Studies toward the total synthesis of dumsin. 2. A second generation approach resulting in enantioselective construction of a functionalized ABC subunit of the tetranortriterpenoid insect antifeedant

Article abstract of DOI:10.1021/jo062068o

A synthesis of the ABC framework of dumsin is described. The optically active intermediate 9b, which is expeditiously assembled from 5-oxobornyl pivalate by the sequential implementation of an oxy-Cope rearrangement and an intramolecular ene reaction, pro

Full text of DOI:10.1021/jo062068o

Studies toward the Total Synthesis of Dumsin. 2. A Second
Generation Approach Resulting in Enantioselective Construction of
a Functionalized ABC Subunit of the Tetranortriterpenoid
Insect Antifeedant
Leo A. Paquette,* Yang Hu, Andreas Luxenburger, and Raynauld L. Bishop
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210-1185
paquette.1@osu.edu
ReceiVed October 5, 2006
A synthesis of the ABC framework of dumsin is described. The optically active intermediate 9b, which
is expeditiously assembled from 5-oxobornyl pivalate by the sequential implementation of an oxy-Cope
rearrangement and an intramolecular ene reaction, proved to be suitably functionalized for ultimate
conversion to 5. The synthesis plan relies on two approaches to this targeted intermediate. In the first,
the exocyclic double bond introduced during EtAlCl2-promoted closure of aldehyde 10b is cleaved to
leave a carbonyl group that is amenable to hydride reduction and elimination of water. Cleavage of the
resulting double bond with ruthenium tetroxide provided the seco ketoacid. The same advanced intermediate
was obtained by initially positioning the double bond internal to the five-membered ring in advance of
transient ring expansion via diketone formation and intramolecular aldolization. Both of these approaches
bypass the complications arising from the substantial steric congestion prevailing in these structural
networks. The task of covalently positioning an oxygen atom adjacent to the gem-dimethyl-substituted
carbon in 5 was properly realized by oxidative decarboxylation. The stereochemical assignments to many
of the intermediates were confirmed by an X-ray crystallographic analysis of 43.
Introduction
cell adhesion inhibitory indications,6 H+-ATPase inhibitory
effects,7 and cytotoxic properties against select human breast
cancer cell lines.8
In 1990, Kubo et al. reported the isolation from Croton
jatrophoides Pax of the tetranortriterpene limonoid called
dumsin (1).1 In line with the wide range of biological effects
discovered in members of the limonoid family, 1 was found to
exhibit potent insect antifeedant properties in several studies.2,3
Additional antifeedant limonoids were also disclosed by Na-
katani and co-workers in 1996 and 1997.4 As a group, this class
of natural products is recognized to display antimalarial activity,5
(3) (a) Chan, B. G.; Waiss, A. C.; Jr.; Stanley, W. L.; Goodban, A. E.
J. Econ. Entomol. 1978, 71, 366. (b) Kubo, I.; Klocke, J. A. In Plant
Resistance To Insects; Hedin, P. A., Ed; ACS Symposium Series 208;
Washington, DC, 1983; pp 329-346. (c) Kubo, I. In Methods In Plant
Biochemistry; Hostettmann, K., Ed; Academic Press: London, U.K., 1991;
Vol. 6; pp 179-193.
(4) (a) Zhou, J.-B.; Minami, Y.; Yagi, F.; Tadera, K.; Nakatani, M.
Heterocycles 1997, 45, 1781. (b) Zhou, J.-B.; Minami, Y.; Yagi, F.; Tadera,
K.; Nakatani, M. Heterocycles 1996, 43, 1477.
(5) (a) Bickii, J.; Njifutie, N.; Foyere, J. A.; Basco, L. K.; Ringwald,
P. J. Ethnopharmacology 2000, 69, 27. (b) Mackinnon, S.; Durst, T.;
Arnason, J. T.; Angerhofer, C.; Pezzuto, J.; Sanchez-Vindas, P. E.; Poveda,
J.; Gbeassor, M. J. Nat. Prod. 1997, 60, 336.
(6) Musza, L. L.; Killar, L. M.; Speight, P.; McElhiney, S.; Barrow,
C. J.; Gillum, A. M.; Cooper, R. Tetrahedron 1994, 50, 11369.
(1) Kubo, I.; Hanke, F. J.; Asaka, Y.; Matsumoto, T.; Cun-Heng, H.;
Clardy, J. Tetrahedron 1990, 46, 1515.
(2) (a) Nihei, K.-I.; Hanke, F. J.; Asaka, Y.; Matsumoto, T.; Kubo, I.
J. Agric. Food Chem. 2002, 5048. See also (b) Nihei, K.; Asaka, Y.; Mine,
Y.; Ito, C.; Furukawa, H.; Ju-Ichi, M.; Kubo, I. J. Agric. Food Chem. 2004,
52, 3325. (c) Nihei, K.; Asaka, Y.; Mine, Y.; Kubo, I. J. Nat. Prod. 2005,
68, 244.
10.1021/jo062068o CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
J. Org. Chem. 2007, 72, 209-222
209

Paquette et al.
SCHEME 1
SCHEME 2
Continuing studies of the same East African plant by the Kubo
team resulted more recently in their characterization of zumsin
(2), which possesses structural features similar to those resident
in 1.2a Differences are found in the orientation of the A ring,
which results in a trans fusion across the B/C sector in 2 in
contrast to the cis-B/C arrangement in 1. Furthermore, zumsin
has no hemiketal functionality at C19, the carbonyl functionality
at C3 in dumsin is shifted to C2 in 2, and the esterified hydroxyl
group at C7 in 1 is oxidized to a ketone carbonyl in 2.
Notwithstanding these structural variations, zumsin exhibits
potent insect antifeedant activity similar to the effects displayed
by 1.2
The first synthetic studies aimed at 1 were undertaken in this
laboratory by Hong and dealt largely with the enantioselective
elaboration of key intermediates derived from (-)-bornyl
acetate.9 Presently, we detail an improved strategy that targets
the highly complex ABC ring scaffold resident in dumsin.
Retrosynthetic Analysis. Our thinking regarding assembly
of the ABC ring system of 1 was guided from the beginning
by the presence therein of a hemiketal subunit. The projected
stability of the O-methyl acetal thereof prompted us to consider
its installation at a point roughly midway in the total synthesis
(Scheme 1). This perception led us back via 3 to 4, whose further
processing in the forward direction would ultimately involve a
Mukaiyama aldol reaction10 followed by suitable implementation
of an intramolecular coupling step11 and a modified Julia
olefination.12 Of more immediate significance was our concern
over proper insertion of the oxygen atom in ring B as defined,
for example, by 5. Although methods are, of course, available
for oxidative cleavage of the double bond in both 7b and 8b,
neither process installs the requisite functionality directly. As a
result, acetal 5 emerged as a key tricyclic intermediate and
became the central target of the present study.
(7) Achnine, L.; Malta, R.; Lotina-Hennsen, B. Pest. Biochem. Physiol.
1999, 63, 139.
(8) (a) Guthrie, N.; Morley, K.; Hasegawa, S.; Manners, G. D.;
Vandenberg, T. In Citrus Limonoids-Functional Chemicals in Agriculture
and Foods; Berhow, M. A.; Hasegawa, S.; Manners, G. D., Eds.; ACS
Symposium Series 758; American Chemical Society: Washington, DC,
2000; pp 165-184. (b) Lam, L. K. T.; Hasegawa, S.; Bergstrom, C.; Lam,
S. H.; Kenney, P. In Citrus Limonoids-Functional Chemicals in Agriculture
and Foods; Berhow, M. A.; Hasegawa, S.; Manners, G. D., Eds; ACS
Symposium Series 758; American Chemical Society: Washington, DC,
2000; pp 185-200.
One abbreviated plan for generating 8b was to rely first on
an enantiodefined oxy-Cope rearrangement within the exo-
norbornenol 12 (Scheme 2). It was our ambition to exploit the
(10) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039.
(11) Yamamoto, Y.; Hattori, R.; Itoh, K. Chem. Commun. 1999, 825.
(12) (a) Blakemore, P. R. J. Chem. Soc. Perkin Trans. 1 2002, 2563. (b)
Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett. 1998,
26. (c) Julia, M.;. Paris, J.-M. Tetrahedron Lett. 1973, 4833.
(9) (a) Hong, F.-T.; Paquette, L. A. Tetrahedron Lett. 1994, 35, 9153.
(b) Paquette, L. A.; Hong, F.-T. J. Org. Chem. 2003, 68, 6905.
210 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
SCHEME 3
SCHEME 4
well-defined transition state that would be utilized by this
strained bicyclic framework to set the four stereogenic centers
as desired in 11b. Beyond that, the projection was made that
aldehyde 10b would be amenable to an intramolecular ene
reaction,13,14 whose role was to fashion the second cyclopentane
ring resident in 9b.
4). The coupling of 13 with the lithiated derivative of alkenyl
bromide 21, whose three-step synthesis was based on Corey’s
protocol,19 proceeded as expected from the endo face to deliver
the exo allylic alcohol 12. The evaluation of 12 as a feasible
substrate for the projected anionic oxy-Cope rearrangement20
followed.
Results and Discussion
When the key [3,3] sigmatropic shift was induced by way of
the lithium alkoxide in THF, a chromatographically separable
mixture of the epimeric ketones 11a and 11b resulted, with 11a
predominating by a ratio of 5:1 (Scheme 5). The carbon
indicated by an “x” in these products must ultimately be made
quaternary, thereby minimizing stereochemical concerns at this
stage. Notwithstanding, the stereoselectivity of protonation in
the enolate intermediate proved to be subject to alkali metal
counterion control. For example, generation of the potassium
enolate led instead almost exclusively to 11b. The potential
significance of these results has been outlined elsewhere.21
Treatment of 11a with DIBAL-H at -78 °C resulted in
predominant conversion to â-alcohol 23a (15:1), the acylation
of which with pivaloyl chloride gave rise to the desired 24a.
Subsequently, the MOM group was cleaved chemoselectively
with 9-bromo-9-borabicyclo[3.3.1]nonane22 to provide the pri-
mary carbinol 27a whose oxidation with the Dess-Martin
periodinane (DMP) reagent served to provide aldehyde 10a in
near-quantitative yield. The intramolecular ene cyclization now
had to be confronted. After numerous experiments with different
Lewis acids, it was determined that ethylaluminum dichloride14
constitutes the most efficient reagent for this transformation.
As with many of its precursors, the stereostructure of 9a was
established by 2D-NMR spectroscopy. The product of simple
ethylation, Viz. 28a, was formed concomitantly in variable low
yields that peaked at 15%.
Keto pivalate 14 was prepared efficiently by saponification
of the known (-)-5-oxobornyl acetate15 followed by re-
esterification of the alcohol so formed with pivaloyl chloride
(Scheme 3).
Adaptation of the Barton method for generating vinyl iodides
from ketone hydrazones16 to 14 furnished 15 thereby allowing
for Stille coupling17 with allyltributylstannane. The ensuing
regioselective hydroboration of 16 with thexylborane resulted
in the predominant formation of primary carbinol 17. A lesser
quantity of the dihydro byproduct 18 was simultaneously
generated.
The route continued by protection of the primary hydroxyl
group in 17 as the MOM ether. This tactic allowed for
uncomplicated reductive removal of the pivaloyl group and
Dess-Martin oxidation18 of norbornenol 20 so formed (Scheme
(13) Snider, B. B. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon Press Inc.: New York, 1991,
Vol. 2, Chap.1, 21, pp 527.
(14) Marshall, J. A.; Andersen, M. W. J. Org. Chem. 1993, 58, 3912.
(15) (a) Allen, M. S.; Darby, N.; Salisbury, P.; Sigurdson, E. R.; Money,
T. Can. J. Chem. 1979, 57, 733. (b) Meinwald, J.; Shelton, J. C.;Buchanan,
G. L.; Courtin, A. J. Org. Chem. 1968, 33, 99. (c) Fabris, F.; Bellotto, L.;
De Lucchi, O. Tetrahedron Lett. 2003, 44, 1211.
(16) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron
Lett. 1983, 24, 1605. (b) Williams, D. R.; Heidebrecht; R. W., Jr. J. Am.
Chem. Soc. 2003, 125, 1843. (c) Helliwell, M.; Thomas, E. J.; Townsend,
L. A. J. Chem. Soc., Perkin Trans. 1 2002, 1286. (d) Pen˜a-Cabrera, E.;
Norrby, P.-O.; Sjo¨gren, M.; Vitagliano, A.; De Felice, V.; Oslob, J.; Ishii,
S.; O‘Neill, D.; Åkermark, B.; Helquist, P. J. Am. Chem. Soc. 1996, 118,
4299.
(17) Ritter, K. Synthesis 1993, 735. (b) Espinet, P.; Echavarren, A. M.
Angew. Chem. 2004, 116, 4808. (c) Stille, J. K.; Angew. Chem., Int. Ed.
Engl. 1986, 25, 508. (d) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978,
100, 363.
(19) (a) Corey, E. J.; Bock, M. G.; Kozikowski, A. V.; Rao, R.; Floyd,
D.; Lipshutz, B. Tetrahedron Lett. 1978, 12, 1051. (b) Roush, R. W.; Brown,
B. B. J. Am. Chem. Soc. 1993, 115, 2268. (c) Corey, E. J.; Kania, R. S.
J. Am. Chem. Soc. 1996, 118, 1229.
(20) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Chem. Soc. ReV. 1995, 9. (c) Paquette, L. A. Angew. Chem., Int. Ed.
Engl. 1990, 29, 609.
(21) Hu, Y.; Bishop, R. L.; Luxenburger, A.; Dong, S.; Paquette, L. A.
Org. Lett. 2006, 8, 2735.
(22) Bhatt, M. V. J. Organomet. Chem. 1978, 156, 221.
(18) (a) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Synth. 1999, 77,
141. (b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (c) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (d) Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899.
J. Org. Chem, Vol. 72, No. 1, 2007 211

Paquette et al.
SCHEME 5
SCHEME 6
generation of lactone 32. Alternatively, the heterocyclic B ring
might arise via precursors such as 41-44. In this approach, the
loss of two carbons might be effected in a single maneuver,
causing the route to be more economic in synthetic steps.
Customarily, the ozonolysis of alkenes proceeds with full
involvement of all three atoms of the O3 molecule in product
formation. Examples exist, however, where only one oxygen
of the ozone becomes incorporated with resultant epoxide
formation.24 Exocyclic olefin 29b happens to share in the latter
pattern of reactivity. Its response to a broad range of ozonolysis
conditions was to produce 30 in good yield with the co-
formation of only small levels (5-9%) of 31 (Scheme 6).
This ketone was made available in satisfactory quantities by
alternative application of Johnson-Lemieux conditions.25 At
this juncture, our quest for lactone 32 was cut short by virtue
of the complete unreactivity of 31 to reagents such as MCPBA,26
TFAA/30% H2O2,27 Oxone/NaHCO3,28 MMPP,29 and the like.
Evidently, the substantive steric compression that deters opera-
tion of the “normal” ozonolytic pathway for 29b acts compa-
rably to prevent key 1,2-addition of the oxidizing species to
the carbonyl group of 31.
As we undertook to explore the chemistry of 9a, we were
made increasingly aware of the steric congestion present in this
tricyclic framework. The first reflection of this fact was the
unreactivity of 9a to the action of MOM chloride in the presence
of Hu¨nig’s base. The successful implementation of this step
required the use of potassium hydride and a catalytic quantity
of tetrabutylammonium iodide in THF at 50 °C.23 The discovery
of additional reactivity differences prompted us to undertake a
parallel series of steps that would eventuate in the acquisition
of 29b from 11b (Scheme 5). In this way, comparative analysis
of the responses of 29a and 29b to more advanced chemical
transformations would be made possible as warranted. Thus,
co-exploration of the R/â stereoisomers (or series a and b) was
likewise undertaken.
From this point, the cause of synthetic directness could be
well served in one of two ways. The first would consist of
introducing a double bond in ring B with subsequent excision
of the unneeded carbon atom. This variant is exemplified by
the structural features present in 38 and 39. A pathway along
these lines might facilitate elaboration of the challenging
tetrahydrofuran substructural unit while also allowing for the
application of more direct routes exemplified by the hypothetical
Experiments of a different type proved to be substantially
more encouraging. Thus, ketone 31 was smoothly reduced with
sodium borohydride. Reaction proceeded slowly and required
the use of ethanol as the medium to minimize the rate of
competing degradation of the NaBH4 by solvent. Carbinols 33
and 34 (ratio 1:3) were formed in quantitative yield. â-Face
(24) Bailey, P. S. Ozonization in Organic Chemistry; Academic Press:
New York, 1978; Vol. 1.
(25) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(26) Krow, G. R. Org. React. 1993, 43, 251.
(27) Emmons, W. D.; Lucas, G. B. J. Am. Chem. Soc. 1955, 77, 2287.
(28) Gonzalez-Nunez, M. E.; Mallo, R.; Olmos, A.; Asensio, G. J. Org.
Chem. 2005, 70, 10879.
(23) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
105, 1988.
(29) Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913.
212 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
SCHEME 7
SCHEME 9
SCHEME 8
borohydride reduction, the chromatographically separable allylic
alcohols 43 and 44 resulted. The crystallinity of â-stereoisomer
43 provided the opportunity for stereochemical corroboration
by X-ray crystallographic analysis. Although the corresponding
acetates proved readily available, this protecting group was
insufficiently robust in later steps. Consequently, the MOM ether
7b was selected in the expectation that it would be more well
suited to the task at hand. At this juncture, the tetrasubstituted
double bond in 7b was readily cleaved with ruthenium tetroxide
as generated from RuO2 and NaIO4.30 As in the case of 31, the
resulting diketone 45 proved not to be amenable to Baeyer-
Villiger oxidation under a broad selection of conditions. A more
circuitous means for proper insertion of the ring B oxygen atom
had to be devised.
attack corresponds to hydride delivery from the less hindered
direction, thereby giving rise to 34 as the major component.
Although no attempts have been made to invert this product
distribution, a simplification subsequently presented itself.
Whereas the hydroxyl substituent in â-alcohol 33 could be
routinely functionalized as in 35, its R-epimer 34 proved
resistant to either O-acylation or O-alkylation. Consequently,
acetate 35 could be readily accessed, freed of its MOM
protecting group with Oxone on silica gel,30 and subjected to
the action of the Dess-Martin periodinane in CH2Cl2. The
assumption was made that the syn elimination envisaged for
37 (Scheme 7) would not prove problematic in light of the
possible operation of the E1cb mechanistic option. At the
experimental level, the 37 f 38 conversion proceeded ef-
ficiently. When 38 was admixed with sodium borohydride in
ethanol, â-face attack leading predominantly to 39 was sub-
stantially favored (85% yield). Moreover, no tendency on the
part of 38 to experience 1,4-hydride addition was noted. In any
case, a straightforward synthetic route to 40 had been opened.
The plan for generating the tricyclic methyl-bearing homo-
logues 43 and 44 called for oxidizing 9b to 41, the isomerization
of which to the conjugated counterpart 42 was expected to take
place readily (Scheme 8). Such was indeed the case in near-
quantitative yield. When enone 42 was next subjected to
To meet this challenge, advantage was taken of the ease with
which 45 undergoes intramolecular base-promoted aldol ring
closure to give 46 and 47 (Scheme 9). Following reprotection
of the primary carbinol, it proved easy to generate the silyl enol
ether as found to be present in 48 concurrently.31 Ozonolysis
of 48 at -78 °C delivered in 80% yield the R,â-dihydroxy
1
ketone 49, a compound whose H and 13C NMR spectra are
very broad and ill-defined because of multiple hydrogen bond
ineractions.32 Reduction of 49 with sodium borohydride gave
exclusively the triol 50. Although attempts to cleave this highly
functionalized intermediate with sodium periodate resulted in
(30) Martin, V. S.; Palazon, J. M.; Rodriquez, C. M. In Encyclopedia of
Reagents in Organic Synthesis; Paquette, L. A., Ed.; John Wiley and Sons:
Chichester, 1995; Vol. 6, pp 4414-4422.
(31) Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C. Farrugia, L. J.;
Muir, K.; Boyle, F. T. J. Chem. Soc. Perkin Trans. 1 2000, 2357.
(32) Friedrich, D.; Paquette, L. A. J. Org. Chem. 1991, 56, 3831.
J. Org. Chem, Vol. 72, No. 1, 2007 213

Paquette et al.
SCHEME 10
The relative stereochemistry of both advanced intermediates was
corroborated by X-ray crystallographic analysis of 43. The
shorter of the two sequences involves 22 steps and is preferred.
We expect that the anticipated adaptability of 5 to structural
modification will enable the rational arrival at dumsin (1) which
is currently being pursued in this laboratory.
Experimental Section
1,7,7-Trimethyl-5-oxobicyclol[2.2.1]heptan-2-yl Pivalate (14).
5-Hydroxy-4,7,7- trimethylbicyclo[2.2.1] heptan-2-one15 (75.0 g.
446 mmol) was dissolved in dry CH2Cl2 (1200 mL) and dry pyridine
(72.7 mL, 892 mmol). The solution was cooled to 0 °C before
pivaloyl chloride (219 mL, 1.78 mol) and DMAP (54.5 g. 446
mmol) were introduced. The reaction mixture was warmed to rt,
stirred for 72 h, returned to 0 °C, and treated dropwise with
concentrated NaHCO3 solution (100 mL). Water (800 mL) was
added, the separated aqueous layer was extracted three times with
CH2Cl2, and the combined organic layers were washed with water
and brine, dried, and concentrated in Vacuo. The residue distilled
at 120-121 °C and 0.2 mm to yield 100 g (89%) of 14 as a colorless
no reaction, lead tetraacetate proved to be quite effective33 and
delivered in 69% yield the keto aldehyde 51 and keto acid 52
in a 1:1 ratio. Before proceeding with elaboration of the key
subtarget, we decided to establish that 52 could also be prepared
by the ruthenium tetroxide oxidation of 40. This was indeed
the case, thus opening two complementary routes to this
substance. This interconversion also served to substantiate the
stereochemical assignments accorded to all of the intermediates.
In line with our earlier observations, it was not possible to
transform 51 to the keto formate upon treatment with m-
chloroperbenzoic acid.
The task of covalently positioning an oxygen atom adjacent
to the gem-dimethyl-substituted carbon as in 5 was properly
realized by making recourse to the process known as oxidative
decarboxylation.34 For the present purposes, 52 was admixed
with hydrogen peroxide and mercuric trifluoroacetate in THF.35
These conditions resulted in generation of the nor derivative
through the loss of carbon dioxide, with subsequent capture by
H2O2 to give the hydroperoxide. In the present context,
intramolecular cyclization subsequently operates to form 53
(Scheme 10). This result is in accord with prevailing steric
congestion, which is expediently released by ring formation.
The weak peroxidic linkage in 53 is conducive to efficient
reduction with sodium borohydride, thus producing hemiketal
54. O-Methylation was ultimately accomplished with silver(I)
oxide and methyl iodide in refluxing acetonitrile as solvent.36
1
solid, mp 46-48 °C; IR (film, cm-1) 1748, 1480, 1457; H NMR
(300 MHz, CDC13) δ 5.10-5.04 (m, 1H), 2.69-2.58 (m, 1H), 2.54
(d, J ) 18.7 Hz, 1H), 2.19 (d, J ) 5.3 Hz, 1H), 2.01 (d, J ) 18.7
Hz, 1H), 1.26 (dd, J ) 14.8, 3.6 Hz, 1H), 1.19 (s, 9H), 1.03 (s,
3H) 1.00 (s, 3H), 0.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 215.9,
178.3, 77.0, 59.7, 49.5, 47.0, 41.9, 38.7, 31.8, 27.0, 20.0, 17.5, 12.7;
HRMS (EI) m/z calcd for C15H24O3Na+ 252.1720, obsd 252.1725;
[R]24 +88.8 (c 1.09, CHCl3).
D
5-Iodo-1,7,7-trimethylbicyclo[2.2.1]hept-5-en-2-yl Pivalate (15).
To a mixture of hydrazine monohydrate (125 mL), triethylamine
(125 mL), and ethanol (250 mL) was added dropwise a solution of
14 (25 g, 99 mmol) in ethanol (150 mL). After 3 d of reflux, most
of the ethanol and triethylamine were distilled off. The residue was
cooled to rt, poured into cold water (400 mL), and extracted with
ether (3 × 400 mL). The combined organic layers were washed
with brine, dried, and concentrated to afford crude hydrazone (24
g, 91%) as a light yellow oil; IR (film, cm-1) 3388, 3216, 1729,
1
1674, 1627; H NMR (300 MHz, CDCl3) δ 4.99 (ddd, J ) 9.8,
3.6, 2.0 Hz, 1H), 2.61-2.48 (m, 1H), 2.45 (d, J ) 17.1 Hz, 1H),
2.31 (d, J ) 4.6 Hz, 1H), 1.93 (dd, J ) 17.1, 1.6 Hz, 1H), 1.24-
1.18 (m, 1H), 1.19 (s, 9H), 0.97 (s, 3H), 0.96 (s, 3H), 0.84 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 178.4, 160.6, 77.7, 53.3, 49.9, 48.2,
38.8, 34.1, 30.7, 27.1, 19.8, 18.0, 13.2.
To a solution of iodine (98.5 g, 387mmol) in dry ether (360
mL) was added slowly 1,1,3,3-tetramethylguanidine (109 mL, 870
mmol) at rt. A solution of the hydrazone (24 g, 90 mmol) in dry
ether (100 mL) was then introduced dropwise at rt. After 4 h of
stirring, the reaction mixture was cooled to 0 °C and treated slowly
with 10% aqueous hydrochloric acid (200 mL). The organic phase
was separated and washed with saturated Na2S2O3 (2 × 200 mL)
and saturated NaHCO3 (200 mL) solutions and brine. After drying,
the solvent was evaporated and the residue was purified by flash
chromatography to give iodide 15 (27 g, 82%) as a red-brown oil;
IR (film, cm-1) 1730, 1572, 1479; 1H NMR (300 MHz, CDCl3) δ
6.07 (s, 1H), 5.04 (dd, J ) 7.2, 2.6 Hz, 1H), 2.48 (d, J ) 3.6 Hz
1H), 2.46-2.37 (m,1H), 1.14 (s, 9H), 1.05 (s, 3H), 0.95 (dd, J )
13.1, 2.6 Hz 1H), 0.94 (s, 3H), 0.87 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 178.7, 144.5, 97.4, 80.3, 62.8, 59.7, 58.7, 38.7, 35.2,
27.0, 19.8, 19.0, 10.5; HRMS m/z calcd for C15H23IO2Na+ 385.0635,
Conclusion
The ABC ring skeleton of dumsin has been constructed in
optically active form from (+)-5-oxobornyl pivalate, whose
structural elements proved adequate for introduction of the
additional necessary stereogenic centers present in 5. Our
objectives in the design and execution of this synthesis were
(i) to utilize the mild conditions underlying application of
anionic [3,3] sigmatropy to build a suitable bicyclic scaffold,
(ii) to deploy an intramolecular ene reaction for assembly of
the A-ring, and (iii) to involve oxidative decarboxylation as the
means for introducing the oxygen atom in ring B. This last tactic
has received little attention in total synthesis.
The access routes to keto acid 52 were realized via tricyclic
allylic alcohol 39 on the one hand and triol 50 on the other.
obsd 385.0629; [R]24 +61.3 (c 0.88, CHCl3).
D
5-Allyl-1,7,7-trimethylbicyclo[2.2.1]hept-5-en-2-yl Pivalate (l6).
A round-bottomed flask was charged with Pd(CH3CN)2Cl2 (1.78
g, 7.4 mmol), PPh3 (5.84 g, 22.2 mmol), and a solution of 15 (27
g, 74 mmol) in dry DMF (400 mL). After 15 min, allyltributyltin
(33) Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher, M. J.; Danishefsky,
S. J. J. Org. Chem. 1991, 56, 5836.
(34) (a) Trahanovsky, W. S.; Cramer, J.; Brixiuss, D. W. J. Am. Chem.
Soc. 1974, 96, 1077. (b) Serguchev, Yu. A.; Beletskaya, I. P. Usp. Khim.
1980, 49, 2257. (c) Elmore, P. R.; Reed, R. T.; Terkle-Huslig, Y.; Welch,
J. S.; Young, S. M.; Landolt, R. G. J. Org. Chem. 1989, 54, 970. (d) Sayre,
L. M.; Jensen, F. R. J. Org. Chem. 1978, 43, 4700.
(35) Tkachev, A. V.; Denisov, A. Y. Tetrahedron 1993, 50, 2591.
(36) Finch, N.; Fitt, J. J.; Hsu, I. H. S. J. Org. Chem. 1975, 40, 206.
214 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
(23 mL, 74 mmol) and LiCl (9.43 g, 222 mmol) was introduced.
The resulting mixture was heated to 100 °C for 24 h, taken up in
water (400 mL), and extracted with hexane (3 × 400 mL). The
organic layers were combined, and most of the solvent was
evaporated. The residue was treated with a saturated KF solution
(100 mL) at rt. The precipitate so formed was filtered off and
washed with hexane (50 mL). The organic layer was washed with
brine, dried, and evaporated. The residue was purified by column
chromatography (silica gel, ethyl acetate/hexane 1:100) to give 16
(17 g, 83%) as a colorless oil; IR (film, cm-1) 1728, 1480, 1461;
1H NMR (300 MHz, CDCl3) δ 5.87-5.72 (m,1H) 5.24 (d, J ) 1.3
Hz, 1H), 5.11-4.98 (m, 3H), 2.85 (dd, J ) 6.9, 1.3 Hz, 2H), 2.51-
2.41 (m, 1H), 2.17 (d, J ) 3.6 Hz, 1H), 1.13 (s, 9H), 1.00 (s, 3H)
5-(3-(Methoxymethoxy)propyl-1,7,7-trimethylbicyclo[2.2.1]-
hept-5-en-2-ol (20). A solution of 19 (735 mg, 2.17 mmol) in dry
CH2Cl2 (30 mL) was cooled to -78 °C and DIBAL-H (1.0 M in
hexanes, 2.40 mL, 2.40 mmol) was added dropwise. After complete
deprotection (TLC analysis), the reaction mixture was quenched
with saturated NaHCO3 solution (1.5 mL), and saturated K-Na
tartrate solution (3 mL) was added. The mixture was warmed to rt,
stirred overnight, and diluted with water (40 mL). The separated
aqueous layer was extracted with ether (3 × 20 mL). The combined
organic layers were washed with brine, dried, and concentrated.
The crude product was purified by flash column chromatography
(silica gel, ethyl acetate/hexanes 1:9 to 1:3) to give 520 mg (94%)
of 20 as a colorless oil; IR (film, cm-1) 3447, 1472, 1463; 1H NMR
(300 MHz, CDCl3) δ 5.25 (s, 1H), 4.61 (s, 2H), 4.09 (dd, J ) 7.6,
2.3 Hz, 1H), 3.56 (t, J ) 6.6 Hz, 2H), 3.35 (s, 3H), 2.46-2.36 (m,
1H), 2.21 (td, J ) 7.6, 1.6 Hz, 2H), 2.13 (d, J ) 3.6 Hz, 1H),
1.87-1.65 (m, 2H), 1.04 (s, 3H), 0.82 (s, 3H), 0.76 (s, 3H), 0.76
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 153.0, 126.0, 96.4, 78.9,
67.6, 58.2, 57.7, 55.3, 55.1, 38.0, 27.3, 27.1, 20.4, 19.0, 10.8; HRMS
m/z calcd for C20H34O4Na+ 254.1882, obsd 254.1873; [R]24D +33.8
(c 0.855, CHCl3).
0.85, (dd, J ) 13.1, 3.0 Hz, 1H), 0.844 (s, 3H), 0.838 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 178.8, 147.6, 135.5, 128.7, 115.8, 81.3,
57.5, 56.8, 54.7, 38.7, 35.6, 35.0, 27.0, 19.9, 11.1; HRMS (ES)
m/z calcd for C18H28O2Na+ 299.1981, obsd 299.1962; [R]24D +52.7
(c 0.97, CHCl3).
5-(3-Hydroxypropyl)-1,7,7-trimethylbicyclo[2.2.1]hept-5-en-
2-yl Pivalate (17). To a solution of 2,3-dimethyl-2-butene (1 M in
THF, 66 mL) at 0 °C was added a solution of BH3 (1 M in THF,
66 mL). After 1 h of stirring at 0 °C, a solution of 16 (17 g, 61
mmol) in dry THF (100 mL) was introduced by cannula and the
resulting reaction mixture was stirred for 3 h at 0 °C, treated with
hydrogen peroxide (30%, 66 mL) followed by the slow addition
of a 15% aqueous NaOH solution (66 mL) in the cold. After a
further 1 h of stirring at 0 °C, water (100 mL) was added and the
whole was extracted several times with ether. The combined organic
layers were washed with brine, dried, and concentrated. The residue
was purified by flash chromatography (silica gel, ethyl acetate/
hexanes 1:9 to 1:3) to give 15 g (85%) of 17 as a colorless oil. In
addition, 854 mg (5%) of 18 was also isolated as a colorless oil.
For 17: IR (film, cm-1) 3435, 1727, 1708; 1H NMR (300 MHz,
CDCl3) δ 5.24 (d, J ) 1.3 Hz, 1H), 5.11 (dd, J ) 7.6, 2.6 Hz, 1H),
3.69 (t, J ) 6.6 Hz, 2H) 2.52-2.42 (m, 1H), 2.22-2.13 (m, 3H),
1.84-1.62 (m. 2H), 1.34 (br s, 1H, OH), 1.13 (s, 9H), 1.00 (s,
3H), 0.84 (s, 3H), 0.84 (dd, J ) 13.1, 2.6, Hz, 1H): 13C NMR (75
MHz, CDCl3) δ 178.9, 149.0, 127.8, 81.2, 62.7, 57.5, 56.5, 55.0,
38.6, 35.5, 30.2, 27.0, 26.4, 19.9, 19.2, 11.2; HRMS (ES) m/z calcd
for C18H30O3Na+ 317.2087, obsd 317.2080; [R]24D + 21.6 (c 1.23,
CHCl3).
5-(3-(Methoxymethoxy)propyl)-1,7,7-trimethylbicyclo[2.2.1]-
hept-5-en-2-on e (13). To a solution of 20 (519 mg, 2.04 mmol)
in dry CH2Cl2 (35 mL) was added Dess-Martin periodinane (1.30
g, 3.06 mmol) portionwise at 0 °C. After being stirred at rt for 24
h, the reaction mixture was cooled again to 0 °C, treated with
saturated NaHCO3 (14 mL) and Na2S2O3 (14 mL) solutions, and
stirred for a further 15 min at 0 °C. The separated aqueous layer
was extracted another two times with CH2Cl2. The organic layers
were combined, washed with brine, dried, and evaporated to leave
a residue that was purified by flash chromatography (silica gel,
ethyl acetate/hexanes 1:9) to yield 494 mg (96%) of 13 as a colorless
oil; IR (film, cm -1) 1742, 1469, 1447; 1H NMR (300 MHz, CDCl3)
δ 4.86 (s,1H), 4.46 (s, 2H), 3.35 (t, J ) 1.7 Hz, 2H), 3.17 (s, 3H),
2.00-1.88 (m, 4H), 1.66-1.49 (series of m, 3H), 0.98 (s, 3H),
0.83 (s, 3H), 0.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 213.4,
156.5, 124.3, 96.4, 67.2, 65.6, 59.2, 55.1, 52.0, 36.2, 27.7, 26.6,
19.5, 19.1, 7.0; HRMS (ES) m/z calcd for C15H24O3Na+ 252.1725,
obsd 252.1724; [R]24 +594.1 (c 0.41, CHCl3).
D
2-[3-(tert-Butyldiphenylsilyloxy)-1-methyl-propenyl]-5(3-meth-
oxymethoxypropyl-1,7,7-trimethylbicyclo[2.2.1]hept-5-en-2-ol (12).
To a solution of 21 (26.3 g, 67.6 mmol) in dry THF (175 mL) was
added t-BuLi (1.7 M in pentane, 79.6 mL, 135.3 mmol) dropwise
at -78 °C. The mixture was stirred for another 30 min at -78 °C
and was subsequently transferred with vigorous stirring into a
solution of 13 (5.69 g, 22.6 mmol) in dry THF (260 mL) which
was cooled to -40 °C. After being stirred for another 4 h at -40
°C, the reaction mixture was quenched with saturated NH4Cl
solution (88 mL) and allowed to warm to rt. Water (350 mL) was
added, the separated aqueous layer was extracted with ether (1 ×
200 mL and 2 × 50 mL) and the organic layers were combined,
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography (silica gel, ethyl acetate/hexanes 1:32, 1:19
and 1:9) to yield 7.67 g (61%) of 12 as a colorless oil; IR (film,
For 18: IR (film, cm-1) 1728, 1480, 1458; 1H NMR (300 MHz,
CDCl3) δ 5.19 (d, J ) 1.0 Hz, 1H), 5.09 (dd, J ) 7.6, 2.6 Hz, 1H)
2.50-2.40 (m, 1H), 2.13 (d, J ) 3.6 Hz, 1H), 2.11-2.02 (m, 2H),
1.55-1.38 (m, 2H), 1.25 (br s, 1H, OH), 1.13 (s, 9H), 0.99 (s,
3H), 0.93 (t, J ) 7.2 Hz, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.83 (dd,
J ) 13.1, 2.6 Hz 1H); 13C NMR (75 MHz, CDCl3) δ 178.9, 149.6,
127.5, 81.3, 57.4, 56.4, 55.0, 38.5, 32.5, 27.0, 20.4, 19.9, 19.3, 14.1,
11.2; HRMS (ES) m/z calcd for C18H30O2Na+ 301.2138, obsd
301.2141; [R]24 +43.3 (c 1.17, CHCl3).
D
5-(3-(Methoxymethoxy)propyl)-1,7,7-trimethylbicyclo[2.2.1]-
hept-5-en-2-yl Pivalate (19). A solution of 17 (680 mg, 2.31 mmol)
and diisopropylethylamine (0.46 mL, 2.77 mmol) in dry CH2Cl2
(10 mL) was cooled to 0 °C, treated dropwise with MOMCl (0.19
mL, 2.54 mmol), allowed to warm to rt, and stirred overnight prior
to quenching with saturated NaHCO3 solution (3.5 mL) and water
(40 mL), and extraction with ether (1 × 20 mL and 2 × 15 mL).
The combined ethereal layers were washed with brine, dried, and
concentrated. The residue was purified by flash column chroma-
tography (silica gel, ethyl acetate/hexanes 1:32) to provide 735 mg
(94%) of 19 as a colorless oil; IR (film, cm-1) 1728, 1480, 1457;
1H NMR (300 MHz, CDCl3) δ 5.22 (d, J ) 1.3 Hz, 1H), 5.09 (dd,
J ) 7.6, 2.6 Hz, 1H), 4.61 (s, 2H), 3.55 (td, J ) 6.6, 1.6 Hz, 2H),
3.35 (s, 3H), 2.51-2.41 (m, 1H), 2.21-2.12 (m, 3H), 1.86-1.63
(m, 2H), 1.12 (s, 9H), 0.99 (s, 3H), 0.83 (s, 3H), 0.83 (dd, J )
12.8, 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 178.8, 149.0,
127.8, 96.4, 81.2, 67.5, 57.5, 56.5, 55.1, 55.0, 38.7, 35.5, 27.4, 27.0,
26.7, 19.9, 19.3, 11.2; HRMS (ES) m/z calcd for C20H34O4Na+
1
cm-1) 3482, 1472, 1463; H NMR (300 MHz, CDCl3) δ 7.71-
7.65 (m, 4H), 7.44-7.34 (m, 6H), 5.44 (dt, J ) 5.9, 1.0 Hz, 1H),
5.06 (d, J ) 1.3 Hz, 1H), 4.60 (s, 2H), 4.24 (d, J ) 5.9 Hz, 1H)
3.50 (dt, J ) 6.6, 1.0 Hz, 2H), 3.34 (s, 3H), 2.13 (d, J ) 1.3 Hz,
1H), 2.08-1.97 (m, 3H), 1.82-1.60 (m, 3H), 1.40 (s, 3H), 1.13
(s, 3H), 1.04 (s, 9H), 1.02 (s, 3H), 0.91 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 147.2, 140.7, 135.6, 134.0, 133.9, 131.1, 129.6,
127.6, 126.1, 96.4, 86.3, 67.6, 61.6, 60.7, 59.9, 55.1, 54.2, 38.4,
27.1, 26.85, 26.77, 22.2, 21.5, 19.1, 15.4, 8.8; HRMS (ES) m/z
calcd for C35H50O4Na+ 585.3371, obsd 585.3419; [R]24D +42.5 (c
1.09, CHCl3).
(3aR,5S,6R,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-(methoxy methoxy)propyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-
hexahydro-3H-inden-5-ol (23a). To a solution of 11a21 (7.25 g,
12.9 mmol) in dry CH2Cl2 (725 mL) was added DIBAL-H (1.0 M
361.2349, obsd 361.2385; [R]24 +38.9 (c 1.26, CHCl3).
D
J. Org. Chem, Vol. 72, No. 1, 2007 215

Paquette et al.
in hexane, 28.3 mL, 28.3 mmol) dropwise at -78 °C. After being
stirred for 3 h at this temperature, the reaction mixture was quenched
with saturated Na-K tartrate solution (100 mL), allowed to warm
to rt, and diluted with water (400 mL). The separated aqueous layer
was extracted with CH2Cl2 (3 × 200 mL). The combined organic
phases were washed with brine, dried, and evaporated, and the crude
product was purified by flash chromatography (silica gel, ethyl
acetate/hexanes 1:19) to provide 6.35 g (87%) of 23a as a colorless
oil. In addition, 422 mg (6%) of 25a also was isolated.
(125 MHz, CDCl3) δ 178.4, 144.9, 135.7, 135.6, 133.8, 133.8,
129.5, 129.2, 127.6, 127.6, 96.4, 74.6, 68.6, 62.3, 55.1, 51.4, 50.9,
48.7, 47.7, 38.7, 38.3, 34.3, 29.9, 29.2, 27.1, 26.8, 25.7, 21.9, 19.1,
16.4, 12.4; HRMS (ES) m/z calcd for C40H60O5SiNa+ 671.4102,
obsd 671.4132; [R]24 -15.7 (c 1.02, CHCl3).
D
(3aR,5S,6R,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-hydroxypr opyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-hexahydro-
3H-inden-5-yl Pivalate (27a). A solution of 24a (102 mg, 0.157
mmol) in dry CH2Cl2 (10 mL) was cooled to -40 °C and 9-BBNBr
(1.0 M in CH2Cl2, 0472 mL, 0.472 mmol) was added dropwise.
After being stirred for 3 h at -40 °C, the reaction mixture was
quenched with saturated NaHCO3 solution (2.5 mL) and water (15
mL), and the separated aqueous layer was extracted with CH2Cl2
(3 × 8 mL). The combined organic layers were washed with brine,
dried, and concentrated. The residue so obtained was purified by
flash chromatography (silica gel, ethyl acetate/hexanes 1:19 and
For 23a: IR (film, cm-1) 3446, 1472, 1462; 1H NMR (300 MHz,
CDCl3) δ 7.71-7.65 (m, 4H), 7.45-7.33 (m, 6H), 5.25 (d, J )
1.3 Hz, 2H), 4.59 (s, 2H), 3.77-3.64 (m, 2H), 3.48-3.36 (m, 2H),
3.35 (s, 3H), 2.16-2.03 (m, 1H), 1.82-1.34 (series of m, 8H) 1.55
(d, J ) 1.3 Hz, 3H), 1.10 (s, 3H), 1.04 (s, 9H), 0.94-089 (m, 3H),
0.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.4, 135.6, 135.6,
133.8, 129.5, 129.5, 128.8, 127.6, 96.3, 70.8, 68.5, 62.6, 55.1, 51.0.
50.9, 47.4, 46.9, 38.4, 33.9, 31.9, 29.6, 26.8, 25.6, 23.4, 19.1, 12.5,
10.9; HRMS (EI) m/z calcd for C35H50O4-C4H9 507.2931, obsd
1:9) to yield 72 mg (76%) of 27a as a colorless oil; IR (film, cm-1
)
1
3450, 1724, 1709; H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m,
4H), 7.44-7.33 (m, 6H), 5.46 (d, J ) 1.0 Hz, 1H), 4.82 (dd, J )
15.2, 7.1 Hz, 1H) 3.71 (dd, J ) 10.6, 3.5 Hz, 1H), 3.62-3.53 (m,
3H), 2.09-2.00 (m, 1H), 1.92-1.84 (m, 1H), 1.77-1.72 (m, 1H),
1.71-1.39 (m, 8H), 1.59 (d, J ) 1.5 Hz, 3H) 1.11 (s, 3H), 1.06 (s,
9H) 0.97 (s, 9H), 0.86-0.82 (m, 3H), 0.85 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 178.0, 145.0, 135.7, 133.9, 129.5, 129.5, 128.3,
127.6, 72.5, 63.7, 63.1, 52.2, 50.7, 47.7, 47.2, 38.6, 38.2, 31.9, 30.1,
29.4, 28.6, 27.0, 26.9, 23.2, 19.1, 13.2, 12.6; HRMS (ES) m/z calcd
for C38H56O4SiNa+ 627.3840, obsd 627.3795; [R]24D +14.6 (c 0.93,
CHCl3).
507.2970; [R]24 +15.5 (c 1.30, CHCl3).
D
For 25a: IR (film, cm-1) 3359, 1472, 1438; 1H NMR (500 MHz,
CDCl3) δ 7.68-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.23 (d, J )
1.3 Hz, 1H), 4.62 (s, 2H), 3.57-3.44 (m, 4H), 3.36 (s, 3H), 3.55-
3.28 (m, 1H), 1.86 (t, J ) 6.9 Hz, 2H), 1.77-1.69 (m, 1H), 1.65-
1.41 (m, 8H), 1.55 (d, J ) 1.3 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H),
1.03 (s, 9H) 1.02 (s, 3H), 0.81 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 144.7, 135.6, 133.8, 133.8, 129.5, 129.3, 127.6, 127.5, 96.4, 71.6,
68.6, 62.3, 55.1, 51.6, 50.8, 47.5, 38.1, 37.4, 32.9, 30.0, 26.7, 25.6,
21.9, 19.0, 16.6, 12.4; HRMS (ES) m/z calcd for C35H52O4SiNa+
587.3527, obsd 585.3510; [R]24 +9.15 (c 1.11, CHCl3).
D
(3aR,5S,6R,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-
2,3,3,6-tetramethyl-7a-(3-oxopropyl)-3a,4,5,6,7,7a-hexahydro-
3H-inden-5-yl Pivalate (10a). To a solution of 27a (500 mg, 0.827
mmol) in dry CH2Cl2 (210 mL) was added Dess-Martin periodi-
nane (526 mg, 1.24 mmol) portionwise at 0 °C. The reaction mixture
was stirred overnight at rt, returned to 0 °C, and diluted with
saturated NaHCO3 (50 mL) and Na2S2O3 solutions (50 mL). The
mixture was stirred until all suspended solids had dissolved, at
which point the separated aqueous phase was extracted with CH2-
Cl2 (3 × 35 mL). The combined organic layers were washed with
brine, dried, and concentrated. The residue was purified by flash
column chromatography (silica gel, ethyl acetate/hexanes 1:19) to
give 442 mg (89%) of 10a as a colorless oil; IR (film, cm-1) 1725,
(3aR,5S,6R,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-(methoxy methoxy)propyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-
hexahydro-3H-inden-5-yl Pivalate (24a). To a solution of 23a
(6.35 g, 11.2 mmol) in dry CH2Cl2 (450 mL) at 0 °C was added
pyridine (1.83 mL, 22.5 mmol), pivaloyl chloride (5.53 mL, 45
mmol), and DMAP (1.37 g, 11.2 mmol). The reaction mixture was
allowed to warm to rt, stirred for 24 h, returned to 0 °C, and
quenched with saturated NaHCO3 solution (100 mL) and water (200
mL). The separated aqueous layer was extracted with CH2Cl2 (3
× 80 mL). The organic layers were combined, washed with brine,
dried, and freed of solvent. The residue was chromatographed on
silica gel (ethyl acetate/hexanes 1:49 and 1:19) to yield 7.13 g (98%)
1
of 24a as a colorless oil; IR (film, cm-1) 1725, 1479, 1472; H
1
1478, 1472; H NMR (400 MHz, CDCl3) δ 9.78 (t, J ) 1.5 Hz,
NMR (500 MHz, CDCl3) δ 7.71-7.63 (m, 4H), 7.43-7.33 (m,
6H), 5.47 (s, 1H), 4.83 (dd, J ) 13.6, 7.6 Hz, 1H), 4.62 (s, 2H),
3.70 (dd, J ) 10.4, 3.2 Hz, 1H), 3.56 (dd, J ) 10.4, 6.9 Hz, 1H),
3.53-3.43 (m, 2H), 3.37 (s, 3H), 2.09-2.00 (m, 1H), 1.93-1.84
(m, 1H), 1.80-1.73 (m, 1H), 1.73-1.44 (overlapping signals: d,
J ) 1.3 Hz, 3H and m, 5H), 1.11 (s, 3H), 1.06 (s, 9H), 0.97 (s,
9H), 0.87-0.81 (m, 3H), 0.85 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 178.0, 144.9, 135.7, 133.9, 129.5, 129.4, 128.4, 127.5, 96.4, 72.5,
68.6, 63.2, 55.1, 52.4, 50.8, 47.8, 47.3, 38.7, 38.6, 31.9, 30.1, 29.5,
27.0, 26.9, 25.5, 23.2, 19.1, 13.3, 12.5; HRMS (ES) m/z calcd for
1H), 7.69-7.63 (m, 4H), 7.44-7.33 (m, 6H), 5.45 (d, J ) 1.0 Hz,
1H), 4.83 (dd, J ) 14.2, 8.1 Hz, 1H), 6.70 (dd, J ) 10.6, 3.0 Hz,
1H), 3.52 (dd, J ) 10.6, 7.1 Hz, 1H), 2.49 (dt, J ) 1.5, 8.1 Hz,
2H), 2.04-19.0 (m, 2H), 1.88-1.71 (s, 2H), 1.61 (d, J ) 1.5 Hz,
3H), 1.60-1.57 (m, 2H), 1.12 (s, 3H) 1.07 (s, 9H), 0.95 (s, 9H),
0.86 (s, 3H), 0.82 (d, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 202.9, 178.0, 146.5, 135.6, 133.7, 129.6, 129.5, 127.6, 127.1,
72.1, 63.0, 52.2, 50.7, 48.2, 47.3, 40.4, 38.6, 33.6, 31.9, 30.1, 29.7,
27.0, 26.9, 23.2, 19.1, 13.5, 12.6; HRMS (ES) m/z calcd for
C38H54O4SiNa+ 625.3684, obsd 625.3666; [R]24 +30.7 (c 1.08,
C40H60O5SiNa+ 671.4102, obsd 671.4095; [R]24 +31.5 (c 1.33,
D
D
CHCl3).
CHCl3).
Ene Reaction Involving 10a. (3R,3aR,5aR,7S,8R,9S,9aR)-9-
((tert-Butyldiphenylsilyloxy)methyl)-3-hydroxy-5,5,8-trimethyl-
4-methylene-decahydro-1H-cyclopenta[i]inden-7-yl Pivalate (9a).
A flask containing dry CH2Cl2 (35 mL) was cooled to -78 °C,
and EtAlCl2 (1 M in hexanes, 0.71 mL, 0.705 mmol) was added.
In a separate flask, aldehyde 10a (106 mg, 0.176 mmol) was
dissolved in dry CH2Cl2 (31 mL), 4 Å molecular sieves were added,
and the mixture was cooled to -78 °C. At this point, the aldehyde
solution was cannulated slowly into the EtAlCl2 solution in the
cold. The mixture was stirred for 3 h, quenched with saturated
NaHCO3 (5.6 mL) and Na-K tartrate solutions (12 mL) at -78
°C, allowed to warm to rt, and stirred overnight. Water (10 mL)
was introduced, the separated aqueous layer was extracted with
CH2Cl2 (3 × 10 mL), and the combined organic layers were washed
with brine, dried, and concentrated. The residue was purified by
(3aR,5R,6R,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-(methoxy methoxy)propyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-
hexahydro-3H-inden-5-yl Pivalate (26a). A solution of 25a (104
mg, 0.185 mmol) and pyridine (31 µL, 0.369 mmol) in dry CH2-
Cl2 (10 mL) was treated with pivaloyl chloride (91 µL, 0.739 mmol)
and DMAP (22.6 mg, 0.185 mmol) according to the procedure
described above to yield 101 mg (84%) of 26a as a colorless oil;
IR (film, cm-1) 1724, 1479, 1472; 1H NMR (500 MHz, CDCl3) δ
7.66-7.63 (m, 4H), 7.44-7.34 (m, 6H), 5.15 (d, J ) 1.3 Hz, 1H),
4.62 (s, 2H), 4.48-4.41 (m, 1H), 3.60 (dd, J ) 10.4, 4.4 Hz, 1H),
3.56 (dd, J ) 10.4, 5.7 Hz, 1H), 3.52-3.45 (m, 2H), 3.37 (s, 3H),
2.04-1.96 (m, 1H), 1.89 (dd, J ) 10.1, 5.0 Hz, 1H), 1.82 (t, J )
6.6 Hz, 1H), 1.68-1.50 (overlapping signals: 1.53, d, J ) 1.3 Hz,
1H and m, 5H), 1.48-1.39 (m, 1H), 1.18 (s, 9H), 1.03 (s, 9H),
0.99 (s, 3H), 0.95 (d, J ) 6.9 Hz, 3H), 0.85 (s, 3H); 13C NMR
216 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
flash chromatography (silica gel, ethyl acetate/hexanes 1:32) to yield
72 mg (68%) of 9a and 16 mg (14%) of 28a, both as colorless
oils.
d, J ) 1.3 Hz, 3H and m, 5H), 1.17 (d, J ) 6.9 Hz, 3H), 1.13 (d,
J ) 12.0 Hz, 1H), 1.06 (s, 9H), 0.99 (s, 3H), 0.72 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 144.7, 135.7, 135.7, 134.1, 134.0, 129.6,
129.5, 128.2, 127.6, 96.4, 74.3, 68.4, 68.3, 55.1, 52.7, 51.2, 50.4,
47.8, 41.4, 40.2, 33.4, 29.3, 26.9, 25.6, 23.5, 21.3, 19.2, 12.0; HRMS
For 9a: IR (film, cm-1) 3548, 1726, 1471; 1H NMR (500 MHz,
CDCl3) δ 7.66-7.62 (m, 4H), 7.44-7.34 (m, 6H), 5.06 (d, J )
1.6 Hz, 1H), 4.89 (d, J ) 1.6 Hz, 1H), 4.83 (dt, J ) 9.8, 6.0 Hz,
1H), 4.24-4.18 (m, 1H), 3.71 (dd, J ) 10.7, 5.0 Hz, 1H), 3.56
(dd, J ) 10.7, 6.6 Hz, 1H), 3.44 (d, J ) 6.0 Hz, 1H), 2.21-2.13
(m, 1H), 1.94-1.83 (m, 4H), 1.71 (dd, J ) 13.9, 5.0 Hz, 1H) 1.68-
1.60 (m, 1H), 1.53-1.46 (m, 1H), 1.21 (s, 3H), 1.05 (s, 9H), 1.01
(s, 12H), 0.99-0.94 (m, 1H), 0.84 (d, J ) 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 178.0, 161.7, 135.6, 135.6, 133.5, 129.7, 129.7,
127.7, 127.7, 108.6, 74.6, 72.9, 62.7, 56.6, 54.5, 53.3, 52.1, 46.2,
40.5, 38.7, 33.9, 32.9, 32.2, 29.6, 27.0, 26.9, 26.8, 19.2; HRMS
(ES) m/z calcd for C35H52O4SiNa+ 587.3527, obsd 587.3523; [R]24
D
+13.5 (c, 1.11, CHCl3).
(3aR,5S,6S,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-(methoxymethoxy)propyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-
hexahydro-3H-inden-5-yl Pivalate (24b). A solution of alcohol
23b (3.09 g, 5.47 mmol) and pyridine (0.892 mL, 10.9 mmol) in
dry CH2Cl2 (220 mL) was treated with pivaloyl chloride (2.69 mL,
21.9 mmol) and DMAP (668 mg, 5.47 mmol) according to the
procedure described above to provide 3.29 g (93%) of 24b as a
colorless oil; IR (film, cm-1) 1724, 1479, 1472; 1H NMR (500 MHz,
CDCl3) δ 7.69-7.64 (m, 4H), 7.45-7.34 (m, 6H), 4.80 (d, J )
1.3 Hz, 1H), 4.67 (dt, J ) 10.4, 3.8 Hz, 1H), 4.69 (s, 2H), 3.61
(dd, J ) 10.4, 5.0 Hz, 1H), 3.49-3.39 (m, 2H), 3.35 (s, 3H), 3.32
(t, J ) 9.8 Hz, 1H), 2.07-1.98 (m, 1H), 1.90 (dd, J ) 11.4, 7.3
Hz, 1H), 1.75-1.69 (m, 1H), 1.67-1.62 (m, 1H), 1.52-1.45
(overlapping signals: 1.46, d, J ) 1.3 Hz, 3H and m, 3H), 1.22 (s,
9H), 1.07-1.04 (overlapping signals: 1.06, s, 9H and m, 3H), 0.97
(s, 3H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.6, 145.1,
135.7, 135.6, 133.9, 133.7, 129.6, 127.7, 127.6, 96.3, 76.8, 68.3,
67.7, 55.1, 52.0, 51.4, 49.7, 47.8, 40.8, 38.7, 35.8, 29.5, 29.3, 27.2,
26.8, 25.5, 23.4, 20.7, 19.2, 12.1; HRMS (ES) m/z calcd for
(ES) m/z calcd for C38H54O4SiNa+ 625.3684, obsd 625.3712; [R]24
+9.5 (c 0.67, CHCl3).
D
For 28a: IR (film, cm-1) 3504, 1725, 1710; 1H NMR (400 MHz,
CDCl3) δ 7.72-7.64 (m, 4H), 7.44-7.33 (m, 6H), 5.47 (s, 1H),
4.86-4.78 (m, 1H), 3.70 (dd, J ) 10.6, 3.5 Hz, 1H), 3.56 (dd, J )
10.6, 7.1 Hz, 1H), 3.48-3.40 (m, 1H), 2.08-1.98 (m, 1H), 1.81-
1.62 (m, 2H), 1.59 (s, 3H), 1.58-1.36 (m, 8H, 1.12 (s, 3H), 1.06
(s, 9H), 0.99-0.93 (m, 3H), 0.97 (s, 9H), 0.85 (s, 3H), 0.82 (d, J
) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 145.0, 145.0,
135.7, 133.9, 129.5, 129.5, 128.3, 128.2, 127.8, 127.5, 74.1, 73.9,
72.5, 72.5, 63.1, 63.0, 52.4, 52.3, 50.8, 47.9, 47.6, 47.2, 38.6, 38.0,
37.9, 32.5, 31.9, 30.2, 30.1, 30.1, 29.5, 29.5, 27.0, 26.9, 23.3, 19.2,
13.3, 13.2, 12.6, 9.8; HRMS (ES) m/z calcd for C40H60O4SiNa+
655.4153, obsd 655.4164.
C40H60O5SiNa+ 671.4102, obsd 671.4133; [R]24 +21.5 (c 1.05,
D
CHCl3).
(3aR,5S,6S,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-hydroxypropyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-hexahydro-
3H-inden-5-yl Pivalate (27b). Compound 24b (3.73 g, 5.73 mmol)
dissolved in dry CH2Cl2 (324 mL) was deprotected with 9-BBNBr
(1.0 M in CH2Cl2, 17.2 mL, 17.2 mmol) following the procedure
described above so that 2.80 g (81%) of 27b was isolated as a
(3R,3aR,5aR,7S,8R,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)-
methyl)-3-(methoxymethoxy)-5,5,8-trimethyl-4-methylene-decahy-
dro-1H-cyclopenta[i]inden-7-yl Pivalate (29a). Potassium hydride
(30% in mineral oil; 16.6 mg, 0.124 mmol) was suspended in dry
THF (7 mL), and a solution of 9a (15 mg, 0.025 mmol) in dry
THF (3 mL) was added via cannula at rt. After 30 min of stirring,
MOMCl (0.04 mL, 5.27 mmol) was introduced, and the reaction
mixture was stirred for 48 h at 50 °C. The same amount of MOMCl
was introduced again and agitation with heating was continued for
another 48 h. If necessary, more MOMCl was added and the
reaction time was extended to complete the conversion. The reaction
mixture was cooled to 0 °C, quenched with saturated NaHCO3
solution (3 mL) and water (15 mL), and extracted with ether (3 ×
10 mL). The organic layers were combined, washed with brine,
dried, and freed of solvent. The residue was purified by column
chromatography (silica gel, ethyl acetate/hexanes 1:32) to yield 9.5
mg (63%) of 29a as a colorless oil; IR (film, cm-1) 1726, 1472,
1
colorless oil; IR (film, cm-1) 3448, 1724, 1706, 1664; H NMR
(400 MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.46-7.34 (m, 6H), 4.80
(d, J ) 1.5 Hz, 1H), 4.66 (dt, J ) 10.1, 4.0 Hz, 1H), 3.61, (dd, J
) 10.1, 5.1 Hz, 1H), 3.59-3.51 (m, 2H), 3.33 (t, J ) 10.1 Hz,
1H), 2.07-1.96 (m, 2H), 1.89 (dd, J ) 11.1, 7.1 Hz, 1H), 1.77-
1.69 (m, 1H), 1.66-1.60 (m, 1H), 1.46 (d, J ) 1.5 Hz, 3H), 1.46-
1.40 (m, 3H), 1.22 (s, 9H), 1.06, (s, 9H), 1.06 (d, J ) 7.1 Hz, 3H),
0.97 (s, 3H), 0.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.6,
145.2, 135.7, 135.7, 133.9, 133.7, 129.6, 127.6, 76.7, 67.6, 63.5,
52.2, 51.4, 49.6, 47.9, 40.4, 38.7, 35.8, 29.5, 29.3, 38.6, 27.2, 26.9,
23.4, 20.6, 19.2, 12.1; HRMS (ES) m/z calcd for C38H56O4SiNa+
627.3840, obsd 627.3836; [R]24 +18.8 (c 0.895, CHCl3).
1
1461; H NMR (400 MHz, CDCl3) δ 7.68-7.64 (m, 4H), 7.45-
D
7.34 (m, 6H), 5.01-4.99 (m, 1H), 4.94 (dd, J ) 2.0, 1.0 Hz, 1H),
4.82 (dt, J ) 9.6, 5.6 Hz, 1H), 4.60 (d, J ) 6.6 Hz, 1H), 4.74 (d,
J ) 6.6 Hz, 1H), 4.15 (dd, J ) 13.1, 6.6 Hz, 1H), 3.66 (dd, J )
10.6, 5.6 Hz, 1H), 3.62 (dd, J ) 10.6, 6.1 Hz, 1H), 3.31 (s, 3H),
3.29 (d, J ) 6.6 Hz, 1H), 2.24-2.14 (m, 1H), 1.86-1.66 (m, 6H),
1.63-1.51 (m, 2H), 1.89 (s, 3H), 1.06 (s, 9H), 1.03 (s, 9H), 0.97
(s, 3H), 0.83 (d, J ) 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
178.0, 160.0, 135.6, 133.6, 133.6, 129.6, 127.7, 108.2, 95.9, 81.0,
73.1, 63.0, 55.3, 54.0, 53.1, 51.6, 45.6, 40.5, 38.7, 32.9, 31.2, 30.8,
29.1, 27.2, 27.1, 26.9, 19.1, 11.4; HRMS (ES) m/z calcd for
(3aR,5S,6S,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-
2,3,3,6-tetramet hyl-7a-(3-oxopropyl)-3a,4,5,6,7,7a-hexahydro-
3H-inden-5-yl Pivalate (10b). Alcohol 27b (2.76 g, 4.57 mmol)
dissolved in dry CH2Cl2 (500 mL) was oxidized by the portionwise
addition of DMP (4.23 g, 9.97 mmol) according to the procedure
described above to yield 2.07 g (75%) of 10b as a colorless oil; IR
(film, cm-1) 1724, 1479, 1474; 1H NMR (400 MHz, CDCl3) δ 9.68
(t, J ) 1.8 Hz, 1H), 7.71-7.59 (m, 4H), 7.48-7.33 (m, 6H), 4.70
(d, J ) 1.0 Hz, 1H), 4.64 (td, J ) 10.1, 4.0 Hz, 1H), 3.61 (dd, J
) 10.1, 5.1 Hz, 1H), 3.33 (t, J ) 10.1 Hz, 1H), 2.28 (dt, J ) 8.1,
1.5 Hz, 2H), 2.08-1.96 (m, 1H), 1.87-1.52 (m, 6H), 1.47 (d, J )
1.5 Hz, 3H), 1.22 (s, 9H), 1.06 (s, 9H), 1.06 (d, J ) 7.1 Hz, 3H),
0.97 (s, 3H), 0.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.5,
178,5, 146.6, 135.7, 135.6, 133.8, 133.6, 129.6, 127.7, 126.9, 76.4,
67.4, 51.5, 51.2, 50.3, 48.0, 40.3, 38.7, 35.6, 35.6, 29.2, 29.1, 27.1,
26.9, 23.4, 20.7, 19.2, 12.1; HRMS (ES) m/z calcd for C38H54O4-
C40H58O5SiNa+ 669.3946; obsd 699.3966; [R]24 +15.8 (c 0.61,
D
CHCl3).
(3aR,5S,6S,7S,7aR)-7-((tert-Butyldiphenylsilyloxy)methyl)-7a-
(3-(methoxymethoxy)propyl)-2,3,3,6-tetramethyl-3a,4,5,6,7,7a-
hexahydro-3H-inden-5-ol (23b). Ketone 11b21 (3.38 g, 6.01 mmol)
dissolved in dry CH2Cl2 (340 mL) was treated with DIBAL-H (1.0
M in hexane, 13.2 mL, 13.2 mmol) according to the procedure
detailed above to yield 2.86 g (84%) of 23b as a colorless oil; IR
SiNa+ 625.3684, obsd 625.3693; [R]24 +22.3 (c 1.02, CHCl3).
D
(3R,3aR,5aR,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)-
methyl)-3-hydrox y-5,5,8-trimethyl-4-methylene-decahydro-1H-
cyclopenta[i]inden-7-yl Pivalate (9b). Aldehyde 10b (115 mg,
0.183 mmol) was dissolved in dry CH2Cl2 (33 mL) and reacted
with a solution of EtAlCl2 (1 M in hexane, 0.762 mL, 0.762 mmol)
in dry CH2Cl2 (37 mL) according to the protocol detailed earlier
1
(film, cm-1) 3423, 1472, 1447; H NMR (500 MHz, CDCl3) δ
7.69-7.62 (m, 4H), 7.45-7.35 (m, 6H), 4.80 (d, J ) 1.3 Hz, 1H),
4.60 (s, 2H), 3.61 (dd, J ) 10.1, 5.0 Hz, 1H), 3.50-3.42 (m, 3H),
3.35 (s, 3H), 3.31 (t, J ) 9.8 Hz, 1H), 1.83 (dd, J ) 12.3, 7.3 Hz,
1H), 1.69-1.61 (m, 3H), 1.54-1.31 (overlapping signals: 1.46,
J. Org. Chem, Vol. 72, No. 1, 2007 217

Paquette et al.
to give 42.9 mg (25%, or 40% based on recovered material) of 9b
with water and ethyl acetate. The separated aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic
layers were washed with brine, dried, and concentrated. The residue
was purified by flash chromatography on silica gel (ethyl acetate/
hexane 1:8) to provide ketone 31 (70 mg, 98%) as a colorless oil;
IR (neat, cm-1) 1727, 1161, 1039; 1H NMR (300 MHz, CDCl3) δ
7.66-7.61 (m, 4H), 7.46-7.35 (m, 6H), 4.74-4.65 (m, 1H), 4.59
(d, J ) 6.9 Hz, 1H), 4.52 (d, J ) 6.9 Hz, 1H), 4.27-4.24 (m, 1H),
3.57-3.44 (m, 2H), 3.30 (s, 3H), 2.79 (d, J ) 8.4 Hz, 1H), 2.15
(dd, J ) 12.0, 7.5 Hz, 1H), 1.93-1.73 (m, 6H), 1.55-1.52 (m,
1H), 1.21 (s, 9H), 1.08-1.04 (m, 13H), 0.72 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 222.3, 135.6, 133.2, 133.1, 129.8, 129.8, 177.8,
98.7, 95.4, 79.6, 75.6, 67.5, 58.9, 55.4, 53.6, 53.4, 50.2, 49.6, 43.1,
38.7, 37.5, 32.4, 30.1, 29.3, 27.1, 26.9, 26.8, 21.9, 20.4, 19.1; HRMS
1
as a colorless oil; IR (film, cm-1) 3548, 1725, 1480; H NMNR
(500 MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.46-7.35 (m, 6H), 4.98
(d, J ) 1.6 Hz, 1H), 4.85 (d, J ) 1.6 Hz, 1H), 4.56 (ddd, J ) 13.6,
10.1, 3.5 Hz, 1H), 4.07 (quint, J ) 7.6 Hz, 1H), 3.69 (dd, J )
10.4, 3.8 Hz, 1H), 3.58 (dd, J ) 10.4, 6.6 Hz, 1H), 2.94 (d, J )
8.2 Hz, 1H), 1.89-1.71 (m, 6H), 1.56-1.49 (m, 1H), 1.47-1.35
(m, 2H), 1.20 (s, 9H), 1.12 (s, 3H), 1.09 (s, 9H), 0.96 (d, J ) 6.9
Hz, 3H), 0.90 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 178.4, 161.7,
135.8, 133.6, 133.5, 129.7, 127.7, 127.6, 109.0, 76.5, 73.7, 66.0,
56.7, 55.8, 54.1, 53.9, 45.9, 40.2, 38.8, 37.3, 33.9, 32.0, 31.1, 27.3,
27.2, 27.0, 19.2, 18.4; HRMS (ES) m/z calcd for C38H54O4SiNa+
625.3684; obsd 625.3712; [R]24 -2.76 (c 0.61, CHCl3).
D
(3R,3aR,5aR,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)-
methyl)-3-(metho xymethoxy)-5,5,8-trimethyl-4-methylene-decahy-
dro-1H-cyclopenta[i]inden-7-yl Pivalate (29b). Compound 9b
(33.6 mg, 0.056 mmol) dissolved in dry THF (20 mL) was treated
with potassium hydride (30% in mineral oil, 37.5 mg, 0.279 mmol),
MOMCl (0.25 mL, 3.29 mmol), and a catalytic amount of n-Bu4-
NI at 50 °C according to the procedure described earlier. Flash
chromatography (silica gel, ethyl acetate/hexanes 1:32) provided
35.1 mg (97%) of 29b as a colorless oil; IR (film, cm-1) 1725,
(ES) m/z calcd for C39H56O6SiNa+ 671.3744, obsd 671.3751; [R]24
D
+ 26 (c 0.6, CHCl3).
(3R,3aR,4S,5aR,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)-
methyl)-4-hydroxy-3-(methoxymethoxy)-5,5,8-trimethyl-decahy-
dro-1H-cyclopenta[i]inden-7 -yl Pivalate (33). To a solution of
31 (20 mg, 0.03 mmol) in anhydrous ethanol (6 mL) was added
sodium borohydride (100 mg, 2.63 mmol) at 0 °C. The reaction
mixture was stirred overnight at rt, freed of solvent on a rotary
evaporator, and diluted with ethyl acetate and water. The separated
aqueous phase was extracted with ethyl acetate (3 × 20 mL),
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography on silica gel (ethyl acetate/hexane 1:4)
to give 5 mg (25%) of the more polar 33 and 14 mg (74%) of the
less polar 34, both as colorless oils.
1
1644, 1590, 1479; H NMR (300 MHz, CDCl3) δ 7.69-7.63 (m,
4H), 7.47-7.34 (m, 6H), 4.83 (s, 1H), 4.79 (s, 1H), 4.62 (s, 2H),
4.55 (m, 1H), 3.67 (dd, J ) 10.2, 4.3 Hz, 1H), 3.53 (dd, J ) 10.2,
7.5 Hz, 1H), 3.30 (s, 3H), 2.81 (d, J ) 7.9 Hz, 1H), 1.89 (dd, J )
12.8, 6.9 Hz, 1H), 1.85-1.55 (m, 6H), 1.46-1.37 (m, 1H), 1.99
(s, 9H), 1.12 (s, 3H), 1.07 (s, 9H), 0.97 (d, J ) 6.9 Hz, 3H), 0.84
(s, 3H), 13C NMR (75 MHz, CDCl3) δ 178.4, 160.7, 135.8, 135.7,
133.7, 129.7, 127.6, 108.0, 95.4, 80.0, 77.2, 66.9, 56.8, 55.2, 55.0,
54.3, 53.2, 45.6, 40.9, 38.8, 37.5, 31.5, 31.3, 31.3, 29.7, 27.1, 26.9,
19.3, 19.2; HRMS (ES) m/z calcd for C40H58O5SiNa+ 669.3946,
For 33: IR (neat, cm-1) 3518, 1160; 1H NMR (300 MHz, CDCl3)
δ 7.69-7.65 (m, 4H), 7.47-7.41 (m, 6H), 4.63-4.56 (m, 3H), 4.01
(dd, J ) 15.0, 7.5 Hz, 1H), 3.85-3.77 (m, 2H), 3.50 (t, J ) 9.3
Hz, 1H), 3.30 (s, 3H), 2.55 (d, J ) 1.8 Hz, 1H), 2.48 (dd, J ) 9.0,
6.9 Hz, 1H), 1.97-1.89 (m, 2H), 1.73-1.49 (m, 7H), 1.21 (s, 9H),
1.08 (s, 9H), 1.04 (d, J ) 7.2 Hz, 3H), 0.96 (s, 3H), 0.62 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 178.5, 135.7, 135.6, 133.6, 129.7,
127.7, 96.2, 80.2, 80.1, 68.7, 55.7, 55.4, 53.7, 52.9, 49.3, 44.4, 43.5,
38.7, 37.3, 29.7, 29.4, 27.7, 27.4, 27.1, 26.9, 21.7, 19.2, 16.6; HRMS
obsd 669.3917; [R]24 +15.7 (c 1.59, CHCl3).
D
Ozonolytic Epoxidation of 29b. Compound 29b (35.7 mg, 0.552
mmol) was dissolved in dry CH2Cl2 (4 mL) and anhydrous methanol
(4 mL). The solution was treated with ozone at -78 °C for 1 h
and followed by the addition of triphenylphosphine and column
chromatography. There was isolated 31.9 mg (87%) of epoxide 30
as a colorless oil; IR (film, cm-1) 1724, 1479, 1462; 1H NMR (400
MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.44-7.34 (m, 6H), 4.61 (ddd,
J ) 11.6, 10.1, 3.5 Hz, 1H), 4.56 (d, J ) 6.6 Hz, 1H), 4.49 (d, J
) 6.6 Hz, 1H), 3.94 (dd, J ) 13.6, 7.1 Hz, 1H), 3.89 (dd, J )
10.6, 4.6 Hz, 1H), 3.58 (dd, J ) 10.1, 9.1 Hz, 1H), 3.31 (s, 3H),
3.13 (d, J ) 4.6 Hz, 1H), 2.59 (d, J ) 4.6 Hz, 1H), 2.30 (d, J )
7.6 Hz, 1H), 2.08-1.97 (m, 1H), 1.89 (dd, J ) 12.1, 7.1 Hz, 1H),
1.79-1.62 (m, 5H), 1.52-1.45 (m, 1H), 1.21 (s, 9H), 1.09 (s, 9H),
1.04 (d, J ) 7.1 Hz, 3H), 0.96 (s, 3H), 0.54 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 178.5, 135.7, 135.8, 135.7, 133.8, 133.7, 129.6,
129.6, 127.6, 95.8, 79.6, 76.5, 69.5, 67.3, 56.5, 55.5, 54.0, 53.5,
52.5, 48.7, 42.6, 41.9, 38.7, 36.8, 31.2, 30.1, 27.9, 27.1, 27.0, 26.9,
20.6, 20.2, 19.3; HRMS (ES) m/z calcd for C40H58O6SiNa+
(ES) m/z calcd for C39H58O6SiNa+ 673.3900, obsd 673.3898; [R]24
+4 (c 0.5, CHCl3).
D
For 34: IR (neat, cm-1) 3532, 1725, 1164, 1035; 1H NMR (300
MHz, CDCl3) δ 7.69-7.66 (m, 4H), 7.45-7.37 (m, 6H), 4.62-
4.57 (m, 3H), 4.27-4.25 (m, 1H), 3.72-3.67 (m, 1H), 3.58 (s,
1H), 3.44 (t, J ) 8.7 Hz, 1H), 3.34 (s, 3H), 2.80 (dd, J ) 8.4, 4.8
Hz, 1H), 2.24 (dd, J ) 12.8, 6.6 Hz, 1H), 2.00-1.83 (m, 4H),
1.67-1.59 (m, 2H), 1.49-1.43 (m, 1H), 1.21 (s, 9H), 1.07 (s, 9H),
1.04 (d, J ) 6.9 Hz, 3H), 1.01 (s, 3H), 0.66 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 178.4, 135.7, 135.6, 133.5, 133.4, 129.9, 129.8,
127.8, 96.0, 83.0, 80.4, 77.3, 68.6, 55.6, 55.2, 55.1, 53.4, 50.7, 47.1,
44.5, 38.7, 37.8, 33.0, 28.3, 27.2, 26.9, 23.4, 23.0, 22.0, 19.2; HRMS
(ES) m/z calcd for C39H58O6SiNa+ 673.3900, obsd 673.3890; [R]24
+7.5 (c 5.0, CHCl3).
D
685.3895, obsd 685.3851; [R]24 +7.1 (c 0.67, CHCl3).
(3R,3aS,4S,5aR,7S,8S,9S,9aR)-4-Acetoxy-9-((tert-butyldiphe-
nylsilyloxy)methyl)-3-(methoxymethoxy)-5,5,8-trimethyl-decahy-
dro-1H-cyclopenta[i]inden-7-yl Pivalate (35). A solution of 33
(27 mg, 0.04 mmol) and pyridine (0.065 mL, 0.8 mmol) in dry
CH2Cl2 (4 mL) was cooled to 0 °C, treated dropwise with acetic
anhydride (0.04 mL, 0.4 mmol), and admixed with DMAP (10 mg).
The reaction mixture was stirred overnight at rt, quenched with
saturated NaHCO3 solution (2 mL) and water, and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with brine, dried, and concentrated to leave a residue that was
chromatographed on silica gel (ethyl acetate/hexane 1:4) to furnish
24 mg (85%) of 35 as a colorless oil; IR (neat, cm-1) 1725, 1046;
1H NMR (300 MHz, CDCl3) δ 7.70-7.67 (m, 4H), 7.45-7.38 (m,
6H), 5.14 (d, J ) 9.0 Hz, 1H), 4.67-4.58 (m, 1H), 4.50 (d, J )
6.6 Hz, 1H), 4.47 (d, J ) 6.6 Hz, 1H), 4.01 (dd, J ) 10.2, 5.7 Hz,
1H), 3.82 (dd, J ) 10.2, 8.1 Hz, 1H), 3.51 (t, J ) 9.0 Hz, 1H),
3.29 (s, 3H), 2.81 (dd, J ) 9.0, 7.2 Hz, 1H), 1.98 (s, 3H), 1.90-
1.51 (m, 9H), 1.19 (s, 9H), 1.08 (s, 9H), 1.02 (d, J ) 7.2 Hz, 3H),
D
(3R,3aS,5aR,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)-
methyl)-3-(metho xymethoxy)-5,5,8-trimethyl-4-oxo-decahydro-
1H-cyclopenta[i]inden-7-yl Pivalate (31). A solution of OsO4 (20
mg, 0.08 mmol) in t-BuOH (4 mL) was treated with a solution of
29b (140 mg, 0.2 mmol) in THF/pH 7 buffer (5 mL/2 mL).
N-Methylmorpholine N-oxide (60 mg, 0.44 mmol) was added in
one portion, and the reaction mixture was stirred at rt for 4 days,
cooled to 0 °C, and treated with 1.5 g of NaHSO3. After 15 min of
stirring, ethyl acetate and water were introduced. The separated
aqueous layer was extracted with ethyl acetate (3 × 20 mL), and
the combined organic layers were washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:2) to provide the
diol (71 mg, 45%) as a colorless oil.
The diol was subsequently dissolved in THF (5 mL) and treated
with a solution of sodium periodate (120 mg, 0.56 mmol) in water
(1 mL). The reaction mixture was stirred for 2 days and diluted
218 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
0.92 (s, 3H), 0.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.4,
169.9, 135.7, 135.6, 133.5, 133.4, 129.8, 129.7, 127.7, 98.7, 95.1,
80.3, 68.3, 55.1, 52.8, 50.4, 49.8, 44.1, 43.7, 38.7, 37.2, 31.9, 29.7,
29.6, 29.5, 29.3, 27.7, 27.6, 27.1, 26.8, 22.6, 21.2, 21.1, 19.1, 17.9,
14.1; HRMS (ES) m/z calcd for C41H60O7SiNa+ 715.4006, obsd
penta[i]inden-7-yl Pivalate (39). To a solution of 38 (7 mg, 0.012
mmol) in anhydrous ethanol (3 mL) was added NaBH4 (50 mg) at
0 °C. The reaction mixture was allowed to warm to rt, stirred for
4 h, and evaporated. The residue was diluted with ethyl acetate
and water, and the separated aqueous layer was extracted with ethyl
acetate (3 × 4 mL). The combined organic layers were washed
with brine, dried, and concentrated. The residue was purified by
flash chromatography on silica gel (ethyl acetate/hexane 1:4) to
give 39 (6 mg, 85%) as a colorless oil; IR (neat, cm-1) 3429, 1725,
715.3993; [R]24 +32 (c 0.15, CHCl3).
D
(3R,3aS,4S,5aR,7S,8S,9S,9aR)-4-Acetoxy-9-((tert-butyldiphe-
nylsilyloxy)methyl)-3-hydroxy-5,5,8-trimethyl-decahydro-1H-cy-
clopenta[i]inden-7-yl Pivalate (36). To a solution of 35 (24 mg,
0.034 mmol) in CH2Cl2 (4 mL) was added Oxone-silica gel (360
mg, 2 mmol) in CH2Cl2 (4 mL) in one portion at rt. Two hours
later, the solvent was evaporated and the residue was purified by
flash chromatography on silica gel (ethyl acetate/hexane 1:2) to
provide 36 (12 mg, 53%) as a colorless oil; IR (neat, cm-1) 3733,
1
1163; H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.46-
7.36 (m, 6H), 5.11 (d, J ) 1.8 Hz, 1H), 4.53 (ddd, J ) 12.3, 10.2,
3.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.45-3.43 (m, 2H), 2.28-2.18
(m, 1H), 2.11-2.03 (m, 2H), 1.86-1.79 (m, 1H), 1.70-1.53 (m,
5H), 1.23 (s, 9H), 1.12 (d, J ) 6.8 Hz, 3H), 1.08 (s, 9H), 1.02 (s,
3H), 0.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.5, 153.4,
135.7, 135.6, 133.9, 133.6, 129.9, 129.8, 129.7, 127.7, 127.7, 68.6,
68.4, 58.5, 55.7, 51.5, 47.8, 41.4, 38.8, 36.5, 35.7, 32.2, 31.6, 28.4,
27.2, 26.9, 25.0, 22.4, 19.2; HRMS (ES) m/z calcd for C37H52O4-
1
1718, 1164; H NMR (300 MHz, CDCl3) δ 7.69-7.65 (m, 4H),
7.45-7.37 (m, 6H), 4.91 (d, J ) 8.4 Hz, 1H), 4.60 (m, 1H), 4.20
(m, 1H), 3.80 (dd, J ) 10.2, 5.7 Hz, 1H), 3.51 (dd, J ) 10.2, 8.1
Hz, 1H), 2.72-2.67 (m, 2H), 2.05 (s, 3H), 1.85-1.50 (m, 9H),
1.21 (s, 9H), 1.08 (s, 9H), 1.00 (d, J ) 7.2 Hz, 3H), 0.95 (s, 3H),
0.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.4, 172.1, 135.7,
135.6, 133.5, 133.4, 129.8, 127.7, 81.2, 76.1, 73.2, 67.7, 55.1, 53.1,
52.9, 51.5, 44.5, 43.5, 38.7, 37.3, 32.8, 31.9, 29.7, 29.6, 29.3, 28.2,
SiNa+ 611.3533, obsd 611.3530; [R]24 -2.0 (c 2.0, CHCl3).
D
(3R,5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
3-(methoxym ethoxy)-5,5,8-trimethyl-2,3,5,5a,6,7,8,9-octahydro-
1H-cyclopenta[i]inden-7-yl Pivalate (40). A solution of 39 (26
mg, 0.044 mmol) and diisopropylethylamine (0.28 mL, 1.6 mmol)
in dry CH2Cl2 (4 mL) was cooled to 0 °C, treated dropwise with
MOMCl (0.1 mL, 1.3 mmol), followed by DMAP (20 mg). The
reaction mixture was allowed to warm to rt, stirred overnight,
quenched with saturated NaHCO3 solution (3 mL) and water, and
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine, dried, and concentrated. The residue was
purified by flash chromatography on silica gel (elution with ethyl
acetate/hexane 1:16) to provide 40 (25 mg, 90%) as a colorless
oil; IR (neat, cm-1) 3071, 1725, 1162; 1H NMR (400 MHz, CDCl3)
δ 7.72-7.68 (m, 4H), 7.48-7.39 (m, 6H), 5.17 (d, J ) 1.6 Hz,
1H), 4.61 (d, J ) 6.8 Hz, 1H), 4.55 (d, J ) 6.8 Hz, 1H), 4.56-
4.54 (m, 1H), 4.07 (dd, J ) 6.4, 2.0 Hz, H), 3.53-3.45 (m, 2H),
3.34 (s, 3H), 2.28-2.04 (m, 3H), 1.87 (dd, J ) 11.2, 8.0 Hz, 1H),
1.80-1.72 (m, 1H), 1.69-1.53 (m, 2H), 1.42-1.32 (m, 2H), 1.25
(s, 9H), 1.16 (d, J ) 6.4 Hz, 3H), 1.09 (s, 9H), 1.07 (s, 3H), 0.62
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.5, 149.9, 135.7, 135.6,
133.9, 133.7, 130.6, 129.7, 129.7, 127.7, 96.1, 77.1, 73.2, 68.5,
58.0, 55.5, 55.4, 51.4, 47.8, 41.5, 38.8, 36.5, 32.7, 32.2, 28.4, 27.2,
26.9, 25.0, 22.5, 19.2; HRMS (ES) m/z calcd for C39H56O5SiNa+
27.8, 27.1, 26.8, 22.7, 21.2, 20.7, 19.2, 18.3, 14.1; [R]24 +40 (c
D
0.1, CHCl3).
(3aR,4S,5aR,7S,8S,9S,9aR)-4-Acetoxy-9-((tert-butyldiphenyl-
silyloxy)methyl )-5,5,8-trimethyl-3-oxo-decahydro-1H-cyclopen-
ta[i]inden-7-yl Pivalate (37). To a solution of 36 (12 mg, 0.018
mmol) in CH2Cl2 (4 mL) was added Dess-Martin periodinane (52
mg, 0.12 mmol) portionwise at 0 °C. The reaction mixture was
allowed to warm to rt, stirred for 5 h, recooled to 0 °C, and diluted
with saturated NaHCO3 (1 mL) and Na2S2O3 solutions (1 mL).
Stirring was maintained until all suspended solids had dissolved.
The aqueous phase was extracted with CH2Cl2 (3 × 4 mL), and
the organic layers were combined, washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (ethyl acetate/hexane 1:8) to furnish 37 (10 mg, 85%)
as a colorless oil; IR (neat, cm-1) 1745, 1727; 1H NMR (300 MHz,
CDCl3) δ 7.66-7.60 (m, 4H), 7.46-7.36 (m, 6H), 5.01 (d, J )
7.6 Hz, 1H), 4.53-4.49 (m, 1H), 3.70 (dd, J ) 10.5, 6.3 Hz, 1H),
3.50 (dd, J ) 10.5, 9.6 Hz, 1H), 2.94 (d, J ) 7.4 Hz, 1H), 2.42-
2.31 (m, 1H), 2.20-2.13 (m, 1H), 2.05 (s, 3H), 1.96 (dd, J ) 12.6,
6.0 Hz, 1H), 1.88-1.78 (m, 2H), 1.72-1.65 (m, 2H), 1.62-1.53
(m, 2H), 1.19 (s, 9H), 1.05 (s, 9H), 0.98 (d, J ) 6.8 Hz, 3H), 0.93
(s, 3H), 0.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 217.3, 178.3,
170.1, 135.7, 135.6, 133.1, 133.0, 129.9, 127.8, 80.9, 76.4, 66.6,
58.5, 56.4, 50.8, 50.1, 46.3, 41.3, 37.9, 37.2, 29.7, 29.4, 29.3, 27.3,
27.1, 26.8, 22.7, 20.1, 19.1, 18.4, 14.1; HRMS (ES) m/z calcd for
643.3795, obsd 643.3790; [R]24 +4.7 (c 1.6, CHCl3).
D
(3aR,5aR,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
5,5,8-trimet hyl-4-methylene-3-oxo-decahydro-1H-cyclopenta-
[i]inden-7-yl Pivalate (41). A solution of 9b (900 mg, 1.5 mmol)
in CH2Cl2 (100 mL) was treated with Dess-Martin periodinane
(954 mg, 2.25 mmol) portionwise at 0 °C. The reaction mixture
was allowed to warm to rt, stirred for 3 h, recooled to 0 °C, and
diluted with saturated NaHCO3 (20 mL) and NaS2O3 solutions (20
mL) prior to stirring until all suspended solids were dissolved. The
aqueous phase was extracted with CH2Cl2 (3 × 40 mL), and the
combined organic layers were washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (ethyl acetate/hexane 1:16) to provide 41 (810 mg,
90%) as a colorless oil; IR (neat, cm-1) 1736, 1724, 1167; 1H NMR
(400 MHz, CDCl3) δ 7.67-7.59 (m, 4H), 7.47-7.38 (m, 6H), 5.09
(d, J ) 2.0 Hz, 1H), 4.90 (d, J ) 2 Hz, 1H), 4.50 (ddd, J ) 12.0,
11.2, 3.2 Hz, 1H), 3.62 (dd, J ) 11.2, 4.8 Hz, 1H), 3.57 (dd, J )
11.2, 3.6 Hz, 1H), 3.24 (s, 1H), 2.43-2.36 (m, 1H), 2.25-2.17
(m, 1H), 2.01-1.79 (m, 4H), 1.66-1.54 (m, 1H), 1.49-1.45 (m,
1H), 1.40-1.37 (m, 1H), 1.20 (s, 9H), 1.14 (s, 3H), 1.08 (s, 9H),
1.01 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 218.0,
178.3, 158.1, 135.9, 135.8, 133.2, 133.1, 129.9, 129.8, 127.7, 108.2,
76.3, 64.3, 60.5, 56.0, 54.9, 51.6, 46.6, 38.8, 37.4, 36.8, 36.7, 33.8,
31.9, 31.6, 27.2, 27.0, 25.8, 19.1, 16.2, 14.1; HRMS (ES) m/z calcd
for C38H52O4SiNa+ 623.2533, obsd 623.3529; [R]24D -11 (c 0.71,
CHCl3).
C39H54O6SiNa+ 669.3587; obsd 669.3579; [R]24 +18 (c 4.0,
D
CHCl3).
(5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
5,5,8-trimethyl-3 -oxo-2,3,5,5a,6,7,8,9-octahydro-1H-cyclopenta-
[i]inden-7-yl Pivalate (38). To a solution of 37 (10 mg, 0.015
mmol) in CH2Cl2 (3 mL) was added 5 drops of DBU. The reaction
mixture was stirred overnight before the solvent was evaporated,
and the residue was purified by flash chromatography on silica gel
(ethyl acetate/hexane 1:16) to provide 38 (7 mg, 85%) as a colorless
1
oil; IR (neat, cm-1) 1725, 1162; H NMR (300 MHz, CDCl3) δ
7.64-7.59 (m, 4H), 7.43-7.34 (m, 6H), 6.03 (s, 1H), 4.59-4.52
(m, 1H), 3.53 (dd, J ) 10.2, 5.7 Hz, 1H), 3.38 (t, J ) 10.2 Hz,
1H), 2.41-2.33 (m, 2H), 2.25-2.16 (m, 2H), 2.01-1.95 (m, 1H),
1.85-1.78 (m, 1H), 1.58-1.45 (m, 3H), 1.20 (s, 9H) 1.13 (d, J )
7.2 Hz, 3H), 1.10 (s, 3H), 1.02 (s, 9H), 0.78 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.2, 178.5, 147.8, 142.4, 135.7, 135.5,
133.5, 133.5, 129.8, 129.7, 127.8, 127.7, 76.2, 68.6, 57.2, 56.3,
52.0, 48.3, 41.0, 39.6, 38.8, 36.6, 31.7, 28.4, 27.2, 26.9, 24.0, 22.1,
19.1; HRMS (ES) m/z calcd for C37H50O4SiNa+ 609.3376, obsd
609.3373; [R]24 -122 (c 0.1, CHCl3).
D
(3R,5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
3-hydroxy-5,5,8-trimethyl-2,3,5,5a,6,7,8,9-octahydro-1H-cyclo-
J. Org. Chem, Vol. 72, No. 1, 2007 219

Paquette et al.
(5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
4,5,5,8-tetrameth yl-3-oxo-2,3,5,5a,6,7,8,9-octahydro-1H-cyclo-
penta[i]inden-7-yl Pivalate (42). A solution of 41 (290 mg, 0.48
mmol) in CH2Cl2 (20 mL) was treated dropwise with DBU (0.35
mL, 2.3 mmol) and stirred overnight prior to dilution with CH2Cl2
(40 mL) and water (10 mL). The organic layer was separated,
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography on silica gel (ethyl acetate/hexane 1:16)
rt, stirred overnight, quenched with saturated NaHCO3 solution (5
mL) and water, and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:16) to provide 7b
1
(400 mg, 93%) as a colorless oil; IR (neat, cm-1) 1725, 1163; H
NMR (400 MHz, CDCl3) δ 7.74-7.70 (m, 4H), 7.48-7.40 (m,
6H), 4.65 (d, J ) 6.8 Hz, 1H), 4.63 (m, 1H), 4.58 (d, J ) 6.8 Hz,
1H), 4.27 (d, J ) 8.4 Hz, 1H), 3.51 (dd, J ) 10.0, 4.8 Hz, 1H),
3.44 (d, J ) 10.0 Hz, 1H), 3.39 (s, 3H), 2.32-2.23 (m, 2H), 1.88-
1.80 (m, 2H), 1.73-1.65 (m, 2H), 1.42-1.38 (m, 2H), 1.27 (s,
9H), 1.17 (d, J ) 7.2 Hz, 3H), 1.11 (s, 9H), 1.03 (s, 3H), 0.69 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 178.5, 141.0, 138.1, 135.7,
135.6, 133.9, 133.7, 129.7, 129.7, 127.7, 95.9, 73.8, 68.7, 56.9,
55.7, 54.4, 53.7, 48.1, 41.2, 38.8, 37.2, 33.6, 30.4, 28.5, 27.2, 26.9,
22.9, 22.4, 19.2, 14.2, 9.8; HRMS (ES) m/z calcd for C40H58O5-
to furnish 42 (275 mg, 95%) as a colorless oil; IR (neat, cm-1
)
1
1714, 1164; H NMR (400 MHz, CDCl3) δ 7.68-7.59 (m, 4H),
7.48-7.35 (m, 4H), 4.61 (dt, J ) 11.2, 1.4 Hz, 1H), 3.53 (dd, J )
10.0, 6.0 Hz, 1H), 3.35 (t, J ) 10.0 Hz, 1H), 2.50-2.40 (m, 1H),
3.53 (dd, J ) 10.0, 6.0 Hz, 1H), 3.35 (t, J ) 10.0 Hz, 1H), 2.50-
2.40 (m, 1H), 2.32 (dd, J ) 10.2, 5.7 Hz, 1H), 2.23-2.15 (m, 2H),
2.00-1.93 (m, 2H), 1.82 (s, 3H), 1.75-1.69 (m, 1H), 1.59-1.48
(m, 2H), 1.26 (s, 3H), 1.23 (s, 9H), 1.15 (d, J ) 6.4 Hz, 1H), 1.07
(s, 9H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.7, 178.4,
154.6, 140.8, 135.7, 135.5, 133.6, 133.5, 129.7, 127.7, 127.7, 76.2,
69.6, 56.5, 54.6, 53.9, 49.6, 41.5, 40.3, 38.8, 36.9, 31.9, 29.8, 29.7,
29.7, 29.4, 28.4, 27.2, 26.9, 23.1, 22.7, 22.0, 19.1, 14.1, 10.3; HRMS
SiNa+ 669.3951, obsd 669.3947; [R]24 +8.4 (c 1.0, CHCl3).
D
Diketone 45. Compound 7b (263 mg, 0.40 mmol) was dissolved
in a mixture of CCl4 (6 mL), acetonitrile (6 mL), and water (9
mL). To this mixture was added sodium periodate (1.08 g, 5 mmol)
and ruthenium dioxide (15 mg, 0.1 mmol). The resulting yellow
solution was stirred vigorously for 15 min and then diluted with
CH2Cl2 (60 mL) and water (5 mL). The organic layer was separated,
washed with 10% NaHSO3 solution and brine, dried, and concen-
trated. The residue was purified by flash chromatography on silica
gel (elution with ethyl acetate/hexane 1:4) to provide 45 (219 mg,
79%) as a colorless oil; IR (neat, cm-1) 1723, 1702, 1152; 1H NMR
(400 MHz, CDCl3) δ 7.66-7.60 (m, 4H), 7.47-7.28 (m, 6H), 4.61
(s, 2H), 4.50-4.43 (m, 1H), 3.86 (t, J ) 10.0 Hz, 1H), 3.74 (dd,
J ) 11.6, 2.8 Hz, 1H), 3.52 (dd, J ) 11.6, 3.2 Hz, 1H), 3.32 (s,
3H), 2.35-2.23 (m, 2H), 2.22 (s, 3H), 2.22-2.13 (m, 1H), 1.95-
1.76 (m, 3H), 1.70-1.60 (m, 1H), 1.53-1.43 (m, 1H), 1.38-1.28
(m, 1H), 1.23 (s, 9H), 1.07 (s, 9H), 0.98 (s, 3H), 0.94 (s, 3H), 0.79
(d, J ) 5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 218.8, 212.2,
178.4, 135.9, 135.7, 133.0, 132.8, 130.0, 129.9, 127.8, 127.8, 96.0,
79.4, 77.6, 63.2, 55.6, 55.5, 51.8, 51.4, 50.5, 38.9, 34.7, 28.4, 27.7,
27.2, 27.0, 26.9, 26.3, 24.7, 21.7, 19.3, 15.8; HRMS (ES) m/z calcd
(ES) m/z calcd for C38H52O4SiNa+ 623.3533, obsd 623.3532; [R]24
-29 (c 0.8, CHCl3).
D
(3S,5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
3-hydroxy-4,5,5,8-tetramethyl-2,3,5,5a,6,7,8,9-octahydro-1H-cy-
clopenta[i]inden-7-yl Pivalate (43) and (3R,5aS,7S,8S,9S,9aR)-
9-((tert-Butyldiphenylsilyloxy)methyl)-3-hydroxy-4,5,5,8-tetramethyl-
2,3,5,5a,6,7,8,9-octahydro-1H-cyclopenta[i]inden-7-yl Pivalate
(44). To a solution of 42 (330 mg, 0.55 mmol) in anhydrous ethanol
(15 mL) was added NaBH4 (105 mg, 2.8 mmol) at 0 °C. The
reaction mixture was allowed to warm to rt, stirred for 4 h, and
evaporated. The residue was treated with ethyl acetate and water.
The separated aqueous layer was extracted with ethyl acetate (3 ×
10 mL), and the combined organic layers were washed with brine,
dried and concentrated. The residue was purified by flash chro-
matography on silica gel (ethyl acetate/hexane 1:8) to provide 43
(100 mg) as a colorless oil. An increase in solvent polarity to ethyl
acetate/hexane 1:4 gave 44 (205 mg, combined yield 90%) as a
colorless oil.
for C40H58O7SiNa+ 701.3850, obsd 701.3839; [R]24 +13 (c 0.6,
D
For 43: IR (neat, cm-1) 3462, 1725; 1H NMR (400 MHz, CDCl3)
δ 7.68-7.62 (m, 4H), 7.48-7.38 (m, 6H), 4.58 (dt, J ) 11.2, 2.8
Hz, 1H), 4.51 (dd, J ) 7.2, 3.6 Hz, 1H), 3.74 (dd, J ) 10.0, 6.4
Hz, 1H), 3.39 (t, J ) 10.0 Hz, 1H), 2.39-2.32 (m, 2H), 2.13-
1.82 (m, 6H), 1.70-1.63 (m, 1H), 1.59 (s, 3H), 1.22 (s, 9H), 1.16
(d, J ) 6.4 Hz, 3H), 1.09 (s, 9H), 0.98 (s, 3H), 0.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 178.5, 144.3, 141.2, 135.7, 133.5, 133.3,
129.7, 127.7, 127.7, 76.9, 70.0, 67.0, 56.1, 56.0, 52.5, 49.3, 42.9,
38.8, 38.3, 37.2, 33.8, 33.8, 30.3, 29.7, 28.6, 27.2, 26.8, 23.0, 22.1,
19.1, 10.2; HRMS (ES) m/z calcd for C38H54O4SiNa+ 625.3689,
CHCl3).
(3R,3aR,6aR,8S,9S,10S,10aR)-3a-Hydroxy-10-(hydroxymethyl)-
3-(methoxymethoxy)-6,6,9-trimethyl-5-oxo-dodecahydrocyclo-
penta[j]naphthalen-8-yl Pivalate (46) and (3R,3aR,6aR,8S,
9S,10S,10aR)-10-((tert-Butyldiphenylsilyloxy)methyl)-3a-hydroxy-
3-(methoxymethoxy)-6,6,9-trimethyl-5-oxo-dodecahydrocyclo-
penta[j]nap hthalen-8-yl Pivalate (47). A solution of diketone 45
(300 mg, 0.44 mmol) in THF (10 mL) was treated with a solution
of NaOH (600 mg, 15 mmol) in water (4 mL). The reaction mixture
was stirred overnight, treated with 1 M HCl (15 mL), and diluted
with ether (50 mL). The aqueous layer was extracted with ether
(20 mL × 3). The combined organic layers were washed with brine,
dried, and concentrated. The residue was purified by flash chro-
matography on silica gel (elution with ethyl acetate/hexane 1:4) to
provide 47 (110 mg, 37%) as a colorless oil. An increase in solvent
polarity to ethyl acetate/ hexane 1:2 gave 46 (66 mg, 34%) as a
colorless oil.
For 46: 1H NMR (400 MHz, CDCl) δ 5.07 (s, 1H), 4.76 (d, J
) 6.8 Hz, 1H), 4.72 (d, J ) 6.8 Hz, 1H), 4.51 (dt, J ) 10.8, 4.0
Hz, 1H), 4.26 (t, J ) 10.0 Hz, 1H), 3.97-3.91 (m, 1H), 3.88 (t, J
) 12.0 Hz, 1H), 3.64 (d, J ) 5.2 Hz, 1H), 3.45 (s, 3H), 3.06 (d, J
) 12.8 Hz, 1H), 2.74 (d, J ) 12.8 Hz, 1H), 2.53-2.46 (m, 1H),
2.15-2.10 (m, 1H), 1.98-1.66 (m, 4H), 1.48-1.38 (m, 2H), 1.38-
1.30 (m, 4H), 1.22 (s, 9H), 1.16 (s, 3H), 0.98 (d, J ) 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 216.8, 178.5, 97.7, 87.8, 86.0, 78.3,
58.3, 56.0, 55.8, 52.3, 49.6, 47.0, 42.6, 38.9, 34.3, 32.2, 2.99, 27.9,
27.2, 26.1, 15.9.
For 47: IR (neat, cm-1) 3423, 1721, 1112; 1H NMR (400 MHz,
CDCl3) δ 7.71-7.66 (m, 4H), 7.50-7.38 m, 6H), 4.66 (d, J ) 6.8
Hz,1H), 4.58 (s, 1H), 4.55 (d, J ) 6.8 Hz, 1H), 4.25 (br, 1 H),
4.02-3.91 (m, 2H), 3.88 (dd, J ) 11.6, 4.0 Hz, 1H), 3.39 (s, 3H),
obsd 625.3679; [R]24 +34 (c 2.8, CHCl3).
D
Details pertaining to the crystallographic analysis of 43 are
provided in Supporting Information.
For 44: IR (neat, cm-1) 3498, 1725; 1H NMR (400 MHz,
CDCl3) δ 7.70-7.65 (m, 4H) 7.48-7.38 (m, 6H), 4.58 (dt, J )
11.2, 2.8 Hz, 1H), 4.21 (d, J ) 8.4 Hz, 1H), 3.47-3.37 (m, 2H),
3.39-3.29 (m, 1H), 2.03-1.93 (m, 2H), 1.79 (dd, J ) 12.0, 7.6
Hz, 1H), 1.70-1.58 (m, 4H), 1.57 (s, 3H), 1.43 (m, 1H), 1.20 (s,
9H), 1.13 (d, J ) 6.4 Hz, 3H), 1.08 (s, 9H), 0.99 (s, 3H), 0.69 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 178.5, 144.4, 137.7, 135.7,
135.6, 133.9, 133.7, 129.7, 129.6, 127.7, 69.2, 68.8, 57.5, 54.5,
53.7, 48.1, 41.1, 38.8, 37.4, 37.2, 30.5, 28.5, 27.2, 26.9, 22.8, 22.3,
19.2, 9.8; HRMS (ES) m/z calcd for C38H54O4SiNa+ 625.3689, obsd
625.3676; [R]24 +12 (c 1.8, CHCl3).
D
(3R,5aS,7S,8S,9S,9aR)-9-((tert-Butyldiphenylsilyloxy)methyl)-
3-(methoxymethoxy)-4,5,5,8-tetramethyl-2,3,5,5a,6,7,8,9-octahy-
dro-1H-cyclopenta[i]inden-7-yl Pivalate (7b). A solution of 44
(420 mg, 0.7 mmol) and diisopropylethylamine (0.73 mL, 4.2
mmol) in dry CH2Cl2 (15 mL) was cooled to 0 °C and treated
dropwise with MOMCl (0.2 mL, 2.6mmol), followed by DMAP
(85 mg, 0.7 mmol). The reaction mixture was allowed to warm to
220 J. Org. Chem., Vol. 72, No. 1, 2007

Total Synthesis of Dumsin
3.04 (d, J ) 13.2 Hz, 1H), 2.76 (d, J ) 13.2 Hz, 1H), 2.37 (br,
1H), 2.11-2.08 (m, 1H), 1.98-1.71 (m, 5H), 1.65-1.38 (m, 2 H),
1.30 (s, 3H), 1.23 (s, 9H), 1.14 (s, 9H), 1.13 (s, 3H), 0.69 (d, J )
5.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 217.2, 178.4, 136.2,
135.9, 132.7, 132.3, 130.2, 130.0, 127.8, 96.9, 87.9, 85.8, 55.8,
52.2, 49.9, 46.9, 42.9, 38.8, 36.2, 34.7, 32.2, 31.6, 29.5, 28.2, 27.2,
27.0, 25.3, 22.6, 20.7, 19.2, 14.1; HRMS (ES) m/z calcd for
separated and extracted with EtOAc (5 mL × 2). The combined
organic layers were washed with brine, dried, and concentrated.
The residue was purified by flash chromatography on silica gel
(elution with ethyl acetate/hexane 1:2) to provide the triol 50 (35
mg, 81%) as a colorless oil; IR (neat, cm-1) 3476, 1720, 1112; 1H
NMR (400 MHz, CDCl3) δ 7.70-7.68 (m, 4H), 7.46-7.38 (m,
6H), 4.52 (d, J ) 6.4 Hz, 1H), 4.47 (d, J ) 6.4 Hz, 1H), 4.36 (dt,
J ) 10.8, 4.4 Hz, 1H), 4.08 (m, 1H), 3.91 (s, 1H), 3.91-3.80 (m,
3H), 3.60 (s, 1H), 3.54 (br s, 1H), 3.31 (s, 3H), 2.57 (br s, 1H),
2.50-2.42 (m, 1H), 2.24-2.14 (m, 1H), 2.05-1.95 (m, 2H), 1.61-
(s, 1H), 1.53 (dd, J ) 13.6, 4.4 Hz, 1H), 1.46-1.33 (m, 3H), 1.22
(s, 9H), 1.17 (s, 3H), 1.15 (s, 3H), 1.11 (s, 9H), 0.95 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.4, 135.9, 135.8, 133.6,
133.5, 129.8, 129.7, 127.7, 96.5, 87.9, 82.3, 78.7, 68.6, 64.7, 59.9,
55.7, 49.2, 47.8, 38.8, 37.9, 37.3, 34.1, 32.8, 31.3, 29.7, 27.6, 27.2,
27.0, 26.5, 19.2, 16.7; HRMS (ES) m/z calcd for C40H60O8SiNa+
C40H58O8SiNa+ 701.3850, obsd 701.3839; [R]24 +4.1 (c 3.0,
D
CHCl3).
Conversion of 46 to 47. Alcohol 46 (70 mg, 0.16 mmol) was
taken up in DMF (1 mL) and treated with imidazole (39 mg, 0.58
mmol) and tert-butyldipenylchlorosilane (0.1 mL, 0.38 mmol) at
rt. The reaction mixture was allowed to stir overnight prior to being
partitioned between hexane (30 mL) and water (10 mL). The
combined organic phases were washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:4) to provide 47
(90 mg, 83%) as a colorless oil.
719.3955, obsd 719.3948; [R]24 +22 (c 3.6, CHCl3).
D
Keto Aldehyde 51 and Keto Acid 52. A solution of triol 50
(35 mg, 0.05 mmol) in benzene (4 mL) was allowed to react with
lead tetraacetate (66 mg, 0.15 mmol) at rt for 10 min. At this time,
the reaction mixture was filtered through Celite, and the filtrate
was concentrated. The residue was passed through a plug of silica
gel (elution with ethyl acetate/hexane 1:8) to provide aldehyde 51
(12 mg, 35%). An increase in solvent polarity to ethyl acetate/
hexane (1:2) gave 52 (13 mg, 34%) as a colorless oil.
(3R,3aR,6aS,8S,9S,10S,10aR)-5-(tert-Butyldimethylsilyloxy)-
10-((tert-butyld iphenylsilyloxy)methyl)-3a-hydroxy-3-(meth-
oxymethoxy)-6,6,9-trimethyl-1,2,3 ,3a,6,6a,7,8,9,10-decahydro-
cyclopenta[j]naphthalen-8-yl Pivalate (48). To a solution of 47
(130 mg, 0.19 mmol) in CH2Cl2 (6 mL) was added triethylamine
(0.22 mL, 1.72 mmol) under argon. The mixture was cooled to 0
°C, and tert-butyldimethylsilyl triflate (0.2 mL, 0.85 mmol) was
added dropwise. After 30 min, the reaction mixture was quenched
with saturated NaHCO3 solution (5 mL) and allowed to warm to
rt. The aqueous layer was extracted with CH2Cl2 (10 mL × 3).
The combined organic layers were washed with brine, dried, and
concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:32) to provide 48
1
For 51: IR (neat, cm-1) 1720; H NMR (400 MHz, CDCl3) δ
9.58 (s, 1H), 7.68-7.58 (m, 4H), 7.47-7.36 (m, 6H), 4.63 (d, J )
6.4 Hz, 1H), 4.59 (d, J ) 6.4 Hz, 1H), 4.46 (dt, J ) 10.8, 4.4 Hz,
1H), 3.88 (t, J ) 10.4 Hz, 1H), 3.76 (dd, J ) 11.6, 2.8 Hz, 1H),
3.51 (dd, J ) 11.6, 3.2 Hz, 1H), 3.32 (s, 3H), 2.28-2.15 (m, 2H),
2.07-1.80 (m, 5H), 1.57-1.51 (m, 1H), 1.45-1.39 (m, 1H), 1.25
(s, 9H), 1.08 (s, 9H), 0.98 (s, 3H), 0.86 (s, 3H), 0.80 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 218.3, 202.4, 178.4, 135.9,
135.7, 133.0, 132.8, 130.0, 139.9, 127.8, 127.8, 96.1, 80.0, 63.3,
55.6, 55.0, 51.6, 50.1, 49.7, 38.9, 34.7, 28.2, 27.2, 27.1, 27.0, 26.1,
25.3, 25.0, 19.3, 18.1, 15.8; HRMS (ES) m/z calcd for C39H56O7-
1
(65 mg, 47%) as a colorless oil; H NMR (400 MHz, CDCl3) δ
7.73-7.68 (m, 4H), 7.48-7.36 (m, 6H), 4.80 (s, 1H), 4.70 (d, J )
6.8 Hz, 1H), 4.58 (d, J ) 6.8 Hz, 1H), 4.17-4.12 (m, 2H), 3.97-
3.89 (m, 2H), 3.40 (s, 3H), 2.43-2.37 (m, 1H), 2.02-1.36 (m,
8H), 1.29 (s, 3H), 1.19 (s, 9H), 1.15 (s, 9H), 1.10 (s, 3H), 0.97 (s,
9H), 0.62 (d, J ) 6.4 Hz, 3H), 0.25 (s, 3H), 0.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 178.4, 156.0, 136.3, 136.0, 133.0, 132.5,
130.1, 129.9, 127.7, 127.6, 102.8, 97.0, 88.7, 82.1, 78.8, 63.0, 57.4,
55.6, 51.5, 48.5, 38.9, 38.8, 35.8, 31.6, 30.1, 27.2, 27.1, 25.8, 25.3,
22.6, 19.3, 18.2, 16.6, 14.1, -3.4, -5.0.
SiNa+ 687.3693, obsd 687.3693; [R]24 +33 (c 0.2, CHCl3).
D
For 52: IR (neat, cm-1) 3566-3150 (br), 1724, 1698; 1H NMR
(400 MHz, CDCl3) δ 7.67-7.61 (m, 4H), 7.47-7.38 (m, 6H), 4.63
(d, J ) 8.0 Hz, 1H), 4.61 (d, J ) 8.0 Hz, 1H), 4.47 (dt, J ) 10.4,
4.4, 1H), 3.93 (t, J ) 9.2 Hz, 1H), 3.79 (dd, J ) 11.6, 2.4 Hz, 1H),
3.56 (dd, J ) 11.6, 2.8 Hz, 1H), 3.32 (s, 3H), 2.36-2.17 (m, 3H),
2.05-1.85 (m, 5H), 1.43-1.38 (m, 1H), 1.23 (s, 9H), 1.18 (s, 3H),
1.08 (s, 9H), 1.02 (s, 3H), 0.78 (d, J ) 5.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 218.8, 184.1, 178.4, 136.0, 135.7, 133.0,
132.8, 130.0, 129.9, 127.8, 127.8, 96.0, 79.6, 77.6, 62.9, 55.5, 55.2,
51.6, 50.5, 45.1, 38.9, 34.5, 31.9, 29.8, 29.7, 29.4, 27.4, 27.2, 27.0,
26.8, 26.5, 22.7, 21.6, 19.3, 15.8, 14.1; HRMS (ES) m/z calcd for
(3R,3aS,4S,6aR,8S,9S,10S,10aR)-10-((tert-Butyldiphenylsilyl
oxy)methyl)-3a,4-dihydroxy-3-(methoxymethoxy)-6,6,9-trimethyl-
5-oxo-dodecahydrocyclopenta[j]naphthalen-8-yl Pivalate (49).
A solution of silyl enol ether 48 (60 mg, 0.075 mmol) in CH2Cl2
(1 mL) and methanol (4 mL) was treated with excess ozone at -78
°C for 30 min. The blue solution was purged with N2 until the
color faded. Triphenylphosphine (64 mg) was added, and the
reaction mixture was allowed to warm to rt. The solvent was
evaporated, and the residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:4) to provide 49
(43 mg, 80%) as a colorless oil; IR (neat, cm-1) 3425, 1721, 1159;
1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (m, 4H), 7.44-7.37 (m,
6H), 4.58 (d, J ) 6.4 Hz, 1H), 4.54 (s, 1H), 4.50 (d, J ) 6.4 Hz,
1H), 4.51-4.48 (m, 1H), 4.10-3.72 (m, 5H), 3.32 (s, 3H), 2.37-
2.26 (m, 1H), 2.06-1.83 (m, 4H), 1.72-1.62 (m, 2H), 1.45-1.33
(m, 4H), 1.l8 (s, 9H), 1.12 (s, 3H), 1.08 (s, 9H), 1.00 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.4, 178.4, 135.8, 135.7,
133.5, 133.5, 129.8, 127.8, 96.8, 87.1,83.3, 65.8, 55.7, 53.0, 48.2,
46.9, 38.8, 37.8, 31.9, 30.8, 29.7, 29.6, 29.4, 27.8, 27.2, 26.9, 24.5,
22.7, 19.2, 14.1; HRMS (ES) m/z calcd for C40H58O8SiNa+
C39H56O8SiNa+ 703.3642, obsd 703.3640; [R]24 +28 (c 0.3,
D
CHCl3).
Conversion of 40 to 52. Olefin 40 (12 mg, 0.019 mmol) was
dissolved in a mixture of CCl4 (1 mL), acetonitrile (1 mL), and
water (1.5 mL). To this mixture was added sodium periodate (42
mg, 0.19 mmol) and ruthenium dioxide (1.5 mg). The resulting
yellow solution was stirred vigorously for 15 min and then diluted
with CH2Cl2 (20 mL) and water (5 mL). The organic layer was
separated, washed with 10% NaHSO3 solution and brine, dried,
and concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:2) to provide 52
(9 mg, 70%) as a colorless oil identical in all respects with the
keto acid described above.
Hydroxy Peroxide 53. A solution of Na2CO3 (93 mg, 0.88
mmol) in water (0.5 mL) was cautiously added dropwise to a hot
solution (50-60 °C) of 52 (30 mg, 0.044 mmol) and mercuric
trifluoroacetate (187.7 mg, 0.44 mmol) in a mixture of THF (4
mL) and 30% H2O2 (0.25 mL). The reaction mixture was kept at
the same temperature for 30 min and then cooled to rt. A solution
of NaOH (8.8 mg, 0.22 mmol) was introduced followed by addition
of a solution of NaBH4 (38 mg) in water (2 mL) until a black
717.3799; obsd 717.3818; [R]24 + 46 (c 1.0, CHCl3).
D
(3R,3aS,4R,5R,6aS,8S,9S,10S,10aR)-10-((tert-Butyldiphenyl-
silyloxy)methyl)-3a,4,5-trihydroxy-3-(methoxymethoxy)-6,6,9-
trimethyldodecahydrocyclopent a[j]naphthalen-8-yl Pivalate
(50). A solution of 49 (43 mg, 0.06 mmol) in methanol (4 mL)
was treated with sodium borohydride (38 mg, 1.0 mmol) at rt. One
hour later, the methanol was evaporated and the residue was diluted
with EtOAc (10 mL) and water (5 mL). The aqueous layer was
J. Org. Chem, Vol. 72, No. 1, 2007 221

Paquette et al.
precipitate formed. The reaction mixture was diluted with ether
(20 mL) and water (2 mL), the aqueous layer was separated and
extracted with ether (5 mL × 2), and the combined organic layers
were washed with brine, dried, and concentrated. The residue was
purified by flash chromatography on silica gel (elution with ethyl
acetate/hexane 1:8) to provide peroxide 53 (13 mg, 43%) as a
colorless oil; IR (neat, cm-1) 3356, 1720, 1108; 1H NMR (400 MHz,
CDCl3) δ 7.69-7.66 (m, 4H), 7.49-7.42 (m, 6H), 5.44 (br s, 1H),
4.61 (d, J ) 6.8 Hz, 1H), 4.42 (d, J ) 6.8 Hz, 1H), 4.40 (dt, J )
10.8, 4.0 Hz, 1H), 3.84 (dd, J ) 10.8, 4.8 Hz, 1H), 3.59 (d, J )
10.8 Hz, 1H), 3.47 (s, 3H), 3.21 (br s, 1H), 2.20 (br s, 1H), 2.08-
1.75 (m, 6H), 1.55-1.48 (m, 1H), 1.38-1.35 (m, 1H), 1.33 (s,
3H), 1.29 (s, 3H), 1.24 (s, 9H), 1.10 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 178.5, 135.9, 135.7, 133.7, 133.6, 129.9, 129.7,
127.7, 127.7, 107.6, 98.8, 91.2, 81.1, 77.8, 66.3, 56.7, 48.7, 47.8,
38.9, 38.5, 33.9, 33.8, 29.7, 29.0, 28.3, 27.2, 26.9, 25.8, 19.1, 16.6;
HRMS (ES) m/z calcd for C38H56O8SiNa+ 691.3642, obsd 691.3660;
5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.4, 135.9, 135.8,
133.4, 133.4, 129.9, 129.8, 127.8, 127.7, 111.2, 97.6, 87.5, 83.5,
77.2, 64.5, 55.6, 54.6, 54.1, 53.8, 38.8, 32.4, 30.6, 27.9, 27.6, 27.2,
26.9, 19.1, 16.3; HRMS (ES) m/z calcd for C38H56O7SiNa+
675.3693, obsd 675.3696; [R]24 -12 (c 0.5, CHCl3).
D
O-Methylation of 54. A solution of 54 (10 mg, 0.015 mmol) in
acetonitrile (2 mL) and methyl iodide (2 mL) was stirred at reflux
in the presence of silver(I) oxide (700 mg). The solids were removed
by filtration, and the filtrate was concentrated. The residue was
purified by flash chromatography on silica gel (elution with ethyl
acetate/hexane 1:8) to provide ketal 5 (9 mg, 90%) as a colorless
1
oil; IR (neat, cm-1) 1722, 1041; H NMR (400 MHz, CDCl3) δ
7.73-7.69 (m, 4H), 7.47-7.40 (m, 6 H), 4.60 (s, 2H), 4.40 (dt, J
) 10.8, 4.0 Hz, 1H), 3.95 (dd, J ) 9.2, 2.8 Hz, 1H), 3.88 (dd, J )
11.2, 4.0 Hz, 1H), 3.81 (dd, J ) 11.2, 5.6 Hz, 1H), 3.39 (s, 3H),
3.33 (s, 3H), 2.00 (dd, J ) 12.4, 6.0 Hz, 1H), 1.88-1.81 (m, 1H),
1.75-1.60 (m, 6H), 1.47-1.42 (m, 1H), 1.39 (s, 3H), 1.28 (s, 3H),
1.21 (s, 9H), 1.09 (s, 9H), 0.83 (d, J ) 5.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 178.4, 135.8, 135.8, 133.7, 133.6, 129.7,
129.7, 127.7, 127.7, 114.2, 95.9, 84.4, 83.0, 76.8, 64.8, 55.6, 54.5,
53.7, 50.5, 38.8, 37.6, 35.9, 32.0, 30.5, 29.7, 28.2, 27.2, 27.0, 26.9,
19.1, 16.5; HRMS (ES) m/z calcd for C39H58O7SiNa+ 689.3850,
[R]24 +19 (c 0.8, CHCl3).
D
Hemiketal 54. A solution of 53 (13 mg, 0.02 mmol) in ethanol
(4 mL) was treated with sodium borohydride (76 mg, 2.0 mmol)
at rt. After 30 min, another portion of sodium borohydride (76 mg)
was added, and the reaction mixture was stirred for another 3 h
until reaction was complete. The ethanol was evaporated, and the
residue was diluted with EtOAc (10 mL) and water (5 mL). The
aqueous layer was separated and extracted with EtOAc (5 mL ×
2). The combined organic layers were washed with brine, dried,
and concentrated. The residue was purified by flash chromatography
on silica gel (elution with ethyl acetate/hexane 1:8) to provide 54
(12 mg, 92%) as a colorless oil; IR (neat, cm-1) 3398, 1721, 1112;
1H NMR (400 MHz, CDCl3) δ 7.73-7.66 (m, 4H), 7.48-7.38 (m,
6H), 4.88 (s, 1H), 4.65 (d, J ) 6.8 Hz, 1H), 4.50 (d, J ) 6.8 Hz,
1H), 4.41 (dt, J ) 10.8, 4.4 Hz, 1H), 3.89 (d, J ) 4.4 Hz, 2H),
3.67 (t, J ) 8.4 Hz, 1H), 3.43 (s, 3H), 2.04 (dd, J ) 12.0, 6.8 Hz,
1H), 1.98-1.92 (m, 1H), 1.85-1.62 (m, 6H), 1.49-1.43 (m, 1H),
1.35 (s, 3H), 1.28 (s, 3H), 1.21 (s, 9H), 1.09 (s, 9H), 0.83 (d, J )
obsd 689.3835; [R]24 -12 (c 0.7, CHCl3).
D
Acknowledgment. The authors thank Dr. Judith Gallucci
for performing the X-ray analysis of 43. Fellowship support by
the Alexander von Humboldt Foundation (Feodor Lynen Award
to A.L.) and the National Cancer Institute (Minority Award to
R.L.B.) is gratefully acknowledged.
Supporting Information Available: Details of the X-ray
1
crystallographic analysis of 43 and high-field H and 13C NMR
spectra for all stable new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO062068O
222 J. Org. Chem., Vol. 72, No. 1, 2007