Total synthesis and determination of relative and absolute configuration of multiplolide A

Article abstract of DOI:10.1021/jo7027568

(Chemical Equation Presented) A flexible approach for total syntheses of possible multiplolide A diastereomers establishing the relative and absolute configuration is documented. The adopted strategy features ring-closing metathesis (RCM) as the key reaction and screening of a set of substrates for the feasibility of RCM in general and for the requisite E-configuration of ring olefin in particular. Selective protecting groups manipulation prior to the assembly of the central macrocyclic core was instrumental in installing the epoxide functionality on a fully deprotected nonenolide at the end of the synthesis.

Full text of DOI:10.1021/jo7027568

Total Synthesis and Determination of Relative and Absolute
Configuration of Multiplolide A
C. V. Ramana,* Tushar P. Khaladkar, Soumitra Chatterjee, and Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Vr.chepuri@ncl.res.in
ReceiVed December 27, 2007
A flexible approach for total syntheses of possible multiplolide A diastereomers establishing the relative
and absolute configuration is documented. The adopted strategy features ring-closing metathesis (RCM)
as the key reaction and screening of a set of substrates for the feasibility of RCM in general and for the
requisite E-configuration of ring olefin in particular. Selective protecting groups manipulation prior to
the assembly of the central macrocyclic core was instrumental in installing the epoxide functionality on
a fully deprotected nonenolide at the end of the synthesis.
Introduction
into account the positive optical rotation shown by both 1 and
2, similar absolute configurations of C-7, C-8, and C-10 were
proposed for multiplolide A (1) (Figure 1).
Though modern day analytical techniques have bestowed
isolation chemists with deeper insights toward understanding
the structures of isolated natural products, the opportunities for
synthetic chemists to contribute in the area of natural product
structure elucidation are not totally exhausted.1 Nature some-
times tests and even teases the awesome influence of the
analytical techniques by presenting simple looking structures
out of its bag. Such was the case with the multiplolides A (1)
and B (2), two new antifungal 10-membered lactones which
were isolated in 2001 by Kittakoop and co-workers from the
crude ethyl acetate extract of the culture broth of Xylaria
multiplex.2
Multiplolides A (1) and B (2) exhibited antifungal activity
against Candida albicans with IC50 values of 7 and 2 µg/mL,
respectively. Chemical structures of 1 and 2 were elucidated
on the basis of their spectral data (Figure 1). The relative
stereochemistry of C-7, C-8, and C-10 was ascertained with
the help of extensive 2D-NMR analysis. The absolute config-
uration at C-7 of 2 was determined as S by the application of
the Mosher method,3 which indirectly established the absolute
configurations of both C-8 and C-10 centers as R,R. By taking
The most striking features of multiplolides from a structural
elucidation point of view are the epoxide functionality set in
between lactone carbonyl and olefin and that the epoxide protons
(H-C3, H-C4) are spatially isolated from the protons on other
chiral centers resulting in partial structural elucidation, leaving
the two possible diastereomeric structures (3, 4) for the central
core of multiplolides. Very recently, Tan et al. isolated 8-acetyl
multiplolide A and concluded it was the derivative of multi-
plolide A by extensive 2D NMR analyses; however, this left
the relative configuration of the oxirane ring in question.4 The
intriguing structure and its promising biological activity make
these compounds attractive targets for total synthesis. This paper
describes the first total synthesis of both the possible diaster-
eomers of multiplolide A (1) and establishes the relative and
absolute configurations.
The basic premise of our synthetic plan is to utilize a ring-
closing metathesis (RCM) reaction5,6 to construct the macro-
(4) Tan, Q.; Yan, X.; Lin, X.; Huang, Y.; Zheng, Z.; Song, S.; Lu, C.; Shen,
Y. HelV. Chim. Acta 2007, 90, 1811.
(5) Ferraz, H. M. C.; Bombonato, F. I.; Longo, L. S., Jr Synthesis 2007,
3261.
* Corresponding author. Tel.: +91-20-25902577. Fax: +91-20-25902629.
(1) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012.
(2) Boonphong, S.; Kittakoop, P.; Isaka, M.; Pittayakhajonwut, D.; Tanti-
charoen, M.; Thebtaranonth, Y. J. Nat. Prod. 2001, 64, 965.
(3) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143. (b) Dale, J. A.; Dull, L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543. (c)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. J. Am. Chem. Soc. 1991,
113, 4092.
(6) For general reviews on RCM, see:(a) Grubbs, R. H. Angew. Chem., Int.
Ed. 2006, 45, 3760. (b) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3741. (c)
Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748. (e) Fürstner, A.; Müller,
C. Chem. Commun. 2005, 5583. (f) Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199. (g) Fürstner, A. Angew. Chem., Int. Ed 2000, 39, 3012. Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (h) Fürstner, A.; Langemann, K. Synthesis
1997, 792.
10.1021/jo7027568 CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3817–3822 3817

Ramana et al.
FIGURE 1. Chemical structures of multiplolide A and B and retrosynthetic analysis.
SCHEME 1. Synthesis of Coupling Partners 6-8a
a Reagents and conditions: (a) (i) KOtBu, DMSO, 100 °C, 1 h, (ii) HgO, HgCl2, rt, 8 h; (b) Ph3PdCH2, THF, DMSO, rt, 24 h; (c) (i) NaH, PMBBr, DMF,
0 °C f rt, 16 h, (ii) TBAF, THF, rt, 16 h; (d) PPh3, CBr4, Et3N, CH2Cl2, rt, 40 h; (e) (i) Zn, EtOH, reflux, 0.5 h, (ii) NaH2PO4, NaClO2, 2-methyl-2-butene,
t-BuOH/H2O (3:1), rt, 1 h; (f) PPTS, MeOH, 0 °C f rt, 12 h; (g) (i) MsCl, Et3N, CH2Cl2, 0 °C f rt, 1 h, (ii) NaI, 2-butanone, 80 °C, 10 h; (h) PPTS, MeOH,
rt, 36 h; (i) (i) NaIO4, CH2Cl2, rt, 1 h, (ii) NaH2PO4, NaClO2, t-BuOH/H2O (3:1), 2-methyl-2-butene, rt, 1 h.
cyclic framework. A vicinal diol unit was designated as the
surrogate for the epoxide. We opted PMB protection for both
the hydroxyl groups of the vicinal diol anticipating selective
mono PMB deprotection at an advanced stage.7 Taking into
account the difficulty in the prediction of the stereochemical
outcome of the RCM reaction, the path was chosen so as to
offer enough flexibility with the substrates for RCM by means
of changing R and R′ to attain the required E configuration at
the olefin under construction (Figure 1).
of the double bond with potassium tert-butoxide-DMSO
followed by treatment with Hg2+ salts to give 10.8 One-carbon
homologation of 10 with Ph3PdCH2 completed the synthesis
of the alcohol 6.
D-Xylose was converted into the known derivative 11.9
Protection of the secondary hydroxyl functions in 11 as their
PMB ethers and the removal of TBS protection of the resulting
compound afforded the primary alcohol 12. Conversion of
alcohol 12 to the corresponding bromo derivative 13, subsequent
Bernet–Vasella fragmentation,10 and oxidation of the intermedi-
ate aldehyde using sodium chlorite11 gave acid 7 (Scheme 1).
Results and Discussion
The syntheses of the alcohol 6 and the enantiomeric acids 7
and 8 were achieved through functional group manipulations
on corresponding sugar building blocks, keeping the requisite
stereochemical information intact. The synthesis of the alcohol
6 started with the known allyl 4-deoxy-2,3-O-isopropylidene-
L-rhamnopyranoside (9) (Scheme 1).8 The removal of the allyl
group at the anomeric oxygen was effected first by isomerization
(8) (a) Valente, L.; Olesker, A.; Rabanal, R.; Barata, L. E. S.; Lukacs, G.;
Thang, T. Tetrahedron Lett. 1979, 20, 1153. (b) Mitsunobu, O.; Ebina, M.;
Ogihara, T. Chem. Lett. 1982, 373. (c) Barton, D. H. R.; McCombie, S. W.
J. Chem. Soc., Perkin Trans. 1 1975, 1574. (d) Gigg, J.; Gigg, R. J. Chem. Soc.
C 1966, 82. (e) Gigg, R.; Warren, C. D. J. Chem. Soc. C 1968, 1903.
(9) (a) Hansen, F. G.; Bundgaard, E.; Madsen, R. J. Org. Chem. 2005, 70,
10139. (b) Velazquez, S.; Camarasa, M. J. Tetrahedron: Asymmetry 1994, 5,
2141.
(10) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990.
(11) Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 1372.
(7) Ramana, C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K. J. Org. Chem.
2005, 70, 8216.
3818 J. Org. Chem. Vol. 73, No. 10, 2008

Total Synthesis of Multiplolide A
SCHEME 2. Synthesis of RCM Substratesa
tosylate 22 and consequently the penultimate epoxide diene 23,
as the attempted RCM of 22 was a failure. Eventually, the RCM
of 23 was successful with Grubbs’ second-generation catalyst
in refluxing dichloromethane, however, resulted in 24 with
exclusive Z-configuration. The success of RCM of compound
23 containing an activated oxirane ring and two potential
nucleophiles in the form of free –OH groups highlights the high
functional group tolerance of Grubbs’ catalyst.16
Although, the synthesis of the diastereomer 3 was narrowly
missed due to the undesired stereochemical outcome of the RCM
reaction in the very last step, we proceeded further for the
synthesis of diastereomer 4 with the available E-configured
lactone 21. The synthesis of (3S,4S)-multiplolide A (4) was
completed in three steps (Scheme 4) from 21. The analytical
and spectral data for 4 were found to be in excellent agreement
with those for natural product, barring the deviation in the
magnitude of specific rotation: [R]syntheticD +22.6 (c 0.3, CHCl3)
[lit.2 [R]lit. +6.7 (c 0.18, CHCl3)].
D
a Reagents and conditions: (a) PPh3, DEAD, THF, 0 °C f rt, 3 h; (b)
DDQ, CH2Cl2, buffer, 0 °C f rt, 4 h; (c) TsCl, i-Pr2NEt, DMAP, CH2Cl2,
rt, 36 h; (d) TFA, CH2Cl2, rt, 35 h then i-Pr2NEt, 0.5 h, rt.
In the context of the discrepancy in the magnitudes of the
specific rotations, total synthesis of the other possible diaste-
reomer 3 was thought even more important to establish the
relative and absolute configuration of multiplolide A beyond
any ambiguity. Having met the failure in our attempt to tune
the RCM reaction for the synthesis of 3, we now focused our
attention to tune the position of leaving group starting from the
compound 21 in our hands. As outlined in Scheme 5, by
exchanging the positions of the leaving group and nucleophile,
subsequent epoxide formation and acetonide deprotection af-
forded 3.
Interestingly, compound 3 was found to exist as an equilibrat-
ing mixture of conformational isomers (3:1, at 25 °C) in solution.
The major:minor ratio was observed to be temperature depend-
ent to some extent. Maximum separation in the signals due to
each isomers was observed when the 1H NMR was recorded at
0 °C in CDCl3. Whereas a substantial increment in the ratio of
major isomer was noticed when the NMR was recorded at high
temperatures in DMSO-d6.When the NMR was recorded at 80
°C the peaks due to major and minor isomer merged into each
other at the expense of the multiplicity of the peaks. From the
comparison of the data from natural product and 4 with the
Synthesis of another key intermediate 8 (Scheme 1) was
initiated from the known di-O-isopropylidene-D-mannitol de-
rivative (14).12 The controlled hydrolysis of C2-symmetric
diacetonide 14 was efficiently dealt with by employing PPTS
in methanol. In order to derive the olefin from the resulting
diol 15, it was first mesylated and then the resulting dimesylate
was treated with NaI in refluxing 2-butanone to yield the olefin
16.13 The acid-catalyzed hydrolysis of 16 with PPTS in methanol
followed by sodium periodate cleavage and oxidation of the
resulting aldehyde with sodium chlorite afforded 8.
Alcohol 6 was coupled with acids 7 and 8 under Mitsunobu
conditions14 to afford the diene esters 17 and 18, respectively.
The inversion of configuration was confirmed in each case by
the hydrolysis of the resulting esters 17/18 and comparing the
analytical data of so as obtained epi-6 with 6. The first set of
substrates (17 and 18) for RCM was examined under various
reaction conditions anticipating all the possible geometrical
outcomes of the cylization, but to a little surprise RCM of both
the substrates resulted in complex mixtures under any of the
conditions attempted. Attributing this failure to the crowding
around the reaction centers because of protecting groups, the
attempted deprotection of 17 and 18 with DDQ resulted into
exclusive allylic –OPMB removal to afford the second set of
substrates 19 and 20, respectively, for the RCM. After various
conditions with 19 and 20 were explored, though unsuccessful
with diene 19, the RCM of substrate 20 was successful with
Grubbs’ second-generation catalyst in refluxing dichloromethane
(36 h) and/or benzene (6 h) and resulted in the formation of
compound 21 with exclusive E-configuration at the newly
formed olefin in each case. The difference in the outcome of
the RCM reaction with respect to reversal of stereochemistry
on the one side of the diene (19 and 20) is particularly striking
and nicely exemplifies the substrate specific nature of the
reaction.15
3major and 3minor it is evident that both the components represent
the same constitution and configuration and presumably are
conformational isomers. The fact that the natural product did
not exist as the mixture of conformational isomers and no
correlation of the data of any of the conformers of 3 with natural
multiplolide A unequivocally designated 4 as the natural product
and established the absolute stereochemistry of multiplolide A
as 3S,4S,7S,8R,10R.
To conclude, the objective of establishing relative and
absolute stereochemistry of multiplolide A has been accomp-
lished by total synthesis of the possible diastereomers. The
(15) Selected references for substrate specific nature of the RCM reaction:
(a) Fürstner, A.; Müller, T. Synlett 1997, 1010. (b) Fürstner, A.; Radkowski, K.;
Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002,
124, 7061. (c) Fürstner, A.; Schlede, M. AdV. Synth. Catal. 2002, 344, 657. (d)
Elena, D.; Darren, D. J.; Steven, L. V.; Alessandra, P.; Felix, R. Synlett 2003,
1186. (e) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086.
(f) Fürstner, A.; Nagano, T.; Müller, C.; Seidel, G.; Müller, O. Chem. Eur. J.
2007, 13, 1452. (g) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.;
Chorghade, M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48,
2621.
With the hope that the RCM would click at some stage,
compound 19 was processed further to prepare the proposed
(12) Bozó, E.; Medgyes, A.; Boros, S.; Kuszmann, J. Carbohydr. Res. 2000,
329, 25.
(13) Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.; Murugan, A.
Tetrahedron Lett. 2003, 44, 5183.
(16) For RCM reactions of vinyl epoxides: (a) Garbaccio, R. M.; Stachel,
S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903.
(b) Fürstner, A.; Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Porée, F.-H.; Gilmour,
R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265.
(14) (a) Hughes, D. L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967. (b)
Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. J. Am. Chem.
Soc. 1988, 110, 6487. (c) Mitsunobu, O. Synthesis 1981, 1.
J. Org. Chem. Vol. 73, No. 10, 2008 3819

Ramana et al.
SCHEME 3. Summary of RCM Reactions Carried out on Various Dienesa
a Reagents and conditions: (a) Grubbs’ second-generation catalyst, benzene, reflux, 6 h; (b) Grubbs’ second-generation catalyst, CH2Cl2, reflux, 1 h.
SCHEME 4. Total Synthesis of Multiplolide A (4)a
1H), 4.11 (dd, J ) 4.8, 7.7 Hz, 1H), 4.13–4.23 (m, 1H), 4.33, 4.42,
4.54, 4.70 (4d, J ) 11.6 Hz, 4H), 4.44 (dd, J ) 5.3, 13.7 Hz, 1H),
5.01–5.17 (m, 1H), 5.20–5.35 (m, 4H), 5.65–5.96 (m, 2H), 6.82,
6.83, 7.19, 7.24 (4d, J ) 8.8 Hz, 8H). 13C NMR (CDCl3, 50 MHz):
19.6 (q), 25.6 (q), 28.1 (q), 36.3 (t), 55.0 (q), 69.4 (d), 70.3 (t),
72.4 (t), 74.5 (d), 79.4 (d), 80.5 (d), 80.6 (d), 108.3 (s), 113.45 (d),
113.50 (d), 118.5 (t), 119.3 (t), 129.1 (d), 129.2 (s), 129.6 (d), 129.9
(s), 133.9 (d), 134.3 (d), 158.9 (s), 159.9 (s), 169.6 (s) ppm. ESI-
MS m/z: 563 [M + Na]+. Anal. Calcd for C31H40O8: C, 68.89; H,
7.41. Found: C, 69.14; H, 7.67.
a Reagents and conditions: (a) p-TsCl, i-Pr2NEt, DMAP, CH2Cl2, rt, 20 h;
(b) TFA, CH2Cl2, rt, 48 h; (c) NaH, THF; 0 °C, 1 h.
Coupling of 6 and 8. To a solution of 6 (200 mg, 1.07 mmol),
8 (500 mg, 1.34 mmol), and PPh3 (563 mg, 2.15 mmol) in THF (8
mL) at 0 °C was added DEAD (0.34 mL, 2.16 mmol). Stirring
was continued at 0 °C for 1 h and then at rt for the next 2 h, at
which time it was concentrated and the crude residue was purified
on silica gel by eluting with ethyl acetate-light petroleum (1:9) to
afford 18 (467 mg, 80%). [R]25D ) –38.9 (c 1, CHCl3); IR (CHCl3):
2934, 1736, 1612, 1513, 1464, 1381, 1249, 1173, 1037, 667 cm–1;
1H NMR (CDCl3, 200 MHz): δ 1.20 (d, J ) 6.3 Hz, 3H), 1.32 (s,
3H), 1.47 (s, 3H), 1.54 (ddd, J ) 4.9, 6.6, 14.0 Hz, 1H), 1.86 (ddd,
J ) 6.6, 9.1, 14.0 Hz, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 3.92 (d, J )
4.7 Hz, 1H), 4.09 (br dd, J ) 4.7, 7.9 Hz, 1H), 4.17 (ddd, J ) 5.0,
6.0, 9.1 Hz, 1H), 4.31, 4.40, 4.54, 4.69 (4d, J ) 11.7 Hz, 4H),
4.48 (br.dd, J ) 6.3, 7.7 Hz, 1H), 5.10 (q, J ) 6.5 Hz, 1H),
5.20–5.36 (m, 4H), 5.66–5.96 (m, 2H), 6.81, 6.83, 7.19, 7.24 (4d,
J ) 8.7 Hz, 8H); 13C NMR (CDCl3, 100 MHz): 19.7 (q), 25.7 (q),
28.3 (q), 36.5 (t), 55.2 (q), 69.5 (d), 70.4 (t), 72.6 (t), 74.9 (d),
79.6 (d), 80.5 (d), 80.8 (d), 108.5 (s), 113.6 (d), 113.7 (d), 118.7
(t), 119.4 (t), 129.4 (d), 129.5 (s), 129.7 (d), 130.1 (s), 134.0 (d),
134.6 (d), 159.1 (s), 159.4 (s), 169.6 (s) ppm. ESI-MS m/z: 563
(M + Na)+. Anal. Calcd for C31H40O8: C, 68.89; H, 7.41. Found:
C, 69.22; H, 7.54.
SCHEME 5. Total Synthesis of Diastereomer 3a
a Reagents and conditions: (a) TBDPS-Cl, Imidazole, CH2Cl2, reflux,
10 h; (b) DDQ, CH2Cl2-H2O (18:1), rt, 3 h; (c) MsCl, Et3N, DMAP,
CH2Cl2, 0 °C f rt, 2 h; (d) TBAF (1 M solution in THF), THF, 0 °C f
rt, 8 h; (e) TFA, CH2Cl2, 0 °C f rt, 4 h.
summary of the results of RCM reactions of closely related
substrates indicates the influence of conformation control on
the outcome of the transformation. Further studies to understand
this in details are in progress.
Selective Mono-PMB Deprotection of 17. To a solution of 17
(350 mg, 0.65 mmol) in CH2Cl2 (30 mL) at 0 °C were added
aqueous NaH2PO4/Na2HPO4 (pH 7) buffer (12 mL) and DDQ (700
mg, 3.08 mmol). The reaction was allowed to warm to rt. After
4 h at rt, the reaction mixture was filtered through a Celite pad,
and layers were separated. The aqueous layer was extracted with
CH2Cl2, and the combined organic layer was dried over sodium
sulfate and concentrated. The residue was purified on silica gel by
eluting with ethyl acetate-light petroleum (1:6) to afford 19 (104
Experimental Section
Coupling of 6 and 7. To a solution of 6 (200 mg, 1.07 mmol),
7 (500 mg, 1.34 mmol), and PPh3 (563 mg, 2.15 mmol) in THF (8
mL) at 0 °C was added DEAD (0.34 mL, 2.16 mmol). Stirring
was continued at 0 °C for 1 h and then at rt for 2 h, at which time
the solution was concentrated and the crude residue was purified
on silica gel by eluting with ethyl acetate-light petroleum (1:9) to
mg, 56%, on the basis of recovered starting material 110 mg). [R]25
)
D
+37.7 (c 0.9, CHCl3). IR (CHCl3): 3565, 3464, 2988, 1741, 1613,
1586, 1250, 1100, 1038 cm-1. 1H NMR (CDCl3, 400 MHz): δ 1.29
(d, J ) 6.3 Hz, 3H), 1.34 (s, 3H), 1.48 (s, 3H), 1.57–1.62 (m, 1H),
1.86 (ddd, J ) 8.0, 9.0, 14.6 Hz, 1H), 2.85 (br. d, J ) 7.3 Hz, 1H),
3.80 (s, 3H), 3.88 (d, J ) 4.5 Hz, 1H), 4.22 (ddd, J ) 4.5, 6.0, 9.3
Hz, 1H), 4.36–4.40 (br. m, 1H), 4.43, 4.72 (2d, J ) 11.4 Hz, 2H),
4.51 (dd, J ) 6.8, 7.3 Hz, 1H), 5.10–5.18 (m, 1H), 5.20–5.37 (m,
4H), 5.76 (ddd, J ) 7.8, 10.3, 17.1 Hz, 1H), 5.87 (ddd, J ) 5.8,
afford 17 (423 mg, 73%). [R]25 ) +47.7 (c 1.4, CHCl3). IR
D
(CHCl3): 2936, 1736, 1613, 1586, 1248, 1037 cm-1
.
1H NMR
(CDCl3, 200 MHz): δ 1.25 (d, J ) 6.3 Hz, 3H), 1.31 (s, 3H), 1.47
(s, 3H), 1.53 (ddd, J ) 5.3, 7.6, 14.0 Hz, 1H), 1.86 (ddd, J ) 6.6,
8.7, 14.0 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.93 (d, J ) 4.8 Hz,
3820 J. Org. Chem. Vol. 73, No. 10, 2008

Total Synthesis of Multiplolide A
10.6, 17.1 Hz, 1H), 6.86, 7.25 (2d, J ) 8.6 Hz, 4H). 13C NMR
(CDCl3, 100 MHz): 20.2 (q), 25.5 (q), 28.0 (q), 36.6 (t), 55.1 (q),
70.1 (d), 72.3 (t), 73.2 (d), 75.3 (d), 79.6 (d), 80.4 (d), 108.6 (s),
113.7 (d), 116.9 (t), 118.7 (t), 129.0 (s), 129.8 (d), 134.0 (d), 136.2
(d), 159.5 (s), 169.8 (s) ppm. ESI-MS m/z: 443 [M + Na]+. Anal.
Calcd for C23H32O7: C, 65.71; H, 7.62. Found: C, 65.48; H, 7.50.
Selective Mono-PMB Deprotection of 18. To a solution of 18
(400 mg, 0.74 mmol) in CH2Cl2 (35 mL) at 0 °C were added
aqueous NaH2PO4/Na2HPO4 (pH 7) buffer (15 mL) and DDQ (800
mg, 3.52 mmol). The reaction was allowed to warm to room
temperature. After 4 h at rt, it was filtered through Celite, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2, and the combined organic layer was dried over sodium
sulfate and concentrated. The residue was purified on silica gel by
eluting with ethyl acetate-light petroleum (1:6) to afford unreacted
18 (94 mg) and 20 (162 mg, 68%). [R]25D ) +4.3 (c 1.2, CHCl3).
IR (CHCl3): 3436, 2925, 2854, 1744, 1615, 1518, 1459, 1379, 1250,
dry CH2Cl2 (5 mL) was stirred at rt for 20 h and concentrated. The
residue was purified on silica gel by eluting with ethyl acetate-light
petroleum (1:4) to afford 25 (79 mg, 81%). [R]25D ) +16.2 (c 0.6,
CHCl3). IR (CHCl3): 2923, 1733, 1613, 1459, 1374, 1174, 1112,
1
1070 cm–1; H NMR (CDCl3, 400 MHz): δ 1.32 (s, 3H), 1.35 (d,
J ) 7.0 Hz, 3H), 1.40 (s, 3H), 1.45–1.53 (m, 1H), 2.36–2.41 (m,
1H), 2.44 (s, 3H), 3.81 (s, 3H), 4.20 (d, J ) 3.5 Hz, 1H), 4.31 (d,
J ) 11.0 Hz, 1H), 4.42 (br. dd, J ) 6.7, 9.5 Hz, 1H), 4.44 (d, J )
11.0 Hz, 1H), 4.66 (dd, J ) 6.7, 7.7 Hz, 1H), 5.10 (dd, J ) 3.0,
3.5 Hz, 1H), 5.13–5.18 (m, 1H), 5.71 (dd, J ) 7.8, 16.3 Hz, 1H),
5.80 (dd, J ) 3.0, 16.3 Hz, 1H), 6.85, 7.16 (2d, J ) 8.5 Hz, 4H),
7.29, 7.77 (2d, J ) 8.2 Hz, 4H); 13C NMR (CDCl3, 125 MHz):
18.2 (q), 21.7 (q), 25.2 (q), 27.9 (q), 35.2 (t), 55.2 (q), 68.6 (d),
72.5 (t), 75.3 (d), 75.4 (d), 78.3 (d), 81.5 (d), 108.6 (s), 114.0 (d),
127.1 (d), 128.0 (d), 129.4 (s), 129.5 (d), 129.8 (d), 129.9 (d), 133.4
(s), 144.9 (s), 159.7 (s), 167.6 (s) ppm. ESI-MS m/z: 569 (M +
Na)+. Anal. Calcd for C28H34O9S: C, 61.54; H, 6.23. Found: C,
61.77; H, 6.41.
1
1171, 1097, 1037 cm–1; H NMR (CDCl3, 200 MHz): δ 1.24 (s,
3H), 1.29 (d, J ) 6.3 Hz, 3H), 1.34 (s, 3H), 1.49 (s, 3H), 1.60
(ddd, J ) 4.6, 5.8, 14.2 Hz, 1H), 1.89 (ddd, J ) 7.2, 8.9, 14.2 Hz,
1H), 2.70 (s, 1H), 3.81 (s, 3H), 3.88 (d, J ) 4.8 Hz, 1H), 4.23
(ddd, J ) 4.6, 6.0, 9.0 Hz, 1H), 4.41 (br. d, J ) 11.2 Hz, 1H), 4.52
(t, J ) 7.0 Hz, 1H), 4.50 (br. dd, J ) 6.2, 7.6 Hz, 1H), 4.70 (d, J
) 11.2 Hz, 1H), 5.14–5.40 (m, 5H), 5.70–5.95 (m, 2H), 6.88, 7.27
(2d, J ) 8.7 Hz, 4H); 13C NMR (CDCl3, 125 MHz): 20.0 (q), 25.6
(q), 28.2 (q), 36.6 (t), 55.2 (q), 70.0 (d), 72.5 (t), 73.4 (d), 75.1 (d),
79.7 (d), 80.7 (d), 108.6 (s), 113.9 (d), 117.2 (t), 118.7 (t), 128.9
(s), 129.9 (d), 134.0 (d), 136.0 (d), 159.6 (s), 169.9 (s) ppm. ESI-
MS m/z: 443 (M + Na)+. Anal. Calcd for C23H32O7: C, 65.71; H,
7.62. Found: C, 65.95; H, 7.80.
Synthesis of Multiplolide A (4). A solution of 25 (47 mg, 86.1
µmol) and trifluroacetic acid (0.05 mL) in CH2Cl2 (10 mL) was
stirred at rt for 48 h. Diisopropylethylamine (0.5 mL) was intro-
duced and concentrated. The crude product (23 mg, 59.6 µmol)
was dissolved in THF (4 mL) and cooled to 0 °C, and then sodium
hydride (60% dispersion in mineral oil, 25 mg, 0.62 mmol) was
added. After 1 h, the reaction mixture was diluted with ice–water
and extracted with ethyl acetate. The combined organic extract was
dried over sodium sulfate and concentrated. The residue was purified
on silica gel by eluting with ethyl acetate-light petroleum (1:1) to
afford 4 (11 mg, 60%). [R]25D ) +22.6 (c 0.3, CHCl3). IR (CHCl3):
3430, 1716, 1280, 1217, 1060 cm–1. 1H NMR (CDCl3, 400 MHz):
δ 1.28 (dd, J ) 4.0, 16.0 Hz, 1H), 1.36 (d, J ) 6.7 Hz, 3H), 2.24
(ddd, J ) 3.4, 8.5, 16.0 Hz, 1H), 2.24 (br.s, overlapped, 1H), 3.65
(d, J ) 4.6 Hz, 1H), 3.79–3.81 (m, 1H), 4.05 (dd, J ) 3.0, 8.4 Hz,
1H), 4.53–4.57 (m, 1H), 5.27–5.34 (m, 1H), 5.76 (ddd, J ) 1.4,
2.1, 15.6 Hz, 1H), 5.93 (ddd, J ) 1.1, 2.5, 15.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): 17.8 (q), 35.4 (t), 54.5 (d), 55.1 (d), 67.9 (d),
68.3 (d), 72.4 (d), 117.7 (d), 133.3 (d), 167.2 (s) ppm. ESI-MS
m/z: 254 (M + H + K)+. Anal. Calcd for C10H14O5: C, 56.07; H,
6.54. Found: C, 55.83; H, 6.68.
RCM Reaction of 20. A degassed solution of 20 (124 mg, 0.3
mmol) and Grubbs’ second-generation catalyst (7 mg, 8 µmol) in
dry benzene (150 mL) was heated under reflux under argon for 6 h
and then concentrated. The residue was purified on silica gel by
eluting with ethyl acetate-light petroleum (1:4) to furnish com-
pound 21 (74 mg, 64%). [R]25 ) +36.4 (c 1.1, CHCl3). IR
D
(CHCl3): 3448, 2983, 2934, 1719, 1607, 1514, 1458, 1381, 1253,
1
1170, 1103 cm–1; H NMR (CDCl3, 200 MHz): δ 1.34 (s, 3H),
1.39 (d, J ) 6.8 Hz, 3H), 1.42 (s, 3H), 1.48–1.50 (m, 1H), 2.31
(br. s, 1H), 2.52 (ddd, J ) 4.3, 9.8, 15.8 Hz, 1H), 3.79 (s, 3H),
4.08 (d, J ) 3.9 Hz, 1H), 4.32 (d, J ) 11.2 Hz, 1H), 4.42 (dd, J )
6.4, 9.8 Hz, 1H), 4.51 (d, J ) 11.2 Hz, 1H), 4.48–4.52 (m, 1H),
4.78 (dd, J ) 6.6, 8.1 Hz, 1H), 5.05–5.19 (m, 1H), 5.71 (ddd, J )
1.2, 8.0, 16.5 Hz, 1H), 5.97 (dd, J ) 3.0, 16.5 Hz, 1H), 6.85, 7.21
(2d, J ) 8.7 Hz, 4H); 13C NMR (CDCl3, 100 MHz): 18.2 (q), 25.2
(q), 28.0 (q), 35.2 (t), 55.2 (q), 69.3 (d), 70.0 (d), 72.4 (t), 75.3 (d),
78.5 (d), 83.2 (d), 108.5 (s), 114.0 (d), 126.1 (d), 128.8 (s), 129.8
(d), 133.3 (d), 159.7 (s), 170.7 (s) ppm. ESI-MS m/z: 415 (M +
Na)+. Anal. Calcd for C21H28O7: C, 64.29; H, 7.14. Found: C, 64.64;
H, 7.07.
TBDPS Protection of 21. To a solution of 21 (150 mg, 0.38
mmol) and imidazole (39 mg, 0.57 mmol) in dry CH2Cl2 (10 mL)
was added tert-butyldiphenylchlorosilane (126 µL, 0.49 mmol), and
the reaction mixture was refluxed for 10 h and then concentrated.
The residue was purified on silica gel column by eluting with ethyl
acetate-light petroleum (1:9) to afford 26 (203 mg, 84%). [R]25
D
) +2.9 (c 3.3, CHCl3). IR (CHCl3): 3018, 2929, 2856, 2742, 1725,
1701, 1685, 1601, 1578, 1501 cm–1; 1H NMR (CDCl3, 400 MHz):
δ 1.11 (s, 9H), 1.34 (d, J ) 6.9 Hz, 3H), 1.39 (s, 3H), 1.47 (s, 3H),
1.44–1.52 (m, overlapped, 1H), 2.50 (ddd, J ) 3.9, 9.9, 15.2 Hz,
1H), 3.66 (d, J ) 3.8 Hz, 1H), 3.78 (s, 3H), 3.93, 4.11 (2d, J )
11.1 Hz, 2H), 4.44– 4.51 (m, 2H), 4.83 (dd, J ) 6.5, 7.4 Hz, 1H),
5.13–5.21 (m, 1H), 5.93 (dd, J ) 2.4, 16.0 Hz, 1H), 6.06 (dd, J )
7.0, 16.0 Hz, 1H), 6.76, 6.96 (2d, J ) 8.6 Hz, 4H), 7.32–7.44 (m,
6H), 7.57–7.61 (m, 2H), 7.76–7.81 (m, 2H). 13C NMR (CDCl3,
100 MHz): δ 18.2 (q), 19.3 (s), 25.3 (q), 26.9 (q), 28.0 (q), 35.3
(t), 55.2 (q), 67.8 (d), 71.1 (d), 72.1 (t), 75.5 (d), 78.9 (d), 83.6 (d),
108.3 (s), 113.7 (d), 127.1 (d), 127.68 (d), 127.73 (d), 129.0 (d),
129.6 (d), 129.8 (d), 129.9 (s), 132.9 (s), 133.3 (d), 133.6 (d), 134.8
(d), 135.7 (d), 136.1 (d), 159.4 (s), 168.7 (s) ppm. ESI-MS m/z:
653 [M + Na]+. Anal. Calcd for C37H46O7Si: C, 70.48; H, 7.30.
Found: C, 70.73; H, 7.17.
RCM of Vinyl Epoxide 23. To a thoroughly degassed solution
of 23 (12 mg, 49.59 µmol) in anhydrous CH2Cl2 (15 mL) was added
Grubbs’ second-generation catalyst (3 mg, 3.42 µmol) under argon
atmosphere, and the resulting solution was heated to reflux under
argon for 1 h. Volatiles were removed under reduced pressure, and
the residue was purified on silica gel by eluting with ethyl
acetate-light petroleum (2:1) to furnish 24 (4 mg, 38%). [R]25
)
D
-13.5 (c 0.15, CHCl3). IR (CHCl3): 3426, 1755, 1057, 1029 cm-1
.
1H NMR (CDCl3, 400 MHz): δ 1.39 (d, J ) 6.9 Hz, 3H), 1.62 (dt,
J ) 2.3, 15.2 Hz, 1H), 2.15 (ddd, J ) 4.6, 11.9, 15.2 Hz, 1H),
3.79 (d, J ) 4.6 Hz, 1H), 3.82 (d, J ) 4.6 Hz, 1H), 4.22 (ddd, J )
2.8, 3.2, 11.9 Hz, 1H), 4.62–4.68 (m, 1H), 5.15–5.21 (m, 1H),
5.84–5.87 (m, 2H). 13C NMR (CDCl3, 100 MHz): 17.7 (q), 35.8
(t), 51.6 (d), 54.9 (d), 68.8 (d), 69.2 (d), 70.6 (d), 126.2 (d), 131.3
(d), 166.5 (s) ppm. ESI-MS m/z: 237 [M + Na]+. Anal. Calcd for
C10H14O5: C, 56.07; H, 6.54. Found: C, 55.85; H, 6.71.
PMB Deprotection of 26. At rt, a solution of 26 (190 mg, 0.30
mmol) and DDQ (170 mg, 0.75 mmol) in CH2Cl2-water (6 mL,
18:1) was stirred for 3 h. To this was added aqueous sodium
bicarbonate solution, and the contents were partitioned between
water and DCM. The aqueous layer was extracted with CH2Cl2,
and the combined organic layer was dried over sodium sulfate and
concentrated. The residue was purified on silica gel column by
eluting with ethyl acetate-light petroleum (1:6) to give 27 (110
Tosylation of 21. A solution of 21 (71 mg, 0.18 mmol),
diisopropylethylamine (100 µL, 0.58 mmol), p-toluenesulfonyl
chloride (69 mg, 0.36 mmol), and DMAP (27 mg, 0.22 mmol) in
J. Org. Chem. Vol. 73, No. 10, 2008 3821

Ramana et al.
mg, 71%) as a colorless oil. [R]25 ) +1.43 (c 2.6, CHCl3); IR
1H), 2.25 (ddd, J ) 1.7, 9.8, 15.9 Hz, 1H), 3.75 (ddd, J ) 0.7, 2.2,
3.9 Hz, 1H), 3.78 (d, J ) 4.1 Hz, 1H), 4.39 (dd, J ) 6.2, 9.6 Hz,
1H), 4.73 (dd, J ) 7.1, 8.3 Hz, 1H), 4.93–4.99 (m, 1H), 5.58 (dd,
J ) 9.0, 16.2 Hz, 1H), 5.95 (d, J ) 16.2 Hz, 1H). 13C NMR
(acetone-d6, 100 MHz): 24.6 (q), 27.4 (q), 29.4 (t), 52.7 (d), 57.3
(d), 69.8 (d), 75.4 (d), 77.9 (d), 107.9 (s), 127.4 (d), 128.0 (d),
166.3 (s) ppm. ESI-MS m/z: 277 [M + Na]+. Anal. Calcd for
C13H18O5: C, 61.42; H, 7.09. Found: C, 61.63; H, 7.26.
D
(CHCl3): 3448, 3072, 3015, 2984, 2931, 2858, 1735, 1680, 1599,
1
1578, 1511 cm–1. H NMR (CDCl3, 400 MHz): δ 1.12 (s, 9H),
1.35 (d, J ) 6.9 Hz, 3H), 1.39 (s, 3H), 1.48 (s, 3H), 1.57 (br. dd,
J ) 5.2, 7.1 2H), 2.56 (ddd, J ) 4.2, 9.9, 15.8 Hz, 1H), 3.97 (t, J
) 4.8 Hz, 1H), 4.37–4.45 (m, 2H), 4.80 (dd, J ) 6.4, 8.1 Hz, 1H),
5.12–5.26 (m, 1H), 5.95 (dd, J ) 3.0, 16.1 Hz, 1H), 6.14 (ddd, J
) 1.0, 8.1, 16.1 Hz), 7.37–7.43 (m, 6H), 7.60–7.65 (m, 2H),
7.79–7.84 (m, 2H). 13C NMR (CDCl3, 100 MHz): 18.2 (q), 19.3
(s), 25.3 (q), 26.9 (q), 28.0 (q), 35.2 (t), 68.7 (d), 71.8 (d), 75.4
(d), 76.9 (d), 78.8 (d), 108.5 (s), 127.7 (d), 127.8 (d), 128.8 (d),
129.8 (d), 130.0 (d), 132.0 (d), 132.8 (s), 133.4 (s), 135.7 (d), 136.0
(d), 167.7 (s) ppm. ESI-MS m/z: 533 [M + Na]+. Anal. Calcd for
C29H38O6Si: C, 68.23; H, 7.45. Found: C, 68.38; H,7.67.
Synthesis of Multiplolide A Diastereomer 3. At 0 °C, a solution
of 29 (20 mg, 78.7 µmol) in dry CH2Cl2 (1 mL) was treated with
TFA (10 µL) and stirred for 4 h at rt. The reaction mixture was
concentrated under reduced pressure, and the resulting residue was
purified on silica gel column by eluting with ethyl acetate- light
petroleum (1: 1) to furnish 3 (10 mg, 60%). [R]25D ) –11.8 (c 0.5,
CHCl3). IR (CHCl3): 3401, 2926, 2854, 1731, 1648, 1460, 1369,
1221, 1103, 1065 cm–1. ESI-MS m/z: 237 [M + Na]+, 254 [M +
H + K]+. Anal. Calcd for C10H14O5: C, 56.07; H, 6.54. Found: C,
55.79; H, 6.27.
Methanesulfonylation of 27. At 0 °C, a solution of 27 (100
mg, 0.19 mmol), triethylamine (66 µL, 0.475 mmol), and DMAP
(catalytic) in CH2Cl2 was treated with methanesulfonyl chloride
(34 µL, 0.437 mmol), and the reaction mixture was warmed to rt
and stirred for 2 h. The reaction was portioned between water
and CH2Cl2, and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was dried over sodium sulfate and
concentrated. Purification of the resulting crude product by column
chromatography (1:6 ethyl acetate- light petroleum) afforded 28
(95 mg, 82%) as a sticky white solid. [R]25D ) +2 (c 1.4, CHCl3).
1
Spectral Data of Major Conformer. H NMR (CDCl3, 400
MHz, 25 °C): δ 1.38 (d, J ) 6.7 Hz, 3H), 1.53 (dd, J ) 6.3, 16.1
Hz, 1H), 2.28 (ddd, J ) 2.3, 7.7, 16.1 Hz, 1H), 3.68–3.73 (m, 2H),
3.90 (dd, J ) 3.1, 7.4 Hz, 1H), 4.19 (dd, J ) 3.1, 8.3 Hz, 1H),
5.18–5.25 (m, 1H), 5.64 (dd, J ) 8.3, 16.1 Hz, 1H), 5.80 (dd, J )
1.8, 16.1 Hz, 1H). 13C NMR (CDCl3, 125 MHz): 19.7 (q), 35.7 (t),
53.0 (d), 58.0 (d), 69.7 (d), 72.1 (d), 75.6 (d), 125.9 (d), 129.3 (d),
166.7 (s) ppm.
1
IR (CHCl3): 3018, 2986, 2932, 2859, 1741, 1589 cm–1; H NMR
(CDCl3, 400 MHz): δ 1.14 (s, 9H), 1.35 (d, J ) 6.8 Hz, 3H), 1.40
(s, 3H), 1.49 (s, 3H), 1.53 (br. m, 1H), 2.49–2.56 (m, 1H), 2.51 (s,
3H), 4.37 (d, J ) 3.8 Hz, 1H), 4.47 (dd, J ) 6.5, 9.5 Hz, 1H), 4.55
(dt, J ) 1.3, 3.7 Hz, 1H), 4.84 (dd, J ) 7.0, 8.0 Hz, 1H), 5.20–5.23
(m, 1H), 5.88 (dd, J ) 3.0, 16.1 Hz, 1H), 6.16 (ddd, J ) 1.0, 8.5,
16.1 Hz, 1H), 7.38–7.48 (m, 6H), 7.60–7.62 (m, 2H), 7.83–7.85
(m, 2H). 13C NMR (CDCl3, 100 MHz): 17.9 (q), 19.3 (s), 25.3 (q),
26.8 (q), 27.9 (q), 35.2 (t), 37.4 (q), 69.2 (d), 70.1 (d), 75.4 (d),
78.6 (d), 80.2 (d), 108.6 (s), 127.9 (d), 128.1 (d), 129.4 (d), 130.1
(d), 130.4 (d), 130.8 (d), 132.1 (s), 133.0 (s), 135.7 (d), 136.1 (d),
164.5 (s) ppm. ESI-MS m/z: 611 [M + Na]+. Anal. Calcd for
C30H40O8SSi: C, 61.22; H, 6.80. Found: C, 61.48; H, 6.73.
Preparation of 29. To a solution of 28 (90 mg, 0.15 mmol) in
dry THF (2 mL) was added a 1 M solution of TBAF in THF (0.36
mL, 0.36 mmol) at 0 °C, and the contents were stirred at rt for 8 h.
To this was added saturated ammonium chloride, the aqueous layer
was extracted with ethyl acetate, and the combined organic layer
was dried with sodium sulfate and concentrated. The residue was
purified on silica gel column by eluting with ethyl acetate-light
1
Spectral Data of Minor Conformer. H NMR (CDCl3, 400
MHz, 0 °C): δ 1.37–1.42 (m, 1H, merged with methyl peaks), 1.41
(d, J ) 6.9 Hz, 3H), 2.51 (ddd, J ) 2.3, 7.8, 16.1 Hz, 1H), 3.25
(br. s, 2H), 3.79 (d, J ) 4.5 Hz, 1H), 3.93–3.95 (m, 1H) 3.98 (dd,
J ) 2.9, 8.2 Hz, 1H), 4.49–4.51 (m, 1H), 5.18–5.25 (m, 1H, merged
with major conformer peak), 5.71 (dt, J ) 2.0, 16.8 Hz, 1H),
5.80–5.84 (1H, merged with the major conformer peak). 13C NMR
(CDCl3, 125 MHz): 17.9 (q), 34.9 (t), 53.03 (d), 55.2 (d), 68.9 (d),
70.3 (d), 72.5 (d), 121.3 (d), 137.4 (d), 167.6 (s) ppm.
Acknowledgment. T.P.K. thanks UGC (New Delhi) and S.C.
thanks to CSIR (New Delhi) for financial assistance in the form
of research fellowships.
Supporting Information Available: Experimental details,
spectral and analytical data of all new compounds, 1H, 13C, and
DEPT spectra for compounds 6–8, 21, 3, and 4, and 2D NMR
of 21 and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
petroleum (1: 9) to afford 29 (24 mg, 63%) as colorless oil. [R]25
D
) + 3.6 (c 1.7, CHCl3); IR (CHCl3): 2986, 2927, 2855, 1737, 1456,
1371, 1221, 1167, 1080 cm–1. 1H NMR (acetone-d6, 400 MHz): δ
1.31 (s, 3H), 1.40 (d, J ) 6.9 Hz, 3H), 1.40 (s, 3H), 1.65–1.71 (m,
JO7027568
3822 J. Org. Chem. Vol. 73, No. 10, 2008