General Stereodivergent Enantioselective Total Synthetic Approach toward Macrosphelides A-G and M

Article abstract of DOI:10.1021/acs.joc.5b01171

A straightforward enantioselective total synthesis algorithm for the preparation of 8 out of 13 macrosphelides within 9-11 steps starting from tert-butyl sorbate is presented. The use of a cyclic sulfate as both protecting and reactivity directing group is the key element within this algorithm. A high-pressure transesterification allows for the selective ring-enlargement of the 15-membered macrosphelides into the 16-membered counterparts. The absolute configurations of the natural products were unambiguously assigned both by the chemical synthesis and by X-ray structure analysis.

Full text of DOI:10.1021/acs.joc.5b01171

Article
pubs.acs.org/joc
General Stereodivergent Enantioselective Total Synthetic Approach
toward Macrosphelides A−G and M
Christine Hacker and Bernd Plietker*
̈
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A straightforward enantioselective total syn-
thesis algorithm for the preparation of 8 out of 13
macrosphelides within 9−11 steps starting from tert-butyl
sorbate is presented. The use of a cyclic sulfate as both
protecting and reactivity directing group is the key element
within this algorithm. A high-pressure transesterification allows
for the selective ring-enlargement of the 15-membered
macrosphelides into the 16-membered counterparts. The
absolute configurations of the natural products were
unambiguously assigned both by the chemical synthesis and
by X-ray structure analysis.
configuration within the vic-diol motif in the C6-building block
and to set the stage for a regioselective esterification of only one
out of the two adjacent OH-groups.4 With regard to the
interesting biological activity, we became interested in
developing chemistry, in which the central diol-motif in the
C6-building block is manipulated in a way that the diol is
protected if necessary but that the protecting group also serves
as a synthon that allows an inverting hydrolytic deprotection,
an inverting esterificative deprotection, or a deoxygentative
deprotection.
In the present manuscript, we report the successful synthesis
of 8 out of 13 macrosphelide members within 9−11 steps
starting from commercial t-butyl sorbate (Figure 1). Hence, to
the best of our knowledge this represents the shortest total
synthesis approach published to date. The straightforwardness
and modularity is based on the following basic ideas:
INTRODUCTION
■
The macrosphelide-type natural product family consists
currently of 13 members that are 15- or 16-membererd
macrotriolides (Figure 1).1,2 Since the first isolation of
macrosphelide A in 19953 from Microsphaeropsis sp. FO-5050,
strong research efforts devoted to the isolation of further
macrosphelide members, the exploration of their bioactivity,
and the total synthesis of these natural products were
undertaken.4 The main driving force for these investigations
certainly lies in the fact that selected members were shown to
inhibit the cell−cell adhesion of HL-60 cells to human umbilical
vein endothelial cells (HUVECs).1,3−5 This process might be
regarded as a key step within the metastasis process,6 and hence
there is significant interest in the elaboration of a versatile and
short total synthetic approach.
Among the various total syntheses published to date the
cleavage of the ester groups represents the most common
disconnection leading to one C4- and two C6-building blocks.4
The C6-building blocks differ in their oxidation state. Although
allylic γ-hydroxyl-, -carbonyl- or even -methylene groups are
found within the C6-building block, all macrosphelides that
were isolated to date possess an (S)-configured hydroxyl group
at the δ-carbon. However, the stereocenter in the β-hydroxy
butyric acid motif can be either (R)- or (S)-configured. In
summary, the structural diversity of the macrosphelide family is
the consequence of a combination of ring size, oxidation state
of the C6-building blocks, and absolute configuration of the
C4-building block. This structural similarity represents one of
the key synthetic challenges, that is, the development of
chemo-, regio-, and stereoselective functional group trans-
formations within a molecular scaffold possessing various
almost identical functional groups.
• The cyclic sulfate as a functional protecting group:
Elaboration of efficient stereoselective synthetic methods
to convert (S,S)-syn-dihydroxysorbate derived cyclic
sulfate into the various oxygenated C6-building blocks.
• Elaboration of an efficient ring-enlarging transesterifca-
tion method using high pressure chemistry.
RESULTS AND DISCUSSION
■
We started our investigations with the development of a
straightforward synthetic strategy for the preparation of both
the C4- and the C6-building blocks. The former were obtained
using the enantioselective reduction of t-butyl acetoacetate
following a protocol reported by Noyori.7 The corresponding
(R)- or (S)-configured alcohols 7 were obtained in exclusive
enantioselectivities of >98% ee. The t-butyl esters were used
Traditionally, well-elaborated protecting group manipula-
tions were used in order to establish the correct relative
Received: May 27, 2015
© XXXX American Chemical Society
A
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Figure 1. Macrosphelide natural product family1,2 and retrosynthetic approach.
throughout the entire synthesis and were chosen for their
Scheme 1. Cyclic Sulfates: Protecting and Reactivity
Directing Group
a
ability to be cleaved under slightly acidic conditions using a
silane and trifluoroacetic acid thus avoiding the undesired and
literature known β-elimination of the β-acylbutyrates to the
corresponding crotonates.8
For the C6-building blocks, we applied slightly modified
conditions for a Sharpless asymmetric dihydroxylation of t-butyl
sorbate.9 After careful optimization, the desired (S,S)-
configured vic-diol 1 was obtained in good yields and
significantly improved enantiomeric excess of >94% ee.
Depending on the specific macrosphelide diol, (S,S)-1 needed
to be converted into the various oxygenated C6-building blocks
(Scheme 1). Different from the literature reports, we were
seeking for a method to protect the diol motif albeit with the
option of using the protecting group to generate an electronic
bias between the two C−O-bonds in a way that the
deprotection goes hand in hand with the selective activation
of the C-4−O-bonds, like the inversion of the C-4 stereocenter,
C-4 deoxygenation, or an inverting esterification.
After detailed analysis of suitable protecting groups (cyclic
carbonates, sulfites, etc.), 1-derived cyclic sulfate 210 turned out
to be the optimum choice (eq 1, Scheme 1). This protecting
group proved to be stable in the t-butyl ester cleavage using
TFA to give the corresponding carboxylic acid 3 (eq 2, Scheme
1), but it sets the stage for a deprotection with inversion of the
C-4 stereochemistry upon treatment with ammonium formate
and subsequent saponification of the resulting sulfate
monoester with methanolic HCl solution to give the (R,S)-
diol 4 (eq 3, Scheme 1). The change of the ammonium
carboxylate allows the introduction of an ester motif at C-4
with inversion of the stereochemistry to give the corresponding
acyloxyalcohol 6 in good enantiomeric ratio (eq 5, Scheme 1).
The change of the nucleophile to NaBH4 results in an exclusive
deoxygenation at C-4 to the homoallylic alcohol 5 with full
a
Reagents and conditions: (a) SO2Cl2 (1 equiv), DMAP (40 mol %),
Et3N (4 equiv), CH2Cl2, −80 °C, 15 h, 60%; (b) Et3SiH (1.1 equiv),
TFA (40 equiv), CH2Cl2, 0 °C to rt, 3 h, quant.; (c) NH3*HCOOH
(1 equiv), DMF, rt, 15 h, then HCl(MeOH) (2 equiv), THF, 0 °C, 15 h,
80%; (d) NaBH4 (1.5 equiv), DMA, rt, 15 min, then HCl(MeOH) (2
equiv), THF, 0 °C, 3 h, 63%; (e) CH3COOH (1 equiv), NEt3 (1.5
equiv), DMF, rt, 15 h, then HCl(MeOH) (2 equiv), THF, 0 °C, 4.5 h,
72% (regioselectivity 74:26).
conservation of the enantiopurity (eq 4, Scheme 1).
Importantly, the t-butyl ester remained unaffected under
these conditions. Having in hand the desired chemical toolbox,
we turned our attention to the application of these methods in
total synthesis.
The Total Synthesis of Macrosphelides A, C, D, E, F,
and M. A closer structural analysis of macrosphelides A, C, D,
B
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a
Scheme 2. Total Syntheses of Macrosphelides A, D, E, and M
a
Reagents and conditions: (a) DCC (1.5 equiv), DMAP (5 mol %), CH2Cl2, 0 °C to rt, 15 h, 53%; (b) NH3*HCOOH (1 equiv), DMF, rt, 3.5 h,
then HCl(MeOH) (2 equiv), THF, 0 °C, 3.5 h; (c) NaBH4 (1.0 equiv), DMA, rt, 30 min, then HCl(MeOH) (2 equiv), THF, 0 °C, 3 h; (d) (i) TFA (40
equiv), Et3SiH (1.1 equiv), CH2Cl2, 0 °C to rt, 2 h; (ii) 2 (1 equiv), NEt3 (1.5 equiv), DMF, rt, 9 h, then HCl(MeOH) (2 equiv), THF, 0 °C, 4 h; (e)
(i) TFA (100 equiv), Et3SiH (1.1 equiv), CH2Cl2, 0 °C to rt, 1.5 h; (ii) 2-methyl-6-nitrobenzoic anhydride (1.2 equiv), NEt3 (2.2 equiv), DMAP
(0.25 equiv), CH2Cl2/THF, rt, 8 h; (f) Ti(iOPr)4 (50 equiv), CH2Cl2, rt, 15 h, 7 kbar.
E, F, and M reveals that they differ (a) in the ring size (D and
M are 15-membered macrotriolides; A, C, E, and F are 16-
membered macrotriolides), (b) in the oxygenation degree (A,
D, E, and M possess a hydroxy group at C-8; C and F are
deoxygenated at C-8), and (c) in the configuration at C-3 ((S)-
configuration for A, C, and D; (R)-configuration for E, F, and
M).
The total synthesis of this set of natural products started with
the esterification of the respective (S)- or (R)-configured β-
hydroxybutyric acid 7 with building block 3 under slightly
modified Steglich conditions (Scheme 2). The corresponding
diastereomeric sulfates 8 and 9 were obtained in good yields.
For the synthesis of macrosphelides A, D, E, and M, an
inverting cleavage of the sulfate group using ammonium formate
and HCl was performed that led to the formation of the
corresponding trans-configured diols 11 and 12 in good
diastereoselectivities. For macrosphelides C and F, the
deoxygenative cleavage of the sulfate group and subsequent
saponification of the sulfate monoester using HCl led to the
formation of the corresponding homoallyl alcohols 10 and 13.
All subsequent transformations toward macrosphelides A, C, D,
E, F, and M were performed using identical reaction conditions.
The chemoselective saponification of the t-butyl ester in 10−13
allowed the liberation of the corresponding carboxylic acids,
which were directly employed in an inverting esterification−
sulfate cleavage using sulfate building block 2 to give the
respective triesters 14−17 in good yields and excellent
diastereoselectivities. After the subsequent selective saponifica-
tion of the t-butyl ester moiety, the respective carboxylic acids
underwent a clean Shiina macrolactonization reaction11 to the
15-membered ring products 18, 19, and macrosphelides D and
M. Importantly, no acyl group migration with formation of the
16-membered macrosphelides were observed under these
conditions.
The correct relative and absolute configurations of macro-
sphelide D and M were confirmed by comparison of the
spectral data with literature reports.2a Furthermore, we were
able to obtain a crystal structure of macrosphelide D confirming
the correct relative and absolute configuration of all stereo-
centers (Supporting Information, Supplementary Figure 65).
With the 15-membered macrotriolides in hand, we finally set
out to develop the ring-enlarging transesterification. A plethora
of conditions were tested, but only mixtures of 15- and 16-
membered rings were observed. At this point, we revisited the
C
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X-ray structures of macrosphelide D and A1a (Figure 2). Based
on these solid phase structures, we assumed that, in order to
a
Scheme 3. Total Synthesis of Macrosphelide G
a
Reagents and conditions: (a) (i) TFA (40 equiv), Et3SiH (1.1 equiv),
CH2Cl2, 0 °C to rt, 2 h; (ii) 5 (0.5 equiv), DCC (1.7 equiv), DMAP
(0.1 equiv), camphorsulfonic acid (4 mol %), ClCH2CH2Cl, −20 °C,
15 h; (b) NH3*HCOOH (1 equiv), DMF, rt, 5 h, then: HCl(MeOH) (2
equiv), THF, 0 °C, 2.5 h; (c) (i) TFA (100 equiv), Et3SiH (1.1 equiv),
CH2Cl2, 0 °C to rt, 1.5 h; (ii) 2-methyl-6-nitrobenzoic anhydride (1.3
equiv), NEt3 (2.3 equiv), DMAP (0.25 equiv), CH2Cl2/THF, rt, 8 h;
(d) Sc(OTf)3 (0.7 equiv), DMAP (3.3 equiv), CH2Cl2, rt, 5 min.
significant influence on the ring-size selectivity of the
subsequent Shiina macrolactonization. Different from the
macrosphelide C and F synthesis, a 1:1-mixture of 15- and
16-membered macrotriolides was obtained. Separation of the
isomers and subsequent treatment of the 15-membered ring 22
with Sc(OTf)3/DMAP13 however led to a transesterificative
ring-enlargement to the desired 16-membered natural product
macrosphelide G in 84% yield. The application of the high-
pressure Ti-mediated transesterification that proved successful
for the other macrosphelide synthesis turned out to be less
suitable for this substrate and gave comparable lower yields of
the 16-membered ring product (40%). Hence, starting from the
acylic precursor 21, the natural product was obtained in 54%
combined isolated yield over two (respectively, three) steps.
Also in this case, we were able to obtain a crystal structure of
macrosphelide G confirming the correct relative and absolute
configuration of all stereocenters (Supporting Information,
Supplementary Figure 66).
Site Selectivity in Macrosphelide Oxidations: Total
Synthesis of Macrosphelide B. At the end of our study, we
were wondering whether a site selective oxidations of bis-
hydroxyl macrosphelides like macrosphelide A would allow
access to macrosphelides with differently oxidized C6-building
blocks (e.g., macrosphelide B). However, we envisioned the site
selecitvity to be particularly challenging since the respective two
hydroxyl groups at C-8 and C-14 (Figure 1) differ only in the
substitution of the adjacent ester moiety at C-9 and C-15,
respectively (Figure 1).9 Despite these structural similarities, we
were surprised to find that treatment of macrosphelide A with
Dess−Martin periodinane at low temperatures gave the desired
macrosphelide B in 36% isolated yield and good chemo-
Figure 2. Conformation driven selective ring-enlarging transester-
ification under high pressure.
allow the transesterification to proceed, the 15-membered
macrocycle needs to undergo a conformational change in such
a way that the migrating ester carbonyl group is not oriented
into the ring but needs to flip out of the ring in order to
approach the free exocyclic secondary alcohol (Figure 2).
One way to provide the energy that allows the 15-membered
macrocycle to adopt this desired reactive conformation and to
favor the more ordered (and sterically disfavored) transition
state is the application of high pressure conditions.12 We found
that after intense screening of various transesterification
methods, the corresponding 16-membered macrocyclic macro-
sphelides A, C, E, and F were obtained in high yields with
exclusive selectivity using an excess of Ti(Oi-Pr)4 at 7 kbar
(Scheme 2). We disclose a total synthesis algorithm that allows
six natural and two non-natural macrosphelides to be prepared
from t-butyl sorbate in 9−10 steps.
The Total Synthesis of Macrosphelide G. With these
total syntheses in hands, we turned our attention to the
synthesis of macrosphelide G. This natural product is an isomer
of macrosphelide F and possesses a C-8-hydroxyl group but is
deoxygenated at C-14. In order to generate this substitution
pattern, sulfate 2-derived deoxygenated C6-building block 5
(Scheme 1) was subjected to an esterification using 9-derived
carboxylic acid (Scheme 3) to give triester 20 in good overall
yield. The inverting sulfate hydrolysis to diol 21 proceeded in
good yields using the established conditions (vide supra). Very
much to our surprise, the missing hydroxyl group in 21 had a
D
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column chromatography (petroleum ether/ethyl acetate, 1:1) to yield
1 (1.1 g, 71%, 94 % ee). The enantiomeric excess was detected by
chiral HPLC (Chiralcel OD, heptane/2-propanol (95:5), 1.0 mL/min,
220 nm), tR(R) = 12.25, tR(S) = 13.49), Rf = 0.35 (1:1 petroleum
selectivity (Scheme 4). The corresponding regioisomer of
macrosphelide B was formed in about 14% isolated yield.
a
Scheme 4. Total Synthesis of Macrosphelide B
22
1
ether/ethyl acetate); [α]D = −40.3 (c = 9.7 mg cm−3 in EtOH); H
NMR (300 MHz, CDCl3) δ (ppm) = 6.81 (dd, J = 15.7, 5.3 Hz, 1H),
6.07 (dd, J = 15.7, 1.6 Hz, 1H), 4.02−4.07 (m, 1H), 3.69−3.79 (m,
1H), 1.49 (s, 9H), 1.25 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ (ppm) = 165.7, 145.1, 124.4, 80.8, 75.7, 70.3, 28.1 (3C),
19.0; IR (film) ν (cm−1) = 3398 (m), 1712 (s), 1694 (s), 1657 (w),
1368 (w), 1151 (s), 982 (m); MS (EI) m/z (%) = 203 (1), 187 (1),
129 (8), 102 (100), 84 (23), 73 (12), 57 (37), 45 (12); HRMS (ESI-
TOF) (m/z) [M + Na]+ calculated for C10H18O4Na 225.1097, found
225.1104.
(E)-tert-Butyl 3-((4S,5S)-5-Methyl-2,2-dioxido-1,3,2-dioxa-
thiolan-4-yl)acrylate, 2. (4S,5S,E)-tert-Butyl-4,5-dihydroxyhex-2-
enoate, 1 (202 mg, 1 mmol), was dissolved in 22 mL of
dichloromethane. 4-Dimethylaminopyridine (DMAP; 50 mg, 0.4
mmol, 0.4 equiv) was added, and the mixture was cooled to −78
°C. After triethylamine (553.3 μL, 4 mmol, 4 equiv) was added, the
mixture was stirred for 10 min. Sulfuryl chloride (freshly distilled, 80.8
μL, 1 mmol, 1 equiv) was dissolved in 22 mL of dichloromethane and
added to the reaction mixture over 14 h via syringe pump. Meanwhile,
the solution was allowed to warm to −60 °C. Afterward, the mixture
was stirred for additional 30 min at −60 °C. The mixture was poured
into a separation funnel containing pentane and sat. sodium
bicarbonate solution. The organic layer was washed with brine. The
aqueous layers were extracted 3× with ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(petroleum ether/ethyl acetate, 5:1) to yield 2 (159.8 mg, 60%) as a
white solid (amorphous). Rf = 0.31 (5:1 petroleum ether/ethyl
a
Reagents and conditions: (a) Dess−Martin periodinane (1.3 equiv),
CH2Cl2, −20 °C, 6 h.
Importantly, the starting material was recovered to about 44%.
Only minor amounts of the corresponding overoxidation
product, that is, the diketone, were formed.
CONCLUSION
■
22
1
acetate); [α]D = −24.5 (c = 8.5 mg cm−3 in EtOH); mp 66 °C; H
NMR (300 MHz, CDCl3) δ (ppm) = 6.71 (dd, J = 15.7, 6.5 Hz, 1H),
6.19 (dd, J = 15.6, 1.2 Hz, 1H), 5.02 (ddd, J = 8.9, 6.5, 1.2 Hz, 1H),
4.78 (dq, J = 8.9, 6.2 Hz, 1H), 1.61 (d, J = 6.2 Hz, 3H), 1.50 (s, 9H);
13C NMR (125 MHz, CDCl3) δ (ppm) = 163.5, 134.1, 129.7, 86.0,
Herein we report a straightforward enantioselective total
synthesis algorithm for the preparation of 8 out of 13
macrosphelides within 9−11 steps starting from tert-butyl
sorbate. The use of a cyclic sulfate as both protecting and
reactivity directing group set the stage for a flexible mild
introduction and derivatization of a common C6-building
blocka either within the synthesis or at a separate stage. X-ray
structure-derived molecular consideration led to the develop-
ment of a highly selective ring-enlarging transesterification that
is to date without precedence in the literature. Future work is
dedicated to the application of this algorithm to the synthesis of
defined libraries of macrosphelide analogues in order to
investigate cell−cell adhesion effects.
82.7, 82.1, 28.0 (3C), 16.4; IR (film) ν (cm−1) = 1718 (s), 1666 (w),
1371 (s), 1208 (s), 1155 (s), 980 (m), 953 (m), 831 (m); HRMS
(ESI-TOF) (m/z) [M + Na]+ calculated for C10H16O6SNa 287.0560,
found 287.0561.
(E)-3-((4S,5S)-5-Methyl-2,2-dioxido-1,3,2-dioxathiolan-4-yl)-
acrylic Acid, 3. To a solution of sulfate 2 (26.4 mg, 0.1 mmol) in 0.5
mL of dichloromethane, triethylsilane (17 μL, 0.11 mmol, 1.1 equiv)
and TFA (309 μL, 4.0 mmol, 40 equiv) were added subsequently at 0
°C. The reaction mixture was allowed to warm to room temperature.
After the conversion was completed (3 h), the solvent was removed
under reduced pressure. The TFA was coevaporated with toluene 10
times. The crude product (20.8 mg, quant.) was used in the next step
without any further purification. Rf = 0.17 (2:1 petroleum ether/ethyl
EXPERIMENTAL SECTION
■
General Remarks. All reactions and manipulations of reagents
sensitive to air or moisture were performed under nitrogen
atmosphere using standard Schlenk techniques. Chemical shifts are
expressed in ppm with residual chloroform (δ = 7.26 ppm (1H), δ =
77.0 ppm (13C)) as reference or with TMS as internal standard. For
HRMS (ESI) measurments Q-TOF was used as mass analyzer. tert-
Butyl-3-hydroxybutanoate (7)7 and tert-butylsorbate14 were prepared
according to known methods.
22
1
acetate); [α]D = −30.2 (c = 5.8 mg cm−3 in EtOH); H NMR (250
MHz, CDCl3) δ (ppm) = 9.04 (bs, 1H, COOH), 6.94 (dd, J = 15.6,
5.9 Hz, 1H), 6.30 (dd, J = 15.6, 1.1 Hz, 1H), 5.09 (ddd, J = 8.6, 6.0, 1.0
Hz, 1H), 4.80 (dq, J = 8.6, 6.2 Hz, 1H), 1.64 (d, J = 6.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ (ppm) = 169.2, 138.1, 126.2, 85.3, 82.5,
16.5; IR (film) ν (cm−1) = 2939 (m), 1696 (s), 1667 (m), 1650 (m),
1374 (s), 1202 (s), 1138 (w), 982 (m), 940 (m), 817 (s); HRMS
(ESI-TOF) (m/z) [M − H]+ calculated for C6H7O6S 206.9958, found
206.9972.
(4S,5S,E)-tert-Butyl-4,5-dihydroxyhex-2-enoate, 1. K2CO3
(3.4 g, 24.8 mmol, 3.2 equiv), K3[Fe(CN)6] (8.2 g, 24.8 mmol, 3.2
equiv), K2OsO4·2H2O (11.9 mg, 0.03 mmol, 0.4 mol %), hydro-
quinine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2PYR, 69.3
mg, 0.08 mmol, 1 mol %], and methane sulfonamide (727.2 mg, 7.6
mmol, 1 equiv) were dissolved in 76 mL of a 1:1 mixture of tert-
butanol and water. After 1 h of vigorous stirring, the mixture was
cooled to 0 °C and tert-butyl sorbate (1.3 g, 7.7 mmol) was added.
After stirring overnight at 0 °C, saturated Na2SO3 solution was added,
and the reaction mixture was allowed to warm to room temperature (1
h). Water was added to the mixture, which was then extracted with
dichloromethane (5×). The organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
(4R,5S,E)-tert-Butyl-4,5-dihydroxyhex-2-enoate, 4. To a sol-
ution of sulfate 2 (27.8 mg, 0.1 mmol) in 0.8 mL of DMF, ammonium
formate (6.3 mg, 0.1 mmol, 1 equiv) was added. The mixture was
stirred overnight at room temperature. The solvent was coevaporated
with ethyl acetate. The residue was dissolved in 0.8 mL of THF, and
methanolic HCl (1.25 M, 160 μL, 0.2 mmol, 2 equiv) was added at 0
°C. The reaction mixture was stirred overnight at 0 °C. Then sodium
bicarbonate (20 mg, 0.24 mmol, 2.4 equiv) was added. The mixture
was stirred for additional 20 min. After addition of water and ethyl
acetate, the organic layer was washed with brine. The aqueous layers
were extracted with ethyl acetate (3×). The combined organic layers
E
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were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (petroleum
ether/ethyl acetate, 1:1). Compound 4 (16.2 mg, 80%, 70% ee) was
obtained as a colorless oil. The enantiomeric excess was detected by
chiral HPLC (Chiralcel OD-H, heptane/2-propanol (95:5), 0.5 mL/
min, 220 nm), tR(5R) = 24.45, tR(5S) = 26.06), Rf = 0.28 (1:1
= 170.8, 165.4, 143.1, 124.7, 80.7, 73.1 (2C), 28.1 (3C), 21.2, 14.4; IR
(film) ν (cm−1) = 3462 (m), 1737 (m), 1713 (s), 1659 (m), 1369 (m),
1149 (s), 982 (m); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated
for C12H20O5Na 267.1203, found 267.1198.
(S)-tert-Butyl 3-(((E)-3-((4S,5S)-5-Methyl-2,2-dioxido-1,3,2-di-
oxathiolan-4-yl)acryloyl)oxy)butanoate, 8. Sulfate 2 (515 mg, 2.0
mmol) was dissolved in 10 mL of dichloromethane, and the solution
was cooled to 0 °C. Triethylsilane (330 μL, 2.1 mmol, 1.1 equiv) and
TFA (5.9 mL, 77 mmol, 40 equiv) were added subsequently, and the
mixture was allowed to warm slowly to room temperature. After
complete conversion (2−3 h), the solvent was removed under reduced
pressure. TFA was coevaporated with toluene 10 times. The residue
was dissolved in 10 mL of THF, the solution was cooled to 0 °C, and
(S)-alcohol (S)-7 (1.5 g, 9.6 mmol, 5 equiv), DCC (602.4 mg, 2.9
mmol, 1.5 equiv), and DMAP (11.9 mg, 0.1 mmol, 5 mol %) were
added subsequently. The mixture was stirred overnight at room
temperature, diluted with ethyl acetate, and washed with a diluted
CuSO4-solution and brine. The aqueous solutions were extracted with
ethyl acetate (3×). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (petroleum ether/ethyl acetate,
7:1 then 5:1) to yield 8 as a colorless oil (362.1 mg, 53%); 68% of (S)-
alcohol (S)-7 (1.05 g) could be reisolated, Rf = 0.19 (5:1 petroleum
22
petroleum ether/ethyl acetate); [α]D = 27.7 (c = 13.3 mg cm−3 in
1
EtOH); H NMR (300 MHz, CDCl3) δ (ppm) = 6.84 (dd, J = 15.7,
5.2 Hz, 1H), 6.04 (dd, J = 15.7, 1.7 Hz, 1H), 4.29 (ddd, J = 5.2, 3.6, 1.6
Hz, 1H), 3.96 (dq, J = 6.5, 3.6 Hz, 1H), 1.49 (s, 9H), 1.18 (d, J = 6.5
Hz, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) = 165.5, 143.9, 124.6,
80.7, 74.6, 70.0, 28.1 (3C), 17.5; IR (film) ν (cm−1) = 3428 (m), 1714
(s), 1690 (s), 1657 (w), 1368 (w), 1148 (s), 981 (m); HRMS (ESI-
TOF) (m/z) [M + Na]+ calculated for C10H18O4Na 225.1097, found
225.1094.
(S,E)-tert-Butyl 5-Hydroxyhex-2-enoate, 5. To a solution of
sulfate 2 (100 mg, 0.38 mmol) in 4.2 mL of DMA, 21.5 mg of NaBH4
(0.57 mmol, 1.5 equiv) was added. After 15 min stirring at room
temperature, the solvent was coevaporated with ethyl acetate. The
residue was dissolved in 4.2 mL of THF and cooled to 0 °C before
addition of a 1.25 M solution of HCl in methanol (606 μL, 0.76 mmol,
2 equiv). The reaction mixture was stirred for 3 h at 0 °C. Then
NaHCO3 (75.8 mg, 0.90 mmol, 2.4 equiv) was added, and the mixture
was stirred for an additional 20 min. After addition of water and ethyl
acetate, the organic layer was washed with brine. The aqueous layers
were extracted with ethyl acetate (3×). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (petroleum
ether/ethyl acetate, 3:1). Compound 5 (44.1 mg, 63%) was obtained
22
1
ether/ethyl acetate); [α]D = −12.1 (c = 5.7 mg cm−3 in EtOH); H
NMR (300 MHz, CDCl3) δ (ppm) = 6.80 (dd, J = 15.6, 6.3 Hz, 1H),
6.25 (dd, J = 15.7, 1.2 Hz, 1H), 5.30−5.41 (m, 1H), 5.01−5.06 (m,
1H), 4.73−4.82 (m, 1H), 2.60 (dd, J = 15.5, 7.7 Hz, 1H), 2.47 (dd, J =
15.5, 5.5 Hz, 1H), 1.61 (d, J = 6.2 Hz, 3H), 1.43 (s, 9H), 1.34 (d, J =
6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) = 169.2, 163.5,
135.4, 127.7, 85.7, 82.6, 81.1, 68.9, 42.0, 28.0 (3C), 19.7, 16.4; IR
(film) ν (cm−1) = 1719 (s), 1668 (w), 1384 (m), 1367 (w), 1209 (s),
1159 (s), 963 (m), 818 (m); HRMS (ESI-TOF) (m/z) [M + Na]+
calculated for C14H22O8SNa 373.0928, found 373.0946.
22
as a colorless oil, Rf = 0.48 (2:1 petroleum ether/ethyl acetate); [α]D
= 9.4 (c = 3.1 mg cm−3 in EtOH); H NMR (300 MHz, CDCl3) δ
1
(ppm) = 6.85 (dt, J = 15.3, 7.6 Hz, 1H), 5.83 (dt, J = 15.5, 1.5 Hz,
1H), 3.91−4.01 (m, 1H), 2.31−2.36 (m, 2H), 1.48 (s, 9H), 1.24 (d, J
= 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) = 165.7, 143.6,
125.7, 80.3, 66.7, 41.7, 28.1 (3C), 23.2; IR (film) ν (cm−1) = 3416
(w), 1713 (s), 1654 (w), 1368 (w), 1156 (s), 981 (w); HRMS (ESI-
TOF) (m/z) [M + Na]+ calculated for C10H18O3Na 209.1148, found
209.1145.
(R)-tert-Butyl 3-(((E)-3-((4S,5S)-5-Methyl-2,2-dioxido-1,3,2-di-
oxathiolan-4-yl)acryloyl)oxy)butanoate, 9. Compound 9 was
prepared according to the procedure described for 8, starting from
sulfate 2 (600 mg, 2.3 mmol) and (R)-7 (1.79 g, 11.2 mmol, 5 equiv).
Compound 9 was obtained as a colorless oil (445.4 mg, 56%), Rf =
0.32 (3:1 petroleum ether/ethyl acetate); [α]D22 = −18.1 (c = 1.3 mg
cm−3 in EtOH); 1H NMR (300 MHz, CDCl3) δ (ppm) = 6.81 (dd, J =
15.6, 6.2 Hz, 1H), 6.25 (dd, J = 15.6, 1.2 Hz, 1H), 5.29−5.41 (m, 1H),
5.01−5.07 (m, 1H), 4.78 (dq, J = 8.8, 6.2 Hz, 1H), 2.60 (dd, J = 15.5,
7.8 Hz, 1H), 2.47 (dd, J = 15.5, 5.5 Hz, 1H), 1.61 (d, J = 6.2 Hz, 3H),
1.43 (s, 9H), 1.34 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
(ppm) = 169.2, 163.5, 135.4, 127.6, 85.7, 82.6, 81.1, 68.9, 42.0, 28.0
(3C), 19.8, 16.4; IR (film) ν (cm−1) = 1719 (s), 1668 (w), 1385 (m),
1367 (m), 1210 (s), 1160 (m), 964 (m), 819 (m); HRMS (ESI-TOF)
(m/z) [M + Na]+ calculated for C14H22O8SNa 373.0928, found
373.0934.
(4R,5S,E)-tert-Butyl 4-acetoxy-5-hydroxyhex-2-enoate, 6. To
a solution of sulfate 2 (27.2 mg, 0.1 mmol) in 0.8 mL of DMF, acetic
acid (5.7 μL, 0.1 mmol, 1 equiv) and triethylamine (20.8 μL, 0.15
mmol, 1.5 equiv) were added subsequently at room temperature. The
reaction mixture was stirred overnight. The solvent was coevaporated
with ethyl acetate. The residue was dissolved in 0.8 mL of THF, and
methanolic HCl (1.25 M, 160 μL, 0.2 mmol, 2 equiv) was added at 0
°C. After the mixture was stirred for 4 h 20 min at 0 °C, NaHCO3 (20
mg, 0.24 mmol, 2.4 equiv) was added. The mixture was stirred for
additional 20 min. After addition of water and ethyl acetate, the
organic layer was washed with brine. The aqueous layers were
extracted with ethyl acetate (3×). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography (petroleum ether/
ethyl acetate, 1:1) and semipreparative HPLC (petroleum ether/ethyl
acetate, 2:1). Compound 6 (13.3 mg, 53%) was obtained as a colorless
oil, Rf = 0.18 (3:1 petroleum ether/ethyl acetate); [α]D22 = −21.8 (c =
6.8 mg cm−3 in EtOH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 6.79
(dd, J = 15.8, 5.8 Hz, 1H), 5.95 (dd, J = 15.8, 1.4 Hz, 1H), 5.35 (ddd, J
= 5.5, 4.0, 1.4 Hz, 1H), 4.01 (dq, J = 6.5, 3.8 Hz, 1H), 2.15 (s, 3H),
1.49 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm) = 170.1, 164.9, 139.7, 126.0, 80.9, 76.4, 68.9, 28.1 (3C), 21.0,
18.1; IR (film) ν (cm−1) = 3466 (m), 1741 (m), 1713 (s), 1660 (w),
1368 (m), 1150 (s), 981 (m); HRMS (ESI-TOF) (m/z) [M + Na]+
calculated for C12H20O5Na 267.1203, found 267.1183.
(S,E)-(S)-4-(tert-Butoxy)-4-oxobutan-2-yl 5-Hydroxyhex-2-
enoate, 10. To a solution of sulfate 8 (17.5 mg, 0.05 mmol) in
0.55 mL of DMA, NaBH4 (1.9 mg, 0.05 mmol, 1 equiv) was added.
After 30 min of stirring at room temperature, the solvent was
coevaporated with ethyl acetate. The residue was dissolved in 0.55 mL
of THF and cooled to 0 °C before addition of a 1.25 M solution of
methanolic HCl (80.2 μL, 0.1 mmol, 2 equiv). The reaction mixture
was stirred for 2 h 40 min at 0 °C; then NaHCO3 (10 mg, 0.12 mmol,
2.4 equiv) was added, and the mixture was stirred for additional 20
min. After addition of water and ethyl acetate, the organic layer was
washed with brine. The aqueous layers were extracted with ethyl
acetate (3×). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
column chromatography (ethyl acetate) and semipreparative HPLC
(petroleum ether/ethyl acetate, 1:1). Compound 10 (7.6 mg, 56%)
was obtained as a colorless oil, Rf = 0.45 (1:1 petroleum ether/ethyl
As a side product, regioisomer (4S,5R,E)-tert-butyl 5-acetoxy-4-
hydroxyhex-2-enoate, S6, was isolated in 19% yield (4.6 mg), Rf = 0.69
(1:1 petroleum ether/ethyl acetate); [α]D22 = 4.2 (c = 1.7 mg cm−3 in
22
1
acetate); [α]D = 17.6 (c = 6.4 mg cm−3 in EtOH); H NMR (500
MHz, CDCl3) δ (ppm) = 6.95 (dt, J = 15.2, 7.6 Hz, 1H), 5.87 (dt, J =
15.6, 1.5 Hz, 1H), 5.27−5.34 (m, 1H), 3.93−3.99 (m, 1H), 2.58 (dd, J
= 15.2, 7.6 Hz, 1H), 2.45 (dd, J = 15.2, 5.8 Hz, 1H), 2.35−2.37 (m,
2H), 1.74 (bs, 1H, OH), 1.43 (s, 9H), 1.31 (d, J = 6.3 Hz, 3H), 1.24
1
EtOH); H NMR (500 MHz, CDCl3) δ (ppm) = 6.79 (dd, J = 15.7,
4.9 Hz, 1H), 6.06 (dd, J = 15.8, 1.8 Hz, 1H), 5.01 (dq, J = 6.5, 3.2 Hz,
1H), 4.40−4.42 (m, 1H), 2.37 (bs, 1H, OH), 2.08 (s, 3H), 1.49 (s,
9H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
F
DOI: 10.1021/acs.joc.5b01171
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) = 169.5,
165.4, 145.1, 123.9, 80.8, 67.6, 66.7, 42.3, 41.8, 28.0 (3C), 23.2, 19.8;
IR (film) ν (cm−1) = 3436 (m), 1718 (s), 1655 (m), 1368 (m), 1159
(s), 982 (m); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for
C14H24O5Na 295.1516, found 295.1501.
and triethylamine (10.4 μL, 0.075 mmol, 1.5 equiv) were added. The
mixture was stirred at room temperature for 9 h. The solvent was
coevaporated with ethyl acetate. The residue was dissolved in 0.4 mL
of THF and cooled with an ice-bath; then 1.25 M methanolic HCl
(80.6 μL, 0.1 mmol, 2 equiv) was added. After the mixture was stirred
for 4 h at 0 °C, sodium bicarbonate (10.1 mg, 0.12 mmol, 2.4 equiv)
was added, and the mixture was stirred for additional 20 min. Water
and ethyl acetate were added, the organic layer was washed with brine,
and the aqueous layers were extracted with ethyl acetate (3×). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified via column
chromatography (ethyl acetate) and preparative HPLC (petroleum
ether/ethyl acetate, 1:2) to yield 14 (10.7 mg, 54%). Rf = 0.27 (1:1
(4R,5S,E)-(S)-4-(tert-Butoxy)-4-oxobutan-2-yl 4,5-Dihydroxy-
hex-2-enoate, 11. To a solution of 8 (95.8 mg, 0.27 mmol) in 2.2
mL of DMF, ammonium formiate (17.2 mg, 0.27 mmol, 1 equiv) was
added. The mixture was stirred for 3 h 30 min at room temperature.
The solvent was coevaporated with ethyl acetate. The residue was
dissolved in 2.2 mL of THF and cooled to 0 °C, and then 1.25 M
methanolic HCl (436 μL, 0.55 mmol, 2 equiv) was added. After
stirring for 3 h 20 min at 0 °C, sodium bicarbonate (59.4 mg, 0.71
mmol, 2.6 equiv) was added, and the mixture was stirred for additional
20 min. Water and ethyl acetate were added, the organic layer was
washed with brine, and the aqueous layers were extracted with ethyl
acetate (3×). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified via
column chromatography (petroleum ether/ethyl acetate, 1:1) to yield
11 (55.7 mg, 71%) as a diastereomeric mixture (dr 80:20). Because the
diastereomeres could not be separated by standard methods, 11 was
used within the next step without further purification. Rf = 0.33 (1:1
22
petroleum ether/ethyl acetate); [α]D = −0.7 (c = 1.5 mg cm−3 in
1
EtOH); H NMR (500 MHz, CDCl3) δ (ppm) = 6.99 (dt, J = 15.3,
7.6 Hz, 1H), 6.75 (dd, J = 15.7, 6.0 Hz, 1H), 5.90 (app. t, J = 15.6 Hz,
2H), 5.45−5.51 (m, 1H), 5.36−5.38 (m, 1H), 3.93−3.99 (m, 2H),
2.64−2.69 (m, 2H), 2.30−2.40 (m, 2H), 2.09 (bs, 2H, OH), 1.48 (s,
9H), 1.36 (d, J = 6.3 Hz, 3H), 1.24 (d, J = 6.1 Hz, 3H), 1.18 (d, J = 6.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) = 169.1, 165.8,
164.9, 146.4, 139.5, 125.9, 123.5, 81.0, 76.8, 68.5, 67.2, 66.6, 41.9, 41.5,
28.1 (3C), 23.3, 20.2, 17.8; IR (film) ν (cm−1) = 3436 (m), 1712 (s),
1656 (m), 1368 (m), 1152 (s), 981 (m); HRMS (ESI-TOF) (m/z)
[M + Na]+ calculated for C20H32O8Na 423.1989, found 423.1990.
(4R,5S,E)-(S)-4-(((2S,3R,E)-6-(tert-Butoxy)-2-hydroxy-6-oxo-
hex-4-en-3-yl)oxy)-4-oxobutan-2-yl 4,5-Dihydroxyhex-2-
enoate, 15. Compound 15 was prepared according to the procedure
described for 14, starting from 11 (19.3 mg, 0.067 mmol) and sulfate 2
(17.7 mg, 0.067 mmol, 1 equiv). The crude material was purified using
column chromatography (ethyl acetate) and semipreparative HPLC
(ethyl acetate). Compound 15 was obtained as colorless oil (16.6 mg,
60%). Rf = 0.15 (1:2 petroleum ether/ethyl acetate); [α]D22 = 6.1 (c =
7.4 mg cm−3 in EtOH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 6.98
(dd, J = 15.8, 5.0 Hz, 1H), 6.74 (dd, J = 15.8, 5.8 Hz, 1H), 6.09 (dd, J
= 15.6, 1.3 Hz, 1H), 5.89 (dd, J = 15.8, 1.6 Hz, 1H), 5.42−5.49 (m,
1H), 5.34−5.36 (m, 1H), 4.24−4.27 (m, 1H), 3.93−4.00 (m, 2H),
2.71 (dd, J = 15.0, 8.9 Hz, 1H), 2.66 (dd, J = 15.0, 4.2 Hz, 1H), 2.52
(bs, 3H, OH), 1.48 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.5
Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, d6-acetone) δ
(ppm) = 169.9, 166.1, 165.5, 149.7, 142.6, 125.2, 121.5, 80.9, 77.3,
75.6, 70.6, 68.7, 68.0, 41.3, 28.2 (3C), 20.1, 19.1 (2C); IR (film) ν
(cm−1) = 3435 (s), 1699 (s), 1658 (m), 1368 (m), 1151 (s), 981 (s);
HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for C20H32O9Na
439.1939, found 439.1943.
22
petroleum ether/ethyl acetate); [α]D = 27.4 (c = 5.0 mg cm−3 in
1
EtOH); H NMR (500 MHz, CDCl3) δ (ppm) = 6.94 (dd, J = 15.7,
4.9 Hz, 1H), 6.09 (app. d, J = 15.7 Hz, 1H), 5.28−5.35 (m, 1H), 4.29−
4.33 (m, 1H), 3.93−3.98 (m, 1H), 2.58 (dd, J = 15.3, 8.0 Hz, 1H),
2.46 (dd, J = 15.2, 5.6 Hz, 1H), 1.43 (s, 9H), 1.32 (d, J = 6.3 Hz, 3H),
1.16 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) =
169.6, 165.4, 145.7, 122.5, 81.0, 74.5, 69.9, 67.9, 42.2, 28.0 (3C), 19.8,
17.5; IR (film) ν (cm−1) = 3432 (m), 1722 (s), 1658 (w), 1368 (w),
1163 (m), 986 (w); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated
for C14H24O6Na 311.1465, found 311.1465.
(4R,5S,E)-(R)-4-(tert-Butoxy)-4-oxobutan-2-yl 4,5-Dihydroxy-
hex-2-enoate, 12. Compound 12 was prepared according to the
procedure described for 11, starting from 9 (180 mg, 0.51 mmol).
Compound 12 was isolated as colorless oil (94.6 mg, 64%). Rf = 0.27
(1:1 petroleum ether/ethyl acetate); [α]D22 = 8.4 (c = 2.3 mg cm−3 in
1
EtOH); H NMR (500 MHz, CDCl3) δ (ppm) = 6.93 (dd, J = 15.7,
4.9 Hz, 1H), 6.10 (dd, J = 15.7, 1.4 Hz, 1H), 5.28−5.35 (m, 1H),
4.30−4.32 (m, 1H), 3.96 (dq, J = 6.4, 3.7 Hz, 1H), 2.59 (dd, J = 15.2,
7.7 Hz, 1H), 2.46 (dd, J = 15.2, 5.7 Hz, 1H), 2.42 (bs, 2H, OH), 1.43
(s, 9H), 1.32 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ (ppm) = 169.6, 165.3, 145.5, 122.6, 81.0, 74.5,
69.9, 67.9, 42.2, 28.0 (3C), 19.8, 17.4; IR (film) ν (cm−1) = 3431 (s),
1718 (s), 1657 (w), 1368 (w), 1160 (s), 983 (m); HRMS (ESI-TOF)
(m/z) [M + Na]+ calculated for C14H24O6Na 311.1465, found
311.1480.
(4R,5S,E)-(R)-4-(((2S,3R,E)-6-(tert-Butoxy)-2-hydroxy-6-oxo-
hex-4-en-3-yl)oxy)-4-oxobutan-2-yl 4,5-Dihydroxyhex-2-
enoate, 16. Compound 16 was prepared according to the procedure
described for 14, starting from 12 (8.5 mg, 0.029 mmol) and sulfate 2
(7.8 mg, 0.03 mmol, 1 equiv). The crude material was purified using
column chromatography (ethyl acetate) and semipreparative HPLC
(ethyl acetate). Compound 16 was obtained as colorless oil (6.4 mg,
(S,E)-(R)-4-(tert-Butoxy)-4-oxobutan-2-yl 5-Hydroxyhex-2-
enoate, 13. Compound 13 was prepared according to the procedure
for 10 starting from 9 (17.5 mg, 0.05 mmol). Compound 13 was
yielded as colorless oil (7.4 mg, 54%). Rf = 0.59 (1:1 petroleum ether/
22
52%). Rf1 = 0.53 (ethyl acetate); [α]D = 4.4 (c = 0.9 mg cm−3 in
22
1
ethyl acetate); [α]D = 3.4 (c = 3.6 mg cm−3 in EtOH); H NMR
(500 MHz, CDCl3) δ (ppm) = 6.94 (dt, J = 15.3, 7.6 Hz, 1H), 5.86
(dt, J = 15.8, 1.3 Hz, 1H), 5.26−5.32 (m, 1H), 3.92−3.98 (m, 1H),
2.57 (dd, J = 15.2, 7.7 Hz, 1H), 2.43 (dd, J = 15.2, 5.7 Hz, 1H), 2.33−
2.36 (m, 2H), 1.71 (bs, 1H, OH), 1.41 (s, 9H), 1.30 (d, J = 6.3 Hz,
3H), 1.22 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
= 169.5, 165.4, 145.2, 123.9, 80.8, 67.6, 66.7, 42.3, 41.8, 28.0 (3C),
23.2, 19.8; IR (film) ν (cm−1) = 3440 (m), 1722 (s), 1655 (w), 1368
(m), 1164 (s), 984 (w); HRMS (ESI-TOF) (m/z) [M + Na]+
calculated for C14H24O5Na 295.1516, found 295.1517.
EtOH); H NMR (300 MHz, CDCl3) δ (ppm) = 7.05 (dd, J = 15.7,
5.3 Hz, 1H), 6.68 (dd, J = 15.8, 6.3 Hz, 1H), 6.11 (dd, J = 15.8, 1.3 Hz,
1H), 5.90 (dd, J = 15.8, 1.2 Hz, 1H), 5.45−5.52 (m, 1H), 5.27−5.31
(m, 1H), 4.21−4.23 (m, 1H), 3.90−4.04 (m, 2H), 2.80 (bs, 3H, OH),
2.74 (dd, J = 15.7, 8.2 Hz, 1H), 2.67 (dd, J = 15.5, 4.5 Hz, 1H), 1.48
(s, 9H), 1.35 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.0 Hz, 3H), 1.16 (d, J =
6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) = 169.2, 165.8,
165.3, 147.3, 139.7, 126.2, 122.4, 81.4, 76.9, 74.8, 70.0, 68.6, 67.1, 41.1,
28.0 (3C), 20.1, 18.0, 17.9; IR (film) ν (cm−1) = 3435 (s), 1715 (s),
1659 (w), 1369 (m), 1155 (s), 984 (m); HRMS (ESI-TOF) (m/z) [M
+ Na]+ calculated for C20H32O9Na 439.1939, found 439.1940.
(4R,5S,E)-tert-Butyl 5-Hydroxy-4-(((S)-3-(((S,E)-5-hydroxyhex-
2-enoyl)oxy)butanoyl)oxy)hex-2-enoate, 14. To a solution of 10
(13.6 mg, 0.051 mmol) in 205 μL of dichloromethane, triethylsilane
(9.0 μL, 0.057 mmol, 1.1 equiv) and TFA (157.2 μL, 2.0 mmol, 40
equiv) were added subsequently at 0 °C. The mixture was allowed to
warm slowly to room temperature. After the conversion was
completed (2 h), the solvent was removed under reduced pressure.
The TFA was coevaporated with toluene 10 times. The residue was
dissolved in 0.4 mL of DMF. Sulfate 2 (13.2 mg, 0.05 mmol, 1 equiv)
(4R,5S,E)-tert-Butyl 5-Hydroxy-4-(((R)-3-(((S,E)-5-hydroxyhex-
2-enoyl)oxy)butanoyl)oxy)hex-2-enoate, 17. Compound 17 was
prepared according to the procedure described for 14, starting from 13
(17.4 mg, 0.064 mmol) and sulfate 2 (16.9 mg, 0.064 mmol, 1 equiv).
Compound 17 was obtained as colorless oil (12.7 mg, 50%). Rf = 0.13
(1:1 petroleum ether/ethyl acetate); [α]D22 = 9.4 (c = 1.2 mg cm−3 in
1
EtOH); H NMR (500 MHz, CDCl3) δ (ppm) = 6.99 (dt, J = 15.3,
G
DOI: 10.1021/acs.joc.5b01171
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The Journal of Organic Chemistry
Article
7.6 Hz, 1H), 6.73 (dd, J = 15.8, 6.0 Hz, 1H), 5.91 (dd, J = 15.7, 1.2 Hz,
1H), 5.89 (dt, J = 15.6, 1.4 Hz, 1H), 5.38−5.44 (m, 1H), 5.34 (ddd, J
= 5.8, 3.4, 1.4 Hz, 1H), 3.94−4.03 (m, 2H), 2.75 (dd, J = 15.6, 8.4 Hz,
1H), 2.63 (dd, J = 15.5, 4.4 Hz, 1H), 2.29−2.42 (m, 2H), 1.48 (s, 9H),
1.35 (d, J = 6.4 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.17 (d, J = 6.6 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ (ppm) = 169.4, 165.7, 164.9,
146.2, 139.4, 126.2, 123.6, 81.0, 76.9, 68.6, 67.1, 66.6, 41.8, 41.1, 28.1
(3C), 23.3, 20.2, 18.0; IR (film) ν (cm−1) = 3434 (m), 1716 (s), 1656
(m), 1369 (m), 1156 (s), 982 (m); HRMS (ESI-TOF) (m/z) [M +
Na]+ calculated for C20H32O8Na 423.1989, found 423.1984.
2.04 (bs, 1H, OH), 1.45 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 6.3 Hz, 3H),
1.17 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, d6-acetone) δ (ppm) =
169.1, 166.2, 164.7, 147.3, 144.4, 126.2, 122.9, 78.2, 75.2, 75.1, 69.0,
68.5, 42.1, 20.1, 19.1, 17.9; IR (film) ν (cm−1) = 3460 (m), 1716 (s),
1657 (w), 1381 (w), 1171 (m), 984 (m); HRMS (ESI-TOF) (m/z)
[M + Na]+ calculated for C16H22O8Na 365.1207, found 365.1201.
(2R,6R,7E,11S,13E)-6-((S)-1-Hydroxyethyl)-2,11-dimethyl-
1,5,10-trioxacyclopentadeca-7,13-diene-4,9,15-trione, 19.
Compound 19 was prepared according to the procedure described
for 18, starting from 17 (9.8 mg, 0.025 mmol). Compound 19 was
obtained as a colorless oil (3.8 mg, 48%). Rf = 0.49 (1:2 petroleum
(2S,6R,7E,11S,13E)-6-((S)-1-Hydroxyethyl)-2,11-dimethyl-
1,5,10-trioxacyclopentadeca-7,13-diene-4,9,15-trione, 18. To a
solution of ester 14 (7.4 mg, 0.019 mmol) in 150 μL of
dichloromethane, triethylsilane (3.2 μL, 0.02 mmol, 1.1 equiv) and
TFA (144.0 μL, 1.9 mmol, 100 equiv) were added at 0 °C. The
mixture was stirred for 20 min at 0 °C and then for 1 h at room
temperature. The solvent was removed under reduced pressure, and
the TFA was coevaporated with toluene 10 times. The residue was
dissolved in a THF/dichloromethane-mixture (1:1, 3.8 mL). The
solution was added to a solution of 2-methyl-6-nitrobenzoic anhydride
(7.7 mg, 0.022 mmol, 1.2 equiv), DMAP (0.6 mg, 4.9 μmol, 0.25
equiv), and triethylamine (5.7 μL, 0.041 mmol, 2.2 equiv) in 5.6 mL of
dichloromethane over 7 h. Afterward, the reaction mixture was stirred
for an additional hour. The solvent was removed under reduced
pressure. The crude product was purified by column chromatography
(ethyl acetate) and semipreparative HPLC (petroleum ether/ethyl
acetate, 1:1). Compound 18 (2.6 mg, 43%) was isolated as a colorless
22
1
ether/ethyl acetate); [α]D = 25.3 (c = 0.8 mg cm−3 in EtOH); H
NMR (500 MHz, CDCl3) δ (ppm) = 6.94 (ddd, J = 15.6, 10.0, 5.6 Hz,
1H), 6.49 (dd, J = 15.8, 9.5 Hz, 1H), 5.98 (app. d, J = 15.8 Hz, 1H),
5.69 (app. d, J = 15.6 Hz, 1H), 5.24−5.31 (m, 1H), 5.18 (app. dd, J =
9.5, 4.2 Hz, 1H), 5.10−5.16 (m, 1H), 3.99 (dq, J = 6.4, 4.3 Hz, 1H),
2.76−2.82 (m, 1H), 2.79 (dd, J = 14.8, 4.2 Hz, 1H), 2.55 (dd, J = 14.9,
9.9 Hz, 1H), 2.29−2.33 (m, 1H), 1.86 (bs, 1H, OH), 1.42 (d, J = 6.7
Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, d6-acetone) δ (ppm) = 169.0, 165.6, 165.1, 144.3, 143.3,
127.4, 126.1, 78.1, 69.9, 68.9, 68.2, 42.0, 37.2, 20.1, 19.6, 19.3; IR
(film) ν (cm−1) = 3480 (m), 1717 (s), 1655 (w), 1381 (w), 1179 (m),
983 (m); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for
C16H22O7Na 349.1258, found 349.1243.
Macrosphelide A. Macrosphelide D (4 mg, 0.012 mmol) was
dissolved in 0.69 mL of dichloromethane and transferred into a 1.5 mL
vial. A 0.77 M Ti(iOPr)4 solution (in dichloromethane, 760 μL, 0.59
mmol, 50 equiv) was added, and the vial was shaken before being put
into the high-pressure chamber. A pressure of 7 kbar was adjusted, and
the reaction mixture was left in the chamber overnight. The mixture
was washed subsequently with 1 M hydrochloric acid and saturated
sodium bicarbonate solution. The combined aqueous layers were
filtered and extracted with ethyl acetate (3×x). The combined organic
layers were dried over Na2SO4, the solvent was evaporated, and the
crude material was purified via column chromatography (ethyl acetate)
and semipreparative HPLC (petroleum ether/ethyl acetate, 1:2).
Macrosphelide A (3.1 mg, 77%) was obtained as colorless oil. Rf = 0.34
(1:1 petroleum ether/ethyl acetate); [α]D22 = 81.0 (c = 1.0 mg cm−3 in
CH3OH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 6.87 (dd, J = 15.7,
4.6 Hz, 1H), 6.87 (dd, J = 15.7, 4.8 Hz, 1H), 6.05 (dd, J = 15.8, 1.1 Hz,
1H), 6.04 (dd, J = 15.7, 1.4 Hz, 1H), 5.36−5.42 (m, 1H), 4.96 (dq, J =
6.4, 4.8 Hz, 1H), 4.86 (dq, J = 6.5, 6.5 Hz, 1H), 4.22−4.24 (m, 1H),
4.13−4.15 (m, 1H), 2.92 (bs, 1H, OH), 2.62 (dd, J = 15.6, 9.1 Hz,
1H), 2.57 (dd, J = 15.5, 3.3 Hz, 1H), 1.64 (bs, 1H, OH), 1.45 (d, J =
6.6 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ (ppm) = 170.2, 165.8, 164.6, 146.0, 145.0,
122.7, 122.3, 75.0, 74.8, 74.1, 73.1, 67.7, 41.0, 19.7, 18.0, 17.8; IR
(film) ν (cm−1) = 3435 (m), 1716 (s), 1646 (w), 1379 (w), 1186 (m),
982 (m); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for
C16H22O8Na 365.1207, found 365.1219.
22
oil. Rf = 0.40 (1:1 petroleum ether/ethyl acetate); [α]D = 36.0 (c =
0.7 mg cm−3 in EtOH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 6.71
(ddd, J = 15.6, 10.6, 5.1 Hz, 1H), 6.59 (dd, J = 16.1, 8.5 Hz, 1H), 5.93
(app. d, J = 16.1 Hz, 1H), 5.85 (app. d, J = 15.5 Hz, 1H), 5.29−5.36
(m, 1H), 5.04 (app. dd, J = 8.4, 3.9 Hz, 1H), 4.94−5.01 (m, 1H),
4.03−4.08 (m, 1H), 2.63 (dd, J = 13.4, 11.8 Hz, 1H), 2.46−2.52 (m,
2H), 2.34−2.41 (m, 1H), 1.38 (d, J = 6.2 Hz, 3H), 1.34 (d, J = 6.3 Hz,
3H), 1.22 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
= 169.8, 164.8, 164.3, 143.1, 140.4, 127.0, 126.1, 77.9, 69.0, 68.9, 68.3,
41.7, 39.7, 20.8, 20.3, 18.3; IR (film) ν (cm−1) = 3485 (m), 1717 (s),
1658 (w), 1364 (w), 1176 (s), 981 (m); HRMS (ESI-TOF) (m/z) [M
+ Na]+ calculated for C16H22O7Na 349.1258, found 349.1266.
Macrosphelide D. Macrosphelide D was prepared according to
the procedure described for 18, starting from 15 (15.3 mg, 0.037
mmol). The crude material was purified using column chromatography
(ethyl acetate) and semipreparative HPLC (petroleum ether/ethyl
acetate, 1:2). Macrosphelide D was obtained as a colorless oil (5.9 mg,
47%). Macrosphelide D was crystallized from CDCl3 (white crystals).
22
Rf = 0.16 (1:1 petroleum ether/ethyl acetate); [α]D = 55.0 (c = 0.9
1
mg cm−3 in CH3OH); mp 171 °C; H NMR (500 MHz, CDCl3) δ
(ppm) = 6.65 (dd, J = 15.8, 7.9 Hz, 1H), 6.58 (dd, J = 16.0, 8.4 Hz,
1H), 5.95 (app. d, J = 15.9 Hz, 2H), 5.31−5.38 (m, 1H), 5.05 (app. dd,
J = 8.5, 3.9 Hz, 1H), 4.76 (dq, J = 8.2, 6.4 Hz, 1H), 4.16 (app. t, J = 8.2
Hz, 1H), 4.06 (dq, J = 6.1, 5.1 Hz, 1H), 2.64 (dd, J = 13.7, 11.7 Hz,
1H), 2.52 (dd, J = 13.8, 3.0 Hz, 1H), 1.47 (d, J = 6.3 Hz, 3H), 1.35 (d,
J = 6.3 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ (ppm) = 169.7, 164.3, 164.1, 145.6, 140.8, 126.9, 124.4,
77.7, 76.0, 72.5, 69.2, 68.2, 41.5, 20.2, 18.4, 17.8; IR (film) ν (cm−1) =
3456 (m), 1719 (s), 1660 (w), 1367 (w), 1183 (w), 982 (m); HRMS
(ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O8Na 365.1207,
found 365.1219.
Macrosphelide C. Macrosphelide C was prepared according to the
procedure described for macrosphelide A, starting from 18 (1.8 mg,
5.5 μmol). The crude material was purified using column
chromatography (ethyl acetate) and semipreparative HPLC (petro-
leum ether/ethyl acetate, 1:1). Macrosphelide C was obtained as a
colorless oil (1.5 mg, 83%). Rf = 0.45 (1:1 petroleum ether/ethyl
22
1
acetate); [α]D = 42.9 (c = 0.6 mg cm−3 in EtOH); H NMR (500
MHz, CDCl3) δ (ppm) = 6.89 (dd, J = 15.7, 4.9 Hz, 1H), 6.86 (ddd, J
= 15.6, 9.2, 6.3 Hz, 1H), 6.06 (dd, J = 15.7, 1.6 Hz, 1H), 5.80 (app. d, J
= 15.7 Hz, 1H), 5.27−5.33 (m, 1H), 5.07−5.13 (m, 1H), 4.92 (dq, J =
6.4, 6.4 Hz, 1H), 4.16 (app. dd, J = 5.1, 5.1 Hz, 1H), 2.63 (dd, J = 14.7,
2.9 Hz, 1H), 2.52−2.57 (m, 1H), 2.51 (dd, J = 14.7, 8.4 Hz, 1H),
2.33−2.40 (m, 1H), 2.06 (bs, 1H, OH) 1.37 (d, J = 6.7 Hz, 3H), 1.36
(d, J = 6.6 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ (ppm) = 170.0, 165.0, 164.8, 144.9, 143.8, 124.7, 123.0,
73.7, 72.9, 69.0, 67.4, 40.9, 38.8, 20.5, 19.5, 17.5; IR (film) ν (cm−1) =
3468 (m), 1718 (s), 1659 (w), 1381 (w), 1177 (m), 979 (m); HRMS
(ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O7Na 349.1258,
found 349.1282.
Macrosphelide M. Macrosphelide M was prepared according to
the procedure described for 18, starting from 16 (13.1 mg, 0.031
mmol). The crude material was purified using column chromatography
(ethyl acetate) and semipreparative HPLC (petroleum ether/ethyl
acetate, 1:2). Macrosphelide M was obtained as a colorless oil (3.6 mg,
33%). Rf = 0.30 (1:2 petroleum ether/ethyl acetate); [α]D22 = 34.0 (c
1
= 2.5 mg cm−3 in EtOH); H NMR (500 MHz, CDCl3) δ (ppm) =
7.06 (dd, J = 15.8, 3.2 Hz, 1H), 6.47 (dd, J = 15.8, 9.5 Hz, 1H), 6.08
(dd, J = 15.8, 1.9 Hz, 1H), 6.02 (app. d, J = 15.8 Hz, 1H), 5.32−5.38
(m, 1H), 5.28 (app. q, J = 6.9 Hz, 1H), 5.19 (app. dd, J = 9.5, 4.4 Hz,
1H), 4.42−4.44 (m, 1H), 3.98−4.02 (m, 1H), 3.11−3.12 (m, 1H,
OH), 2.76 (dd, J = 14.8, 4.1 Hz, 1H), 2.59 (dd, J = 14.8, 11.1 Hz, 1H),
H
DOI: 10.1021/acs.joc.5b01171
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Macrosphelide E. Macrosphelide E was prepared according to the
procedure described for macrosphelide A, starting from macrosphelide
ution of sulfate 20 (18.6 mg, 0.04 mmol) and ammonium formate (2.5
mg, 0.04 mmol, 1 equiv) in 320 μL of DMF was stirred at room
temperature for 5 h. The solvent was coevaporated with ethyl acetate.
The residue was dissolved in 320 μL of THF and cooled to 0 °C, and
then 1.25 M methanolic HCl (64 μL, 0.08 mmol, 2 equiv) was added.
The mixture was stirred for 2.5 h at 0 °C. NaHCO3 (8 mg, 0.10 mmol,
2.4 equiv) was added, and the mixture was stirred for additional 20
min at 0 °C. Then ethyl acetate and water were added. The organic
layer was washed with brine. The aqueous layers were extracted 3×
with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The
crude product was purified by column chromatography (petroleum
ether/ethyl acetate, 1:1) to yield 21 (11.5 mg, 71%) as a
diastereomeric mixture (dr 80:20). Because the diastereomeres could
not be separated using standard methods, 21 was used as mixture
within the next step. Rf = 0.40 (1:1 petroleum ether/ethyl acetate);
M (2.6 mg, 7.6 μmol). Macrosphelide E was obtained as a colorless oil
22
(2.0 mg, 77%). Rf = 0.23 (1:1 petroleum ether/ethyl acetate); [α]D
=
1
64.4 (c = 0.9 mg cm−3 in EtOH); H NMR (500 MHz, CDCl3) δ
(ppm) = 7.02 (dd, J = 15.6, 4.2 Hz, 1H), 6.80 (dd, J = 15.7, 5.1 Hz,
1H), 6.11 (dd, J = 15.7, 1.3 Hz, 1H), 6.07 (dd, J = 15.7, 1.2 Hz, 1H),
5.29−5.35 (m, 1H), 5.12 (dq, J = 6.8, 1.7 Hz, 1H), 4.98 (dq, J = 6.5,
4.4 Hz, 1H), 4.36−4.38 (m, 1H), 4.18−4.19 (m, 1H), 3.37 (d, J = 6.7
Hz, 1H, OH), 3.09 (d, J = 5.4 Hz, 1H, OH), 2.72 (dd, J = 16.0, 3.0 Hz,
1H), 2.60 (dd, J = 16.0, 7.5 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.39 (d,
J = 6.5 Hz, 3H), 1.32 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ (ppm) = 170.9, 166.8, 165.3, 145.4, 145.0, 123.0, 122.3,
76.1, 75.4, 75.2, 73.8, 66.6, 40.5, 19.6, 17.8, 17.3; IR (film) ν (cm−1) =
3456 (m), 1716 (s), 1662 (w), 1358 (m), 1191 (m), 984 (m); HRMS
(ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O8Na 365.1207,
found 365.1210.
22
[α]D = 0.8 (c = 1.3 mg cm−3 in EtOH); 1H NMR (500 MHz,
CDCl3) δ (ppm) = 6.98 (dd, J = 15.7, 5.0 Hz, 1H), 6.73 (dt, J = 15.1,
7.5 Hz, 1H), 6.09 (dd, J = 15.7, 1.4 Hz, 1H), 5.78 (dt, J = 15.5, 1.4 Hz,
1H), 5.31−5.37 (m, 1H), 5.00−5.06 (m, 1H), 4.27−4.29 (m, 1H),
3.96 (dq, J = 6.3, 4.1 Hz, 1H), 2.65 (dd, J = 15.4, 7.8 Hz, 1H), 2.55
(dd, J = 15.5, 5.2 Hz, 1H), 2.40−2.43 (m, 2H), 1.48 (s, 9H), 1.33 (d, J
= 6.3 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ (ppm) = 169.6, 165.8, 165.2, 146.1, 142.5,
125.8, 122.4, 80.7, 74.6, 69.9, 69.7, 67.3, 41.1, 38.1, 28.1 (3C), 19.8,
19.7, 17.7; IR (film) ν (cm−1) = 3466 (m), 1715 (s), 1656 (m), 1368
(m), 1160 (s), 982 (m); HRMS (ESI-TOF) (m/z) [M + Na]+
calculated for C20H32O8Na 423.1989, found 423.1997.
Macrosphelide F. Macrosphelide F was prepared according to the
procedure described for macrosphelide A, starting from 19 (1.7 mg,
5.2 μmol). The crude material was purified using column
chromatography (ethyl acetate) and semipreparative HPLC (petro-
leum ether/ethyl acetate, 1:1). Macrosphelide F was obtained as a
colorless oil (1.2 mg, 71%). Rf = 0.52 (1:1 petroleum ether/ethyl
22
1
acetate); [α]D = 24.0 (c = 0.7 mg cm−3 in EtOH); H NMR (500
MHz, CDCl3) δ (ppm) = 6.88 (dt, J = 14.9, 7.4 Hz, 1H), 6.84 (dd, J =
15.6, 4.3 Hz, 1H), 6.09 (dd, J = 15.5, 1.7 Hz, 1H), 5.80 (app. d, J =
15.8 Hz, 1H), 5.27−5.33 (m, 1H), 5.12−5.18 (m, 1H), 4.94 (dq, J =
6.5, 3.9 Hz, 1H), 4.19−4.23 (m, 1H), 2.98 (d, J = 7.6 Hz, 1H, OH),
2.69−2.74 (m, 1H), 2.67 (dd, J = 15.9, 2.9 Hz, 1H), 2.59 (dd, J = 15.8,
7.8 Hz, 1H), 2.39 (ddd, J = 14.5, 7.2, 7.2 Hz, 1H), 1.39 (d, J = 6.4 Hz,
3H), 1.36 (d, J = 6.5 Hz, 3H), 1.31 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ (ppm) = 171.0, 165.1, 165.0, 144.2, 143.6, 124.7,
123.1, 76.0, 73.6, 68.9, 66.5, 40.7, 37.7, 19.8, 19.7, 17.4; IR (film) ν
(cm−1) = 3471 (m), 1714 (s), 1656 (w), 1361 (w), 1181 (s), 979 (m);
HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O7Na
349.1258, found 349.1256.
Macrosphelide G. To a solution of ester 21 (6.6 mg, 0.017 mmol)
in 140 μL of dichloromethane, triethylsilane (3.0 μL, 0.018 mmol, 1.1
equiv) and TFA (133.3 μL, 1.7 mmol, 100 equiv) were added at 0 °C.
The mixture was stirred for 20 min at 0 °C and then for 1 h at room
temperature. The solvent was removed under reduced pressure, and
TFA was coevaporated with toluene 10 times. The residue was
dissolved in a THF/dichloromethane-mixture (1:1, 3.6 mL). The
solution was added to a solution of 2-methyl-6-nitrobenzoic anhydride
(7.2 mg, 0.02 mmol, 1.3 equiv), DMAP (0.5 mg, 4.1 μmol, 0.25 equiv),
and triethylamine (5.3 μL, 0.038 mmol, 2.3 equiv) in 5.2 mL of
dichloromethane over 7 h. Afterward, the reaction mixture was stirred
for an additional hour. The solvent was removed under reduced
pressure. The crude product was purified by column chromatography
(ethyl acetate) and semipreparative HPLC (petroleum ether/ethyl
acetate, 1:1). Macrosphelide G (1.4 mg) and 1.8 mg of 22 were
isolated as colorless oils (59%, 1:1.3). Afterward, 22 could be
transesterified into macrosphelide G. Macrosphelide G was crystallized
from CDCl3 (white needles). Rf = 0.47 (1:1 petroleum ether/ethyl
(S,E)-tert-Butyl 5-(((R)-3-(((E)-3-((4S,5S)-5-Methyl-2,2-dioxido-
1,3,2-dioxathiolan-4-yl)acryloyl)oxy)butanoyl)oxy)hex-2-
enoate, 20. To a solution of sulfate 9 (37.6 mg, 0.11 mmol, 2 equiv)
in 0.48 mL of dichloromethane, triethylsilane (18 μL, 0.11 mmol, 2.2
equiv) and TFA (320.8 μL, 4.2 mmol, 80 equiv) were added at 0 °C.
The mixture was allowed to warm slowly to room temperature. After
complete conversion (2−3 h), the solvent was removed under reduced
pressure. The TFA was coevaporated with toluene 10 times. The
residue was dissolved in 0.6 mL of 1,2-dichloroethane and cooled to
−20 °C. Alcohol 5 (10 mg, 0.05 mmol, 1 equiv), DCC (36.5 mg, 0.18
mmol, 3.3 equiv), DMAP (1.3 mg, 0.01 mmol, 0.2 equiv), and β-
camphorsulfonic acid (1 mg, 4.3 μmol, 8 mol %) were added
subsequently. The mixture was stirred overnight at −20 °C, then
diluted with ethyl acetate and washed with a diluted CuSO4 solution
and brine. The aqueous solutions were extracted with ethyl acetate
(3×). The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified by
column chromatography (ethyl acetate) and semipreparative HPLC
22
1
acetate); [α]D = 36.0 (c = 4.7 mg cm−3 in EtOH); mp 86 °C; H
NMR (500 MHz, CDCl3) δ (ppm) = 7.05 (dd, J = 15.6, 3.7 Hz, 1H),
6.80 (ddd, J = 15.3, 8.7, 6.3 Hz, 1H), 6.11 (dd, J = 15.5, 1.6 Hz, 1H),
5.80 (dt, J = 15.6, 1.3 Hz, 1H), 5.21−5.27 (m, 1H), 5.05−5.11 (m,
2H), 4.34−4.37 (m, 1H), 3.37 (d, J = 8.2 Hz, 1H, OH), 2.76 (dd, J =
15.7, 3.9 Hz, 1H), 2.35−2.53 (m, 3H), 1.45 (d, J = 6.5 Hz, 3H), 1.41
(d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ (ppm) = 169.4, 167.1, 165.5, 145.5, 145.5, 123.4, 121.9,
76.4, 75.3, 70.0, 67.2, 39.9, 38.3, 20.2, 19.2, 17.8; IR (film) ν (cm−1) =
3469 (m), 1718 (s), 1660 (w), 1374 (w), 1194 (m), 981 (m); HRMS
(ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O7Na 349.1258,
found 349.1258.
(petroleum ether/ethyl acetate, 1:1) to yield 20 as colorless oil (14.0
22
mg, 56%). Rf = 0.63 (3:1 petroleum ether/ethyl acetate); [α]D
=
−23.1 (c = 5.8 mg cm−3 in EtOH); H NMR (500 MHz, CDCl3) δ
(ppm) = 6.81 (dd, J = 15.6, 6.3 Hz, 1H), 6.74 (dt, J = 15.1, 7.6 Hz,
1H), 6.26 (app. d, J = 15.6 Hz, 1H), 5.79 (app. d, J = 15.8 Hz, 1H),
5.33−5.40 (m, 1H), 5.00−5.09 (m, 2H), 4.80 (dq, J = 8.6, 6.2 Hz,
1H), 2.67 (dd, J = 15.7, 7.6 Hz, 1H), 2.54 (dd, J = 15.7, 5.5 Hz, 1H),
2.37−2.47 (m, 2H), 1.61 (d, J = 6.2 Hz, 3H), 1.48 (s, 9H), 1.35 (d, J =
6.3 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm) = 169.4, 165.5, 163.5, 141.8, 135.7, 127.5, 126.0, 85.7, 82.6,
80.4, 69.8, 68.5, 40.8, 38.1, 28.1 (3C), 19.7, 19.6, 16.5; IR (film) ν
(cm−1) = 1728 (s), 1656 (w), 1390 (m), 1369 (w), 1211 (s), 1159 (s),
976 (m), 823 (w); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for
C20H30O10SNa 485.1471, found 485.1452.
1
(4R,7E,9R,12E,15S)-9-((S)-1-Hydroxyethyl)-4,15-dimethyl-1,5,10-
trioxacyclopentadeca-7,12-diene-2,6,11-trione, 22. Rf = 0.47 (1:1
22
petroleum ether/ethyl acetate); [α]D = 27.5 (c = 1.5 mg cm−3 in
1
EtOH); H NMR (250 MHz, CDCl3) δ (ppm) = 6.95 (dd, J = 16.2,
5.7 Hz, 1H), 6.84 (dt, J = 15.5, 7.7 Hz, 1H), 5.96−6.09 (m, 2H),
5.34−5.39 (m, 1H), 5.12−5.23 (m, 1H), 4.90−5.03 (m, 1H), 4.08−
4.17 (m, 1H), 2.71 (dd, J = 14.0, 5.4 Hz, 1H), 2.44−2.50 (m, 2H),
2.34 (dd, J = 14.0, 2.4 Hz, 1H), 1.97 (bs, 1H, OH), 1.49 (d, J = 6.6 Hz,
3H), 1.31 (d, J = 6.2 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ (ppm) = 169.6, 166.8, 164.6, 146.6, 140.3, 126.6,
124.6, 77.3, 71.7, 67.9, 67.6, 39.7, 38.2, 20.6, 18.5 (2C); IR (film) ν
(cm−1) = 3489 (m), 1723 (s), 1655 (w), 1369 (m), 1193 (s), 980 (m);
(4R,5S,E)-(R)-4-(((S,E)-6-(tert-Butoxy)-6-oxohex-4-en-2-yl)-
oxy)-4-oxobutan-2-yl 4,5-Dihydroxyhex-2-enoate, 21. A sol-
I
DOI: 10.1021/acs.joc.5b01171
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for C16H22O7Na
349.1258, found 349.1251.
NMR data for all reported compounds and crystal
structures of macrosphelide D and G (PDF)
X-ray structure for macrosphelide G (CIF)
X-ray structure for macrosphelide D (CIF)
Macrosphelide G. Compound 22 (4.4 mg, 0.013 mmol) was
dissolved in 0.56 mL of dichloromethane, and scandium triflate (4.7
mg, 0.01 mmol, 0.7 equiv) was added. After the mixture was stirred for
2 min at room temperature, DMAP (5.5 mg, 0.045 mmol, 3.3 equiv)
was added. The reaction mixture was stirred for 5 min. The mixture
was filtered through a silica plug, which was rinsed with ethyl acetate.
The solvent was removed under reduced pressure. The crude product
was purified by column chromatography (ethyl acetate) and
semipreparative HPLC (petroleum ether/ethyl acetate 1:1). Macro-
sphelide G (3.7 mg) was isolated in 84% yield.
AUTHOR INFORMATION
Corresponding Author
*Prof. Dr. Bernd Plietker. E-mail: bernd.plietker@oc.uni-
stuttgart.de.
■
Notes
The authors declare no competing financial interest.
Macrosphelide B. To a solution of macrosphelide A (3.6 mg, 0.01
mmol) in 2.3 mL of dichloromethane, DMP (4.1 mg, 0.01 mmol, 0.92
equiv) was added at −20 °C. More DMP (after 2.5 h, 1 mg, 2.4 μmol,
0.23 equiv; after 3 h 20 min, 0.8 mg, 1.9 μmol, 0.18 equiv) was added
to the reaction mixture. The reaction was stopped after 6 h by filtering
through a silica plug, which was then rinsed with ethyl acetate. The
crude product was purified by column chromatography (ethyl acetate)
and semipreparative HPLC (petroleum ether/ethyl acetate, 1:1).
Macrosphelide B (1.3 mg, 36%) was obtained as the main product. As
side products, 23 (0.5 mg, 14%) and diketone 24 (0.2 mg, 6%) could
be isolated. Macrosphelide A (1.6 mg, 44%) could be reisolated. Rf =
ACKNOWLEDGMENTS
■
Financial support by the Landesgraduiertenforderung Baden-
̈
Wurttemberg (Ph.D.-grant for C.H.) is gratefully acknowl-
̈
edged. The authors are grateful to Dr. Wolfgang Frey for X-ray
analysis.
REFERENCES
■
(1) (a) Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.;
22
0.55 (1:1 petroleum ether/ethyl acetate); [α]D = 9.2 (c = 1.1 mg
Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler, P. A.; Smith, A. B.
̅
cm−3 in CH3OH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 7.03 (d, J
= 15.8 Hz, 1H), 6.92 (dd, J = 15.7, 3.5 Hz, 1H), 6.74 (d, J = 15.8 Hz,
1H), 6.09 (dd, J = 15.7, 2.0 Hz, 1H), 5.44−5.50 (m, 1H), 5.05−5.10
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= 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) = 196.2, 170.3,
165.4, 164.1, 144.2, 132.5, 132.1, 122.6, 76.9, 75.8, 74.9, 67.7, 40.6,
19.8, 17.9, 16.1; IR (film) ν (cm−1) = 3497(m), 1719 (s), 1647 (w),
1388 (m), 1181 (m), 985 (m); HRMS (ESI-TOF) (m/z) [M + Na]+
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1995, 48, 1435−1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.;
EtOH); 1H NMR (500 MHz, CDCl3) δ (ppm) = 7.25 (d, J = 16.0 Hz,
1H), 7.01 (dd, J = 15.8, 5.3 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 6.19
(dd, J = 15.8, 1.3 Hz, 1H), 5.32−5.38 (m, 1H), 5.21 (q, J = 7.2 Hz,
1H), 4.89 (dq, J = 8.4, 6.3 Hz, 1H), 4.17−4.22 (m, 1H), 2.70 (dd, J =
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132.3, 121.8, 75.5, 73.1, 73.0, 68.9, 40.9, 19.5, 17.9, 17.0; IR (film) ν
(cm−1) = 3508 (m), 1723 (s), 1625 (w), 1388 (m), 1187 (m), 984
(m); HRMS (ESI-TOF) (m/z) [M + Na]+ calculated for C16H20O8Na
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22
1
ether/ethyl acetate); [α]D = −13.5 (c = 4.6 mg cm−3 in EtOH); H
NMR (300 MHz, CDCl3) δ (ppm) = 7.36 (d, J = 16.1 Hz, 1H), 7.16
(d, J = 15.8 Hz, 1H), 6.85 (d, J = 15.8 Hz, 1H), 6.63 (d, J = 16.0 Hz,
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163.5, 163.1, 134.3, 132.3, 132.3, 132.0, 76.3, 75.5, 69.2, 40.6, 19.5,
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(w), 1180 (m), 980 (m); HRMS (ESI-TOF) (m/z) [M + Na]+
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ASSOCIATED CONTENT
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(14) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
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S
* Supporting Information
Copies of NMR for all reported compounds and cif-files for the
reported X-ray structures. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.5b01171.
J
DOI: 10.1021/acs.joc.5b01171
J. Org. Chem. XXXX, XXX, XXX−XXX