Studies for the synthesis of xenicane diterpenes. A stereocontrolled total synthesis of 4-hydroxydictyolactone

Article abstract of DOI:10.1021/ja902677t

The stereocontrolled total synthesis of 4-hydroxydictyolactone (4), a member of the xenicane diterpene family of natural products, is described. These studies feature the development of the B-alkyl Suzuki cross-coupling reaction for direct access to (E)-cyclononenes from acyclic precursors. The Ireland-Claisen rearrangement is effectively utilized to establish the backbone asymmetry of the contiguous C₂, C₃, C₁₀ stereotriad of 4. The synthesis strategy has devised an intramolecular Nozaki-Hiyama reductive allylation of a formate ester for the stereoselective formation of five-membered lactols 22. In addition, an internally directed S_E′ propargylation using allenylmagnesium bromide is described to establish the stereochemistry of the C₄ alcohol in 27, and the terminal alkyne is subsequently functionalized via a regioselective syn-silylstannylation to yield 30. Finally, the stereocontrolled phenylselenylation of the ester enolate derived from 43 leads to the desired syn-oxidative elimination to yield the natural product 4.

Full text of DOI:10.1021/ja902677t

Published on Web 06/01/2009
Studies for the Synthesis of Xenicane Diterpenes. A
Stereocontrolled Total Synthesis of 4-Hydroxydictyolactone
David R. Williams,* Martin J. Walsh, and Nathan A. Miller
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
Received April 3, 2009; E-mail: williamd@indiana.edu
Abstract: The stereocontrolled total synthesis of 4-hydroxydictyolactone (4), a member of the xenicane
diterpene family of natural products, is described. These studies feature the development of the B-alkyl
Suzuki cross-coupling reaction for direct access to (E)-cyclononenes from acyclic precursors. The
Ireland-Claisen rearrangement is effectively utilized to establish the backbone asymmetry of the contiguous
C2, C3, C10 stereotriad of 4. The synthesis strategy has devised an intramolecular Nozaki-Hiyama reductive
allylation of a formate ester for the stereoselective formation of five-membered lactols 22. In addition, an
internally directed SE′ propargylation using allenylmagnesium bromide is described to establish the
stereochemistry of the C4 alcohol in 27, and the terminal alkyne is subsequently functionalized via a
regioselective syn-silylstannylation to yield 30. Finally, the stereocontrolled phenylselenylation of the ester
enolate derived from 43 leads to the desired syn-oxidative elimination to yield the natural product 4.
Introduction
In 1979, Fenical and co-workers reported the isolation of
dictyodiol (1), an unusual diterpene from the brown algae,
Dictyota crenulata, which exhibited a rare nonconjugated
(E),(Z)-cyclononadiene motif.1 These efforts also identified
dictyolactone (2) as a related metabolite from the sea hare
Aplysia depilans. The investigation followed in the wake of the
groundbreaking discovery of xenicin (3) from the soft coral
Xenia elongata, which had been unambiguously elucidated by
a single crystal X-ray diffraction study.2 Subsequent reports have
generally adopted a description of marine natural products
displaying a cyclononene framework as examples of the
xenicane family.3 Faulkner offered an expansive viewpoint by
proposing that five distinct diterpene skeletons could be traced
to biosynthetic origins that incorporate xenicane precursors.4
However, Kakisawa and co-workers have proven that the
xenicanes from Dictyotaceae algae possess the antipodal con-
figuration as compared to members of the family from soft coral
in early studies establishing the tenets of the advanced Mosher
ester analysis.5 These findings have been taken into account
for the illustration of the structures of Figure 1 and provide a
(1) Finer, J.; Clardy, J.; Fenical, W.; Minale, L.; Riccio, R.; Battaile, J.;
Kirkup, M.; Moore, R. E. J. Org. Chem. 1979, 44, 2044–2047.
(2) Vanderah, D. J.; Steudler, P. A.; Ciereszko, L. S.; Schmitz, F. J.;
Ekstrand, J. D.; Van der Helm, D. J. Am. Chem. Soc. 1977, 99, 5780–
5784.
(3) Some examples include: (a) Tanaka, J.; Higa, T. Chem. Lett. 1984,
13, 231–232. (b) Matsumoto, T.; Enoki, N.; Ryoichi, I. Chem. Lett.
1982, 11, 1749–1752. (c) Ochi, M.; Masui, N.; Kotsuki, H.; Miura,
I.; Tokoroyama, T. Chem. Lett. 1982, 11, 1927–1930. (d) El-Gamal,
A. A. H.; Wang, S.-K.; Duh, C.-Y. J. Nat. Prod. 2006, 69, 338–341.
(e) Miyaoka, H.; Mitome, H.; Nakano, M.; Yamada, Y. Tetrahedron
2000, 56, 7737–7740.
Figure 1. Xenicane and xenicane-derived marine natural products.
(4) Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251–280.
(5) (a) Ohtani, I.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H. Tetrahedron
Lett. 1989, 30, 3147–3250. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
cautionary note for the assignment of the absolute stereochem-
istry of related metabolites, which may or may not be distributed
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9038 J. AM. CHEM. SOC. 2009, 131, 9038–9045
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Studies for the Synthesis of Xenicane Diterpenes
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of 4
through an aquatic environment of filtering organisms via a
common food chain.
Guella and Pietra first described the isolation and structural
elucidation of 4-hydroxydictyolactone (4) from Dictyota ciliolata
in 1993 along with the identification of a related metabolite,
4-hydroxycrenulide (5).6 The report also demonstrated that the
ultraviolet irradiation of 4 produced a photoisomerization to
yield 5. While this transformation formally presents an intramo-
lecular ene process, the concerted pathway would provide for
an antarafacial homo[1,5]-hydrogen shift giving rise to the C6
diastereomer of 5. These efforts described the thermal isomer-
ization of 4 leading to the corresponding (Z)-6,7-olefin, which
did not afford cyclopropane products upon irradiation. On the
basis of their observations, Guella and Pietra speculated that a
free radical mechanism may be operative in the formation of
4-hydroxycrenulide (5) and may characterize the increased
reactivity of the strained (Z,E)-cyclononadiene ring system of
4-hydroxydictyolactone (4).
Numerous reports provide preliminary accounts of important
biological activity among members of the xenicane family.
Individual compounds have exhibited antibacterial and antifun-
gal properties,3a ichthyotoxicity,7 and the inhibition of HIV-1
reverse transcriptase.8 Xenicanes, such as dictyotalide B9 (6,
Figure 1), display significant levels of cytotoxicity against B16
mouse melanoma cultures, whereas florxenilide A,10 a soft coral
metabolite, exhibits potent cytotoxicity against human colon
cancer cell lines even though these examples represent antipodal
subgroups. Joalin (7) is an unusual member of the xenicane
family bearing a nitrogen atom in addition to the distinctive
bridgehead olefin.11 A recent account has confirmed that several
xenicane diterpenes target proliferating cells by the specific
induction of apoptosis at micromolar concentrations.12 Thus,
this family of natural products may offer a new chemotype for
the development of chemotherapeutic agents. A systematic
structure-activity evaluation has not been undertaken, and many
xenicanes have not been examined.
Our plans for the synthesis of 4-hydroxydictyolactone (4)
were designed to explore the utility of the B-alkyl Suzuki
reaction as a mild palladium-catalyzed cross-coupling event to
incorporate the intact (E)-trisubstituted alkene in a direct ring
closure of the nine-membered carbocycle (Scheme 1). Our
rationale in support of this hypothesis and a preliminary account
of our ongoing efforts have recently been described.13 We
postulated that the selective hydroboration of 9 would set the
stage for the cross-coupling process followed by oxidation to
the trans-fused lactone 8. Further oxidation of 8 would introduce
the R,ꢀ-unsaturation of the natural product 4. Because the
irreversible reductive elimination from a coordinated palladium
intermediate would provide for the ring closure, we rationalized
that the crucial formation of a palladium metallocycle would
overcome the entropic features and steric constraints, which
often dominate processes involving direct closures in 9- and
10-membered carbocycles. The five-membered acetal of 9 was
incorporated as an element of conformational bias to aid these
efforts. However, our modeling suggested that the stereochem-
istry at C1 of 9 would play an important role because the
corresponding cis-disubstituted tetrahydrofuranyl system im-
posed significant steric interactions for transition states leading
to metallocycle formation.
General methods for the direct closure of cyclononene
systems are uncommon. While new opportunities have explored
the synthesis of medium-ring carbocycles using ring-closing
metathesis,14 the formation of cyclononenes has presented
problems for some RCM strategies.15 On the other hand, two
groups have independently described recent results for Nozaki-
Hiyama-Kishi cyclizations directed toward pestalotiopsin, a
caryophyllene sesquiterpenoid.16 In classic studies by Professor
E. J. Corey, the use of the Grob fragmentation was devised to
address the synthesis of (()-caryophyllene.17 This stereocon-
trolled reaction established an important precedent for the
preparation of (E)-cyclononenes via the fragmentation of fused
bicyclic systems. Recently, Corey has reported the Grob
fragmentation leading to a stable, chiral (E,Z)-cyclononadienone
for the enantioselective synthesis of caryophylloids.18 In a
(6) (a) Guella, G.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 20,
1539. (b) Guella, G.; Chiasera, G.; N’Diaye, I.; Pietra, F. HelV. Chim.
Acta 1994, 77, 1203–1221.
(7) Miyamoto, T.; Takenaka, Y.; Yamada, K.; Higuchi, R. J. Nat. Prod.
1995, 58, 924–928.
(8) This activity is described in a patent report: Ninomya, M.; Matsuka,
S.; Kawakubo, A.; Bito, N. Jpn. Kokai Tokkyo Koho. 1995, 07–
285877.
(14) (a) Crimmins, M. T.; McDougall, P. J.; Ellis, J. M. Org. Lett. 2006,
8, 4079–4082. (b) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am.
Chem. Soc. 2006, 128, 1371–1378. (c) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073–2077.
(9) Ishitsuka, M. O.; Kusumi, T.; Kakisawa, H. J. Org. Chem. 1988, 53,
5010–5013.
(10) Cheng, Y.-B.; Jang, J.-Y.; Khalil, A. T.; Kuo, Y.-H.; Shen, Y.-C. J.
Nat. Prod. 2006, 69, 675–678.
(15) Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135–
7147.
(11) Guella, G.; N’Diaye, I.; Chiasera, G.; Pietra, F. J. Chem. Soc., Perkin
Trans. 1 1993, 14, 1545–1546.
(16) (a) Takao, K.; Hayakawa, N.; Yamada, R.; Yamaguchi, T.; Morita,
U.; Kawasaki, S.; Tadano, K. Angew. Chem., Int. Ed. 2008, 47, 3426–
3429. (b) Baker, T. M.; Edmonds, D. J.; Hamilton, D.; O’Brien, C. J.;
Procter, D. J. Angew. Chem., Int. Ed. 2008, 47, 5631–5633.
(17) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1964, 86, 485–
492.
(12) Adrianasolo, E. H.; Haramaty, L.; Degenhardt, K.; Mathew, R.; White,
E.; Lutz, R.; Falkowski, P. J. Nat. Prod. 2007, 70, 1551–1557.
(13) Our preliminary results appear in the edited transcript of the IUPAC
lecture entitled “Studies for the synthesis of marine natural products”
presented at the 17th International Conference on Organic Synthesis
(ICOS17), June 2008, Daejeon, Korea. Williams, D. R.; Walsh, M. J.;
Claeboe, C. D.; Zorn, N. Pure Appl. Chem. 2009, 81, 181–194.
(18) Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 2954–
2955.
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A R T I C L E S
Williams et al.
Scheme 2. Development of the C2, C3, C10 Stereotriad of 16a
Scheme 3. Intramolecular Nozaki-Hiyama Coupling of Formate
Ester 20a
a Reagents and conditions: (a) DIBAL, CH2Cl2, -78 °C, 98%; (b)
PMBCl, NaH, DMF, 0 °C to room temperature, 97%; (c) 1 M HCl, MeOH,
100%; (d) TBSCl, imidazole, CH2Cl2, 92%; (e) 14, EDCI, DMAP, CH2Cl2,
97%; (f) TMSCl, Et3N, -78 °C, then LDA, -78 °C, then reflux, 85%, dr
) 94:6; (g) DDQ, CH2Cl2, H2O, 0 °C; (h) EDCI, DMAP, CH2Cl2.
similar fashion, the Grob strategy has been successfully applied
for total synthesis of the xeniolide, coraxeniolide A.19
The analysis of Scheme 1 readily identified the (E)-alkenylio-
dide 9 as the penultimate intermediate for a direct cyclization
to afford the xenicane framework, and we envisioned the
preparation of 9 via two sequential SE′ allylation processes. The
latter of these events would establish the chirality at C4 and
accommodate stereospecific incorporation of the (E)-alkenyl
iodide from the aldehyde 10. The initial SE′ allylation was
projected as a stereocontrolled intramolecular reaction stemming
from the reduction of bromide 11 to yield the tetrahydrofuranyl
lactol of 10.
a Reagents and conditions: (a) MeI, K2CO3, DMF, 97%; (b) DIBAL,
CH2Cl2, -78 °C, 100%; (c) PivCl, pyr, CH2Cl2, 95%; (d) DDQ, pH 7.0
buffer, CH2Cl2, 0 °C, 76%; (e) formic acid, EDCI, DMAP, CH2Cl2, 96%;
(f) Bu4N+ Ph3SiF2-, AcOH, THF, 99%; (g) CBr4, PPh3, CH2Cl2; (h) CrCl2,
THF, 92% (two steps), dr > 95:5 at C1; (i) PPTs, MeOH, 100%; (j) TIPSOTf,
2,6-lutidine, CH2Cl2, 0 °C, 90%, dr ) 91:9 at C19.
(DIBAL) reduction, the resulting Z-allylic alcohol was protected
as its para-methoxybenzyl ether (PMB), and ketal hydrolysis
led to O-silylation of the primary alcohol to yield 13. Esteri-
fication of 13 with (R)-(+)-citronellic acid (14)22 produced a
single diastereomer 15 for subsequent kinetic deprotonation at
-78 °C. However, the introduction of 15 into a THF solution
containing lithium diisopropylamide (LDA) followed by trim-
ethylsilyl chloride (TMSCl) and Et3N led to substantial amounts
of products derived from base-induced elimination, which were
identified as the TBS ether of (E,E)-5-para-methoxybenzyloxy-
2,4-pentadien-1-ol and (R)-(+)-citronellic acid. The inverse
addition of LDA into a cold reaction mixture containing 15,
TMSCl, and Et3N provided excellent conversion to the antici-
pated E(O)-trimethylsilyl ketene acetal, and heating at 70 °C
resulted in the isolation of carboxylic acid 16 (dr 94:6) in high
yield. The minimization of steric factors in the chairlike
arrangement 17 accounts for the formation of the major
diastereomer 16, and the relative assignment of stereochemistry
was confirmed by conversion to the cis-disubstituted butyro-
lactone 18 for NMR studies leading to the observed nuclear
Overhauser enhancement correlations (NOESY) illustrated in
Scheme 2.
Results and Discussion
The preparation of chiral, nonracemic 11 of Scheme 1
required a high degree of stereocontrol for the assembly of the
contiguous stereotriad presented at C2, C3, and C10. This
objective can be problematic for synthesis because the consecu-
tive tertiary centers of asymmetry are uniquely characterized
by an arrangement of carbon alkyl substituents. The Claisen
rearrangement appeared to be particularly well suited to meet
this challenge.20 As illustrated in Scheme 2, the synthesis of
the nonracemic Ireland-Claisen precursor 15 began with the
known oxidative cleavage of the diacetonide of D-mannitol, and
a direct Wittig olefination in methanol yielded a 9:1 (Z:E) ratio
of methyl esters leading to 12 (68% yield) after purification by
flash chromatography.21 Upon diisobutylaluminum hydride
(19) (a) Liu, G.; Smith, T. C.; Pfander, H. Tetrahedron Lett. 1995, 36,
4979–4982. (b) Renneberg, D.; Pfander, H.; Leumann, C. J. J. Org.
Chem. 2000, 65, 9069–9079.
Carboxylic acid 16 was transformed into the pivaloate (Piv)
19 of Scheme 3 in four straightforward steps (70% overall from
(20) For a leading reference: Ireland, R. E.; Wipf, P.; Armstrong, J. D. J.
Org. Chem. 1991, 56, 650–657.
(21) (a) Tronchet, J. M. J.; Gentile, B. HelV. Chim. Acta 1979, 62, 2091–
2098. (b) Mann, J.; Weymouth-Wilson, A. C. Org. Synth. 1997, 75,
139.
(22) Obtained via oxidation of (R)-(+)-citronellal (TCI, >95% (GC), [R]20
D
+12.5° (neat)). See: Muto, S.; Bando, M.; Mori, K. Eur. J. Org. Chem.
2004, 9, 1946–1952.
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Studies for the Synthesis of Xenicane Diterpenes
A R T I C L E S
Scheme 5. Diastereoselective Propargylation of Aldehyde 25a
Scheme 4. Transition State Analysis toward the Formation of 22
16), and esterification with formic acid led to 20 upon
introduction of the allylic bromide. Adaptation of the Nozaki-
Hiyama conditions23 provided facile intramolecular cyclization
to the lactol 22. To the best of our knowledge, Nozaki-Hiyama
cyclizations of formate esters have not been previously explored.
Our results suggest that this strategy offers versatility and
efficiency for the stereoselective synthesis of five- and six-
membered lactols and related derivatives.24 Indeed, high ste-
reocontrol at C1 was observed for the SE′ allylation via internal
coordination of the allylchromium species as suggested in 21
by the antiperiplanar disposition of HA and HB.
It is well-known that crotyl halides undergo reduction to form
(E)-allylic chromium(III) reagents regardless of the geometry
of the starting butene, and the chromium species coordinate
aldehydes for nucleophilic additions via closed six-membered
transition states.23 In Scheme 4, four possible arrangements are
featured for a detailed analysis of the intramolecular SE′ reaction.
The octahedral coordination complex of chromium is character-
ized by a combination of halogen (Cl, Br) and solvent (THF)
ligands (L) in addition to the reactive partners of the allylation
process. While our analysis does not consider boatlike transition
states, two chairlike arrangements, 21a and 21b, may account
for the formation of the observed diastereomer (1S)-22. The
trans-fused bicyclic 21a favorably illustrates complexation with
the carbonyl, which is synclinal with respect to the formate
hydrogen, and minimizes nonbonded interactions by pseu-
doequatorial placement of the highly branched C2 substituent.
Although the cis-fused transition state of 21b displays the large
pseudoaxial C2 substituent on the convex face of the bicycle,
the axial ligand LA may be destabilizing for electronic as well
a Reagents and conditions: (a) DIBAL, CH2Cl2, -78 °C, 96%; (b) TPAP,
NMO, 4 Å MS, CH2Cl2, 99%; (c) SnCl4, CH2Cl2, -78 °C; (d) propargyl
bromide, Mg0, HgCl2, Et2O, -20 °C, 96%, dr ) 84:16.
as steric reasons. Our considerations for the diastereofacial
reactions leading to the cis-disubstituted lactol (1R)-22 are
illustrated in 21c and 21d. The less stable, pseudoaxial disposi-
tion of the branched C2 substituent in 21c also appears to present
nonbonded interactions with axial LB (THF), and these consid-
erations become more severe in the cis-fused arrangement of
21d. Our spectroscopic characterization of the lactols 22 (1:1
ratio) provided no evidence of the ring-opened hydroxyaldehyde
tautomer, and the subsequent quantitative conversion of 22 to
the corresponding methyl acetals (Scheme 3) gave an inseparable
mixture of diastereoisomers 23a and 23b (dr 58:42). On the
other hand, the tri-isopropylsilyl ether 24 was formed with
excellent stereoselectivity (dr 91:9) and provided important
advantages for the simplicity of reaction and product analysis
in subsequent studies.
Upon preparation of aldehyde 25 (Scheme 5), we began
studies of SE′ allylation reactions with Lewis acid activation.
Our initial reactions with allylic silanes25 and allenylic stan-
nanes26 were undertaken to probe aspects of inherent diaste-
reofacial selectivity, which were not readily apparent from
Felkin-Anh modeling of 25. Unfortunately, a significant side
reaction was encountered with the production of the diastere-
omeric acetals 26 resulting from a facile Lewis acid-catalyzed
intramolecular Prins reaction and ketalization. Attempts to secure
C4 stereocontrol using nonracemic allenyl and allyl boron
(23) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179–3181. (b) Buse, C. T.; Heathcock, C. H. Tetrahedron
Lett. 1978, 19, 1685–1688. (c) Hiyama, T.; Kimura, K.; Nozaki, H.
Tetrahedron Lett. 1981, 22, 1037–1040. For reviews, see: (d) Cintas,
P. Synthesis 1992, 3, 248–257. (e) Fu¨rstner, A. Chem. ReV. 1999, 99,
991–1046.
(25) We have explored an SE′ allylation process to directly install the desired
(E)-trisubstituted alkenylsilane moiety required for 9 of Scheme 1 with
a high degree of stereocontrol. See: Williams, D. R.; Morales-Ramos,
´
A. I.; Williams, C. M. Org. Lett. 2006, 8, 4393–4396.
(26) For reviews of SE′ reactions of organostannanes: (a) Marshall, J. A.
Chem. ReV. 1996, 96, 31–48. (b) Williams, D. R.; Nag, P. P. Reactions
of SE′ Substitution for Organostannanes in Organic Synthesis. In Tin
Chemistry; Davies, A. G., Ed.; John Wiley & Sons: Chichester, 2008;
pp 515-560.
(24) Keck and coworkers have described SmI2-mediated intramolecular
reductive cyclization processes to afford 2-alkyl-2-methoxypyranyl
motifs. See: Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9, 1951–
1954.
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A R T I C L E S
Williams et al.
Scheme 7. Attempted Cyclization via C4-C5 Bond Formationa
Scheme 6. Functionalization of Alkyne 27a
a Reagents and conditions: (a) AlMe3, Cp2ZrCl2, CH2Cl2, 0 °C, 62%;
(b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 94%; (c) Me2SiSnBu3, Pd(PPh3)4,
THF, reflux, 85%; (d) I2,2,6-di-t-butyl-4-methylpyridine, CH2Cl2, -40 °C,
93%; (e) MeLi, Cul, THF, -20 °C, 98%; (f) NIS, CH3CN, room
temperature, 82%.
reagents27 displayed poor reactivity toward this sterically
congested aldehyde with slow conversion to many products.
These observations led to the use of allenylmagnesium bro-
mide28 as a reactive nucleophile, which proved to be operation-
ally efficient for preparative scale reactions. Ethereal solutions
of the Grignard reagent conveniently gave high yields of SE′
propargylation to afford the desired secondary alcohols (96%).
Moreover, the carbonyl addition proceeded with good diaste-
reofacial selectivity (dr 84:16), and subsequent flash chroma-
tography led to useful quantities of pure 27. This stereochemical
outcome is rationalized by the internal γ-coordination of the
divalent magnesium cation for SE′ delivery of the allenyl
nucleophile via a cyclic six-membered arrangement depicted
in 28, and the C4 stereochemistry of the secondary alcohol 27
was assigned by an advanced Mosher ester analysis.5
Our plans to utilize homopropargylic alcohol 27 for the
stereocontrolled synthesis of the desired (E)-alkenyliodide 31
(Scheme 6) examined the Negishi zirconium-catalyzed car-
boalumination methodology,29 which led to low conversions and
a number of side products. A major component of these attempts
was isolated and identified as the bicyclic ketal 29 resulting
from Lewis acid-catalyzed transketalization. Proton NMR
studies demonstrated a distinctive NOESY correlation of HA
and HB in 29, which offered additional confirmation of the C4
stereochemical assignment in 27. However, the participation of
a proximate propargylic or homopropargylic alcohol is known
to greatly improve yields in carboalumination reactions.29a,30
Thus, it was not surprising that ketal 29 was found to be
unreactive in further reactions to utilize this carboalumination
to elaborate the terminal alkyne. In addition, we explored several
a Reagents and conditions: (a) 23, 9-BBN, THF, room temperature, then
32, PdCl2(dppf), Cs2CO3, AsPh3, H2O, DMF, 60% (unopt.); (b) Bu4N+
Ph3SiF2-, AcOH, THF, 93%; (c) I2, PPh3, imidazole, CH2Cl2; (d) sodium
tolylsulfinate, DMF, room temperature, 86% (two steps); (e) DIBAL,
CH2Cl2, -78 °C; (f) Dess-Martin periodinane, pyr, CH2Cl2, 94% (two
steps); (g) DIBAL, CH2Cl2, -78 °C, 97%; (h) Dess-Martin periodinane,
pyr, CH2Cl2, 93%; (i) SmI2, THF, -78 °C.
protecting groups for the C4 alcohol in 27, and we observed
very slow, low yielding conversions to the desired alkenyl
iodide, as well as other byproducts, in these attempts to apply
the Negishi protocol. To resolve these issues, the O-silylation
of 27 and subsequent application of a regioselective syn-
silylstannylation as described by RajanBabu and co-workers31
was undertaken yielding 30. A convenient three-step protocol
from 30 cleanly allowed for the sequential replacement of
stannyl and silyl substituents with complete retention of olefin
geometry to give the (E)-trisubstituted alkene of 31. Although
this sequence has added three steps to our overall route, it is
particularly noteworthy that these reactions can be efficiently
applied as a general solution, which is amenable to preparative
scale processes.
Our studies of the B-alkyl Suzuki cross-coupling reaction32
initially explored the reactivity of alkene 23 (Scheme 3), which
was submitted for selective hydroboration at 22 °C. Coupling
with the known iodide 3233 (Scheme 7) was observed to give
(31) (a) Apte, S.; Radetich, B.; Shin, S.; RajanBabu, T. V. Org. Lett. 2004,
6, 4053–4056. (b) Chenard, B. L.; Laganis, E. D.; Davidson, F.;
RajanBabu, T. V. J. Org. Chem. 1985, 50, 3667–3669. (c) Mitchell,
T. N.; Wickenkamp, R.; Dicke, A. R.; Schneider, U. J. Org. Chem.
1987, 52, 4868–4874.
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483–486. (b) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc.
1989, 111, 5495–5496.
(28) (a) Hopf, H.; Bo¨hm, I.; Kleinschroth, J. Org. Synth. 1981, 60, 41. (b)
Yamamoto, H. Comp. Org. Synth. 1991, 2, 81–98.
(32) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Sato, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–321. For a review, see:
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544–4568.
(29) (a) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org.
Chem. 1981, 46, 4093–4096. (b) Wipf, P.; Lim, S. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1068–1071.
(33) Lipshutz, B. H.; Lee, C.-T.; Servesko, J. M. Org. Lett. 2007, 9, 4713–
4716.
(30) Tius, M. A.; Trehan, S. J. Org. Chem. 1986, 51, 765–767.
9
9042 J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009

Studies for the Synthesis of Xenicane Diterpenes
A R T I C L E S
Scheme 8. Initial Studies of B-Alkyl Suzuki Macrocyclizationa
33 in 60-65% unoptimized yields using PdCl2(dppf), the most
widely selected palladium catalyst and reaction conditions for
B-alkyl Suzuki processes. The convenient preparation of the
diol derivative 33 presented obvious opportunities to explore
(E)-cyclononene formation. One approach was examined by the
conversion of 33 into the aldehydic sulfone 34 as a precursor
for an intramolecular Julia condensation. Our previous syntheses
of dolabelladienones have described Julia condensations for
direct ring closures leading to the formation of 11-membered
carbocycles.34 In addition, two unrelated examples of the use
of R-sulfonyl carbanions in cyclization reactions leading to (E)-
cyclononenes have also been reported. A novel intramolecular
transacylation strategy was devised for the synthesis of (()-
caryophyllene by Oishi and co-workers,35 and Corey has
described the successful capture of a π-allyl palladium inter-
mediate via a ꢀ-ketosulfone for the recent total synthesis of
antheliolide A.36 Based on these encouraging reports, the allylic
sulfone 34 was prepared from 33 (Scheme 7) by desilylation
and subsequent displacement using sodium tolylsulfinate prior
to deprotection and oxidation. Unfortunately, our efforts to
obtain the cyclic ꢀ-hydroxysulfones 35 upon treatment with
various bases only resulted in the recovery of starting 34 despite
evidence of R-sulfonyl carbanion formation via deuterium
incorporation. As an alternative, we examined a reductive
coupling strategy toward an effective closure by the straight-
forward conversion of 33 into the dialdehyde 36 (Scheme 7).
Our previous studies for the total synthesis of (+)-4,5-
deoxyneodolabelline demonstrated the use of [V2Cl3(THF)6]-
ZnCl6 for reductive coupling leading to nine-membered
syn-diol formation.37 However, the application of this vanadium-
based pinacol reaction, in addition to experiments utilizing
McMurry conditions,38 with dialdehyde 36 led to the formation
of many products. Reactions of samarium diiodide39 with 36
produced the anticipated cycloheptanol 37 as an inseparable
mixture of diastereomers.
a Reagents and conditions: (a) 9-BBN (4 equiv), THF, 40 °C, then
PdCl2(dppf), TlOEt, AsPH3 THF/DMF/H2O (6:3:1), 60 °C; then TBAF,
THF, 0 °C; (b) TBAF, THF, 0 °C, 95%; (c) PPTs, MeOH, room temperature,
99%; (d) 9-BBN (1.2 equiv), THF, 0 °C to room temperature, then
PdCl2(dppf), TlOEt, AsPh3, THF/DMF/H2O (6:3:1), 60 °C.
Concomitant studies of the intramolecular B-alkyl Suzuki
cross coupling40 of 31 began to show promise (Scheme 8). Our
initial reactions produced low yields (10-15%) of (E)-cy-
clononene product 38, and small improvements were observed
with the additions of thallium(I) ethoxide41 and triphenylarsine.
However, we noted a substantial difference in the rate of
hydroboration of 31 as compared to the corresponding methyl
acetals 39 (Scheme 8).
(34) (a) Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P. Angew.
Chem., Int. Ed. 2007, 46, 915–918. (b) Williams, D. R. Synthesis
Studies of Dolabellanes and Transannular Processes Leading to Related
Diterpenes. In Strategies and Tactics in Organic Synthesis; Harmata,
M., Ed.; Elsevier: Amsterdam, 2008; Vol. 7, pp 243-267.
(35) Ohtsuka, Y.; Niitsuma, S.; Tadokoro, H.; Hayashi, T.; Oishi, T. J.
Org. Chem. 1984, 49, 2326–2332.
(36) Mushti, C. S.; Kim, J.-H.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
14050–14052.
(37) (a) Williams, D. R.; Heidebrecht, R. W. J. Am. Chem. Soc. 2003, 125,
18431850]. (b) Generated by reduction of VCl3(THF)3 with zinc
dust: Freudenberger, J. H.; Konradi, A. W.; Pedersen, S. F. J. Am.
Chem. Soc. 1989, 111, 8014–8016.
(38) (a) McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989, 54,
3748–3749. (b) For recent reviews: Ephritikhine, M. J. Chem. Soc.,
Chem. Commun. 1998, 2549–2554.
(39) For a review, see: Molander, G. A. Chem. ReV. 1992, 92, 29–68.
(40) (a) Miyaura, N.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992,
33, 2571–2574. (b) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000, 2,
2687–2690. (c) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2,
2695–2698.
Figure 2. Hydroboration studies.
These evaluations are summarized in Figure 2 and illustrate
results for hydroboration with complete consumption of starting
material followed by the usual basic oxidative quench. The
(41) (a) Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem.
Soc. 1987, 109, 4756–4758. (b) Frank, S. A.; Chen, H.; Kunz, R. K.;
Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691–2694.
9
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A R T I C L E S
Williams et al.
Scheme 9. Optimization of B-Alkyl Suzuki Cyclizationa
Figure 3. Ring conformers of 43 and 4.
Scheme 10. Completion of the Total Synthesis of 4a
a Reagents and conditions: (a) 9-BBN (1.5 equiv), THF, room temper-
ature, 12 h, then Pd(PPh3)4 (0.5 equiv), NaOH (5.0 equiv), CH3CN/H2O
(15:1) [0.005 M], 85 °C, 18 h; then aq AcOH, THF, 85 °C, 66%, dr )
80:20 at C19; (b) TPAP, NMO, 4 Å mol. sieves, CH2Cl2, 79%.
triisopropylsiloxy acetal 31 (entry 1) reacted slowly and required
excess reagent at elevated temperature for 72 h. An analysis of
the product distribution confirmed a competing hydroboration
of the trisubstituted C13-C14 alkene, which led to substantial
amounts of the C8, C13 diol (product C). Our modeling of 31
suggested that the remote silyl ethers at C4 and C19 imposed
considerable steric hindrance blocking access to each face of
the terminal olefin. Indeed, the removal of either of these silyl
protecting groups led to more favorable reaction conditions and
the chemoselective production of the expected primary alcohol
(product A of Figure 2; see entries 2 and 3).
Based on these results, the B-alkyl Suzuki cyclization of 40
(Scheme 8) was examined with an improved outcome, which
generated approximately 65% mass recovery of the crude
product 42 after flash silica gel chromatography. However, the
starting alcohol 40 was susceptible to the internal ketalization
as previously noted with the isolation of 29 of Scheme 6, and
the cyclononene 42 demonstrated instability requiring repeated
chromatography with diminishing yields. Thus, optimizations
of the cyclization process focused on 39, and modest incremental
improvements, including the use of thallium carbonate, aqueous
THF (10:1 by volume), and optimized dilution conditions,
afforded reproducible and scalable reactions at room temperature
leading consistently to 30% yields of pure 41. Higher catalyst
loading of PdCl2(dppf) and reaction attempts that screened a
selection of other related catalysts did not lead to improved
yields. On the other hand, a significant breakthrough was
achieved when we explored the use of Pd(PPh3)4 as a catalyst
for the Suzuki cyclization event (Scheme 9). Adapting conditions
as described by Nakada and co-workers,42 the ring closure of
39 proceeded with surprising efficiency, and the crude product
was treated with aqueous acetic acid to yield the diastereomeric
lactols 38 (66% yield) after silica gel chromatographic purifica-
tion. Subsequent oxidation of 38 under mild conditions produced
the trans-fused cyclononene lactone 43.
a Reagents and conditions: (a) LDA, THF, -78 °C, then PhSeBr; (b)
mCPBA, CH2Cl2, -78 °C, then Et3N, then warm to room temperature, 89%
(two steps); (c) TBAF, THF, 40 °C, 83%; (d) LDA, THF, -78 °C, then
PhSeBr; (e) mCPBA, CH2Cl2, -78 °C, then Et3N, then warm to room
temperature, 55% (two steps).
Our studies leading to the characterization of 43 suggested
substantial conformational rigidity in this carbocyclic frame-
1
work. Key NOESY correlations obtained from the H NMR
data are illustrated in Figure 3. Our conclusions parallel
observations of the natural product itself, which exists as two
slowly equilibrating ring conformers 4a (major) and 4b (minor)
at 23 °C (ratio 95:5).6b
The completion of the synthesis of 4-hydroxydictyolactone
(4) required a final oxidation for introduction of the C1/C9
unsaturation from cyclononene 43. As shown in Scheme 10,
the syn-elimination of an intermediate selenoxide proved to be
the most effective choice for this task. In fact, kinetic depro-
tonation of 43 led to a single phenylselenide (89% yield), and
low temperature oxidation quantitatively produced the skipped
cyclononadiene 44. Unfortunately, rapid decomposition of 44
was observed under basic conditions of fluoride-induced desi-
lylation, whereas 44 was found to be remarkably robust under
acidic conditions. Finally, the total synthesis of 4 was completed
(42) Kawada, H.; Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada, M. Org.
Lett. 2004, 6, 4491–4494.
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Studies for the Synthesis of Xenicane Diterpenes
A R T I C L E S
via the initial deprotection of the C4 silyl ether 43, which was
followed by formation of the R-phenylselenide 45 and oxidative
elimination. Synthetic 4 proved to be identical in all respects,
with the exception of optical rotation data, to naturally occurring
4-hydroxydictyolactone by comparisons with NMR spectra and
HRMS data, which were kindly provided by Professor Graziano
Guella.43
example of the xenicane family of marine diterpenes. Key
features of our investigation include the use of an intramolecular
Nozaki-Hiyama reductive SE′ allylation of a formate ester for
the facile stereoselective synthesis of five-membered lactols as
well as an example of γ-chelation for an internally directed SE′
propargylation using allenylmagnesium bromide. Finally, our
studies have documented the development of the B-alkyl Suzuki
cross-coupling reaction as a useful strategy for cyclizations to
directly afford complex (E)-cyclononene systems.
In conclusion, we have reported an efficient, enantiocontrolled
total synthesis of 4-hydroxydictyolactone (4), a prototypical
Acknowledgment. This work is dedicated to Professor E. J.
Corey for his pioneering efforts toward the caryophylloid terpenes.
We gratefully acknowledge Indiana University for financial support
of our work, as well as partial support from the National Institutes
of Health (GM-42897).
(43) We gratefully acknowledge Professor Graziano Guella of the Uni-
versity of Trento for his timely assistance in providing detailed
authentic 1H and 13C NMR spectra and HRMS data for the natural
product 4. Although our synthetic material precisely matched the NMR
spectra and the HRMS data for 4-hydroxydictyolactone, we report
some disparity for the data recorded for optical rotations. Guella and
Pietra (ref 6b) have described the optical rotation of naturally occurring
4 ([R]25D-247° (c 0.17, CCl4)), whereas Tanaka and Higa (ref 3a)
had previously obtained a sample of 4 ([R]D-153° (c 2.01, CHCl3))
via the hydride reduction and Fetizon oxidation of 4-hydroxydictyodial.
Although we have no reason to doubt the purity of our samples (>95%
purity), our optical rotation data for synthetic 4 ([R]22D-175° (c 0.13,
CCl4)) did not agree with the isolation reports.
Supporting Information Available: Full experimental details.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA902677T
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J. AM. CHEM. SOC. VOL. 131, NO. 25, 2009 9045