Synthesis and structural revision of symbiodinolide C23-C34 fragment

Article abstract of DOI:10.1021/jo900546k

(Chemical Equation Presented) Stereoselective synthesis of the C23-C34 fragment of symbiodinolide, which possesses the originally proposed stereochemistry, and its diastereomers was achieved in 19 steps from L-aspartic acid, respectively. Comparison of sp

Full text of DOI:10.1021/jo900546k

Synthesis and Structural Revision of Symbiodinolide C23-C34
Fragment
Takeshi Murata,† Masayuki Sano,† Hiroyoshi Takamura,*,‡ Isao Kadota,*,‡ and
Daisuke Uemura§
Graduate School of Science, Nagoya UniVersity, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan,
Graduate School of Natural Science and Technology, Okayama UniVersity, 3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan, and Faculty of Science and Technology, Keio UniVersity, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
takamura@cc.okayama-u.ac.jp
ReceiVed March 12, 2009
Stereoselective synthesis of the C23-C34 fragment of symbiodinolide, which possesses the originally
proposed stereochemistry, and its diastereomers was achieved in 19 steps from L-aspartic acid, respectively.
Comparison of spectroscopic data of the synthetic products with those of the degraded product of
symbiodinolide led to a structural revision of the C23-C34 fragment.
Introduction
using Grubbs’ second-generation catalyst5 (Scheme 1).3 Relative
stereochemistry of 2 was elucidated to be as shown in Scheme
1 by 1H-1H coupling constants and NOE correlations. Herein,
we report the enantio- and stereocontrolled synthesis of 2
possessing the originally proposed stereochemistry and its
diastereomers, which has resulted in the structural revision of
the C23-C34 fragment.
Various secondary metabolites have been isolated from
marine organisms.1 In particular, huge polyol and polyether
compounds, such as palytoxins and halichondrins, are some of
the most attractive molecules due to their remarkable biological
activities and chemical structures.2 Although the biological
activities of these compounds have been well investigated, the
true physiological functions have rarely been clarified.
Results and Discussion
Symbiodinolide (1), a novel polyol compound, has been
recently isolated from the marine dinoflagellate Symbiodinium
sp., which exhibits a voltage-dependent N-type Ca2+ channel-
opening activity at 7 nM and COX-1 inhibitory effect at 2 µM
(Figure 1).3 The planar structure and partial stereochemistry of
1 were elucidated by spectroscopic analysis3 and chemical
synthesis.4 Previously, we obtained the C23-C34 fragment 2
by the degradation of 1 via the cross-metathesis with ethylene
Determination of the Absolute Stereochemistries at the
C26 and C32 Positions. First, the absolute stereochemistries
of the C26 and C32 positions of the degraded product 2 were
determined by the modified Mosher method.6,7 Figure 2 depicts
the selected ∆δS-R values of the corresponding bis-(S)- and (R)-
MTPA esters, (S)-3 and (R)-3, prepared from 2 by the standard
procedures (MTPACl/Et3N/DMAP). The signs at the C23, C24,
and C25 positions showed negative, and those of the C33 and
C34 positions exhibited positive. Therefore, the absolute ste-
reochemistries of the C26 and C32 positions were assigned to
be 26S and 32S, respectively.
† Nagoya University.
‡ Okayama University.
§ Keio University.
Synthesis of the Diepoxide 2. Our synthetic plan of 2 is
outlined in Scheme 2. We envisaged that 2 would be synthesized
from aldehyde 4 through a stereoselective allylation. The
(1) (a) Uemura, D. Bioorganic Marine Chemistry; Scheuer, P. J., Ed.;
Springer: Berlin, Heidelberg, 1991; Vol. 4, pp 1-31. (b) Shimizu, Y. Chem.
ReV. 1993, 93, 1685.
(2) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897. (b) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293.
(3) Kita, M.; Ohishi, N.; Konishi, K.; Kondo, M.; Koyama, T.; Kitamura,
M.; Yamada, K.; Uemura, D. Tetrahedron 2007, 63, 6241.
(4) (a) Takamura, H.; Ando, J.; Abe, T.; Murata, T.; Kadota, I.; Uemura, D.
Tetrahedron Lett. 2008, 49, 4626. (b) Takamura, H.; Kadonaga, Y.; Yamano,
Y.; Han, C.; Aoyama, Y.; Kadota, I.; Uemura, D. Tetrahedron Lett. 2009, 50,
863.
(5) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(6) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(7) For determination of the absolute stereochemistry of secondary/secondary
diols by modified Mosher method, see: Freire, F.; Seco, J. M.; Quin˜oa´, E.;
Riguera, R. J. Org. Chem. 2005, 70, 3778.
10.1021/jo900546k CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009
J. Org. Chem. 2009, 74, 4797–4803 4797

Murata et al.
FIGURE 1. Structure of symbiodinolide (1).
selectively (dr ) 12:1).11 The alcohol 11 was converted to allylic
alcohol 12 by the following three-step sequence: (1) Swern
oxidation,12 (2) Horner-Wadsworth-Emmons olefination,13
and (3) DIBALH reduction of the resulting R,ꢀ-unsaturated
ester. Sharpless asymmetric epoxidation was utilized for the
stereoselective construction of contiguous epoxide moiety of
13. However, chemical yield and stereoselectivity were ex-
tremely low. Therefore, we carried out m-CPBA epoxidation
of 12 to give diepoxides 13ꢀ and 13r in 90% yield at a 1:1
diastereomeric ratio.14
SCHEME 1. Cross-Metathesis Degradation of 1 with
Ethylene
The diepoxide 13ꢀ, which possesses the absolute stere-
ochemistries at C27 and C28 positions corresponding to those
of 2, was derivatized for the structural elucidation (Scheme
4). Thus, regioselective Red-Al reduction of 13ꢀ proceeded
smoothly to give 1,3-diol 14.15 Intramolecular etherification
of 14 took place in CDCl3 to yield five-membered ether 15.
Treatment of the resulting diol 15 with carbonyl diimidazole
provided bicyclic carbonate 16ꢀ. The stereostructure of 16ꢀ
was determined by coupling constant and NOE correlation.
The large magnitude of Ja,b (11.7 Hz) indicated that Ha and
Hb were in an anti orientation to each other. The observed
NOE between C30-Me and Ha confirmed that they were in
a syn relationship.
FIGURE 2. Chemical shift differences (∆δS-R) of bis-MTPA esters
derived from 2. R ) MTPA. MTPA ) R-methoxy-R-(trifluorometh-
yl)phenylacetyl.
construction of the diepoxide moiety was based on the stepwise
chain elongation-epoxidation process of allylic alcohol 5, which
might be readily prepared from L-aspartic acid.
The synthesis of 2 commenced from L-aspartic acid which
was converted to epoxide 6 by the standard procedures (Scheme
3).8 Treatment of the epoxide 6 with the lithium acetylide,
derived from ethyl propiolate, gave acetylenic alcohol 7.9 The
resulting hydroxy moiety of 7 was protected to give TBS ether
8. Conjugate addition of benzenethiol to 8 provided the
corresponding (Z)-thioether, which was reacted with MeMgBr
and CuI to give (E)-R,ꢀ-unsaturated ester 9 with complete
configurational retention at the alkene.10 Ester 9 was reduced
with DIBALH to afford allylic alcohol 10. The allylic alcohol
10 was subjected to Sharpless asymmetric epoxidation using
D-(-)-diethyl tartrate to give desired epoxy alcohol 11, stereo-
Completion of the synthesis of 2 is described in Scheme 5.
The alcohol 13ꢀ was oxidized under Swern conditions,12
followed by Roush’s asymmetric allylation16 to furnish ho-
moallylic alcohol 17.17 The resulting hydroxy group was
(11) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Lee, D.-H.; Rho, M.-D. Tetrahedron Lett. 2000, 41, 2573.
(12) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(14) It was difficult to determine the absolute configuration of 27,28-epoxide
moiety of 13ꢀ and 13r at this stage.
(15) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719.
(16) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186.
(8) Robinson, J. E.; Brimble, M. A. Chem. Commun. 2005, 1560.
(9) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(10) (a) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1974, 3, 705. (b)
Hollowood, C. J.; Yamanoi, S.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 1664.
(c) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321.
(17) The absolute stereochemistry at C26 position was determined by the
modified Mosher method.
4798 J. Org. Chem. Vol. 74, No. 13, 2009

Synthesis of the C23-C34 Fragment of Symbiodinolide
SCHEME 2. Synthetic Plan of 2
SCHEME 3. Synthesis of 13ꢀ
SCHEME 4. Structural Determination of 13ꢀ
protected with TBSOTf/2,6-lutidine affording silyl ether 18.
Selective removal of TBDPS group with NH4F in methanol18
gave alcohol 19. Treatment of 19 with o-NO2PhSeCN/n-Bu3P
followed by oxidative workup19 gave the corresponding alkene.
Final desilylation with TBAF provided diol 2.
Unfortunately, however, the 1H NMR spectrum of the
synthetic 2 was different from that of the degraded product of
natural symbiodinolide (1). Since the absolute configurations
of C26 and C32 positions were unambiguously elucidated by
modified Mosher method, the absolute stereochemistry of the
diepoxide moiety was deemed to be misassigned. Therefore,
we decided to synthesize the other three possible diastereomers
20-22 in Scheme 6.
Synthesis of the Diepoxides 20-22. Synthesis of epoxy
alcohol 26, the key synthetic intermediate for the synthesis
of the diepoxide 21, is described in Scheme 7. Sharpless
asymmetric epoxidation11a of the allylic alcohol 10 with
L-(+)-diethyl tartrate provided epoxy alcohol 23 in a 20:1
diastereoselectivity. Further transformation toward 26 is
analogous to that toward 13ꢀ. Swern oxidation12 of 23 and
(18) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
J. Org. Chem. Vol. 74, No. 13, 2009 4799

Murata et al.
SCHEME 5. Synthesis of 2
SCHEME 6. Possible Stereoisomers of the C23-C34
Fragment
Conclusion
We have determined the absolute configurations at C26 and
C32 by applying modified Mosher method to the degraded
C23-C34 fragment. Furthermore, we have synthesized the
possible four diastereomers of the diepoxide moiety, 2, 20, 21,
and 22, based on the chain extension-epoxidation approach.
Comparison of the spectroscopic data of the synthetic four
diastereomers to those of the degraded product unambiguously
elucidated that the correct absolute configuration of the C23-C34
fragment of 1 was that described in 21. Further structural and
synthetic studies on 1 are underway in our laboratories.
subsequent Horner-Wadsworth-Emmons olefination13 gave
R,ꢀ-unsaturated ester 24. DIBALH reduction of 24 provided
allylic alcohol 25. The allylic alcohol 25 was epoxidized with
m-CPBA to give the epoxy alcohol 26 and its 27,28-epimer
with a 1:1 ratio.
Experimental Section
Allylic Alcohol 12. To a solution of oxalyl chloride (0.32 mL,
3.78 mmol) in CH2Cl2 (11 mL) was added DMSO (0.54 mL, 7.56
mmol) dropwise at -78 °C. After 30 min, epoxy alcohol 11 (1.00
g, 1.89 mmol) in CH2Cl2 (3 mL) was added dropwise. The mixture
was stirred at -78 °C for 2 h before Et3N (1.6 mL, 11.3 mmol)
was added slowly. The mixture was stirred for 20 min at -78 °C
and then allowed to reach 0 °C for 20 min. The reaction was
quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organic phase was washed with water and
brine and dried over MgSO4. Concentration and short column
chromatography (silica gel, EtOAc/hexane ) 1:40, 1:20) afforded
the corresponding aldehyde (765 mg) as a yellow oil, which was
used immediately in the next reaction without further purification.
To a stirred suspension of LiCl (74 mg 1.75 mmol) and the
aldehyde (765 mg) obtained above in CH3CN (7.5 mL) was added
trimethyl phosphonoacetate (0.28 mL, 1.75 mmol). The mixture
was cooled to 0 °C, and DBU (0.26 mL, 1.75 mmol) was added.
The mixture was stirred for 10 min at 0 °C and then allowed to
reach room temperature for 2 h. The reaction was quenched with
saturated aqueous NaHCO3 and extracted with Et2O. The organic
layer was washed successively with water and brine and dried over
Na2SO4. Concentration and short column chromatography (silica
gel, EtOAc/hexane ) 0:1, 1:30) afforded the corresponding R,ꢀ-
unsaturated ester (822 mg) as a light yellow oil, which was used
in the next reaction without further purification.
The epoxy alcohol 26 was derivatized for structural deter-
mination of the 27,28-epoxide moiety as shown in Scheme 8.
Thus, Red-Al reduction of 26 gave 1,3-diol 27.15 The primary
hydroxy group of 27 was selectively protected to give the
corresponding TBDPS ether. The resulting alcohol was con-
verted to MTPA esters (S)-28 and (R)-28. Figure 3 describes
the ∆δS-R values of (S)-28 and (R)-28. The signs at the C26
and C27 showed positive, and the signs at the C29 and
C31-C34 exhibited negative. Thus, the absolute stereochemistry
at the C28 position of 27 was elucidated to be 28R.6 From this
result, the absolute configuration of the 27,28-epoxide moiety
was determined to be that described in 26.
Scheme 9 describes the synthesis of the diepoxide 21.20 Swern
oxidation12 of 26 and subsequent asymmetric allylation16
afforded homoallylic alcohol 29.17 The resulting alcohol was
protected to give TBS ether 30. Selective desilylation of TBDPS
group with NH4F18 provided alcohol 31. Terminal olefin was
introduced by Grieco’s protocol19 to give alkene 32. Final
deprotection with TBAF provided diol 21. The synthetic
C23-C34 fragment 21 was identical to the degraded C23-C34
fragment of symbiodinolide (1) in all aspects (1H NMR, HRMS,
and optical rotation21) indicating the absolute configuration of
this fragment was that described in 21.22
To a solution of the R,ꢀ-unsaturated ester (822 mg) obtained
above in CH2Cl2 (12 mL) was added DIBALH (1.0 M solution in
hexane, 2.9 mL, 2.96 mmol) dropwise at -78 °C. After being stirred
for 2 h at -78 °C, the solution was poured directly into a stirring
mixture of saturated sodium potassium tartrate aqueous solution
and MeOH. The aqueous layer was extracted with EtOAc. The
organic layer was washed with brine and dried over Na2SO4.
(20) For the synthesis of 20 and 22, see the Supporting Information.
(21) The degraded C23-C34 fragment: [R]21D-11.2 (c 0.05, CH3OH). The
synthetic C23-C34 fragment 21: [R]24D-14.2 (c 0.20, CH3OH).
1
(22) The H NMR spectra of the synthetic 20 and 22 were clearly different
from those of the degraded C23-C34 fragment, respectively.
4800 J. Org. Chem. Vol. 74, No. 13, 2009

Synthesis of the C23-C34 Fragment of Symbiodinolide
SCHEME 7. Synthesis of 26
SCHEME 8. Synthesis of (S)-28 and (R)-28
1471, 1428, 1387, 1255, 1111 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.65-7.63 (m, 4 H), 7.44-7.41 (m, 2 H), 7.39-7.36 (m, 4 H),
4.08-4.04 (m, 1 H), 3.95 (d, J ) 13.8 Hz, 1 H), 3.77-3.65 (m, 4
H), 3.09 (dd, J ) 3.4, 2.8 Hz, 1 H), 2.98 (dd, J ) 5.5, 2.8 Hz, 1
H), 2.61 (d, J ) 5.5 Hz, 1 H), 1.97 (dd, J ) 13.8, 5.5 Hz, 1 H),
1.77-1.69 (m, 1 H), 1.67-1.61 (m, 1 H), 1.48 (dd, J ) 13.8, 7.6
Hz, 1 H), 1.41 (s, 3 H), 1.05 (s, 9 H), 0.85 (s, 9 H), 0.06 (s, 3 H),
0.03 (s, 3 H); 13C NMR (200 MHz, CDCl3) δ 135.7, 133.9, 129.9,
127.8, 67.1, 62.0, 60.7, 60.6, 59.4, 55.5, 52.9, 46.3, 40.1, 27.0, 26.0,
19.3, 18.5, 18.1, -4.2, -4.4; HRMS (FAB) calcd for C32H51O5Si2
(M + H)+ 571.3275, found 571.3282. Epoxy alcohol 13r: [R]21
D
+4.3 (c 0.20, CHCl3); IR (neat) 3448, 2953, 2929, 2857, 2359,
1471, 1428, 1387, 1255, 1111 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.66-7.63 (m, 4 H), 7.43-7.40 (m, 2 H), 7.39-7.37 (m, 4 H),
4.12-4.07 (m, 1 H), 4.00-3.96 (m, 1 H), 3.77-3.67 (m, 4 H),
3.19 (dd, J ) 3.4, 2.1 Hz, 1 H), 2.99 (dd, J ) 6.2, 2.1 Hz, 1 H),
2.65 (d, J ) 6.2 Hz, 1 H), 1.94 (dd, J ) 13.8, 5.5 Hz, 1 H),
1.81-1.74 (m, 1 H), 1.66-1.61 (m, 1 H), 1.54 (dd, J ) 14.4, 5.5
Hz, 1 H), 1.40 (s, 3 H), 1.05 (s, 9 H), 0.85 (s, 9 H), 0.07 (s, 3 H),
0.05 (s, 3 H); 13C NMR (200 MHz, CDCl3) δ 135.7, 134.0, 133.9,
129.8, 129.7, 127.8, 127.8, 66.9, 61.0, 60.9, 60.6, 59.8, 57.2, 52.6,
46.0, 39.9, 27.0, 26.0, 19.3, 18.1, 18.0, -4.2, -4.4; HRMS (FAB)
calcd for C32H51O5Si2 (M + H)+ 571.3275, found 571.3253.
Bicyclic Carbonate 16ꢀ. To a solution of epoxy alcohol 13ꢀ
(15.0 mg, 26.3 µmol) in THF (0.5 mL) was added sodium bis(2-
methoxyethoxy)aluminum hydride solution (65% in toluene, 50 µL,
0.161 mmol) at 0 °C. After being stirred for 12 h at room
temperature, the solution was poured into the saturated sodium
potassium tartrate aqueous solution at 0 °C and stirred for 30 min.
The aqueous layer was extracted with Et2O. The organic layer was
successively washed with water and brine, dried over Na2SO4, and
concentrated.
FIGURE 3. Chemical shift differences (∆δS-R) of (S)-28 and (R)-28.
R ) MTPA. MTPA ) R-methoxy-R-(trifluoromethyl)phenylacetyl.
Concentration and column chromatography (silica gel, EtOAc/
hexane ) 1:15) afforded allylic alcohol 12 (690 mg, 66% in three
steps) as a light yellow oil: [R]25D +8.5 (c 0.42, CHCl3); IR (neat)
1
3437, 2958, 2858, 1472, 1428, 1388, 1253, 1111 cm-1; H NMR
(600 MHz, CDCl3) δ 7.66-7.63 (m, 4 H), 7.44-7.40 (m, 2 H),
7.39-7.35 (m, 4 H), 6.03 (dt, J ) 15.5, 5.2 Hz, 1 H), 5.61 (ddt, J
) 15.5, 7.5, 1.2 Hz, 1 H), 4.21 (dd, J ) 5.2, 1.2 Hz, 2 H),
4.10-4.05 (m, 1 H), 3.78-3.68 (m, 2 H), 3.22 (d, J ) 7.5 Hz, 1
H), 2.03 (dd, J ) 13.8, 5.5 Hz, 1 H), 1.77-1.71 (m, 1 H),
1.66-1.59 (m, 1 H), 1.50 (dd, J ) 13.8, 8.0 Hz, 1 H), 1.29 (s, 3
H), 1.04 (s, 9 H), 0.85 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 135.7, 135.6, 134.0, 129.7, 127.8, 126.3,
67.0, 63.1, 61.2, 60.7, 46.7, 40.1, 27.0, 26.0, 19.3, 18.1, 17.8, -4.2,
-4.4; HRMS (FAB) calcd for C32H51O4Si2 (M + H)+ 555.3326,
found 555.3314.
The residue was dissolved in CDCl3, and the solution was stirred
for 1 h. Concentration and preparative TLC (silica gel, EtOAc/
hexane ) 1:4) afforded cyclic ether 15 (11.0 mg) as a light yellow
oil, which was used immediately in the next reaction without further
purification.
To a solution of diol 15 (11.0 mg) obtained above in toluene
(1.0 mL) was added 1,1′-carbonyldiimidazole (9.3 mg, 57.6 µmol).
The solution was stirred for 30 min at 60 °C. The crude reaction
mixture was directly purified by column chromatography (silica
gel, EtOAc/hexane ) 1:20) afforded bicyclic carbonate 16ꢀ (8.5
mg, 54% in three steps) as a light yellow oil: [R]24D -1.3 (c 0.10,
CHCl3); IR (neat) 2953, 2928, 2855, 2359, 1818, 1473, 1428, 1361,
Epoxy Alcohols 13ꢀ and 13r. To a solution of allylic alcohol
12 (1.41 g, 2.54 mmol) in CH2Cl2 (35 mL) was added m-CPBA
(1.25 g, 5.58 mmol) at 0 °C. After the solution was stirred at room
temperature for 12 h, to it were added dimethyl sulfide and saturated
aqueous NaHCO3 at 0 °C. After being stirred for 10 min, the
aqueous layer was extracted with Et2O. The organic layer was
washed with water and brine and dried over MgSO4. Concentration
and column chromatography (silica gel, EtOAc/hexanes ) 1:8)
afforded epoxy alcohols 13ꢀ (655 mg, 45%) and 13r (655 mg,
1254, 1174, 1109, 1074 cm-1 1H NMR (600 MHz, C6D6) δ
;
7.82-7.79 (m, 4 H), 7.29-7.24 (m, 6 H), 4.32-4.28 (m, 1 H),
3.89-3.86 (m, 1 H), 3.81-3.77 (m, 1 H), 3.57 (td, J ) 11.7, 4.1
Hz, 1 H), 3.48 (d, J ) 11.7 Hz, 1 H), 3.18 (ddd, J ) 13.1, 4.1, 2.1
Hz, 1 H), 2.73 (td, J ) 11.7, 2.1 Hz, 1 H), 1.99-1.94 (m, 1 H),
45%), respectively, as a light yellow oil. Epoxy alcohol 13ꢀ: [R]25
D
-14.8 (c 0.42, CHCl3); IR (neat) 3448, 2953, 2929, 2857, 2359,
J. Org. Chem. Vol. 74, No. 13, 2009 4801

Murata et al.
SCHEME 9. Synthesis of 21
1.85 (dd, J ) 14.4, 4.1 Hz, 1 H), 1.79-1.74 (m, 1 H), 1.66 (dd, J
) 14.4, 6.2 Hz, 1 H), 1.38-1.30 (m, 1 H), 1.23-1.17 (m, 10 H),
0.98 (s, 9 H), 0.88 (s, 3 H), 0.14 (s, 3 H), 0.13 (s, 3 H); 13C NMR
(200 MHz, C6D6) δ 153.5, 136.0, 134.3, 134.3, 130.1, 84.6, 76.1,
76.1, 65.4, 61.1, 59.4, 48.4, 42.0, 31.3, 27.2, 26.2, 19.5, 18.3, 15.2,
-4.0, -4.2; HRMS (FAB) calcd for C33H51O6Si2 (M + H)+
599.3224, found 599.3226.
Homoallylic Alcohol 17. To a solution of oxalyl chloride (55
µL, 0.642 mmol) in CH2Cl2 (0.5 mL) was added DMSO (68 µL,
0.963 mmol) dropwise at -78 °C. After 30 min, alcohol 13ꢀ (55.0
mg, 96.3 µmol) in CH2Cl2 (0.6 mL) was added dropwise. The
mixture was stirred at -78 °C for 2 h before Et3N (0.28 mL, 1.93
mmol) was added slowly. The mixture was stirred for an additional
1 h at -78 °C. The reaction was quenched with saturated aqueous
NaHCO3, and the aqueous layer was extracted with CH2Cl2. The
combined organic phase was washed with water and brine and dried
over MgSO4. Concentration and short column chromatography
(silica gel, EtOAc/hexane ) 1:40, 1:20) afforded the corresponding
aldehyde (48.0 mg) as a yellow oil, which was used immediately
in the next reaction without further purification.
Silyl Ether 18. To a mixture of homoallylic alcohol 17 (10.0
mg, 16.4 µmol) and 2,6-lutidine (9.0 µL, 75.3 µmol) in CH2Cl2
(0.5 mL) was added tert-butyldimethylsilyl trifluoromethane-
sulfonate (13 µL, 56.5 µmol) at 0 °C. The reaction mixture was
stirred at 0 °C for 20 min and then quenched by the addition of
MeOH. The mixture was diluted with Et2O and extracted. The
organic layer was washed with water and brine, dried over Na2SO4,
and concentrated. Purification by column chromatography (silica
gel, EtOAc/hexane ) 1:40) afforded silyl ether 18 (12.0 mg, quant)
as a light yellow oil: [R]23D +32.6 (c 0.33, CHCl3); IR (neat) 2956,
2929, 2854, 2351, 1729, 1471, 1426, 1389, 1359, 1255, 1111 cm-1
;
1H NMR (600 MHz, CDCl3) δ 7.66-7.62 (m, 4 H), 7.43-7.40
(m, 2 H), 7.39-7.36 (m, 4 H), 5.83-5.77 (m, 1 H), 5.08 (dd, J )
17.2, 1.4 Hz, 1 H), 5.05 (d, J ) 10.3 Hz, 1 H), 4.04-4.00 (m, 1
H), 3.74-3.67 (m, 2 H), 3.42 (q, J ) 6.2 Hz, 1 H), 2.94 (dd, J )
6.2, 2.1 Hz, 1 H), 2.77 (dd, J ) 6.2, 2.1 Hz, 1 H), 2.56 (d, J ) 6.2
Hz, 1 H), 2.33-2.30 (m, 2 H), 1.94 (dd, J ) 13.8, 4.8 Hz, 1 H),
1.78-1.73 (m, 1 H), 1.67-1.62 (m, 1 H), 1.48 (dd, J ) 13.8, 7.6
Hz, 1 H), 1.39 (s, 3 H), 1.05 (s, 9 H), 0.90 (s, 9 H), 0.82 (s, 9 H),
0.11 (s, 3 H), 0.06 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H); 13C NMR
(150 MHz, CDCl3) δ 135.7, 135.7, 134.0, 133.9, 133.9, 129.8,
129.8, 127.8, 127.8, 117.9, 73.4, 67.0, 62.3, 60.7, 59.0, 58.9, 54.0,
46.3, 39.9, 39.8, 27.1, 26.0, 19.3, 18.6, 18.3, 18.1, -4.2, -4.3,
-4.4, -4.8; HRMS (FAB) calcd for C41H69O5Si3 (M + H)+
725.4453, found 725.4479.
To a mixture of the aldehyde (48.0 mg) obtained above and
powdered molecular sieves 4A (12 mg) in toluene (1.2 mL) was
added (R,R)-tartrate allylboronate (54.5 µL, 0.211 mmol) at -78
°C. The reaction was stirred for 1 h at -78 °C. Saturated aqueous
NaHCO3 was added, the mixture was stirred for 30 min, and then
the organic phase was separated. The aqueous phase was extracted
with Et2O. The combined organic extract was dried over Na2SO4
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, EtOAc/hexane ) 1:20, 1:10) to afford homoallylic
alcohol 17 (35.0 mg, 60% in two steps) and its 26-epimer (7.0 mg,
12% in 2 steps) as a yellow oil, respectively. Homoallylic alcohol
17: [R]25D +30.8 (c 0.50, CHCl3); IR (neat) 3428, 2956, 2928, 2857,
Alcohol 19. To a solution of TBDPS ether 18 (10.0 mg, 13.8
µmol) in MeOH (0.5 mL) was added NH4F (10 mg, 0.276 mmol).
After stirring for 9 h at room temperature, the reaction mixture
was quenched by the addition of a saturated aqueous NaHCO3. The
aqueous layer was extracted with Et2O and the organic layer was
washed with water and brine, dried over Na2SO4, and concentrated.
Purification by column chromatography (silica gel, EtOAc/hexane
) 1:30, 1:10) afforded alcohol 19 (5.2 mg, 77%) as a yellow oil:
1
2359, 1470, 1427, 1388, 1255, 1109 cm-1; H NMR (600 MHz,
CDCl3) δ 7.65-7.62 (m, 4 H), 7.43-7.41 (m, 2 H), 7.39-7.36
(m, 4 H), 5.87-5.80 (m, 1 H), 5.17 (dd, J ) 17.2, 1.4 Hz, 1 H),
5.15 (d, J ) 10.3 Hz, 1 H), 4.06-4.02 (m, 1 H), 3.76-3.69 (m, 2
H), 3.66-3.63 (m, 1 H), 2.99 (dd, J ) 4.1, 2.1 Hz, 1 H), 2.96 (dd,
J ) 5.5, 2.1 Hz, 1 H), 2.61 (d, J ) 5.5 Hz, 1 H), 2.42-2.35 (m,
2 H), 1.96 (dd, J ) 13.8, 5.5 Hz, 1 H), 1.83 (brd, J ) 5.5 Hz, 1
H), 1.76-1.71 (m, 1 H), 1.67-1.62 (m, 1 H), 1.49 (dd, J ) 13.8,
7.6 Hz, 1 H), 1.41 (s, 3 H), 1.05 (s, 9 H), 0.83 (s, 9 H), 0.05 (s, 3
H), 0.01 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 135.7, 135.7,
133.9, 133.3, 129.8, 127.8, 127.8, 118.9, 69.4, 67.0, 61.8, 60.7,
59.4, 57.9, 53.6, 46.3, 40.0, 39.4, 27.0, 26.0, 19.3, 18.5, 18.1, -4.2,
-4.4; HRMS (FAB) calcd for C35H55O5Si2 (M + H)+ 611.3588,
found 611.3575.
[R]24 -2.9 (c 0.10, CHCl3); IR (neat) 2951, 2928, 2854, 2364,
D
1
1472, 1387, 1255, 1103 cm-1; H NMR (600 MHz, CDCl3) δ
5.86-5.77 (m, 1 H), 5.10 (d, J ) 17.2 Hz, 1 H), 5.08 (d, J ) 9.7
Hz, 1 H), 4.04-4.00 (m, 1 H), 3.79-3.72 (m, 2 H), 3.44 (q, J )
6.3 Hz, 1 H), 2.92 (dd, J ) 6.3, 2.3 Hz, 1 H), 2.76 (dd, J ) 6.3,
2.3 Hz, 1 H), 2.55 (d, J ) 6.3 Hz, 1 H), 2.33-2.30 (m, 2 H), 2.04
(dd, J ) 13.8, 4.6 Hz, 1 H), 1.87-1.81 (m, 1 H), 1.65-1.55 (m,
2 H), 1.40 (s, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.10
(s, 3 H), 0.09 (s, 3 H), 0.06 (s, 3 H); 13C NMR (150 MHz, CDCl3)
δ 134.0, 117.8, 73.2, 68.9, 62.6, 60.0, 58.9, 58.7, 54.0, 45.9, 39.8,
38.6, 25.9, 18.6, 18.1, 18.0, -4.3, -4.3, -4.6, -4.8; HRMS (FAB)
calcd for C25H51O5Si2 (M + H)+ 487.3275, found 487.3254.
4802 J. Org. Chem. Vol. 74, No. 13, 2009

Synthesis of the C23-C34 Fragment of Symbiodinolide
Diepoxide 2. To a mixture of alcohol 19 (3.5 mg, 7.18 µmol)
and o-nitrophenyl selenocyanate (16 mg, 71.8 µmol) in THF (0.4
mL) were added pyridine (6.0 µL, 71.8 µmol) and tributylphosphine
(18 µL, 71.8 µmol). The mixture was stirred for 1 h at room
temperature. To the resulting mixture were added NaHCO3 (4.8
mg, 57 µmol) and 30% H2O2 (100 µL) at 0 °C. The stirring was
continued for 2 h at 40 °C. The mixture was diluted with Et2O and
then washed with water, saturated aqueous Na2CO3, and brine.
Concentration and short column chromatography (silica gel, EtOAc/
hexane ) 1:50) gave the corresponding alkene (2.5 mg), which
was used in the next reaction without further purification.
17.9; HRMS (FAB) calcd for C13H20NaO4 (M + Na)+ 263.1259,
found 263.1260.
Diepoxide 20. The title compound was synthesized from 13r
following a procedure similar to that used for the synthesis of 2:
[R]21 +6.4 (c 0.13, CHCl3); IR (neat) 3451, 2925, 2851, 1736,
D
1
1458, 1375, 1262, 1066 cm-1; H NMR (600 MHz, CD3OD) δ
5.94-5.82 (m, 2 H), 5.24 (dt, J ) 17.2, 1.4 Hz, 1 H), 5.13-5.07
(m, 3 H), 4.22-4.18 (m, 1 H), 3.56-3.53 (m, 1 H), 3.04 (dd, J )
4.8, 2.1 Hz, 1 H), 2.99 (dd, J ) 4.8, 2.1 Hz, 1 H), 2.83 (d, J ) 4.8
Hz, 1 H), 2.37-2.34 (m, 2 H), 1.93 (dd, J ) 14.4, 7.6 Hz, 1 H),
1.59 (dd, J ) 14.4, 6.2 Hz, 1 H), 1.44 (s, 3 H); 13C NMR (150
MHz, CD3OD) δ 142.2, 135.4, 117.8, 114.9, 70.8, 61.8, 60.3, 54.5,
49.6, 46.2, 39.8, 30.8, 18.1; HRMS (ESI) calcd for C13H20NaO4
(M + Na)+ 263.1259, found 263.1244.
To a solution of the diene (2.5 mg) obtained above in THF was
added TBAF (1.0 M solution in THF, 107 µL, 0.107 mmol), and
the mixture was stirred for 1 h at room temperature. The mixture
was diluted with Et2O and then washed with water and brine.
Concentration and column chromatography (silica gel, EtOAc/
hexane ) 1:10, 1:1) gave diepoxide 2 (1.2 mg, 70% in two steps)
Diepoxide 22. The title compound was synthesized from 10
following a procedure similar to that used for the synthesis of 2:
[R]21 -9.6 (c 0.13, CHCl3); IR (neat) 3357, 2921, 2851, 1736,
D
1
1459, 1375, 1262, 1087 cm-1; H NMR (600 MHz, CD3OD) δ
as a colorless oil: [R]24 +40.9 (c 0.10, CH3OH); IR (neat) 3377,
D
1
2921, 2850, 1719, 1421, 1384, 1266, 1080 cm-1; H NMR (600
5.92-5.86 (m, 2 H), 5.25 (dd, J ) 17.2, 1.4 Hz, 1 H), 5.14 (dd, J
) 17.2, 1.4 Hz, 1 H), 5.09-5.06 (m, 2 H), 4.28-4.25 (m, 1 H),
3.53-3.50 (m, 1 H), 3.04-3.02 (m, 2 H), 2.80 (d, J ) 4.8 Hz, 1
H), 2.37-2.31 (m, 2 H), 1.87 (dd, J ) 14.4, 4.1 Hz, 1 H), 1.52
(dd, J ) 14.4, 9.6 Hz, 1 H), 1.44 (s, 3 H); 13C NMR (150 MHz,
CD3OD) δ 142.5, 135.2, 118.0, 114.4, 71.5, 70.7, 62.6, 61.0, 54.3,
46.6, 39.8, 30.8, 17.5; HRMS (ESI) calcd for C13H20NaO4 (M +
Na)+ 263.1259, found 263.1231.
MHz, CD3OD) δ 5.87 (ddt, J ) 16.5, 10.1, 6.4 Hz, 1 H), 5.83
(ddd, J ) 16.5, 10.1, 6.4 Hz, 1 H), 5.24 (dt, J ) 16.5, 1.4 Hz, 1
H), 5.15 (dq, J ) 16.5, 1.4 Hz, 1 H), 5.11-5.07 (m, 2 H),
4.18-4.15 (m, 1 H), 3.47-3.45 (m, 1 H), 2.95 (dd, J ) 5.5, 1.8
Hz, 1 H), 2.88 (dd, J ) 6.4, 1.8 Hz, 1 H), 2.65 (d, J ) 6.4 Hz, 1
H), 2.36-2.33 (m, 2 H), 1.98 (dd, J ) 13.8, 7.3 Hz, 1 H), 1.54
(dd, J ) 13.8, 6.4 Hz, 1 H), 1.43 (s, 3 H); 13C NMR (200 MHz,
CD3OD) δ 142.3, 135.3, 118.0, 115.2, 72.0, 70.9, 63.7, 60.3, 59.6,
55.0, 46.4, 39.9, 18.7; HRMS (FAB) calcd for C13H20NaO4 (M +
Na)+ 263.1259, found 263.1245.
Acknowledgment. We thank Okayama Foundation for Sci-
ence and Technology, NOVARTIS Foundation (Japan) for the
Promotion of Science, and The Mitsubishi Foundation for their
financial supports. This research was partially supported by
Grant-in-Aid for Scientific Research (19710184, 21710231, and
16GS0206) from the Japan Society for the Promotion of Science.
Diepoxide 21. The title compound was synthesized from 10
following a procedure similar to that used for the synthesis of 2:
[R]24D -14.2 (c 0.20, CH3OH); IR (neat) 3411, 2916, 2857, 1642,
1
1422, 1387, 1258, 1067 cm-1; H NMR (600 MHz, CD3OD) δ
5.91 (ddt, J ) 17.4, 10.1, 7.3 Hz, 1 H), 5.88 (ddd, J ) 17.4, 10.1,
5.5 Hz, 1 H), 5.25 (d, J ) 17.4 Hz, 1 H), 5.15 (dd, J ) 17.4, 1.8
Hz, 1 H), 5.09-5.07 (m, 2 H), 4.26-4.24 (m, 1 H), 3.66-3.64
(m, 1 H), 2.98 (dd, J ) 4.6, 1.8 Hz, 1 H), 2.94 (dd, J ) 6.4, 1.8
Hz, 1 H), 2.65 (d, J ) 6.4 Hz, 1 H), 2.40-2.36 (m, 1 H), 2.31-2.28
(m, 1 H), 1.92 (dd, J ) 13.8, 3.7 Hz, 1 H), 1.46 (s, 3 H), 1.43 (dd,
J ) 13.8, 10.1 Hz, 1 H); 13C NMR (200 MHz, CD3OD) δ 142.5,
135.3, 117.9, 114.4, 70.7, 70.1, 64.5, 60.6, 58.8, 54.5, 46.9, 39.8,
Supporting Information Available: Experimental proce-
dures and spectral and analytical data for new compounds not
1
given in the Experimental Section and copies of H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900546K
J. Org. Chem. Vol. 74, No. 13, 2009 4803