A carbohydrate-based approach for the total synthesis of aculeatin D and 6-epi-aculeatin D

Article abstract of DOI:10.1021/jo800026n

(Chemical Equation Presented) A concise approach for the total synthesis of aculeatin D and 6-epi-aculeatin D employing differentially protected anti,anti-1,3,5-triol alkyne prepared from α-D-glucoheptonic-γ- lactone derivative is documented. Phenol protecting group manipulation for selective O-debenzylation during the hydrogenation of the diyne intermediate and one-pot phenolic oxidation with concomitant spiroketalization highlight the accomplished total synthesis.

Full text of DOI:10.1021/jo800026n

center present by either asymmetric aldol or chiral allylation
protocols and finally phenolic oxidation of a 3,5-syn- or anti-
diol ketone. A flexible total synthesis that would allow access
to modified aculeatins like functional group addition to the
cyclohexadienone unit and/or alterations on the aliphatic side
chain should give access to various synthetic analogues for
structure-activity studies. It was reasoned that addition of these
units at a late stage in the synthesis would support this criteria.
Herein we report a concise approach by selecting aculeatin D
(4) as a target considering its documented superior cytotoxicity
(IC50 ) 0.38 µg/mL).
A Carbohydrate-Based Approach for the Total
Synthesis of Aculeatin D and 6-epi-Aculeatin D
C. V. Ramana* and Burgula Srinivas
DiVision of Organic Chemistry, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Vr.chepuri@ncl.res.in
ReceiVed January 4, 2008
A concise approach for the total synthesis of aculeatin D
and 6-epi-aculeatin D employing differentially protected
anti,anti-1,3,5-triol alkyne prepared from R-D-glucoheptonic-
γ-lactone derivative is documented. Phenol protecting group
manipulation for selective O-debenzylation during the hy-
drogenation of the diyne intermediate and one-pot phenolic
oxidation with concomitant spiroketalization highlight the
accomplished total synthesis.
FIGURE 1. Aculeatins A-D and 6-epi-aculeatin D and retrosynthetic
strategy for aculeatin D.
As outlined in Figure 1, our retrosynthetic disconnection
identified an alkyne epoxide 7 as the key intermediate which
can be extended to the advanced keto 3,5-diol unit 6 by the
Yamaguchi protocol8 at one end and the Sonogashira coupling9
on the alkyne end, thus keeping flexibility at both sides. In
agreement with our previous observation, we hypothesized a
selective propargylic-OBn cleavage during the Raney Ni
hydrogenation of the alkyne units.10,11 Oxidation of the released
free C6-OH and subsequent global deprotection and phenolic
oxidation should complete the total synthesis of aculeatin D
(4) and its 6-epimer (5).
Aculeatins A-D are the spiroketals isolated from the terrestrial
plant species Amomum aculeatum. They were assigned structures
1-4, respectively (Figure 1).1,2 Aculeatins were found to display
antiprotozoal activity against some Plasmodium and Trypanosoma
species. In addition, they showed potential antibacterial activity
and cytotoxicity against the KB cell line. Because of their promising
biological activity taken together with the presence of structurally
fascinating 1,7-dioxadispiro[5.1.5.2]pentadecane spirocyclic archi-
tecture, aculeatins A-D aroused substantial interest culminating
in several total syntheses.3–7
The syntheses reported for aculeatins3–7 in general are linear
in nature and involve a stepwise construction of each chiral
To explore in this direction, commercially available gluco-
heptono-1,4-lactone (9) was advanced to the key intermediate
(1) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. HelV. Chim. Acta
2000, 83, 2939–2945.
(8) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467–4470. (b) Nguefack, J.-F.; Bolitt, V.; Sinou, D. Tetrahedron Lett. 1996,
31, 5527–5530. (c) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729–1731. (d) Witulski, B.; Alayrac, C.; Arnautu, A.; Collot,
V.; Rault, S.; Azcon, J. R. Synthesis 2005, 771–780.
(2) Heilmann, J.; Brun, R.; Mayr, S.; Rali, T.; Sticher, O. Phytochemistry
2001, 57, 1281–1285.
(3) (a) Wong, Y.-S. Chem. Commun. 2002, 686–687. (b) Peuchmaur, M.;
Wong, Y.-S. J. Org. Chem. 2007, 72, 5374–5379. (c) Peuchmaur, M.; Wong,
Y.-S. Synlett 2007, 2902–2906.
(10) Ramana, C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K. J. Org. Chem.
2005, 70, 8216–8219.
´
(4) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2005, 46, 8407–8410.
(11) (a) Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O. Tetrahedron Lett.
1984, 25, 5397–5400. (b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021–3028. (c) Perosa, A.; Tundo, P.;
Zinovyev, S. Green Chem. 2002, 4, 492–494. (d) Weissman, S. A.; Zewge, D.
Tetrahedron 2005, 61, 7833–7863. (e) Lla`cer, E.; Romea, P.; Urp´ı, F. Tetrahedron
Lett. 2006, 47, 5815–5818. (f) Vincent, A.; Prunet, J. Tetrahedron Lett. 2006,
47, 4075–4077.
(5) Baldwin, J. E.; Adlington, R. M.; Sham, V. W.-W.; Marquez, R.; Bulger,
P. G. Tetrahedron 2005, 61, 2353–2363.
´
(6) Alvarez-Bercedo, P.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron
2006, 62, 9641–9649.
(7) Chandrasekhar, S.; Rambabu, C.; Shyamsunder, T. Tetrahedron Lett.
2007, 48, 4683–4685.
10.1021/jo800026n CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3915–3918 3915

SCHEME 1. Synthesis of Epoxide 7
SCHEME 2. Yamaguchi Protocol, Sonogashira Coupling,
and Hydrogenation with Raney Ni
lactone 8 following our established procedure (Scheme 1).10
Controlled reduction of lactone 8 with DIBAL-H and subsequent
Ohira-Bestmann alkynylation12 of intermediate lactol afforded
the alkyne 10.
Treatment of 10 with p-methoxybenzyl chloride in the
presence of NaH in DMF followed by acetonide hydrolysis of
resulting product 11 by using PPTS in MeOH afforded the diol
12. The diol 12 was transformed to the oxirane 7 by selective
primary OH tosylation using TsCl, Bu2SnO, and triethylamine
in dichloromethane followed by cyclization with K2CO3 in
methanol.
SCHEME 3. Total Synthesis of Aculeatin D (4) and
6-epi-Aculeatin D (5)
After having the epoxide 7, we next focused our efforts on
the synthesis of the keto-3,5-diol unit 6. Thus, the projected
opening of 7 with dodec-1-nyllithium in the presence of
BF3 · Et2O delivered the diyne 13 in near quantitative yields
(Scheme 2).8 Protection of the free hydroxyl group in 13 as its
TBS ether followed by Sonogashira coupling of resulting 14
with p-iodophenol gave the required coupling product 15 along
with small amounts of self-dimerized product 16.9 Our next
concern was the hydrogenation of diyne 15 along with the
desired selective propargyl-O-debenzylation.10 To our surprise,
hydrogenation of 15 was facile, but resulted exclusively in diyne
reduction to afford product 17.
After careful experimentation by employing protected p-
iodophenol derivatives for Sonogashira coupling and subsequent
Raney Ni hydrogenation, we concluded that TBS was the
optimal protecting group that improved the yield in Sonogashira
coupling and, to our delight, the anticipated O-debenzylation
during the hydrogenation of respective intermediate 18 affording
19. Oxidation of 19 under Swern conditions afforded the keto-
3,5-diol unit 20.
Having the keto-3,5-anti-diol 20, the stage was set for the
global deprotection and subsequent phenol oxidation. Attempted
global deprotection of PMB, TBS-ethers in acidic conditions
(TFA, PTSA, or PPTS) in solvents like methanol or dichlo-
romethane yielded an unidentified complex mixture. Sequential
deprotection of PMB-ether by using DDQ in dichloromethane
under buffered conditions followed by, TBS-ether deprotection
in presence of TBAF in THF produced the free diol. Oxidative
spiroacetalization of intermediate ketodiol by using phenyliodi-
ne(III) bis(trifluroacetate) (PIFA) in acetone/water (10:1, v/v
solution) completed the synthesis of epimeric aculeatins 4 and
5. Physical and spectral data of these compounds were in
agreement with the data reported for natural aculeatin D4 and
synthetic 6-epi-aculeatin D,5 respectively.
In conclusion, a chiral pool approach employing an easily
accessible 1,3-polyol unit for the total synthesis of naturally
occurring aculeatin D and its 6-epimer was documented. As
such, this route employs the addition of the both the terminal
(12) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Roth, G. J.; Liepold,
B.; Mu¨ller, S. G.; Bestmann, H. J. Synlett 1996, 521–522.
3916 J. Org. Chem. Vol. 73, No. 10, 2008

(3S,5R,7R)-5-O-(4-Methoxybenzyl)-7-O-tert-butyldimethylsilyl-
1-(4-tert-butyldimethylsilyloxyphenyl)icosane-3,5,7-triol (19). A sus-
pension of di-TBS derivative 18 (1 g, 1.17 mmol) and Raney-Ni
(100 mg) in ethanol (30 mL) was flushed with hydrogen gas and
stirred under hydrogen (20 psi) atmosphere at 55 °C for 18 h. The
reaction mixture was filtered through a plug of filter aid, washed
with methanol thoroughly (5 × 20 mL), and concentrated. Purifica-
tion of crude product by column chromatography (10% ethyl acetate
in petroleum ether) yielded hydrogenated product 19 (800 mg, 88%)
units (phenol and side chain) at the late stage of the synthesis
thus provide sufficient flexibility for related analogues synthe-
sis.13
Experimental Section
Preparation of Epoxide (7). To a solution of diol 12 (600 mg,
1.56 mmol) in dry CH2Cl2 (15 mL) were added Bu2SnO (7 mg)
and p-TsCl (327 mg, 1.71 mmol) followed by triethylamine (435
µL, 3.12 mmol) and DMAP (20 mg) at 0 °C. The reaction mixture
was slowly warmed to rt and stirred for 1.5 h. The reaction mixture
was diluted with CH2Cl2 and extracted. The combined organic
phases were washed with water and brine, dried (Na2SO4), and
concentrated. The crude tosylate (840 mg) was dissolved in
methanol (20 mL) and stirred with anhydrous K2CO3 (270 mg) for
30 min at 0 °C and concentrated. The crude was dissolved in ethyl
acetate, washed with water and brine, dried (Na2SO4), and
concentrated. Purification of the crude by column chromatography
(15% ethyl acetate in petroleum ether) gave the epoxide 7 (470
mg, 82% for two steps) as a colorless oil. [R]25D ) +86.9 (c ) 1,
CHCl3). IR (CHCl3): ν 3432, 3289, 2927, 2110, 1612, 1513, 1248,
as a colorless oil. [R]25 ) -5.1 (c ) 1, CHCl3). IR (CHCl3): ν
D
3480, 2855, 1611, 1510, 1252, 1039, 836, 758, 692 cm-1. 1H NMR
(500 MHz, CDCl3): δ 7.23 (dt, J ) 8.6, 2.9 Hz, 2H), 7.03 (dt, J )
8.4, 2.9 Hz, 2H), 6.86 (dt, J ) 8.6, 2.9 Hz, 2H), 6.73 (dt, J ) 8.4,
2.9 Hz, 2H), 4.51 (d, J ) 10.9 Hz, 1H), 4.42 (d, J ) 10.9 Hz, 1H),
3.93-3.90 (m, 1H), 3.84-3.79 (m, 1H), 3.79 (s, 3H), 3.77-3.71
(m, 1H), 3.11 (br.s, 1H), 2.73-2.67 (m, 1H), 2.60-2.54 (m, 1H),
1.90-1.83 (m, 2H), 1.78-1.71 (m, 1H), 1.68-1.59 (m, 3H),
1.56-1.51 (m, 2H), 1.44-1.40 (m, 2H), 1.28-1.25 (m, 20H), 0.97
(s, 9H), 0.87 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H), 0.17 (s, 6H), 0.03
(s, 3H), 0.02 (s, 3H). 13C NMR (125 MHz, CDCl3): δ -4.4 (q,
2C), -4.4 (q), -4.0 (q), 14.1 (q), 18.1 (s), 18.2 (s), 22.7 (t), 24.7
(t), 25.7 (q, 3C), 25.9 (q, 3C), 29.3 (t), 29.7 (t), 29.7 (t), 29.9 (t),
31.1 (t), 31.9 (t), 37.7 (t), 39.5 (t), 39.8 (t), 41.5 (t), 55.3 (q), 68.1
(d), 69.8 (d), 70.6 (t), 74.9 (d), 113.9 (d, 2C), 119.8 (d, 2C), 129.2
(d, 2C), 129.4 (d, 2C), 130.2 (s), 134.9 (s), 153.6 (s), 159.3 (s)
ppm. ESI-MS: m/z 793.98 (100, [M + Na]+). Anal. Calcd for
C46H82O5Si2: C, 71.63; H, 10.72. Found: C, 71.58; H, 10.60.
1
1069, 753, 699 cm-1. H NMR (200 MHz, CDCl3): δ 7.36-7.27
(m, 5H), 7.14 (dt, J ) 8.7, 2.8 Hz, 2H), 6.82 (dt, J ) 8.7, 2.8 Hz,
2H), 4.79 (d, J ) 11.4 Hz, 1H), 4.48 (d, J ) 10.8 Hz, 1H), 4.39
(d, J ) 11.4 Hz, 1H), 4.28 (d, J ) 10.8 Hz, 1H), 4.34-4.25 (m,
1H), 3.86 (ddd, J ) 12.7, 11.9, 5.9 Hz, 1H), 3.76 (s, 3H), 3.03
(ddt, J ) 5.8, 3.9, 2.7 Hz, 1H), 2.78 (dd, J ) 5.0, 4.0 Hz, 1H),
2.49 (dd, J ) 5.0, 2.7 Hz, 1H), 2.47 (d, J ) 2.1 Hz, 1H), 2.01 (dd,
J ) 7.0, 5.9 Hz, 2H), 1.74 (t, J ) 5.8 Hz, 2H). 13C NMR (50
MHz, CDCl3): δ 37.6 (t), 41.7 (t), 47.3 (t), 49.2 (d), 55.1 (q), 64.8
(d), 70.5 (t), 71.4 (t), 72.6 (d), 73.9 (d), 82.7 (s), 113.6 (d, 2C),
127.7 (d), 128.1 (d, 2C), 128.3 (d, 2C), 129.4 (d, 2C), 130.3 (s),
137.5 (s), 159.1 (s) ppm. ESI-MS: m/z 389.22 (100, [M + Na]+).
Anal. Calcd for C23H26O4: C, 75.38; H, 7.15. Found: C, 75.30; H,
7.08.
(5S,7R) 5-(4-Methoxybenzyloxy)-7-(tert-butyldimethylsilyloxy-
1-(4-tert-butyldimethylsilyloxyphenyl)icosan-3-one (20). In a
flame-dried, two necked, round-bottom flask (25 mL) was dissolved
oxalyl chloride (67 µL, 0.77 mmol) under N2 in dry CH2Cl2 (5
mL). After the solution was cooled to -78 °C, dry DMSO (100
µL, 1.42 mmol) was added dropwise with stirring for 15 min. A
solution of alcohol 19 (200 mg, 0.25 mmol) in dry CH2Cl2 (5 mL)
was added dropwise and stirred for 30 min. To this was added Et3N
(216 µL, 1.55 mmol) and stirring continued for 15 min at -78 °C.
The reaction mixture was partitioned between CH2Cl2 and water,
the organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. Combined organic phases were washed with
brine, dried (Na2SO4), and concentrated. Purification of the crude
by column chromatography (5% ethyl acetate in petroleum ether)
afforded ketone 20 (190 mg, 95%) as a colorless oil. [R]25D ) -4.5
(c ) 1, CHCl3). IR (CHCl3): ν 3415, 2927, 1715, 1612, 1511, 1252,
(3S,5R,7R)-3-O-Benzyl-5-O-(4-methoxybenzyl)-7-O-tert-butyl-
dimethylsilyl-1-(4-hydroxyphenyl)icosane-3,5,7-triol (17). A suspen-
sion of dialkyne 15 (200 mg, 0.27 mmol) and Raney-Ni (20 mg)
in ethanol (10 mL) was flushed with hydrogen gas and stirred under
hydrogen (20 psi) atmosphere for 10 h at rt. The reaction mixture
was filtered through a plug of filter aid, washed with methanol
thoroughly (5 × 10 mL), and concentrated. Purification of the crude
product by column chromatography (10% ethyl acetate in petroleum
ether) yielded hydrogenated product 17 (168 mg, 83%) as a
colorless oil. [R]25D ) +14.9 (c ) 1, CHCl3). IR (CHCl3): ν 3368,
2854, 1613, 1514, 1216, 1039, 834, 758, 697 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.34-7.24 (m, 5H), 7.17 (dt, J ) 8.6, 2.8 Hz,
2H), 7.01 (dt, J ) 8.4, 3.0 Hz, 2H), 6.83 (dt, J ) 8.6, 2.8 Hz, 2H),
6.72 (dt, J ) 8.4, 2.9 Hz, 2H), 5.00 (br.s, 1H), 4.49 (d, J ) 11.4
Hz, 1H), 4.41 (d, J ) 10.9 Hz, 1H), 4.34 (d, J ) 11.4 Hz, 1H),
4.27 (d, J ) 10.9 Hz, 1H), 3.83 (dt, J ) 12.2, 5.5 Hz, 1H), 3.77 (s,
3H), 3.70 (dt, J ) 12.2, 6.3 Hz, 1H), 3.60 (dt, J ) 11.7, 5.8 Hz,
1H), 2.61 (t, J ) 8.0 Hz, 2H), 1.90-1.76 (m, 3H), 1.74 (t, J ) 6.2
Hz, 2H), 1.55 (ddd, J ) 13.4, 6.8, 6.0 Hz, 1H), 1.46-1.39 (m,
2H), 1.31-1.25 (m, 22H), 0.88 (s, 9H), 0.87 (t, J ) 7.0 Hz, 3H),
0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (125 MHz, CDCl3) δ -4.3
(q), -4.1 (q), 14.1 (q), 18.1 (s), 22.7 (t), 24.7 (t), 26.0 (q, 3C),
29.3 (t), 29.6 (t), 29.7 (t), 29.7 (t), 29.9 (t), 30.4 (t), 31.9 (t), 36.1
(t), 37.6 (t), 40.4 (t), 42.6 (t), 55.2 (q), 69.5 (d), 70.3 (t), 70.8 (t),
73.3 (d), 75.3 (d), 113.7 (d, 2C), 115.2 (d, 2C), 127.4 (d), 127.8
(d, 2C), 128.3 (d, 2C), 129.3 (d, 2C), 129.4 (d, 2C), 130.9 (s), 134.3
(s), 138.8 (s), 153.6 (s), 159.0 (s) ppm. ESI-MS: m/z 770.04 (100,
[M + Na]+). Anal. Calcd for C47H74O5Si: C, 75.55; H, 9.98. Found:
C, 75.48; H, 9.90.
1
1040, 836, 759, 686 cm-1. H NMR (500 MHz, CDCl3): δ 7.19
(dt, J ) 8.6, 2.9 Hz, 2H), 6.99 (dt, J ) 8.4, 2.9 Hz, 2H), 6.85 (dt,
J ) 8.6, 2.9 Hz, 2H), 6.72 (dt, J ) 8.4, 2.9 Hz, 2H), 4.42 (d, J )
10.9 Hz, 1H), 4.39 (d, J ) 10.9 Hz, 1H), 4.09-4.02 (m, 1H),
3.84-3.79 (m, 1H), 3.78 (s, 3H), 2.80 (t, J ) 7.4 Hz, 2H), 2.71
(dd, J ) 15.5, 7.1 Hz, 1H), 2.69 (t, J ) 7.4 Hz, 2H), 2.49 (dd, J
) 15.6, 5.0 Hz, 1H), 1.76-1.69 (m, 1H), 1.51-1.41 (m, 3H), 1.25
(m, 22H), 0.97 (s, 9H), 0.88 (s, 9H), 0.87 (t, J ) 7.18 Hz, 3H),
0.17 (s, 6H), 0.04 (s, 6H). 13C NMR (125 MHz, CDCl3): δ -4.5
(q, 2C), -4.4 (q), -4.0 (q), 14.1 (q), 18.1 (s), 18.2 (s), 22.7 (t,
24.7 (t), 25.7 (q, 3C), 25.9 (q, 3C), 28.7 (t), 29.3 (t), 29.6 (t), 29.7
(t), 29.8 (t), 31.9 (t), 37.9 (t), 42.7 (t), 45.6 (t), 48.8 (t), 55.2 (q),
69.5 (d), 71.1 (t), 73.1 (d), 113.8 (d, 2C), 119.9 (d, 2C), 129.1 (d,
2C), 129.2 (d, 2C), 130.7 (s), 133.6 (s), 153.8 (s), 159.1 (s), 208.6
(s) ppm. ESI-MS: m/z 807.83 (100, [M + K]+). Anal. Calcd for
C46H80O5Si2: C, 71.82; H, 10.48. Found: C, 71.78; H, 10.40.
Synthesis of Aculeatin D (4) and 6-epi-Aculeatin D (5). To a
solution of PMB ether 20 (100 mg, 0.2 mmol) in CH2Cl2 (10 mL)
and buffer (2 mL) was added DDQ (45 mg, 0.18 mmol) portionwise
at 0 °C and stirring continued for another 30 min at the same
temperature. The reaction mixture was filtered through a plug of
filter aid and washed with CH2Cl2. The organic phase was washed
with water and brine, dried (Na2SO4), and concentrated. The crude
(84 mg) was dissolved in dry THF (5 mL) and treated with TBAF
(250 µL of 1 M solution in THF, 0.25 mmol) at 0 °C. After the
mixture was stirred for 15 min at the same temperature, solvent
(13) For isolation of truncated aculeatins A and B, see: Chin, Y.-W.; Salim,
A. A.; Su, B.-N.; Mi, Q.; Chai, H.-B.; Riswan, S.; Kardono, L. B. S.; Ruskandi,
A.; Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod. 2008, 71,
390–395.
J. Org. Chem. Vol. 73, No. 10, 2008 3917

was evaporated under reduced pressure. The crude ketal (50 mg)
was dissolved in acetone/H2O (2.5 mL, 10:1 v/v solution), and PIFA
(68 mg, 0.16 mmol) was added in one portion at room temperature.
After the mixture was stirred for 15 min in darkness, a saturated
aqueous solution of NaHCO3 (4 mL) was added and the resulting
mixture extracted with ethyl acetate (3 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated. The
crude product was purified by flash column chromatography (30%
and 35% ethyl acetate in petroleum ether) to afford 5 (16 mg, 30%)
and 4 (15 mg, 28%) as colorless oils.
(+)-6-epi-Aculeatin D. [R]25 ) +14.6 (c ) 0.2, CHCl3) [lit.
D
D
[R]26 ) +15.0 (c ) 1, CHCl3)]. IR (neat): ν 3410, 2916, 2849,
1664, 1628, 1053, 1005 cm-1. 1H NMR (400 MHz, CDCl3): δ 6.81
(dd, J ) 10.4, 3.2 Hz, 1H), 6.76 (dd, J ) 10.4, 3.2 Hz, 1H), 6.11
(dd, J ) 10.1, 1.9 Hz, 1H), 6.10 (dd, J ) 10.1, 1.9 Hz, 1H),
4.15-4.02 (m, 1H), 3.83-3.75 (m, 1H), 2.42-2.32 (m, 1H), 2.24
(dd, J ) 10.3, 8.2 Hz, 1H), 2.08 (ddd, J ) 12.4, 4.7, 1.6 Hz, 1H),
2.04-1.94 (m, 3H), 1.62 (dd, J ) 11.8, 11.8 Hz, 1H), 1.52-1.41
(m, 2H), 1.32-1.22 (m, 22H), 1.18 (ddd, J ) 11.6, 11.6, 11.6 Hz,
1H), 0.87 (t, J ) 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
14.1 (q), 22.7 (t), 25.7 (t), 29.3 (t), 29.7 (t), 31.9 (t), 34.6 (t), 35.9
(t), 38.8 (t), 40.6 (t), 43.0 (t), 65.3 (d), 69.1 (d), 79.0 (s), 108.9 (s),
127.0 (d), 127.1 (d), 149.2 (d), 151.4 (d), 185.5 (s) ppm. ESI-MS:
m/z 419.4 [M + H]+, 441.4 [M + Na]+. Anal. Calcd for C26H42O4:
C, 74.60; H, 10.11. Found: C, 74.51; H, 10.02.
(+)-Aculeatin D. [R]25 ) +47.7 (c ) 0.2, CHCl3) [lit. [R]23
D
D
) +46.5 (c ) 1, CHCl3)]. IR (neat): ν 3410, 2916, 2849, 1665,
1628, 1057, 1009 cm-1. 1H NMR (400 MHz, CDCl3): δ 6.98 (dd,
J ) 10.5, 3.2 Hz, 1H), 6.77 (dd, J ) 10.5, 3.2 Hz, 1H), 6.13 (dd,
J ) 10.3, 1.9 Hz, 1H), 6.12 (dd, J ) 10.3, 1.9 Hz, 1H), 3.88-3.80
(m, 1H), 3.40-3.32 (m, 1H), 2.39 (ddd, J ) 12.7, 7.4, 2.0 Hz,
1H), 2.26 (ddd, J ) 12.5, 11.3, 7.3 Hz, 1H), 2.12 (ddd, J ) 12.1,
4.4, 1.6 Hz, 1H), 2.06 (ddd, J ) 12.7, 8.4, 2.0 Hz, 1H), 1.95 (m,
1H), 1.87-1.75 (m, 2H), 1.69-1.57 (m, 1H), 1.53-1.43 (m, 2H),
1.35-1.23 (m, 22H), 0.87 (t, J ) 6.7 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 14.1 (q), 22.7 (t), 25.9 (t), 29.3 (t), 29.4 (t), 29.6
(t), 29.6 (t), 29.7 (t), 31.9 (t), 33.4 (t), 34.9 (t), 35.7 (t), 40.8 (t),
43.6 (t), 66.8 (d), 71.6 (d), 78.1 (s), 109.2 (s), 127.2 (d), 127.4 (d),
148.8 (d), 151.5 (d), 185.5 (s) ppm. ESI-MS: m/z 419.4 [M + H]+,
441.4 [M + Na]+. Anal. Calcd for C26H42O4: C, 74.60; H, 10.11.
Found: C, 74.48; H, 10.00.
Acknowledgment. B.S. thanks CSIR (New Delhi) for finan-
cial assistance in the form of a research fellowship.
Supporting Information Available: General Experimental
Methods and experimental procedures for preparation and com-
pound characterization data of 10-16 and 18 and copies of NMR
spectra of compounds 7, 13, 16-20, 4, and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800026N
3918 J. Org. Chem. Vol. 73, No. 10, 2008