Stereocontrolled and convergent total synthesis of amphidinolide T3

Article abstract of DOI:10.1021/jo0605086

Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic scheme was constructed that led to the recognition of readily available and enantiomerically related compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment 6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5- hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this approach also provides a flexible and practical synthesis of amphidinolide T macrolides.

Full text of DOI:10.1021/jo0605086

Stereocontrolled and Convergent Total Synthesis of
Amphidinolide T3
Li-Sheng Deng, Xiao-Ping Huang, and Gang Zhao*
Laboratory of Modern Organic Synthetic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, P. R. China
zhaog@mail.sioc.ac.cn
ReceiVed March 8, 2006
Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic
scheme was constructed that led to the recognition of readily available and enantiomerically related
compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building
blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment
6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5-
hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric
allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the
dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis
olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond
formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional
transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this
approach also provides a flexible and practical synthesis of amphidinolide T macrolides.
Introduction
oxygenated and stereochemically rich macrocycle ranging in
size from 12 to 29 atoms. Due to their scarcity, biological
activity, and challenging structure, amphidinolides represent
attractive synthetic targets.4
A family of structurally diverse macrolides-amphidinolides
were isolated from marine dinoflagellates of the genus Amphi-
dinium living in symbiosis with Okinawan acoel flatworm
Amphiscolops sp.1,2 They have exhibited significant antitumor
properties and cytotoxicity against a variety of National Cancer
Institute (NCI) tumor cell lines as well as human epidermoid
carcinoma KB cells.1c,3 Amphidinolides display a common
feature with one or more exo-methylene units, a highly
Amphidinolide T class (Figure 1), a 19-membered macro-
lactone, has included five members (T1-T5) bearing a trisub-
stituted tetrahydrofuran ring, a hydroxyl ketone, and an exocyclic
methylene group since the isolation of T1 in 2000.5 Amphidi-
nolide T2 is the only exception containing an additional
hydroxymethyl substitution in the alkyl side chain. T3-T5 have
very similar construction, only differing in their configuration
at C12 and C14. Amphidinolide T1 possesses the reversed
hydroxyl ketone moiety in contrast to T3-T5.
* To whom correspondence should be addressed. Phone: 0086-21-
54925182. Fax: 0086(21)64166128.
(1) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y. Tetrahedron
Lett. 1986, 27, 5755-5758.
(2) Reviews: (a) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44,
543-575. (b) Kobayashi, J.; Ishibashi, M. In Comprehensive Natural
Products Chemistry, Mori, K., Ed.; Elsevier: New York, 1999; Vol. 8, pp
619-649. (c) Chakraborty, T. K.; Das, S. Curr. Med. Chem.: Anti-Cancer
Agents 2001, 1, 131-149. (d) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep.
2004, 21, 77-93.
Synthetic studies on the amphidinolide T series have attracted
a great deal of attention. So far, several groups have reported
total syntheses of T1 and T3-5. The Fu¨rstner group reported
the first total syntheses of T4 in 2002 and T1, T3, T4, and T5
in 2003 by utilizing an efficient ring-closing metathesis (RCM)
to obtain the macrocycles.4h,j Amphidinolide T1 was synthesized
(3) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2001, 66, 134-
142.
10.1021/jo0605086 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/17/2006
J. Org. Chem. 2006, 71, 4625-4635
4625

Deng et al.
FIGURE 1. Amphidinolide T family.
SCHEME 1. Retrosynthetic Analysis
by the Ghosh group in 2003 through a Yamaguchi macrolat-
conization reaction.4i The syntheses of T1 and T4 were also
reported by Jamison and co-wokers in 2004 and 2005 using a
nickel-catalyzed, alkyne-aldehyde coupling reaction to form
the 19-membered ring.4o,p In the present paper, we describe a
full account of our efforts on total syntheses of amphidinolide
T3 and T4.
Results and Discussion
Retrosynthetic Analysis and Synthetic Strategies. As
shown in Scheme 1, our synthetic strategy for amphidinolides
T3, T4 was highly convergent. We envisioned that the dithiane
coupling reaction of C1-12 segment 6 and C13-21 segment
7 with stereogenic centers at C12 and C13; the selective
formation of macrocycle would be furnished by Yamaguchi
macrolactonization. The segment 7 could derive from compo-
nents 10 and 11. The synthesis of dithiane 10 involved a Noyori
asymmetric hydrogenation of ethyl 3-oxohexanoate.6 The
subunit 11 was prepared from commercial methyl (S)-hydroxyl-
2-methylpropionate. The aldehyde 6 could be disconnected at
C3-4 and divided into subunits 8 and 9; the subunit 9 was
accessible by a diastereoselective alkylation of N-propionylox-
(4) For total syntheses of other amphidinolides, see: (a) Williams, D.
R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198-11199. (b) Williams,
D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-948. (c) Williams, D.
R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765-766. (d) Lam, H. W.;
Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508-511. (e) Chakraborty,
T. K.; Das, S. Tetrahedron Lett. 2001, 42, 3387-390. (f) Maleczka, R. E.;
Terrell, L. R.; Geng, F.; Ward, J. S. Org. Lett. 2002, 4, 2841-2844. (g)
Trost, B. M.; Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am. Chem.
Soc. 2002, 124, 12420-12421. (h) Fu¨rstner, A.; A¨ıssa, C.; Riveiros, R.;
Ragot, J. Angew. Chem., Int. Ed. 2002, 41, 4763-4766. (i) Ghosh, A. K.;
Liu, C. J. Am. Chem. Soc. 2003, 125, 2374-2375. (j) A¨ıssa, C.; Riveiros,
R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003, 125, 15512-15520.
(k) Lepage, O.; Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126,
15970-15971. (l) Ghosh, A. K.; Gong, G. J. Am. Chem. Soc. 2004, 126,
3704-3705. (m) Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004,
126, 5028-5029. (n) Trost, B. M.; Papillon, J. P. N. J. Am. Chem. Soc.
2004, 126, 13618-13619. (o) Colby, E. A.; O’Brien, K. C.; Jamison, T. F.
J. Am. Chem. Soc. 2004, 126, 998-999. (p) Colby, E. A.; O’Brien, K. C.;
Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297-4307. (q) Trost, B. M.;
Harrington, P. E.; Chisholm, J. D.; Wrobleski, S. T. J. Am. Chem. Soc.
2005, 127, 13589-13597. (r) Trost, B. M.; Harrington, P. E.; Chisholm, J.
D.; Wrobleski, S. T. J. Am. Chem. Soc. 2005, 127, 13598-13610. (s) Trost,
B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127,
17921-17937.
(5) (a) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2000, 65, 1349-
1352. (b) Kobayashi J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem.
2001, 66, 134-142. (c) Kubota, T.; Endo, T.; Tsuda, M.; Shiro, M.;
Kobayashi, J. Tetrahedron 2001, 57, 6175-6179.
(6) Crombie L., Jones, R. C. F.; Plamer, C. J. J. Chem. Soc., Perkin
Trans. 1 1987, 317-331.
4626 J. Org. Chem., Vol. 71, No. 12, 2006

Total Synthesis of Amphidinolide T3
SCHEME 2. Synthesis of Sulfone 9a
SCHEME 3. Synthesis of Aldehyde 23a
a Reagents and conditions: (a) TiCl4, i-PrNEt2, CH2Cl2, 0 °C, then
BOMCl, 99%, dr > 99:1; (b) LiBH4, MeOH, THF, 0 °C, 99%; (c) I2, PPh3,
imidazole, THF; (d) PhSO2Na, DMF, 35 °C, 76% over two steps. BOMCl
) benzyloxymethyl chloride.
a Reagents and conditions: (a) TrCl, Py, CH2Cl2, reflux, 76%; (b) n-BuLi,
i-Pr2NH, -15 °C, then -78 °C, 17, CH3I, 81%, dr ) 11:1; (c) LiAlH4,
THF, >99%; (d) TBSCl, imidazole, DMF, 0 °C, 99%; (e) Ac2O, DMAP,
Et3N, 99%; (f) TBAF, THF, 96%; (g) DMP, CH2Cl2, 92%. TrCl ) trityl
chloride, TBS ) tert-butyldimethylsilyl chloride, DMAP ) 4-(dimethyl-
amino) pyridine, TBAF ) tetrabutylammonium fluoride, DMP ) Dess-
Martin periodinane.
azolidinone with BOMCl. The trisubstituted and stereochemical
tetrahydrofuran ring can be obtained from commercially avail-
able D-glutamic acid or its synthetically equivalent (R)-5-
hydroxymethyltetrahydrofuran-2-one 16.
SCHEME 4. Synthesis of Aldehyde 6a
Preparation of C1-C12 Fragment 6. As outlined in Scheme
2, the segment 9 was prepared via a sequence of high-yielding
steps. The Lewis acid mediated alkylation of Evans oxazolidi-
none 12 with BOMCl7 provided 13 in extremely high dia-
stereomeric purity8 on a multigram scale for a subsequent
reduction with LiBH4 to afford the primary alcohol 14, which
also can be prepared from the commercially available methyl
(R)-3-hydroxyl-2-methylpropionate.9 Alcohol 14 was then con-
verted to iodide 15; the derived iodide 15 was efficiently
transformed into the sulfone 9 by displacement with sodium
benzenesulfinate in DMF.9
The synthesis of the C7-C11 fragment was investigated using
commercially available alcohol 16 as a starting material conven-
iently prepared via three steps by a known procedure10 (Scheme
3). Protection of the hydroxyl group of 16 with trityl chloride
and a subsequent methylation afforded compound 18 with high
diastereoselectivity (dr ) 11:1). Reduction of 18 with LiAlH4
gave diol 19 quantitatively.11 Selective protection of the primary
hydroxyl group of 19 was achieved with TBSCl,12 and then the
secondary hydroxyl group in the resulting silyl ether 20 was
acetylated to give ester 21. After desilylation of 21 with TBAF,
oxidation of the alcohol using the Dess-Martin periodinane
gave the aldehyde 23.13 The overall yield from 16 to 23 was
55.5%.
The stereocontrolled synthesis of the required trisubstituted
tetrahydrofuran subunit 6 is a key to the total syntheses of
(7) Connor, D. S.; Klein G. W.,; Taylor, G. N.; Boeckman, Jr, R. K.;
Medwid, J. B. Org. Synth. 1972, 52, 16-18.
(8) (a) Cage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77-82. (b) Tyrrell,
E.; Tsang, M. W. H.; Skimer G. A.; Fawcett, J. Tetrahedron 1996, 52,
9841-9852. (c) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler,
R. J. Am. Chem. Soc. 1990, 112, 5290-5313.
(9) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292-5300.
(10) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron 1978, 34,
1449-1452.
(11) (a) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J. Org. Chem. 1988,
53, 4094-4098. (b) Kigoshi, H.; Suenaga, K.; Mutou, T.; Ishigaki, T.;
Atsumi, T.; Ishiwata, H.; Sakakura, A.; Ogawa, T.; Ojika, M.; Yamada, K.
J. Org. Chem. 1996, 61, 5326-5351.
(12) For general application of protecting group in organic synthesis,
see: Kocien˜ski, P. H. Protecting Group, 3rd ed.; Georg Thieme: New York,
2004; and reference therein.
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
a Reagents and conditions: (a) (R,R)-1,2-diamino-1,2-diphenylethane-
bis(sulfonamide), BBr3, CH2Cl2, 0 °C, then allyltributylstannane, rt, 6 h,
23, -78 °C, 2 h, 85%, dr >99:1; (b) TsCl, pyridine, rt, 99%; (c) KOH,
diglyme, ethylene glycol, 40 °C, 99%; (d) BH3‚Me2S, THF, then 30% H2O2,
NaOH, 83%; (e) I2, PPh3, imidazole, THF, 95%; (f) n-BuLi, HMPA, THF,
9, -78 °C, then 27; (g) 6% Na-Hg, EtOH, 80% over two steps; (h) 80%
HOAc, 35-40 °C, 95%; (i) PPh3, I2, imidazole, THF, 91%; (j) 1,3-dithiane,
t-BuLi, THF/HMPA, then 31, -78 °C, 83%; (k) NaHCO3, CH3I, CH3CN-
H2O (v/v, 4:1), rt, 16 h, 95%. TsCl ) p-toluenesulfony chloride.
amphidinolide T (Scheme 4).14 Diastereomeric allylation of
aldehyde 23 was first investigated using a catalytic system of
(14) For a review on the stereoselective synthesis of natural products
with polysubstituted tetrahydrofuran moiety, see: Koert, U. Synthesis 1995,
115-132.
J. Org. Chem, Vol. 71, No. 12, 2006 4627

Deng et al.
SCHEME 5. Synthesis of Segment Dithiane 7a
titanium/(R)-BINOL.15a-c To our disappointment, yield and
diastereoselectivity for this allylation turned out to be low (dr
) 1:2.2, determined by 1H NMR, 37% combined yield). Several
aspects were tried in order to improve the yield and diastereo-
selectivity, including temperature, concentration, and reaction
time, but no such efforts were successful. We assumed that the
hindrance of R-methyl of aldehyde 23 resulted in the lack of
success, which is in line with previous observations.16 In addi-
tion, using p-nitrobenzoic acid as a promoter,15d we carried out
the allylation reaction of aldehyde 23 with allytributyltin in CH3-
CN to afford a quantitative yield of the corresponding homoal-
lylic alcohol (dr ) 1.2:1.0). Fortunately, asymmetric allylation
of the aldehyde 23 was quite successful by the tin-to-boron
transmetalation of allyltributylstannane using the boron bromide
reagent generated in situ from (R,R)-1,2-diamino-1, 2-diphe-
nylethane bis(sulfonamide) and boron tribromide,17 furnishing
the desired homoallylic alcohol 24 in 85% yield with excellent
diastereoselectivity for the desired isomer (dr ) >99:1,
determined by 1H NMR).18 Subsequent O-protection with tosyl
chloride12 and treatment of 25 in the presence of potassium
hydroxide in a mixed solvent of diglyme and ethylene glycol
at 40 °C was successful in the formation of the trisubstituted
tetrahydrofuan ring. Importantly, the “so-called” two-step reac-
tion highly proceeded in favor of the desired 2,4,5-cis-trans
single isomer 8 on the basis of the strong NOE effect indicated
in Scheme 4.19 After hydroboration-oxidation of 8,20 the
resulting primary alcohol 26 was converted into the correspond-
ing iodide 27 under standard conditions,21 which was a suitable
electrophile for the desired alkylation reaction. Alkylation of
the carbanion generated from the sulfone 9 with iodide 27 in a
solvent mixture of THF/HMPA and subsequent reductive
removal of the sulfonyl group with 6% sodium amalgam (in
situ) afforded benzyl ether 29 in 80% yield. Addition of HMPA
as a cosolvent in this alkylation reaction remarkably improved
the yield. Cleavage of trityl ether in 29 by exposure to 80%
aqueous HOAc gave the primary alcohol 30 (95%), followed
by conversion of the alcohol 30 to its corresponding iodide 31.
Elongation of the iodide 31 with 1, 3-dithiane/t-BuLi in 10%
HMPA/THF at -78 °C provided the corresponding dithiane 32
(83%). Then, treatment of 32 with MeI /NaHCO3 in aqueous
acetonitrile led to the desired aldehyde 6 in excellent yield.22
Preparation of C13-C21 Fragment 7. The segment dithiane
7 was synthesized by a sequence of steps as outlined in Scheme
5. Thus, hydrogenation of ethyl-3-oxohexanote in the presence
of [(R)-BINAP-RuCl2](DMF)n as a catalyst provided 34 with
high enantiomeric purity (ee > 99%).23 The hydroxyl group in
a Reagents and conditions: (a) [(R)-BINAP-RuCl2](DMF)n, H2, MeOH,
20 atm, 100 °C, 92%; (b) TBSCl, imidazole, DMF, 91%; (c) DIBAL-H,
CH2Cl2, -78 °C, 91%; (d) HS(CH2)3SH, BF3‚ Et2O, 92%; (e) TBSOTf,
2,6-lutidine, CH2Cl2, 97%; (f) i-PrNEt2, CH2Cl2; (g) LiAlH4, Et2O, 93%,
over two steps; (h) PPh3, I2, imidazole, THF, 97%; (i) t-BuLi, HMPA, THF,
10, -78 °C, then 11; 83%; (j) I2, NaHCO3, acetone/H2O (v/v, 5:1), 0 °C,
82%; (k) Cp2TiMe2, toluene, 110 °C, 86%; (l) Li, NH3(l), THF, -78 °C,
99%; (m) DMP, CH2Cl2, 95%; (n) ZnCl2, TMSS(CH2)3SSTMS, Et2O, 0-rt,
92%. BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
34 was protected with TBSCl to give silyl ether 35, followed
by reduction with DIBAL-H to give the corresponding aldehyde
36. Then, treatment of the aldehyde 36 with 1,3-propanedithiol
and boron trifluoride etherate furnished the dithiane. Unfortu-
nately, the TBS group was removed simultaneously to give the
dithiane 37.24 The resulting secondary alcohol was protected
again with TBSOTf and 2,6-lutidine to afford the dithiane 10
in excellent yield.12,25 It was noteworthy that the dithiane 10
can be readily prepared on a multigram scale. The synthesis of
iodide 11 began with methyl (S)-3-hydroxy-2-methylpropionate,
followed by protection and reduction with LiAlH4 to afford the
known alcohol 39,26 which underwent smooth iodination to give
the iodide 11. With the required two segments in hand,
alkylation of dithiane 10 with iodide 11 gave the segment 40
in 83% yield. Deprotection of dithiane12 provided ketone 41,
which was subject to Petasis olefination conditions27 with
Cp2TiMe2 in the presence of toluene at 110 °C to give the
corresponding alkene 42. Reductive removal of BOM group in
resulting alkene 42 by using Li/NH3 afforded the primary
alcohol 43. Aldehyde 44 was obtained by oxidation of 43
with Dess-Martin periodinane. A series of Lewis acid (AlCl3,
TiCl4, MgCl2, SnCl4, and ZnCl2) mediated dithioacetaliza-
tions of aldehyde 44 with 1,3-propanedithiol did not give
(15) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467-8468. (b) Keck, G. E.; Krishanmurthy, D. Org. Synth.
1989, 67, 12-17. (c) Denmark, S. E.; Fu, J.-P. Chem. ReV. 2003, 103,
2763-2793. (d) Zhao, G.; Li, G. L. J. Org. Chem. 2005, 70, 4272-78.
(16) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827-7828.
(17) (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y.-B. J. Am.
Chem. Soc. 1989, 111, 5493-5495. (b) Corey, E. J.; Yu, C. M.; Kim, S. S.
J. Am. Chem. Soc. 1989, 111, 5495-5496. For development of this
asymmetric allylation approach, see: Williams, D. R.; Brooks, D. A.; Meyer,
K. G.; Clark, M. P. Tetrahedron Lett. 1998, 39, 7251-7254.
(18) See the Supporting Information for details.
(19) NOE studies on compound 8 assigned the stereochemistry of the
2,4,5-cis-trans isomer. See the Supporting Information for details.
(20) Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552-
1558.
(21) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866-2869. (b) Fu¨rstner, A.; Jumbam, D.; Teslic, J.; Weidmann, H.
J. Org. Chem. 1991, 56, 2213-2217.
(22) Cardani, S.; Bernard, A.; Colombo, L.; Gennari, C.; Scolastico, C.;
Venturini, I. Tetrahedron 1988, 44, 5563-5572.
(23) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth.
1992, 71, 1-13. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
(24) For a similar example, see: Sato, T.; Otera, J.; Nozaki, H. J. Org.
Chem. 1993, 58, 4971-4978.
(25) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.
(26) Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B.
H. J. Am. Chem. Soc. 1991, 113, 5337-5353.
(27) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-
6394.
4628 J. Org. Chem., Vol. 71, No. 12, 2006

Total Synthesis of Amphidinolide T3
SCHEME 6. Completion of the Total Synthesis of Amphidinolide T3a
a Reagents and conditions: (a) t-BuLi, HMPA/THF (v/v, 1:9), 7, -78 °C, 10 min, then -78 °C, 6; 80%; isomers were easily separated by column
chromatograph; (b) DMP, NaHCO3, CH2Cl2, rt, 3 h, 91%; (c) see Table 1; (d) Ac2O, DMAP, pyridine, 24 h, 92%; (e) DDQ, CH2Cl2/H2O (v:v, 10:1), 30
h, 95%; (f) PCC, NaOAc, CH2Cl2; 4 Å MS, 0 °C, 12 h, 96%; (g) AgNO3, NaOH, THF, H2O, 0 °C, 2 h, 81%; (h) HF‚Py, THF, rt, 24 h, 94%; (i) LiOH,
MeOH/H2O (v/v, 5:1), 40 °C, 15 h, 95%; (j) 2,4,6-Cl3PhCOCl, i-PrNEt2, 45 °C, 10 h, then DMAP, toluene, 10 h, 66%; (k) PhI(CF3CO2)2, MeOH/H2O (v/v,
10:1), 15 °C, 15 min, 82%. DDQ ) 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, PCC ) pyridium chlorochromate.
satisfactory results. Eventually, the dithiane 7 was accessible
in excellent yield (92%) by anhydrous zinc chloride catalyzed
thioacetalization using thiosilane (TMSS(CH2)2STMS) under
mild conditions.28
Completion of the Total Synthesis of Amphidinolide T3.
With the successful synthesis of two fragments 6 and 7, our
subsequent designed strategy called for the assembly of the
aldehyde 6 and dithiane 7. We applied Smith’s protocol as
shown in Scheme 6.29 Treatment of the dithiane 7 with tert-
butyllithium in 10% HMPA/THF at -78 °C followed by adding
of the precooled aldehyde 6 led to a 1.7:1 mixture of C12
epimers 45a and 45b in 80% combined yield. Various attempts
directed toward improving the diastereoseletivity of this reaction,
(28) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J.
Am. Chem. Soc. 1977, 99, 5009-5017.
J. Org. Chem, Vol. 71, No. 12, 2006 4629

Deng et al.
of 3 were identical with those of natural amphidinolide T3 (1H
NMR, 13C NMR, HRMS, optical rotation).
TABLE 1. Diastereoselective Reduction of Ketone 46
In addition, it was noteworthy that the completion of the total
synthesis of amphidinolide T3 (3) indicated T4 (4) might be
synthesized from 45b by the same routes to 3. To some extent,
the intermediate 46 should be also suitable for synthesis of
amphidinolide T5 (5) as we changed the starting material in
the preparation of iodide 11.
(isolated yield, %)
entry
reducing reagent
45a
45b
1
2
3
4
5
Li(n-Bu)BH3
L-Selectride
LiBH4
NaBH4
(S)-54, BMS
11
24
Conclusion
NR
2
49
68
88
46
In summary, we have achieved the total synthesis of T3 and
formal synthesis of T4 via a highly flexible, concise, and
convergent strategy using the readily available and inexpensive
chiral building blocks. The fragment 6 was synthesized in 15
steps and 31% overall yield from the diol 19; the other fragment
7 was prepared in 11 steps and 33% overall yield from 33. We
completed the synthesis of amphidinolide T3(3) in 25 steps for
the longest linear sequence and 5.0% overall yield. Asymmetric
allylation reactions of stannyl-derived allyldiazaborolanes proved
to be a powerful protocol for the enantiocontrolled assembly
of functional components in organic syntheses. A stereocon-
trolled and practical synthesis of the trisubstituted tetrahydro-
furan ring has been demonstrated by a new approach. Mutual
transformations of 45a and 45b could be conveniently accessed
via the intermediate 46. Efficient couplings of dithiane with
electrophiles were featured in the approach.
including addition of Lewis acid and changing the temperature
and the addition rate of aldehyde 6, completely failed.30 How-
ever, for preparative purposes, it proved convenient to enhance
the diasteromeric ratio in favor of 45a (or 45b) by a two-step
oxidation-reduction sequence via the ketone 46, which can be
obtained in high yield by the oxidation of the mixture 45a and
45b with DMP (the stereochemistry of newly formed 45a was
confirmed according to amphidinolide T3 subsequently com-
pleted and also consistent with the mechanistic model by CBS
catalyst (S)-5431a). Among the screened reagents (Table 1),
reduction ketone 46 with LiBH4 afforded 45b as the major
product (a precursor of synthesis of amphidinolide T4), whereas
the use of oxazaborolidine-catalyzed borane reduction by (S)-
5431 gave the single isomer 45a, which was used for subsequent
synthetic investigations. Protection of hydroxyl group in 45a
with acetic anhydride followed by removal of benzyl group with
DDQ provided the primary alcohol 48. Next, the conversion of
the primary hydroxyl moiety in 48 to the corresponding
carboxylic acid was investigated, but the dithiane ring was liable
to be oxidized. Our initial path using modified SmI2-promoted
Evans-Tischenko reduction, developed by Smith in the syn-
thesis of (+)-13-deoxytedanolide,32 did not afford a satisfactory
yield. This transformation was achieved later via a two-step
oxidation reaction under mild conditions, and the dithiane ring
was not affected. Thus, the exposure of the resulting acid 50 to
HF‚Py complex, followed by hydrolysis in the presence of
LiOH, gave the hydroxyl acid 52. Selective macrocyclization
carried out under Yamaguchi conditions,33 as expected, provided
macrolactone 53 with high chemoselectivity (73%). Removal
of dithiane with bis(trifluoroacety) iodobenzene34 led to the
synthetic amphidinolide T3. Spectral data of a synthetic sample
Experimental Section
Ester 21. To a stirred solution of diol 19 (16.88 g, 45 mmol) in
DMF (165 mL) cooled at 0 °C were added imidazole (7.65 g, 112
mmol) and tert-butyldimethylsilyl chloride (7.53 g, 50 mmol). After
being stirred for 2 h at 0 °C, the reaction was quenched by addition
of H2O (90 mL), and the resulting solution was stirred at room
temperature for another 30 min. The mixture was extracted with
Et2O (3 × 40 mL). The combined extracts were washed with brine
(40 mL), dried over anhydrous Na2SO4, and concentrated on the
rotary evaporator. The residue was purified by flash chromatography
(hexane/ethyl acetate 5:1 v/v) to afford ether 20 (21.85 g, 99%) as
a colorless oil. Ether 20 (21.85 g, 44.6 mmol) was dissolved in
CH2Cl2 (210 mL). Ac2O (10.7 mL, 111.7 mol), Et3N (15.8 mL,
111.7 mmol), and DMAP (1.36 g, 11.2 mmol) were added to the
solution, and the mixture was stirred at room temperature for 12 h
and then quenched by addition of H2O (100 mL). The resulting
solution was stirred at room temperature for 1 h, and the aqueous
phase was extracted with CH2Cl2 (3 × 30 mL). The combined
extracts were washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated on the rotary evaporator. The residue
was purified by flash chromatography (hexane/ethyl acetate 20:1
v/v) to afford ester 21 (28.9 g, 99%) as a white solid: Rf (hexane/
(29) (a) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J.
L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119,
947-961. (b) Smith, A. B., III; Condon, S. M.; Mccauler, J. A. Acc. Chem.
Res. 1998, 31, 35-46.
(30) Typical examples of stereochemically controlled dithiane coupling
reactions, see: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K.
C.; Choi, H.-S. J. Am. Chem. Soc. 2002, 124, 2190-2201. (b) Nicolaou,
K. C.; Li, Y.-W.; Sugita, K.; Monenschein, H.; Guntupalli, P.; Mitchell, H.
J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.; O’Brate, A. J.
Am. Chem. Soc. 2003, 125, 15443-15454. (c) See ref 29a.
(31) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012. (b) DeNinno, M. P.; Perner, R. J.; Lijewski, L. Tetrahedron Lett.
1990, 31, 7415-7418. (c) Kanematsu, K.; Nishizaki, A.; Sao, Y.; Shiro,
M. Tetrahedron Lett. 1992, 33, 4967-4970. (d) Xu, J.-X.; Wei, T.-Z.;
Zhang, Q.-H. J. Org. Chem. 2003, 68, 10146-10151.
(32) (a) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447-6449. (b) Smith, A. B., III; Lee, D.; Adams, C. M.; Kozlowski, M.
C. Org. Lett. 2002, 4, 4539-4541. (c) Smith, A. B., III; Adams, C. M.;
Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc. 2003, 125, 350-351.
(33) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
ethyl acetate 15:1 v/v) 0.52; mp 82-83 °C; [R]24 +21.8 (c 1.06
D
CHCl3); IR (neat, cm-1) ν 2954, 2946, 1743, 1449, 1232, 1100,
767; 1H NMR (300 MHz, CDCl3) δ 7.43-7.22 (m, 15H), 5.19(m,
1H), 3.39 (dd, J ) 2.8, 2.4 Hz, 2H), 3.10 (m, 2H), 2.09 (s, 3H),
1.65-1.72 (m, 1H), 1.40 (ddd, J ) 7.2, 6.7, 5.2 Hz, 2H), 0.87(d,
J ) 5.3 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.6, 144.0, 128.7, 127.8, 127.0,
86.5, 71.9, 67.5, 65.3, 34.4, 32.4, 26.0, 21.3, 18.2, 17.4, -5.40,
-5.42; MALDI-MS calcd for C33H44O4Si found 532, m/z [M +
Na]+ 555; HRMS (MALDI) m/z 555.2915, [M + Na]+ calcd for
C33H44O4SiNa+ 555.2901.
Alcohol 22. To a stirred solution of ester 21 (4.40 g, 8.3 mmol)
in THF (80 mL) was added TBAF (16.6 mL of a 1.0 M solution in
(34) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
4630 J. Org. Chem., Vol. 71, No. 12, 2006

Total Synthesis of Amphidinolide T3
THF, 16.6 mmol) at room temperature. After the solution was
allowed to sit overnight, saturated aqueous NH4Cl (50 mL) was
added, and the mixture was extracted with Et2O (3 × 25 mL). The
combined extracts were washed with brine (25 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane/ethyl acetate
1:4 f 1:1 v/v) to afford alcohol 22 (3.32 g, 96%) as a viscous
liquid: Rf (hexane/ethyl acetate 3:1 v/v) 0.39; [R]21D +19.9 (c 0.90
CHCl3); IR (film, cm-1) ν 3450, 3059, 2927, 1738, 1597, 1491,
1449, 1372, 1240, 706; 1H NMR (300 MHz, CDCl3) δ 7.43-7.23
(m, 15H), 5.20(m, 1H), 3.45 (dd, J ) 2.7, 9.2 Hz, 2H), 3.08-3.18
(ddd, J ) 3.3, 10.4, 14.4 Hz, 2H), 2.11 (s, 3H), 1.47-1.72 (m,
5H), 0.90 (d, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 143.9,
128.7, 127.8, 127.1, 86.4, 71.9, 67.6, 65.2, 34.6, 32.3, 21.3, 17.3;
ESI-MS calcd for C27H30O4Si found 418, m/z [M + Na]+ 441;
HRMS (ESI) m/z 441.2054 [M + Na]+ calcd for C27H30O4SiNa+
441.2036.
38.3, 35.2, 33.6, 21.4, 13.3; ESI-MS calcd for C30H34O4, found
458 m/z [M + Na]+ 481; HRMS (ESI) m/z 481.2347, [M + Na]+
calcd for C30H34O4Na+ 481.2349.
Alkene 8. To a solution of 24 (6.29 g, 13.7 mmol) in pyridine
(32 mL) cooled to 0 °C was added TsCl (6.54 g, 34.3 mmol). After
being stirring for 5 min, the reaction mixture was warmed to room
temperature, stirred for 48 h, and then quenched with ice-water.
The resulting solution was stirred at room temperature for 0.5 h;
the mixture was extracted with Et2O (3 × 20 mL). The combined
extracts were successively washed with 2 M HCl (3 × 15 mL),
saturated NaHCO3 (15 mL), and brine (50 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane/ethyl acetate
20:1 v/v) to afford tosylate 25 (8.36 g, 99%) as a colorless oil: Rf
(hexane/ethyl acetate 8:1 v/v) 0.45; [R]21 +22.5 (c 1.45 CHCl3);
D
IR (neat, cm-1) ν 3052, 2919, 1738, 1597, 1486, 1449, 1365, 1238,
1
1177, 901, 708; H NMR (300 MHz, CDCl3) δ 7.74 (d, J ) 8.4
Aldehyde 23. To a solution of alcohol 22 (1.67 g, 4 mmol) in
CH2Cl2 (33 mL) was added DMP (2.71 g, 6.4 mmol) in one portion
at room temperature. After being stirred for 30 min, the reaction
was diluted with Et2O (20 mL) and quenched by addition of
saturated aqueous Na2S2O3 (20 mL) and NaHCO3 (5 mL). The
aqueous phase was extracted with Et2O (3 × 10 mL). The combined
extracts were washed with brine (20 mL), dried over anhydrous
Na2SO4, and concentrated on the rotary evaporator to give a pale
yellow-white product. Recrystallization from hexane afforded 23
(1.54 g, 92%) as white needles: Rf (hexane/ethyl acetate 8:1 v/v)
Hz, 2H), 7.23-7.43 (m, 17H), 5.46-5.33 (m, 3H), 5.05 (m, 1H),
4.94-4.83 (m, 2H), 4.43 (m, 2H), 3.10 (ddd, J ) 3.9, 10.5, 14.4
Hz, 2H), 2.42 (s, 3H), 2.28-2.25 (m, 2H), 2.11 (s, 3H), 1.92 (m,
1H), 1.67-1.76 (m, 1H), 1.41-1.48 (m, 1H), 0.85 (d, J ) 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 170.5, 144.4, 143.8, 134.4,
132.5, 129.6, 128.6, 127.9, 127.8, 127.1, 118.3, 86.6, 85.8, 71.1,
64.7, 34.7, 33.0, 32.9, 32.7, 29.7, 21.6, 21.2, 15.3; ESI-MS calcd
for C37H40O6S found 612, m/z [M + NH4]+ 630; HRMS (ESI) m/z
635.2439 [M + Na]+, calcd for C37H40O6SNa+ 635.2437. A solution
of KOH (2.02 g, 36 mmol) in ethylene glycol (20 mL) was added
to a solution of 25 (1.11 g, 1.8 mmol) in diglyme (10 mL). The
mixture was warmed to 40 °C for 90 min. The solution was then
cooled and quenched with water (20 mL). The aqueous phase was
extracted with Et2O (3 × 15 mL), and the combined organic phases
were washed with water (15 mL) and brine (30 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane/ethyl acetate
50:1 v/v) to afford alkene 8 (0.71 g, 99%) as a colorless oil: Rf
(hexane/ethyl acetate 40:1 v/v) 0.32; [R]21D +4.37 (c 0.84 CHCl3);
IR (film, cm-1) ν 3059, 2962, 2928, 1638, 1594, 1491, 1448, 1089,
0.48; mp 87-88 °C; [R]21D +30.6 (c 0.70 CHCl3); IR (neat, cm-1
)
ν 3059, 3033, 2934, 1742, 1701, 1590, 1491, 1449, 1373, 1237;
1H NMR (300 MHz, CDCl3) δ 9.61 (d, J ) 1.4 Hz, 1H), 7.44-
7.22 (m, 15H); 5.16-5.09 (m, 1H), 3.16 (ddd, J ) 4.4, 10.4, 12.8
Hz, 2H), 2.43-2.34 (m, 1H), 2.08 (s, 3H), 2.01 (ddd, J ) 3.7, 6.9,
11.5 Hz, 1H), 1.86 (ddd, J ) 4.9, 9.1, 14.1 Hz, 1H), 1.08 (d, J )
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.6, 170.4, 203.6,
170.4, 143.8, 128.7, 127.9, 127.1, 86.6, 70.8, 64.8, 42.9, 31.7, 21.1,
13.5; ESI-MS calcd for C27H28O4 found 416, m/z [M + Na]+ 439;
HRMS (ESI) m/z 439.1867, [M + Na]+ calcd for C27H28O4Na+
439.1879.
1
704, 632; H NMR (300 MHz, CDCl3) δ 7.42-7.14 (m, 15H),
5.76-5.89 (m, 1H), 4.99-5.11 (m, 2H), 4.26 (m, 1H), 3.88 (m,
1H), 3.05 (dd, J ) 5.7, 9.3 Hz, 1H), 2.89 (dd, J ) 5.1, 9.9 Hz,
1H), 2.15-2.33 (m, 3H), 1.78-1.87 (m, 1H), 1.58-1.66 (ddd, J
) 2.7, 7.5, 10.2 Hz, 1H), 0.87 (d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 144.3, 135.7, 128.8, 127.7, 126.9, 116.3, 86.4, 80.9,
76.1, 66.8, 36.7, 35.7, 35.3, 14.1; ESI-MS calcd for C28H30O2 found
398, m/z [M + Na]+ 421; HRMS (ESI) m/z 421.2139, [M + Na]+
calcd for C28H30O2Na+ 421.2138.
Alcohol 24. To a three-necked flask (50 mL) containing (R,R)-
1,2-bis-p-toluenesulfonyl-1, 2-diphenylethane (242.5 mg, 0.47
mmol) in CH2Cl2 (4.5 mL) cooled to 0 °C was added boron
tribromide (0.47 mL of a 1 M solution in CH2Cl2, 0.47 mmol).
The mixture was stirred at 0 °C for 10 min, warmed to room
temperature, and stirred for 2 h. After the solvent and HBr (this
was key to yield) were completely removed under reduced pressure,
the resulting solid was diluted with CH2Cl2 (4.5 mL) and cooled
to 0 °C. Allyltributylstannane (172 mg, 0.52 mmol) was added
dropwise. After the mixture was stirred for 6 h at room temperature,
the reaction was cooled to -78 °C, and a solution of aldehyde 23
(137 mg, 0.33 mmol) in CH2Cl2 (1 mL) was added. After being
stirred for 2 h at -78 °C, the reaction was quenched with pH ) 7
buffer solution (5 mL) and warmed to room temperature. The
mixture was diluted with CH2Cl2 (50 mL). The organic phase was
washed with brine (30 mL). The combined aqueous phases were
extracted with CH2Cl2 (15 mL). The combined organic phases were
dried over anhydrous Na2SO4 and concentrated on the rotary
evaporator. The resulting solid was washed with ether to recover
the bissulfonamide chiral auxiliary. The filtrate was concentrated
in vacuo and purified by flash chromatography (hexane/ethyl acetate
10:1 v/v) to afford alcohol 24 (128 mg, 85%) as a colorless oil and
recover 23 (10 mg) simultaneously: Rf(hexane/ethyl acetate 6:1
Alcohol 26. A solution of borane-dimethyl sulfide (16 mL of
a 2.0 M solution in THF, 32 mmol) was added to a solution of 8
(3.54 g, 8.9 mmol) in dry THF (100 mL) and cooled to 0 °C. After
being warmed to room temperature and stirred, the mixture was
again cooled to 0 °C and carefully quenched by successively
addition of EtOH (60 mL), NaOH aq (60 mL, 3.0 M), and 30%
H2O2 (60 mL). The mixture was stirred for 2 h at room temperature.
The aqueous phase was extracted with Et2O (3 × 40 mL), and the
combined organic phases were washed with brine (40 mL), dried
over anhydrous Na2SO4, and concentrated on the rotary evaporator.
The residue was purified by flash chromatography (hexane/ethyl
acetate, 8:1 f 6:1 v/v) to afford alcohol 26 (3.2 g, 83%) as a
colorless oil: Rf (hexane/ethyl acetate 4:1 v/v): 0.17; [R]20D +8.77
(c 1.10 CHCl3); IR (film, cm-1) ν 3400, 2935, 1594, 1491, 1448,
1
1071, 749, 704; H NMR (300 MHz, CDCl3) δ 7.51-7.21 (m,
v/v) 0.40; [R]21 +33.0 (c 0.63 CHCl3); IR (neat, cm-1) ν 3511,
15H), 4.37-4.29 (m, 1H), 3.92 (td, J ) 4.8, 8.7 Hz, 1H), 3.72
(ddd, J ) 6.0, 10.8, 6.3 Hz, 2H), 3.13 (dd, J ) 5.7, 9.3 Hz, 1H),
3.00 (dd, J ) 4.5, 9.9 Hz, 1H), 2.56 (br. s, 1H), 2.24 (m, 1H),
1.94-1.85 (m, 1H), 1.53-1.80 (m, 5H), 0.94(d, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 144.2, 128.8, 128.73 127.9, 127.7,
126.9, 81.9, 76.2, 66.7, 63.0, 36.6, 36.2, 30.6, 27.8, 14.2; ESI-MS
calcd for C28H32O3, found 416 m/z [M + Na]+ 439; HRMS (ESI)
m/z 439.2246, [M + Na]+ calcd for C28H32O3 Na+ 439.2243.
D
1
3052, 2926, 1734, 1638, 1490, 1446, 1240, 703; H NMR (300
MHz, CDCl3) δ 7.46-7.23 (m, 15H), 5.85-5.71 (m, 1H), 5.18-
5.15 (m, 1H), 5.13 (s, 1H), 5.09 (s, 1H), 3.43(br,1H), 3.13 (ddd, J
) 3.3, 10.1, 14.3 Hz, 2H), 2.23-2.28 (m, 1H), 2.14 (s, 3H), 2.00-
2.10 (m, 1H), 1.84-1.89 (m, 1H), 1.71 (m, 1H), 1.47-1.49 (m,
2H), 0.88 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.7,
143.9, 135.1, 128.7, 127.8, 127.0, 118.1, 86.5, 74.4, 72.5, 64.9,
J. Org. Chem, Vol. 71, No. 12, 2006 4631

Deng et al.
Iodide 27. PPh3 (6.03 g, 23.0 mmol) and imidazole (3.13 g, 46.0
mmol) were added sequentially to a solution of alcohol 26 (3.19 g,
7.67 mmol) in THF (105 mL) at 0 °C. After the solution was stirred
for 10 min, I2 (5.84 g, 23 mmol) was added in three portions and
the mixture maintained at this temperature for 10 min. The reaction
mixture was warmed to room temperature, stirred for another 2 h,
and then quenched with saturated aqueous Na2S2O3 (45 mL). The
aqueous phase was extracted with Et2O (3 × 15 mL), and the
combined organic phases were washed with brine (30 mL), dried
over anhydrous Na2SO4, and concentrated on the rotary evaporator.
The residue was purified by flash chromatography (hexane/ethyl
acetate 100:1 v/v) to afford iodide 27 (3.81 g, 95%) as a colorless
10:1 f 5:1 v/v) to afford alcohol 30 (2.92 g, 95%) as a colorless
oil: Rf (hexane/ethyl acetate 3:1 v/v) 0.28; [R]20 -9.9 (c 1.57
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 4.50
(s, 3H), 4.17 (tdd, J ) 7.1, 7.1, 3.2 Hz, 1H), 3.85 (m, 1H), 3.61
(m, 1H), 3.46 (dt, J ) 11.6, 5.8 Hz, 1H), 3.32 (dd, J ) 9.0, 6.1
Hz, 1H), 2.24 (m, 1H), 2.03 (t, J ) 6.6 Hz, 1H), 1.85 (dd, J )
12.4, 7.6 Hz, 1H), 1.76 (dd, J ) 12.4, 6.6 Hz, 1H), 1.65 (ddd, J )
12.4, 7.3, 3.3 Hz, 1H), 1.40-1.36 (m, 7H), 1.10 (m, 1H), 0.92 (d,
J ) 6.6 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.7, 128.3, 127.5, 127.3, 81.7, 77.4, 75.9, 72.9, 65.5,
35.8, 35.4, 33.5, 33.4, 30.3, 27.1, 26.8, 17.1, 13.9; IR (film, cm-1
)
3430, 2931, 2858, 1454, 1205, 1096; ESI-MS calcd for C20H32O3
found 320, m/z [M + H]+ 321; HRMS (ESI) m/z 343.2249, [M +
Na]+ calcd for C20H32O3Na+ 343.2244.
oi: Rf (hexane/ethyl acetate 30:1 v/v) 0.48; [R]20 +12.8 (c 0.88
D
in CHCl3); IR (film, cm-1) ν 3052, 2960, 1594, 1490, 1448, 1224,
1
1075, 703; H NMR (300 MHz, CDCl3) δ 7.52-7.22 (m, 15H),
Iodide 31. Iodide 31 was prepared as the same approach to 27:
Rf (hexane/ethyl acetate 25:1 v/v) 0.38; [R]20 +20.6 (c 0.25
4.29 (m, 1H), 3.88 (m, 1H), 3.34-3.19 (m, 2H), 3.10 (dd, J ) 5.4,
9.3 Hz, 1H), 2.97 (dd, J ) 4.2, 9.6 Hz, 1H), 2.20(m, 1H), 1.89 (dt,
J ) 6.9, 19.8 Hz, 2H), 1.67 (ddd, J ) 3.3, 7.5, 10.2 Hz, 1H), 1.57
(dd, J ) 7.2, 14.4 Hz, 3H), 0.92(d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 144.2, 128.8, 127.7, 126.9, 86.4, 80.5, 76.0, 66.9,
36.5, 36.0, 31.7, 31.2, 14.2, 7.2. Anal. Calcd for C28H31IO2: C,
63.88; H, 5.94. Found: C, 63.67; H, 5.82.
D
CHCl3); IR (neat, cm-1) ν 2961, 2856, 1496, 1454, 1362, 1096;
1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 4.51 (s, 2H),
4.12 (tdd, J ) 7.5, 7.5, 4.6 Hz, 1H), 3.98 (m, 1H), 3.28 (dd, J )
9.6, 4.5 Hz, 1H), 3.29 (m, 2H), 3.17 (dd, J ) 9.5, 7.6 Hz, 1H),
2.29 (m, 1H), 1.90 (ddd, J ) 12.4, 7.1, 3.7 Hz, 2H), 1.79 (m, 1H),
1.49-1.26 (m, 7H), 1.14 (m, 1H), 0.93 (d, J ) 6.5 Hz, 3H), 0.92
(d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.8, 128.3,
127.5, 127.4, 82.5, 77.4, 75.9, 72.9, 40.5, 36.3, 33.5, 33.4, 30.4,
27.1, 26.7, 17.1, 13.9, 12.1; ESI-MS calcd for C20H31IO2 found
430, m/z [M + NH4]+ 448; HRMS (ESI) m/z 453.1266 [M + Na]+
calcd for C20H31IO2Na+ 453.1261.
Benzyl Ether 29. To a stirred solution of the sulfone 9 (2.64 g,
8.69 mmol) in THF (20 mL) and HMPA (7.8 mL) cooled at -78
°C was added n-BuLi (6.5 mL of a 1.6 M solution in THF, 10.4
mmol) dropwise. The mixture gradually turned amaranth and was
warmed to -30 °C for 30 min and then recooled to -78 °C. A
solution of iodide 27 (3.81 g, 7.24 mmol) in THF (28 mL) was
added dropwise. After being stirred for 2 h, the reaction was
quenched by addition of saturated aqueous NH4Cl (10 mL) and
then warmed to room temperature. The mixture was extracted with
Et2O (3 × 10 mL), and the combined extracts were washed with
brine (10 mL), dried over anhydrous Na2SO4, and concentrated on
the rotary evaporator. The residue was purified by flash chroma-
tography (hexane/ethyl acetate 20:1 f 10:1 f 6:1 v/v) to afford a
diastereomeric mixture of sulfones (4.89 g) as a colorless oil, which
was employed in the next experiment without separation of the
diastereomers. To a vigorously stirred solution of the diastereomeric
mixture of sulfones (4.89 g, 6.97 mmol) in EtOH (93 mL) cooled
at 0 °C was added 6% sodium amalgam (50 g, 130 mmol) in one
portion. After 5 min, the mixture was warmed to room temperature,
stirred for 2-3 h, diluted with saturated aqueous NH4Cl (30 mL),
and stirred at room temperature for 2 h. The aqueous phase was
extracted with Et2O (3 × 15 mL), and the combined organic phases
were washed with brine (15 mL), dried over anhydrous Na2SO4,
and concentrated on the rotary evaporator. The residue was purified
by flash chromatography (hexane/ethyl acetate 50:1 f 10: 1 v/v)
to afford benzyl ether 29 (3.26 g, 80%) as a colorless oil: Rf
(hexane/ethyl acetate 15:1 v/v) 0.56; [R]20D +14.6 (c 0.51 CHCl3);
IR (film, cm-1) ν 3052, 3022, 2929, 1594, 1491, 1449, 1095, 698;
1H NMR (300 MHz, CDCl3) δ 7.50-7.19 (m, 20H), 4.48 (s, 2H),
4.29 (m, 1H), 3.83 (m, 1H), 3.32 (dd, J ) 6.3, 9.0 Hz, 1H), 3.22
(dd, J ) 6.6, 9.0 Hz, 1H), 3.11 (dd, J ) 6.3, 9.6 Hz, 1H), 2.95 (dd,
J ) 4.5, 9.9 Hz, 1H), 2.17 (m, 1H), 1.91-1.82 (m, 1H), 1.77-
1.75 (m, 1H), 1.66 (ddd, J ) 2.4, 7.2, 9.6 Hz, 1H), 1.29-1.63 (m,
7H), 1.12-1.16 (m, 1H), 0.89-0.93 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 144.3, 138.9, 128.8, 128.3, 127.9, 127.7, 127.5, 127.4,
127.3,126.8, 86.3, 81.5, 76.0, 75.8, 72.9, 66.9, 36.7, 35.8, 33.7,
33.5, 30.7, 27.3, 27.3, 17.2, 14.1; ESI-MS calcd for C39H46O3 found
562, m/z [M + NH4]+ 580; HRMS (ESI) m/z 585.3336 [M + Na]+
calcd for C39H46O3Na+ 585.3339.
2-Substituted Dithiane 32. 1,3-Dithiane (3.67 g, 30.6 mmol)
was dissolved in 10% HMPA/THF (32 mL, v/v) cooled to -78
°C. After the solution was stirred for 20 min, a solution of iodide
31 (4.37 g, 10.2 mmol) in 10% HMPA/THF (16 mL) was added
dropwise. The mixture was stirred for 1.5 h and quenched with
saturated aqueous NH4Cl (10 mL). The aqueous phase was extracted
with Et2O (2 × 10 mL), and the combined organic phases were
washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated on the rotary evaporator. The residue was purified by
flash chromatography (hexane/ethyl acetate 100:1 f 50:1) to afford
dithiane 32 (3.59 g, 83%) as a colorless oil: Rf (hexane/ethyl acetate
15:1 v/v) 0.49; [R]20 -26.4 (c 0.35 CHCl3); IR (neat, cm-1) ν
D
1
2931, 2855, 1454, 1268, 1091, 998, 735; H NMR (300 MHz,
CDCl3) δ 7.35-7.27 (m, 5H), 4.50 (s, 2H), 4.35 (ddd, J ) 15.7,
7.6, 4.1 Hz, 1H), 4.21 (dd, J ) 9.2, 5.0 Hz, 1H), 3.80 (dt, J ) 7.5,
4.9 Hz, 1H), 3.32 (dd, J ) 9.1, 5.9 Hz, 1H), 3.23 (dd, J ) 9.2, 6.9
Hz, 1H), 2.97-2.78 (m, 4H), 2.20 (m, 2H), 1.94-1.75 (m, 6H),
1.67-1.37 (m, 7H), 1.13 (m, 1H), 0.92 (d, J ) 6.5 Hz, 3H), 0.89
(d, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 128.2,
127.4, 127.3, 80.8, 75.9, 72.8, 72.7, 44.5, 42.5, 40.1, 35.7, 33.5,
33.3, 30.4, 30.3, 30.0, 27.1, 26.8, 25.9, 17.0, 13.9; ESI-MS calcd
for C24H38O2S2 found 422, m/z [M + NH4]+ 440; HRMS (ESI)
m/z 445.2211, [M + Na]+ calcd for C24H38O2S2Na+ 445.2205.
Aldehyde 6. NaHCO3 (383 mg, 4.6 mmol) and CH3I (457 µL,
7.36 mmol) were successively added to a solution of dithiane 32
(193 mg, 0.46 mmol) in 80% CH3CN/H2O (6 mL). The mixture
was stirred for 16 h at room temperature and diluted by addition
of water (5 mL). The aqueous layer was extracted with Et2O (3 ×
5 mL), and the combined organic phases were washed with brine
(8 mL), dried over anhydrous Na2SO4, and concentrated on the
rotary evaporator. The residue was purified by flash chromatography
(hexane/ethyl acetate 20:1 f 10:1 v/v) to afford aldehyde 6 (150
mg, 95%) as a colorless oil: Rf (hexane/ethyl acetate 8:1 v/v): 0.25;
[R]20 -6.5 (c 1.95 CHCl3); IR (film, cm-1) ν 3030, 2929, 2854,
D
Alcohol 30. A mixture of ether 29 (5.36 g, 9.54 mmol) in 80%
(v/v) aqueous HOAc (64 mL) was warmed at 50-55 °C for 3 h
under stirred. The mixture was cooled to room temperature and
quenched with saturated aqueous NaHCO3 (50 mL). The aqueous
phase was extracted with Et2O (3 × 20 mL), and the combined
organic phases were washed with brine (25 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane/ethyl acetate
1726, 1454, 1376, 1096, 736, 698; 1H NMR (300 MHz, CDCl3) δ
9.82 (d, J ) 2.2 Hz, 1H), 7.36-7.27 (m, 5H), 4.54 (m, 1H), 4.5
(m, 1H), 3.89 (m, 1H), 3.32 (dd, J ) 9.1, 6.2 Hz, 1H), 3.24 (dd, J
) 9.1, 7.2 Hz, 1H), 2.68 (ddd, J ) 16.3, 7.4, 2.7 Hz, 1H), 2.55
(ddd, J ) 16.0, 5.1, 1.7 Hz, 1H), 2.26 (m, 1H), 1.88 (m, 1H), 1.77
(dt, J ) 12.2, 7.1 Hz, 1H), 1.39-1.26 (m, 7H), 1.13 (m, 1H), 0.93
(d, J ) 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 201.7, 138.7,
128.2, 127.4, 127.3, 81.5, 75.9, 72.9, 71.4, 50.5, 40.4, 35.7, 33.5,
4632 J. Org. Chem., Vol. 71, No. 12, 2006

Total Synthesis of Amphidinolide T3
33.3, 30.2, 27.1, 26.7, 17.0, 13.8; ESI-MS calcd for C21H32O3 found
332, m/z [M + H]+ 333; HRMS (ESI) m/z 355.2249, [M + Na]+
calcd for C21H32O3Na+ 355.2244.
found 420, m/z [M + Na]+ 443; HRMS (ESI) m/z 443.2957, [M +
Na]+ calcd for C25H44O3SiNa+ 443.2952.
Alcohol 43. To a solution of lithium (347 mg, 49.6 mmol) in
liquid ammonia (220 mL) cooled to -78 °C was added alkene 42
(1.94 g, 4.6 mmol) in THF (22 mL). The resulting dark blue mixture
was stirred for 1.5 h. Solid NH4Cl was then added until the blue
disappeared. After the liquid was evaporated at room temperature,
water and diethyl ether were added. The aqueous phase was
extracted with Et2O (3 × 10 mL). The combined extracts were
washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated on the rotary evaporator. The residue was purified by
flash chromatography (hexane/ethyl acetate 20:1 f 10:1 v/v) to
afford 43 (1.36 g, 99%) as a colorless oil: Rf (hexane/ethyl acetate
8:1 v/v) 0.46; [R]20D +14.9 (c 1.00 CHCl3); IR (neat, cm-1) ν 3347,
Disubstituted Dithiane 40. To a solution of 10 (4.34 g, 13.5
mmol) in dry THF (45 mL) cooled to -78 °C were added t-BuLi
(9.0 mL of a 1.5 M soln in THF, 13.5 mL) over a period of 10 min
and HMPA (4.9 mL). After the solution was stirred for 30 min, a
solution of the iodide 11 (3.1 g, 9.7 mmol) in THF (30 mL) was
added dropwise. The resulting solution was stirred at -78 °C for
1 h and quenched with saturated aqueous NH4Cl (25 mL). The
aqueous phase was extracted with Et2O (3 × 10 mL). The combined
extracts were washed with brine (25 mL), dried over anhydrous
Na2SO4, and concentrated on the rotary evaporator. The residue
was purified by flash chromatography (hexane/ethyl acetate 100:1
v/v) to afford 40 (4.1 g, 83%) as a colorless oil: Rf (hexane/ethyl
1
2959, 1644, 1463, 1362, 1255, 1126, 1040; H NMR (300 Hz,
acetate 50:1 v/v) 0.25; [R]20D -4.7 (c 0.97 CHCl3); IR (neat, cm-1
)
CDCl3) δ 4.82 (s, 2H), 3.80 (m, 1H), 3.50 (m, 2H), 2.17 (m, 3H),
1.86 (dd, J ) 16.1, 7.3 Hz, 2H), 1.48-1.27 (m, 5H), 0.91 (d, J )
6.5 Hz, 3H), 0.89 (s, 12H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 145.2, 113.5, 70.9, 68.2, 43.7, 40.7, 39.1, 33.8, 25.9,
18.5, 18.1, 16.7, 14.2, -4.4, -4.6; ESI-MS calcd for C17H36O2Si
found 300, m/z [M + H]+ 301; HRMS (ESI) m/z 323.2382, [M +
Na]+ calcd for C17H36O2SiNa+ 323.2377.
ν 2957, 1380, 1255, 1110, 1047; 1H NMR (300 Hz, CDCl3) δ 7.38-
7.27 (m, 5H), 4.78 (s, 2H), 4.63 (s, 2H), 4.10 (m, 1H), 3.57 (dd, J
) 9.3, 5.5 Hz, 1H), 3.42 (dd, J ) 9.0, 7.0 Hz, 1H), 2.83 (m, 4H),
2.20 (dd, J ) 15.1, 4.1 Hz, 2H), 2.03-1.98 (m, 2H), 1.90 (m, 2H),
1.82 (dd, J ) 15.3, 5.7 Hz, 1H), 1.62 (m, 1H), 1.51-1.30 (m, 3H),
1.10 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 7.1 Hz, 3H), 0.89 (s, 9H),
0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.9,
128.4, 127.9, 127.6, 94.5, 73.9, 69.8, 69.2, 53.6, 46.8, 43.4, 41.4,
30.3, 26.5, 26.2, 26.1, 24.9, 20.1, 18.1, 17.9, 14.3, -3.8, -4.0;
ESI-MS calcd for C27H48O3S2Si found 512, m/z [M + NH4]+ 530;
HRMS (ESI) m/z 535.2712, [M + Na]+ calcd for C27H48O3S2SiNa+
535.2706.
Aldehyde 44. Aldehyde 44 (94%) was prepared from alcohol
43 using the above procedure for aldehyde 23: Rf (hexane/ethyl
acetate 40:1 v/v) 0.52; [R]20D +1.6 (c 1.07 CHCl3); IR (neat, cm-1
)
ν 3077, 2959, 1731, 1645, 1463, 1362, 1126, 1092; 1H NMR (300
Hz, CDCl3) δ 9.64 (d, J ) 2.0 Hz, 1H), 4.84 (d, J ) 11.7 Hz, 2H),
3.79 (m, 1H), 2.56 (td, J ) 6.8, 1.9 Hz, 1H), 2.49 (m, 1H), 2.16
(d, J ) 6.6 Hz, 2H), 2.04 (m, 1H), 1.41-1.26 (m, 4H), 1.09 (d, J
) 7.3 Hz, 3H), 0.88 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 204.7, 143.4, 114.3, 71.0, 44.3, 43.7, 39.1,
37.5, 25.9, 18.5, 18.1, 14.2, 13.4, -4.4, -4.6; ESI-MS calcd for
C17H34O4Si found 298, m/z [M + Na]+ 321; HRMS (ESI) m/z
321.2226, [M + Na]+ calcd for C17H34O4SiNa+ 321.2220.
Ketone 41. NaHCO3 (5.94 g, 70.7 mmol) and I2 (7.98 g, 31.4
mmol) were successively added to a solution of 40 (4.03 g, 7.86
mmol) in acetone/H2O (130 mL, 5:1, v/v) cooled to 0 °C. After
being stirred for 1 h, the reaction mixture was quenched with
saturated aqueous Na2S2O3 (30 mL) and extracted with Et2O (3 ×
20 mL). The combined extracts were washed with brine (15 mL),
dried over anhydrous Na2SO4, and concentrated on the rotary
evaporator. The residue was purified by flash chromatography
(hexane/ethyl acetate 100:1 f 50:1 v/v) to afford 41 (2.75 g, 83%)
Dithiane 7. To a 100-mL, three-necked flask containing ZnCl2
(730 mg, 5.36 mmol) in Et2O (55 mL) cooled to 0 °C was added
1, 3-propanedithiobis(trimethylsilane) (1.13 mL, 5.36 mmol). After
5 min, the solution of aldehyde 44 (805 mg, 2.68 mmol) in Et2O
(26 mL) was added dropwise. The reaction mixture was then
warmed to room temperature and stirred for 1 h. The reaction was
quenched by addition of aqueous ammonia (20 mL) and water (30
mL). The aqueous phase was extracted with Et2O (3 × 15 mL).
The combined extracts were washed with brine (15 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane) to afford 7
(944 mg, 91%) as a colorless oil: Rf (hexane/ethyl acetate 60:1)
0.54; [R]20D +13.4 (c 0.95 CHCl3); IR (neat, cm-1) ν 3074, 2958,
1643, 1255, 1125, 1041; 1H NMR (300 Hz, CDCl3) δ 4.84 (s, 2H),
4.47 (d, J ) 3.1 Hz, 2H), 3.80 (m, 1H), 2.89 (m, 4H), 2.40 (dd, J
) 13.2, 5.2 Hz, 2H), 2.21 (dd, J ) 13.7, 6.0 Hz, 1H), 2.16-2.02
(m, 3H), 1.96 (dd, J ) 13.3, 8.8 Hz, 1H), 1.86 (m, 1H), 1.44-1.28
as a colorless oil: Rf (hexane/ethyl acetate 40:1 v/v) 0.28; [R]20
D
-13.8 (c 0.97 CHCl3); IR (neat, cm-1) ν 2958, 1716, 1462, 1387,
1257, 1048; 1H NMR (300 Hz, CDCl3) δ 7.37-7.27 (m, 5H), 4.74
(s, 2H), 4.59 (s, 2H), 4.18 (dt, J ) 12.2, 5.6 Hz, 1H), 3.47 (dd, J
) 9.4, 5.8 Hz, 1H), 3.38 (dd, J ) 9.5, 6.4 Hz, 1H), 2.64-2.56 (m,
2H), 2.45 (dd, J ) 15.4, 5.2 Hz, 1H), 2.34 (m, 1H), 2.25 (dd, J )
15.8, 7.7 Hz, 1H), 1.44-1.26 (m, 4H), 0.93 (dd, J ) 13.7, 6.9 Hz,
3H), 0.87 (s, 12H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 209.1, 137.8, 128.4, 127.8, 127.7, 94.6, 72.5, 69.3, 68.6,
50.6, 48.4, 39.9, 29.3, 25.8, 18.3, 18.0, 17.2, 14.2, -4.6, -4.7;
ESI-MS calcd for C24H42O4Si found 422, m/z [M + H]+ 423;
HRMS (ESI) m/z 445.2750, [M + Na]+ calcd for C24H42O4Si Na+
445.2745.
Alkene 42. To a solution of 41 (1.73 g, 4.08 mmol) in toluene
(40 mL) was added Cp2TiMe2 (24.5 mL of a 0.5 M soln in toluene,
12.24 mmol). The resulting mixture shielded from light was stirred
vigorously and refluxed for 3 h. After being cooled to room
temperature, the solvent was removed under reduced pressure and
diluted with petroleum ether. The resulting yellow-orange precipitate
was removed by filtration, and the filtration was concentrated. The
residue was purified by flash chromatography (hexane) to afford
42 (1.53 g, 86%) as a colorless oil: Rf (hexane/ethyl acetate 50:1
(m, 4H), 1.07(d, J ) 6.9 Hz, 3H), 0.89 (m, 12H), 0.07 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 144.2, 114.3, 70.6, 54.9, 40.7, 38.9, 36.5,
31.1, 30.7, 26.3, 25.9, 18.5, 18.0, 16.7, 14.2, -4.3, -4.6; ESI-MS
calcd for C20H40OS2Si found 388, m/z [M + H]+ 389; HRMS (ESI)
m/z 411.2187, [M + Na]+ calcd for C20H40OS2SiNa+ 411.2182.
Alcohols 45a and 45b. To a solution of dithiane 7 (1.54 g, 3.99
mmol) in 10% HMPA/THF (15 mL) cooled to -78 °C was added
t-BuLi (2.67 mL of a 1.5 M soln in pentane, 4.0 mmol) over a
period 3 min. The precooled (-78 °C) aldehyde 6 (442 mg, 1.33
mmol) in 10% HMPA/THF (12 mL) was immediately added to
the dark orange anion mixture, and the reaction was stirred at -78
°C for 1 h. Then, it was quenched with saturated aqueous NH4Cl
(10 mL). The organic phase was separated, and the aqueous phase
was extracted with Et2O (3 × 10 mL). The combined organic phases
were washed with water (10 mL) and brine (15 mL), dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography (hexanes-ethyl acetate, 50:1-
25:1) to recover 7 (750 mg, 73%) and afford 45a (488 mg, 51%)
v/v) 0.63; [R]20 +4.8 (c 1.00 CHCl3); IR (neat, cm-1) ν 3070,
D
2958, 1643, 1463, 1255, 1107, 1047, 774; 1H NMR (300 Hz,
CDCl3) δ 7.37-7.27 (m, 5H), 4.80 (d, J ) 4.3 Hz, 2H), 4.77 (s,
2H), 3.79 (m, 1H), 3.47 (dd, J ) 9.5, 5.7 Hz, 1H), 3.40 (dd, J )
9.0, 6.4 Hz, 1H), 2.20 (dd, J ) 13.3, 5.6 Hz, 2H), 2.12 (dd, J )
13.7, 7.3 Hz, 1H), 1.93 (m, 1H), 1.81(dd, J ) 13.5, 8.5 Hz, 1H),
1.45-1.25 (m, 4H), 0.94 (d, J ) 6.4 Hz, 3H), 0.89 (s, 12H), 0.06
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.8, 137.9, 128.4, 127.9,
127.6, 113.5, 94.7, 73.2, 70.8, 69.2, 43.9, 40.7, 39.0, 31.5, 25.9,
18.5, 18.1, 17.0, 14.2, -4.4, -4.6; ESI-MS calcd for C25H44O3Si
J. Org. Chem, Vol. 71, No. 12, 2006 4633

Deng et al.
as a colorless oil and 45b (277 mg, 29%). 45a: Rf (hexane/ethyl
acetate 8:1 v/v) 0.53; [R]20D +16.4 (c 1.03 CHCl3); IR (neat, cm-1
reaction mixture was stirred for 12 h and quenched with MeOH
(100 µL). After the mixture was stirred for 2 h, 1 M HCl (200 µL)
was added, and the resulting mixture was diluted with Et2O (15
mL), washed with water (2 mL) and brine (3 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography (hexane/ethyl acetate 20:1 v/v)
to afford single alcohol 45a (43.6 mg, 68%) as a colorless oil.
Alcohol 48. To a solution of 45a (300 mg, 0.42 mmol) in
pyridine (4 mL) were successively added DMAP (18 mg, 0.15
mmol) and Ac2O (325 µL, 3.42 mmol). After being stirred at room
temperature for 24 h, the mixture was quenched by addition of
ice-water (10 mL), stirred for an additional 30 min, and extracted
with Et2O (3 × 6 mL). The combined extracts were washed with
brine (50 mL), dried over anhydrous Na2SO4, and concentrated on
the rotary evaporator. The residue was purified by flash chroma-
tography (hexane/ethyl acetate 20:1 v/v) to afford ester 47 (293
mg, 92%) as a colorless oil: Rf (hexane/ethyl acetate 8:1 v/v) 0.56;
[R]20D +36.4 (c 1.68 CHCl3); IR (neat, cm-1) ν 2933, 1741, 1643,
)
ν 3461, 2929, 1641, 1255, 1095; 1H NMR (300 Hz, CDCl3) δ 7.34-
7.27 (m, 5H), 4.80 (d, J ) 8.4 Hz, 2H), 4.50 (s, 2H), 4.34 (m, 1H),
4.23 (d, J ) 9.7 Hz, 1H), 4.05 (s, 1H), 3.89 (m, 2H), 3.32 (dd, J
) 9.1, 6.2 Hz, 1H), 3.23 (dd, J ) 9.3, 6.7 Hz, 1H), 2.91 (m, 3H),
2.71 (m, 2H), 2.23 (m, 3H), 2.04 (m, 4H), 1.92-1.71(m, 5H), 1.44-
1.26 (m, 11H), 1.13 (d, J ) 6.1 Hz, 3H), 1.13 (m, 1H), 0.90 (m,
9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.2, 138.7, 128.2, 127.4, 127.3, 114.1, 81.4, 77.4, 75.9,
74.0, 72.9, 70.3, 62.4, 43.7, 40.5, 39.5, 38.5, 37.7, 37.6, 35.5, 33.5,
33.4, 30.4, 27.1, 26.9, 25.9, 25.4, 24.7 18.3, 18.0, 17.0, 15.2, 14.2,
13.9, -4.2, -4.5; ESI-MS calcd for C41H72O4S2Si found 720, m/z
[M + Na]+ 743; HRMS (ESI) m/z 743.4539, [M + Na]+ calcd for
C41H72O4S2SiNa+ 743.4533. 45b: Rf (hexane/ethyl acetate 8:1 v/v)
0.40; [R]20 -4.5 (c 0.61 CHCl3); IR (neat, cm-1) ν 3461, 2931,
D
1
1641, 1463, 1254, 1095; H NMR (300 Hz, CDCl3) δ 7.35-7.27
(m, 5H), 4.78 (d, J ) 10.3 Hz, 2H), 4.50 (s, 2H), 4.44 (m, 2H),
3.82 (m, 2H), 3.31 (dd, J ) 9.1, 6.3 Hz, 1H), 3.23 (dd, J ) 9.2,
6.9 Hz, 1H), 3.14 (m, 2H), 3.01 (s, 1H), 2.86 (d, J ) 12.2 Hz,
1H), 2.61 (m, 2H), 2.21 (m, 3H), 2.02-1.69 (m, 9H), 1.45-1.26
(m, 11H), 1.08 (d, J ) 6.2 Hz, 3H), 1.08 (m, 1H), 0.90 (m, 9H),
0.88 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 145.2,
138.8, 128.3, 127.5, 127.4, 113.7, 82.0, 80.5, 76.0, 74.4, 73.0, 70.5,
63.1, 43.9, 40.4, 39.4, 38.8, 37.8, 37.7, 36.2, 33.7, 33.5, 30.6, 27.2,
26.4, 25.9, 25.7, 24.6, 18.4, 18.1, 17.2, 14.8, 14.3, 14.2, -4.2, -4.5;
ESI-MS calcd for C41H72O4S2Si found 720, m/z [M + Na]+ 743;
HRMS (ESI) m/z 743.4539, [M + Na]+ calcd for C41H72O4S2SiNa+
743.4533.
1
1371, 1236, 1097; H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m,
5H), 5.47 (d, J ) 10.2 Hz, 1H), 4.82 (s, 1H), 4.77 (s, 1H), 4.50 (s,
2H), 4.05 (m, 1H), 3.86 (m, 2H), 3.32 (dd, J ) 9.1, 6.0 Hz, 1H),
3.23 (dd, J ) 9.0, 6.4 Hz, 1H), 3.05 (m, 2H), 2.92 (d, J ) 12.9 Hz,
1H), 2.66 (d, J ) 4.4 Hz, 1H), 2.51 (d, J ) 5.1 Hz, 1H), 2.26 (m,
3H), 2.11(s, 3H), 2.09-1.81(m, 9H), 1.47-1.26 (m, 11H), 1.05
(m, 1H), 1.04 (d, J ) 6.3 Hz, 3H), 0.92 (m, 9H), 0.89 (s, 9H), 0.09
(s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.7, 145.0,
138.7, 128.2, 127.4, 127.3, 114.4, 81.2, 75.9, 74.8, 72.9, 71.6,
70.2, 61.1, 43.7, 39.8, 38.5, 37.5, 36.5, 35.9, 33.6, 33.4, 30.5, 27.2,
27.0, 26.8, 25.9, 25.6, 24.6, 21.2, 18.3, 18.1, 17.1, 14.4, 14.2, 14.0,
-4.1, -4.5; ESI-MS calcd for C43H74O5S2Si found 762, m/z [M +
Na]+ 785; HRMS (ESI) m/z 785.4645, [M + Na]+ calcd for
C43H74O5S2SiNa+ 785.4639.
Ketone 46. To a mixture of alcohol isomers 45a/45b (250 mg,
0.35 mmol) in CH2Cl2 (15 mL) were added DMP (295 mg, 0.69
mmol) and NaHCO3 (35 mg, 0.42 mmol) at room temperature. After
being stirred for 2 h, the reaction was diluted with Et2O (10 mL)
and quenched by addition of saturated aqueous Na2S2O3 (10 mL)
and NaHCO3 (3 mL). The aqueous phase was extracted with Et2O
(2 × 10 mL). The combined extracts were washed with brine (15
mL), dried over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography (hexane/ethyl acetate
50:1 f 30:1 v/v) to afford 46 (229 mg, 91%) as a colorless oil: Rf
DDQ (1.3 g, 5.75 mmol) was added to the solution of ester 47
(146 mg, 0.19 mmol) in CH2Cl2/H2O (17.6 mL 10:1 v/v). The
reaction mixture was stirred for 18 h at room temperature and
quenched with saturated aqueous NaHCO3 (30 mL). The aqueous
phase was extracted with Et2O (3 × 15 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (15 mL) and brine
(20 mL), dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by flash chromatography (hexane/ethyl
acetate 6:1 v/v) to afford alcohol 48 (122 mg, 95%) as a colorless
(hexane/ethyl acetate 8:1 v/v) 0.61; [R]25 -5.3 (c 0.50 CHCl3);
D
IR (neat, cm-1) ν 2927, 1705, 1640, 1462, 1254, 1097, 1040, 836,
774; 1H NMR (300 Hz, CDCl3) δ 7.34-7.26 (m, 5H), 4.85 (s, 1H),
4.81 (s, 1H), 4.62 (m, 1H), 4.49 (s, 2H), 3.83 (m, 2H), 3.29 (dd, J
) 9.0, 6.0 Hz, 1H), 3.21 (dd, J ) 9.0, 6.3 Hz, 1H), 3.09 (m, 2H),
2.86-2.50 (m, 5H), 2.23-1.98 (m, 7H), 1.92-1.63 (m, 4H), 1.45-
1.26 (m, 10H), 1.02 (d, J ) 6.3 Hz, 3H), 0.91 (m, 9H), 0.89 (s,
9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
201.9, 144.2, 138.8, 128.3, 127.5, 127.4, 114.5, 81.2, 76.0, 73.3,
73.0, 70.7, 68.5, 43.7, 42.8, 40.0, 38.9, 37.1, 36.0, 33.7, 33.5, 30.5,
27.7, 27.2, 27.0, 26.0, 24.9, 18.3, 18.1, 17.2, 14.6, 14.3, 14.0, -4.1,
-4.4; MALDI-MS calcd for C41H70O4S2Si found 718, m/z [M +
Na]+ 741; HRMS (MALDI) m/z 741.4362, [M + Na]+ calcd for
C41H70O4S2SiNa+ 741.4377.
oil: Rf (hexane/ethyl acetate 7:3 v/v) 0.63; [R]20 +33.5 (c 0.50
D
CHCl3); IR (neat, cm-1) ν 3454, 2931, 1741, 1641, 1463, 1236,
1
1040; H NMR (300 MHz, CDCl3) δ 5.40 (d, J ) 9.9 Hz, 1H),
4.75 (s, 1H), 4.69 (s, 1H), 3.98 (m, 1H), 3.81(d, J ) 4.7 Hz, 2H),
3.44 (dd, J ) 10.4, 5.7 Hz, 1H), 3.35 (dd, J ) 10.2, 6.4 Hz, 1H),
2.98 (m, 2H), 2.85 (d, J ) 12.9 Hz, 1H), 2.58 (dd, J ) 14.0, 3.7
Hz, 1H), 2.44 (d, J ) 14.3 Hz, 1H), 2.27-2.12 (m, 3H), 2.10 (s,
3H), 2.08-1.95 (m, 8H), 1.68 (m, 2H), 1.46-1.26 (m, 11H), 1.16
(m, 1H), 1.05 (d, J ) 6.6 Hz, 3H), 0.92 (d, J ) 6.9 Hz, 3H), 0.90
(s, 15H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.7, 145.2, 114.2, 81.3, 75.0,72.1, 70.4, 68.3, 61.4, 43.8, 40.3,
39.9, 38.6, 37.8, 36.7, 36.0, 33.1, 30.5, 27.2, 27.0, 26.8, 26.0, 25.6,
24.6, 21.3, 18.3, 18.1, 16.6, 14.6, 14.3, 14.1, -4.1, -4.4; ESI-MS
calcd for C36H68O5S2Si found 672, m/z [M + Na]+ 695; HRMS
(ESI) m/z 695.4175, [M + Na]+ calcd for C36H68O5S2SiNa+
695.4169.
Reduction of Ketone 46 with LiBH4. To a stirring solution of
ketone 46 (85 mg, 0.12 mmol) in THF (5 mL) and MeOH (25 µL)
at 0 °C was added lithium borohydride (300 µL of a 1.0 M soln in
THF, 0.3 mmol) dropwise. After being stirred at 0 °C for 30 min,
the reaction mixture was warmed to 25 °C, maintained at this
temperature for 2 h, and then quenched with water, The aqueous
phase was extracted with Et2O (3 × 5 mL), and the combined
organic phases were washed with brine (5 mL), dried over
anhydrous Na2SO4, and concentrated on the rotary evaporator. The
residue was purified by flash chromatography (hexane/ethyl acetate
20:1 v/v) to afford alcohol 45b (75 mg, 88%) as a colorless oil
and small amounts of 45a.
Aldehyde 49. To a solution of 48 (46 mg, 0.068 mmol) in
CH2Cl2 (6 mL) were added 4 Å MS (29 mg) and NaOAc (5.6 mg,
0.068 mmol). The mixture was cooled to 0 °C, and PCC (44 mg,
0.204 mmol) was added. The resulting solution was stirred for 24
h at 0 °C and diluted with petroleum ether (12 mL). The resulting
precipitate was removed by filtration, and the filtrate was concen-
trated. The residue was purified by flash chromatography (hexane)
to afford 49 (44 mg, 96%) as a colorless oil: Rf (hexane/ethyl
Reduction of Ketone 46 Using (S)-54. To a solution of ketone
46 (64 mg, 0.09 mmol) and (S)-5431d (900 µL of a 0.2 M soln in
THF, 0.18 mmol) in THF (2 mL) was added borane-dimethyl
sulfide (100 µL of a 2.0 M soln in THF, 0.20 mmol) at 15 °C. The
acetate 15:1 v/v) 0.42; [R]20D +28.6 (c 1.15 CHCl3); IR (neat, cm-1
)
ν 2934, 1740, 1641, 1463, 1372, 1236, 1040; 1H NMR (300 MHz,
CDCl3) δ 9.62 (d, J ) 1.8 Hz, 1H), 5.47 (d, J ) 10.1 Hz, 1H),
4.82 (s, 1H), 4.77 (s, 1H), 4.05 (m, 1H), 3.88 (m, 2H), 3.05 (m,
4634 J. Org. Chem., Vol. 71, No. 12, 2006

Total Synthesis of Amphidinolide T3
2H), 2.92 (d, J ) 13.0 Hz, 1H), 2.66 (d, J ) 14.2 Hz, 1H), 2.51(d,
J ) 14.6 Hz, 1H), 2.36-2.20 (m, 4H), 2.08 (s, 3H), 2.10-1.72
(m, 10H), 1.45-1.26 (m, 10H), 1.10 (d, J ) 7.0 Hz, 3H), 1.04
(d, J ) 6.3 Hz, 3H), 0.90 (s, 15H), 0.09 (s, 3H), 0.07 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 205.1, 170.7, 145.11, 114.3, 81.2,
74.9, 71.9, 70.4, 61.3, 46.2, 43.8, 40.2, 39.8, 38.6, 37.7, 36.0,
30.5, 27.2, 26.82, 26.8, 26.0, 21.2, 18.3, 18.1, 14.5, 14.2, 14.1, 13.3,
-4.1, -4.5; ESI-MS calcd for C36H66O5S2Si found 670, m/z [M +
Na]+ 693; HRMS (ESI) m/z 693.4019 [M + Na]+, calcd for
C36H66O5S2SiNa+ 693.4013.
3.92 (m, 1H), 3.81 (m, 1H), 3.01-2.88 (m, 3H), 2.78-2.69 (m,
2H), 2.46 (m, 1H), 2.30-1.80 (m, 12 H), 1.68 (m, 1H), 1.58-1.27
(m, 11H), 1.18 (d, J ) 7.1 Hz, 3H), 1.16 (d, J ) 5.8 Hz, 3H),
0.96-0.91 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 180.5, 145.7,
113.6, 81.4, 77.2, 74.5, 69.4, 62.5, 44.6, 40.5, 39.9, 39.1, 38.3, 38.0,
35.7, 33.5, 30.1, 29.7, 27.2, 26.6, 25.7, 24.7, 18.9, 17.0, 15.6, 14.1,
14.0; ESI-MS calcd for C28H50O5S2 found 530, m/z [M - H]- 529;
HRMS (ESI) m/z 553.2997, [M + Na]+ calcd for C28H50O5S2Na+
553.2992.
Macrolactone 53. To a solution of the hydroxyl acid 52 (22.4
mg, 0.042 mmol) in toluene (5 mL) were added 2,4,6-tirchloroben-
zoyl chloride (222 µL, 1.46 mmol) and diisopropylethylamine (444
µL, 2.92 mmol). The mixture was stirred for 12 h at room
temperature. Then, the solution was diluted by addition of toluene
(5 mL) and added by a syringe pump slowly to a solution of DMAP
(192 mg, 1.56 mmol) in toluene (110 mL) at 45 °C over 12 h. The
reaction was stirred for an additional 10 h at 45 °C and quenched
with saturated aqueous NH4Cl (50 mL). The aqueous phase was
extracted with EtOAc (3 × 20 mL). The combined extracts were
washed with brine (30 mL), dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatography
(hexane/ethyl acetate 20:1 v/v) to afford macrolactone 53 (15.4 mg,
70%) as a colorless oil: Rf (hexane/ethyl acetate 8:1 v/v) 0.50;
[R]20D +17.7 (c 0.32 CHCl3); IR (neat, cm-1) ν 3474, 2929, 1725,
1638, 1462, 1054, 899; 1H NMR (300 Hz, CDCl3) δ 5.00 (m, 1H),
4.85 (s, 1H), 4.82 (s, 1H), 4.38 (m, 1H), 4.18 (d, J ) 10.2 Hz,
1H), 4.05 (m, 1H), 3.43 (s, 1H), 3.08-2.99 (m, 2H), 2.78-2.67
(m, 3H), 2.47-1.76 (m, 13 H), 1.63 (m, 11H), 1.15 (d, J ) 7.1
Hz, 3H), 1.14 (d, J ) 6.4 Hz, 3H), 0.93-0.88 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 175.8, 144.1, 114.7, 77.7, 75.3, 73.1, 72.1,
63.3, 39.9, 39.6, 39.1, 38.5, 37.9, 36.9, 36.2, 35.3, 32.7, 27.0, 26.9,
25.7, 24.9, 24.5, 18.6, 17.2, 15.2, 14.8, 14.1; ESI-MS calcd for
C28H48O4S2 found 512, m/z [M + Na]+ 535; HRMS (ESI) m/z
535.2886, [M + Na]+ calcd for C28H48O4S2Na+ 535.2886.
Amphidinolide T3. A solution of macrolactone 53 (15 mg, 0.03
mmol) in MeOH/H2O (2.75 mL, 10:1) was cooled to 0 °C and
treated with PhI (O2CCF3)2 (24 mg, 0.06 mmol). After 15 min, the
reaction was diluted with Et2O (20 mL) and quenched with saturated
aqueous NaHCO3 (5 mL). The organic phase was separated, washed
with brine (5 mL), dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
(hexane/ethyl acetate 30:1 v/v) to afford synthetic amphidinolide
T3 (10.1 mg, 82%) as a colorless oil: Rf (hexane/ethyl acetate 8:1
v/v) 0.28; [R]20D -39.9 (c 0.16 CHCl3) (lit.4j [R]20D -40.0 (c 0.075
CHCl3); IR (neat, cm-1) 3450, 2932, 1729; 1H NMR (500 Hz, C6D6)
δ 5.19 (m, 1H), 4.87 (m, 1H), 4.85 (m, 1H), 4.51 (d, J ) 2.8 Hz,
1H), 4.37 (dt, J ) 9.2, 2.8 Hz, 1H), 4.04 (ddd, J ) 10.6, 7.9, 2.8
Hz, 1H), 3.78 (dt, J ) 10.0, 3.8 Hz, 1H) 3.53 (m, 1H), 2.60 (dd,
J ) 13.4, 5.4 Hz, 1H), 2.55 (dd, J ) 13.4, 5.4 Hz, 1H), 2.44 (m,
1H), 2.16 (dd, J ) 13.5, 8.5 Hz, 1H), 1.94 (dt, J ) 14.5, 2.4 Hz,
1H), 1.87 (dd, J ) 13.5, 8.9 Hz, 1H), 1.77-1.20 (m, 15H), 1.67
(dt, J ) 14.8, 7.8 Hz, 1H), 1.13 (d, J ) 6.6 Hz, 3H), 1.12 (d, J )
7.0 Hz, 3H), 0.86 (t, J ) 7.6 Hz, 3H), 0.67 (d, J ) 7.0 Hz, 3H);
13C NMR (125 MHz, C6D6) δ 215.7, 174.8, 143.3, 114.7, 79.2,
76.2, 76.1, 72.1, 41.4, 41.2, 40.6, 39.9, 39.3, 38.4, 36.3, 35.9, 34.6,
29.7, 26.5, 26.5, 18.8, 17.7, 15.5, 14.2, 14.1; ESI-MS calcd for
C25H42O5 found 422, m/z [M + Na]+ 445; HRMS (ESI) m/z
445.2930 [M + Na]+ calcd for C25H42O5Na+ 445.2925.
Acid 50. To a solution of silver nitrate (41.4 mg, 0.244 mmol)
in water (1.6 mL) cooled to 0 °C was added a solution of aldehyde
49 (69 mg, 0.103 mmol) in THF (3.2 mL) followed by a solution
of NaOH (1.6 mL of a 0.3 M soln in water) over a period of 5
min. The mixture was stirred intensively for 1.5 h at 0 °C, and the
deposited silver was filtered off and washed with water. The filtrate
was cooled and acidified with aq HCl (1.0 M) to pH ) 5. The
mixture was extracted with Et2O (3 × 6 mL). The combined extracts
were washed with brine (5 mL), dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (hexane/ethyl acetate 5:1 f 3:1 v/v) to afford acid
50 (57.6 mg, 81%) as a colorless oil: Rf (hexane/ethyl acetate 2:1
v/v) 0.53; [R]24 +22.7 (c 1.27 CHCl3); IR (neat, cm-1) ν 2926,
D
1
1741, 1708, 1640, 1463, 1372, 1235, 1040, 836; H NMR (300
MHz, CDCl3) δ 5.48 (d, J ) 10.1 Hz, 1H), 4.83 (s, 1H), 4.77 (s,
1H), 4.06 (m, 1H), 3.88 (m, 2H), 3.05 (m, 2H), 2.92 (d, J ) 13.2
Hz, 1H), 2.66 (d, J ) 13.8 Hz, 1H), 2.55-2.42 (m, 2H), 2.36-
2.21 (m, 3H), 2.09 (s, 3H), 2.08-1.69 (m, 10H), 1.45-1.26 (m,
10H), 1.18 (d, J ) 7.2 Hz, 3H), 1.04 (d, J ) 6.2 Hz, 3H), 0.90 (s,
15H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
182.4, 170.8, 145.1, 114.4, 81.3, 75.0, 71.9, 70.4, 61.3, 43.8, 40.3,
39.9, 39.3, 38.6, 37.7, 36.6, 36.0, 33.5, 30.4, 27.4, 26.7, 26.0, 25.7,
24.7, 21.3, 18.4, 18.1, 14.6, 14.3, 14.1, -4.1, -4.4; MALDI-MS
calcd for C36H66O6S2Si found 686, m/z [M + H]+ 687; HRMS
(MALDI) m/z 709.4078, [M + Na]+ calcd for C36H66O6S2SiNa+
709.4083.
Hydroxyl Acid 52. To a solution of 50 (55 mg, 0.08 mmol) in
THF (3 mL) was added HF‚Py complex (3.2 mL of a 1.0 M soln
in THF, 3.2 mmol) at room temperature. The mixture was stirred
for 24 h and quenched with ice-water (6 mL). The resulting
mixture was diluted with Et2O (30 mL). The organic phase was
successively washed with saturated aqueous NaHCO3 (5 mL) and
brine (5 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography (hexane/
ethyl acetate 3:1 f 1: 1 v/v) to afford alcohol 51 (43 mg, 94%) as
a colorless oil: Rf (hexane/ethyl acetate 1:1 v/v) 0.47; [R]24D +29.7
(c 0.95 CHCl3); IR (neat, cm-1) ν 3424, 3072, 2927, 1738, 1709,
1642, 1463, 1373, 1222, 733; 1H NMR (300 MHz, CDCl3) δ 5.46
(d, J ) 10.8 Hz, 1H), 4.91 (s, 1H), 4.88 (s, 1H), 4.04 (m, 1H),
3.86 (m, 2H), 3.08-3.00 (m, 3H), 2.65 (d, J ) 14.1 Hz, 1H), 2.53-
2.45 (m, 2H), 2.34-2.24 (m, 2H), 2.16 (d, J ) 6.3 Hz, 1H), 2.09
(s, 3H), 2.08-1.69 (m, 10H), 1.48-1.28 (m, 13H), 1.18 (d, J )
6.9 Hz, 3H), 1.07 (d, J ) 5.2 Hz, 3H), 0.96-0.89 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 181.2, 170.8, 145.4, 113.8, 81.1, 74.9,
71.8, 69.4, 61.3, 44.5, 40.6, 39.8, 39.2, 39.0, 38.1, 36.6, 36.0, 33.6,
30.3, 27.3, 26.5, 25.7, 24.7, 21.3, 18.8, 16.9, 15.0, 14.2, 14.1; ESI-
MS calcd for C30H53O6S2 found 572. m/z [M + Na]+ 595; HRMS
(ESI) m/z 573.3279, [M + H]+ calcd for C30H53O6S2H+ 573.3278.
To a solution of acid 51 (42 mg, 0.073 mmol) in MeOH/H2O (3
mL, 5:1) was added hydrate LiOH (30 mg, 0.71 mmol). After the
mixture was warmed to 40-50 °C and stirred for 12 h, 1 M HCl
was added and acidified to pH ) 5. The mixture was extracted
with Et2O (3 × 5 mL). The combined extracts were washed with
brine (5 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography (hexane/
ethyl acetate 3:2 v/v) to afford 52 (37 mg, 95%) as a colorless oil:
Rf (hexane/ethyl acetate 1:1 v/v) 0.36; [R]20D +26.9 (c 0.31 CHCl3);
Acknowledgment. We are grateful to the National Natural
Science Foundation of China for financial support (Nos.
20525208, 20532040, 20390057, and 20372072), the QT pro-
gram, and the Shanghai Natural Science Council.
Supporting Information Available: Experimental general
1
information, procedures, and H NMR and 13C NMR spectra for
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
IR (neat, cm-1) ν 3443, 2935, 1708, 1642; H NMR (300 Hz,
CDCl3) δ 4.90 (s, 2H), 4.31 (m, 1H), 4.19 (d, J ) 10.1 Hz, 1H),
JO0605086
J. Org. Chem, Vol. 71, No. 12, 2006 4635