The synthesis of velloziolide via Nicholas reaction based γ-carbonyl cations

Article abstract of DOI:10.1021/jo901471b

(Chemical Equation Presented) The total synthesis of the 9,11-seco-rosane diterpene velloziolide (1) has been accomplished by employing the Nicholas reaction chemistry of 2a as a γ-carbonyl cation equivalent. An initial model study demonstrated the utilit

Full text of DOI:10.1021/jo901471b

pubs.acs.org/joc
The Synthesis of Velloziolide via Nicholas Reaction Based γ-Carbonyl
Cations
James R. Green* and Andy A. Tjeng
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, Canada
jgreen@uwindsor.ca
Received July 9, 2009
The total synthesis of the 9,11-seco-rosane diterpene velloziolide (1) has been accomplished by
employing the Nicholas reaction chemistry of 2a as a γ-carbonyl cation equivalent. An initial model
study demonstrated the utility of Nicholas reactions of 2 in the generation of 4-arylalkynoate-
Co2(CO)6 complexes, and in conjunction with Gilman cuprate addition and Johnson-Claisen
rearrangement chemistry, the preparation of a 3-methyl-3-vinyl-4-arylalkanoate model for vellozio-
lide. The Nicholas reaction/γ-carbonyl cation methodology was then employed twice in the total
synthesis to incorporate onto 3,4-methylenedioxytoluene the 4-carbon unit that became the gem-
dimethyltetralin portion of the velloziolide and, subsequently, to incorporate the γ-arylalkanoate
function of the ε-lactone.
Introduction
Our group was attracted to velloziolide by virtue of our
continued interest in the chemistry of γ-carbonyl cation
equivalents,7-10 normally based on transition-metal-stabi-
lized cations.7,8 Of particular relevance is our work on the
Nicholas reaction chemistry11 of 4-hydroxyalkynoate-Co2(CO)6
Velloziolide (1) is a diterpene isolated from the Brazilian
plant Vellozia candida Mikan,1 which possesses an unusual
9,11-seco-rosane skeleton. Its biological activity is unre-
ported, although the crude extracts of this plant and other
seco-rosanes isolated from Vellozia candida show activity in
bioassays as DNA-damaging agents.2 Velloziolide is also
noteworthy for the benzo-fused ε-lactone unit contained
within its structure; this function is encountered more fre-
quently, being present in the floresolides,3 in amarulone,4
and in urdamycin L.5 Velloziolide has never been synthesized
successfully; Marco and Rodriguez have prepared a bicyclic
ester analogue with the correct carbon connectivity but were
unable to remove the phenolic methyl ether protecting
groups.6
(7) (a) Vizniowski, C. S.; Green, J. R.; Breen, T. L.; Dalacu, A. V. J. Org.
Chem. 1995, 60, 7496–7502. (b) Green, J. R. Chem. Commun. 1998, 1751–
1752. (c) Taj, R. A.; Green, J. R. Synlett 2009, 292–296.
(8) For γ-carbonyl cation equivalents by way of iron allyl and dienyl cations,
see: (a) Green, J. R.; Carroll, M. K. Tetrahedron Lett. 1991, 32, 1141–1144.
(b) Zhou, T.; Green, J. R. Tetrahedron Lett. 1993, 34, 4497–4950. (c) Charlton,
M. A.; Green, J. R. Can. J. Chem. 1997, 75, 965–974. (d) Enders, D.; Jandeleit, B.;
Von Berg, S. Synlett 1997, 421-431 and references therein. (e) Pearson, A. J.
Adv. Met.-Org. Chem. 1988, 1, 1-49, and references therein. (f) Pearson, A. J.
Iron Compounds in Organic Synthesis; Academic: London, 1994; Chapter 5.
(9) For γ-carbonyl cation equivalents by way of π-allylpalladium com-
plexes, see: (a) Nemoto, T.; Fukuda, T.; Matsumoto, T.; Hitomi, T.;
Hamada, Y. Adv. Synth. Catal. 2005, 347, 1504–1506. (b) Nemoto, T.; Fukuda,
T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 4365-4368 and references therein.
(10) For γ-carbonyl cation equivalents by way of carbonyl-substituted
cyclopropanes, see: (a) Lifchits, O.; Alberico, D.; Zakharian, I.; Charette, A. B.
J. Org. Chem. 2008, 73, 6838-6840 and references therein. (b) Harrington, P. A.;
Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949–5952. (c) Danishefsky, S. Acc.
Chem. Res. 1979, 12, 66–72.
*To whom correspondence should be addressed. E-mail: jgreen@uwindsor.
ca. Phone: (519)-253-3000, Ext. 3545. Fax: (519)-973-7098.
(1) Pinto, A. C.; Gonc-alves, M. L. A.; Filho, R. B.; Neszmely, A.; Lukacs,
G. J. Chem. Soc., Chem. Commun. 1982, 293–295.
(2) Valente, L. M. M.; Gunatilaua, A. A. L.; Kingston, D. G. I.; Patitucci,
M. L.; Pinto, A. C. J. Nat. Prod. 1997, 60, 478–481.
(3) (a) Issa, H. H.; Tanaka, J.; Rachmat, R.; Higa, T. Tetrahedron Lett.
2003, 44, 1243–1245. (b) Briggs, T. F.; Dudley, G. B. Tetrahedron Lett. 2005,
46, 7793–7796. (c) Nicolaou, K. C.; Xu, H. Chem. Commun. 2006, 600–602.
(4) Foo, L. Y. Nat. Prod. Lett. 1993, 3, 45–52.
(11) For recent reviews dedicated to the Nicholas reaction, see: (a) Diaz,
D. D.; Betancort, J. M.; Martin, V. S. Synlett 2007, 343–353. (b) Teobald, B.
J. Tetrahedron 2002, 58, 4133–4170. (c) Green, J. R. Curr. Org. Chem. 2001, 5,
809–826. For reviews covering Nicholas reactions in part, see: (d) Fletcher,
A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000, 1657–1668.
€
(e) Welker, M. E. Curr. Org. Chem. 2001, 5, 785–807. (f) Muller, T. J. J. Eur. J.
(5) (a) Rix, U.; Remsing, L. L.; Hoffmeister, D.; Bechthold, A.; Rohr, J.
ChemBioChem 2003, 4, 109–111.
(6) Marco, J. L.; Rodriguez, B. An. Quim. 1985, 81, 80–82.
Org. Chem. 2001, 2021–2033. (g) Omae, I. Appl. Organomet. Chem. 2007, 21,
318–344. (h) Green, J. R. Eur. J. Org. Chem. 2008, 6053–6062. (i) Bromfield,
ꢀ
K. M.; Graden, H.; Ljungdahl, N.; Kann, N. Dalton Trans. 2009, 5051–5061.
DOI: 10.1021/jo901471b
r
Published on Web 09/01/2009
J. Org. Chem. 2009, 74, 7411–7416 7411
2009 American Chemical Society

Green and Tjeng
JOCArticle
SCHEME 1. Retrosynthetic Analysis of Velloziolide
derivatives,7 as the derived propargyldicobalt cations pos-
sess sufficient stability despite the remote electron-withdraw-
ing group substitution and yet have sufficient electrophilicity
to undergo reaction with electron-rich arenes.12 Since we
consider the most compelling structural feature of vellozio-
lide to be the β,β-disubstituted γ-aryl lactone unit, retro-
synthetically the Nicholas reaction/γ-carbonyl cation chemis-
try is well positioned for the incorporation of this portion of
vellioziolide (A, Scheme 1). There is additional relevance of
this chemistry to velloziolide by virtue of the gem-dimethyl-
tetralin also present in the natural product. This structural
unit (B) is one which also is expected to be readily accessible
by γ-carbonyl cation chemistry, based on the assumption
that the gem-dimethyl function could be derived from a
tertiary alcohol, whose source would in turn be an ester
function (C).
TABLE 1. Reactions of 2 with Aromatic Nucleophilesa
2
nucleophile
4-methoxytoluene
4-methoxytoluene
product, yield (%)
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2a
3a, 81
3a, 91b
3b, 64
3c, 39
3d, 53c
3e, 61
3f, 57
3g, 68
3h, 61
3i, 77
3j, 52
3k, 78
3l, 65
4-benzyloxytoluene
4-(4-nitrobenzyloxy)toluene
4-(4-triisopropylsiloxy)toluene
1-hexyl-4-methoxybenzene
1,4-dimethoxybenzene
1,3,5-trimethoxybenzene
4-methoxytoluene
1,3,5-trimethoxybenzene
1,4-dimethoxybenzene
4-methoxytoluene
Results and Discussion
3,4-dimethoxytoluene
As the necessity of ultimately incorporating a γ-carbonyl
cation equivalent ortho to a para-substituted phenol deriva-
tive is an essential consideration in the synthesis of vellozio-
lide, we considered it of importance to investigate the Lewis
acid induced substitution reactions of simple para-substi-
tuted phenol derivatives with 4-methoxyalkynoate-Co2(CO)6
complexes (2a-c) (Table 1). Our initial choice of substrate,
4-methoxytoluene, underwent condensation with 2a only
sluggishly in the presence of BF3-OEt2 (rt, 24 h, 22% yield),
as has been observed in our group in related cases of
Nicholas reaction precursors bearing remote Lewis basic
functions.7b Conversely, in the presence of Bu2BOTf (0 °C,
CH2Cl2, 1 h), reaction occurred rapidly and without com-
plication, affording 3a in 81% yield using a modest excess
(1.5 equiv) of arene (Table 1). While the yield of 3a could
be increased further using a greater excess of arene (91% at
2.5 equiv of 4-methylanisole) under otherwise identical
reaction conditions, we made the choice to impose a limit
of 1.5 equiv in further experiments. Alternatives to methyl
substitution on the phenol were less successful; while acetoxy
and methoxymethyl derivatives of 4-methylphenol gave no
condensation product whatsoever, 4-benzyloxytoluene affor-
ded 3b in moderate yield (64%). Use of the more electron-
deficient p-nitrobenzyl (PNB)-protected 4-(4-nitrobenzyloxy)-
toluene did not improve the results for condensation; in fact,
aReactions carried out with 2a-c, arene (1.5 equiv), Bu2BOTf (1.0
equiv), at 0 °C in CH2Cl2 for 1 h. bCarried out using 2.5 equiv of arene.
cReaction conducted in the presence of molecular sieves with inverse
addition of 2a to a solution of Lewis acid and arene.
the condensation product 3c appeared to be somewhat
unstable to the reaction conditions and could be isolated
only in poor yield (3c, 39%). Conversely, reaction of TIPS-
protected 4-(triisopropylsiloxy)toluene did give a fair yield of
condensation product 3d under slightly modified conditions
involving the presence of molecular sieves, but the silyl
function was lost from the phenol (3d, 53% yield). The
additional of a base (iPr2NEt) did not suppress this loss of
the phenolic silyl function.13
Since neither benzyl, PNB, nor TIPS phenolic protecting
groups were superior to a methyl group for the Nicholas
reaction chemistry of 2a, the remaining methodological
examples were examined on phenolic methyl ethers. Repla-
cing the para-methyl function by n-hexyl- (1-hexyl-4-meth-
oxybenzene) or methoxy (1,4-dimethoxybenzene) functions
allowed the formation of 3e (61%) and 3f (57%) in accep-
table yields, while use of 1,3,5-trimethoxybenzene as nucleo-
phile gave a reasonable yield of 3g (68%). Substitution of
the alkynedicobalt complex with a methyl function at the
(12) (a) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 900–
907. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(13) TMS or TBS protecting groups gave lower yields of condensation
products.
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SCHEME 2. Preparation of Model γ-Arylalkanoate 7
SCHEME 3. Preparation of gem-Dimethyltetralin 13
propargylic reaction site (2b) resulted in only trace amounts
of competition from methanol elimination from 2b; conse-
quently, the adducts with 4-methoxytoluene (3h, 61%),
1,3,5-trimethoxybenzene (3i, 77%), and 1,4-dimethoxyben-
zene (3j, 52%) were formed in acceptable yields. In addition,
phenyl-substituted alkynedicobalt complex 2c reacted with
4-methoxytoluene to give 3k without complication (78%).
Finally, 3,4-dimethoxytoluene, which we considered to be a
model substrate for the gem-dimethyltetralin unit of vello-
ziolide, reacted with 2a to give 3l in 65% yield.
We chose 4-methoxytoluene condensation product 3a as a
model to study the creation of the γ-aryl, β,β-disubstituted
ester function of velloziolide. Removal of the dicobalt unit
from the alkyne function proceeded poorly with several of
the conventional decomplexation reagents (CAN, Me3NO)
but was readily accomplished with I2 in THF (4, 97%)
(Scheme 2). Conjugate addition to 4 with Gilman cuprate
Me2CuLi incorporated the β-methyl group cleanly, giving 5
as its Z-isomer (75%). The identification of 5 as the Z-isomer
was supported by the 1H NMR NOESY cross-peak between
the vinylic proton (δ 5.81) and the methyl function β to the
ester (δ 1.78). Conversely, 5 was not susceptible to conjugate
addition by either vinylcuprate14 or rhodium-catalyzed alkenyl-
borane chemistry15 and was recovered unchanged upon
these attempted reactions. As a result, a synthetic equivalent
of β-vinylation was accomplished by reduction of the ester
function to allylic alcohol 6; when 6 was subjected to heating
with triethyl orthoacetate and a catalytic amount of propio-
nic acid in xylenes at reflux, it underwent a Johnson-Claisen
rearrangement16 to give 7 (61% yield from 5).
With this protocol in hand, attention was turned to the
synthesis of velloziolide itself. Given the difficulty in pheno-
lic methyl ether deprotection in the Marco and Rodriguez
approach,6 we chose to employ 3,4-methylenedioxytoluene
(8) as a starting material. Under the previously outlined
conditions, compound 8 underwent Nicholas reaction chem-
istry with 2a in good yield (9, 85%) (Scheme 3). Decom-
plexation of 9 with I2/THF was straightforward, affording
10 in excellent yield (89%). Catalytic hydrogenation of the
alkyne function was sluggish under catalysis with Pd/C but
proceeded cleanly over Rh/C to give 11 (96%). Reaction with
excess methyllithium gave tertiary alcohol 12, which as the
crude reaction product was subjected to reaction with excess
(14) (a) Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318–
7319. (b) House, H. L.; Chu, C.-Y.; Wilkens, J. M.; Umem, M. J. J. Org.
Chem. 1975, 40, 1460–1469. (c) Fujisawa, T.; Sato, T.; Kawara, T.; Kawashima,
M.; Shimizu, H.; Ito, Y. Tetrahedron Lett. 1980, 21, 2181–2184. (d) Tamura,
R.; Tamai, S.; Katayama, H.; Suzuki, H. Tetrahedon Lett. 1989, 30, 3685–
3688.
(16) (a) Langlois, Y. In The Claisen Rearrangement; Hiersemann, M., Nubbe-
meyer U., Eds.; Wiley-VCH: Weinheim, Germany; Chapter 6. (b) Castro, A. M. M.
Chem. Rev. 2004, 104, 2939–3002. (c) Nebbemeyer, U. Synthesis 2003, 961–1008.
(15) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229–4231. (b) Hayashi, T. Synlett 2001, 879–887.
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SCHEME 4. Synthesis of Velloziolide
followed by subjecting the crude reaction product to wet
AgNO3;18 under these conditions, velloziolide could be
isolated in 82% yield. Synthetic 1 was found to be identical
to natural velloziolide based on a comparison of physical
and spectral data, save for the optical activity of the natu-
ral product.
In conclusion, velloziolide has been prepared from 2a and
3,4-methylenedioxytoluene (8) in 10 steps in 25% overall
yield. The Nicholas reaction chemistry of 4-methoxy-2-
alkynoate-Co2(CO)6 complexes 2 is effective in condensation
reactions with electron-rich aromatic nucleophiles, requiring
only a modest excess of nucleophile to give acceptable yields
when multiple arene C-H are present, and giving excellent
yields when only one substitution is possible. As a result, 2a is
useful in the construction of both the dimethylcyclohexene
and ε-lactone rings of velloziolide, without the need for the
one-carbon extension reactions often required for umpolung
functional group relationships.
Experimental Section
Hexacarbonyl[μ-η4-(methyl 4-(2-methoxy-5-methylphenyl)-2-
butynoate)]dicobalt (3a). General Procedure A:. To a solution of
2a (0.4909 g, 1.19 mmol) and 4-methoxytoluene (0.23 mL, 1.8 mmol)
in CH2Cl2 (40 mL) at 0 °C was added dibutylboron triflate
(1 M in CH2Cl2, 1.20 mL, 1.2 mmol) slowly. The reaction
mixture was stirred at 0 °C for 1 h. Addition of saturated
NH4Cl(aq) and a conventional extractive workup (CH2Cl2),
followed by column chromatography (10:1 petroleum ether/
diethyl ether), gave 3a (0.4870 g, 81% yield) as a red-brown
BF3-OEt2, resulting in cyclization to the gem-dimethylte-
trahydronaphthalene 13 (78% yield from 11).
With the carbocyclic ring system constructed, attention
was now turned to the incorporation of the β-arylalkanoate/
ε-lactone portion of velloziolide. Since the prospect of poly-
alkylation by 13 no longer existed, it was subjected to Bu2-
BOTf-mediated reaction with slight excess (1.2 equiv) of 2a,
and the crude reaction mixture was subjected to the oxidative
decomplexation conditions (I2, THF). Under this protocol,
compound 14 was formed in excellent yield (92% from 13)
(Scheme 4). Conjugate addition of Me2CuLi occurred to give
15 cleanly (95% yield), with the Z-isomer present exclusively
within the 1H NMR detection limits, provided the reaction
was conducted in THF.17 Compound 15 behaved similarly to
5 in its reluctance to undergo conjugate addition, while
reduction of 15 (Z-isomer) with DIBAL-H gave the allyl
alcohol readily (16, quantitative). While use of the exact
conditions previously employed for Johnson-Claisen reac-
tion only gave small amounts of 17 when applied to 16, the
use of triethyl orthoacetate as solvent afforded 17 in accep-
table yield (63%).
Final removal of the methylenedioxy protecting group
required slightly specialized conditions. Attempted depro-
tection of 17 with BBr3 gave nonproductive decomposi-
tion. The use of BCl3 in reaction with 17 gave a mixture of
velloziolide (1) and chloromethylated 18, the latter as
evidenced by an additional δ 6.09 singlet in the 1H NMR
spectrum, and presence of m/e 362/364 in the mass spec-
trum of the crude reaction product. Consequently, the
final protocol involved the reaction of 17 with BCl3,
oil: IR (KBr) νmax 2952, 2098, 2062, 2029, 1710 cm-1 1H
;
NMR δ 7.05 (dd, J=1.9, 8.3 Hz, 1H), 7.00 (d, J=1.9 Hz, 1H),
6.76 (d, J=8.3 Hz, 1H), 4.11 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H),
2.29 (s, 3H); 13C NMR δ 198.2, 170.8, 154.8, 131.6, 129.6,
128.7, 127.5, 110.0, 101.1, 78.5, 54.6, 52.8, 33.4, 20.3; MS m/e
476 (M - COþ), 448 (M - 2COþ), 420 (M - 3COþ), 392 (M -
4COþ), 364 (M - 5COþ); HRMS m/e for C19H14Co2O9 calcd
475.9353 (M - COþ), found 475.9365.
Methyl 4-(2-methoxy-5-methylphenyl)-2-butynoate (4): To
a solution of 3a (0.3698 g, 0.0.733 mmol) in THF (30 mL) was
added excess iodine (1.5 g). The solution was stirred for 10 h at
room temperature. The solution was treated with NaHSO3(aq)
and subjected to a conventional extractive workup (Et2O).
Radial chromatography (15:1 petroleum ether/Et2O) gave 4
(0.1554 g, 97% yield) as a colorless oil: bp 90-95 °C (0.2 Torr)
(bulb-to-bulb); IR (KBr) νmax 3003, 2925, 2240, 1717 cm-1; 1H
NMR δ 7.23 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.6, 8.3 Hz, 1H),
6.78 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.71 (s, 2H),
2.33 (s, 3H); 13C NMR δ 154.5, 154.2, 129.8, 129.6, 128.6,
122.1, 110.1, 87.4, 74.0, 55.4, 52.5, 20.4, 19.3; MS m/e 218
(Mþ); HRMS m/e for C13H14O3 calcd 218.0943 (Mþ), found
218.0945.
(Z)-Methyl 4-(2-methoxy-5-methylphenyl)-3-methyl-2-butenoate
(5): To a suspension of CuI (0.248 g, 1.30 mmol) in THF (10 mL)
at 0 °C was added MeLi (1.6 mL of a 1.6 M solution in Et2O).
After stirring for 15 min, the solution was cooled to -78 °C, and
a solution of 4 (0.1895 g, 0.868 mmol) in THF (10 mL) was
added slowly. Following stirring at -78 °C for 2 h, saturated
NH4Cl(aq) was added, and a conventional extractive workup
(Et2O) was performed. Preparative TLC (20:1 hexanes/Et2O)
afforded 5 (0.1521 g, 75% yield) as a colorless oil: bp 95-100 °C
(0.1 Torr) (bulb-to-bulb); IR (KBr) νmax 2948, 1716, 1652 cm-1
;
1HNMRδ6.99(d, J=8.0Hz, 1H), 6.96(s, 1H),6.76(d,J=8.0Hz,
1H), 5.81 (d, J = 1.3 Hz, 1H), 4.06 (s, 2H), 3.80 (s, 3H), 3.74
(s, 3H), 2.26 (s, 3H), 1.78 (d, J=1.3 Hz, 3H); 13C NMR δ 166.9,
158.9, 155.5, 130.6, 129.7, 127.7, 126.9, 116.5, 110.3, 55.4, 50.8,
(17) The use of Et2O as solvent also allowed the conjugate addition
process to proceed (89% yield) but gave an isomeric mixture of 15 (Z:E =
14:86).
(18) De Amorim, M. B.; da Silva, A. J. M.; Costa, P. R. R. J. Braz. Chem.
Soc. 2001, 12, 346–353.
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Green and Tjeng
JOCArticle
32.2, 24.4, 20.5; MS m/e 234 (Mþ); HRMS m/e for C14H18O3
calcd 234.1256 (Mþ), found 234.1253.
extractive workup (Et2O). The crude reaction product was
dissolved in CH2Cl2 (35 mL) and cooled to 0 °C. BF3-OEt2
(4.0 mL, 15 equiv) was added, and the solution was stirred at
0 °C for 0.5 h followed by rt for 1 h. Following the addition of
H2O and a conventional extractive workup (CH2Cl2), prepara-
tive TLC (50:1 hexanes/Et2O) gave 13 (0.3703 g, 78% yield) as a
colorless oil: bp 90-95 °C (0.1 Torr) (bulb-to-bulb); IR (KBr)
Ethyl 3-(2-methoxy-5-methylbenzyl)-3-methyl-4-pentenoate (7):
To a solution of 5 (0.1405 g, 0.600 mmol) in Et2O(15 mL) at-78 °C
was added DIBAL-H (1.8 mL of a 1 M solution in hexanes). The
solution was allowed to warm to rt for 1 h, at which time the solution
was recooled to -78 °C and H2SO4 (1 M) was added. Following a
conventional extractive workup (Et2O), the residue was dissolved in
xylenes (15 mL), and propionic acid (10 μL) and triethyl orthoace-
tate (0.44 mL, 2.4 mmol) were added. The solution was heated to
reflux for 15 h, and after cooling, the volatiles were removed under
reduced pressure. Preparative TLC (10:1 hexanes/Et2O) afforded 7
(0.1016 g, 61% yield) as a colorless oil: bp 105-110 °C (0.2 Torr)
(bulb-to-bulb); IR (KBr) νmax 3083, 2960, 1732 cm-1; 1H NMR δ
6.99 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J=8.3 Hz, 1H), 5.99
(dd, J=10.8, 17.5 Hz, 1H), 4.98 (d, J=10.8 Hz, 1H), 4.89 (d, J=
17.5 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 2.79 (1/2 of
ABquartet, J=13.0 Hz, 1H), 2.74 (1/2 of ABquartet, J=13.0 Hz,
1H), 2.42 (1/2 of ABquartet, J = 13.9 Hz, 1H), 2.31 (1/2 of
ABquartet, J = 13.9 Hz, 1H), 2.28 (s, 3H), 1.26 (t, J = 7.1 Hz,
3H), 1.15 (s, 3H); 13C NMR δ 172.0, 156.0, 145.6, 133.3, 128.8,
127.8, 126.0, 111.4, 110.3, 59.8, 55.1, 44.4, 40.6, 40.2, 22.6, 20.4, 14.3;
MS m/e 276 (Mþ); HRMS m/e for C17H24O3 calcd (Mþ) 276.1725,
found 276.1731.
ν
max 2927, 1625,1605 cm-1; 1H NMR δ 6.60 (s, 1H), 5.90 (s, 2H),
2.55 (t, J=6.3 Hz, 2H), 2.19 (s, 3H), 1.82 (m, 2H), 1.66 (m, 2H),
1.39 (S, 6H); 13C NMR δ 144.8, 143.4, 128.9, 128.50, 128.47,
108.1, 99.7, 40.0, 33.3, 28.4, 27.9, 20.1, 19.9; MS m/e 218 (Mþ);
HRMS m/e for C14H18 O2 calcd 218.1307 (Mþ), found 218.1305.
Methyl 4-(5,9,9-trimethyl-6,7,8,9-tetrahydronaphtho[1,2-d][1,3]-
dioxol-4-yl)-2-butynoate (14): To a solution of 13 (0.3703 g, 1.70
mmol) and 2a (0.843 g, 2.04 mmol) in CH2Cl2 (40 mL) at 0 °C
was added Bu2BOTf (2.0 mL of 1 M solution in CH2Cl2). The
mixture was stirred for 1 h, saturated NH4Cl(aq) was added, and
the mixture was subjected to a conventional extractive workup.
The residue was dissolved in THF (25 mL), I2 (1 g) added, and
the solution stirred for 12 h. Saturated Na2SO3(aq) was added,
and the mixture was subjected to a conventional extractive
workup (Et2O). Preparative TLC (15:1 hexanes/Et2O) afforded
14 (0.4904 g, 92% yield) as a colorless oil; bp 150-155 °C
(0.1 Torr) (bulb-to-bulb); IR (KBr) νmax 2959, 2233,1706 cm-1
;
1HNMRδ5.90 (s, 2H), 3.74 (s, 3H), 3.64 (s, 2H), 2.55 (t, J=6.3Hz,
2H), 2.17 (s, 3H), 1.78 (m, 2H), 1.61 (m, 2H), 1.34 (s, 6H); 13C
NMR δ 154.1, 143.6, 143.0, 129.3, 127.9, 127.6, 111.9, 99.9, 86.5,
72.4, 52.4, 39.8, 33.2, 28.5, 28.4, 19.9, 16.6, 15.0; MS m/e 314
(Mþ); HRMS m/e for C19H22O4 calcd 314.1518 (Mþ), found
314.1504.
Hexacarbonyl[μ-η4-(methyl 4-(6-methylbenzo[d][1,3]dioxol-5-
yl)-2-butynoate)]dicobalt (9): Subjecting a solution of 2a (0.9721 g,
2.35 mmol) and 3,4-methylenedioxytoluene (0.42 mL, 3.5 mmol)
in CH2Cl2 (60 mL) with Bu2BOTf (2.4 mL of 1 M solution in
CH2Cl2) according to General Procedure A, followed by flash
chromatography (20:1 petroleum ether/Et2O), gave 9 (1.0396 g,
85% yield) as a red-brown oil: IR (KBr) νmax 2954, 2100, 2060,
(Z)-Methyl 3-methyl-4-(5,9,9-trimethyl-6,7,8,9-tetrahydrona-
phtho[1,2-d][1,3]dioxol-4-yl)-2-butenoate (15): To a suspension
of CuI (0.229 g, 1.20 mmol) in THF (10 mL) at 0 °C was added
MeLi (1.50 mL of a 1.6 M solution in Et2O). The solution was
stirred for 15 min and then added slowly to a solution of 14
(0.1892 g, 0.602 mmol) in THF at -78 °C. The solution was
stirred for 2 h at -78 °C, at which time saturated NH4Cl(aq) was
added and the mixture allowed to warm to rt. Following a
conventional extractive workup (Et2O), preparative TLC (20:1
hexanes/Et2O) afforded 15 (0.1880 g, 95% yield) as a viscous
colorless oil: bp 130-135 °C (0.1 Torr) (bulb-to-bulb); IR (KBr)
2029, 1709 cm-1; H NMR δ 6.71 (s, 1H), 6.64 (s, 1H), 5.89
1
(s, 2H), 4.07 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H); 13C NMR δ 198.0,
170.6, 146.6, 145.9, 131.0, 128.7, 110.3, 110.0, 100.8, 99.9, 78.6,
53.0, 36.5, 19.2; MS m/e 490 (M - COþ), 462 (M - 2COþ), 434
(M - 3COþ), 416 (M - 4COþ); HRMS m/e for C19H12 Co2O10
calcd 517.9094 (Mþ), found 517.9092.
Methyl 4-(6-methylbenzo[d][1,3]dioxol-5-yl)-2-butynoate (10):
To a solution of 9 (1.0396 g, 2.006 mmol) in THF (25 mL) was
added I2 (1.5 g). The solution was stirred 12 h. Following the
addition of saturated Na2SO3(aq) and a conventional extractive
workup (Et2O), flash chromatography (18:1 petroleum ether/
Et2O) gave 10 (0.4140 g, 89% yield) as a colorless oil: bp
125-130 °C (0.1 Torr) (bulb-to-bulb); IR (KBr) νmax 2954,
ν
max 2929, 1717, 1645 cm-1; 1H NMR δ 5.87 (s, 2H), 5.79 (br s,
1H), 4.16 (s, 2H), 3.75 (s, 3H), 2.52 (t, J = 6.5 Hz, 2H), 2.02
C
(s, 3H), 1.77 (m, 2H), 1.72 (s, 3H), 1.61 (m, 2H), 1.35 (s, 6H); 13
2237,1714 cm-1; H NMR δ 6.85 (s, 1H), 6.66 (s, 1H), 5.92
1
NMR δ 166.8, 158.6, 144.5, 142.4, 128.8, 128.5, 126.9, 116.6,
115.9, 99.4, 50.8, 39.8, 33.2, 30.0, 28.53, 28.50, 23.9, 20.0, 14.6;
MS m/e 330 (Mþ); HRMS m/e for C20H26 O4 calcd 330.1831
(Mþ), found 330.1830.
(s, 2H), 3.77 (s, 3H), 3.57 (s, 2H), 2.24 (s, 3H); 13C NMR δ 154.1,
146.7, 145.9, 129.1, 125.0, 110.5, 108.9, 100.9, 86.5, 74.3, 52.6,
22.8, 19.2; MS m/e 232 (Mþ); HRMS m/e for C13H12 O4 calcd
232.0736 (Mþ), found 232.0737.
(Z)-3-Methyl-4-(5,9,9-trimethyl-6,7,8,9-tetrahydronaphtho-
[1,2-d][1,3]dioxol-4-yl)-2-buten-1-ol (16): To a solution of 15
(0.1161 g, 0.352 mmol) in Et2O (15 mL) at -78 °C was added
DIBAL-H (1.5 mL of a 1 M solution in hexanes). The solution
was stirred at -78 °C for 1 h and allowed to warm to rt for 1 h.
Following the addition of H2SO4 (1 M) and a conventional
extractive workup (Et2O), preparative TLC (2:1 hexanes/Et2O)
gave 16 (0.1059 g, 100%) as an undistillable glass: IR (KBr) νmax
3346, 2928, 1666 cm-1; 1H NMR δ 5.86 (s, 2H), 5.52 (dt, J=1.2,
7.1 Hz, 1H), 4.30 (d, J=7.1 Hz, 2H), 3.46 (s, 2H), 2.54 (t, J=6.3Hz,
2H), 2.09 (s, 3H), 1.92 (br s, 1H), 1.78 (m, 2H), 1.62 (s, 3H), 1.61
(m, 2H), 1.35 (s, 6H); 13C NMR 144.0, 142.5, 137.8, 128.9, 127.8,
126.8, 124.5, 117.2, 99.4, 58.9, 39.8, 33.2, 28.9, 28.7, 28.5, 22.8,
20.0, 15.0; MS m/e 302 (Mþ); HRMS m/e for C19H26O3 calcd
302.1882 (Mþ), found 302.1882.
Methyl 4-(6-methylbenzo[d][1,3]dioxol-5-yl)butanoate (11): To a
solution of 10 (0.4140 g, 0.178 mmol) in MeOH (20 mL) was added
5% Rh/C (0.1 g). H2 was bubbled through solution, while stirring
for 10 h. The mixture was filtered and concentrated under reduced
pressure. The crude reaction mixture was filtered through a plug of
neutral alumina and again concentrated under reduced pressure.
Bulb-to-bulb distillation gave 11 (0.4048 g, 96% yield) as a color-
less oil: bp 105-100 °C (0.1 Torr) (bulb-to-bulb); IR (KBr) νmax
2952, 1738 cm-1; 1H NMR δ 6.62 (apparent s, 2H), 5.86 (s, 2H),
3.68 (s, 3H), 2.54 (m, 2H), 2.36 (t, J=7.3 Hz, 2H), 2.21 (s, 3H), 1.86
(m, 2H); 13C NMR δ 173.7, 145.5, 132.4, 128.6, 110.2, 109.0, 100.4,
51.3, 33.3, 32.2, 25.4, 18.9; MS m/e 236 (Mþ); HRMS m/e for
C13H16 O4 calcd 236.1049 (Mþ), found 236.1048.
5,9,9-Trimethyl-6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxole (13):
To a solution of 11 (0.5106 g, 2.16 mmol) in Et2O was added
MeLi (5.0 mL, 1.53 M in Et2O, 7.7 mmol) at -78 °C. The
cooling bath was removed and the solution allowed to warm to
rt; stirring was continued for 2 h. Saturated NH4Cl(aq) was
added and the reaction mixture subjected to a conventional
Ethyl 3-methyl-3-((5,9,9-trimethyl-6,7,8,9-tetrahydronaphtho-
[1,2-d][1,3]dioxol-4-yl)methyl)-4-pentenoate (17): To a solution
of (Z)-allyl alcohol 16 (0.0543 g, 0.180 mmol) in triethyl
orthoacetate (4 mL) was added propionic acid (2 μL). The
mixture was heated to reflux for 47 h. The solvent was removed
J. Org. Chem. Vol. 74, No. 19, 2009 7415

Green and Tjeng
JOCArticle
under reduced pressure, and preparative TLC (10:1 petroleum
hexanes), lit.1 mp 138-140 °C; IR (KBr) νmax 3445 (br), 3085,
ether/ether) gave 17 (0.0423 g, 63% yield): bp 160-165 °C
2926, 1761 cm-1 1 H NMR δ 5.93 (dd, J=10.7, 17.4 Hz, 1H),
;
(0.15 Torr) (bulb-to-bulb); IR (KBr) νmax 3083, 2928, 1733
5.62 (s, 1H), 5.12 (d, J=17.4 Hz, 1H), 5.08 (d, J=10.7 Hz, 1H),
2.79 (1/2 AB quartet, J=14.2 Hz, 1H), 2.69 (1/2 AB quartet, J=
14.2 Hz, 1H), 2.58 (t, J=6.3 Hz, 2H), 2.48 (1/2 AB quartet, J=
12.1 Hz, 1H), 2.29 (1/2 AB quartet, J = 12.1 Hz, 1H), 2.10
1
cm-1
;
H NMR δ 5.98 (dd, J = 17.5, 11.0 Hz, 1H), 5.83 (d,
J=1.4 Hz, 1H), 5.81 (d, J=1.4 Hz, 1H), 4.97 (d, J=11.0 Hz,
1H), 4.94 (d, J=17.5 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.80 (1/2
AB quartet, J=14.0 Hz, 1H), 2.78 (1/2 AB quartet, J=14.0 Hz,
1H), 2.50 (t, J=6.3 Hz, 2H), 2.47 (1/2 AB quartet, J=14.0 Hz,
1H), 2.38 (1/2 AB quartet, J = 14.0 Hz, 1H), 2.05 (s, 3H), 1.77
(m,2H),1.60(m,2H),1.343(s,3H),1.339(s,3H),1.24(t,J=7.1Hz,
3H), 1.20 (s, 3H); 13C NMR δ 172.0, 145.4, 144.8, 142.3, 129.1,
128.7, 126.9, 116.3, 111.6, 99.1, 59.9, 44.9, 41.7, 39.9, 38.2, 33.2,
28.8, 28.5, 22.6, 20.0, 16.6, 14.3; MS m/e 372 (Mþ); HRMS m/e
for C23H32O4 calcd 372.2301 (Mþ), found 372.2282.
Velloziolide (1):. To a solution of 17 (0.0423 g, 0.114 mmol) in
CH2Cl2 (5 mL) cooled to -78 °C was added BCl3 (0.5 mL of 1 M
solution in heptane). The mixture was allowed to stir 1 h at -78 °C
and subsequently warmed to rt and stirred for 12 h. Following a
conventional extractive workup (CH2Cl2) and concentration
under reduced pressure, the residue was dissolved in H2O
(1 mL)/THF (2 mL) and AgNO3 (25 mg) added. The mixture
was shielded from light and stirred for 24 h at rt. Following
a conventional extractive workup (Et2O), the crude reaction
was subjected to preparative TLC (9:1 hexanes/Et2O) to give
1 (velloziolide, 0.0292 g, 82% yield): mp 137-139 °C (CH2Cl2/
(s, 3H), 1.77 (m, 2H), 1.62 (m, 2H), 1.43 (s, 6H), 1.23 (s, 3H); 13
C
NMR δ 170.0, 144.0, 142.5, 137.3, 134.3, 131.6, 125.7, 124.0,
112.5, 44.1, 42.6, 41.5, 36.9, 34.4, 29.6, 28.1, 28.0, 25.1, 19.6,
15.3; MS m/e 314 (Mþ); HRMS m/e for C20H26O3 calcd
314.1882 (Mþ), found 314.1869.
Acknowledgment. The authors thank NSERC (Canada),
the Canada Foundation for Innovation (CFI), and the
Ontario Innovation Trust (OIT) for support of this research.
We thank Prof. Tomas Hudlicky (Brock University) for
helpful discussion on the Johnson-Claisen rearrangement
of 16.
Supporting Information Available: Experimental details for
the preparation of 1-hexyl-4-methoxybenzene, 2a-2c, 3b-3k,
and 6, 1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7416 J. Org. Chem. Vol. 74, No. 19, 2009