 5.62 (d, J ) 1.2 Hz, 1 H), 4.63 (s, 2 H), 4.39 (d,
J ) 2.0 Hz, 1 H), 3.97 (t, J ) 2.5 Hz, 1 H), 3.54 (m, 2 H), 3.37
(s, 3 H), 2.50 (dd, J ) 5.5, 0.7 Hz, 1 H), 2.37 (d, J ) 8.4 Hz, 1
H), 2.32 (dd, J ) 13.8, 1.5 Hz, 1 H), 2.30 (m, 1 H), 2.16-2.03
(m, 1 H), 1.94-1.81 (m, 2 H), 1.66-1.30 (series of m, 6 H),
1.53 (d, J ) 1.3 Hz, 3 H), 1.28 (s, 3 H), 1.06 (s, 3 H), 0.94 (s, 9
H), 0.84 (s, 3 H), 0.15 (s, 3 H), 0.12 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 224.2, 142.8, 132.0, 96.6, 74.2, 68.2, 67.7, 55.3, 51.4,
50.7, 50.2, 48.9, 46.2, 39.9, 38.4, 32.8, 31.4, 26.0, 24.8, 23.9,
21.9, 18.0, 15.0, 12.2, -3.6, -4.3; MS m/z (M+ + 1) calcd
495.3505, obsd 495.3464.
1
For 96b: IR (neat, cm-1) 3457, 1712, 1255; H NMR (300
MHz, CDCl3) δ 5.62 (d, J ) 1.2 Hz, 1 H), 4.62 (s, 2 H), 4.38 (d,
J ) 1.8 Hz, 1 H), 3.98 (s, 1 H), 3.53 (m, 2 H), 3.37 (s, 3 H),
2.54-1.80 (series of m, 7 H), 1.68-1.30 (series of m, 6 H), 1.53
(d, J ) 1.2 Hz, 3 H), 1.28 (s, 3 H), 1.06 (s, 3 H), 0.94 (s, 9 H),
0.84 (s, 3 H), 0.15 (s, 3 H), 0.11 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 221.5, 142.5, 135.5, 96.5, 75.1, 68.4, 68.3, 55.2, 52.1,
50.6, 50.4, 48.7, 42.3, 40.2, 38.1, 31.5, 28.8, 26.0, 24.9, 23.6,
21.9, 21.3, 18.0, 12.2, -3.6, -4.4; MS m/z (M+) calcd 494.3428,
obsd 494.3417.
1
For 103: IR (neat, cm-1) 3495, 1054; H NMR (300 MHz,
CDCl3) δ 5.91 (m, 1 H), 4.68 (d, J ) 6.5 Hz, 1 H), 4.61 (d, J )
6.5 Hz, 1 H), 4.58 (s, 2 H), 4.33 (br s, 1 H), 3.74 (m, 1 H), 3.57
(m, 1 H), 3.51-3.35 (series of m, 4 H), 3.34 (s, 3 H), 3.09 (d, J
) 4.2 Hz, 1 H), 2.08-1.56 (series of m, 8 H), 1.53 (d, J ) 1.2
Hz, 3 H), 1.48-1.18 (series of m, 6 H), 1.16 (s, 3 H), 1.03 (s, 3
H), 0.95 (s, 9 H), 0.94 (s, 3 H), 0.12 (s, 3 H), 0.09 (s, 3 H), 0.01
(s, 9 H); 13C NMR (75 MHz, CDCl3) δ 141.2, 133.3, 96.3, 94.1,
79.8, 70.7, 68.4, 67.2, 65.9, 55.1, 50.0, 46.9, 45.3, 42.0, 41.3,
36.7, 33.4, 28.5, 28.1, 26.1, 25.1, 24.0, 22.0, 18.1, 17.8, 16.1,
12.3, -1.5, -3.2, -4.4; MS m/z (M+ - C5H11O2) calcd 523.3639,
(3a R ,5a R ,6R ,9S ,9a R ,9b R )-9-(t er t -B u t y ld im e t h ylsi-
loxy)-3,3a,4,5a,6,7,8,9,9a,9b-decahydro-9b-[3-(methoxymeth-
oxy)propyl]-2,3,3,5a-tetramethyl-6-[[2-(trimethylsilyl)ethoxy]-
m eth oxy]-5H-ben z[e]in d en -5-on e (97a ). To a stirred solu-
tion of 96a (35 mg, 0.071 mmol) in CH2Cl2 (1 mL) were added
diisopropylethylamine (0.25 mL, 1.43 mmol), SEMCl (0.13 mL,
0.71 mmol), and tetrabutylammonium iodide (cat). The reac-
tion mixture was stirred overnight prior to being quenched
with saturated NaHCO3 solution and diluted with CH2Cl2 (5
mL). The separated aqueous solution was extracted with CH2-
Cl2 (5 mL × 3), and the combined organic phases were washed
with brine, dried, and concentrated. The residue was purified
by flash chromatography (ethyl acetate/hexanes, 1:5) to provide
97a (42 mg, 77%) as a colorless syrup: IR (neat, cm-1) 1709,
obsd 523.3665; [R]24 -36.7 (c 0.45, CHCl3).
D
1
1038; H NMR (300 MHz, CDCl3) δ 5.51 (d, J ) 1.1 Hz, 1 H),
4.64 (d, J ) 7.4 Hz, 1 H), 4.61 (s, 2 H), 4.40 (d, J ) 7.4 Hz, 1
H), 4.28 (br s, 1 H), 3.67-3.37 (series of m, 5 H), 3.36 (s, 3 H),
2.53 (dd, J ) 13.8, 8.8 Hz, 1 H), 2.37 (d, J ) 13.8 Hz, 1 H),
2.32 (d, J ) 8.8 Hz, 1 H), 2.29-1.53 (series of m, 8 H), 1.50 (d,
J ) 1.1 Hz, 3 H), 1.37 (s, 3 H), 1.30 (m, 1 H), 1.05 (s, 3 H),
0.93 (s, 9 H), 0.91 (s, 3 H), 0.86 (m, 2 H), 0.12 (s, 3 H), 0.11 (s,
3 H), 0.00 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 216.2, 143.1,
131.6, 96.5, 94.5, 79.2, 68.1, 67.4, 64.9, 55.2, 52.2, 51.3, 50.9,
48.2, 47.3, 39.4, 37.0, 33.3, 31.6, 25.9, 24.9, 24.3, 21.8, 18.2,
For 105: IR (neat, cm-1) 3496, 1033; 1H NMR (300 MHz,
CDCl3) d 5.89 (d, J ) 1.2 Hz, 1 H), 4.85 (d, J ) 6.9 Hz, 1 H),
4.71 (d, J ) 6.9 Hz, 1 H), 4.60 (s, 1 H), 4.53 (s, 1 H), 4.23 (m,
1 H), 3.74-3.51 (m, 2 H), 3.49-3.37 (two sets of m, 3 H), 3.35
J . Org. Chem, Vol. 68, No. 18, 2003 6917

Paquette and Hong
1
(s, 3 H), 2.17-1.57 (series of m, 6 H), 1.54 (d, J ) 1.2 Hz, 3
H), 1.51-1.18 (series of m, 5 H), 1.17 (s, 3 H), 1.14 (s, 3 H),
0.98 (s, 3 H), 0.96 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H), 0.02 (s,
9 H); 13C NMR (75 MHz, CDCl3) δ 141.7, 132.9, 96.4, 92.3,
87.0, 79.6, 68.2, 66.5, 66.1, 55.2, 50.2, 49.4, 47.8, 46.9, 42.4,
36.2, 33.2, 30.9, 28.5, 26.1, 25.2, 24.2, 21.0, 18.2, 18.1, 12.3,
9.4, -1.3, -3.3, -4.3; MS m/z (M+ - C6H12O) calcd 526.3510,
For 111: IR (neat, cm-1) 3378, 1707, 1108; H NMR (300
MHz, CDCl
3) δ 10.37 (s, 1 H), 4.75 (s, 2 H), 4.65 (m, 2 H), 4.48
(d, J ) 18.1 Hz, 1 H), 4.24 (d, J ) 18.1 Hz, 1 H), 4.04 (s, 1 H),
3.98 (s, 1 H), 3.78 (m, 1 H), 3.59 (m, 1 H), 3.49-3.30 (series of
m, 3 H), 3.37 (s, 3 H), 2.95 (dd, J ) 13.4, 2.9 Hz, 1 H), 2.20 (t,
J ) 3.8 Hz, 1 H), 1.94-1.47 (series of m, 7 H), 1.35 (s, 3 H),
1.31-1.11 (series of m, 2 H), 1.06-0.90 (series of m, 19 H),
0.87 (s, 9 H), 0.65 (m, 6 H), 0.01 (s, 15 H); 13C NMR (75 MHz,
CDCl3) δ 214.6, 207.3, 96.2, 95.0, 81.2, 71.7, 67.6, 66.7, 65.0,
64.9, 56.3, 55.1, 48.3, 45.9, 43.6, 40.4, 32.0, 28.4, 27.1, 26.9,
26.2, 22.9, 22.2, 20.2, 18.2, 17.7, 7.2, 5.3, -1.5, -3.3, -4.9; FAB
obsd 526.3499; [R]24 -40.0 (c 0.035, CHCl3).
D
(3a R,5S,5a R,6R,9S,9a R,9b R)-9-(ter t-Bu t yld im et h ylsi-
lo x y )-3a ,4,5,5a ,6,7,8,9,9a ,9b -d e c a h y d r o -9b -[3-(m e t h -
oxym et h oxy)p r op yl]-2,3,3,5a -t et r a m et h yl-5-(t r iet h ylsi-
l o x y )-6 -[[2 -(t r i m e t h y l s i l y l )e t h o x y ]m e t h o x y ]-3 H -
ben z[e]in d en e (104). To a stirred solution of 103 (16.9 mg,
0.027 mmol) in CH2Cl2 were added diisopropylethylamine (75
µL, 0.54 mmol), DMAP (catalytic amount), and chlorotrieth-
ylsilane (45 µL, 0.27 mmol). The resulting mixture was stirred
at 35-40 °C for 60 h prior to being quenched by saturated
NaHCO3 solution (2 mL) and extracted with CH2Cl2 (2 mL ×
3). The combined organic layers were washed with brine, dried,
and concentrated to provide a reddish brown residue that was
purified by flash chromatography (ethyl acetate/hexanes, 1:15)
MS m/z (M+ + 1) calcd 788.51, obsd 788.31; [R]24 +15.6 (c
D
0.35, CHCl3).
B. By Ru th en iu m Tetr a oxid e Oxid a tion . A solution of
104 (20 mg, 0.027 mmol) in CCl4-CH3CN-H2O (1:1:1.5, 7 mL)
was charged with sodium periodiate (23 mg, 0.108 mmol)
followed by a catalytic amount of ruthenium trichloride
hydrate (1 mg) at room temperature, and the dark brown
mixture was stirred for 2 h. The workup procedure described
above was followed (flash chromatography, ethyl acetate/
hexanes, 1:8) to provide 110 (14.3 mg, 69%) as a single product.
to yield 104 as a pale yellow oil (15 mg, 75%): IR (neat, cm-1
)
1
(1R,2R,4a R,5S,8S,8a S)-8-(ter t-Bu t yld im et h ylsiloxy)-
2-(1,1-d im eth yla ceton yl)d eca h yd r o-1-[3-(m eth oxym eth -
oxy)propyl]-4a-methyl-4-oxo-5-[[2-(trimethylsilyl)ethoxy]methoxy]-
1-n a p h th a ld eh yd e (116). A vigorously stirred hetereogenous
mixture of 97b (14 mg, 0.022 mmol) in CCl4-CH3CN-H2O
(1:1:1.5, 7 mL) was charged with sodium periodiate (19 mg,
0.09 mmol) followed by ruthenium trichloride hydrate (1 mg,
catalytic amount) at room temperature. The dark brown
mixture was stirred for 2 h, diluted with water and CH2Cl2 (1
mL of each), and extracted with CH2Cl2 (2 mL × 3). The
combined organic layers were washed with brine, dried, and
concentrated under reduced pressure to give a residue that
was subjected to flash chromatographic purification (ethyl
acetate/hexanes, 1:5) to furnish 116 as a colorless oil (9.6 mg,
1472, 1372, 1251; H NMR (300 MHz, CDCl3) δ 5.91 (s, 1 H),
4.71 (s, 2 H), 4.59 (s, 2 H), 4.29 (br s, 1 H), 3.77 (td, J ) 9.8,
6.7 Hz, 1 H), 3.70 (d, J ) 2.7 Hz, 1 H), 3.60 (dd, J ) 11.6, 4.5
Hz, 1 H), 3.44 (m, 3 H), 3.34 (s, 3 H), 2.05-1.56 (series of m,
9 H), 1.52 (d, J ) 1.2 Hz, 3 H), 1.50-1.18 (series of m, 5 H),
1.14 (s, 3 H), 1.01 (s, 3 H), 0.98 (m, 9 H), 0.95 (s, 9 H), 0.90 (s,
3 H), 0.64 (m, 6 H), 0.11 (s, 3 H), 0.09 (s, 3 H), 0.01 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 140.7, 133.9, 96.3, 95.8, 80.7, 71.7,
68.4, 67.2, 64.7, 55.0, 50.1, 46.7, 45.6, 42.7, 41.0, 36.8, 33.2,
29.1, 28.8, 26.2, 25.0, 24.1, 23.4, 18.2, 18.1, 16.5, 12.2, 7.2, 5.4,
-1.5, -3.1, -4.7; FAB MS m/z (M+) calcd 740.53, obsd 740.42;
[R]24 +23.1 (c 1.78, CHCl3).
D
(1R ,2R ,4S ,4a R ,5R ,8S ,8a S )-8-(t er t -B u t y ld im e t h y l-
siloxy)-2-(1,1,-dimethylacetonyl)decahydro-1-[3-(methoxymeth-
oxy)p r op yl]-4a -m et h yl-4-(t r iet h ylsiloxy)-5-[[2-(t r im et h -
ylsilyl)et h oxy]m et h oxy]-1-n a p h t h a ld eh yd e (110) a n d
(1R,2R,4S,4a R,5R,8S,8a S)-8-(ter t-Bu t yld im et h ylsiloxy)-
decah ydr o-2-(3-h ydr oxy-1,1-dim eth ylaceton yl)-1-[3-(m eth -
oxym et h oxy)p r op yl]-4a -m et h yl-4-(t r iet h ylsiloxy)-5-[[2-
(tr im eth ylsilyl)eth oxy]m eth oxy]-1-n aph th aldeh yde (111).
A. Via Ozon olysis. Into a stirred solution of 104 (46 mg, 0.062
mmol) in a mixture of methanol (4 mL), CH2Cl2 (4 mL), and
pyridine (4 drops) was bubbled ozone at -78 °C until a blue
color persisted. The excess ozone was removed with nitrogen,
the colorless solution was treated with dimethyl sulfide
(excess), and the reaction mixture was allowed to warm to
room temperature during 2 h. The crude syrup isolated by
removing all of the volatile materials was subjected to flash
chromatographic purification (ethyl acetate/hexanes, 1:1) to
yield 110 (13 mg, 55%, colorless oil) along with 111 (27 mg,
27%, colorless oil).
1
65%): IR (neat, cm-1) 1710, 1112, 1029; H NMR (300 MHz,
CDCl3) δ 10.32 (s, 1 H), 5.05 (d, J ) 6.7 Hz, 1 H), 4.77 (d, J )
6.7 Hz, 1 H), 4.48 (dd, J ) 10.4, 6.4 Hz, 1 H), 4.42 (m, 1 H),
4.27 (m, 1 H), 3.75 (m, 1 H), 3.64 (m, 1 H), 3.51 (m, 1 H), 3.28
(m, 1 H), 3.22 (s, 3 H), 2.83 (s, 1 H), 2.86-2.74 (m, 1 H), 2.71
(d, J ) 1.3 Hz, 1 H), 2.43 (m, 2 H), 1.92-1.71 (series of m, 3
H), 1.70 (s, 3 H), 1.69-1.51 (m, 1 H), 1.50 (s, 3 H), 1.41-1.31
(series of m, 3 H), 1.17-1.00 (m, 2 H), 0.98 (s, 9 H), 0.74 (s, 3
H), 0.57 (s, 3 H), 0.22 (s, 3 H), 0.04 (s, 3 H), 0.03 (s, 9 H); 13C
NMR (75 MHz, CDCl3) δ 210.7, 210.6, 205.5, 96.6, 95.5, 79.0,
68.6, 67.7, 65.5, 54.9, 54.1, 52.7, 50.4, 45.6, 45.1, 37.5, 29.2,
28.3, 27.4, 26.3, 25.6, 23.5, 23.0, 22.5, 21.2, 18.4, 18.3, -1.3,
-3.5, -4.7; MS m/z (M+ - 1) calcd 655.4061, obsd 655.4096;
[R]24 +11.1 (c 0.14, CHCl3).
D
Ack n ow led gm en t. Financial support provided by
the National Institutes of Health is very much appreci-
ated.
1
For 110: IR (neat, cm-1) 1707, 1108, 1055; H NMR (300
MHz, CDCl3) δ 10.37 (s, 1 H), 4.75 (s, 2 H), 4.73 (m, 1 H), 4.61
(d, J ) 2.6 Hz, 1 H), 4.58 (m, 1 H), 4.07 (m, 1 H), 3.96 (d, J )
3.0 Hz, 1 H), 3.78 (m, 2 H), 3.66-3.33 (series of m, 5 H), 3.36
(s, 3 H), 2.87 (dd, J ) 14.5, 3.0 Hz, 1 H), 2.16 (s, 3 H), 2.13 (t,
J ) 14.5 Hz, 1 H), 1.95-1.78 (series of m, 4 H), 1.56 (m, 3 H),
1.34 (s, 3 H), 1.25 (m, 4 H), 1.10 (s, 3 H), 1.01-0.89 (series of
m, 12 H), 0.88 (s, 9 H), 0.64 (m, 6 H), 0.01 (s, 15 H); 13C NMR
(75 MHz, CDCl3) δ 213.4, 207.3, 96.4, 95.0, 81.2, 71.7, 67.9,
66.7, 64.8, 56.4, 55.1, 50.7, 45.8, 43.5, 39.1, 32.0, 27.6, 27.1,
26.8, 26.6, 26.2, 23.3, 22.9, 22.8, 18.2, 18.1, 17.7, 7.2, 5.3, -1.5,
Su p p or tin g In for m a tion Ava ila ble: Text presenting
experimental details and full spectral data for all compounds
for which information is not recorded in the Experimental
1
Section, together with copies of the high-field H NMR spectra
of all intermediates and tables giving all of the crystallographic
details and structure refinement infomation for 21, 51, and
76. This material is available free of charge via the Internet
at http://pubs.acs.org.
-3.3, -4.9; FAB MS m/z (M+) calcd 772.52, obsd 772.32; [R]24
+24.3 (c 0.35, CHCl3).
D
J O0301346
6918 J . Org. Chem., Vol. 68, No. 18, 2003