Formal synthesis of (+)-brefeldin A: application of a zinc-mediated ring expansion reaction

Article abstract of DOI:10.1021/jo0701379

(Chemical Equation Presented) An efficient formal synthesis of (+)-brefeldin A was accomplished through a synthetic approach that relied upon three keys steps. The five-membered ring was generated in a stereocontrolled fashion through application of a tan

Full text of DOI:10.1021/jo0701379

Formal Synthesis of (+)-Brefeldin A: Application of a
Zinc-Mediated Ring Expansion Reaction
Weimin Lin and Charles K. Zercher*
Department of Chemistry, UniVersity of New Hampshire, Durham, New Hampshire 03824
ckz@cisunix.unh.edu
ReceiVed January 25, 2007
An efficient formal synthesis of (+)-brefeldin A was accomplished through a synthetic approach that
relied upon three keys steps. The five-membered ring was generated in a stereocontrolled fashion through
application of a tandem conjugate addition-intramolecular cyclization method developed by Toru. Ring-
closing metathesis provided access to a twelve-membered â-keto lactone, which was ring-expanded to
the R,â-unsaturated-γ-keto lactone through a zinc carbenoid-mediated reaction. Conversion of this lactone
to (+)-brefeldin A has been reported previously.
Introduction
Brefeldin A has received attention due to its potential service
as an anticancer agent5 and as an immunosuppressive agent.6
This combination of wide ranging biological activity and
unusual structural features has made (+)-brefeldin A an
attractive synthetic target. An impressive array of synthetic
approaches has been described for this molecule, including a
number of approaches that are noteworthy due to their efficiency
and brevity.7 Many of these approaches have used the natural
product as a proving ground for the development and assessment
of new synthetic methods. Macrocyclic lactonization methods
and strategies for the stereoselective formation of five-membered
rings have dominated this methodology development.
(+)-Brefeldin A is a bicyclic compound that possesses a 13-
membered macrocyclic lactone. Although the isolation of (+)-
brefeldin A from fungal sources (such as Penicillium decumbens,
Penicillium brefeldianum, and Phyllosticta medicaginis) was
reported in 1958,1 the structure of this fungal metaboliate was
not established until 1971.2
Our interest in (+)-brefeldin A was based upon the presence
of the γ-oxygenated R,â-unsaturated lactone. We recently
reported a tandem chain extension-oxidation-elimination
reaction in which â-keto esters are converted in a single step to
γ-keto-R,â-unsaturated esters through treatment with a zinc
carbenoid.8 We further demonstrated that the reaction facilitates
efficient formation of macrocyclic â-keto lactones with ring sizes
A wide range of biological properties has been attributed to
this molecule, including antiviral, cytostatic, and antibiotic
activities.3 Furthermore, a recent study has demonstrated that
(+)-brefeldin A can drive Golgi complex disassembly and
redistribution to the endoplasmic reticulum and can inhibit
protein transport to post-Golgi compartments in the cell.4 (+)-
(5) Zhu, J.-W.; Hori, H.; Nojiri, H.; Tsukuda, T.; Taira, Z. Bioorg. Med.
Chem. Lett. 1997, 7, 139.
(6) Nauchtern, J. G.; Bonifacino, J. S.; Biddison, W. E.; Klausner, R.
D. Nature 1989, 339, 223-226.
* Author to whom correspondence should be addressed. Phone: 603-862-
2697. Fax: 603-862-4278.
(1) Singleton, V. L.; Bohonos, N.; Ullstrupp, A. J. Nature 1958, 181,
(7) (a) Wang, Y.; Romo, D. Org. Lett. 2002, 4, 3231. (b) Kobayashi,
Y.; Watatani, K.; Kikori, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 6125-
6128. (c) Carnell, A. J.; Casy, G.; Gorins, Gilles.; Kompany-Saeid, A.;
McCague, R.; Olivo, H. F.; Roberts, S. M.; Willetts, A. J. J. Chem. Soc.
Perkin Trans. 1 1994, 23, 3431-3439. (d) Huebscher, T.; Helmchen, G.
SynLett. 2006, 9, 1323. (e) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc.
2002, 124, 9328-9329. (f) Haynes, R. K.; Lam, W. W.-L.; Yeung, L-L.;
Williams, I. D.; Ridley, A. C.; Starling, S. M.; Vonwiller, S. C.; Hambley,
T. W.; Lelandais, P. J. Org. Chem. 1997, 62, 4552-4553. (g) Bernardes,
V.; Kann, N.; Riera, A.; Moyano, A.; Pericas, M. A.; Greene, A. E. J. Org.
Chem. 1995, 60, 6670-6671.
1072.
(2) Weber, H. P.; Hauser, D.; Sigg, H. P. HelV. Chim. Acta 1971, 54,
2763.
(3) (a) Harri, E.; Loeffler, W.; Sigg, H. P.; Staehein, H.; Tamm, C. HelV.
Chim. Acta. 1963, 46, 1235. (b) Baker, C. J.; Barrett, F. F.; Clark, D. J. J.
Antibiot. 1974, 27, 65. c) Batina, V. Neoplasma 1969, 16, 23. (d) Betina,
V.; Montainer, L. Bull. Soc. Chim. Biol. 1966, 48, 194.
(4) (a) Chardin, P.; McCormick, F. Cell 1999, 97, 153. (b) Miller, S.;
Carnell, L.; Moore, H. P. H. J. Biol. Chem. 1992, 118, 267.
10.1021/jo0701379 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/12/2007
4390
J. Org. Chem. 2007, 72, 4390-4395

Formal Synthesis of (+)-Brefeldin A
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Preparation of 6
of 13 or greater,9 although smaller macrocylic rings proved to
be more resistant to the ring expansion. The chain extension
(ring expansion) reaction is performed through treatment of the
â-keto carbonyl with the Furukawa-modified Simmons-Smith
reagent derived from diethylzinc and diiodomethane.10
A
although it can also be prepared conveniently through reduction
of (S)-malic acid with borane.14 Two different approaches were
utilized for the preparation of compound 6 from the diol. An
indirect route involved formation of the tosylate 9 from the
diol,15 followed by protection of the secondary alcohol with a
methoxymethyl group. Substitution of the tosylate with bromide
provided the ethyl (5S,2E) 6-bromo-5-(methoxymethoxy)hex-
2-enoate 6. (Scheme 2).
A more direct approach to compound 6 was developed in
which the primary alcohol was selectively brominated using
triphenylphosphine and carbon tetrabromide.16 Reaction between
compound 11 and methoxymethyl chloride using N,N-diisoprop-
ylethylamine (DIEA) as the base provided the targeted elec-
trophile 6.
Formation of compound 13 through the conjugate addition
of the R-sulfinyl carbanion derived from a chiral tolylsulfoxide
to compound 6 was investigated (Scheme 3). The stereoselective
cyclization method,17 developed by Toru, was particularly
attractive due to the strong preference for trans stereochemistry
on the five-membered ring and for the ease by which the vinyl
group can be generated through fluoride-mediated elimination
of the sulfinic acid. Toru’s studies had established that the
absolute stereochemistry of the newly formed stereocenters is
controlled by the chiral sulfoxide. Formation of the stereocenters
in (+)-brefeldin A required the utilization of the (S)-sulfoxide
12, which could be prepared via the (D)-menthyl tolylsulfi-
nate.18,19 Because of its remote position, the existing stereocenter
on compound 6 was not anticipated to influence the stereose-
lective formation of the cyclopentane.
traditional use of this electrophilic carbenoid has been in the
cyclopropanation of olefinic functionalities, usually those pos-
sessing allylic oxygenation. The presence of both the electron-
rich alkene and the ring-fused 13-membered ring lactone in (+)-
brefeldin A presented challenges to the application of the zinc-
carbenoid-mediated ring expansion protocol.
Results and Discussion
The key step in our synthetic approach to (+)-brefeldin A
was, therefore, the conversion of the â-keto lactone to the
γ-keto-R,â-unsaturated lactone. Since Bartlett,11 and more
recently Kim,12 reported a synthesis of (+)-brefeldin A through
intermediate 2, we targeted the formation of 3 as the penultimate
compound in our approach to (+)-brefeldin A (Scheme 1). Our
previous studies had established that ring-closing metathesis
(RCM) of â-keto esters could provide useful amounts of the
corresponding â-keto lactones. While alkene-stereoselectivity
was inconsequential in our earlier studies, (+)-brefeldin A
presented a synthetic target in which control of olefin geometry
was required. Assuming that the ring-closing metathesis reaction
of 4 could provide the necessary E-alkene 3, we anticipated
that the metathesis precursor could be prepared through a mixed
Claisen condensation involving the activation of carboxylic acid
5. Formation of the substituted cyclopentane 5 was anticipated
to be available from R,â-unsaturated ester 6, derivable from
the optically active triol 7.
Enantiomerically pure (S)-1,2,4-butanetriol (7) was converted
to the unsaturated diol 8 in four steps via the route reported by
Labelle.13 The starting material is commercially available,
Upon exposure of the carbanion of 12 to the unsaturated
bromide 6, one predominant diastereomer 13 (de > 95%) was
(8) Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 4535-
4538.
(13) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J. P. J. Am.
Chem. Soc. 1998, 110, 4533.
(14) Hanessian, S.; Ugolini, A.; Dube´, D.; Glymyan, A. Can. J. Chem.
1984, 62, 2126.
(15) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933.
(16) Miyazawa, M.; Ishibashi, N.; Onhuma, S.; Miyashita, M. Tetrahe-
dron Lett. 1997, 38, 3419.
(17) Nakamura, S.; Watanabe, Y.; Toru, T. J. Org. Chem. 2000, 65, 1758.
(18) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(19) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50, 1045.
(9) Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 1878-
1885.
(10) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron
1968, 24, 53.
(11) Bartlett, P. A.; Green, F. R., III. J. Am. Chem Soc. 1978, 100, 4858-
4865.
(12) Kim, D.; Lee, J.; Shim, P. J.; Lin, J. I.; Jo, H.; Kim, S. J. Org.
Chem. 2002, 67, 764.
J. Org. Chem, Vol. 72, No. 12, 2007 4391

Lin and Zercher
SCHEME 5. Ring Closing Metathesis (RCM) for the
SCHEME 3. Cyclization to the Cyclopentane
Preparation of 3A and 3B
macrolide 3 through a ring closing metathesis (RCM) reaction
(Scheme 5). Dichloromethane proved to be a better solvent than
toluene for full conversion of the starting material to the targeted
compound 3, although addition of a second portion of catalyst
to the refluxing solution was necessary. Two macrolides 3A
and 3B, separable by column chromatography, were formed with
SCHEME 4. Preparation of Compound 17
1
an E:Z ratio ) 3.5:1. The stereochemistry was assigned by H
NMR and 1D NOE analysis of the crude reaction mixture.
Iodine-catalyzed double bond isomerization in the macrocyclic
compound was unsuccessful for converting compound 3B to
compound 3A. However, isomerization of the Z to the E double
bond was accomplished by treatment with thiophenol in the
presence of AIBN at 80 °C.20
Before a full investigation of the zinc-mediated chain
extension-oxidation-elimination reaction for the preparation
of compound 2 was performed, the efficiency of the simple chain
extension reaction was studied.21 Following generation of the
zinc-carbenoid (7.5 equiv), the macrolide 3A was added to the
solution and allowed to react for 30 min. In addition to product
formation, starting material was still observed under these
conditions even after the reaction time was extended from 30
min to 2 h. The reason for the presence of unreacted starting
material is unknown, although slow deprotonation of â-keto
macrocyclic compounds, as observed in earlier studies,9 and
decomposition of the carbenoid22 over time may be factors.
Increasing the equivalents of carbenoid from 7.5 to 10 did result
in more efficient chain extension, although minor amounts of
inseparable cyclopropanated products appeared to form under
these conditions. The location and stereochemistry of the
cyclopropane were investigated no further.
A modification of the reaction was performed, in which
carbenoid (overall 7.5 equiv) was added in two portions (Scheme
6). After treatment of the â-keto macrolide 3A for 30 min with
5 equiv of carbenoid prepared in advance, second portions of
diethyl zinc and 1,1-diiodomethane (2.5 equiv) were added
sequentially. After an additional 30 min of reaction time,
complete conversion to the ring-expanded product 18 was
accomplished.
detected by analysis of the 13C NMR spectrum, although the
stereochemistry could not be assigned. The configuration of the
newly generated stereocenters was clarified after tetrabutylam-
monium fluoride (TBAF) induced elimination and lithium
aluminum hydride (LAH) reduction of the ester (Scheme 3).
Treatment with TBAF immediately after purification of 13 was
necessary due to rapid decomposition of 13, presumably through
syn-elimination of the arylsulfinic acid. A comparison of the
spectroscopic data of the alcohol 15 to those reported in the
literature20 confirmed that the homoallylic primary alcohol
possessed the necessary relative stereochemistry for approaching
(+)-brefeldin A. Saponification of 14 with 3 M lithium
hydroxide produced the targeted homoallylic carboxylic acid 5
in an excellent yield with no epimerization.
With the successful formation of the key intermediate 5, a
simple two-step reaction sequence9 was performed to prepare
compound 17, the precursor for the modified Claisen condensa-
tion (Scheme 4). Generation of the cuprate from 1-bromo-3-
butene (16) and addition to (S)-propylene oxide provided an
intermediate alkoxide that could be acetylated in almost
quantitative yield. After treatment of compound 17 with LDA,
a solution of an acyl imidazole was transferred to the enolate
solution by cannula. Compound 4 was generated in higher than
80% yield without detectable epimerization.
These conditions were repeated and excess iodine was added
to the solution to trap the intermediate formed in the chain
extension reaction (Scheme 6). After elimination of iodide by
treatment with DBU, the targeted R,â-unsaturated-γ-keto-
macrolide was produced. The newly formed double bond,
generated from the zinc-mediated chain extension-oxidation-
After obtaining the unsaturated â-keto ester 4, Grubbs’s first
generation catalyst was used to prepare the unsaturated â-keto
(20) Kim, D.; Lee, J.; Shim, P. J.; Lin, J. I.; Doi, T.; Kim, S. J. Org.
Chem. 2002, 67, 772.
(21) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444-6446.
(22) Charette, A. B.; Marcoux, J. -F. J. Am. Chem. Soc. 1996, 118, 4539.
4392 J. Org. Chem., Vol. 72, No. 12, 2007

Formal Synthesis of (+)-Brefeldin A
SCHEME 6. Ring Expansion Reactions of Compound 3A
77.1, 66.8, 62.2, 56.9, 47.4, 47.0, 37.9, 35.0, 22.7, 15.8, 10.6, 0.0.
IR (neat, cm-1): 2964, 2882, 1727, 1614, 1596.
Ethyl (1R,2S,4S)-4-(Methoxymethoxy)-2-vinylcyclopentane-
carboxylate (14). A 25-mL oven-dried, round-bottomed flask,
equipped with a septum with a flow of nitrogen through a needle
and a stir bar, was charged with tetrahydrofuran (5 mL) and
compound 13 (0.09 g, 2 mmol, in 2 mL of tetrahydrofuran) in order.
After the solution was cooled to 0 °C in the ice bath, TBAF (1.0
M in tetrahydrofuran, 3.0 mL, 3.0 mmol) was added in one portion.
After TLC analysis (hexanes:ethyl acetate ) 3:1; Rf ) 0.15)
indicated that the starting material was consumed, the solution was
quenched by cautious addition of saturated aqueous ammonium
chloride (3 mL). The mixture was extracted with diethyl ether (2
× 5 mL). The combined organic layers were washed with brine (5
mL) and dried over anhydrous sodium sulfate. The resulting liquid
was filtered and concentrated under reduced pressure. The product
was purified by flash chromatography on silica (hexanes:ethyl
acetate ) 10:1, Rf ) 0.25) to afford 0.39 g (85%) of 14 as a
colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80 (m, 1H), 5.04
(dd, 1H, J ) 0.9, 16.4 Hz), 4.98 (dd, 1H, J ) 1.0, 10.1 Hz), 4.62
(s, 2H), 4.23 (m, 1H), 4.18-4.10 (m, 2H), 3.36 (s, 3H), 2.76-
2.68 (m, 2H), 2.30 (m, 1H), 2.08-2.02 (m, 2H), 1.58 (m, 1H),
1.26-1.23 (t, 3H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ
175.3, 140.6, 114.8, 95.5, 66.1, 60.6, 55.6, 48.4, 46.6, 39.7, 37.2,
elimination reaction, was assigned the E-configuration based
on 1H-1H coupling constant (J ) 16.0 Hz), as well as through
comparison to the known literature data.12 The spectroscopic
data of the material in the chain extension-oxidation-elimina-
tion sequence was identical to that reported in the literature.
Therefore, the successful preparation of 2 completed the formal
synthesis of (+)-brefeldin A.
In summary, an efficient approach to (+)-brefeldin A was
developed, in which a zinc-mediated chain extension-oxida-
tion-elimination reaction was used as a key step. Combination
of this 12-step linear sequence with the reduction and depro-
tection steps reported in the literature provides, to the best of
our knowledge, the shortest synthetic route to (+)-brefeldin
reported to date. This efficient synthetic approach demonstrates
the power and utility of Toru’s cyclopentane-formation method
and of the zinc-mediated chain extension reaction.
14.5. IR (neat, cm-1): 3035, 2964, 2954, 1723, 1642. [R]25
)
D
-35 (c ) 0.001 g/mL, CHCl3); HRMS (FAB+) m/z Calcd for
C12H21O4 (M + 1): 229.1440. Found 229.1425.
((1R,2S,4S)-4-(Methoxymethoxy)-2-vinylcyclopentyl)metha-
nol (15). A 10-mL oven-dried, round-bottomed flask, equipped with
a septum with a flow of nitrogen through a needle and a stir bar, was
charged with tetrahydrofuran (3 mL), lithium aluminum hydride
(15 mg, 0.4 mmol), and compound 14 (18 mg, 0.075 mmol) in the
indicated order. The solution was refluxed till TLC analysis (hexanes:
ethyl acetate ) 3:1; Rf ) 0.20) indicated that the starting material
was consumed. The solution was cooled to room temperature and
quenched by cautious and sequential addition of water (1 mL), 10%
aqueous sodium hydroxide (1 mL), and water (3 mL). After being
stirred for 10 min, the solution was filtered and concentrated under
reduced pressure. The product was purified by flash chromatography
on silica (hexanes:ethyl acetate ) 7:1, Rf ) 0.10) to afford 7 mg
(50%) 15 as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 5.82
(m, 1H), 5.04 (dd, 1H, J ) 1.0, 17.1 Hz), 4.96 (dd, 1H, J ) 1.7,
10.1 Hz), 4.63 (s, 2H), 4.16 (m, 1H), 3.68 (dd, 1H, J ) 5.4, 10.8
Hz), 3.54 (dd, 1H, J ) 6.1, 10.8 Hz), 3.36 (s, 3H), 2.27-2.18 (m,
Experimental Section
Ethyl (1R,2R,4R)-4-(Methoxymethoxy)-2-((1R)-1-(p-tolylsul-
finyl)-2-(trimethylsilyl)-ethyl)cyclopentanecarboxylate (13). A
10-mL oven-dried, round-bottomed flask, equipped with a septum
with a flow of nitrogen through a needle and a stir bar, was charged
with tetrahydrofuran (3 mL) and diisopropylamine (0.1 mL, 0.75
mmol) in order. After the solution was cooled to 0 °C, n-BuLi (2.0
M in hexanes, 0.37 mL, 0.75 mmol) was added in one portion.
After being stirred for 10 min, the reaction mixture was cooled to
-78 °C using dry ice in acetone, and compound 12 (0.06 g, 0.25
mmol, in 0.5 mL of THF) was added. After the solution was stirred
for 15 min, compound 6 (0.09 g, 0.33 mmol, in 0.33 mL of THF)
was added in one portion. The solution was stirred for 15 min at
-78 °C and then warmed to 0 °C. After TLC analysis (hexanes:
ethyl acetate ) 3:1; Rf ) 0.20) indicated that the starting material
was consumed, the solution was quenched by cautious addition of
saturated aqueous ammonium chloride (2 mL). The mixture was
extracted with diethyl ether (3 × 5 mL) and washed with brine (5
mL). The combined organic layers were dried over anhydrous
sodium sulfate. The resulting liquid was filtered and concentrated
under reduced pressure. The product was purified by flash chro-
matography on silica (hexane:ethyl acetate ) 3:1, Rf ) 0.15) to
afford 88 mg (80%) of 13 as a colorless liquid. (To prevent
decomposition of the product, treatment with TBAF was performed
immediately after characterization data was obtained.) [R]25D ) -52
3H), 2.05 (m, 1H), 1.92 (m, 1H), 1.67 (m, 1H), 1.56 (m, 1H); [R]25
D
) -39 (c ) 0.001 g/mL, CHCl3); 13C NMR (100 MHz, CDCl3) δ
142.5, 114.5, 95.5, 76.9, 65.7, 55.5, 46.0, 45.8, 40.4, 36.2. IR (neat,
cm-1): 3450, 2960, 1621. HRMS (FAB+) m/z Calcd for C10H19O3
(M + 1): 187.1334. Found 187.1341.
(1R,2S,4S)-4-(Methoxymethoxy)-2-vinylcyclopentanecarbox-
ylic Acid (5). Compound 14 (0.46 g, 2.0 mmol) was dissolved in
a 25-mL round-bottomed flask with 4 mL of THF. Water (4 mL),
and lithium hydroxide monohydrate (0.38 g, 8.0 mmol) were added
to the solution in the indicated order. The mixture was stirred
overnight at room temperature, and the solution was brought to
pH ) 1.0 with 1 M HCl and then extracted with diethyl ether (3 ×
5 mL). The combined organic layers were dried carefully over
anhydrous sodium sulfate and concentrated in Vacuo to yield 0.32
g (80%) of 5 as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ
5.85 (m, 1H), 5.09 (d, 1H, J ) 17.2 Hz), 5.01 (d, 1H, J ) 10.2
Hz), 4.63 (s, 2H), 4.25 (m, 1H), 3.36 (s, 3H), 2.78-2.76 (m, 2H),
2.32 (m, 1H), 2.12-2.10 (m, 2H), 1.62 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 180.5, 140.4, 115.1, 95.5, 55.6, 48.2, 46.3, 39.7,
37.2. IR (neat, cm-1): 3300, 2960, 1710. [R]25D ) -40 (c ) 0.002
g/ mL, CHCl3). HRMS (FAB+) m/z Calcd for C10H17O4 (M + 1):
201.1127. Found 201.1131.
1
(c ) 0.003 g/mL, THF). H NMR (400 MHz, CDCl3) δ 7.60-
7.58 (d, 2H, J ) 8.0 Hz), 7.50-7.48 (d, 2H, J ) 8.0 Hz), 4.90 (dd,
1H, J ) 6.9 Hz), 4.84 (d, 1H, J ) 6.9 Hz), 4.44 (m, 1H), 4.41-
4.37 (q, 2H, J ) 7.1, Hz), 3.66-3.54 (m, 2H), 3.58 (s, 3H), 3.02
(m, 1H), 2.69 (m, 1H), 2.60 (s, 3H), 2.60-2.34 (m, 3H), 1.52-
1.49 (t, 3H, J ) 7.1 Hz), 0.99-0.97 (m, 2H), 0.20 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 176.2, 141.8, 141.8, 131.0, 125.4, 96.4,
(S)-Hept-6-en-2-yl Acetate (17). A 100-mL oven-dried, round-
bottomed flask, equipped with a septum with a flow of nitrogen
through a needle and a stir bar, was charged with magnesium
J. Org. Chem, Vol. 72, No. 12, 2007 4393

Lin and Zercher
turnings (0.6 g, 25 mmol), THF (30 mL), and a crystal of iodine.
1-Bromo-3-butene (16) (1.3 mL, 13 mmol) was dissolved in
tetrahydrofuran (10 mL). A portion of the bromobutene solution
(1 mL) was added, and the mixture was stirred until the brown
color of the mixture disappeared. The solution was stirred for an
additional 10 min, and then 4-bromo-1-butene solution was added
dropwise over a 1-h period using a syringe pump. The mixture
was stirred for an additional 1 h and was brought to -40 °C, and
copper(I) iodide (50 mg, 0.26 mmol) was added. The resulting light
green mixture was stirred for an additional 10 min, at which time
(S)-propylene oxide (0.35 mL, 5 mmol) was added in a single
portion. The mixture was allowed to warm to -15 °C, stirred for
an additional 2.5 h, and then quenched with saturated aqueous
ammonium chloride (10 mL). The layers were separated, and the
organic layer was washed with H2O (10 mL) and brine (10 mL).
The layers were separated, the combined aqueous layers were
extracted with diethyl ether (3 × 50 mL), and the combined organic
layers were dried over anhydrous sodium sulfate. The solution was
filtered and concentrated under reduced pressure. The resulting
crude residue was dissolved in a 25-mL oven-dried round-bottomed
flask with 8 mL of diethyl ether. Acetyl chloride (0.71 mL, 10
mmol, freshly distilled) was added to the solution followed with
addition of pyridine (0.80 mL, 10 mmol). The solution was allowed
to reflux till TLC analysis (hexane:ethyl acetate ) 3:1; Rf ) 0.10)
indicated that the starting material was consumed. After being
cooled to the room temperature, the solution was washed with 1
M HCl (3 × 10 mL). The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was chromatographed on silica (hexanes:ethyl acetate
) 15:1, Rf ) 0.15) to yield 0.66 g (85%) of 17 as a colorless
liquid. 1H NMR (500 MHz, CDCl3) δ 5.71 (m, 1H), 4.93 (dd, 1H,
J ) 1.7, 17.1 Hz), 4.88 (dd, 1H, J ) 0.9, 11.2 Hz), 4.83 (m, 1H),
2.01-1.96 (m,2H), 1.95 (s, 3H), 1.56-1.18 (m, 4H), 1.14 (d, 3H,
J ) 6.3 Hz); 13C NMR (125 MHz, CDCl3) δ 169.7, 137.4, 113.7,
69.8, 34.3, 32.5, 23.7, 20.2, 18.9. IR (neat, cm-1): 3052, 2975,
1740. HRMS (FAB+) m/z Calcd for C9H17O2 (M + 1): 157.1229.
Found 157.1232.
5,6,7,8,11,12,13,13a-Octahydrocyclo-penta[e][1]oxacyclododecine-
1,3(2H,10aH)-dione (3B). A 250-mL oven-dried, round-bottomed
flask, equipped with a septum with a flow of nitrogen through a
needle and a stir bar, was charged with dichloromethane (100 mL),
compound 4 (0.16 g, 0.6 mmol, in 1 mL of dichloromethane), and
bis(cyclohexylphosphine)benzylidine ruthenium(IV) dichloride (20
mg, 0.024 mmol) in the indicated order. This solution was heated
to reflux for 8 h and another portion of catalyst was added (20 mg,
0.024 mmol). Reflux was continued for an additional 8 h till TLC
analysis (hexanes:ethyl acetate ) 15:1, Rf ) 0.20) indicated that
the starting material was consumed. The solution was allowed to
cool and concentrated in Vacuo. The residue was chromatographed
on silica to yield 100 mg (64%) of two isomers 3A (50%) and 3B
(14%). The compounds were produced in E:Z ) 3.5:1 ratio (based
on 1H NMR of the crude reaction mixture). E-isomer (3A):
1
(hexanes:ethyl acetate ) 10:1, Rf ) 0.20); H NMR (500 MHz,
CDCl3) δ 5.38 (m, 1H), 5.30 (dd, 1H, J ) 8.5, 16.2 Hz), 5.04
(m,1H), 4.61 (s, 2H), 4.15 (m, 1H), 3.44 (m, 1H), 3.40-3.38 (m,
2H), 3.36 (s, 3H), 2.59 (m, 1H), 2.26-2.15 (m, 2H), 2.04-1.92
(m, 2H), 1.72-1.52 (m, 5H), 1.33 (m, 1H), 1.19 (d, 3H, J ) 6.5
Hz); 13C (100 MHz, CDCl3) δ 205.4, 167.3, 133.6, 131.7, 95.4,
77.4, 71.6, 55.6, 53.9, 50.8, 46.0, 40.3, 36.0, 32.0, 31.6, 20.7, 18.5.
IR (neat, cm-1): 3036, 2956, 1740, 1713. [R]25D ) +4 (c ) 0.001
g/mL, CHCl3). HRMS (FAB+) m/z Calcd for C17H27O5 (M + 1):
311.1858. Found 311.1841. Z-isomer (3B) (hexanes:ethyl acetate
) 7:1, Rf ) 0.15): 1H NMR (500 MHz, CDCl3) δ 5.42 (ddd,
1H, J ) 1.4, 5.4, 5.4 Hz), 5.30 (ddd, 1H, J ) 1.4, 5.4, 5.4 Hz),
5.05 (m, 1H), 4.62 (s, 2H), 4.24 (m, 1H), 3.50 (d, 1H, J ) 14.0
Hz), 3.38 (d, 1H, J ) 14.2 Hz), 3.35 (s, 3H), 3.16 (m, 1H), 2.98
(dd, 1H, J ) 8.2, 16.4 Hz), 2.37-2.22 (m, 2H), 2.04-1.74 (m,
5H), 1.58-1.43 (m, 3H), 1.23 (d, 3H, J ) 6.4 Hz); 13C (100 MHz,
CDCl3) δ 203.8, 165.0, 132.1, 129.8, 94.4, 76.7, 72.0, 56.5, 54.4,
47.8, 39.3, 38.8, 35.2, 30.7, 25.8, 22.9, 17.8. [R]25 ) +53 (c )
D
0.011 g/mL, CHCl3). HRMS (CI+) m/z Calcd for C17H27O5 (M +
1): 311.1856. Found 311.1841.
Isomerization of 3B to 3A. A 10-mL oven-dried, round-
bottomed flask, equipped with a septum with a flow of nitrogen
through a needle and a stir bar, was charged with toluene (4 mL).
Compound 3B (10 mg, 0.04 mmol), thiophenol (0.014 mL, 0.14
mmol), and AIBN (10 mg, 0.06 mmol) were added sequentially to
the flask. The solution was heated to 80 °C for 8 h. The mixture
was concentrated in Vacuo, and the resulting residue was purified
by column chromatography on silica gel (hexanes:ethyl acetate )
10:1, Rf ) 0.20) to give 6 mg (60%, based on 75% conversion)
of 3A.
(6S,11aS,13S,14aR,E)-13-(Methoxymethoxy)-6-methyl-
2,3,6,7,8,9,12,13,14,14a-decahydro-1H-cyclopenta[f][1]oxacyclo-
tridecine-1,4(11aH)-dione (18). A 10-mL oven-dried, round-
bottomed flask equipped with a stir bar and a septum with a flow
of nitrogen through a needle was charged with 3 mL of methylene
chloride and diethyl zinc (1.0 M in hexanes, 1.0 mL, 1.0 mmol).
The solution was cooled to 0 °C and compound 3A (62 mg, 0.2
mmol, in 1 mL of methylene chloride) was added to the solution.
After the mixture was stirred for 10 min, methylene iodide (0.08
mL, 1.0 mmol) was added dropwise by syringe. The mixture was
stirred for 0.5 h at room temperature. Diethyl zinc (1.0 M in
hexanes, 0.5 mL, 0.5 mmol) was added to the solution at room
temperature, and after 10 min, methylene iodide (0.04 mL, 0.5
mmol) was added dropwise by syringe. The mixture was stirred
for 0.5 h at room temperature and quenched by cautious addition
of saturated aqueous ammonium chloride (2 mL). The mixture was
extracted with diethyl ether (3 × 5 mL). The combined organic
extracts were washed with brine (5 mL) and dried over anhydrous
sodium sulfate. The resulting liquid was filtered and concentrated
under reduced pressure. The product was purified by flash chro-
matography on silica (hexanes:ethyl acetate ) 7:1; Rf ) 0.20) to
afford 49 mg (75%) of 18 as a colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 5.56 (ddd, 1H, J ) 5.0, 10.0, 15.0 Hz), 5.31 (dd, 1H, J
) 8.8, 15.2 Hz), 4.78 (m, 1H), 4.62 (s, 2H), 4.21 (m, 1H), 3.36 (s,
(S)-Hept-6-en-2-yl 3-((1R,2S,4S)-4-(Methoxymethoxy)-2-vin-
ylcyclopentyl)-3-oxopropanoate (4). A 5-mL oven-dried, round-
bottomed flask, equipped with a septum with a flow of nitrogen
through a needle and a stir bar, was charged with anhydrous THF
(2 mL), compound 5 (0.10 g, 0.5 mmol, in 1 mL of THF), and
1,1-dicarbonylimidazole (0.10 g, 0.6 mmol) in the indicated order.
A separate 25-mL oven-dried, round-bottomed flask, equipped with
a septum with a flow of nitrogen through a needle and a stir bar,
was charged with tetrahydrofuran (8 mL) and diisopropylamine
(0.28 mL, 2 mmol) in order. After the solution was cooled to 0 °C
in the ice bath, n-BuLi (2.0 M in hexanes, 1.0 mL, 2.0 mmol) was
added dropwise. After being stirred for 10 min, the reaction mixture
was cooled to -78 °C, compound 17 (0.31 g, 2 mmol, in 3 mL of
THF) was added in 1 h using syringe pump. The acyl imidazole
solution was transferred to the enolate solution by cannula. After
being stirred for 30 min, the reaction was quenched by cautious
addition of 1 M HCl (2 mL). The solution was extracted with diethyl
ether (3 × 5 mL), and the combined organic layers were washed
by brine (5 mL). The organic layers were dried over anhydrous
sodium sulfate, filtered, and concentrated in Vacuo. The residue
was chromatographed on silica (hexanes:ethyl acetate ) 10:1, Rf
1
) 0.20) to yield 0.14 g (85%) of 4 as a colorless liquid. H NMR
(500 MHz, CDCl3) δ 5.87-5.74 (m, 2H), 5.08-4.93 (m, 4H), 4.62
(s, 2H), 4.17 (m, 1H), 3.44 (s, 2H), 3.35 (s, 3H), 3.04 (dd, 1H, J )
8.9, 17.6 Hz), 2.70 (m, 1H), 2.26 (m, 1H), 2.11-1.96 (m, 4H),
1.64-1.35 (m, 6H), 1.23 (d, 3H, J ) 6.3 Hz); 13C NMR (125 MHz,
CDCl3) δ 204.3, 167.0, 141.8, 138.6, 115.4, 115.0, 95.5, 77.4, 72.4,
55.7, 55.6, 49.9, 45.8, 40.0, 36.1, 35.4, 33.6, 24.8, 20.1. [R]25
)
D
-26 (c ) 0.001 g/mL, CHCl3); HRMS (FAB+) m/z Calcd for
C19H31O5 (M + 1): 339.2195. Found 339.2171.
(10aS,13aR,E)-5,6,7,8,11,12,13,13a-Octahydrocyclopenta[e][1]-
oxacyclododecine-1,3(2H,10aH)-dione (3A) and (10aS,13aR,Z)-
4394 J. Org. Chem., Vol. 72, No. 12, 2007

Formal Synthesis of (+)-Brefeldin A
3H), 3.01-2.91 (m, 2H), 2.80 (m, 1H), 2.66-2.54 (m, 2H), 2.39-
2.28 (m, 2H), 2.05-1.81 (m, 4H), 1.64-1.46 (m, 2H), 1.28-1.10
(m, 3H), 1.19 (d, 3H, J ) 6.3 Hz); 13C NMR (125 MHz, CDCl3)
δ 210.9, 172.9, 133.2, 132.2, 95.5, 71.8, 56.6, 55.6, 46.7, 40.3,
38.8, 36.6, 32.6, 31.1, 29.5, 24.2, 19.6. IR (neat, cm-1): 3040, 2980,
aqueous ammonium chloride (5 mL), and extracted with diethyl
ether (3 × 5 mL). The combined organic layers were dried with
anhydrous sodium sulfate and concentrated in Vacuo. The residue
was chromatographed on silica (hexanes:ethyl acetate ) 7:1; Rf
) 0.25) to yield 12 mg (46%) of 2 as a yellow oil. 1H NMR (500
MHz, CDCl3) δ 7.76 (d, 1H, J ) 16.0 Hz), 6.44 (d, 1H, J ) 15.8
Hz), 5.86 (ddd, 1H, J ) 4.1, 10.9, 15.1 Hz), 5.52 (ddd, 1H, J )
1.3, 9.6, 15.2 Hz), 4.56 (m, 1H), 4.63 (s, 2H), 4.10 (m, 1H), 3.36
(s, 3H), 2.88 (q, 1H, J ) 9.1 Hz), 2.56 (q, 1H, J ) 9.1 Hz), 2.30-
2.21 (m, 2H), 2.14 (m, 1H), 2.02 (m, 1H), 1.96-1.88 (m, 2H),
1.80 (m, 1H), 1.68-1.58 (m, 2H), 1.33 (d, 3H, J ) 6.1 Hz), 1.22
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 200.5, 166.1, 140.2, 135.7,
132.9, 128.3, 95.2, 77.2, 73.7, 56.0, 55.3, 45.2, 40.3, 34.2, 32.7,
32.2, 25.6, 20.2. [R]25 ) -20 (c ) 0.001 g/mL, CHCl3).
1750, 1720. [R]25 ) +22.5 (c ) 0.002 g/mL, CHCl3). HRMS
D
(FAB+) m/z Calcd for C18H29O5 (M + 1): 325.2015. Found
325.2020.
(2E,6S,10E,11aS,13S,14aR)-13-(Methoxymethoxy)-6-methyl-
6,7,8,9,12,13,14,14a-octahydro-1H-cyclopenta[f][1]oxacyclotri-
decine-1,4(11aH)-dione (2). A 10-mL oven-dried, round-bottomed
flask equipped with a stir bar and a septum with a flow of nitrogen
through a needle was charged with 3 mL of methylene chloride
and diethyl zinc (1.0 M in hexanes, 0.5 mL, 0.5 mmol). The solution
was cooled to 0 °C, and compound 3A (25 mg, 0.08 mmol, in 1
mL of methylene chloride) was added to the solution. After the
mixture was stirred for 10 min, methylene iodide (0.02 mL, 0.5
mmol) was added dropwise by syringe. The mixture was stirred
for 0.5 h at room temperature. Diethyl zinc (1.0 M in hexanes,
0.25 mL, 0.25 mmol) was added to the solution at room temperature,
and after 10 min, methylene iodide (0.02 mL, 0.25 mmol) was
added dropwise by syringe. The mixture was stirred for 0.5 h at
room temperature. Iodine (0.5 g, 2.0 mmol) was added to the
reaction mixture in a single portion and stirred until a pink color
persisted for 30 s. A saturated solution of sodium thiosulfate (2
mL) was added, and the mixture was stirred until the pink color
had disappeared. To this solution was added DBU (0.15 mL, 1.0
mmol), and the mixture was stirred for 1 min, washed with saturated
Literature12 [R]25 ) -D18.5 (c ) 0.50 g/mL, CH3OH). HRMS
D
(FAB+) m/z Calcd for C18H27O5 (M + 1): 323.1859. Found
323.1852.
Acknowledgment. We acknowledge NIH (2 R15 GM060967)
for support of this research.
Supporting Information Available: 1H NMR spectra of 2, 3A,
3B, 4, 5, 6, 9, 10, 11, 13, 14, 15, 17, and 18. 13C NMR spectra of
2, 3A, 3B, 4, 5, 6, 10, 11, 13, 14, 15, 17, and 18. This material is
available free of charge via the Internet at http://pubs.acs.org
JO0701379
J. Org. Chem, Vol. 72, No. 12, 2007 4395