Total synthesis of trifluoromethylated analogs of macrosphelide A

Article abstract of DOI:10.1016/j.tet.2007.10.019

Trifluoromethylated analogs of macrosphelide A 1 and 2 were designed and synthesized. The key segment 6 was efficiently constructed via a series of high stereoselective transformations from trifluoromethylated diol 8. Methoxymethylation of compound 9 with

Full text of DOI:10.1016/j.tet.2007.10.019

Tetrahedron 63 (2007) 12671–12680
Total synthesis of trifluoromethylated analogs of macrosphelide A
Bing-Lin Wang,a Zhong-Xing Jiang,a Zheng-Wei Youa and Feng-Ling Qinga,b,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
bInstitute of Biological Sciences and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
Received 28 July 2007; revised 30 September 2007; accepted 2 October 2007
Available online 6 October 2007
Abstract—Trifluoromethylated analogs of macrosphelide A 1 and 2 were designed and synthesized. The key segment 6 was efficiently
constructed via a series of high stereoselective transformations from trifluoromethylated diol 8. Methoxymethylation of compound 9 with
1.0 equiv of sodium hydride gave optically pure compound 23a in 73% yield. From 23a a novel route was developed to prepare key segment
7. The condensation and macrolactonization were smoothly proceeded under our modified Keck’s protocol.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Macrosphelide A (Fig. 1), isolated from the Macrosphaero-
psis sp. FO-5050 by the Omura group, strongly inhibit the
adhesion of human leukemia HL-60 cells to human umbili-
cal-vein endothelial cells (HUVEC) in a dose-dependent
manner.7 The total synthesis of macrosphelide A has been
reported by several groups.8 Furthermore, macrosphelide
A served as a lead compound for the development of new
anti-cancer drugs.9 In view of strong electron-withdrawing
character and large hydrophobic parameter of trifluoro-
methyl (CF3) group,10 we were interested in the replacement
of methyl group of macrosphelide A by trifluoromethyl
group. Herein we report on the total synthesis of trifluoro-
methylated macrosphelide A 1 and 2 (Fig. 1).
Currently more than half of the prescription drugs are of
natural product origin1 and the expectations from combinato-
rial libraries in drug screening have not been realized.2
Therefore, the natural product-inspired drug discovery and
development has received renewed attention in recent years.2
The synthesis of natural products’ analogs by removing sus-
pected sites of toxicity or by introducing additional structural
features may enhance potency or stability of natural medi-
cines. The most versatile approach to analogs preparation is
the design of a synthetic route to a given natural product
that allow for the introduction of deep-seated structural vari-
ations en route to the target molecule, termed by Danishefsky
et al. as diverted total synthesis.3 The interest of fluorinated
analogs of natural products is increasing continuously, be-
cause the incorporation of fluorine atom(s) or fluoroalkyl
groups may greatly modify the chemical properties and bio-
logical activities of those molecules.4,5 A notable recent ex-
ample is diverted total synthesis of trifluoromethylated
analog of epothilone B: ‘fludelone’.6 Fludelone shows an ex-
tremely high therapeutic efficacy against various carcinomas.
2. Results and discussion
To explore a flexible synthetic strategy not only for trifluoro-
methylated macrosphelide A 1 and 2, but also for various
analogs of macrosphelide for in-depth investigation of the
structure–activity relationship, a convergent route to 1
and 2 was designed as shown in Scheme 1. Key elements
O
Me
O
O
CF3
Me
O
O
CF3
Me
OH
OH
OH
O
O
O
8
HO
Me
HO
HO
Me
O
Me
14
O
O
O
F3C
O
O
O
1
O
O
O
1
2
Macrosphelide A
Figure 1.
Keywords: Asymmetric synthesis; Keck reaction; Kinetic resolution; Macrosphelide A; Trifluoromethyl group.
* Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128; e-mail: flq@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.019

12672
B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
O
O
CF3
O
O
CF3
OH
OP1
O
O
HO
R
P1O
R
CH3
O
CH3
CO2P
O
O
O
OTBS
R = CH3, 3
R = CF3, 4
R = CF3, 1
R = CH3, 2
OP2
CH3
CO2P
HO2C
+
R
OTBS
OP1
R = CF3
R = CF3, 6
R = CH3, 7
5
R = CH3
O
OH
OH
F3C
OBn
OH
8
O
9a
Scheme 1.
of this approach include efficient construction of the stereo-
centers, suitable choice of protection groups, and sequential
coupling of the fragments followed by macrolactonization.
Trifluoromethylated building block 6 is central moiety for
the synthesis of target molecules 1 and 2. We envisioned
that trifluoromethylated a,b-unsaturated ester 6 would be
prepared from trifluoromethylated diol 8 via inversion of hy-
droxy configuration and lengthening of terminal carbon. The
common intermediate 7 for target molecule 2 and other con-
geners of macrosphelide was expected to be derived from
chiral alcohol 9a. The third fragment, acid 5, can be prepared
according to the published procedures.11
then acidic hydrolysis gave compound 11 in 97% yield.
The resulting hydroxy group was protected as a methoxy-
methyl (MOM) ether, 12, in 95% yield. Hydrogenation
of compound 12 for the cleavage of the benzyl group fol-
lowed by treatment with tert-butyldimethylsilyl chloride
and imidazole afforded the tert-butyldimethylsilyl (TBS)
ether 13 in quantitative yield. Removal of the benzoyl group
of 13 with DIBAL-H in CH2Cl2 at ꢀ78 ꢁC produced alcohol
14, which was benzylated to give benzyl ether 15. Removal
of TBS of compound 15 followed by Swern oxidation of the
resulting alcohol and then Wittig reaction gave the desired
fragment 6 in 82% yield over three steps.
Our synthesis commenced with the preparation of the tri-
fluoromethylated a,b-unsaturated ester 6 (Scheme 2). We
have developed an efficient and practical route to diol 8 in
high enantioselectivity (99% ee) by Sharpless asymmetric
dihydroxylation of trifluoromethylated olefin.12 The inver-
sion of a hydroxy configuration was based upon the regiose-
lective and stereoselective nucleophilic ring opening of the
trifluoromethylated cyclic sulfate recently developed in our
laboratory.13 Treatment of the vicinal diol 8 with SOCl2 fol-
lowed by oxidation with RuO4 (generated in situ from
NaIO4/catalytic RuCl3) provided cyclic sulfate 10 in 91%
yield. The regioselective and stereoselective nucleophilic
ring opening of the cyclic sulfate 10 with PhCO2NH4 and
With the key fragment 6 in hand, we embarked on the syn-
thesis of target molecule 1 as shown in Scheme 3. Selective
cleavage of trichloroethyl ester 6 gave the acid 16 in 84%
yield,14 whereas desilylation generated the alcohol 17 in
95% yield. At this point, we focused our efforts on the
coupling of 16 and 17. The condensation of carboxylic acids
and alcohols via Keck protocol15 had been successfully used
in total synthesis of macrosphelide A.8a–c,8k Unfortunately,
the coupling of 16 and 17 by esterification employing the
Keck procedure (the addition of the solution of 16 and 17
in CH2Cl2 to the solution of DCC/DMAP in CH2Cl2 at
room temperature) failed to give the desired product 18,
but the dehydrated product of alcohol 17 was isolated. In
O
O
1) SOCl2, Et3N, CH2Cl2, 0 °C
2) NaIO4, RuCl3, H2O-CH3CN-CCl4
OH
OH
1) PhCO2NH4, DMF, 80 °C
2) H2SO4, H2O, THF, rt
S
O
O
F3C
OBn
F3C
OBn
91%
97%
OH
8
OBz
11
F3C
OBn
10
1) Pd/C, H2, EtOH
2) TBSCl, imidazole
DMF, rt
MOMCl, iPr2NEt, DMAP
CH2Cl2, reflux
OMOM
OMOM
DIBAL-H, CH2Cl2, -78 °C
quant.
F3C
F3C
OTBS
OBn
95%
99%
OBz
12
OBz
13
1) TBAF, THF, rt
2) (ClCO)2, DMSO, Et3N, CH2Cl2, -78 °C-rt
3) Ph3PCHCO2CH2CCl3, CH2Cl2, rt
OMOM
OMOM
CO2CH2CCl3
F3C
OTBS
F3C
82%
OR
OBn
6
R = H (14)
R = Bn (15)
BnBr, NaH, THF
95%
Scheme 2.

B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
12673
OMOM
CO2H
Zn, Buffer, THF, rt
84%
F3C
F3C
OBn
16
OMOM
DCC, DMAP, CH2Cl2
80%
CO2CH2CCl3
F3C
OH
OBn
6
TFA, CH2Cl2, rt
95%
CO2CH2CCl3
OBn
17
CH3
O
CF3
O
O
CF3
HO2C
OTBS
5
OBn
OBn
O
TFA, CH2Cl2, rt
95%
BnO
F3C
DCC, DMAP, CH2Cl2
80%
BnO
F3C
CO2CH2CCl3
CO2CH2CCl3
OMOM
18
OH
19
O
O
CF3
CH3
O
CF3
1) TFA, CH2Cl2, rt
2) Zn, Buffer, THF, rt
OBn
OBn
O
O
BnO
F3C
BnO
F3C
80%
O
CH3
CO2CH2CCl3
CO2H
O
O
OTBS
OH
4
20
Scheme 3.
O
O
CF3
O
O
CF3
our opinion, the failure of condensation was attributed to the
fact that the acidity of hydroxy group of compound 17 was
enhanced greatly by the adjacent trifluoromethyl, which
made alcohol 17 to react with DCC prior to acid 16 and
led to dehydration. We envisioned that the first activation
of carboxylic acid 16 and the condensation at low tempera-
ture should furnish our desired product. To our delight, treat-
ment of 16 with DCC/DMAP at 0 ꢁC followed by addition of
alcohol 17 produced compound 18 in 80% yield. Subsequent
removal of MOM group afforded alcohol 19 in 95% yield.
The condensation of 19 and 5 via Keck procedures also
failed to provide compound 4. When the reaction conditions
of the formation of 19 were used for the coupling of 19 and 5,
the desired product 4 was isolated in 80% yield. Removal of
the TBS and 2,2,2-trichloroethyl groups of compound 4
provided seco acid 20.
OBn
OH
O
O
O
BCl3, CH2Cl2, -40 °C
BnO
F3C
HO
F3C
CH3
CH3
O
90%
O
O
O
O
21
1
Scheme 4.
As outlined in Scheme 1, compound 7 was another key
intermediate for the completion of the synthesis of trifluoro-
methylated macrosphelide A 2. Although several groups
have reported the preparation of fragment 7 for total syn-
thesis of macrosphelide A,8a–h,8k we sought another prac-
tical method for accessing the key intermediate 7. The
preparation of 9a in an optically active fashion was key
Yamaguchi’s macrolactonization protocol16 had been suc-
cessfully used for macrolactone construction of macrosphe-
lide.8a–h,8k However, all attempts on macrolactonization of
seco acid 20 under the conditions of Yamaguchi failed.
The change of reaction conditions such as solvent and reac-
tion temperature had no pronounced beneficial effect on the
reaction outcome (Table 1, entries 1–5). 19F NMR spectra of
the reaction mixture showed that the reaction was complex
and elimination reaction took place. The mild reaction con-
ditions without strong base such as Et3N was expected to
avoid the side reaction. Therefore, the macrolactonization
of seco acid 20 under the conditions of Keck15 was investi-
gated. Although treatment of seco acid 20 with typical
Keck’s conditions (at reflux in CHCl3) still resulted in a com-
plex mixture (Table 1, entry 6), the reaction was proceeded
at 25 ꢁC to give the desired product 21 in 30% yield (Table
1, entry 7). We were pleased to find that the isolated yield of
compound 21 was improved to 50% when the reaction
temperature was lowered to 0 ꢁC (Table 1, entry 8). Finally,
deprotection of the Bn groups of 21 with BCl3 in CH2Cl2 af-
forded the trifluoromethylated macrosphelide A 1 in 90%
yield (Scheme 4).
Table 1. Macrolactionization of compound 20
O
CF3
O
O
CF3
OBn
OBn
O
O
O
Conditions
BnO
F3C
BnO
F3C
O
CH3
CH3
O
CO2H
O
O
OH
20
21
Entry Conditions
Yield
1
2
3
4
5
(a) 21, 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, rt Complex
(b) DMAP, toluene, reflux
(a) 21, 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, rt Complex
(b) DMAP, benzene, reflux
(a) 21, 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, rt Complex
(b) DMAP, benzene, 40 ꢁC
(a) 21, 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, rt Complex
(b) DMAP, toluene, 25 ꢁC
(a) 21, 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, rt Complex
(b) DMAP, Toluene, 0 ꢁC
6
7
8
9
DCC, DMAP, DMAP$HCl, CHCl3, reflux
DCC, DMAP, DMAP$HCl, CHCl3, 25 ꢁC
DCC, DMAP, DMAP$HCl, CHCl3, 0 ꢁC
DCC, DMAP, DMAP$HCl, CHCl3, ꢀ10 ꢁC
Complex
30%
50%
35%

12674
B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
OMOM
OMOM
i-Pr2NEt, MOMCl
CH2Cl2
+
O
O
O
O
O
O
85%
R1 R2
O
CH3MgBr
85%
23a
23b
OH
H
O
O
OMOM
+
O
O
1.0 eq NaH
MOMCl,THF
22
R1=OH, R2=H (9a)
R1=H, R2=OH (9b)
9a : 9b = 3.3 : 1
O
O
23a
9
Scheme 5.
step for preparation of 7 (Scheme 1). We anticipated that
compound 7 could be made from the nucleophilic addition
of methyl metal reagent to 1-(R)-glyceraldehyde acetonide
22. Accordingly, treatment of 22 with MeMgBr provided
predominantly the desired anti-adduct 9a (9a/9b¼3.3:1,
acid (TCCA) and catalytic amounts of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO),19 and then Wittig reaction
gave the desired fragment 7 in 70% yield over three steps.
With three coupling partners in hand and our experience in
total synthesis of the target molecule 1, the synthesis of
trifluoromethylated macrosphelide A 2 proceeded in a
straightforward manner (Scheme 6). Selective cleavage of
trichloroethyl ester 7 provided acid 26 in 85% yield. The
condensation of 26 with alcohol 17 using our modified
Keck’s procedure gave compound 27 in 40% yield. Removal
of MOM group of 27 afforded alcohol 28 in 90% yield. The
coupling 28 with 5 produced compound 29 in 62% yield.
Removal of the TBS and 2,2,2-trichloroethyl groups of 29
gave seco acid 30. To our delight, our modified Keck’s
protocol in synthesis of compound 21 smoothly promoted
the macrolactonation of seco acid 30 to afford macrolactone
31 in 55% yield, which was then subjected to BCl3 in
CH2Cl2 at ꢀ40 ꢁC to give the desired trifluoromethylated
macrosphelide A 2.
1
determined by H NMR) (Scheme 5).17 However, the two
diastereomers could not be separated by column chromato-
graphy. Protection of the hydroxy group of 9 with
MOMCl/iPr2NEt provided methoxymethyl ethers 23a and
23b, which were still very difficult to be separated. Enlight-
ened by our previous work,18 epimerization of compound 9
in the methoxymethylation under different equivalents of
sodium hydride was investigated. To our delight, a kinetic
resolution was discovered and reactivity of 9a seemed to
be much more active than that of 9b. The single 23a was
obtained by controlling the amount of sodium hydride.
When 1.0 equiv of sodium hydride was used in the methoxy-
methylation of 9, compound 23a was isolated in 73% yield
along with 15% recovered 9.
Acidic hydrolysis of the isopropylidene group of 23a with
75% acetic acid followed by the selective protection of pri-
mary hydroxy group with TBSCl gave 24, which was further
benzylated to provide compound 25 (Scheme 6). Removal of
TBS of compound 25 followed by oxidation of the resulting
alcohol in the presence of excessive trichloroisocyanuric
In conclusion, we accomplished the total synthesis of
trifluoromethylated macrosphelide A 1 and 2. Our approach
integrated highly effective asymmetric reaction to generate
key chiral trifluoromethylated building block 6, a novel
route to common intermediate 7 via a kinetic resolution in
methoxymethylationofalcohol9andelaboratemanipulations
1) TBAF
OMOM
OMOM 2) TCCA, TEMPO
3) Ph3PCHCO2CH2CCl3, CH2Cl2, rt
1) 75% AcOH, r.t.
2) TBSCl, 0 °C
O
TBSO
70%
O
75%
RO
R = H (24)
R = Bn (25)
NaH, BnBr, THF
92%
23a
O
CF3
OBn
OBn
DCC, DMAP
DCC, DMAP
O
5, CH2Cl2
17, CH2Cl2
BnO
Me
CO2R
40%
62%
OMOM
CO2CH2CCl3
OR
R = CH2CCl3 (7) Zn, Buffer, THF
R = H (26)
R = MOM (27) TFA, CH2Cl2, rt
85%
R = H (28)
90%
O
O
CF3
O
O
CF3
OR
.
OBn
DCC, DMAP, DMAP HCl
CHCl3, 0 °C
O
O
BnO
Me
RO
Me
Me
Me
55%
CO2R2
OR1
O
O
O
O
R1=TBS, R2 =CH2CCl2 (29)
R1=R2 =H (30)
1) TFA, CH2Cl2, rt
2) Zn, Buffer, THF, rt
80%
R = Bn (31)
R = H (2)
BCl3, CH2Cl2, -40 °C
80%
Scheme 6.

B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
12675
of protection groups. Notably the unexpected side reactions
in coupling reactions and macrolactonization werewell over-
come under our improved reaction conditions. The synthesis
of other trifluoromethylated analogs of macrosphelide and
their biological evaluation are in progress in our group.
anhydrous Na2SO4. After filtration and removal of the sol-
vent, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate¼10:1) to afford 13
(3.54 g, 99%) as a clear oil. [a]2D0 +20.7 (c 0.600, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.05 (dd, J¼7.5, 1.5 Hz,
2H), 7.58 (t, J¼7.5 Hz, 1H), 7.46 (t, J¼7.5 Hz, 2H), 5.40–
5.44 (m, 1H), 4.86 (d, J¼6.6 Hz, 1H), 4.77 (d, J¼6.6 Hz,
1H), 4.41–4.50 (m, 1H), 4.00 (d, J¼4.5 Hz, 2H), 3.45 (s,
3H), 0.87 (s, 9H), 0.03 (s, 6H); 19F NMR (282 MHz,
CDCl3) d ꢀ73.51 (d, J¼6.2 Hz); IR (thin film) nmax 2957,
1730, 1276 cmꢀ1; MS (EI) m/z 423 (M++1, <1), 45 (100).
Anal. Calcd for C19H29O5F3Si: C, 54.01; H, 6.92. Found:
C, 54.33; H, 6.49.
3. Experimental section
3.1. General information
All reagents were used as received from commercial sour-
ces, unless specified otherwise, or prepared as described in
the literature. Reactions requiring anhydrous conditions
were performed in vacuum heat-dried glassware under nitro-
gen atmosphere. Reaction mixtures were stirred magneti-
3.4. (2R,3R)-1-(tert-Butyldimethylsilyloxy)-4,4,4-
trifluoro-3-(methoxymethoxy)butan-2-ol (14)
1
cally. H NMR and 13C NMR spectra were recorded on
To a solution of 13 (2.66 g, 6.3 mmol) in CH2Cl2 (40 mL) at
ꢀ78 ꢁC was added DIBAL-H (10 mL, 1.0 M in hexane,
10 mmol) dropwise. After stirring for 1.5 h, the reaction
was quenched with saturated Rochelle’s salt (20 mL) at
ꢀ78 ꢁC. Warming up to room temperature, the mixture
was stirred for 1 h. The aqueous phase was extracted with
CH2Cl2, and the combined organic layers were dried over
Na2SO4. After filtration and removal of the solvent in vacuo,
the residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼20:1) to provide 14
(2.03 g, quant.) as a clear oil. [a]2D0 ꢀ3.90 (c 0.850,
CHCl3); 1H NMR (300 MHz, CDCl3) d 4.72–4.81 (m,
2H), 4.04–4.14 (m, 1H), 3.90–3.96 (m, 1H), 3.67–3.83 (m,
2H), 3.44 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H); 19F NMR
(282 MHz, CDCl3) d ꢀ73.83 (d, J¼7.5 Hz); IR (thin film)
nmax 3500, 2934, 1271 cmꢀ1; MS (EI) m/z 319 (M++1,
<1), 45 (100). Anal. Calcd for C12H25O4F3Si: C, 45.26; H,
7.91. Found: C, 45.45; H, 8.01.
a Bruker AM300 spectrometer. 19F NMR was recorded on
a Bruker AM300 spectrometer (FCCl3 as outside standard
and low field is positive). Chemical shifts (d) are reported
in parts per million, and coupling constants (J) are in Hertz.
The following abbreviations were used to explain the multi-
plicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼
multiplet.
3.2. (2R,3R)-1-(Benzyloxy)-4,4,4-trifluoro-3-(methoxy-
methoxy)butan-2-yl benzoate (12)
To a solution of 11 (3.19 g, 9.0 mmol) and (iPr)2NEt (2.07 g,
18 mmol) in CH2Cl2 (50 mL) was added MOMCl (1.46 g,
18 mmol). After stirring at reflux for 30 h, the reaction mix-
ture was quenched with saturated NaHCO3 solution. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate¼30:1) to afford 12 (3.37 g,
95%) as a clear oil. [a]2D0 +18.4 (c 0.370, CHCl3); 1H
NMR (300 MHz, CDCl3) d 8.07 (dd, J¼7.5, 1.5 Hz, 2H),
7.6 (t, J¼7.5 Hz, 1H), 7.47 (t, J¼7.5 Hz, 2H), 7.28–7.32
(m, 5H), 5.57–5.61 (m, 1H), 4.81 (d, J¼6.9 Hz, 1H), 4.75
(d, J¼6.9 Hz, 1H), 4.61 (d, J¼12.3 Hz, 1H), 4.55 (d, J¼
12.3 Hz, 1H), 4.45–4.50 (m, 1H), 3.85–3.91 (m, 2H), 3.41
(s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.42 (d, J¼
7.8 Hz); IR (thin film) nmax 2905, 1728, 1275 cmꢀ1; MS
(EI) m/z 399 (M++1, <1), 91 (100). Anal. Calcd for
C20H21O5F3: C, 60.30; H, 5.31. Found: C, 60.54; H, 5.18.
3.5. ((2R,3R)-2-(Benzyloxy)-4,4,4-trifluoro-3-(methoxy-
methoxy)butoxy)(tert-butyl)dimethylsilane (15)
To a suspension of NaH (378 mg, 0.19 mol) in THF (20 mL)
at 0 ꢁC was added a solution of alcohol 14 (2.03 g, 6.3 mol)
in THF (5 mL). After the mixture was stirred for about 1 h,
Bu4NI (0.28 g, 0.63 mmol) and BnBr (1.28 g, 7.6 mol) were
added. After stirring at room temperature for 5 h, the reac-
tion mixture was diluted with Et2O (20 mL), washed with
water, brine, and dried over anhydrous Na2SO4. Filtration
and removal of the solvent provided the compound 15
(2.44 g, 95%) as a clear oil. [a]2D0 +6.10 (c 1.05, CHCl3);
1H NMR (300 MHz, CDCl3) d 7.28–7.37 (m, 5H), 4.81 (d,
J¼6.6 Hz, 1H), 4.73 (d, J¼6.6 Hz, 1H), 4.70 (d, J¼2.7 Hz,
2H), 4.22–4.25 (m, 1H), 3.78–3.90 (m, 3H), 3.41 (s, 3H),
0.91 (s, 9H), 0.07 (s, 6H); 19F NMR (282 MHz, CDCl3)
d ꢀ73.37 (d, J¼7.3 Hz); IR (thin film) nmax 2932, 1473,
1363, 1258 cmꢀ1; MS (EI) m/z 407 (M+ꢀ1, <1), 91 (100).
Anal. Calcd for C19H31O4F3Si: C, 55.86; H, 7.65. Found:
C, 56.23; H, 7.56.
3.3. (2R,3R)-1-(tert-Butyldimethylsilyloxy)-4,4,4-
trifluoro-3-(methoxymethoxy)butan-2-yl benzoate (13)
A suspension of 10% palladium on charcoal (674 mg) and
12 (3.37 g, 8.6 mmol) in EtOH (40 mL) was stirred under
a hydrogen atmosphere for 10 h. Filtration of the mixture
and removal of the solvent in filtrate in vacuo gave a residue,
which was used without further purification. To a 0 ꢁC solu-
tion of the above residue and DMAP (110 mg, 0.9 mmol) in
DMF (10 mL) was added imidazole (1.17 g, 17.2 mmol) fol-
lowed by TBDMSCl (1.94 g, 12.9 mmol). Then, the mixture
was warmed to room temperature and stirred for 8 h. EtOAc
(40 mL) was added and the resulting mixture was washed
with brine twice. The organic phase was dried over
3.6. (4R,5R,Z)-2,2,2-Trichloroethyl 4-(benzyloxy)-
6,6,6-trifluoro-5-(methoxymethoxy)hex-2-enoate (6)
To an ice-cold solution of 15 (2.03 g 4.8 mmol) in THF
(20 mL) was added a solution of TBAF (4.8 mL, 1.0 M in
THF, 4.8 mmol) dropwise. After the mixture was warmed

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B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
to room temperature, the reaction was stirred for 1 h. Filtra-
tion of the mixture and removal of the solvent in filtrate in
vacuo gave a residue, which was used in next step without
further purification. To a solution of dimethyl sulfoxide
(1.74 g, 19.2 mmol) in CH2Cl2 (30 mL) was added a solution
of oxalyl chloride (1.23 g, 9.6 mmol) in CH2Cl2 (10 mL) at
ꢀ78 ꢁC. After continuous stirring for 30 min, the above
residue was added dropwise to the solution. After 1 h,
Et3N (4.70 mL, 38.7 mmol) was added and the mixture
was warmed to 0 ꢁC, and stirred for 2 h. Then,
Ph3PCHCO2CH2CCl3 (3.25 g, 7.20 mmol) was added at
0 ꢁC. Warming up to room temperature, the mixture was
stirred overnight. Et2O (20 mL) was added and the resulting
mixture was washed with water and brine, and dried
over Na2SO4. After filtration and removal of the solvent in
vacuo, the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate¼10:1) to give es-
ter 6 (2.12 g, 82%) as a clear oil. [a]2D0 +24.6 (c 0.950,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.32–7.38 (m,
5H), 7.12 (dd, J¼15.6, 6.3 Hz, 1H), 6.05 (d, J¼15.6 Hz,
1H), 4.76–4.90 (m, 4H), 4.51–4.62 (m, 2H), 4.27–4.35 (m,
2H), 3.40 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.97
(d, J¼7.2 Hz); IR (thin film) nmax 2960, 1741, 1660,
1273 cmꢀ1; MS (EI) m/z 466 (M+, <1), 91 (100). Anal.
Calcd for C17H18O5F3Cl3: C, 43.84; H, 3.89. Found: C,
43.83; H, 3.99.
2H), 4.69 (d, J¼11.7 Hz, 1H), 4.50 (d, J¼11.7 Hz, 1H),
4.31–4.35 (m, 1H), 4.13–4.23 (m, 1H); 19F NMR
(282 MHz, CDCl3) d ꢀ75.33 (d, J¼6.9 Hz); IR (thin film)
nmax 3466, 2876, 1739, 1660, 1272 cmꢀ1; MS (EI) m/z 421
(M+ꢀ1, <1), 91 (100). Anal. Calcd for C15H14O4F3Cl3: C,
42.73; H, 3.47. Found: C, 42.94; H, 3.71.
3.9. (4R,5R,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-
5-((4R,5R,E)-4-(benzyloxy)-6,6,6-trifluoro-5-(methoxy-
methoxy)hex-2-enoyloxy)-6,6,6-trifluorohex-2-enoate
(18)
To a solution of 1,3-dicyclohexylcarbodiimide (DCC)
(1.08 g, 5.2 mmol) and 4-dimethylaminopyridine (DMAP)
(318 mg, 2.61 mmol) in CH2Cl2 (20 mL) was added a solu-
tion of 16 (924 mg, 2.8 mmol) in CH2Cl2 (5 mL) at 0 ꢁC. Af-
ter stirring for 30 min at 0 ꢁC, a solution of 17 (1.10 g,
2.61 mmol) in CH2Cl2 (5 mL) was added dropwise to the
mixture. The solution was stirred for 6 h at room tempera-
ture. After filtration, the filtrate was washed with 1 M aque-
ous HCl and saturated NaHCO3 solution, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate¼20:1) to afford 18 (1.53 g, 80%)
as a clear oil. [a]D20 +30.4 (c 0.675, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.27–7.41 (m, 10H), 6.99–7.10 (m,
2H), 6.24 (dd, J¼16.8, 1.2 Hz, 1H), 6.19 (dd, J¼15.9,
0.9 Hz, 1H), 5.64–5.72 (m, 1H), 4.74–4.87 (m, 4H), 4.49–
4.63 (m, 4H), 4.41–4.45 (m, 1H), 4.24–4.32 (m, 2H), 3.37
(s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.18 (d, J¼
6.2 Hz, 3F), ꢀ74.03 (d, J¼7.1 Hz, 3F); 13C NMR
(75.5 MHz, CDCl3) d 163.50, 163.16, 145.59, 143.48,
136.63, 136.32, 128.63, 128.42, 128.32, 128.06, 127.94,
127.65, 123.90, 124.00, 122.72, 122.51, 97.22, 94.78,
76.19, 75.55, 74.38, 74.08, 71.94, 69.90, 56.45; IR
(thin film) nmax 2963, 2877, 1744, 1661, 1244 cmꢀ1; MS
(ESI) m/z 759 [M+Na]+; HRMS (ESI) calcd for
C30H29O8F6Cl3Na: 759.0724, found: 759.0722.
3.7. (4R,5R,E)-4-(Benzyloxy)-6,6,6-trifluoro-5-
(methoxymethoxy)hex-2-enoic acid (16)
A solution of 6 (240 mg, 0.50 mmol) in THF (3 mL) was
added to a mixture of Zn dust (260 mg, 4.0 mmol) and
AcOH/AcONa buffer (5 mL) in THF (3 mL) at 0 ꢁC. Warm-
ing up to room temperature, the reaction was stirred for 20 h.
The mixture was filtered and the filtrate was acidified with
1 M aqueous HCl and extracted with Et2O. The organic
phase was dried over anhydrous Na2SO4. After filtration
and removal of the solvent, the resulting residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl
acetate¼4:1) to afford 16 (140 mg, 84%) as a clear oil. [a]D20
+33.8 (c 0.801, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.27–7.40 (m, 5H), 7.07 (dd, J¼15.9, 6.0 Hz, 1H), 6.05
(d, J¼15.9 Hz, 1H), 4.81 (d, J¼7.2 Hz, 1H), 4.77 (d, J¼
7.2 Hz, 1H), 4.63 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz,
1H), 4.27–4.33 (m, 2H), 3.41 (s, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ74.01 (d, J¼5.4 Hz); 13C NMR
(75.5 MHz, CDCl3) d 170.68, 144.65. 136.74, 128.58,
128.20, 127.85, 123.89, 124.35, 97.24, 75.15, 71.82,
67.97, 56.47; IR (thin film) nmax 3300, 2906, 1703, 1662,
1272 cmꢀ1; MS (ESI) m/z 357 [M+Na]+; HRMS (ESI) calcd
for C15H17O5F3Na: 357.0920, found: 357.0928.
3.10. (4R,5R,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-
5-((4R,5R,E)-4-(benzyloxy)-6,6,6-trifluoro-5-hydroxy-
hex-2-enoyloxy)-6,6,6-trifluorohex-2-enoate (19)
To a solution of 18 (735 mg, 1.0 mmol) in CH2Cl2 (5 mL)
was added CF3COOH (5 mL). The solution was stirred at
room temperature for 10 h and concentrated. The resulting
oil was purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate¼10:1) to afford 19 (658 mg, 95%)
as a clear oil. [a]D20 +21.7 (c 0.501, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.28–7.43 (m, 10H), 7.16 (dd, J¼
15.9, 5.4 Hz, 1H), 7.11 (dd, J¼16.2, 6.0 Hz, 1H), 6.33 (d,
J¼15.9 Hz, 1H), 6.24 (d, J¼16.2 Hz, 1H), 5.72–5.79 (m,
1H), 4.89 (d, J¼12.3 Hz, 1H), 4.84 (d, J¼12.3 Hz, 1H),
4.69 (d, J¼11.1 Hz, 2H), 4.62 (d, J¼11.1 Hz, 2H), 4.49–
4.54 (m, 1H), 4.30–4.45 (m, 1H), 4.10–4.16 (m, 1H); 19F
NMR (282 MHz, CDCl3) d ꢀ73.26 (d, J¼7.3 Hz, 3F),
ꢀ75.52 (d, J¼6.7 Hz, 3F); 13C NMR (75.5 MHz, CDCl3)
d 163.80, 163.37, 145.70, 143.70, 137.08, 136.45, 128.70,
128.57, 128.46, 128.07, 127.94, 127.83, 124.17, 123.75,
122.72, 122.49, 94.77, 74.78, 74.10, 72.45, 72.23, 72.16,
69.97, 65.93; IR (thin film) nmax 3482, 2876, 1743, 1660,
1247 cmꢀ1; MS (ESI) m/z 715 [M+Na]+; HRMS (ESI) calcd
for C28H25O7F6Cl3Na: 715.0462, found: 715.0452.
3.8. (4R,5R,E)-2,2,2-Trichloroethyl 4-(benzyloxy)-
6,6,6-trifluoro-5-hydroxyhex-2-enoate (17)
To a solution of 6 (700 mg, 1.5 mmol) in CH2Cl2 (10 mL)
was added CF3COOH (3 mL). The solution was stirred at
room temperature for 5 h and concentrated. The resulting
oil was purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate¼10:1) to afford 17 (600 mg, 95%)
as a clear oil. [a]D20 +21.1 (c 0.500, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.35–7.45 (m, 5H), 7.11 (dd, J¼16.5,
7.5 Hz, 1H), 6.05 (dd, J¼16.5, 1.2 Hz, 1H), 4.81–4.89 (m,

B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
12677
3.11. (4R,5R,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-5-
((4R,5R,E)-4-(benzyloxy)-5-((S)-3-(tert-butyldimethyl-
silyloxy)butanoyloxy)-6,6,6-trifluorohex-2-enoyloxy)-
6,6,6-trifluorohex-2-enoate (4)
74.65, 72.01, 71.88, 70.16, 64.51, 42.51, 22.44; IR (thin
film) nmax 3066, 2962, 1745, 1707, 1662, 1272, 982 cmꢀ1
;
MS (ESI) m/z 649 [M+H]+; HRMS (ESI) calcd for
C30H30O9F6Na: 671.1682, found: 671.1686.
To a solution of 1,3-dicyclohexylcarbodiimide (DCC)
(142 mg, 0.69 mmol) and 4-dimethylaminopyridine (DMAP)
(84 mg, 0.69 mmol) in CH2Cl2 (1 mL) was added a solution
of 5 (100 mg, 0.46 mmol) in CH2Cl2 (1 mL) at 0 ꢁC. After
30 min at 0 ꢁC, a solution of 19 (318 mg, 0.46 mmol) was
added dropwise to the mixture. The solution was stirred
for 6 h at room temperature. The mixture was filtered and
the filtrate was washed with 1 M aqueous HCl and saturated
NaHCO3 solution, dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate¼20:1)
to afford 4 (328 mg, 80%) as a clear oil. [a]2D0 +40.7 (c 1.100,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.20–7.33 (m, 10H),
6.86–6.99 (m, 2H), 6.08–6.21 (m, 2H), 5.52–5.61 (m, 2H),
4.75 (s, 1H), 4.46–4.60 (m, 4H), 4.34–4.37 (m, 1H), 4.27–
4.30 (m, 1H), 4.15–4.21 (m, 1H), 2.36–2.55 (m, 2H), 1.12
(d, J¼5.1 Hz, 3H), 0.80 (s, 9H), 0.04 (s, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ72.79 (d, J¼6.8 Hz, 3F), ꢀ72.87
(d, J¼8.2 Hz, 3F); 13C NMR (75.5 MHz, CDCl3) d 169.10,
163.44, 162.99, 144.26, 143.46, 136.40, 136.34, 128.74,
128.65, 128.37, 128.32, 128.03, 127.98, 124.65, 123.52,
123.18, 94.89, 74.79, 74.64, 74.13, 71.99, 69.49, 65.27,
44.03, 30.80, 25.75, 23.57, 18.00, ꢀ4.60, ꢀ5.03; IR
(thin film) nmax 2959, 1744, 1656, 1252, 835 cmꢀ1; MS
(ESI) m/z 915 [M+Na]+; HRMS (ESI) calcd for
C38H45SiO9F6Cl3Na: 915.1681, found: 915.1695.
3.13. Bn ether of trifluoromethylated analog of
macrosphelide A (21)
To a stirring solution of dicyclohexylcarbodiimide (DCC)
(79 mg, 0.39 mmol), 4-dimethylaminopyridine (DMAP)
(47 mg, 0.39 mmol) and 4-dimethylaminopyridine hydro-
chloride (61 mg, 0.39 mmol) in ethanol-free chloroform
(2 mL) at 0 ꢁC was added via syringe pump a solution of
20 (50 mg, 0.077 mmol) in ethanol-free chloroform
(14 mL) over a period of 5 h. Warming up to room temper-
ature, the mixture was stirred overnight. Filtration and re-
moval of the solvent gave the crude product, which was
purified by column chromatography on silica gel (petroleum
ether/ethyl acetate¼6:1) to give 21 (24 mg, 50%) as an oil.
[a]2D0 +55.1 (c 0.950, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.26–7.39 (m, 10H), 6.66–6.85 (m, 2H), 6.02–6.13 (m,
2H), 5.36–5.48 (m, 3H), 4.57–4.66 (m, 2H), 4.40–4.50
(m, 2H), 4.30–4.38 (m, 1H), 4.25–4.29 (m, 1H), 2.65–2.69
(m, 2H), 1.32 (d, J¼6.3 Hz, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ72.96 (d, J¼6.5 Hz, 3F), ꢀ74.12 (d, J¼6.5 Hz,
3F); 13C NMR (75.5 MHz, CDCl3) d 168.26, 163.59,
162.04, 144.51, 142.07, 136.31, 136.11, 128.61, 128.56,
128.35, 128.27, 128.07, 127.83, 123.84, 121.51, 121.23,
74.84, 74.51, 72.27, 72.09, 72.16, 67.27, 40.11, 19.38; IR
(thin film) nmax 2927, 2855, 1747, 1662, 1272, 982 cmꢀ1
;
MS (ESI) m/z 648 [M+NH4]+; HRMS (ESI) calcd for
C30H28O8F6Na: 653.1578, found: 653.1581.
3.12. (4R,5R,E)-4-(Benzyloxy)-5-((4R,5R,E)-4-(benzyl-
oxy)-6,6,6-trifluoro-5-((S)-3-hydroxybutanoyloxy)hex-
2-enoyloxy)-6,6,6-trifluorohex-2-enoic acid (20)
3.14. Trifluoromethylated analog of macrosphelide A (1)
To a solution of 21 (24 mg, 0.038 mmol) in CH2Cl2 (1 mL) at
ꢀ78 ꢁC was added BCl3 (0.38 mL, 1.0 M in toluene,
0.38 mmol) dropwise. After stirring for 0.5 h, the reaction
was quenched with methanol at ꢀ78 ꢁC. Warming up to
room temperature, the mixture was stirred for 1 h. The aque-
ous phase was extracted with CH2Cl2, and the combined or-
ganic layers were dried over Na2SO4. After filtration and
removal of the solvent in vacuo, the residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl
acetate¼2:1) to provide 1 (15 mg, 90%) as a white solid.
[a]2D0 ꢀ43.9 (c 0.350, CH3OH); 1H NMR (300 MHz,
CD3OD) d 6.86 (dd, J¼15.3, 5.7 Hz, 1H), 6.79 (dd, J¼
15.6, 5.1 Hz, 1H), 6.15 (dd, J¼15.3, 1.2 Hz, 1H), 5.98 (dd,
J¼15.9, 1.5 Hz, 1H), 5.26–5.34 (m, 2H), 5.18–5.23 (m,
1H), 4.61–4.66 (m, 1H), 2.26–2.81 (m, 2H), 1.25 (d, J¼
2.1 Hz, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.72 (d,
J¼7.6 Hz, 3F), ꢀ75.08 (d, J¼7.3 Hz, 3F); 13C NMR
(75.5 MHz, CD3OD) d 168.81, 164.49, 162.89, 147.30,
144.85, 136.31, 136.11, 122.68, 121.33, 71.87, 70.47, 67.40,
39.29, 18.10; IR (thin film) nmax 2927, 1747, 1728, 1662,
1388, 1272, 982 cmꢀ1; MS (ESI) m/z 451 [M+H]+; HRMS
(ESI) calcd for C16H16O8F6Na: 473.0650, found: 473.0642.
To a solution of 4 (200 mg, 0.22 mmol) in CH2Cl2 (2 mL)
was added CF3COOH (1 mL). The solution was stirred at
room temperature for 2 h and diluted with Et2O. The reac-
tion mixture was quenched with saturated NaHCO3 solution.
The layers were separated, and the aqueous layer was ex-
tracted with Et2O. The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated to give
a residue, which was used without further purification. A so-
lution of the above residue in THF (1 mL) was added to
a mixture of Zn dust (57 mg, 0.88 mmol) and AcOH/AcONa
buffer (1 mL) in THF (1 mL) at 0 ꢁC. Warming up to room
temperature, the reaction was stirred for 24 h. After filtra-
tion, the filtrate was acidified with 1 M aqueous HCl and
extracted with Et2O. The organic phase was dried over anhy-
drous Na2SO4. After filtration and removal of the solvent,
the resulting residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate¼2:1) to afford
20 (142 mg, 80%) as a white solid. [a]2D0 +46.3 (c 3.240,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.25–7.38 (m,
10H), 6.84–6.92 (m, 2H), 6.12 (dd, J¼15.9, 6.0 Hz, 2H),
5.54–5.63 (m, 2H), 4.75 (s, 1H), 4.47–4.64 (m, 4H), 4.30–
4.41 (m, 2H), 4.11–4.22 (m, 1H), 2.52–2.56 (m, 2H), 1.12
(d, J¼7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.52
(d, J¼6.8 Hz, 3F), ꢀ73.71 (d, J¼6.5 Hz, 3F); 13C NMR
(75.5 MHz, CDCl3) d 169.99, 169.22, 162.87, 144.04,
142.97, 136.30, 136.24, 128.63, 128.61, 128.35, 128.33,
128.01, 127.96, 125.29, 123.70, 122.35, 94.89, 74.76,
3.15. (R)-4-((S)-1-(Methoxymethoxy)ethyl)-2,2-
dimethyl-1,3-dioxolane (23a)
To a suspension of NaH (60% in oil, 575 mg, 14.4 mmol) in
anhydrous THF (50 mL) was added a solution of 9 (2.10 g,

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B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
14.4 mmol) in anhydrous THF (20 mL) slowly at 0 ꢁC. After
the mixture was stirred for 30 min at the same temperature, it
was allowed to warm to room temperature and stirred for
30 min. Then the resulting reaction mixture was cooled to
0 ꢁC, and treated with MOMCl (1.28 g, 15.8 mmol). After
stirring at room temperature for 20 h, the reaction mixture
was quenched with saturated NaHCO3 solution. The layers
were separated, and the aqueous layer was extracted with
ether. The combined organic extracts were dried over anhy-
drous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate¼8:1) to afford 23a (2.00 g, 73%) as
a clear oil and recovered 9 (15% recovery). [a]2D6 +19.1 (c
to room temperature, the reaction was stirred for 1 h. Filtra-
tion of the mixture and removal of the solvent in filtrate in
vacuo gave a residue, which was used without further puri-
fication. The above residue and trichloroisocyanuric acid
(TCCA) (497 mg, 2.14 mmol) were dissolved in CH2Cl2
(10 mL), then, to this solution was added 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) (3 mg, 0.018 mmol) at
0 ꢁC. After the mixture was warmed to room temperature,
the reaction was stirred for 15 min. Filtration of the mixture
and removal of the solvent in filtrate in vacuo gave a residue.
Then, Ph3PCHCO2CH2CCl3 (1.22 g, 2.70 mmol) was added
to a solution of the residue in CH2Cl2 (10 mL) at 0 ꢁC.
Warming up to room temperature, the mixture was stirred
overnight. Et2O (20 mL) was added and the resulting
mixture was washed with water and brine, and dried over
Na2SO4. After filtration and removal of the solvent in vacuo,
the resultant residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate¼15:1) to give
ester 7 (481 mg, 70%) as a clear oil. [a]2D0 ꢀ43.8 (c 0.950,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.25–7.34 (m,
5H), 7.12 (dd, J¼15.9, 5.7 Hz, 1H), 6.20 (d, J¼15.9 Hz,
1H), 4.82 (s, 2H), 4.49–4.69 (m, 4H), 3.97–4.00 (m, 1H),
3.85–3.89 (m, 1H), 3.34 (s, 3H), 1.22 (d, J¼5.7 Hz, 3H);
IR (thin film) nmax 2958, 1741, 1660, 1273 cmꢀ1; MS
(ESI) m/z 411 [M+H]+. Anal. Calcd for C17H21O5Cl3: C,
49.59; H, 5.14. Found: C, 49.70; H, 5.31.
1
1.400, CHCl3); H NMR (300 MHz, CDCl3) d 6.63 (dd,
J¼18.9, 6.9 Hz, 2H), 3.92–4.04 (m, 2H), 3.78–3.82 (m,
1H), 3.63–3.71 (m, 1H), 3.32 (s, 3H), 3.33 (s, 3H), 3.31 (s,
3H), 1.16 (d, J¼6.3 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) d 109.21, 95.23, 78.78, 73.49, 66.45, 55.41, 26.45,
25.28, 16.63; IR (thin film) nmax 2927, 1189 cmꢀ1; MS
(ESI) m/z 191 [M+H]+; HRMS (ESI) calcd for
C9H18O4Na: 213.1103, found: 213.1115.
3.16. (2R,3S)-1-(tert-Butyldimethylsilyloxy)-3-
(methoxymethoxy)butan-2-ol (24)
A mixture of 23a (1.52 g, 8.0 mmol) and 75% of aqueous
AcOH (40 mL) was stirred at room temperature for 15 h.
The solvent was then removed in vacuo. To a 0 ꢁC solution
of the residue and DMAP (98 mg, 0.80 mmol) in DMF
(40 mL) was added imidazole (654 mg, 9.6 mmol), followed
by TBDMSCl (1.21 g, 8.0 mmol). Then, the mixture was
stirred for 30 h at 0 ꢁC. EtOAc (80 mL) was added and the
resulting mixture was washed with brine. The combined
organic phases were dried over anhydrous Na2SO4. After fil-
tration and removal of the solvent, the resulting residue was
purified by flash chromatography (petroleum ether) to afford
24 (1.59 g, 75%) as a clear oil. [a]2D7 +16.5 (c 1.600, CHCl3);
1H NMR (300 MHz, CDCl3) d 4.61–4.71 (m, 2H), 3.49–3.77
(m, 4H), 3.35 (s, 3H), 2.51 (br, 1H), 2.21 (d, J¼5.7 Hz, 3H),
0.88 (s, 9H), 0.06 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
d 95.40, 75.02, 74.32, 63.84, 55.45, 25.86, 18.26, ꢀ5.39,
3.19. (4R,5S,E)-4-(Benzyloxy)-5-(methoxymethoxy)-
hex-2-enoic acid (26)
It was prepared using the same condition as described for
1
compound 16, clear oil. [a]2D7 ꢀ54.4 (c 0.750, CHCl3); H
NMR (300 MHz, CD3COCD3) d 7.28–7.41 (m, 5H), 6.93
(dd, J¼15.9, 6.3 Hz, 1H), 6.09 (d, J¼15.9 Hz, 1H), 4.52–
4.68 (m, 4H), 4.07–4.10 (m, 1H), 3.85–3.93 (m, 1H), 3.30
(s, 3H), 1.18 (d, J¼6.3 Hz, 3H); 13C NMR (75.5 MHz,
CD3COCD3) d 167.16, 145.61, 137.51, 127.86, 127.17,
123.19, 94.76, 80.63, 74.02, 70.92, 54.84, 15.90; IR (thin
film) nmax 3200, 2907, 1703, 1662 cmꢀ1; MS (ESI) m/z
451 [M+H]+; HRMS (ESI) calcd for C16H16O8F6Na:
473.0650, found: 473.0642.
ꢀ5.41; IR (thin film) nmax 3510, 2934, 1260, 838 cmꢀ1
;
MS (ESI) m/z 287 [M+Na]+; HRMS (ESI) calcd for
C12H28SiO4Na: 287.1655, found: 287.1663.
3.20. (4R,5R,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-5-
((4R,5S,E)-4-(benzyloxy)-5-hydroxyhex-2-enoyloxy)-
6,6,6-trifluorohex-2-enoate (28)
3.17. ((2R,3S)-2-(Benzyloxy)-3-(methoxymethoxy)-
butoxy)(tert-butyl)dimethylsilane (25)
To a solution of DCC (28 mg, 0.13 mmol) and DMAP
(16 mg, 0.13 mmol) in CH2Cl2 (0.6 mL) was added a solu-
tion of 26 (30 mg, 0.11 mmol) in CH2Cl2 (0.4 mL) at 0 ꢁC.
After stirring for 30 min at 0 ꢁC, a solution of 17 (45 mg,
0.09 mmol) in CH2Cl2 (0.4 mL) was added dropwise to
the mixture. The solution was stirred for 6 h at room temper-
ature. Filtration of the mixture and removal of the solvent in
filtrate in vacuo gave a crude product (30 mg, 40%), which
was used without further purification. To a solution of the
crude product in CH2Cl2 (1.0 mL) was added CF3COOH
(0.3 mL). The solution was stirred at room temperature for
8 h and concentrated. The resulting oil was purified by flash
chromatography on silica gel (petroleum ether/ethyl
acetate¼8:1) to afford 28 (25 mg, 90%) as a clear oil.
[a]2D7 +33.6 (c 1.250, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.31–7.40 (m, 10H), 6.93 (dt, J¼15.6, 6.0 Hz, 2H), 6.25
(d, J¼15.9 Hz, 1H), 6.13 (d, J¼15.9 Hz, 1H), 5.62–5.71
It was prepared using the same condition as described for
1
compound 15, clear oil. [a]2D6 +21.1 (c 1.260, CHCl3); H
NMR (300 MHz, CDCl3) d 7.26–7.35 (m, 5H), 4.61–4.80
(m, 5H), 3.85–3.89 (m, 1H), 3.68–3.81 (m, 2H), 3.36 (s,
3H), 1.19 (d, J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); IR
(thin film) nmax 2948, 1272, 1176, 837 cmꢀ1; MS (ESI)
m/z 377 [M+Na]+. Anal. Calcd for C19H34O4Si: C, 64.36;
H, 9.67. Found: C, 64.52; H, 9.59.
3.18. (4R,5S,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-
5-(methoxymethoxy)hex-2-enoate (7)
To an ice-cold solution of 25 (636 mg 1.8 mmol) in THF
(10 mL) was added a solution of TBAF (1.8 mL, 1.0 M in
THF, 1.8 mmol) dropwise. After the mixture was warmed

B.-L. Wang et al. / Tetrahedron 63 (2007) 12671–12680
12679
(m, 1H), 4.81 (s, 2H), 4.55–4.70 (m, 3H), 4.38–4.45 (m, 2H),
3.73–3.83 (m, 2H), 3.34 (br, 1H), 1.15 (d, J¼6.0 Hz, 3H);
19F NMR (282 MHz, CDCl3) d ꢀ72.88 (d, J¼6.8 Hz, 3F);
13C NMR (75.5 MHz, CDCl3) d 163.42, 163.14, 147.96,
143.50, 137.09, 136.20, 128.55, 128.45, 128.26, 128.05,
127.93, 127.85, 123.83, 122.77, 121.70, 94.68, 83.02,
75.03, 74.00, 71.88, 71.82, 70.35, 69.27, 18.30; IR (thin
film) nmax 3225, 2972, 1744, 1656 cmꢀ1; MS (ESI) m/z
656 [M+NH4]+; HRMS (ESI) calcd for C28H28O7F3Cl3Na:
661.0739, found: 661.0742.
74.85, 72.17, 72.09, 71.86, 69.95, 65.81, 40.93, 23.64,
18.48; IR (thin film) nmax 3032, 2927, 1749, 1664 cmꢀ1
;
MS (ESI) m/z 577 [M+H]+; HRMS (ESI) calcd for
C30H31O8F3Na: 599.1869, found: 599.1872.
3.24. Trifluoromethylated analog of macrosphelide A (2)
It was prepared using the same condition as described
for compound 1, white solid. [a]2D5 ꢀ72.5 (c 0.560,
CH3COCH3); 1H NMR (300 MHz, CD3COCD3) d 7.02 (dd,
J¼15.6, 3.6 Hz, 1H), 6.78 (dd, J¼15.6, 5.4 Hz, 1H), 6.07
(dd, J¼15.6, 7.2 Hz, 2H), 5.28–5.35 (m, 1H), 5.14–5.21 (m,
1H), 4.95–5.02 (m, 1H), 4.69–4.83 (m, 1H), 4.49–4.52 (m,
1H), 2.57–2.61 (m, 2H), 1.35 (d, J¼6.3 Hz, 3H), 1.17 (d,
J¼6.3 Hz, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ73.77
(d, J¼6.2 Hz, 3F); 13C NMR (75.5 MHz, CDCl3) d 171.90,
167.64, 166.08, 148.36, 145.98, 137.62, 136.13, 121.93,
76.12, 74.05, 71.45, 66.85, 66.01, 40.06, 23.62, 16.18; IR
(thin film) nmax 3462, 2924, 1746, 1663, 1388, 1275,
1148 cmꢀ1; MS (ESI) m/z 414 [M+NH4]+; HRMS (ESI) calcd
for C16H19O8F3Na: 419.0924, found: 419.0924.
3.21. (4R,5R,E)-2,2,2-Trichloroethyl-4-(benzyloxy)-5-
((4R,5S,E)-4-(benzyloxy)-5-((S)-3-(tert-butyldimethyl-
silyloxy)butanoyloxy)hex-2-enoyloxy)-6,6,6-trifluoro-
hex-2-enoate (29)
It was prepared using the same condition as described for
1
compound 4, clear oil. [a]2D5 +10.4 (c 1.050, CHCl3); H
NMR (300 MHz, CDCl3) d 7.30–7.41 (m, 10H), 6.94 (dt, J¼
15.9, 6.3 Hz, 2H), 6.18 (d, J¼15.9 Hz, 1H), 6.11 (d, J¼
15.9 Hz, 1H), 5.59–5.70 (m, 1H), 4.74 (s, 2H), 4.48–4.66
(m, 3H), 4.39–4.43 (m, 1H), 4.22–4.29 (m, 1H), 4.08–4.11
(m, 1H), 2.46–2.53 (m, 1H), 2.31–2.38 (m, 1H), 1.17 (d,
J¼6.0 Hz, 6H), 0.84 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 19F
NMR (282 MHz, CDCl3) d ꢀ72.89 (d, J¼6.8 Hz, 3F); 13C
NMR (75.5 MHz, CDCl3) d 171.92, 163.59, 163.34,
147.23, 143.58, 137.20, 136.33, 128.65, 128.55, 128.39,
128.32, 127.94, 127.86, 121.66, 121.26, 120.86, 94.82,
78.70, 74.75, 74.17, 72.09, 71.99, 70.62, 70.01, 64.27,
43.03, 25.07, 22.48, 15.58, ꢀ4.58, ꢀ5.01; IR (thin film)
nmax 2959, 1744, 1656, 1252 cmꢀ1; MS (ESI) m/z 861
[M+Na]+; HRMS (ESI) calcd for C38H48SiO9F3Cl3Na:
861.1972, found: 861.1985.
Acknowledgements
We thank the National Natural Science Foundation of China,
Ministry of Education of China, and Shanghai Municipal
Scientific Committee for funding this work.
References and notes
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compound 20, clear oil. [a]2D5 +58.9 (c 0.250, CHCl3); H
NMR (300 MHz, CD3COCD3) d 7.28–7.38 (m, 10H), 6.84
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compound 21, clear oil. [a]2D5 ꢀ36.3 (c 0.260, CHCl3); H
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