Total synthesis of aigialomycin D using a Ramberg - Baecklund/ RCM strategy

Article abstract of DOI:10.1021/jo802561s

The bioactive resorcylic acid lactone aigialomycin D (1) has been synthesized by a novel combination of ring-closing metathesis (RCM) and Ramberg - Baecklund reactions. This synthetic strategy enables the Cl - C2 alkene to be masked as a sulfone during formation of the macrocycle by ring closing metathesis at the C7 - C8 olefin, thus avoiding competing formation of a cyclohexene. A subsequent Ramberg-Baecklund reaction efficiently produces the C1- C2 E-alkene. This combined RCM/ Ramberg-Baecklund reaction strategy should be widely applicable to the synthesis of maerocyclic dienes.

Full text of DOI:10.1021/jo802561s

Total Synthesis of Aigialomycin D Using a Ramberg-Ba¨cklund/
RCM Strategy§
Lynton J. Baird,† Mattie S. M. Timmer,† Paul H. Teesdale-Spittle,‡ and Joanne E. Harvey*,†
School of Chemical and Physical Sciences and School of Biological Sciences, Centre for BiodiscoVery,
Victoria UniVersity of Wellington, P.O. Box 600, Wellington, New Zealand
joanne.harVey@Vuw.ac.nz
ReceiVed NoVember 18, 2008
The bioactive resorcylic acid lactone aigialomycin D (1) has been synthesized by a novel combination
of ring-closing metathesis (RCM) and Ramberg-Ba¨cklund reactions. This synthetic strategy enables the
C1′-C2′ alkene to be masked as a sulfone during formation of the macrocycle by ring closing metathesis
at the C7′-C8′ olefin, thus avoiding competing formation of a cyclohexene. A subsequent
Ramberg-Ba¨cklund reaction efficiently produces the C1′-C2′ E-alkene. This combined RCM/
Ramberg-Ba¨cklund reaction strategy should be widely applicable to the synthesis of macrocyclic dienes.
Introduction
Aigialomycin D (1) was isolated in 2002 from the marine
mangrove fungus Aigialus parVus, along with four other
aigialomycins (A-C, E) and the known macrocyclic natural
product hypothemycin.1 These compounds are structurally
related to other resorcylic acid macrolactones, such as radicicol,
zearalenone, and the pochonins, which are mycotoxins with a
diverse array of biological activities and biochemical targets.2
Aigialomycin D displayed moderate antimalarial activity, with
IC50 ) 6.6 µg/mL for Plasmodium falciparum, and was
cytotoxic in some human cell lines, with IC50 ) 3.0 and 18
µg/mL in KB and BC-1 cells, respectively.1 More recently,
studies into the molecular targets of aigialomycin D have
established that 1 inhibits the kinases CDK1, CDK5, and GSK3
at micromolar levels.3
synthetic routes, which have generally involved major discon-
nections at the macrolactone moiety and the two alkenes.
Unfortunately, difficulties are encountered when the macrocycle-
forming metathesis is performed on a triene precursor in which
one of the alkenes of the natural product is already installed,
due to the competing facile metathesis process that produces a
six-membered ring.3,6 Therefore, some form of masking of one
alkene is required during the RCM, followed by its revelation
at a later stage. To this end, Geng and Danishefsky constructed
the macrocycle by RCM of a precursor in which the C1′-C2′
olefin was masked as a silyl ether, which would be deprotected
and eliminated via Martin’s sulfurane prior to appending the
aromatic portion using a cycloaddition-cycloreversion se-
The structure of aigialomycin D and its promising biology
have resulted in a flurry of synthetic activity,4 culminating so
far in five reported total syntheses of this intriguing target3,5
and a number of synthetic analogues.3,6 Ring-closing metathesis
(RCM)7 has been featured as a theme in several of these
§ We dedicate this article to Professor Richard J. K. Taylor in celebration of
his 60th birthday.
† School of Chemical and Physical Sciences.
‡ School of Biological Sciences.
(1) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561–1566.
(2) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22–36.
10.1021/jo802561s CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2271–2277 2271

Baird et al.
quence.5a Winssinger’s successful total synthesis invoked
elimination of a benzylic phenylselenide to generate the
C1′-C2′ alkene after the key RCM.3 In another approach, Chen
and co-workers described the reduction of a macrocyclic C2′-
ketone and elimination of the resulting hydroxy group in
synthesizing aigialomycin D.5c
SCHEME 1. Retrosynthetic Analysis of Aigialomycin D (1)
An alternative solution could involve use of a sulfone-tethered
diene in the RCM reaction, followed by its transformation into
an E-alkene using the Ramberg-Ba¨cklund reaction. This
strategy has the potential to be applied to the synthesis of a
wide range of macrocycles containing two or more double
bonds.
The Ramberg-Ba¨cklund reaction (RBR)8 produces an alkene
from an R-halo sulfone through formation of an episulfone
(thiirane dioxide) and cheleotropic extrusion of SO2.9,10 Several
variations of this methodology have been developed,10 including
Meyers’ extension of the RBR,11 in which R-halogenation of a
sulfone is additionally achieved, thus making the conversion
of a sulfone into an alkene an efficient one-pot procedure. The
RBR has recently been used extensively in exo-glycal and
C-glycoside formation12 and found application in the synthesis
of natural products, dendritic compounds, enediynes, unsaturated
amino acids, and other targets.10,13 In combination with ring-
closing metathesis, the RBR has previously been applied to the
synthesis of cyclohexadienes and cycloheptadienes.13b The
sulfone substrate for the Meyers-modified Ramberg-Ba¨cklund
reaction represents a masked alkene, a property that can be
exploited in an RCM-based synthesis of macrocyclic dienes,
as demonstrated here in the synthesis of aigialomycin D.
We decided to explore the use of the RBR for incorporating
the conjugated C1′-C2′ alkene while relying on RCM for
installing the C7′-C8′ double bond and closing the macrocycle
(Scheme 1). Thus, our retrosynthetic analysis of aigialomycin
D led to sulfone-containing diene 2 as a key intermediate by
invoking RBR and RCM disconnections. Diene 2 contains a
stable precursor to the C1′-C2′ alkene, in the form of a sulfone,
expected to be fully compatible with the RCM reaction.7b
Compound 2 would, in turn, be derived from the thioether 3,
which could be disconnected to the aromatic fragment 4, thiol
5, and commercially available homoallylic alcohol 6. Substitu-
tion of the benzylic bromide 4 by thiol 5, followed by methyl
SCHEME 2. Synthesis of Benzylic Bromide 4
ester hydrolysis and Mitsunobu reaction with alcohol 6, would
deliver the full carbon skeleton 3, poised for thioether oxidation
to sulfone 2, and the key RCM and RBR sequence.
Results and Discussion
The benzylic bromide 4 was derived from known methyl
orsellinate (7a) (Scheme 2). Surprisingly, the synthesis of methyl
orsellinate was less facile than expected: the one-pot procedures
previously described,14 which involved sequential treatment of
methyl acetoacetate with NaH and BuLi followed by acid-
promoted aromatization, initially yielded extremely poor results.
Eventually, we discovered that this reaction is highly dependent
on the source of the NaH,15 and addressing this issue improved
the reaction sufficiently to afford the required material. Benzylic
bromination of either unprotected methyl orsellinate (7a) or the
dimethyl ether-protected variant (7b) was accompanied by large
amounts of undesired aromatic bromination at C5. Fortunately,
however, acetylation of the phenolic functional groups in 7a
sufficiently deactivated the aromatic ring to allow the desired
bromination at the benzylic position of 7c to proceed efficiently,
producing coupling partner 4 in good yield (71%).
(3) Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger, N.
Angew. Chem., Int. Ed. 2006, 45, 3951–3954.
(4) Zhang, H.-K.; Chen, W.-Q. Gaodeng Xuexiao Huaxue Xuebao (Chem.
J. Chin. UniV.) 2007, 28, 689–691.
(5) (a) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413–416. (b) Lu, J.;
Ma, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2006, 17,
1066–1073. (c) Vu, N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Chen, A.
Tetrahedron 2007, 63, 7053–7058. (d) Chrovian, C. C.; Knapp-Reed, B.;
Montgomery, J. Org. Lett. 2008, 10, 811–814.
(6) Bajwa, N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390–393.
(7) (a) Majumdar, K. C.; Rahaman, H.; Roy, B. Curr. Org. Chem. 2007, 11,
1339–1365. (b) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64,
2361–2366.
(8) Ramberg, L.; Ba¨cklund, B. Ark. Kemi. Mineral. Geol. 1940, 27, 1-50;
Chem. Abstr. 1940, 34, 4725.
(9) (a) Bordwell, F. G.; Cooper, G. D. J. Am. Chem. Soc. 1951, 73, 5187–
5190. (b) Sutherland, A. G.; Taylor, R. J. K. Tetrahedron Lett. 1989, 30, 3267–
3270. (c) Bordwell, F. G.; Doomes, E. J. Org. Chem. 1974, 39, 2526–2531.
(10) (a) Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357–475. (b) Clough,
J. M. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 861-886. (c) Paquette, L. A. Org.
React. 1977, 25, 1–71.
(14) (a) Chiarello, J.; Joullie´, M. M. Tetrahedron 1988, 44, 41–48. (b) Barrett,
A. G. M.; Morris, T. M.; Barton, D. H. R. J. Chem. Soc., Perkin Trans. 1 1980,
2272–2277.
(11) Meyers, C. Y.; Malte, A. M.; Matthews, W. S. J. Am. Chem. Soc. 1969,
91, 7510–7512.
(12) (a) Taylor, R. J. K.; McAllister, G. D.; Franck, R. W. Carbohydr. Res.
2006, 341, 1298–1311. (b) Taylor, R. J. K. Chem. Commun. 1999, 217–227.
(13) (a) Feng, J.-P.; Wang, X.-L.; Cao, X.-P. Chin. J. Org. Chem. 2006, 26,
158–167. (b) Yao, Q. Org. Lett. 2002, 4, 427–430.
(15) (a) Gimbert, Y. Personal communication, 2005. (b) Chevenier, E.;
Lucatelli, C.; Pandya, U.; Wang, W.; Gimbert, Y.; Greene, A. E. Synlett 2004,
2693–2696. (c) Hu, H. Ph.D. Thesis, Department of Chemistry, Simon Fraser
University, Burnaby, BC, Canada, 2004.
2272 J. Org. Chem. Vol. 74, No. 6, 2009

Total Synthesis of Aigialomycin D
TABLE 1. Metal-Catalyzed NaBH4 Reduction of r,ꢀ-Unsaturated
SCHEME 3. Preparation of Thioacetate 8 from D-Ribose
Ester 11a
isolated yields (%)
metal cat./
entry
additive
13
11
byproducts
1
2
3
4
5
6
none
NiCl2
CoCl2
CuCl2
CuCl
CuCl/cyclohexene
0
0
0
45
33
96
100
0
0
24
47
0
0
84
67
21
5
0
a See the Supporting Information for full details.
by NiCl222 (entry 2) or CoCl223 (entry 3) led to the isolation of
the undesired fully saturated ester 15 (see Scheme 3). Use of
CuCl2 (entry 4) or CuCl25 (entry 5) as catalyst provided the
24
sought-after R,ꢀ-saturated ester 13, albeit contaminated with
various byproducts, including the fully saturated ester 15,
unreacted starting material 11, and compounds lacking the
isopropylidene group. Optimization of the most promising
results involved using a combination of sodium borohydride
and cuprous chloride, with cyclohexene present to trap excess
reducing agent and thus prevent over-reduction of the noncon-
jugated alkene (entry 6). In this way, the R,ꢀ-saturated ester 13
was produced in excellent yield (96%).
Reduction of the ester 13 to alcohol 12 was straightforward
and again high yielding. Conversion of this alcohol into the
coupling precursor 8 was achieved by mesylation to provide
the corresponding sulfonate, followed by reaction with potas-
sium thioacetate. It was found that the thiol coupling partner 5
was unstable to storage and that its in situ preparation from the
thioacetate 8 as part of the coupling reaction was therefore
preferable.
Preparation of the coupled thioether 16 was achieved through
methanolysis of thioacetate 8, followed by nucleophilic substitu-
tion of the benzylic bromide within aromatic fragment 4 by the
resultant thiolate (Scheme 4). Concomitant cleavage of the
phenolic protecting groups under these basic conditions provided
the deacetylated dihydroxybenzoate 16 in excellent yield (86%).
Saponification of the ester group within compound 16 proved
problematic: using lithium hydroxide or sodium hydroxide led
to significant amounts of the decarboxylated resorcinol 17
(Scheme 4), in keeping with previous reports of decarboxylation
occurring in benzoates bearing a free OH group at the ortho
position.26 Lithium ethanethiolate also failed to deliver the
desired benzoic acid derivative, returning only starting material
16. To circumvent these problems, the phenolic groups were
protected with methoxymethyl chloride prior to saponification,
which now proceeded smoothly with potassium hydroxide.
Esterification of the resulting carboxylic acid 18 with 4-penten-
Thiol 5 was obtained in its thioacetate-protected form 8 in
eight steps from D-ribose via the known aldehyde 1016 (Scheme
3). The sequence began with a one-pot methylation and
isopropylidenation of D-ribose using methanol and acetone in
the presence of hydrochloric acid.17 The resulting primary
alcohol was converted into the corresponding iodide 917 via a
tosylate. Vasella reaction18 of compound 9 led to the ring-opened
ω-enal 10,16 which underwent a Wittig reaction with the
stabilized ylid methyl (triphenylphosphoranylidene)acetate to
give the R,ꢀ-unsaturated ester 11 as a 4.7:1 mixture of Z- and
E-isomers.19
Methodology was then sought for the selective reduction of
the R,ꢀ-unsaturated ester 11 to the saturated primary alcohol
12 while leaving the terminal alkene intact, either in a single
step or over two consecutive steps via R,ꢀ-saturated ester 13.
An attempt at performing a one-pot dual reduction of R,ꢀ-
unsaturated ester 11 using lithium aluminum hydride afforded
poor yields of the desired saturated alcohol 12 and the ester 13
alongside, as major product, the unwanted allylic alcohol 14.
Use of magnesium in methanol20 did not deliver either desired
product 12 or 13, instead leading to elimination of the
isopropylidene group.21 Therefore, a variety of metal-catalyzed
sodium borohydride systems were investigated (Table 1) for
the selective reduction of the conjugated alkene within 11 to
afford the R,ꢀ-saturated ester 13, which would be subsequently
reduced to alcohol 12 with lithium aluminum hydride. While
treatment of R,ꢀ-unsaturated ester 11 with sodium borohydride
alone failed to convert the starting material 11 (entry 1), catalysis
(16) Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee,
J.-M.; Ohmura, H. Org. Lett. 2006, 8, 5373–5376.
(17) Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849–7856.
(18) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990–2016.
(19) Z-Selective Wittig reactions with stabilized ylids can occur in cases
where the aldehyde contains a ꢀ-heteroatom substituent capable of interacting
with the solvent. (a) See: Harvey, J. E.; Raw, S. A.; Taylor, R. J. K. Org. Lett.
2004, 6, 2611–2614, and references cited therein.
(20) Chow, S.; Fletcher, M. T.; Lambert, L. K.; Gallagher, O. P.; Moore,
C. J.; Cribb, B. W.; Allsopp, P. G.; Kitching, W. J. Org. Chem. 2005, 70, 1808–
1827.
(22) Coumbarides, G. S.; Motevalli, M.; Muse, W. A.; Wyatt, P. B. J. Org.
Chem. 2006, 71, 7888–7891.
(23) He, R.; Deng, M.-Z. Tetrahedron 2002, 58, 7613–7617.
(24) Postema, M. H. D.; Piper, J. L.; Komanduri, V.; Liu, L. Angew. Chem.,
Int. Ed. 2004, 43, 2915–2918.
(25) Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. J. Org. Chem. 1989,
54, 5308–5313.
(26) Pettigrew, J. D.; Wilson, P. D. J. Org. Chem. 2006, 71, 1620–1625,
and references cited therein.
(21) Pak, C. S.; Lee, E.; Lee, G. H. J. Org. Chem. 1993, 58, 1523–1530.
J. Org. Chem. Vol. 74, No. 6, 2009 2273

Baird et al.
SCHEME 4. Construction of the Full Carbon Skeleton of
Aigialomycin D
In contrast, the conventional reaction resulted only in recovered
starting material 2 after 18 h at reflux. The macrocyclic sulfone
19 was subjected to a Ramberg-Ba¨cklund reaction using
Meyers’ conditions, which proceeded efficiently with no
discernible side products observed in the 1H NMR spectrum of
the crude reaction mixture. The proposed mechanism involves
benzylic chlorination, followed by deprotonation at the non-
benzylic sulfone R-center,9a episulfone formation9b,c by in-
tramolecular displacement of the chloride, and cheleotropic SO2
extrusion.10 The E-alkene 20 was isolated in 84% yield, with
no indication of Z-isomer formation. The stereoselectivity
observed here is particularly gratifying because high stereo-
control is not a guaranteed feature of the RBR in nonconstrained
systems.10
Interestingly, model reactions of the RBR using benzyl pentyl
sulfone (generated from benzyl mercaptan and 1-bromopentane)
had produced a complex mixture of products, including the
desired alkene plus a halogenated alkene, presumably arising
by double halogenation at the benzylic position followed by
the standard RBR process.10 The better outcome from the RBR
of macrocycle 19 is consistent with, and extends, the generaliza-
tion that small- and medium-ring sulfones tend to react more
cleanly than acyclic sulfones.27 The fact that the macrocyclic
system reacted so efficiently also highlights the potential utility
of the Ramberg-Ba¨cklund reaction in medium-to-large ring
synthesis, a role in which it has found relatively limited use.28
Final deprotection of macrocycle 20 was achieved using
methanolic aqueous HCl. The resulting material, 1, obtained in
SCHEME 5
1
86% yield, had H and 13C NMR data that matched those
reported from natural and synthetic aigialomycin D.1,3
Conclusions
Overall, this route to aigialomycin D proceeds in 16 steps
(longest linear sequence) from readily available starting materi-
als. The combination of the Ramberg-Ba¨cklund and RCM
reactions proved very effective for producing the diene-
containing macrocycle of aigialomycin D, with high yields and
complete stereoselectivity observed in these key steps. The
preparation of new structural analogs of aigialomycin D for
biological screening, and the scope of the RBR/RCM strategy
in the synthesis of diene-containing macrocycles are currently
being investigated.
Experimental Section
Methyl 2,4-Dihydroxy-6-methylbenzoate (Methyl Orselli-
nate, 7a). To a suspension of NaH (2.56 g of a 60% dispersion in
mineral oil, 64 mmol, washed three times with dry hexanes) in
THF (100 mL) at 0 °C was added methyl acetoacetate (5.0 g, 43
mmol) dropwise. The mixture was stirred for 1 h, warming to rt.
The reaction was cooled to -78 °C and a 1.6 M solution of
n-butyllithium in hexanes (25.6 mL, 41 mmol) was added dropwise
over 2 h. The reaction was then stirred at rt for 12 h. The reaction
mixture was then refluxed for a further 24 h. The cooled orange
solution was acidified with 10% HCl to pH 1 and stirred at rt for
12 h. The organic layer was separated, and the aqueous layer was
2-ol using the Mitsunobu protocol gave better yields than the
corresponding DCC-promoted coupling. It was also found that
the yield of the Mitsunobu reaction was sensitive to the order
of reagent addition. Thus, addition of the acid to the preformed
triphenylphosphonium-activated intermediate provided the full
carbon skeleton of aigialomycin D in its desired (10′S)-
stereoisomeric form (3) and excellent yield.
Oxidation of the thioether 3 to the corresponding sulfone 2
was performed using m-CPBA (Scheme 5). The desired sulfone
was isolated in 84% yield, and only traces of alkene epoxidation
products were observed during this process. Macrocycle forma-
tion by ring-closing metathesis proceeded smoothly and rapidly
under microwave irradiation, the reaction being completed in
30 min with heating up to 75 °C. The product 19 was isolated
in 86% yield, with only the E-alkene isomer being observed.
(27) Page 385 of ref 10a.
(28) (a) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.;
Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866–4868. (b) Mlinaric´-Majerski,
K.; Pavlovic´, D.; Marinic´, Z. Tetrahedron Lett. 1996, 37, 4829–4832. (c) Chan,
T.-L.; Hung, C.-W.; Man, T.-O.; Leung, M.-K. J. Chem. Soc., Chem. Commun.
1994, 1971–1972. (d) Doomes, E.; McKnight, A. A. J. Heterocycl. Chem. 1995,
32, 1467–1471. (e) McGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060–
1066. (f) Wei, C.; Mo, K.-F.; Chan, T.-L. J. Org. Chem. 2003, 68, 2948–2951.
2274 J. Org. Chem. Vol. 74, No. 6, 2009

Total Synthesis of Aigialomycin D
extracted with EtOAc (3 × 75 mL), dried with MgSO4, filtered,
and concentrated under reduced pressure. The product was purified
using flash column chromatography (silica, gradient elution 5:1 to
3:1 hexanes/EtOAc) to provide methyl orsellinate (7a) as a white
solid (1.56 g, 40%): Rf ) 0.44 (2:1 hexanes/EtOAc); mp 141-142
°C [lit.29 mp 139-140 °C]. Spectral data matched those reported
in the literature.14a
(Z)-11 and (E)-11 for characterization. (Z)-11: [R]22D ) +216.8 (c
1.00, CHCl3); Rf ) 0.59 (2:1 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3) δ 6.20 (dd, J ) 11.6, 7.5 Hz, 1H), 5.90 (dd, J ) 11.6, 1.6
Hz, 1H), 5.68 (td, J ) 7.3, 1.5 Hz, 1H), 5.66 (ddd, J ) 17.4, 10.2,
7.2 Hz, 1H), 5.28 (ddd, J ) 17.1, 1.7, 1.3 Hz, 1H), 5.15 (ddd, J )
10.3, 1.9, 1.0 Hz, 1H), 4.87 (tt, J ) 7.1, 0.9 Hz, 1H), 3.72 (s, 3H),
1.55 (s, 3H), 1.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.1,
146.8, 134.0, 121.0, 117.9, 109.2, 79.7, 75.6, 51.5, 27.7, 25.1; IR
(KBr) 2985, 2945, 1722, 1648, 1439, 1406, 1381, 1224, 1198, 1179,
1046, 1001, 927, 876, 825 cm-1; HRMS (ESI) calcd for
C11H16O4Na+ [M + Na]+ 235.0946, found 235.0942. (E)-11: Rf )
Methyl 2,4-Bis(acetyloxy)-6-methylbenzoate (7c). To a solution
of methyl orsellinate (7a) (1.26 g, 6.90 mmol) in CH2Cl2 (17.5
mL) at rt were added NEt3 (5.76 mL, 41.4 mmol) and acetic
anhydride (2.60 mL, 27.6 mmol). The reaction was stirred for 12 h
at rt before being quenched with saturated aqueous NaHCO3
solution (30 mL). The organic layer was separated, dried with
MgSO4, filtered, and concentrated under reduced pressure. The
resulting oil was purified by passing it through a short silica column
(gradient elution 5:1-2:1 hexanes/EtOAc) with a few drops of
AcOH to yield the title compound as a white solid (1.82 g, 98%):
Rf ) 0.31 (2:1 hexanes/EtOAc); mp 53-54 °C; 1H NMR (300 MHz,
CDCl3) δ 6.89 (d, J ) 2.2 Hz, 1H), 6.80 (d, J ) 2.2 Hz, 1H), 3.88
(s, 3H), 2.41 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 168.9, 168.6, 166.3, 151.7, 149.3, 139.8, 121.3,
114.2, 77.2, 52.2, 21.1, 20.8, 20.5; IR (neat) 3086, 2959, 1781,
1732, 1616, 1587, 1446, 1370, 1280, 1174, 1137, 1098, 1054, 1018,
953, 911 cm-1; HRMS (ESI) calcd for C13H14O6Na+ [M + Na]+
289.0683, found 289.0685.
1
0.51 (2:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 6.79
(dd, J ) 15.6 5.5 Hz, 1H), 6.08 (dd, J ) 15.6, 1.6 Hz, 1H), 5.69
(ddd, J ) 17.1, 10.3, 7.6 Hz, 1H), 5.37 (dd, J ) 17.1, 1.5 Hz, 1H),
5.27 (ddd, J ) 10.3, 1.5, 0.9 Hz, 1H), 4.78 (ddd, J ) 7.0, 5.6, 1.6
Hz, 1H), 4.71 (tt, J ) 7.0, 0.9 Hz, 1H), 3.75 (s, 3H), 1.56 (s, 3H),
1.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.4, 143.9, 133.4,
122.2, 119.3, 109.6, 79.8, 77.5, 51.7, 27.7, 25.4.
Methyl (4S,5R)-4,5-O-(1-Methylethylidene)hept-6-enoate (13).
To a solution of R,ꢀ-unsaturated ester 11 (519 mg, 2.45 mmol),
CuCl (186 mg, 1.88 mmol), and cyclohexene (960 µL, 9.43 mmol)
in MeOH (40 mL) at -78 °C was added NaBH4 (446 mg, 11.8
mmol). The reaction mixture was left at -78 °C for 1 h, during
which time it turned from green to brown. While the mixture was
still cold, the solvent was removed on the rotary evaporator. The
products were partitioned between saturated aqueous NH4Cl solution
(50 mL) and Et2O (50 mL). The organic phase was separated, and
the aqueous layer was extracted with more Et2O (4 × 20 mL). The
organic layers were combined, dried with MgSO4, filtered, and
reduced to give a colorless oil (520 mg, 96%). The product was
deemed sufficiently pure by 1H NMR for use without further
Methyl 2,4-Bis(acetyloxy)-6-(bromomethyl)benzoate (4). To
a solution of 7c (440 mg, 1.64 mmol) in CCl4 (15 mL) were added
NBS (180 mg, 1.01 mmol) and benzoyl peroxide (20 mg), and the
reaction mixture was heated to reflux. After 3 h, another portion
of NBS (180 mg, 1.01 mmol) and benzoyl peroxide (20 mg) was
added to the mixture, and the reaction was heated to reflux for a
further 3 h. After this time, the reaction was cooled to rt, the solid
succinimide filtered off, and the solvent removed under reduced
pressure. The resulting orange oil was purified by flash column
chromatography (silica, CH2Cl2) to yield the title compound 4 as a
white solid (400 mg, 71%) and the corresponding dibromide as a
white solid (81 mg, 12%). Compound 4: Rf ) 0.46 (CH2Cl2); mp
purification: Rf ) 0.46 (2:1 hexanes/EtOAc); [R]22 ) -31.0 (c
D
1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.82 (ddd, J ) 17.2,
10.3, 7.6 Hz, 1H), 5.34 (ddd, J ) 17.1, 1.7, 1.1 Hz, 1H), 5.26 (ddd,
J ) 10.3, 1.6, 0.9 Hz, 1H), 4.54 (dd, J ) 7.5, 6.4 Hz, 1H), 4.16
(ddd, J ) 8.8, 6.2, 5.4 Hz, 1H), 3.67 (s, 3H), 2.49 (ddd, J ) 16.3,
8.3, 6.4 Hz, 1H), 2.40 (ddd, J ) 16.4, 8.5, 7.4 Hz, 1H), 1.81-1.70
(m, 2H), 1.47 (s, 3H), 1.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 173.6, 133.7, 118.6, 108.4, 79.5, 77.2, 51.7, 30.7, 28.2, 26.2,
25.7; IR (KBr) 2987, 2935, 1736, 1645, 1440, 1371, 1255, 1217,
1162, 1067, 1011, 931, 871 cm-1; HRMS (ESI) calcd for
C11H18O4Na+ [M + Na]+ 237.1103, found 237.1100.
1
62-64 °C; H NMR (300 MHz, CDCl3) δ 7.12 (d, J ) 2.2, 1H),
6.95 (d, J ) 2.2, 1H), 4.63 (s, 2H), 3.92 (s, 3H), 2.29 (s, 3H), 2.27
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.6, 168.3, 165.2, 152.0,
149.8, 139.3, 123.0, 121.3, 117.0, 52.7, 29.7, 21.1, 20.7; IR (KBr)
3082, 2950, 1770, 1731, 1613, 1434, 1370, 1282, 1187, 1138, 1094,
1033, 1017, 907 cm-1; HRMS (ESI) calcd for C13H13O6BrNa+ [M
+ Na]+ 366.9793, found 366.9798.
(4S,5R)-4,5-O-(1-Methylethylidene)hept-6-en-1-ol (12). To a
suspension of lithium aluminum hydride (115 mg, 3.03 mmol) in
Et2O (30 mL) at -10 °C was added methyl ester 13 (540 mg, 2.52
mmol) in Et2O (15 mL). After 10 min, TLC analysis confirmed
that all the starting material had been consumed. The reaction was
quenched with wet Na2SO4, filtered through a pad of Celite, and
reduced to dryness to yield alcohol 12 as a colorless oil (458 mg,
Methyl (2Z,4S,5R)-4,5-O-(1-Methylethylidene)hepta-2,6-di-
enoate [(Z)-11] and Methyl (2E,4S,5R)-4,5-O-(1-Methyleth-
ylidene)hepta-2,6-dienoate [(E)-11]. To iodide 9 (2.05 g, 6.52
mmol) in MeOH (30 mL) were added activated zinc (3.00 g, 45.9
mmol) and AcOH (100 µL) before the mixture was refluxed for
4 h. After this time, another portion of zinc (1.50 g, 23.0 mmol)
was added and the reaction refluxed for a further 4 h. Once TLC
had confirmed the consumption of starting material, the reaction
mixture was cooled and filtered through a wad of silica to remove
the excess zinc metal and zinc salts. The filtrate was cooled to 0
°C, and methyl (triphenylphosphoranylidene)acetate (2.62 g, 7.83
mmol) was added to the solution. The reaction was allowed to warm
over 12 h. The solvent was removed and the crude product
partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl
solution (100 mL). The aqueous layer was extracted further with
EtOAc (2 × 50 mL). The combined organic fractions were dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting pale yellow oil was purified using flash column chroma-
tography (silica,10:1 hexanes/EtOAc) to yield the R,ꢀ-unsaturated
ester 11 as a colorless oil [1.06 g, 74% (Z/E ) 4.7:1)]. A portion
was subjected to flash column chromatography (silica, gradient
elution 10:1-3:1 hexanes/EtOAc) to yield separated samples of
97%): Rf ) 0.20 (2:1 hexanes/EtOAc); [R]22 ) -6.1 (c 1.00,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.82 (ddd, J ) 17.1, 10.3,
7.8 Hz, 1H), 5.31 (ddd, J ) 17.1, 1.6, 1.1 Hz, 1H), 5.24 (ddd, J )
10.3, 1.6, 0.9 Hz, 1H), 4.52 (dd, J ) 7.4, 6.7 Hz, 1H), 4.18 (ddd,
J ) 8.5, 6.2, 5.0 Hz, 1H), 3.68 (t, J ) 5.8 Hz, 2H), 1.91 (s, 1H),
1.75-1.65 (complex m, 2H), 1.55 (m, 2H), 1.50 (s, 3H), 1.38 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 134.2, 118.4, 108.3, 79.9,
78.2, 62.7, 29.8, 28.3, 27.5, 25.7; IR (KBr) 3435, 2934, 2874, 1644,
1429, 1380, 1248, 1217, 1165, 1047, 1018, 926, 872 cm-1; HRMS
(ESI) calcd for C10H18O3Na+ [M + Na]+ 209.1154, found 209.1152.
(4S,5R)-4,5-O-(1-Methylethylidene)hept-6-ene-1-methane-
sulfonate. To a solution of alcohol 12 (213 mg, 1.15 mmol) in
CH2Cl2 (10 mL) at 0 °C were added NEt3 (320 µL, 2.30 mmol),
DMAP (14 mg, 0.115 mmol), and MsCl (134 µL, 1.70 mmol). The
reaction was allowed to warm to rt and stir for 12 h. After this
time, the reaction was deemed complete by TLC (color change from
purple to black with anisaldehyde dip). The solvent was removed
and the crude product dissolved in EtOAc (20 mL) before being
washed with water (10 mL) and saturated aqueous NaHCO3 solution
(10 mL). The organic layer was dried with MgSO4, filtered, and
(29) Just, G.; Sacripante, G.; Zamir, L. Synth. Commun. 1985, 15, 1007–
1012.
J. Org. Chem. Vol. 74, No. 6, 2009 2275

Baird et al.
concentrated. The resulting oil which was purified using flash
column chromatography (silica, gradient elution 3:1-1:1 hexanes/
EtOAc) yielded the title compound as a colorless oil (294 mg, 97%):
mixture was diluted with Et2O (30 mL) and washed with saturated
aqueous NH4Cl solution (20 mL). The organic layer was separated
and the aqueous layer further extracted with Et2O (2 × 15 mL).
The combined organic fractions were washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated to give a colorless
oil, which was purified using flash column chromatography (silica,
gradient elution, 10:1-5:1 hexanes/EtOAc) to afford the desired
Rf ) 0.26 (2:1 hexanes/EtOAc); [R]22 ) -14.3 (c 1.09, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 5.84 (ddd, J ) 17.1, 10.3, 7.7 Hz,
1H), 5.33 (ddd, J ) 17.1, 1.6, 1.1 Hz, 1H), 5.30 (ddd, J ) 10.3,
1.6, 0.9 Hz, 1H), 4.57 (dd, J ) 7.5, 6.4 Hz, 1H), 4.30 (dt, J ) 9.9,
6.3 Hz, 1H), 4.25 (ddd, J ) 9.8, 7.0, 6.0 Hz, 1H), 4.19 (ddd, J )
9.0, 6.2, 4.7 Hz, 1H), 3.05 (s, 3H), 1.99 (tdd, J ) 12.3, 9.2, 6.2
Hz, 1H), 1.91-1.82 (m, 1H), 1.62-1.54 (complex m, 2H), 1.52
(s, 3H), 1.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 134.2, 118.5,
108.3, 79.7, 77.7, 30.6, 29.6, 28.9, 28.2, 26.3, 25.6; IR (film) 2994,
bis-MOM ether as a colorless oil (562 mg, 74%): Rf ) 0.30 (2:1
1
hexanes/EtOAc); [R]18 ) -30.3 (c 0.08, CHCl3); H NMR (500
D
MHz, CDCl3) δ 6.74 (d, J ) 2.2 Hz, 1H), 6.68 (d, J ) 2.2 Hz,
1H), 5.79 (ddd, J ) 17.1, 10.3, 7.8 Hz, 1H), 5.29 (ddd, J ) 17.1,
1.6, 1.1 Hz, 1H), 5.22 (ddd, J ) 10.3, 1.6, 0.9 Hz, 1H), 5.161 (s,
2H), 5.157 (s, 2H), 4.47 (dd, J ) 7.6, 6.4 Hz, 1H), 4.09 (ddd, J )
8.6, 6.1, 4.7 Hz, 1H), 3.88 (s, 3H), 3.71 (s, 2H), 3.47 (s, 3H), 3.46
(s, 3H), 2.48-2.40 (m, 2H), 1.77-1.67 (m, 1H), 1.60-1.43 (m,
3H), 1.47 (s, 3H), 1.35 (s, H); 13C NMR (125 MHz, CDCl3) δ 167.9,
158.8, 156.0, 139.4, 134.3, 118.3, 110.6, 108.2, 102.5, 95.0, 94.3,
79.7, 77.8, 77.2 56.3, 56.2, 52.2, 34.0, 31.4, 29.5, 28.2, 25.8, 25.6;
IR (neat) 2949, 2906, 1727, 1605, 1434, 1277, 1215, 1144, 1038,
1017, 928, 870 cm-1; HRMS (ESI) calcd for C23H34O8SNa+ [M +
Na]+ 493.1872, found 493.1867.
2939, 1353, 1248, 1212, 1174, 926, 908, 733 cm-1
.
(4S,5R)-4,5-O-(1-Methylethylidene)hept-6-ene-1-thioacetate
(8). To a solution of the mesylate (1.59 g, 6.02 mmol) in DMF (50
mL) at 0 °C was added KSAc (824 mg, 7.23 mmol). The reaction
was allowed to warm to rt and stirred for 12 h. The reaction was
diluted with Et2O (100 mL) and H2O (100 mL). The organic layer
was further washed with saturated aqueous NaHCO3 solution (3 ×
50 mL) before drying with MgSO4, filtering, and concentrating to
give a pale brown oil which was purified using flash column
chromatography (silica, gradient elution 20:1-10:1 hexanes/EtOAc)
(6′S,7′R)-6-(6′,7′-O-(1′′-Methylethylidene)-2′-thianon-8′-enyl)-
2,4-(bismethoxymethoxy)benzoic Acid (18). To a solution of the
bis-MOM methyl ester (455 mg, 0.968 mmol) in 2:1 MeOH/H2O
(15 mL) was added KOH (271 mg, 4.84 mmol), and the reaction
mixture was heated to 90 °C for 48 h. After being cooled to rt, the
mixture was extracted with Et2O (20 mL) and the organic layer
discarded. The aqueous layer was acidified to pH 6 with an aqueous
acetic acid solution (50%, 0.78 mL, 6.8 mmol) and extracted with
Et2O (3 × 15 mL). The combined organic phases were washed
with H2O (4 × 20 mL), dried over MgSO4, filtered, and evaporated
to yield thioacetate 8 as a colorless oil (1.32 g, 90%): Rf ) 0.56
1
(2:1 hexanes/EtOAc); [R]22 ) -9.5 (c 1.05, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 5.79 (ddd, J ) 17.1, 9.7, 7.8 Hz, 1H), 5.30
(d, J ) 17.1 Hz, 1H), 5.24 (d, J ) 10.3 Hz, 1H), 4.49 (t, J ) 6.9
Hz, 1H), 4.13 (m, 1H), 2.95-2.83 (m, 2H), 2.32 (s, 3H), 1.80-1.68
(m, 1H), 1.66-1.50 (m, 2H), 1.49-1.41 (m, 1H), 1.47 (s, 3H),
1.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 195.8, 134.2, 118.5,
108.3, 79.7, 77.7, 30.6, 29.6, 28.9, 28.2, 26.3, 25.6; IR (film) 2986,
2916, 1692, 1455, 1428, 1379, 1369, 1244, 1216, 1134, 1134, 1048,
1012, 929, 871, 625 cm-1; HRMS (ESI) calcd for C12H20O3SNa+
[M + Na]+ 267.1031, found 267.1028.
under reduced pressure to afford the acid 18 as a colorless oil (434
1
mg, 98%): [R]20 ) -32.1 (c 0.2, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 6.77 (d, J ) 2.3 Hz, 1H), 6.73 (d, J ) 2.2 Hz, 1H), 5.79
(ddd, J ) 17.2, 10.2, 7.8 Hz, 1H), 5.28 (ddd, J ) 17.1, 1.6, 1.0
Hz, 1H), 5.22 (s, 2H), 5.22 (dd, J ) 10.3, 1.6, 0.8 Hz, 1H), 5.18
(s, 2H), 4.47 (dd, J ) 7.6, 6.4 Hz, 1H), 4.12 (ddd, J ) 8.4, 6.1, 4.6
Hz, 1H), 3.96 (d, J ) 13.4 Hz, 1H), 3.92 (d, J ) 13.4 Hz, 1H),
3.50 (s, 3H), 3.47 (s, 3H), 2.48 (t, J ) 7.0 Hz, 2H), 1.74 (m, 1H),
1.64-1.38 (m, 3H), 1.47 (s, 3H), 1.35 (s, 3H); IR (neat) 2908,
2845, 1604, 1586, 1462, 1377, 1277, 1216, 1151, 1028, 1020, 927,
744 cm-1; HRMS (ESI) calcd for C22H32O8SNa+ [M + Na]+
479.1716, found 479.1720.
Methyl (6′S,7′R)-6-(6′,7′-O-(1′′-Methylethylidene)-2′-thianon-
8′-enyl)-2,4-dihydroxybenzoate (16). A solution of thioacetate 8
(340 mg, 1.39 mmol) and bromide 4 (485 mg, 1.41 mmol) in dry
MeOH (25 mL) was degassed by bubbling dry argon through the
solution for 10 min. After this time, K2CO3 (466 mg, 3.37 mmol)
was added, and the reaction was stirred at rt for 12 h. After TLC
analysis confirmed the consumption of bromide 4, the solvent was
removed to dryness. The residue was dissolved in EtOAc (50 mL),
and saturated aqueous NH4Cl solution (50 mL) was added. The
organic layer was separated, and the aqueous layer was extracted
with EtOAc (2 × 25 mL). The organic layers were combined,
washed with brine (50 mL), dried with MgSO4, filtered, and reduced
to dryness. The crude residue was purified using column chroma-
tography (silica, gradient elution, 5:1-3:1 hexanes/EtOAc) to yield
(4S,6′S,7′R)-Pent-1-en-4-yl 6-(6′,7′-O-(1′′-Methylethylidene)-
2′-thianon-8′-enyl)-2,4-(bismethoxymethoxy)benzoate (3). To a
solution of alcohol 6 (147 µL, 1.43 mmol) and PPh3 (624 mg, 2.38
mmol) in THF (20 mL) at 0 °C was added DIAD (463 µL, 2.38
mmol). The solution was stirred at 0 °C for 20 min during which
time a white precipitate formed. After this time, a solution of the
acid 18 (434 mg, 0.952 mmol) in THF (15 mL) was added
dropwise, and the reaction was allowed to stir at rt for 2 days. To
the crude reaction mixture was added a small amount of silica gel
before removal of solvent. The silica gel was dry loaded onto a
column and eluted (gradient elution 20:1-5:1 hexanes/EtOAc) to
coupled product 16 as a colorless oil (447 mg, 86%): Rf ) 0.33
1
(2:1 hexanes/EtOAc); [R]18 ) -21.5 (c 1.06, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 11.67 (s, 1H), 6.34 (d, J ) 2.5 Hz, 1H), 6.31
(s, 1H), 6.28 (d, J ) 2.5 Hz, 1H), 5.79 (ddd, J ) 17.2, 10.3, 7.8
Hz, 1H), 5.31 (ddd, J ) 17.1, 1.7, 1.1 Hz, 1H), 5.25 (ddd, J )
10.3, 1.5, 0.9 Hz, 1H), 4.50 (dd, J ) 7.7, 6.4 Hz, 1H), 4.10 (ddd,
J ) 9.1, 6.1, 4.3 Hz, 1H), 3.93 (d, J ) 13.6 Hz, 1H), 3.93 (s, 3H),
3.87 (d, J ) 13.6 Hz, 1H), 2.43 (t, J ) 7.4 Hz, 2H), 1.76-1.66
(m, 1H), 1.65-1.50 (m, 2H), 1.49 (s, 3H), 1.50-1.40 (m, 1H),
1.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.3, 165.7, 160.2,
143.9, 133.8, 118.7, 111.1, 108.4, 104.4, 102.5, 79.8, 77.7, 52.2,
37.0, 31.1, 29.5, 28.2, 25.8, 25.7; IR (KBr) 3272, 2988, 2951, 1655,
1621, 1588, 1441, 1381, 1326, 1259, 1210, 1162, 1109, 1031, 1003,
951, 851 cm-1; HRMS (ESI) calcd for C19H26O6SNa+ [M + Na]+
405.1348, found 405.1345.
yield title compound 3 as a colorless oil (468 mg, 94%): Rf ) 0.60
1
(2:1 hexanes/EtOAc); [R]18 ) -34.9 (c 0.18, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 6.72 (d, J ) 2.2 Hz, 1H), 6.69 (d, J ) 2.1
Hz, 1H), 5.85 (ddt, J ) 17.2, 10.2, 7.0 Hz, 1H), 5.78 (ddd, J )
17.9, 10.3, 7.8 Hz, 1H), 5.28 (d, J ) 17.1 Hz, 1H), 5.25-5.20 (m,
2H), 5.15 (s, 2H), 5.14 (m, 2H), 5.13-5.07 (m, 2H), 4.46 (dd, J )
7.3, 6.6 Hz, 1H), 4.09 (ddd, J ) 8.5, 6.0, 4.8 Hz, 1H), 3.73 (d, J
) 13.7 Hz, 1H), 3.69 (d, J ) 13.7 Hz, 1H), 3.46 (s, 3H), 3.45 (s,
3H), 2.51-2.42 (m, 3H), 2.40-2.33 (m, 1H), 1.72 (m, 1H),
1.60-1.40 (m, 3H), 1.46 (s, 3H), 1.34 (s, 3H), 1.34 (d, J ) 6.2
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.9, 158.6, 155.8, 139.0,
134.3, 133.8, 118.4, 118.3, 117.7, 110.4, 108.2, 102.3, 94.7, 94.3,
79.7, 77.8, 71.2, 56.2, 56.1, 40.2, 33.8, 31.6, 29.5, 28.2, 25.8, 25.6,
19.4; IR (neat) 2984, 2906, 2845, 1715, 1604, 1584, 1434, 1380,
1272, 1216, 1149, 1039, 1019, 926 cm-1; HRMS (ESI) calcd for
C27H40O8SNa+ [M + Na]+ 547.2342, found 547.2342.
Methyl (6′S,7′R)-6-(6′,7′-O-(1′′-Methylethylidene)-2′-thianon-
8′-enyl)-2,4-bis(methoxymethoxy)benzoate. To a solution of
compound 16 (621 mg, 1.62 mmol) in DMF (6 mL) at 0 °C was
added a 60% dispersion of NaH in mineral oil (163 mg, 4.06 mmol).
The reaction was allowed to stir at 0 °C for 20 min before the
addition of MOMCl (370 µL, 4.89 mmol). The reaction mixture
was allowed to warm to rt while stirring for 2 h. The reaction
2276 J. Org. Chem. Vol. 74, No. 6, 2009

Total Synthesis of Aigialomycin D
(4S,6′S,7′R)-Pent-1-en-4-yl 6-(6′,7′-O-(1′′-Methylethylidene)-
2′-thianon-8′-enyl)-2,4-(bismethoxymethoxy)benzoate 2′,2′-Di-
oxide (2). To a solution of thioether 3 (122 mg, 0.230 mmol) in
CH2Cl2 (5 mL) at 0 °C was added 75% m-CPBA (115 mg, 0.501
mmol). The reaction was allowed to warm to rt while stirring for
2 h. The reaction was quenched with the addition of 20% aqueous
Na2SO3 solution (10 mL) and extracted with CH2Cl2 (3 × 10 mL).
The combined organic phases were washed with saturated aqueous
NaHCO3 solution (20 mL), dried over MgSO4, filtered, and reduced
in vacuo to give a colorless oil. The product was purified by flash
column chromatography (silica, gradient elution 3:1-2:1 hexanes/
EtOAc) to yield the title compound 2 as a colorless oil (109 mg,
The aqueous layer was further extracted with EtOAc (2 × 5 mL).
The combined organic phases were dried over MgSO4, filtered and
reduced. The crude product was purified by flash column chromatog-
raphy (silica, gradient elution 20:1-5:1 hexanes/EtOAc) to give the
title compound 20 as a white solid (25 mg, 84%): Rf ) 0.40 (2:1
hexanes/EtOAc); [R]19 ) -118.6 (c 0.15, CHCl3) [lit.5c [R]19
)
D
D
-116.5 (c 0.13, CHCl3) and lit.5a [R]19 ) -120 (c 0.08, CHCl3)];
D
1H NMR (500 MHz, CDCl3) δ 6.81 (d, J ) 2.1 Hz, 1H), 6.69 (d, J )
2.1 Hz, 1H), 6.24 (d, J ) 15.8 Hz, 1H), 6.14 (ddd, J ) 15.3, 9.6, 4.2
Hz, 1H), 5.74 (ddd, J ) 15.3, 9.4, 3.5 Hz, 1H), 5.60 (ddd, J ) 15.4,
9.7, 1.7 Hz, 1H), 5.34 (m, 1H), 5.20-5.12 (m, 4H), 4.57 (dd, J ) 9.6,
5.4 Hz, 1H), 4.19 (ddd, J ) 11.6, 5.4, 3.1 Hz, 1H), 3.46 (s, 3H), 3.46
(s, 3H), 2.58-2.44 (m, 2H), 2.31 (m, 1H), 2.11 (m, 1H), 1.80 (m,
1H), 1.49 (m, 1H), 1.47 (s, 3H), 1.37 (d, J ) 6.3 Hz, 3H), 1.36 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 167.4, 158.9, 155.1, 136.8, 132.3,
131.9, 129.3, 128.4, 117.9, 108.3, 104.8, 102.5, 94.5, 94.3, 80.1, 77.2,
71.6, 56.2, 56.1, 39.5, 29.0, 28.7, 28.6, 25.8, 21.1; IR (neat) 2984,
84%): Rf ) 0.31 (2:1 hexanes/EtOAc); [R]22 ) -11.0 (c 1.05,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.88 (d, J ) 2.2 Hz, 1H),
6.86 (d, J ) 2.2 Hz, 1H), 5.85 (ddt, J ) 17.2, 10.2, 7.0 Hz, 1H),
5.75 (ddd, J ) 17.1, 10.3, 7.7 Hz, 1H), 5.29 (ddd, J ) 17.1, 1.5,
1.1 Hz, 1H), 5.25-5.20 (m, 2H), 5.18 (s, 2H), 5.17-5.14 (m, 3H),
5.11 (ddt, J ) 9.0, 2.0, 1.1 Hz, 1H), 4.48 (dd, J ) 7.5, 6.5 Hz,
1H), 4.38 (d, J ) 14.1 Hz, 1H), 4.28 (d, J ) 14.1 Hz, 1H),
4.12-4.07 (m, 1H), 3.47 (s, 3H), 3.46 (s, 3H), 3.02 (ddd, J ) 13.9,
10.2, 5.7 Hz, 1H), 2.94 (ddd, J ) 13.9, 10.1, 5.7 Hz, 1H), 2.51-2.44
(m, 1H), 2.42-2.35 (m, 1H), 2.02-1.91 (m, 1H), 1.89-1.80 (m,
1H), 1.52 (tdd, J ) 11.2, 7.0, 3.9 Hz, 2H), 1.45 (s, 3H), 1.34 (d, J
) 6.3 Hz, 3H), 1.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.6,
159.0, 156.4, 134.0, 133.7, 128.5, 119.3, 118.6, 117.9, 112.2, 108.4,
104.2, 94.8, 94.3, 79.6, 77.6, 71.7, 56.7, 56.4, 56.3, 51.5, 40.2, 29.3,
28.1, 25.5, 19.5, 18.7; IR (neat) 1708, 1605, 1586, 1285, 1214,
1150, 1122, 1039, 1018, 914, 734; HRMS (ESI) calcd for
C27H40O10SNa+ [M + Na]+ 579.2246, found 579.2240.
2897, 1722, 1601, 1579, 1263, 1218, 1148, 1052, 1018, 925 cm-1
;
HRMS (ESI) calcd for C25H34O8Na+ [M + Na]+ 485.2151, found
485.2147.
Aigialomycin D (1). A solution of compound 20 (45 mg, 97.3
µmol) in 1:1 v/v MeOH/1 M HCl (10 mL) was stirred at rt for 3 days.
The reaction mixture was extracted with EtOAc (3 × 10 mL), washed
with brine (5 mL), dried over MgSO4, filtered, and reduced to give
aigialomycin D as a white solid (28 mg, 86%): Rf ) 0.21 (5% MeOH/
CH2Cl2); [R]19 ) -25.1 (c 0.78, MeOH) [lit.5b [R]19 ) -21.9 (c
D
D
0.35, MeOH)]; 1H NMR (500 MHz, acetone-d6) δ 11.66 (s, 1H), 9.25
(brs, 1H), 7.15 (d, J ) 15.9 Hz, 1H), 6.53 (d, J ) 2.0 Hz, 1H), 6.28
(d, J ) 2.0 Hz, 1H), 6.09 (ddd, J ) 15.9, 5.7, 5.5 Hz, 1H), 5.88 (ddd,
J ) 15.6, 7.4, 1.6 Hz, 1H), 5.69 (ddd, J ) 15.6, 5.2, 1.2 Hz, 1H),
5.44 (m, 1H), 4.35 (brd, J ) 4.1 Hz, 1H), 3.82 (brs, 1H), 3.63 (m,
1H), 3.20 (brs, 1H), 2.57 (ddd, J ) 14.6, 7.4, 3.1 Hz, 1H), 2.43 (m,
1H), 2.36-2.32 (m, 2H), 2.14 (m, 1H), 1.59 (m, 1H), 1.37 (d, J ) 6.4
Hz, 3H); 13C NMR (125 MHz, acetone-d6) δ 172.2, 165.8, 163.1,
144.3, 135.7, 133.6, 130.6, 125.4, 107.8, 104.4, 102.5, 76.5, 73.0, 73.0,
37.9, 28.5, 28.0, 19.1; IR (neat) 3338, 2979, 1644, 1608, 1448, 1312,
1259, 1167, 1110, 1018, 972 cm-1; HRMS (ESI) calcd. for
C18H22O6Na+ [M + Na]+ 357.1308, found 357.1314. Spectral data
matched those reported in the literature.1
(5S,7E,9R,10S)-1,2-(3′,5′-Di-O-methoxymethyl)benzo-4-oxa-
14-thia-3-oxo-5-methyl-9,10-O-(1-methylethylidene)pentadec-7-
ene 14,14-Dioxide (19). To a solution of the diene 2 (55 mg, 99
µmol) in CH2Cl2 (20 mL) in a microwave reactor vessel was added
a catalytic amount of Grubbs’ second-generation catalyst (8.4 mg,
9.9 µmol). The vessel was flushed with argon before sealing with
the cap. The vessel was irradiated for 30 min, heating to 75 °C.
The solvent was removed to yield a brown oil. The crude product
was purified on a silica column (gradient elution, 5:1-2:1 hexanes/
EtOAc) to yield compound 19 as a colorless oil (45 mg, 86%): Rf
) 0.14 (2:1 hexanes/EtOAc); [R]22D ) -28.5 (c 0.50, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.16 (d, J ) 2.2 Hz, 1H), 6.85 (d, J )
2.2 Hz, 1H), 5.71 (ddd, J ) 15.2, 9.3, 4.3 Hz, 1H), 5.55 (ddd, J )
15.4, 9.4, 1.4 Hz, 1H), 5.29 (m, 1H), 5.21-5.16 (m, 4H), 4.47 (d,
J ) 15.3 Hz, 1H), 4.43 (dd, J ) 9.3, 5.8 Hz, 1H), 4.13 (d, J )
15.1 Hz, 1H), 4.11 (m, 1H), 3.47 (s, 3H), 3.47 (s, 3H), 2.83 (ddd,
J ) 14.6, 11.1, 5.3 Hz, 1H), 2.65 (m, 1H), 2.47 (m, 1H), 2.41 (dd,
J ) 15.5, 9.8 Hz, 1H), 1.75 (m, 1H), 1.67 (m, 1H), 1.62-1.53 (m,
2H), 1.43 (s, 3H), 1.40 (d, J ) 6.2 Hz, 3H), 1.32 (s, 3H); 13C NMR
(500 MHz, CDCl3) δ 167.1, 159.3, 156.6, 132.4, 129.0 (2), 118.6,
110.9, 107.9, 103.6, 94.6, 94.4, 76.3, 77.6, 72.3, 56.4, 56.4, 55.4,
51.1, 39.5, 28.3, 27.6, 25.5, 20.8, 18.5; IR (neat) 2982, 2903, 2829,
Acknowledgment. We thank Professor Richard J. K. Taylor
(University of York) for his inspiration and advice and Dr. Brendan
Burkett and Associate Professor Peter Northcote for helpful
discussions during the course of this research. We are indebted to
Dr. Brendan Burkett for the use of the microwave instrument and
training in its use. Funding has been gratefully received from the
Foundation for Research, Science and Technology (NZ) for a
Bright Futures PhD Scholarship (L.J.B.) and Victoria University
of Wellington for the provision of a Vice-Chancellor’s Strategic
Research Scholarship and faculty grants funding.
1708, 1604, 1585, 1277, 1215, 1149, 1122, 1017, 926, 737 cm-1
;
HRMS (ESI) calcd for C25H36O10SNa+ [M + Na]+ 551.1928, found
551.1927.
Supporting Information Available: General experimental
(5′S,6′R,10′S)-2,4-Di-O-(methoxymethyl)-5′,6′-O-(1-methyleth-
ylidene)aigialomycin D (20). To a solution of sulfone 19 (34 mg,
methods; full experimental details for all reactions; characteriza-
1
tion data for all products; copies of H NMR spectra for all
t
64.4 µmol) in BuOH (250 µL) and CH2Cl2 (100 µL) was added
new compounds; further information on selective conjugate
reduction of compound 11; further information on attempted
ester hydrolysis of compound 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
powdered KOH (72 mg, 1.29 mmol) at rt. To the resulting suspension
was added CCl4 (250 µmol) dropwise over 2 min. The reaction mixture
was then heated to 35 °C for 30 min. After the mixture was cooled to
rt, the solvent was removed to dryness and the residue partitioned
between saturated aqueous NH4Cl solution (5 mL) and EtOAc (5 mL).
JO802561S
J. Org. Chem. Vol. 74, No. 6, 2009 2277