Total synthesis of (-)-heptemerone B and (-)-guanacastepene E

Article abstract of DOI:10.1021/ja0660507

A concise, stereoselective, and convergent total synthesis of the unnatural enantiomer of the neodolastane diterpenoid heptemerone B has been completed. Saponification of (-)-heptemerone afforded (-)-guanacastepene E. The absolute stereochemistry of (-)-heptemerone B was thus established as 5-(S), the same as (-)-guanacastepene E. The longest linear sequence of the synthesis comprises 17 (18) steps from simple known starting materials. Our general synthetic approach integrates a diverse set of reactions, including an intramolecular Heck reaction to create one quaternary stereocenter and a cuprate conjugate addition for the establishment of the other. The central seven-membered ring was closed with an uncommon electrochemical oxidation, whereas the five-membered ring was formed through ring-closing metathesis. The absolute configuration of the two key building blocks was established through an asymmetric reduction and an asymmetric ene reaction.

Full text of DOI:10.1021/ja0660507

Published on Web 12/06/2006
Total Synthesis of (-)-Heptemerone B and
(-)-Guanacastepene E
Aubry K. Miller, Chambers C. Hughes,† Joshua J. Kennedy-Smith,‡
Stefan N. Gradl,§ and Dirk Trauner*
Contribution from the Department of Chemistry, UniVersity of California-Berkeley,
Berkeley, California 94720-1460
Received September 8, 2006; E-mail: trauner@berkeley.edu
Abstract: A concise, stereoselective, and convergent total synthesis of the unnatural enantiomer of the
neodolastane diterpenoid heptemerone B has been completed. Saponification of (-)-heptemerone afforded
(-)-guanacastepene E. The absolute stereochemistry of (-)-heptemerone B was thus established as 5-(S),
the same as (-)-guanacastepene E. The longest linear sequence of the synthesis comprises 17 (18) steps
from simple known starting materials. Our general synthetic approach integrates a diverse set of reactions,
including an intramolecular Heck reaction to create one quaternary stereocenter and a cuprate conjugate
addition for the establishment of the other. The central seven-membered ring was closed with an uncommon
electrochemical oxidation, whereas the five-membered ring was formed through ring-closing metathesis.
The absolute configuration of the two key building blocks was established through an asymmetric reduction
and an asymmetric ene reaction.
Introduction
methyl groups in a 1,4 relationship at C8 and C11 and an
additional isopropyl substituent at C12. Although most of the
The guanacastepenes and heptemerones comprise a unique
family of diterpene natural products isolated by the groups of
Clardy and Sterner, respectively (Chart 1). Guanacastepene A
(1), the founding member of the family, stems from an
unidentified endophytic fungus colonizing the Daphnopsis
americana tree in the Guanacaste conservation area of Costa
Rica. It showed interesting activities against drug-resistant strains
of Staphylococcus aureus and Enterococcus faecalis.1 Subse-
quent systematic investigations of the fungal extracts revealed
the presence of 14 other members of the family, termed
guanacastepenes B-O.1b Interestingly, the unidentified fungus
failed to produce guanacastepenes independent from its tree host,
a common phenomenon when complex ecological interactions
between different species are disrupted.
More recently, Sterner et al. reported the isolation of the
heptemerones from an “inkcap” mushroom, Coprinus hepte-
merus.2 The heptemerones strongly inhibit fungal germination
of the plant pathogen Magnaporthe grisea, the cause of rice
blast disease and a major menace to rice cultivating nations.
Their cytotoxic and antibiotic activities, however, were found
to be low.
guanacastepenes and heptemerones share a nonpolar, unfunc-
tionalized “upper rim”, they are distinguished from each other
by their different patterns of oxygenation and unsaturation found
on the “lower rim” of the molecules.
In light of their attractive structures and interesting biological
activities, it is not surprising that the guanacastepenes have
proven to be a fertile ground for total synthesis.3 Although the
initial excitement about the biological activity of guanacastepene
A (1) has been somewhat spoiled by its reported hemolytic
activity,4 the guanacastepenes and heptemerones remain poten-
tial drug leads and continue to inspire synthetic chemists.
Accordingly, numerous approaches toward their total synthesis
have surfaced in the literature in recent years. By contrast, the
total synthesis of a heptemerone has not been reported, reflecting
the relatively recent appearance of these compounds on the
scene.
To date, four total syntheses, a number of formal syntheses,
and myriad approaches toward the guanacastepenes have
surfaced in the literature, representing a remarkably diverse
range of synthetic strategies described in more than 40 publica-
tions.5 Danishefsky and co-workers reported the first total
synthesis of racemic guanacastepene A (1) in 2002,5d,e followed
by an asymmetric version in 2005.5j Snider et al.5n and Hanna
et al.5p published formal total syntheses of racemic guanacaste-
pene A in 2003 and 2004, respectively, and Mehta et al.5v
Structurally, the guanacastepenes and heptemerones share a
tricyclic neodolastane carbon skeleton typified by two angular
† Current address: Scripps Institution of Oceanography, University of
California, San Diego, La Jolla, CA 92093.
‡ Current address: Roche Palo Alto, Palo Alto, CA 94304.
§ Current address: SGX Pharmaceuticals, Inc., San Diego, CA 92121.
(1) Guanacastepene isolation articles: (a) Brady, S. F.; Singh, M. P.; Janso, J.
E.; Clardy, J. J. Am. Chem. Soc. 2000, 122, 2116-2117. (b) Brady, S. F.;
Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123, 9900-9901.
(2) Heptemerone isolation articles: (a) Valdivia, C.; Kettering, M.; Anke, H.;
Thines, E.; Sterner, O. Tetrahedron 2005, 61, 9527-9532. (b) Kettering,
M; Valdivia, C.; Sterner, O.; Anke, H.; Thines, E. J. Antibiot. 2005, 58,
390-396.
(3) For reviews on the total synthesis of guanacastepenes and related diterpenes,
see: (a) Hiersemann, M. Nachr. Chem. 2006, 54, 29-33. (b) Hiersemann,
M.; Helmboldt, H. Top. Curr. Chem. 2005, 243, 73-136. (c) Maifeld, S.
V.; Lee, D. Synlett 2006, 1623-1644. (d) Mischne, M. Curr. Org. Synth.
2005, 2, 261-279.
(4) Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256-261.
9
10.1021/ja0660507 CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 17057-17062
17057

A R T I C L E S
Miller et al.
Chart 1. Selected Guanacastepenes, Heptemerones, and the Neodolastane Skeletona
a Conventional guanacastepene numbering is used on the neodolastane skeleton.
Results and Discussion
reported the total synthesis of racemic guanacastepene C (2) in
2005. In 2006, the asymmetric syntheses of guanacastepene E
(3) and guanacastepene N (4) were completed by Shipe and
Sorensen5x and Overman et al.,5y respectively. In addition to
these completed total syntheses, the groups of Magnus,5z,aa
Lee,4c,5ab,ac Tius,5ad Kwon,5ae,af Srikrishna,5ag Chiu,5ah Brummond,5ai
Stoltz,5aj and Yang5ak,al have published approaches to the
guanacastepenes. Our group has also published approaches
toward a number of guanacastepene architectures.5am-ao We now
report synthetic studies that have culminated in the first total
synthesis of heptemerone B (5) and its conversion into guana-
castepene E (3). For historic and economic reasons, these studies
were conducted in the unnatural enantiomeric series.5ao
Retrosynthetic Analysis. Our retrosynthetic analysis of (-)-
guanacastepene E (3) begins by disconnecting the central seven-
membered ring to arrive at furyl ketone 7 (Scheme 1). In the
forward direction, oxidative coupling of the furan and ketone
functionalities in 7 would close this ring. Further disconnection
of 7 yields the left-hand building block 8 and the right-hand
building block 9. These components would be joined by (formal)
hydrometallation of 8, followed by a diastereoselective conjugate
addition to cyclopentenone 9. Compounds 8 and 9 could be
traced back to iodofuran 10 and dienone 11 through an
intramolecular Heck reaction and ring-closing metathesis (RCM),
respectively. Finally, these components could be fully discon-
nected to known molecules: aldehyde 12, diiodofuran 13,
vinylmagnesium bromide, chiral glyoxylate 14, and heptene 15.
Synthesis of the Left- and Right-Hand Building Blocks.
To reduce this plan to practice, we began to accumulate a
stockpile of known 3,4-diodofuran (13) (Scheme 2). Although
the preparation of this compound from 2-butyne-1,3-diol (16)
according to a published procedure6 proved difficult, our
systematic efforts to improve this transformation were rewarded
with a notable result. When the oxidative cyclization of
diiododiol 17 was run with 1-methyl-2-pyrrolidinone (NMP)
as a cosolvent, we repeatedly observed the formation of large
amounts of a white precipitate lining the reaction vessel. Initially
assuming the precipitate to be an inorganic or polymeric
byproduct, we eventually decided to take a closer look at this
material in order to get a better idea about the mass balance of
the reaction. To our surprise, the white material proved to be
(5) (a) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399-2402. (b)
Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M.; Danishefsky, S. J.
Tetrahedron Lett. 2001, 42, 6789-6791. (c) Dudley, G. B.; Danishefsky,
S. J.; Sukenick, G. Tetrahedron Lett. 2002, 43, 5605-5606. (d) Tan, D.
S.; Dudley, G. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
2185-2188. (e) Lin, S. N.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2002, 41, 2188-2191. (f) Mandal, M.; Danishefsky,
S. J. Tetrahedron Lett. 2004, 45, 3827-3829. (g) Mandal, M.; Danishefsky,
S. J. Tetrahedron Lett. 2004, 45, 3831-3833. (h) Yun, H. D.; Meng, Z.
Y.; Danishefsky, S. J. Heterocycles 2005, 66, 711-725. (i) Yun, H. D.;
Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879-3882. (j) Mandal,
M.; Yun, H. D.; Dudley, G. B.; Lin, S. N.; Tan, D. S.; Danishefsky, S. J.
J. Org. Chem. 2005, 70, 10619-10637. (k) Cheong, P. H. Y.; Yun, H.;
Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513-1516. (l) Snider,
B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572. (m) Snider, B. B.;
Shi, B. Tetrahedron Lett. 2001, 42, 9123-9126. (n) Shi, B.; Hawryluk, N.
A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030-1042. (o) Boyer, F. D.;
Hanna, I. Tetrahedron Lett. 2002, 43, 7469-7472. (p) Boyer, F. D.; Hanna,
I.; Ricard, L. Org. Lett. 2004, 6, 1817-1820. (q) Boyer, F. D.; Hanna, I.
J. Org. Chem. 2005, 70, 1077-1080. (r) Mehta, G.; Umarye, J. D. Org.
Lett. 2002, 4, 1063-1066. (s) Mehta, G.; Umarye, J. D.; Gagliardini, V.
Tetrahedron Lett. 2002, 43, 6975-6978. (t) Mehta, G.; Umarye, J. D.;
Srinivas, K. Tetrahedron Lett. 2003, 44, 4233-4237. (u) Mehta, G.;
Umarye, J. D. Tetrahedron Lett. 2003, 44, 7285-7289. (v) Mehta, G.;
Pallavi, K.; Umarye, J. D. Chem. Commun. 2005, 4456-4458. (w) Shipe,
W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063-2066. (x) Shipe, W. D.;
Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025-7035. (y) Iimura, S.;
Overman, L. E.; Paulini, R.; Zakarian, A. J. Am. Chem. Soc. 2006, 128,
13095-13101. (z) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V.
Tetrahedron Lett. 2001, 42, 4947-4950. (aa) Magnus, P.; Ollivier, C.
Tetrahedron Lett. 2002, 43, 9605-9609. (ab) Nguyen, T. M.; Lee, D.
Tetrahedron Lett. 2002, 43, 4033-4036. (ac) Nguyen, T. M.; Seifert, R.
J.; Mowrey, D. R.; Lee, D. S. Org. Lett. 2002, 4, 3959-3962. (ad) Nakazaki,
A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363-3366. (ae) Du, X.
H.; Chu, H. F. V.; Kwon, O. Org. Lett. 2003, 5, 1923-1926. (af) Du, X.
H.; Chu, H. F. V.; Kwon, O. Y. Tetrahedron Lett. 2004, 45, 8843-8846.
(ag) Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6, 165-168. (ah) Chiu,
P.; Li, S. L. Org. Lett. 2004, 6, 613-616. (ai) Brummond, K. M.; Gao, D.
Org. Lett. 2003, 5, 3491-3494. (aj) Sarpong, R.; Su, J. T.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 13624-13625. (ak) Li, C. C.; Liang, S.;
Zhang, X. H.; Xie, Z. X.; Chen, J. H.; Wu, Y. D.; Yang, Z. Org. Lett.
2005, 7, 3709-3712. (al) Li, C. C.; Wang, C. H.; Liang, B.; Zhang, X. H.;
Deng, L. J.; Liang, S.; Chen, J. H.; Wu, Y. D.; Yang, Z. J. Org. Chem.
2006, 71, 6892-6897. (am) Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.;
Trauner, D. Synlett 2002, 411-414. (an) Hughes, C. C.; Kennedy-Smith,
J. J.; Trauner, D. Org. Lett. 2003, 5, 4113-4115. (ao) Hughes, C. C.; Miller,
A. K.; Trauner, D. Org. Lett. 2005, 7, 3425-3428.
1
highly soluble in chloroform-d, and the H NMR spectrum
revealed an exact 2:1 mixture of NMP and the desired product
13. Thus, the precipitate turned out to be the coordination
polymer 13‚NMP2.
The X-ray structure of 13‚NMP2 reveals the source of its
unusual stability (Figure 1). The carbonyl groups of the amide
moiety in NMP form bonding interactions not only with the
hydrogens in the furan, which are known to act as hydrogen-
bond donors, but also with the iodine atoms. Similar interactions
in iodoalkynes have been studied by Goroff et al.7 Overall, these
bonding interactions lead to the formation of ribbons of
(6) Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28, 1093-1096.
(7) (a) Rege, P. D.; Malkina, O. L.; Goroff, N. S. J. Am. Chem. Soc. 2002,
124, 370-371. (b) Webb, J. A.; Klijn, J. E.; Hill, P. A.; Bennett, J. L.;
Goroff, N. S. J. Org. Chem. 2004, 69, 660-664.
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Total Synthesis of Heptemerone B and Guanacastepene E
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of Guanacastepene E
a
Scheme 2. Synthesis of 13‚NMP2
a (a) ref 6; (b) K2Cr2O7, H2SO4, hexanes, NMP, 85 °C. NMP ) 1-methyl-2-pyrrolidinone.
ylene chloride. With sufficient quantities of 13 thus available,
we proceeded to study the asymmetric synthesis of a left-hand
building block corresponding to 8 (Scheme 3). Mono-lithiation
of 13 at low temperature, followed by addition of the resultant
organolithium species 18 to (E)-4-methylhex-4-enal (12),
gave racemic alcohol (()-19, whose oxidation furnished furyl
ketone 20.
Initially, we explored asymmetric Heck cyclizations of 20 to
achieve the formation of the six-membered ring.8 Although this
cyclization could be effectively carried out racemically under
Jeffery conditions,9 all attempts to perform this reaction with
chiral catalysts proved disappointing. We therefore turned our
attention to diastereoselective Heck cyclizations of enantio-
merically enriched iodofuryl carbinol (+)-19. To this end, 20
Figure 1. ORTEP representation of 13‚NMP2.
diiodofurans in alternating orientations lined on both sides by
NMP molecules.
The coordination polymer 13‚NMP2 could easily be broken
apart by partitioning its components between brine and meth-
(8) For a review of asymmetric intramolecular Heck reactions, see: (a) Donde,
Y.; Overman, L. E. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley: New York, 2000; pp 675-697.
(9) Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
9
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A R T I C L E S
Miller et al.
Scheme 4. Synthesis of the Right-Hand Building Block 29a
Scheme 3. Preparation of Furyl Cyclohexanol Building Block 24a
a (a) 1.1 equiv of SnCl4, CH2Cl2, -78 °C, 64%, 10:1 dr; (b) NaH, benzyl
bromide, (n-Bu)4NI, THF, 100%; (c) DIBAL, CH2Cl2, -78 °C, 85%; (d)
vinylmagnesium bromide, CeCl3, THF, -78 °C, 82%; (e) Dess-Martin
periodinane, CH2Cl2, 86%; (f) Grubbs second-generation catalyst, PhMe,
reflux, 86%. DIBAL ) diisobutylaluminum hydride.
the desired anti adduct 26 as the major product, together with
a small amount of its syn isomer (not shown) (10:1 dr).14
Protection of 26 as a benzyl ether, followed by diisobutylalu-
minum hydride (DIBAL) reduction to remove the chiral
auxiliary, gave aldehyde 27. Addition of vinylmagnesium
bromide in the presence of CeCl315 followed by oxidation then
afforded dienone 28. Cyclization of 28 via RCM proceeded
without incident to afford enantiomerically pure cyclopentenone
29 in excellent yield.16
Conjugate Coupling and Anodic Oxidative Cyclization.
With enantiomerically enriched building blocks 24 and 29 in
hand, we began to study the challenging conjugate addition to
link the two halves of the molecule (Scheme 5). We were
pleased to find that this linkage could be achieved reliably using
a combination of Lipshutz and Yamamoto protocols for cuprate
conjugate additions.17,18 Iodine-lithium exchange involving 24
a (a) n-BuLi, Et2O, -78 °C, then 12, 62%; (b) Dess-Martin periodinane,
CH2Cl2, room temperature, 88%; (c) (+)-DIP-Cl, THF, -20 °C, 75%,
94% ee; (d) Pd(OAc)2, Et3N, (n-Bu)4NBr, MeCN, H2O, 75 °C, 75%; (e)
TBDPSCl, imid, DMAP, CH2Cl2, 0 °C, 98%; (f) (1) 9-BBN, THF, reflux,
(2) EtOH, NaOH, H2O2, room temperature, 81%; (g) I2, PPh3, imid, THF,
0 °C f room temperature, 90%. DIP-Cl ) B-chlorodiisopinocamphey-
lborane, TBDPSCl ) tert-butyldiphenylsilyl chloride, imid ) imidazole,
DMAP)4-N,N-(dimethylamino)pyridine,9-BBN)9-borabicyclo[3.3.1]nonane.
was reduced using (+)-B-chlorodiisopinocampheylborane [(+)-
DIP-Cl],10 affording (+)-19 in 94% enantiomeric excess. After
considerable experimentation, it was found that reaction of (+)-
19 with palladium(II) acetate [Pd(OAc)2], triethylamine (Et3N),
and tetra-n-butylammonium bromide (TBAB) in an acetonitrile
(MeCN) and water mixture gave a 5.1:1 mixture of the desired
diastereomer 21 and its epimer (not shown). The free secondary
hydroxyl group proved to be necessary to achieve high
diastereoselectivity, as cyclizations of the corresponding methyl
or silyl ethers resulted in low diastereomeric ratios. Protection
of the secondary alcohol as the tert-butyldiphenylsilyl (TBDPS)
ether 22, followed by hydroboration/oxidation, gave primary
alcohol 23. Functional group interconversion under Appel
conditions11 then afforded primary iodide 24, our standard left-
hand building block.
(12) (a) Whitesell, J. K.; Chen, H.-H.; Lawrence, R. M. J. Org. Chem. 1985,
50, 4663-4664. (b) Whitesell, J. K.; Lawrence, R. M.; Chem, H.-H. J.
Org. Chem. 1985, 50, 4779-4784. For a review on cyclohexyl-based chiral
auxiliaries, see: (c) Whitesell, J. K. Chem. ReV. 1992, 92, 953-964.
Racemic trans-2-phenylcyclohexanol was made according to: (d) Schwartz,
A.; Madan, P.; Whitesell, J. K.; Lawrence, R. M. Org. Synth. Coll. Vol. 8
1993, 516.
(13) A recently reported enzymatic resolution of racemic trans-2-phenylcyclo-
hexanol was found to be extremely efficient and easy to run on large
scale: She, Y.-H.; Wu, C.-F.; Shia, K.-S.; Wu, J.-D.; Peddinti, R. K.; Liu,
H.-J. Synthesis 2005, 749-752.
(14) In the racemic series, the two diastereomers could be separated by fractional
crystallization, and the relative stereochemistry of the major product was
secured with the X-ray structure of (()-26 (see Supporting Information).
Enantiomerically pure 26, by contrast, was not a solid, and the two
diastereomers proved to be inseparable by chromatographic methods.
Therefore, we proceeded with the 10:1 mixture of diastereomers until
formation of 29, wherein the two diastereomers could be easily separated
by silica gel chromatography.
(15) Takeda, N.; Imamoto, T. Org. Synth. Coll. Vol. 10 2004, p 200.
(16) For a related RCM reaction on a model system, see ref 5am. The ring-
closing metathesis reaction of enone 28 to cyclopentenone 29 has also been
reported in a thesis from the MacMillan group: Jen, W. S. Development
of New Asymmetric Organocatalytic Methods and Progress Towards the
Total Synthesis of Guanacastepene A. California Institute of Technology,
Pasadena, CA, 2003 (available at http://etd.caltech.edu/etd/available/etd-
10282003-13585.7/, accessed November, 2006).
Our next goal was to implement a synthetic route toward an
appropriately functionalized right-hand building block corre-
sponding to 9 (cf. Scheme 1). To establish what would
ultimately become the cis relationship between the C12 iso-
propyl and C13 alkoxy substituents in the target cyclopentenone,
we utilized a chiral auxiliary-mediated carbonyl-ene reaction
developed by Whitesell and co-workers (Scheme 4).12,13 Reac-
tion of the known chiral glyoxylate 25 with 2,4-dimethyl-2-
pentene (15), in the presence of tin(IV) chloride (SnCl4), yielded
(17) (a) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945-948. (b) Lipshutz, B. H. Synthesis 1987, 325-341. (c) Ibuka, T.;
Yamamoto, Y. In Organocopper Reagents: A Practical Approach; Taylor,
R. J. K., Ed.; Oxford: Oxford, U.K., 1994; Chapter 7, p 143.
(18) See ref 5ao for a model study of this conjugate addition. A similar linkage
was explored in Overman et al.’s synthesis of guanacastepene N (ref 5y).
(10) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem.
Soc. 1988, 110, 1539-1546.
(11) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801-811.
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Total Synthesis of Heptemerone B and Guanacastepene E
A R T I C L E S
Scheme 5. Conjugate Additiona
Scheme 7. Conversion of Acetal 36 to (-)-Heptemerone B (5)
and (-)-Guanacastepene E (3)a
a (a) t-BuLi, Et2O, -78 °C, then (2-thienyl)Cu(CN)Li, THF, -40 °C,
then BF3‚OEt2, 29, 54%.
Scheme 6. Anodic Oxidation to Close the Seven-Membered Ringa
a (a) DIBAL, PhMe, -78 °C f room temperature, 61%; (b) MOMCl,
i-Pr2NEt, NaI, THF, reflux, 95%; (c) TBAF, THF, 100%; (d) Na, NH3(l),
THF, -78 °C, 94%; (e) Ac2O, DMAP, p-xylene, reflux, 93%; (f) BF3‚OEt2,
DMS, CH2Cl2, -20 °C; (g) Dess-Martin periodinane, CH2Cl2, 69% (2
steps); (h) K2CO3, MeOH, 28% (39% BORSM). MOMCl ) chlorometh-
ylmethyl ether, TBAF ) tetra-n-butylammonium fluoride, DMS ) dim-
ethylsulfide, BORSM ) based on recovered starting material.
methods for one-electron oxidations could be imagined,20 we
found an electrochemical variant more attractive (Scheme 6).
Moeller and Wright have shown that silyl enol ethers can be
coupled with furans through anodic oxidation in an alcoholic
solvent.21 To adapt this methodology to our system, ketone 31
was converted to silyl enol ether 32 by regioselective depro-
tonation followed by silylation. With 32 in hand, we were in a
unique position to explore the usefulness of electrochemistry
on a relatively complex substrate.
In the event, anodic oxidation of 32, under the conditions
described by Moeller, gave tetracycle 36 in good yield and as
a single isomer. According to Wright et al.’s mechanistic
studies,21e this cyclization probably proceeds through oxidation
of the silyl enol ether to the corresponding radical cation 33,
followed by stereoselective intramolecular attack of the furan.
Interception of the resulting carboxonium radical cation 34 by
methanol, further oxidation, and finally desilylation of inter-
mediary cation 35 furnishes acetal 36.
Total Synthesis of Heptemerone B and Guanacastepene
E. At this stage, all that remained to complete the synthesis of
guanacastepene E or its close congener heptemerone B was
reductive removal of the methoxy group, deprotection, and
a (a) KHMDS, 18-crown-6, TBSOTf, THF, -78 °C, 94%; (b) RVC anode
(0.9 mA), 2,6-lutidine, 0.1 M LiClO4, 20% MeOH in CH2Cl2, room
temperature, 16.5 h, 2.61 F/mol, 81%. KHMDS ) potassium bis-
trimethylsilylamide, TBSOTf ) tert-butyldimethylsilyl triflate, RVC )
reticulated vitreous carbon.
and tert-butyl lithium (t-BuLi), followed by addition of lithium
2-thienylcyanocuprate (“cuprate in a bottle”), gave a mixed
higher-order cyanocuprate (30), which underwent 1,4 addition
to cyclopentenone 29 in the presence of boron trifluoride etherate
(BF3‚OEt2). Under these conditions, furyl ketone 31 was formed
in acceptable yield and as a single stereoisomer.19 Although
these conditions did not allow for trapping of the intermediary
enolate with electrophiles, such as trimethylsilyl chloride, this
did not thwart our synthesis because the requisite enolate could
be cleanly regenerated by regioselective deprotonation (see
below).
(20) Baran and co-workers have recently reported the chemical oxidative
coupling of enolates with indoles and pyrroles: (a) Richter, J. M.; Baran,
P. S. J. Am. Chem. Soc. 2004, 126, 7450-7451. (b) Baran, P. S.; Richter,
J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005, 44, 609-612. (c) Richter,
J. M.; Baran, P. S. J. Am. Chem. Soc. 2005, 127, 15394-15396.
Looking at furyl ketone 31, we reasoned that the formation
of the desired C1-C2 bond would require some form of
umpolung, as both the furan and an enolate formed from the
carbonyl functionality in 31 are nucleophiles. Such an umpolung
could most easily be achieved by oxidizing either reaction
partner to the corresponding radical cation. Although chemical
(21) (a) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2004, 126, 9106-9111.
(b) Mihelcic, J.; Moeller, K. D. J. Am. Chem. Soc. 2003, 125, 36-37. (c)
Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.; Frey, D.
A. Org. Lett. 1999, 1, 1535-1538. (d) Whitehead, C. R.; Sessions, E. H.;
Ghiviriga, I.; Wright, D. L. Org. Lett. 2002, 4, 3763-3765. (e) Sperry, J.
B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R. M.; Wright, D. L. J. Org.
Chem. 2004, 69, 3726-3734. (f) Sperry, J. B.; Wright, D. L. J. Am. Chem.
Soc. 2005, 127, 8034-8035. (g) Sperry, J. B.; Wright, D. L. Tetrahedron
2006, 62, 6551-6557. (h) Sperry, J. B.; Ghiviriga, I. Wright, D. L. Chem.
Commun. 2006, 2, 194-196. For reviews of anodic electrochemistry, see
(i) Moeller, K. D. Tetrahedron 2000, 56, 9527-9554. and (j) Sperry, J.
B.; Wright, D. L. Chem. Soc. ReV. 2006, 35, 605-621.
(19) Cyclopentanone 31 was isolated along with significant amounts of the
corresponding 1,2 adduct (see Supporting Information).
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A R T I C L E S
Miller et al.
respects (NMR, MS, IR) save the optical rotation, reflecting its
unnatural absolute configuration ([R]D -135°, c ) 0.23, CHCl3;
lit. [R]D +25.9°, c ) 0.17, CHCl3).22
Conclusion
In summary, concise syntheses of (-)-heptemerone B and
(-)-guanacastepene E have been developed. Our syntheses are
highly convergent and require 17 (18) steps in their longest
linear sequence. The absolute configuration of the heptemerones
has been established as corresponding to the guanacastepene
series. Our work highlights the usefulness of electrochemistry
in the synthesis of complex target molecules and confirms the
superiority of modern transition-metal-catalyzed methods in
challenging bond formations. The quaternary stereocenters of
the neodolastane skeleton were installed using organopalladium
and organocuprate chemistry, whereas the five-membered ring
was closed through ring-closing metathesis. The convergent
nature of our approach provides access to intermediates that
are potential precursors to additional members of the guana-
castepene and heptemerone family.
Figure 2. X-ray structure of (-)-heptemerone B (5).
acetylation. This seemingly straightforward endgame, however,
proved to be quite challenging, requiring careful differentiation
of functional groups with similar reactivities. Nevertheless, a
satisfactory solution was ultimately found (Scheme 7). First,
the acetal functionality in 36 was reduced by treatment with a
large excess of DIBAL.21a,b Under these conditions, the cyclo-
pentenone was also reduced to afford secondary alcohol 37 as
a single diastereomer, whose relative stereochemistry was
assigned by NOE measurements (see Supporting Information).
All other conditions that were tried in hopes of avoiding this
second reduction (e.g., Et3SiH/BF3‚OEt2) led to elimination of
methanol and aromatization of the dihydrofuran ring.
Although 37 could be cleanly oxidized to the corresponding
R-benzyloxy ketone, all efforts to subsequently remove the
benzyl group were low-yielding and were ultimately abandoned.
After extensive experimentation, we found that this benzyl group
could be removed under dissolving metal conditions, but only
after protection of the secondary hydroxyl group at C13 as a
MOM ether and cleavage of the C5 silyl ether. The resulting
MOM ether 38 was acetylated and subsequently deprotected
and oxidized, which afforded heptemerone B (5) in very good
overall yield. The synthetic material was obtained as a crystalline
solid and was identical in all respects to natural 5, with the
exception of its optical rotation, which had the opposite sign
([R]D -116°, c ) 0.36, CHCl3; lit. [R]D +73°, c ) 0.5,
CHCl3).3a Therefore, natural heptemerone B, and presumably
all of the heptemerones, have the absolute configuration shown
in Chart 1. The X-ray structure of synthetic (-)-heptemerone
B (5) is shown in Figure 2.
Acknowledgment. We thank Prof. Kevin Moeller for his
invaluable advice and encouragement; Dr. Frederick J. Hollander
and Dr. Allen G. Oliver for the crystal structure determination
of compounds 3, 13‚NMP2, and 26; and Prof. F. Dean Toste
for assistance with asymmetric olefin metathesis reactions.
Special thanks are due to Andy Malec (Majda group, UC
Berkeley) for help with the potentiostat. We also thank Amano
Co. for the generous donation of lipase-AK on celite. This work
was supported by PRF Grant 37520-AC1. A.K.M. thanks the
National Science Foundation for a predoctoral fellowship,
J.J.K.S. thanks UC Berkeley for the Klaus and Mary Saegebarth
fellowship. Financial support from the Alfred P. Sloan Founda-
tion as well as Novartis, Glaxo Smith Kline, Eli Lilly, Astra
Zeneca, Amgen and Merck & Co. is also gratefully acknowl-
edged.
Supporting Information Available: Complete experimental
procedures and spectral data for previously unreported com-
pounds; 1H and 13C NMR spectra for selected compounds; X-ray
crystal structure coordinates for 3 (CCDC620339), 13‚NMP2
(CCDC618409), and (()-26 (CCDC618410). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0660507
Finally, selective saponification of (-)-heptemerone B (5)
gave (-)-guanacastepene E (3) (yield not optimized). Synthetic
guanacastepene E was identical to the natural material in all
(22) The optical rotation of natural guanacastepene E was not reported in the
original isolation study (ref 1b). The literature value reported here is from
synthetic guanacastepene E (ref 6x).
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