An intramolecular Diels-Alder strategy for the asbestinins: Enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12

Article abstract of DOI:10.1021/jo0712695

(Chemical Equation Presented) The enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12 have been completed. A glycolate aldol reaction provided a diene useful for ring-closing metathesis to form an oxonene, which was ultimately employed as a template to execute a highly stereoselective intramolecular Diels-Alder cycloaddition, forming the hydroisobenzofuran moiety. The absolute configuration of the asbestinin subclass was confirmed via these synthetic efforts.

Full text of DOI:10.1021/jo0712695

VOLUME 73, NUMBER 5
MARCH 7, 2008
© Copyright 2008 by the American Chemical Society
An Intramolecular Diels-Alder Strategy for the Asbestinins:
Enantioselective Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D
and Asbestinin-12
Michael T. Crimmins* and J. Michael Ellis
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
ReceiVed June 28, 2007
The enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12 have been
completed. A glycolate aldol reaction provided a diene useful for ring-closing metathesis to form an
oxonene, which was ultimately employed as a template to execute a highly stereoselective intramolecular
Diels-Alder cycloaddition, forming the hydroisobenzofuran moiety. The absolute configuration of the
asbestinin subclass was confirmed via these synthetic efforts.
SCHEME 1. Proposed Biosynthetic Pathway of the
C2-C11-Cyclized Cembranoids
Introduction
The C2-C11-cyclized cembranoids are secondary metabolites
of gorgonian octocoral, which include the eunicellins (also
known as the cladiellins), briarellins, asbestinins, and sarcodyc-
tins. Cyclization of the cembranoid diterpene skeleton has been
postulated as the biosynthetic origin of these four subclasses of
marine diterpenes (Scheme 1).1 The presence of an oxygen
bridge from C4 to C7 differentiates the sarcodyctins from the
three other classes which possess a C2-C9 oxygen bridge. The
briarellins and asbestinins, unlike the cladiellins, feature an
oxepane ring, which results from an oxygen bridge from C3 to
C16, forming a tetracyclic core. The asbestinins arise from a
suprafacial 1,2-methyl shift from C11 to C12 of the briarellins,
rendering this subclass the furthest evolved from the original
cembranoid structure in the proposed biosynthesis.
(1) For reviews, see: (a) Rodr´ıguez, A. D. Tetrahedron 1995, 51, 4571.
(b) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531. (c) Sung,
P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705.
10.1021/jo0712695 CCC: $40.75 © 2008 American Chemical Society
Published on Web 10/05/2007
J. Org. Chem. 2008, 73, 1649-1660
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Crimmins and Ellis
FIGURE 1. C2-C11 cyclized cembranoid natural products prepared via total synthesis.
Intense efforts from the synthetic community over the past
decade have been directed toward the C2-C11-cyclized cem-
branoids, and several total syntheses have resulted. Overman
reported the first total synthesis of a cladiellin, (-)-7-deac-
etoxyalcyonin acetate, in 1995 (Figure 1) based on a novel
Prins-pinacol rearrangement to construct the hydroisobenzo-
furan unit.2 Several years later, the Molander group divulged a
strategically different approach to this same molecule.3 The
Paquette and Overman groups detailed concurrent efforts toward
sclerophytin A, resulting in a structural reassignment and
ultimately the total synthesis of the corrected structure.4 The
Overman group also reported the first and only total syntheses
of members of the briarellin subclass in 2003, briarellins E and
F.5 Each of the above approaches relied upon initial formation
of the hydroisobenzofuran unit, followed by formation of the
oxonene portion of the molecules at a late stage of the synthesis.
We have recently developed a general approach for the
construction of seven-,6 eight-,7 and nine-membered rings8 by
exploiting acyclic conformational constraints to facilitate ring-
closing metathesis for the formation of medium ring ethers. This
strategy has been expanded to a novel approach to the eunicellin
diterpenes which relies upon initial construction of the oxonene
ring via a ring-closing metathesis, followed by construction of
the hydroisobenzofuran moiety via a highly selective intramo-
lecular Diels-Alder cycloaddition. The total syntheses of two
cladiellin natural products, ophirin B and astrogorgin, have been
accomplished using this approach.9 Very recently, Kim and co-
workers have utilized a very similar intramolecular Diels-Alder
strategy to prepare several cladiellins, which contain or are
derived from an E-oxonene.10 In 2007, Clark reported a synthesis
of vigulariol featuring formation of the cyclohexene unit through
an intermolecular Diels-Alder cycloaddition.11
Until recently, the asbestinins were the only subclass of C2-
C11 cyclized cembranoid natural products which had not been
prepared by chemical synthesis.12 11-Acetoxy-4-deoxyasbestinin
D (1)13 and asbestinin-12 (2)14 feature a captivating molecular
topography, including 9 and 10 contiguous stereocenters,
respectively, as well as a fully substituted tetrahydrofuran. Our
interest in the asbestinin subclass was further strengthened by
the intriguing biological properties displayed by some members
of this family.1 11-Acetoxy-4-deoxyasbestinin D (1) demon-
strates cytotoxicity against CHO-K1 cells (ED50 ) 4.82 µg/
mL) as well as strong antimicrobial activity against Klebsiella
pneumoniae.13 Additionally, while it seemed likely that the
absolute configuration of the asbestinins followed the cladiellins
and briarellins, some question regarding the absolute configu-
ration of the asbestinins existed in the literature, in part because
no member of the asbestinin subclass had been prepared by total
synthesis.1 We report herein a full account of the approach
developed for the asbestinin subclass, and the application of
this strategy to the total syntheses of 11-acetoxy-4-deoxyas-
(2) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117,
10391.
(3) Molander, G. A.; St. Jean, D. J., Jr.; Haas, J. J. Am. Chem. Soc.
2004, 126, 1642.
(4) (a) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org.
Lett. 2000, 2, 1875. (b) Overman, L. E.; Pennington, L. D. Org. Lett. 2000,
2, 2683. (c) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L.
A.; Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135. (d) Bernardelli, P.;
Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck, B. P.; Doskotch,
R. W.; Lange, T.; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021. (e)
MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2001, 123, 9033.
(5) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2003, 125, 6650.
(9) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
10264. (b) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am. Chem. Soc.
2006, 128, 1371.
(10) Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2006, 128, 15851.
(11) Clark, J. S.; Hayes, S. T.; Wilson, C.; Gobbi, L. Angew. Chem.,
Int. Ed. 2007, 46, 437.
(12) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127, 17200.
(13) Morales, J. J.; Lorenzo, D.; Rodr´ıguez, A. D. J. Nat. Prod. 1991,
54, 1368.
(6) (a) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 899. (b)
Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009.
(7) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029. (b)
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653. (c)
Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473. (d)
Crimmins, M. T.; Cleary, P. A. Heterocycles 2003, 61, 87.
(8) (a) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123,
1533. (b) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002,
58, 1817. (c) Crimmins, M. T.; Powell, M. T. J. Am. Chem. Soc. 2003,
125, 7592.
(14) Rodr´ıguez, A. D.; Co´bar, O. M.; Mart´ınez, N. J. Nat. Prod. 1994,
57, 1638.
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Intramolecular Diels-Alder Strategy for the Asbestinins
SCHEME 2. Retrosynthetic Analysis
Results and Discussion
The synthesis of glycolate 6 began with the addition of
2-propenylmagnesium bromide to (R)-benzyl glycidyl ether (7)
to provide a secondary alcohol 8,17 which was O-alkylated with
sodium bromoacetate (Scheme 3). Standard formation of gly-
colate 6 was accomplished by coupling of the resultant glycolic
acid 9 with (S)-4-benzyloxazolidinethione using N,N′-dicyclo-
hexylcarbodiimide. Alternatively, the oxazolidinone variant 10
of glycolate 6 was formed by acylation of the mixed anhydride
of the glycolic acid with lithiated (S)-4-benzyloxazolidinone to
provide glycolate 10. Concurrent with these efforts, an improved
procedure for asymmetric glycolate aldol reactions was being
developed in our laboratory.16d As part of this program, a variety
of conditions were explored to determine the optimal protocol
for effecting the addition of pent-4-enal18 to each of these
glycolyl imides. Ultimately, it was determined that the ideal
conditions for each of these reactions involved initial formation
of the chlorotitanium enolate of the glycolate, followed by
addition of N-methylpyrrolidinone 10 min prior to addition of
the aldehyde. As has been observed previously in our laboratory,
imide 10 provided a slightly higher yield (78%) but lower
diastereoselectivity (10:1 dr) than the corresponding thioimide
6 (70%, >19:1 dr).7c For our purposes, we chose to proceed
using thioimide adduct 11 since the minor diastereomer was
not observed by 1H NMR, facilitating purification of the desired
product.
bestinin D (1) and asbestinin-12 (2), serving to confirm the
absolute configuration of this family of natural products.
Strategically, ketone 3 was targeted as a point of divergence
for the syntheses of 11-acetoxy-4-deoxyasbestinin D (1) and
asbestinin-12 (2) (Scheme 2). The desire to apply the previously
developed Diels-Alder strategy used for the eunicellins to
complete the first total synthesis of a member of the asbestinin
subclass of natural products resulted in selection of tetraene 4
as the Diels-Alder substrate. Tetraene 4 would be prepared
from diene 5 by ring-closing metathesis followed by further
functionalization. While construction of the diene metathesis
substrate for the ophirin B and astrogorgin syntheses was
accomplished through the use of an asymmetric glycolate
alkylation as the key step,7a,9,15 the strategy for the synthesis of
diene 5 hinged upon the development and application of an
asymmetric glycolate aldol reaction to establish the ether linkage
stereochemistry of the oxonene precursor.16 The required
thioimide 6 for the aldol reaction would be prepared from (R)-
benzyl glycidyl ether (7).
Tetraene 4 was an attractive Diels-Alder substrate in that it
would incorporate the required stereochemistry of the C15
methyl group prior to the Diels-Alder reaction. While the 2,3-
substitution on the diene was viewed as a potential problem
with regard to the ability of the diene to adopt the required s-cis
conformation, and the electronic character of the dienophile was
less than optimal, the facility of the Diels-Alder reaction in
the ophirin synthesis9 provided optimism for the success of the
Diels-Alder reaction of tetraene 4. Thus, we set out to prepare
tetraene 4 and investigate its performance in the designed
cycloaddition.
With the desired diene 11 in hand, the key ring-closing
metathesis reaction was examined. Upon subjecting thioimide
11 to the Grubbs second-generation catalyst in refluxing CH2-
Cl2,19 only dimer 13 was obtained (Scheme 3). Similarly, diol
14, obtained by reduction of thioimide 11, provided dimer 15
as the major product under the same conditions. However,
protection of the secondary alcohol as the tert-butyldimethylsilyl
ether and reduction of the chiral auxiliary provided diene 16,
which underwent smooth formation of oxonene 17 in the
presence of the Grubbs catalyst [Cl2(Cy3P)(IMes)RudCHPh].
Similarly, reduction of the thioimide 11 and protection of the
diol as the corresponding bis-tert-butyldimethylsilyl ether
provided diene 5, which yielded the desired oxonene 18 in 99%
yield using ring-closing metathesis conditions. Importantly, it
was discovered that increasing the concentration of diene 5 in
CH2Cl2 from 2 to 10 mM provided a much more scalable and
a higher yielding reaction without competitive dimerization.
With the crucial oxonene in hand, formation of the diene and
dienophile necessary for the Diels-Alder reaction was exam-
ined. Oxidation of alcohol 17 provided an aldehyde 19, which
was hoped to be useful in an olefination reaction to install the
dienophile with the stereocenter at C15 already in place (Scheme
4).20 A number of reactions were attempted for this olefination,
including a Schlosser-Wittig reaction,21 a Julia-Kocienscki
olefination,22 as well as a cross-metathesis reaction using the
(17) (a) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem.
Soc. 2003, 125, 10160. (b) Hubbs, J. L.; Heathcock, C. H. J. Am. Chem.
Soc. 2003, 125, 12836.
(18) (a) McNeill, A. H.; Thomas, E. J. Tetrahedron Lett. 1993, 34, 1669.
(b) Farquhar, D.; Cherif, A.; Bakina, E.; Nelson, J. A. J. Med. Chem. 1998,
41, 965.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(20) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(21) Shimizu, M.; Ando, R.; Kuwajima, I. J. Org. Chem. 1981, 46, 5246.
(22) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508.
(15) (a) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000,
2, 2165. (b) Crimmins, M. T.; Stanton, M. G.; Allwein, S. P. J. Am. Chem.
Soc. 2002, 124, 5958.
(16) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997,
62, 7548. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem. 2001, 66, 894. (d) Crimmins, M. T.; She, J. Synlett 2004,
1371.
J. Org. Chem, Vol. 73, No. 5, 2008 1651

Crimmins and Ellis
SCHEME 3. Synthesis of the Oxonenea
SCHEME 4. Attempted Unactivated Intramolecular
Diels-Alder Cycloadditiona
a Conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C, 92%;
(b) n-Bu4NF, THF, 85%; (c) p-anisaldehyde dimethyl acetal, PPTS, DMF,
84%; (d) Ph3PCH3Br, t-BuOK, THF, 0 °C, 81%; (e) i-Bu2AlH, CH2Cl2,
0 °C, 89%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C; 91%; (g)
sulfone 23, KHMDS, THF, -78 to +25 °C, 69%; (h) LDBB, THF, -78
°C, 78%; (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C, 91%; (j)
Ph3PdC(OMe)C(O)Me (26), C6H6, 80 °C, 79%; (k) Ph3PCH3Br, KO-t-
Bu, THF, 0 °C, 86%.
reaction at C1. The TBS ether was replaced by a p-methoxy-
benzyl ether by removal of the silyl ether from alcohol 17,
followed by formation of the p-methoxybenzylidene acetal 21.
Regioselective reduction of the acetal provided alcohol 22,
which was oxidized to the aldehyde under Swern conditions.20
A Julia-Kocienscki olefination on the aldehyde using sulfone
23 provided the desired dienophile 24.22 Attention was then
turned to the installation of the diene. A reductive cleavage of
the benzyl ether in the presence of the p-methoxybenzyl ether
was accomplished using lithium di-tert-butyldiphenylide, and
the resultant alcohol was oxidized20 to aldehyde 25. Two
sequential Wittig olefinations provided the desired tetraene 27.24
a Conditions: (a) CH2dC(CH3)MgBr, CuI, THF, -40 °C, 99%; (b) NaH,
BrCH2CO2H, THF, DMF, 95%; (c) (S)-benzyl-1,3-oxazolidine-2-thione,
DCC, DMAP, CH2Cl2, 86%; (d) Me3CCOCl, Et3N, THF, -78 to 0 °C;
(S)-lithio-4-benzyloxazolidin-2-one, 95% (e) TiCl4, i-Pr2NEt, NMP, pent-
4-enal, CH2Cl2, -78 °C, X ) S: 70%, >19:1 dr, X ) O: 78%, 10:1 dr;
(f) Cl2(Cy3P)(IMes)RudCHPh, CH2Cl2, 40 °C; (g) LiBH4, MeOH, Et2O,
0 °C, 95%; (h) TBSCl, imid., DMAP, DMF, 50 °C, 87%; (i) TBSOTf,
2,6-lutidine, CH2Cl2, 96%.
(23) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. (b) Crimmins, M. T.; Caussanel, F. J.
Am. Chem. Soc. 2006, 128, 3128.
(24) Guiney, D.; Gibson, C. L.; Suckling, C. J. Org. Biomol. Chem. 2003,
1, 664.
alkene 20 derived from aldehyde 19 through a methylene Wittig
reaction.23 However, none of these reactions effectively installed
the dienophile. At this point, it was speculated that the steric
effect of the C3 tert-butyldimethylsilyl ether was precluding
1652 J. Org. Chem., Vol. 73, No. 5, 2008

Intramolecular Diels-Alder Strategy for the Asbestinins
SCHEME 5. Intramolecular Diels-Alder Cycloadditiona
FIGURE 2. Proposed Diels-Alder reaction selectivity models.
the resultant alcohol was oxidized using Swern conditions to
yield aldehyde 30.20 Aldehyde 30 was treated with two separate
stabilized ylides to provide the corresponding enoate and enone.
After 1 h in refluxing benzene in the presence of [(ethoxycar-
bonyl)methylene]triphenylphosphorane (31),25 enoate 32 was
isolated. However, using (acetylmethylene)triphenylphosphorane
(33),26 intramolecular Diels-Alder cycloaddition ensued under
the conditions of the Wittig reaction to provide the desired
tricycle 34 (76%, 4:1 dr) favoring the exo-diastereomer.
Encouraged by this result, we set out to improve the diastereo-
selectivity of this transformation and streamline the synthesis
of the Diels-Alder precursor. Based upon the studies of the
Diels-Alder reaction in ophirin B,9 as well as data reported by
Holmes and co-workers,27 it was speculated that the C3
configuration as well as the size of the C3 protecting group
would significantly influence the diastereoselectivity observed
in the cycloaddition. These results were rationalized using the
selectivity models 35 and 36 (Figure 2). As the size of R
increases, the steric interaction between the C14 vinyl proton
and R increases, resulting in an increase in energy of the endo
transition state therefore increasing the proportion of the exo
Diels-Alder adduct 34. Seeking to improve the diastereose-
lectivity of the cycloaddition, as well as shorten the overall
synthesis, the installation of a bulky trialkylsilyl group at C3
of the Diels-Alder precursor seemed the most direct path
forward.
a Conditions: (a) TBSCl, imid., DMAP, CH2Cl2, 96%; (b) LDBB, THF,
-78 °C, 79%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C, 90%; (d)
Ph3PdC(OMe)C(O)Me (26), PhCH3, 110 °C, 86%; (e) Ph3PCH3Br, KO-
t-Bu, THF, 0 °C, 73%; (f) n-Bu4NF, THF, 89%; (g) (COCl)2, DMSO, Et3N,
CH2Cl2, -78 to 0 °C, 86%; (h) Ph3PdCHCO2Et (31), PhCH3, 80 °C, 91%;
(i) Ph3PdCHC(O)Me (33), PhCH3, 110 °C, 71%.
Unfortunately, upon subjecting tetraene 27 to a variety of
conventional thermal and microwave conditions, none of the
desired intramolecular Diels-Alder cycloadduct was observed.
At least two possible sources were postulated for the observed
low reactivity. First, the 2,3-disubstituted diene hinders the
rotation of the C11-C12 carbon-carbon bond due to the
eclipsing interaction present in the necessary s-cis conformation
of the diene. Second, the dienophile is significantly reduced in
reactivity (compared to the dienophile in the cladiellin series
Diels-Alder reactions)9 because of the absence of an electron-
withdrawing group.
A more activated dienophile, still possessing the 2,3-disub-
stituted diene, was constructed to determine whether the low
reactivity was due to the diene or the dienophile. To this end,
alcohol 22 was protected as its tert-butyldimethylsilyl ether, and
the benzyl ether was reductively removed to give alcohol 28
(Scheme 5). Oxidation of the primary alcohol to the aldehyde
under Swern conditions20 followed by two sequential Wittig
reactions, the first with a stabilized ylide [Ph3PdC(OMe)C(O)-
Me] (26)24 and the second with methylentriphenylphosphorane,
provided triene 29. Following deprotection of the silyl ether,
Utilizing oxonene 18 (prepared in seven steps from (R)-benzyl
glycidyl ether), a dissolving metal reduction provided the
primary alcohol 38 (Scheme 6). Swern oxidation20 and two
successive Wittig olefinations as described for diene 29 above24
efficiently provided triene 39. At this point, a variety of
conditions were examined for the selective deprotection of the
primary silyl ether in the presence of the acid-sensitive enol
ether. An assortment of different buffered hydrogen fluoride
conditions provided the primary alcohol with concomitant
hydrolysis of the enol ether to provide enone 40.28 Neither
(25) Chow, S. Y.; Williams, H. J.; Huang, Q.; Nanda, S.; Scott, A. I. J.
Org. Chem. 2005, 70, 9997.
(26) Kuroda, H.; Hanaki, E.; Izawa, H.; Kano, M.; Itahashi, H.
Tetrahedron 2004, 60, 1913.
(27) Davidson, J. E. P.; Gilmour, R.; Ducki, S.; Davies, J. E.; Green,
R.; Burton, J. W.; Holmes, A. B. Synlett 2004, 1434.
(28) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
J. Org. Chem, Vol. 73, No. 5, 2008 1653

Crimmins and Ellis
oxidation at C3 to provide ketone 44,30 the divergence point in
the syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-
12. A suitable crystal for X-ray crystallographic analysis of
ketone 44 was obtained (see the Supporting Information). We
were encouraged to find that the configuration of the five
stereocenters established to this point matched the desired
configurations for the asbestinins. Previous two-dimensional
NMR data (COSY, NOESY) analysis had led us to speculate
that the oxonene of the tricyclic portion of the cladiellins and
asbestinins existed in a concave conformation. This was also
apparent in the solid-state conformation of ketone 44. Encour-
aged by the prospect of operating stereoselectively on this
concave ketone 44, alkylation with methylmagnesium chloride
provided the tertiary alcohol 45 as a single diastereomer (Scheme
7). Hydrolysis of the enol ether provided the R-methyl ketone
46. It was determined by two-dimensional NMR analysis that
the undesired configuration at C12 was the major product of
this reaction. Fortunately, facile epimerization of the C12
configuration was accomplished using sodium methoxide, and
the two diastereomers 46 and 47 were trivially separated via
flash column chromatography. While the thermodynamic ratio
of 46:47 was only 1:1.2, ketone 46 could be easily recycled
and an 85% yield of ketone 47 was obtained after two recycles.
Treatment of the ketone 47 with L-Selectride provided a single
diastereomer of the secondary alcohol, and selective esterifi-
cation of the secondary alcohol provided acetate 48.
SCHEME 6. Synthesis of the Common Ketone
Intermediatea
The stage was set for our proposed substrate-controlled
stereoselective hydroboration of the 1,1-disubstituted olefin.
Much precedent exists in the literature involving similar highly
stereoselective reactions in less conformationally restricted
substrates.31 Treatment of diene 48 with 9-BBN chemoselec-
tively and regioselectively provided the primary alcohol upon
oxidation, however, the diastereoselectivity (∼1:1 dr) observed
for the reaction was poor (Scheme 7). Seeking to improve this
selectivity, we hoped to install a C3 protecting group in an
attempt to impede borane addition from the undesired face of
the alkene. Installation of a trimethylsilyl ether at C3 and
regioselective hydroboration of the 1,1-disubstituted alkene
provided the desired alcohol as the major product, but still with
low diastereoselectivity (1.7:1 dr). Increasing the steric bulk at
C3 further, the triethylsilyl analogue 49 was prepared and treated
with 9-BBN to provide the alcohol (80%, 2.2:1 dr). A tert-
butyldimethylsilyl ether provided identical diastereoselectivity
to the triethylsilyl variant. A triisopropylsilyl ether could not
be installed at C3 presumably due to the sterically crowded
environment of the tertiary alcohol that is likely oriented inside
the concave face of the tricycle. Not satisfied with the
stereoselectivity obtained using 9-BBN, we turned our attention
to a chiral hydroborating reagent. While 1,1-disubstituted olefins
are generally poor substrates for reagent-controlled stereose-
lective hydroboration reactions, upon treatment with (+)-
diisopinocampheylborane, followed by oxidative workup, a
single diastereomer of the primary alcohol 50 was obtained.32
To our knowledge, this stands as only the second example of
the use of (+)-diisopinocampheylborane for a highly diaste-
a Conditions: (a) Na, NH3, THF, -78 °C, 86%; (b) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 to 0 °C, 94%; (c) Ph3PdC(OMe)C(O)Me (26), PhCH3,
110 °C, 84%; (d) Ph3PCH3Br, KO-t-Bu, THF, 0 °C, 87%; (e) NH4F, MeOH,
79%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 0 °C, 93%; (g)
Ph3PdCHC(O)Me (31), PhCH3, 110 °C, 80%; (h) Ph3PCH3Br, KO-t-Bu,
THF, 85%; (i) n-Bu4NF, THF, 95%; (j) Dess-Martin periodinane, pyridine,
CH2Cl2, 98%.
alkaline conditions nor tetrabutylammonium fluoride were
selective in removing the primary silyl ether, even at low
temperature. Eventually, it was found that treatment of triene
39 with ammonium fluoride in methanol provided the desired
alcohol 41 in 79% yield (91% brsm).29 Swern oxidation20 of
the alcohol and treatment of the resultant aldehyde with
(acetylmethylene)triphenylphosphorane (33)26 triggered a rapid
in situ intramolecular Diels-Alder cycloaddition to provide the
desired tricycle 42 in good yield, as a single observable
diastereomer, further supporting the proposed selectivity models
(vide supra).
With an effective route to tricycle 42 in hand, a sequence for
establishing the C15 stereocenter needed to be determined. A
substrate-controlled diastereoselective hydroboration/oxidation
of the corresponding 1,1-disubstituted olefin was envisioned to
accomplish this goal. To this end, methylenation of ketone 42
provided the triene 43 (Scheme 6). Functionalization of the
oxonene ring was next accomplished via a deprotection and
(30) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(31) (a) Brown, H. C.; Midland, M. M.; Levy, A. B.; Kramer, G. W.
Organic Synthesis Via Boranes; Wiley: New York, 1975. (b) Cheng, D.;
Zhu, S.; Yu, Z.; Cohen, T. J. Am. Chem. Soc. 2001, 123, 30. (c) Ebel, H.;
Polborn, K.; Steglich, W. Eur. J. Org. Chem. 2002, 2905. (d) Miyaoka, H.;
Honda, D.; Mitome, H.; Yamada, Y. Tetrahedron Lett. 2002, 43, 7773.
(32) Brown, H. C.; Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982, 47,
5065.
(29) Schinzer, D.; Boehm, O. M.; Altmann, K.-H.; Wartmann, M. Synlett
2004, 1375.
1654 J. Org. Chem., Vol. 73, No. 5, 2008

Intramolecular Diels-Alder Strategy for the Asbestinins
SCHEME 7. Completion of 11-Acetoxy-4-deoxyasbestinin Da
a Conditions: (a) MeMgCl, THF, 0 °C, 98%; (b) HCl, CHCl3, 96%, 46:47 ) 10:1 dr; (c) NaH, MeOH, 99%, 46:47 ) 1:1.2 dr; (d) L-Selectride, THF,
-78 °C, 94%; (e) Ac2O, Et3N, DMAP, CH2Cl2, 99%; (f) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 80%; (g) (+)-Ipc2BH, THF; NaOH, H2O2; (h) n-Bu4NF, THF,
64% (two steps); (i) Tf2O, 2,6-lutidine, CHCl3, 0-25 °C, 66%.
SCHEME 8. Completion of Asbestinin-12a
a Conditions: (a) Davis oxaziridine, KHMDS, THF, -78 °C, 84%; (b) MeMgCl, THF, 0 °C, 83%; (c) HCl, CHCl3, 99%, 11:1 dr; (d) NaH, MeOH, 99%,
1:1.4 dr; (e) L-Selectride, THF, -78 °C, 94%; (f) Ac2O, Et3N, DMAP, CH2Cl2, 85%; (g) (+)-Ipc2BH, THF; NaBO3, 74%; (h) Tf2O, 2,6-lutidine, CHCl3,
0-25 °C, 69%.
reoselective hydroboration of a 1,1-disubstituted olefin.33 Due
to difficulties encountered in separating the primary alcohol from
the isopinocampheol byproduct, the C3 protecting group was
removed using n-Bu4NF to provide the diol 51 in 64% over
two steps. Utilizing conditions employed by Overman in the
syntheses of briarellins E and F,5 the primary triflate was formed
and an in situ etherification ensued to provide 11-acetoxy-4-
deoxyasbestinin D (1) along with recovered diene 48 as a result
of elimination of the primary triflate. Spectroscopic data for
synthetic 1 matched the reported data for the natural product in
all regards.13 The optical rotation for the synthetic and natural
materials were identical when measured under the same condi-
tions.
alcohol 52 as a single diastereomer (Scheme 8).34 Treatment of
the ketone with methylmagnesium chloride as before provided
the diol 53. Hydrolysis again provided the undesired C12
configuration of ketone 54 as the major product. Epimerization
under alkaline conditions gave the desired C12 methyl config-
uration 55. A single diastereomeric triol was obtained upon
reduction of ketone 55 with L-Selectride, whereupon selective
protection of the secondary alcohols was accomplished in the
presence of the tertiary alcohol providing diacetate 56. At this
point, we hoped to examine the role of the C3 protecting group
in the diastereoselectivity of the hydroboration. Earlier, the
triethylsilyl ether was ultimately employed as the hydroboration
substrate for monitoring purposes, but this was not necessary
for diacetate 56. Treatment of diene 56 with (+)-diisopinocam-
pheylborane and oxidation provided the desired diol 57 as a
For asbestinin-12 (2),14 we again hoped to exploit the inherent
concavity of ketone 44 to perform a diastereoselective trans-
formation. This time, an R-hydroxylation of the potassium
enolate of ketone 44 using Davis oxaziridine provided the
(34) (a) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth.
1988, 66, 203. (b) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.;
Reddy, T. J. Org. Chem. 1988, 53, 2087. (c) Di Grandi, M. J.; Coburn, C.
A.; Isaacs, R. C. A.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 7728.
(33) Masamune, S.; Lu, L. D.-L.; Jackson, W. P.; Kaiho, T.; Toyoda, T.
J. Am. Chem. Soc. 1982, 104, 5523.
J. Org. Chem, Vol. 73, No. 5, 2008 1655

Crimmins and Ellis
single diastereomer in good yield,32 confirming that the reagent
controls the selectivity. Oxidation with the milder sodium
perborate conditions proved useful in this case to prevent
hydrolysis of the labile C4 acetate. Using triflic anhydride and
2,6-lutidine,5 asbestinin-12 (2) was obtained in good yield. All
data reported for the natural material again corresponded well
with the data for synthetic asbestinin 12 (2).14
1.80 (s, 3H), 2.01 (dd, J ) 13.2, 11.1 Hz, 1H), 2.15 (ddd, J )
14.9, 7.1, 7.1 Hz, 1H), 2.20-2.36 (m, 3H), 2.41 (dd, J ) 14.0, 7.9
Hz, 1H), 3.20 (dd, J ) 13.3, 2.8 Hz, 1H), 3.51 (dd, J ) 10.3, 2.7
Hz, 1H), 3.68 (dd, J ) 10.3, 7.6 Hz, 1H), 3.92-4.01 (m, 2H),
4.14 (dd, J ) 9.4, 2.1 Hz, 1H), 4.19 (ddd, J ) 9.3, 9.3, 9.3 Hz,
1H), 4.47 (d, J ) 12.3 Hz, 1H), 4.53 (d, J ) 12.3 Hz, 1H), 4.77
(m, 1H), 4.84 (s, 1H), 4.86 (s, 1H), 4.98 (d, J ) 10.2 Hz, 1H),
5.05 (dd, J ) 17.2, 1.5 Hz, 1H), 5.83 (dddd, J ) 17.0, 10.3, 3.6,
3.6 Hz, 1H), 6.34 (d, J ) 2.0 Hz, 1H), 7.08-7.35 (m, 10H); 13C
NMR (100 MHz, CDCl3) δ 22.6, 29.9, 33.2, 36.7, 40.7, 60.9, 70.6,
72.5, 73.1, 74.2, 78.7, 80.8, 114.0, 114.9, 127.22, 127.24, 127.5,
128.4, 128.9, 129.3, 135.6, 138.0, 138.1, 141.6, 172.2, 185.2; IR
(film) 3458 (br), 2924, 1712 (str), 1446, 1361, 1324, 1206, 1128
Conclusion
In summary, highly stereoselective syntheses of 11-acetoxy-
4-deoxyasbestinin D (1) and asbestinin-12 (2) have been
completed in 26 and 25 steps, respectively. The strategy for
completing these two molecules hinged upon the formation of
an oxonene ring using an asymmetric gylcolate aldol reaction.
This oxonene was used as a manifold for an intramolecular
Diels-Alder cycloaddition to form the hydroisobenzofuran
moiety. A chiral hydroborating reagent proved useful in
establishing the stereocenter at C15. These syntheses stand as
the first molecules of the asbestinin subclass to be prepared by
chemical methods and serve to confirm the absolute configu-
ration of the asbestinins.
cm-1; [R]23 ) +25 (c ) 0.43, CH2Cl2); HRMS (electrospray
D
ionization) calcd for C30H38NO5S [M + 1]+ 524.2471, found
524.2473.
(2S,3R,9R)-9-Benzyloxymethyl-3-(tert-butyldimethylsilanyloxy)-
2-(tert-butyldimethylsilanyloxymethyl)-7-methyl-2,3,4,5,8,9-hexahy-
drooxonine (18). Into a flask equipped with a reflux condenser
were added diene 5 (16.56 g, 29.24 mmol) and 2.9 L of CH2Cl2.
The solution was brought to reflux for 30 min, followed by the
addition of Grubbs’ catalyst (1.25 g, 1.47 mmol) and stirring for 3
h at reflux. The solution was cooled to room temperature and
concentrated in vacuo. Purification by flash column chromatography
(1% EtOAc/hexanes) provided 15.53 g (99%) of the oxonene as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.02 (s, 3H), 0.03 (s,
9H), 0.88 (s, 9H), 0.89 (s, 9H), 1.42 (dddd, J ) 3.9, 3.9, 13.5, 13.5
Hz, 1H), 1.73 (m, 1H), 1.79 (s, 3H), 1.86 (m, 1H), 1.98 (d, J )
14.02 Hz, 1H), 2.44 (dd, J ) 14.2, 7.9 Hz, 1H), 2.81 (dddd, J )
13.2, 13.2, 13.2, 4.4 Hz, 1H), 3.29-3.35 (m, 2H), 3.38 (m, 1H),
3.54 (dd, J ) 13.6, 8.9 Hz, 1H), 3.67 (dd, J ) 11.0, 8.5 Hz, 1H),
3.92 (dd, J ) 11.1, 2.4 Hz, 1H), 3.96 (m, 1H), 4.56 (s, 2H), 5.34
(dd, J ) 11.4, 5.3 Hz, 1H), 7.27-7.37 (m, 5H); 13C NMR (100
MHz, CDCl3) δ -5.2, -5.1, -4.8, 18.1, 18.3, 25.3, 25.8, 25.9,
26.0, 26.1, 32.2, 36.1, 61.8, 67.7, 73.0, 73.4, 77.9, 84.3, 126.1,
127.5, 127.6, 128.3, 134.7, 138.4; IR (film) 2928, 1471, 1254, 1089
Experimental Section
(1R′,2S′,3R,4R′)-2-(1-Benzyloxymethyl-3-methylbut-3-enyloxy)-
1-(4-benzyl-2-thioxooxazolidin-3-yl)-3-hydroxyhept-6-en-1-
one (11). Preparation of hex-5-ene-1,2-diol: Into a flask equipped
with a mechanical stirrer, an addition funnel, and a low temperature
thermometer were added allylmagnesium chloride (2.0 M in THF,
800.0 mL, 1.600 mol) and 800 mL of THF. The solution was cooled
to -20 °C. Glycidol (35.40 mL, 533.3 mmol) in 800 mL of THF
was added dropwise via addition funnel keeping the temperature
at -20 °C. The mixture was stirred 1 h at -20 °C and then
quenched by the addition of saturated aqueous NH4Cl. The organic
layer was washed with brine, and the combined aqueous extracts
were washed twice with 50% EtOAc/hexanes. The combined
organic extracts were dried over Na2SO4 and concentrated in vacuo.
Purification by flash column chromatography (10% then 50%
EtOAc/hexanes) provided 57.16 g (93%) of the diol as a colorless
oil. Preparation of pent-4-enal: Into a flask equipped with a
mechanical stirrer was added hex-5-ene-1,2-diol (65.31 g, 562.2
mmol), 800 mL of CH2Cl2, and 800 mL of water. Sodium periodate
(240.52 g, 1.1245 mol) was added to the biphasic solution which
was stirred for 1 h. The reaction was quenched by the addition of
saturated aqueous NaHCO3. The organic layer was washed twice
with 10% Na2S2O3 in water, then dried over Na2SO4. The volume
was reduced to 100 mL in vacuo at 0 °C. Purification via distillation
(bp 96 °C, 760 mmHg) gave 29.33 g (63%) of the aldehyde as a
colorless liquid.18
Into a flask equipped with an addition funnel were added
glycolate 6 (28.63 g, 65.13 mmol) and 435 mL of CH2Cl2. The
solution was cooled to -78 °C, and titanium tetrachloride (7.50
mL, 68.4 mmol) was added dropwise via addition funnel. The
solution was stirred 10 min at -78 °C, and N,N-diisopropylethy-
lamine (26.92 mL, 162.8 mmol) was added dropwise to give a
purple solution that was stirred at -78 °C for 2.5 h. N-Methylpyr-
rolidinone (6.57 mL, 68.3 mmol) was added to the solution via
addition funnel and stirred for 10 min. Pent-4-enal was added
dropwise via addition funnel and stirred at -78 °C for 2 h. The
solution was warmed to -40 °C for 1 h, quenched by the addition
of half-saturated aqueous NH4Cl, and warmed to room temperature.
The aqueous layer was extracted twice with CH2Cl2, and then the
combined organic extracts were dried over Na2SO4 and concentrated
in vacuo. Purification by flash column chromatography (20% then
50% EtOAc/Hexanes) provided 23.61 g (70%) of the alcohol as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.67-1.78 (m, 2H),
cm-1; [R]24 ) +33.6 (c ) 1.16, CH2Cl2); HRMS (electrosray
D
ionization) calcd for C30H54O4Si2Na [M + Na]+ 557.3459, found
557.3455.
(3S,7S,8R,14R,15R,16R)-1-[14-(tert-Butyldimethylsilanyloxy)-
6-methoxy-5,10-dimethyl-15-oxatricyclo[6.6.1.02,7]pentadeca-5,-
10-dien-3-yl]ethanone (42). Into a flask equipped with a reflux
condenser was added the aldehyde (664 mg, 1.68 mmol), 17 mL
of toluene, and 1-(triphenyl-l5-phosphanylidene)propan-2-one (31)
(1.61 g, 5.05 mmol). The solution was brought to reflux overnight
and then cooled to room temperature. The mixture was concentrated
in vacuo and then purified by flash column chromatography (5%
then 10% EtOAc/hexanes) provided 583 g (80%) of the ketone as
a colorless oil: 1H NMR (400 MHz, C6D6, 60 °C) δ 0.007 (s, 3H),
0.011 (s, 3H), 0.89 (s, 9H), 1.56-1.65 (m, 1H), 1.62 (s, 3H), 1.84
(s, 3H), 1.86 (s, 3H), 1.87-2.02 (m, 3H), 2.12 (m, 1H), 2.29 (dd,
J ) 17.2, 6.5 Hz, 1H), 2.67 (m, 1H), 2.70 (d, J ) 14.4 Hz, 1H),
2.89 (ddd, J ) 6.9, 3.6, 3.6 Hz, 1H), 3.10 (m, 1H), 3.22 (m, 1H),
3.26 (s, 3H), 4.02 (dd, J ) 8.4, 3.7 Hz, 1H), 4.20 (ddd, J ) 10.4,
4.5, 4.5 Hz, 1H), 4.45 (ddd, J ) 4.9, 2.5, 2.5 Hz, 1H), 5.49 (m,
1H); 13C NMR (100 MHz, C6D6, 60 °C) δ -4.8, -4.7, 16.2, 18.2,
23.0, 26.1, 27.6, 28.2, 28.5, 33.1, 39.0, 40.1, 41.2, 46.7, 56.7, 73.3,
80.4, 84.3, 113.3, 130.0, 131.2, 149.1, 207.4; IR (film) 2927, 1712
(str), 1445, 1360, 1251, 1088 cm-1; [R]22 ) +40.8 (c ) 1.10,
D
CH2Cl2); HRMS (electrospray ionization) calcd for C25H43O4Si [M
+ 1]+ 435.2931, found 435.2935.
(1R,2S,6S,7R,8R,9R)-6-Isopropenyl-3-methoxy-4,9,13-trimethyl-
15-oxatricyclo[6.6.1.02,7]-pentadeca-3,12-dien-9-ol (45). A flask
was charged with methylmagnesium chloride (3.0 M in THF, 3.47
mL, 10.4 mmol) and 70 mL of THF. The solution was cooled to
0 °C, and the ketone 44 (659 mg, 2.08 mmol) was added in 35 mL
of THF dropwise. The solution was stirred 30 min and then
quenched with saturated aqueous NH4Cl, warmed to room tem-
perature, and diluted with Et2O. The layers were separated, and
1656 J. Org. Chem., Vol. 73, No. 5, 2008

Intramolecular Diels-Alder Strategy for the Asbestinins
the aqueous portion was washed twice with Et2O. The combined
organic extracts were dried over Na2SO4 and concentrated in vacuo.
Purification via flash column chromatography (10% EtOAc/ hex-
anes) provided 678 mg (98%) of the alcohol as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.95 (s, 3H), 1.66 (s, 3H), 1.69 (s,
3H), 1.69-1.79 (m, 1H), 1.85-1.96 (m, 2H), 1.90 (s, 3H), 2.00
(m, 1H), 2.17 (m, 2H), 2.28 (ddd, J ) 11.2, 11.2, 4.5 Hz, 1H),
2.43 (dd, J ) 11.7, 6.9 Hz, 1H), 2.75 (dd, J ) 7.1, 7.1 Hz, 1H),
2.95 (d, J ) 14.7 Hz, 1H), 3.07-3.24 (m, 2H), 3.52 (s, 3H), 3.87
(s, 1H), 4.18 (ddd, J ) 8.6, 3.3, 3.3 Hz, 1H), 4.82 (s, 1H), 4.83
(m, 1H), 5.84 (dd, J ) 10.9, 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 15.8, 19.0, 27.1, 28.3, 28.9, 35.2, 36.7, 38.8, 41.8, 42.9,
45.0, 58.6, 75.3, 83.4, 89.4, 113.0, 116.7, 128.7, 136.5, 147.0, 149.1;
with the ketone 47 (523 mg, 1.64 mmol) was added 16 mL of THF.
The solution was cooled to -78 °C, and L-Selectride (1.0 M in
THF, 1.97 mL, 1.97 mmol) was added dropwise. The reaction was
stirred for 10 min and then quenched by the addition of sodium
hydroxide (3 M, 1.0 mL, 3.0 mmol) and hydrogen peroxide (30%,
2.0 mL, 18 mmol). The mixture was stirred for 3 h at room
temperature and then diluted with Et2O. The layers were separated,
and the aqueous portions were washed twice with Et2O. The
combined organic extracts were dried over Na2SO4, and concen-
trated in vacuo. Purification by flash column chromatography (25%
EtOAc/hexanes) gave 493 mg (94%) of the alcohol as a white
solid: 1H NMR (400 MHz, C6D6, 60 °C) δ 0.95 (d, J ) 7.0 Hz,
3H), 1.19 (m, 1H), 1.28 (s, 3H), 1.33 (m, 2H), 1.56 (m, 1H), 1.64-
1.73 (m, 2H), 1.70 (s, 3H), 1.75 (s, 3H), 1.77-1.94 (m, 2H), 1.89
(m, 1H), 2.19 (ddd, J ) 7.8, 4.2, 4.2 Hz, 1H), 2.69-2.92 (m, 4H),
3.42 (s, 1H), 3.91 (d, J ) 7.5 Hz, 1H), 4.24 (dd, J ) 6.7, 3.8 Hz,
1H), 4.86 (s, 1H), 4.88 (d, J ) 1.3 Hz, 1H), 5.52 (dd, J ) 11.0, 6.1
Hz, 1H); 13C NMR (100 MHz, C6D6, 60 °C) δ 17.2, 22.0, 24.6,
28.4, 28.8, 29.7, 31.8, 38.5, 38.6, 39.8, 42.6, 45.9, 72.2, 74.7, 80.0,
89.5, 110.6, 130.0, 132.3, 149.8; IR (film) 3329 (br), 2921, 1439,
IR (film) 3511 (br), 2914, 1447, 1119, 1058 cm-1; [R]24 ) +74
D
(c ) 0.42, CH2Cl2); HRMS (electrospray ionization) calcd for
C21H32O3Na [M + Na]+ 355.2249, found 355.2251.
(1R,2S,4R,6S,7R,8R,9R)-9-Hydroxy-6-isopropenyl-4,9,13-tri-
methyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-en-3-one (46). A
flask was charged with alcohol 45 (678 mg, 0.255 mmol), 20 mL
of CHCl3, and 2.5 mL of water. Hydrochloric acid (12 M, 2.50
mL, 30.0 mmol) was added to the biphasic solution and stirred for
2 h. The reaction was quenched by the slow addition of saturated
aqueous NaHCO3. The layers were separated, and the aqueous
portion was washed twice with CH2Cl2. The combined organic
extracts were dried over Na2SO4 and concentrated in vacuo.
Purification by flash column chromatography (10% then 25%
EtOAc/hexanes) gave 562 mg (87%) of the ketone as a white solid
and 58 mg (9%) of the (4S)-product (47) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.90 (s, 3H), 1.07 (d, J ) 6.6 Hz, 3H),
1.59 (dd, J ) 25.8, 13.0 Hz, 1H), 1.69 (s, 3H), 1.71-1.78 (m,
1H), 1.85-2.03 (m, 4H), 1.93 (s, 3H), 2.48 (ddd, J ) 12.3, 12.3,
2.8 Hz, 1H), 2.59 (dddd, J ) 11.7, 11.7, 6.5, 6.5 Hz, 1H), 2.69
(dd, J ) 12.0, 7.0 Hz, 1H), 2.91-2.97 (m, 2H), 3.07 (m, 1H), 3.13
(ddd, J ) 11.9, 11.9, 6.4 Hz, 1H), 3.94 (s, 1H), 4.36 (ddd, J ) 9.9,
3.1, 3.1 Hz, 1H), 4.86 (m, 2H), 5.83 (dd, J ) 11.5, 5.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.5, 18.5, 27.2, 28.4, 28.7, 35.2,
38.5, 39.0, 41.8, 46.0, 48.7, 54.1, 74.8, 80.5, 91.3, 113.4, 128.3,
136.6, 146.2, 211.7; IR (film) 3514 (br), 2928, 1702 (str), 1453,
1377, 1184, 1076 cm-1; [R]24D ) +40 (c ) 0.18, CH2Cl2); HRMS
(electrospray ionization) calcd for C20H30O3Na [M + Na]+ 341.2093,
found 341.2094.
1373, 1088 cm-1; [R]25 ) +5.7 (c ) 0.46, CH2Cl2); HRMS
D
(electrospray ionization) calcd for C20H32O3Na [M + Na]+ 343.2249,
found 343.2248.
(1R,2S,3S,4S,6S,7R,8R,9R)-Acetic Acid 9-Hydroxy-6-isopro-
penyl-4,9,13-trimethyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-en-
3-yl Ester (48). Into a flask containing the secondary alcohol (406
mg, 1.27 mmol) in 26 mL of CH2Cl2 were added triethylamine
(707 µL, 5.07 mmol) and 4-dimethylaminopyridine (16.0 mg, 0.127
mmol). Acetic anhydride (240 µL, 2.53 mmol) was added to the
solution, and the resulting solution was stirred overnight. The
reaction was quenched using saturated aqueous NH4Cl, and the
layers were separated. The aqueous portions were washed twice
with CH2Cl2, dried over Na2SO4, and concentrated in vacuo.
Purification via flash column chromatography (25% EtOAc/
hexanes) gave 453 mg (99%) of the ester as a colorless oil: 1H
NMR (400 MHz, C6D6, 60 °C) δ 0.87 (d, J ) 7.0 Hz, 3H), 1.25 (s,
3H), 1.37 (ddd, J ) 13.7, 6.2, 4.1 Hz, 1H), 1.50-1.69 (m, 4H),
1.66 (s, 3H), 1.67 (s, 3H), 1.74 (dd, J ) 14.6, 3.9 Hz, 1H), 1.77-
1.92 (m, 2H), 1.81 (s, 3H), 2.32 (ddd, J ) 4.9, 4.9, 4.9 Hz, 1H),
2.66-2.78 (m, 3H), 2.89 (m, 1H), 3.88 (d, J ) 6.6 Hz, 1H), 4.25
(dd, J ) 7.0, 3.8 Hz, 1H), 4.83 (s, 1H), 4.85 (d, J ) 1.3 Hz, 1H),
5.22 (dd, J ) 5.1, 3.7 Hz, 1H), 5.51 (dd, J ) 11.1, 6.0 Hz, 1H);
13C NMR (100 MHz, C6D6, 60 °C) δ 16.8, 20.7, 21.5, 24.9, 28.4,
29.7, 30.1, 30.2, 38.1, 38.8, 39.7, 43.0, 44.2, 73.8, 74.7, 79.7, 89.3,
111.1, 130.0, 132.6, 149.2, 170.0; IR (film) 3465(br), 2924, 1737
(1R,2S,4S,6S,7R,8R,9R)-9-Hydroxy-6-isopropenyl-4,9,13-tri-
methyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-en-3-one (47). Into
a flask containing the previous ketone 46 (551 mg, 1.73 mmol)
and 17 mL of methanol was added catalytic sodium hydride. After
the mixture was stirred 15 min, the reaction was quenched by the
slow addition of saturated aqueous NH4Cl and diluted with Et2O.
The layers were separated, and the aqueous portion was washed
twice with Et2O. The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification by flash column
chromatography (10% then 25% EtOAc/hexanes) gave 246 mg
(45%) of the ketone as a colorless oil and 303 mg (55%) of the
(4R)-product (46) as a white solid: 1H NMR (400 MHz, CDCl3) δ
1.09 (d, J ) 6.8 Hz, 3H), 1.14 (s, 3H), 1.59-1.71 (m, 2H), 1.77
(s, 3H), 1.80-1.87 (m, 1H), 1.88 (s, 3H), 1.92-1.99 (m, 1H), 2.01
(dd, J ) 14.8, 3.7 Hz, 1H), 2.11 (ddd, J ) 13.9, 8.6, 7.1 Hz, 1H),
2.34 (s, 1H), 2.47 (ddd, J ) 8.6, 8.6, 5.5 Hz, 1H), 2.58 (ddq, J )
21.7, 7.0, 7.0 Hz, 1H), 2.83 (ddd, J ) 7.8, 7.8, 7.8 Hz, 1H), 2.84-
2.93 (m, 2H), 3.02 (ddd, J ) 8.1, 8.1, 4.6 Hz, 1H), 3.72 (d, J )
4.6 Hz, 1H), 4.58 (ddd, J ) 6.3, 3.3, 3.3 Hz, 1H), 4.89 (d, J ) 0.7
Hz, 1H), 4.92 (d, J ) 1.3 Hz, 1H), 5.71 (dd, J ) 11.3, 5.7 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 15.5, 20.0, 25.3, 28.5, 28.9,
34.7, 36.5, 38.4, 40.7, 40.9, 45.9, 53.3, 74.7, 77.7, 89.1, 112.7,
129.2, 134.2, 146.9, 212.9; IR (film) 3443 (br), 2928, 1710 (str),
(str), 1450, 1374, 1237, 1039 cm-1; [R]25 ) +42.2 (c ) 1.32,
D
CH2Cl2); HRMS (electrospray ionization) calcd for C22H35O4 [M
+ 1]+ 363.2536, found 363.2542.
(1R,2S,3S,4S,6S,7R,8R,9R)-Acetic Acid 6-Isopropenyl-4,9,13-
trimethyl-9-triethylsilanyloxy-15-oxatricyclo[6.6.1.02,7]pentadec-
12-en-3-yl Ester (49). A flask was charged with ester 48 (64.0
mg, 0.176 mmol) in 2 mL of CH2Cl2 and cooled to 0 °C. 2,6-
Lutidine (62 µL, 0.53 mmol) and triethylsilyl trifluoromethane-
sulfonate (60 µL, 0.27 mmol) were added sequentially and the
mixture stirred for 1 h at 0 °C. The reaction was quenched by the
addition of saturated aqueous NH4Cl and warmed to room tem-
perature, and the layers were separated. The aqueous portions were
washed twice with CH2Cl2, dried over Na2SO4, and concentrated
in vacuo. Purification via flash column chromatography (5% EtOAc/
hexanes) gave 67 mg (80%) of the alkene as a colorless oil: 1H
NMR (400 MHz, C6D6, 60 °C) δ 0.62 (q, J ) 7.8 Hz, 6H), 0.83
(d, J ) 5.8 Hz, 3H), 1.00 (t, J ) 7.9 Hz, 9H), 1.38 (ddd, J ) 13.9,
3.1, 3.1 Hz, 1H), 1.55-1.65 (m, 2H), 1.57 (s, 3H), 1.71 (s, 3H),
1.73-1.89 (m, 4H), 1.79 (s, 3H), 1.86 (s, 3H), 2.20 (dd, J ) 7.1,
4.6 Hz, 1H), 2.63 (d, J ) 13.9 Hz, 1H), 2.68 (m, 1H), 2.96 (dd, J
) 8.8, 8.8 Hz, 1H), 3.03 (d, J ) 5.3 Hz, 1H), 3.97 (d, J ) 10.4
Hz, 1H), 4.08 (d, J ) 1.63 Hz, 1H), 4.88 (s, 1H), 4.94 (m, 1H),
5.19 (m, 1H), 5.44 (dd, J ) 10.6, 5.6 Hz, 1H); 13C NMR (100
MHz, C6D6, 60 °C) δ 7.3, 7.5, 18.2, 20.7, 23.1, 23.5, 26.7, 28.5,
1642, 1446, 1376, 1081 cm-1; [R]24 ) +92 (c ) 0.19, CH2Cl2);
D
HRMS (electrospray ionization) calcd for C20H30O3Na [M + Na]+
341.2093, found 341.2098.
(1R,2S,3S,4S,6S,7R,8R,9R)-6-Isopropenyl-4,9,13-trimethyl-15-
oxatricyclo[6.6.1.02,7]pentadec-12-ene-3,9-diol. Into a flask charged
J. Org. Chem, Vol. 73, No. 5, 2008 1657

Crimmins and Ellis
28.9, 29.5, 38.5, 39.2, 39.5, 41.4, 44.8, 74.1, 78.4, 79.4, 88.3, 110.1,
130.5, 130.9, 149.4, 170.5; IR (film) 2957, 1739 (str), 1462, 1373,
1235, 1116, 1048 cm-1; [R]23D ) -33 (c ) 0.43, CH2Cl2); HRMS
(electrospray ionization) calcd for C28H48O4SiNa [M + Na]+
499.3220, found 499.3223.
1H), 1.75 (s, 3H), 1.75 (m, 2H), 1.84-2.08 (m, 5H), 2.10 (s, 3H),
2.34 (ddd, J ) 10.4, 10.4, 10.4 Hz, 1H), 2.50 (br d, J ) 14.8 Hz,
1H), 2.55 (ddd, J ) 14.5, 10.3, 4.8 Hz, 1H), 3.48 (dd, J ) 13.2,
3.2 Hz, 1H), 3.86 (d, J ) 15.2 Hz, 1H), 3.87 (d, J ) 8.7 Hz, 1H),
4.10 (ddd, J ) 5.5, 2.9, 2.9 Hz, 1H), 5.31 (dd, J ) 5.1, 2.8 Hz,
1H), 5.47 (dd, J ) 8.1, 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 11.0, 17.9, 21.3, 23.4, 26.1, 28.9, 31.3, 31.5, 37.3, 37.5, 38.0,
38.5, 40.5, 45.8, 67.9, 73.5, 76.4, 81.0, 92.2, 128.7, 130.8, 171.3;
(1R,1S′,2S,3S,4S,6S,7R,8R,9R)-Acetic Acid 9-Hydroxy-6-(2-
hydroxy-1-methylethyl)-4,9,13-trimethyl-15-oxatricyclo[6.6.1.02,7]-
pentadec-12-en-3-yl Ester (51). A flask was charged with alkene
49 (10.4 mg, 21.8 µmol) in 500 µL of THF. (+)-Diisopinocam-
pheylborane (24.0 mg, 83.2 µmol) was added to the solution, and
the resulting solution was allowed to stir 30 min. The reaction was
quenched by the addition of sodium hydroxide (3 M, 130 µL, 0.390
mmol) and then hydrogen peroxide (30%, 260 µL, 2.29 mmol).
The biphasic solution was stirred for 3 h and then diluted with
brine and Et2O. The layers were separated, and the aqueous portion
was washed twice with Et2O, dried over Na2SO4, and concentrated
in vacuo. For purification purposes, the product and isopinocam-
pheol were carried on to the next reaction as a mixture. In a separate
experiment, purification via flash column chromatography (10%
EtOAc/hexanes) gave the alcohol as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.59 (q, J ) 7.8 Hz, 6H), 0.81 (d, J ) 6.5 Hz,
3H), 0.94 (t, J ) 7.9 Hz, 9 H), 1.01 (d, J ) 6.7 Hz, 3H), 1.22 (d,
J ) 15.3 Hz, 1H), 1.47 (s, 3H), 1.59-1.94 (m, 9H), 1.77 (s, 3H),
2.08-2.18 (m, 2H), 2.10 (s, 3H), 2.52 (ddd, J ) 12.2, 12.2, 8.3
Hz, 1H), 2.66 (m, 2H), 3.41 (dd, J ) 10.9, 5.3 Hz, 1H), 3.63 (m,
1H), 3.78 (d, J ) 10.7 Hz, 1H), 3.93 (s, 1H), 5.14 (m, 1H), 5.48
(dd, J ) 11.2, 5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 6.8,
6.9, 7.0, 15.8, 18.3, 21.2, 22.9, 26.7, 28.3, 28.5, 29.8, 32.9, 38.1,
38.7, 38.9, 44.4, 66.5, 73.9, 78.2, 78.8, 87.3, 130.0, 130.7, 171.4;
IR (film) 3446 (br), 2957, 1737 (str), 1457, 1374, 1237, 1137, 1117,
1043 cm-1; [R]26D ) +2.3 (c ) 0.68, CH2Cl2); HRMS (electrospray
ionization) calcd for C28H50O5SiNa [M + Na]+ 517.3326, found
517.3328.
Into a flask containing the alcohol 50 in 500 µL of THF was
added tetrabutylammonium fluoride (1.0 M in THF, 63 µL, 63
µmol). The solution was stirred for 1 h, quenched by the addition
of saturated aqueous NH4Cl, and diluted with Et2O. The layers were
separated, and the aqueous portion was washed three times with
Et2O, dried over Na2SO4, and concentrated in vacuo. Purification
via flash column chromatography (30% EtOAc/hexanes) gave 5.1
mg (64% over two steps) of the diol as a colorless oil: 1H NMR
(500 MHz, CDCl3) δ 0.82 (d, J ) 6.0 Hz, 3H), 0.86-0.99 (m,
1H), 0.88 (d, J ) 6.9 Hz, 3H), 1.17 (d, J ) 9.8 Hz, 1H), 1.42 (s,
3H), 1.64 (dd, J ) 13.9, 8.4 Hz, 1H), 1.75-1.85 (m, 6H), 1.79 (s,
3H), 1.93 (m, 1H), 2.09-2.13 (m, 1H), 2.10 (s, 3H), 2.34 (br s,
1H), 2.49 (dd, J ) 8.7, 8.7 Hz, 1H), 2.60 (dd, J ) 21.1, 11.0 Hz,
1H), 2.69 (d, J ) 14.4 Hz, 1H), 3.46 (dd, J ) 11.6, 5.5 Hz, 1H),
3.53 (dd, J ) 11.5, 11.5 Hz, 1H), 3.78 (d, J ) 10.2 Hz, 1H), 4.04
(s, 1H), 5.18 (d, J ) 3.7 Hz, 1H), 5.52 (dd, J ) 10.7, 5.5 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 1.0, 14.1, 18.4, 21.2, 23.0, 28.4,
29.4, 29.7, 29.8, 30.9, 37.9, 38.1, 42.2, 45.7, 65.4, 74.0, 75.1, 79.9,
89.1, 130.1, 171.4; IR (film) 3355 (br), 2925, 1736 (str), 1455,
1381, 1237, 1017 cm-1; [R]26D ) +33 (c ) 0.39, CH2Cl2); HRMS
(electrospray ionization) calcd for C22H36O5K [M + K]+ 419.3546,
found 419.3545.
IR (film) 2926, 1737 (str), 1459, 1377, 1231, 1088 cm-1; [R]26
)
D
-15 (c ) 0.17, CHCl3); HRMS (electrospray ionization) calcd for
C22H35O4 [M + 1]+ 363.2536, found 363.2539.
An authentic sample of 11-acetoxy-4-deoxyasbestinin D was
provided by Dr. Abimael D. Rodr´ıguez (University of Puerto Rico,
R´ıo Piedras)3 and purified in the same manner as described above,
and an optical rotation was obtained under identical conditions:
[R]25D ) -15 (c ) 0.10, CHCl3). The 1H NMR (500 MHz, CDCl3)
spectrum of the authentic sample also mirrored the synthetic
material.
(1R,2S,6S,7R,8R,10S)-10-Hydroxy-6-isopropenyl-3-methoxy-
4,13-dimethyl-15-oxatricyclo[6.6.1.02,7]pentadeca-3,12-dien-9-
one (52). A flask containing the ketone 44 (280 mg, 0.885 mmol)
in 20 mL of THF was cooled to -78 °C. Potassium hexamethyl-
disilazide (0.5 M in toluene) was added dropwise, and the solution
was allowed to stir for 1 h at -78 °C. Davis oxaziridine (278 mg,
1.062 mmol) was added in 10 mL of THF to the enolate, and the
solution was allowed to stir for 45 min at -78 °C. The reaction
was quenched by the addition of saturated aqueous NH4Cl. The
mixture was diluted with Et2O, and the layers were separated. The
aqueous portions were washed three times with Et2O, dried over
Na2SO4, and concentrated in vacuo. Purification via flash column
chromatography (10% EtOAc/hexanes) gave 245 mg (84%) of the
alcohol as a white solid: 1H NMR (400 MHz, C6D6, 60 °C) δ 1.54
(s, 3H), 1.56 (s, 3H), 1.67 (s, 3H), 1.80 (dd, J ) 16.5, 4.9 Hz, 1H),
1.95 (m, 1H), 2.03 (dd, J ) 14.0, 8.3 Hz, 1H), 2.20-2.31 (m, 2H),
2.44 (m, 1H), 2.61 (dd, J ) 6.3, 6.3 Hz, 1H), 2.76 (m, 1H), 3.03
(dd, J ) 11.4, 7.6 Hz, 1H), 3.14 (br d, J ) 9.6 Hz, 1H), 3.23 (s,
3H), 4.22 (ddd, J ) 10.1, 10.1, 3.7 Hz, 1H), 4.30 (m, 1H), 4.59 (s,
1H), 4.74 (s, 1H), 4.78 (s, 1H), 5.30 (dd, J ) 7.5, 7.5 Hz, 1H); 13
C
NMR (100 MHz, C6D6, 60 °C) δ 16.0, 19.5, 24.8, 34.9, 35.3, 39.9,
42.0, 42.8, 43.7, 57.8, 79.2, 83.6, 84.1, 112.7, 116.7, 121.8, 138.7,
147.1, 149.0, 214.4; IR (film) 3419 (br), 2912, 1715 (str), 1447,
1051 cm-1; [R]24 ) +55.3 (c ) 6.50, CH2Cl2); HRMS (electro-
D
spray ionization) calcd for C20H28O4 [M + Na]+ 355.1886, found
355.1891.
(1R,2S,6S,7R,8R,9R,10S)-6-Isopropenyl-3-methoxy-4,9,13-tri-
methyl-15-oxatricyclo[6.6.1.02,7]pentadeca-3,12-diene-9,10-diol
(53). A flask was charged with methylmagnesium chloride (3.0 M
in THF, 6.42 mL, 19.3 mmol) and 24 mL of THF. The solution
was cooled to 0 °C, and the ketone 52 (320 mg, 0.963 mmol) was
added in 8 mL of THF dropwise. The solution was stirred 30 min,
quenched with saturated aqueous NH4Cl, warmed to room tem-
perature, and diluted with Et2O. The layers were separated, and
the aqueous portion was washed twice with Et2O. The combined
organic extracts were dried over Na2SO4 and concentrated in vacuo.
Purification via flash column chromatography (20% EtOAc/
hexanes) provided 278 mg (83%) of the alcohol as a white solid:
1H NMR (400 MHz, C6D6, 60 °C) δ 1.28 (s, 3H), 1.59 (s, 3H),
1.65 (s, 3H), 1.78 (s, 3H), 1.91 (dd, J ) 16.8, 5.1 Hz, 1H), 1.99-
2.09 (m, 2H), 2.13 (dd, J ) 14.6, 4.4 Hz, 1H), 2.20-2.31 (m, 2H),
2.40 (ddd, J ) 9.7, 9.7, 5.2 Hz, 1H), 2.56 (ddd, J ) 10.3, 7.4, 2.7
Hz, 1H), 2.76-2.85 (m, 2H), 3.12 (m, 1H), 3.29 (s, 3H), 3.51 (dd,
J ) 7.5, 4.3 Hz, 1H), 4.13 (d, J ) 2.6 Hz, 1H), 4.27 (ddd, J ) 7.4,
11-Acetoxy-4-deoxyasbestinin D (1). A flask charged with diol
51 (8.9 mg, 24 µmol) in 1.1 mL of THF was cooled to 0 °C. 2,6-
Lutidine (13.6 µL, 0.117 mmol) followed by trifluoromethane-
sulfonic anhydride (5.8 µL, 34 µmol) were added to the solution,
and the resulting solution was allowed to stir for 45 min at 0 °C.
The solution was warmed to room temperature for 4 h and then
quenched via the addition of saturated aqueous NH4Cl. The mixture
was diluted with Et2O, and the layers were separated. The aqueous
portion was washed three times with Et2O, dried over Na2SO4, and
concentrated in vacuo. Purification via flash column chromatog-
raphy (10% EtOAc/Hexanes) gave 5.5 mg (66%) of 11-acetoxy-
4-deoxyasbestinin D as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 0.91 (d, J ) 7.1 Hz, 3H), 0.92 (d, J ) 7.2 Hz, 3H), 1.01 (m,
1H), 1.35 (s, 3H), 1.52 (ddd, J ) 13.5, 13.5, 9.7 Hz, 1H), 1.61 (m,
4.4, 2.9 Hz, 1H), 4.83 (s, 2H), 5.68 (dd, J ) 10.7, 6.7 Hz, 1H); 13
C
NMR (100 MHz, C6D6, 60 °C) δ 16.0, 19.6, 24.3, 27.7, 35.1, 36.1,
38.0, 42.9, 43.4, 44.1, 58.0, 76.5, 77.4, 82.5, 87.5, 112.5, 115.8,
126.0, 135.9, 147.8, 149.7; IR (film) 3437 (br), 2910, 1445, 1376,
1118, 1092, 1050 cm-1; [R]24D ) +82 (c ) 0.34, CH2Cl2); HRMS
(electrospray ionization) calcd for C21H32O4Na [M + Na]+ 371.2199,
found 371.2202
1658 J. Org. Chem., Vol. 73, No. 5, 2008

Intramolecular Diels-Alder Strategy for the Asbestinins
(1R,2S,4R,6S,7R,8R,9R,10S)-9,10-Dihydroxy-6-isopropenyl-
4,9,13-trimethyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-en-3-one
(54). A flask was charged with diol 53 (220 mg, 0.631 mmol), 10
mL of CHCl3, and 450 µL of water. Hydrochloric acid (12 M, 450
µL, 5.4 mmol) was added to the biphasic solution, and the resulting
solution was stirred for 2 h. The reaction was quenched by the
slow addition of saturated aqueous NaHCO3 and diluted with CH2-
Cl2. The layers were separated, and the aqueous portion was washed
twice with CH2Cl2. The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification by flash column
chromatography (20% EtOAc/hexanes) gave 192 mg (91%) of the
ketone as a white solid and 16 mg (8%) of the (4S)-product (55)
as a colorless oil: 1H NMR (400 MHz, CDCl3, 60 °C) δ 1.06 (d,
J ) 6.6 Hz, 3H), 1.08 (s, 3H), 1.58 (ddd, J ) 13.0, 13.0, 13.0 Hz,
1H), 1.69 (s, 3H), 1.89 (s, 3H), 1.88-1.99 (m, 2H), 2.08 (m, 1H),
2.33 (br s, 1H), 2.46 (ddd, J ) 15.0, 12.3, 2.8 Hz, 1H), 2.48-2.60
(m, 2H), 2.63 (dd, J ) 11.7, 7.6 Hz, 1H), 2.83-3.06 (m, 3H), 3.53
(br dd, J ) 6.9, 6.9 Hz, 1H), 4.09 (s, 1H), 4.36 (ddd, J ) 9.5, 3.2,
3.2 Hz, 1H), 4.86 (s, 2H), 5.76 (dd, J ) 10.6, 6.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3, 60 °C) δ 14.5, 18.6, 24.4, 27.9, 35.9,
36.9, 39.3, 42.1, 46.8, 47.9, 54.4, 76.3, 77.0, 80.5, 89.2, 113.4,
125.0, 137.0, 146.3, 210.9; IR (film) 3523 (br), 2925, 1705 (str),
1450, 1184, 1071 cm-1; [R]22D ) +35 (c ) 0.37, CH2Cl2); HRMS
(electrospray ionization) calcd for C20H30O4Na [M + Na]+ 357.2042,
found 357.2043.
(1R,2S,4S,6S,7R,8R,9R,10S)-9,10-Dihydroxy-6-isopropenyl-
4,9,13-trimethyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-en-3-one
(55). Into a flask containing the previous ketone 54 (242 mg, 0.724
mmol) and 24 mL of methanol was added catalytic sodium hydride.
After being stirred for 15 min, the reaction was quenched by the
slow addition of saturated aqueous NH4Cl and diluted with Et2O.
The layers were separated, and the aqueous portion was washed
twice with Et2O. The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification by flash column
chromatography (20% EtOAc/hexanes) gave 103 mg (42%) of the
ketone as a colorless oil and 139 mg (58%) of the (4R)-product as
a white solid: 1H NMR (400 MHz, CDCl3, 60 °C) δ 1.02 (d, J )
6.8 Hz, 3H), 1.21 (s, 3H), 1.62 (ddd, J ) 14.2, 9.2, 5.5, Hz, 1H),
1.73 (s, 3H), 1.77 (s, 3H), 1.94-2.09 (m, 3H), 2.35-2.55 (m, 4H),
2.72-2.81 (m, 2H), 2.95 (ddd, J ) 13.3, 11.4, 7.5 Hz, 1H), 3.04
(ddd, J ) 7.6, 7.6, 7.6 Hz, 1H), 3.53 (dd, J ) 7.4, 3.0 Hz, 1H),
3.77 (d, J ) 5.7 Hz, 1H), 4.60 (m, 1H), 4.84 (s, 1H), 4.90 (s, 1H),
5.65 (dd, J ) 10.7, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, 60
°C) δ 15.0, 20.2, 22.7, 27.9, 34.7, 34.8, 37.2, 40.2, 41.2, 45.0, 53.5,
76.1, 76.2, 77.2, 87.3, 112.1, 125.8, 134.5, 147.0, 211.9; IR (film)
3459 (br), 2930, 1710 (str), 1448, 1377, 1048 cm-1; [R]21D ) +54
(c ) 1.9, CH2Cl2); HRMS (electrospray ionization) calcd for
C20H30O4Na [M + Na]+ 357.2042, found 357.2041.
(1R,2S,3S,4S,6S,7R,8R,9R,10S)-6-Isopropenyl-4,9,13-trimethyl-
15-oxatricyclo[6.6.1.02,7]pentadec-12-ene-3,9,10-triol. Into a flask
charged with the ketone 55 (158 mg, 0.472 mmol) was added 5
mL of THF. The solution was cooled to -78 °C, and L-Selectride
(1.0 M in THF, 567 µL, 0.567 mmol) was added dropwise. The
reaction was stirred for 10 min and then quenched by the addition
of sodium hydroxide (3 M, 288 µL, 0.864 mmol) and hydrogen
peroxide (30%, 566 µL, 5.184 mmol). The mixture was stirred for
3 h at room temperature and then diluted with CH2Cl2. The layers
were separated, and the aqueous portions were washed twice with
CH2Cl2. The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. Purification by flash column chroma-
tography (50% EtOAc/hexanes) gave 148 mg (94%) of the alcohol
as a white solid: 1H NMR (400 MHz, CDCl3, 60 °C) δ 0.99 (d, J
) 6.1 Hz, 3H) 1.29 (s, 3H), 1.38 (m, 1H), 1.73 (s, 3H), 1.83 (s,
3H), 1.98 (dd, J ) 14.6, 3.9 Hz, 1H), 2.06 (m, 1H), 2.13-2.28 (m,
3H), 2.61 (s, 2H), 2.78 (d, J ) 14.4 Hz, 1H), 3.00 (ddd, J ) 11.6,
8.2, 8.2, Hz, 1H), 3.65 (m, 1H), 3.78 (s, 1H), 3.92 (d, J ) 7.0 Hz,
1H), 4.37 (d, J ) 2.5 Hz, 1H), 4.75 (s, 1H), 4.84 (s, 1H), 5.64 (dd,
J ) 9.8, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 60 °C) δ 16.9,
21.6, 22.9, 28.2, 28.4, 31.4, 34.4, 38.3, 39.5, 41.3, 45.5, 72.2, 75.9,
76.9, 79.8, 88.0, 110.7, 125.8, 134.2, 149.1; IR (film) 3382 (br),
2912, 1440, 1366, 1052 cm-1; [R]21 ) +2.8 (c ) 3.2, CH2Cl2);
D
HRMS (electrospray ionization) calcd for C20H32O4Na [M + K]+
375.3284, found 375.3289.
(1R,2S,3S,4S,6S,7R,8R,9R,10S)-Acetic Acid 9-Hydroxy-6-iso-
propenyl-4,9,13-trimethyl-15-oxatricyclo[6.6.1.02,7]pentadec-12-
en-3,10-yl Diester (56). Into a flask containing the triol (122 mg,
0.363 mmol) in 10 mL of CH2Cl2 were added triethylamine (253
µL, 1.81 mmol) and 4-dimethylaminopyridine (4.4 mg, 0.036
mmol). Acetic anhydride (103 µL, 1.09 mmol) was added to the
solution, and the resulting solution was stirred for 5 h. The reaction
was quenched using saturated aqueous NH4Cl, and the layers were
separated. The aqueous portions were washed twice with CH2Cl2,
dried over Na2SO4, and concentrated in vacuo. Purification via flash
column chromatography (20% EtOAc/hexanes) gave 130 mg (85%)
of the ester as a white solid: 1H NMR (400 MHz, CDCl3, 60 °C)
δ 0.90 (d, J ) 7.0 Hz, 3H), 1.24 (s, 3H), 1.47 (m, 1H), 1.63 (ddd,
J ) 13.5, 8.8, 4.1 Hz, 1H), 1.71 (s, 3H), 1.79 (s, 3H), 1.90 (dd, J
) 14.8, 3.6 Hz, 1H), 1.91-2.08 (m, 2H), 2.04 (s, 3H), 2.07 (s,
3H), 2.25-2.34 (m, 2H), 2.61-2.68 (m, 2H), 2.77 (d, J ) 14.9
Hz, 1H), 3.12 (ddd, J ) 12.9, 11.5, 8.2 Hz, 1H), 3.90 (d, J ) 6.4
Hz, 1H), 4.19 (d, J ) 2.6 Hz, 1H), 4.75 (m 1H), 4.76 (s, 1H), 4.84
(s, 1H), 5.16 (dd, J ) 4.1, 4.1 Hz, 1H), 5.70 (dd, J ) 11.2, 6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3, 60 °C) δ 16.5, 20.9, 21.1, 21.3,
23.5, 28.3, 29.6, 29.8, 32.9, 37.9, 39.2, 42.1, 43.8, 73.7, 75.5, 78.7,
79.6, 87.6, 111.1, 125.2, 134.9, 148.3, 170.51, 170.54; IR (film)
3362 (br), 2933, 1734 (str), 1448, 1374, 1238 (str), 1038 cm-1
;
[R]22 ) +18 (c ) 3.1, CHCl3); HRMS (electrospray ionization)
D
calcd for C24H36O6Na [M + Na]+ 443.2410, found 443.2408.
(1R,1S′,2S,3S,4S,6S,7R,8R,9R,10S)-Acetic Acid 9-Hydroxy-6-
(2-hydroxy-1-methylethyl)-4,9,13-trimethyl-15-oxatricyclo-
[6.6.1.02,7]pentadec-12-en-3,10-yl Diester (57). A flask was charged
with alkene 56 (16.1 mg, 38.3 µmol) in 1 mL of THF. (+)-
Diisopinocampheylborane (33.1 mg, 115 µmol) was added to the
solution, and the resulting solution was allowed to stir 30 min. The
reaction was quenched by the addition of 1 mL of water and sodium
perborate tetrahydrate (53.0 mg, 345 µmol), allowed to stir for 3
h, and then diluted with brine and Et2O. The layers were separated,
and the aqueous portion was washed twice with Et2O, dried over
Na2SO4, and concentrated in vacuo. Purification via flash column
chromatography (10% then 30% EtOAc/hexanes) gave 12.3 mg
(74%) of the diol as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 0.82 (d, J ) 6.0 Hz, 3H), 8.87 (d, J ) 6.9 Hz, 3H), 1.02 (m,
1H), 1.17 (m, 1H), 1.38 (s, 3H), 1.70-1.92 (m, 5H), 1.81 (s, 3H),
2.06 (m, 1H), 2.10 (s, 3H), 2.11 (s, 3H), 2.90 (br s, 1H), 2.46 (dd,
J ) 10.3, 8.1 Hz, 1H), 2.69 (d, J ) 14.8 Hz, 1H), 3.15 (ddd, J )
13.5, 11.5, 7.7 Hz, 1H), 3.53-3.62 (m, 3H), 3.87 (d, J ) 10.7 Hz,
1H), 4.04 (s, 1H), 4.89 (d, J ) 7.6 Hz, 1H), 5.18 (d, J ) 3.3 Hz,
1H), 5.65 (dd, J ) 10.3, 4.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 14.2, 18.4, 21.2, 21.5, 21.8, 23.3, 24.7, 28.3, 29.4, 30.9, 32.5,
36.6, 38.0, 41.0, 45.7, 65.0, 73.8, 75.7, 77.8, 79.9, 88.7, 125.2,
133.9, 171.4, 171.6; IR (film) 3392 (br), 2926, 1735 (str), 1375,
1244 (str), 1024 cm-1; [R]21 ) -11 (c ) 0.40, CH2Cl2); HRMS
D
(electrospray ionization) calcd for C24H38O7Na [M + Na]+ 461.2516,
found 461.2519.
Asbestinin-12 (2). A flask charged with diol 57 (13.7 mg, 31.2
µmol) in 1.6 mL of CHCl3 was cooled to 0 °C. 2,6-Lutidine (18.2
µL, 0.156 mmol) followed by trifluoromethanesulfonic anhydride
(5.80 µL, 34.4 µmol) were added to the solution, and the resulting
solution was allowed to stir 30 min at 0 °C. The solution was
warmed to room temperature for 4 h and then quenched via the
addition of saturated aqueous NH4Cl. The mixture was diluted with
CHCl2, and the layers were separated. The aqueous portion was
washed three times with CH2Cl2, dried over Na2SO4, and concen-
trated in vacuo. Purification via flash column chromatography (15%
EtOAc/hexanes) gave 9.0 mg (69%) of asbestinin-12 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.88 (d, J ) 7.1 Hz, 3H), 0.92
(d, J ) 7.2 Hz, 3H), 1.00 (ddd, J ) 13.4, 3.3, 1.7 Hz, 1H), 1.42 (s,
3H), 1.51 (ddd, J ) 3.8, 3.8, 3.8 Hz, 1H), 1.62 (m, 2H), 1.79 (s,
J. Org. Chem, Vol. 73, No. 5, 2008 1659

Crimmins and Ellis
3H), 1.85 (dd, J ) 14.6, 4.5 Hz, 1H), 1.98 (ddd, J ) 10.8, 3.1, 3.1
Hz, 1H), 2.02 (m, 1H), 2.10 (s, 3H), 2.12 (s, 3H), 2.26 (ddd, J )
11.0, 11.0, 11.0 Hz, 1H), 2.68 (d, J ) 15.1 Hz, 1H), 3.19 (ddd, J
) 13.8, 11.1, 7.4 Hz, 1H), 3.49 (dd, J ) 13.3, 3.8 Hz, 1H), 3.85
(d, J ) 13.1 Hz, 1H), 3.93 (d, J ) 9.1 Hz, 1H), 4.10 (ddd, J ) 3.4,
3.4, 3.4 Hz, 1H), 4.87 (d, J ) 7.4 Hz, 1H), 5.28 (dd, J ) 4.9, 2.9
Hz, 1H), 5.74 (dd, J ) 10.8, 6.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 10.8, 18.2, 19.3, 21.3, 21.6, 29.6, 31.3, 31.4, 33.4, 36.9,
37.6, 38.3, 40.8, 44.9, 67.8, 73.6, 76.7, 79.2, 81.7, 91.3, 126.7,
131.6, 170.8, 171.3; IR (film) 2926, 1737 (str), 1459, 1377, 1231,
1088 cm-1; [R]21D ) -22 (c ) 0.29, CHCl3); HRMS (electrospray
ionization) calcd for C24H36O6 [M + Na]+ 443.2410, found
443.2411.
acknowledge a generous gift of (R)-benzyl glycidyl ether from
Daiso, Inc. We also are grateful to Professor Abimael D.
Rodr´ıguez (University of Puerto Rico, Rio Piedras) for his
donation of an authentic sample of 11-acetoxy-4-deoxyasbestin-
nin D. The assistance of Dr. Peter S. White (University of North
Carolina at Chapel Hill) in obtaining X-ray crystallographic data
is also acknowledged.
Supporting Information Available: Experimental procedures
1
as well as H and 13C NMR spectra for all new compounds, 11-
acetoxy-4-deoxyasbestinin D, and asbestinin-12. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a research
grant from the National Institutes of Health (GM60567). We
JO0712695
1660 J. Org. Chem., Vol. 73, No. 5, 2008