Total synthesis of aculeatin A via double intramolecular oxa-michael addition of secondary/tertiary alcohols

Article abstract of DOI:10.1021/jo4026868

A new synthetic strategy was developed for a concise total synthesis of aculeatin A as a single spiroisomer in both racemic and enantioselective fashions in 8-10 steps with ～10% overall yield from the known alkyne 11, featuring phenol oxidative dearomatization, double intramolecular oxa-Michael addition of secondary/tertiary alcohols, and chemo- and stereoselective reduction of ketone. The new synthetic strategy greatly expedites the access to the potent antiprotozoal aculeatin A, 6-epi-aculeatin D, and their analogues.

Full text of DOI:10.1021/jo4026868

Note
pubs.acs.org/joc
Total Synthesis of Aculeatin A via Double Intramolecular
Oxa-Michael Addition of Secondary/Tertiary Alcohols
Hongliang Yao, Liyan Song, and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
S
* Supporting Information
ABSTRACT: A new synthetic strategy was developed for a
concise total synthesis of aculeatin A as a single spiroisomer in
both racemic and enantioselective fashions in 8−10 steps with
∼10% overall yield from the known alkyne 11, featuring
phenol oxidative dearomatization, double intramolecular oxa-
Michael addition of secondary/tertiary alcohols, and chemo-
and stereoselective reduction of ketone. The new synthetic
strategy greatly expedites the access to the potent
antiprotozoal aculeatin A, 6-epi-aculeatin D, and their
analogues.
culeatins A−C (Figure 1) were reported in 2000 by
Heilmann and co-workers from the petroleum extracts of
developed a highly efficient biomimetic cascade strategy
involving phenyliodine bis(trifluoroacetate)4 (PIFA)-mediated
phenol oxidation5/spiroketalization (Scheme 1). This biomimetic
A
Scheme 1. Synthetic Strategy and Previous Approach for
Aculeatins
Figure 1. Aculeatins A−D.
rhizomes of the plant Amomum aculeatum ROXB,1 which has
been widely used in Papua New Guinea as a traditional
medicine against fever and malaria. Aculeatin D, the fourth
member of the aculeatin family, was identified 1 year later as a
new minor compound from the same petroleum extract.2
Aculeatins A−D have shown potent in vitro antiprotozoal
activity (IC50 0.18−3.0 μM) against Plasmodium falciparum and
Trypanosoma brucei rhodesiense and cruzi and moderate
cytotoxicity (IC50 0.38−2.0 μM) against the KB cell lines.1,2
Structurally, aculeatins A−D represent a novel type of natural
products with a fascinating and unprecedented 1,7-
dioxadispiro[5.1.5.2]pentadecane skeleton (cf., dispiroketal cyclo-
hexadienone). Interestingly, aculeatin B is a spiroepimer (C6) of
aculeatin A and a C4 epimer of aculeatin D. These stereochemical
differences were found to affect their biological potency: aculeatin
A was three times more potent than aculeatin B with similar
cytotoxicity against KB cell lines; aculeatin D exhibited a doubled
cytotoxicity but weaker antiprotozoal activity as compared to
aculeatin B. Due to the structural novelty and potent biological
activities, aculeatins A−D have received intensive attention from
synthetic communities, culminating in many total syntheses.3
The first, racemic total synthesis of aculeatins A and B
(3:1 mixture) was elegantly achieved in 2002 by Wong,3a who
approach was fully exploited in all subsequent syntheses of
aculeatins and their analogues.3 It is therefore not surprising
that all previous total syntheses would yield a similar spiroisomeric
mixture of aculeatins (A/B or D/6-epi-D). It would be highly
desirable to achieve a stereoselective synthesis of the single
spiroisomer aculeatin A because it is more potent (IC50 0.18 μM)
Received: December 4, 2013
Published: January 6, 2014
© 2014 American Chemical Society
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than its spiroepimer aculeatin B. We herein report a new synthetic
strategy that would lead to the single spiroisomer aculeatin A,
featuring (i) phenol oxidative dearomatization/double intra-
molecular oxa-Michael addition6 (POD/DIOMA) and (ii)
chemo- and stereoselective reduction of the C4 carbonyl group
as the final step (Scheme 1). In addition, this late-stage reduction
strategy permitted us to access the 6-epi-aculeatin D, which was
also more potent than its natural counterpart and equipotent to
that of aculeatin A.7
Table 1. Phenol Oxidative Dearomatization and Double
Intramolecular Oxa-Michael Addition; Reaction Progress
Monitored by TLC
Our synthetic strategy (Scheme 1) was primarily inspired by
Forsyth’s pioneering work on double intramolecular oxa-
Michael addition (DIOMA),8 which provided a single
diastereomeric 6,6-spiroketal9 due to the double stabilization
by the anomeric effect.10 We envisioned that the 5,6-spiroketal
moiety of aculeatin A could be constructed as a single
spiroisomer by a similar DIOMA (8 → 7). The employment
of the tertiary alcohol for DIOMA, however, is unprecedented
in the literature, possibly due to being prone to dehydration
under the acidic conditions. Nonetheless, an appropriate acid
might be found to promote the oxa-Michael addition in a
favorable 5-exo-dig mode.11 The resulting carbonyl group at C4
of 7 could be utilized for chemo- and stereoselective reduction
to deliver the required secondary alcohol at C4, furnishing
aculeatin A (1) and/or 6-epi-aculeatin D (6). The required
tertiary alcohol 8 could be derived from phenol oxidative
dearomatization (POD) of 10, which could be easily prepared
in racemic and enantioselective fashions via reductive ring opening
of [3 + 2]-dipolar cycloaddition12 adduct 9 or asymmetric acetate
aldol13 and alkynylation reaction, respectively.
a
b
entry acid/base (equiv)
solvents
temp (°C) yield (7, %)
1
2
3
4
5
6
7
TsOH (2.0)
AgOTf (2.0)
AuCl (2.0)
A-15 (4.0)
CSA (2.0)
CSA (2.0)
PhMe or PhH
CH2Cl2
THF
rt
0
rt
13
9
rt
CH2Cl2
CH2Cl2
THF
rt
45
74
NR
rt
rt
c
KOtBu (0.1)
THF
0 → rt
0
a
A-15 = amberlyst 15. CSA = (R)-(−)-10-camphorsulfonic acid.
Isolated yields from 10. NR = no reaction. Decomposition observed.
b
c
TsOH did not effectively promote the bicyclization of 8 (entry 1),
although partial cyclization (mono-oxa-Michael addition) was
observed by TLC. Lewis acids including AgOTf16 and AuCl17
sluggishly promoted the DIOMA to give 7 in low isolated yield
(9% and 13% yield over two steps, entries 2 and 3), while
extension of the reaction time (>48 h) resulted in a complex
mixture. Basic condition (entry 7) led to decomposition of 8
(other attempted bases including NaH and DBU). Further surveys
of various protic acids proved that amberlyst 1518 (A-15, entry 4)
and (R)-(−)-10-camphorsulfonic acid (CSA, entry 5) in CH2Cl2
were superior for the DIOMA of 8, cleanly providing the
5,6-spiroketal 719 as a single diastereomer in 45% and 74% yields
over two steps, respectively. The exclusive diastereoselectivity may
be attributed to the double stabilization by the anomeric effect
when both C−O bonds (C6) were in axial orientations.9
Noteworthy is that the Michael addition of the two OH groups
to the conjugated triple bond led to only the thermodynamically
more stable isomer of the spiroketal, which was similar to the
exclusive formation of 6-epi-aculeatin D under strongly acidic
conditions.3i Apparently, exclusive access to the thermodynamically
less stable isomer(s) of the spiroketal(s) still remains to be
developed. Most importantly, this unprecedented combination of
POD and DIOMA allowed us to readily access the single
diastereomeric 5,6-spiroketal framework present in aculeatin A,
which could not be achieved by previous synthetic strategies for
aculeatins.3
A large-scale synthesis of racemic 10 was first undertaken to
verify our new synthetic strategy (Scheme 2). Formylation of
Scheme 2. Synthesis of ( )-β-Hydroxyalkynone (10) via 1,3-
Dipolar Cycloaddition
the known alkyne 1114 with nBuLi/DMF and condensation of
the resulting aldehyde 12 with hydroxylamine gave a cis/trans
mixture of alkynyl-subsituted hydroxylimine 13, which upon
treatment of tBuOCl underwent 1,3-dipolar cycloaddition with
1-pentadecene to provide isoxazoline 9 as the single
regioisomer. After removal of the TBS protecting group, the
α,β-unsaturated isoxazoline was chemoselectively reduced by
SmI2 using Carreira’s protocol,15 providing the racemic 10 with
22% overall yield for the five steps.
With over 2 g of ( )-10 in hand, we set out to explore the
phenol oxidative dearomatization (POD) and the subsequent
key DIOMA (Table 1). After preliminary screening of oxidants
(oxone, phenyliodine bis(trifluoroacetate), (diacetoxyiodo)-
benzene) for POD,5 we chose PIFA for the oxidative
dearomatization of ( )-10, which cleanly provided the unstable
8 as the only isolable product. A variety of conditions were then
screened for the DIOMA of the freshly prepared 8 and are
summarized in Table 1. In contrast to Forsyth’s condition,8
Another challenge in our synthetic plan arose from the final-
stage functionalization: chemo- and stereoselective reduction of
( )-7 to ( )-aculeatin A (1). Our initial strategy for this final
functionalization involved two steps (Table 2): (i) stereo-
selective reduction of both carbonyl groups at C4 and C11 and
(ii) chemoselective oxidation of allylic alcohol at C11 to a
ketone. Pleasingly, such strategy proved quite successful:
K-selectride at −78 °C could stereoselectively reduce both
carbonyl groups (C11 and C4), and subsequent chemoselective
20
oxidation of allylic alcohol (C11) with MnO2 furnished
( )-aculeatin A in 48% yield over two steps as a single
diastereomer21 (entry 1). Other reducing agents including
DIBALH, NaBH4−CeCl3, and LiAlH(OtBu)3 generated a
diastereomeric mixture of 1 and 6 after MnO2 oxidation in
good to excellent combined yield (entries 2−4). Interestingly,
LiAlH(OtBu)3 was later found to chemoselectively reduce the
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(Scheme 3). Asymmetric acetate aldol of (−)-14 and aldehyde
15 using the Nagao-Fujita27 protocol followed by silylation gave
(−)-16 in 41% overall yield with excellent diastereoselectivity.
Removal of the chiral auxiliary with DIBALH, alkynylation of
the resulting aldehyde with 11, oxidation with Dess−Martin
periodinane (DMP), and desilylation with HF-pyridine
provided the enantiomerically pure (−)-10 in 51% yield over
four steps. The alkynyl alcohol (−)-10 was subjected to the
same three-step (or four-step) sequence: POD, DIOMA, and
reduction (and MnO2 oxidation), furnishing the (−)-aculeatin
A with optical purity of >99% ee as the single spiroisomer. All
spectrascopic data of the synthetic aculeatin A were identical to
those reported for the authentic sample (−)-aculeatin A in the
literature.1,3
In summary, we have developed a new cascade strategy for a
concise total synthesis of aculeatin A as a single spiroisomer in
both racemic and enantioselective fashions in eight steps with
10.7% overall yield and in nine steps with 10.2% overall yield
from known alkyne 11 and the known 14, respectively. This
constituted the first example that did not employ the final
phenol oxidation/spiroketalization in total syntheses of aculeatins
and that yielded the single spiroisomeric, more potent aculeatin A.
Total synthesis of the racemic 6-epi-aculeatin D was also
accomplished by taking advantage of the final stereoselective
reduction of DIOMA adducts. The key features of our synthesis
include (i) construction of the single diastereomeric 5,6-spiroketal
framework of aculeatins via phenol oxidative dearomatization
(POD) and double intramolecular oxa-Michael addition
(DIOMA) and (ii) chemo- and/or stereoselective reduction of a
ketone to install the required secondary alcohol at C4 as the final
step. This new POD/DIOMA synthetic strategy coupled with
chemo- and stereoselective reduction of the ketone may be
exploited in synthesis of other aculeatins and their analogues for
biological activity evaluation.
Table 2. Reduction of Ketone ( )-7 to ( )-Aculeatin A (1)
and ( )-6-epi-Aculeatin D (6); Reaction Run with 20 mg of
( )-7
a
b
entry
[H−]
solvent
THF
DCM
MeOH/DCM −78 83 (1.1:1)
temp yield (%, 1:6)
-78 48 (>20:1)
−78 51 (10:1)
1
2
3
4
5
K-Selectride
DIBALH
NaBH4/CeCl3
LiAlH(OtBu)3
(R)-CBS (cat.)
c
THF
0
69 (1:3)
THF
−20 <10
catecholborane
d
6
7
8
(R)-CBS (cat.) BH3-SMe2
(R)-alpine-borane
THF
THF
DCM
−20 44 (3:1)
rt
0
c,d
Ru*/HCO2H-Et3N
rt
83 (3.8:1)
a
(R)-CBS = (R)-(+)-2-methyl-CBS-oxazaborolidine. Ru* = RuCl(p-
cymene)[(S,S)-Ts-DPEN]. Isolated yield over 2 steps, diastereomeric
ratio based on isolated yield. Combined yield of 1 and 6 without
MnO2 oxidation. Enantiomeric excess of 1 was determined by chiral
b
c
d
HPLC to be 1−10% ee.
ketone on C4 to afford a 1:3 diastereomeric mixture of 1 and 6
in 69% combined yields without MnO2 oxidation (entry 4).
The diastereoselectivity favoring 6 was particularly noteworthy
since all other conditions (except entry 3) examined gave 1 as
the major or only product. Although attempts to perform
reductive kinetic resolution22 of the racemic ketone 7 were not
successful (entries 5−8) due to the low conversion and/or
enantioselectivity (<10% ee), we unexpectedly observed that
Noyori reduction23 of the ketone ( )-7 (entry 8) was chemo-
and stereoselective to provide aculeatin A without additional
MnO2 oxidation in 66% yield (along with 17% yield of 6). The
tolerance of the labile cyclohexadienone24 that readily under-
went rearomatization was worthy of notice. To the best of our
knowledge, this was the first example that C4 secondary alcohol
was installed chemo- and stereoselectively in the final step of
total synthesis of aculeatins.
EXPERIMENTAL SECTION
■
NMR spectra were recorded on a 400 MHz spectrometer (400 MHz
for H, 100 MHz for 13C). Chemical shifts are reported in parts per
1
million (ppm) as values relative to the internal chloroform (7.26 ppm
for 1H and 77.16 ppm for 13C). Infrared (IR) spectra were recorded as
neat samples (liquid films on KBr plates). HRMS spectra were
recorded with a TOF detector. Normal phase HPLC was used to
determine enantiomeric excess of chiral compounds with eluents of
hexane/i-PrOH. Reactions were carried out in oven or flame-dried
glassware under a nitrogen atmosphere, unless otherwise noted.
Tetrahydrofuran (THF) was freshly distilled before use from sodium
using benzophenone as indicator. Dichloromethane (CH2Cl2) was
freshly distilled before use from calcium hydride (CaH2). All other
anhydrous solvents were dried over 3 or 4 Å molecular sieves.
After considerable efforts on reductive kinetic resolution of
the racemic ketone ( )-7 (Table 2) and lipase-catalyzed kinetic
resolution25 of the racemic aculeatin A proved fruitless, we
developed an alternative route to prepare the optically active
(−)-1026 for an enantioselective total synthesis of aculeatin A as
the single spiroisomer using the new POD/DIOMA strategy
Scheme 3. Enantioselective Total Synthesis of (−)-Aculeatin A
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Compounds 1128 and 1427 have been reported and were prepared
according to the literatures.
To a solution of isoxazoline ( )-9 (4.80 g, 9.40 mmol) in THF
(90 mL) at 0 °C was added tetrabutylammonium fluoride (TBAF,
20.7 mL, 1.0 M in THF, 20.7 mmol). After 1 h, the reaction was
quenched with saturated aqueous NH4Cl solution. The organic layer
was collected, and the aqueous layer was extracted with Et2O (3 ×
20 mL). The combined organic fractions were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 5:1) to afford the desired product (3.20 g, 85%
yield) as a light yellow oil. IR (neat, cm−1): 3628, 3412, 2920, 2852,
2300, 1614, 1516, 1465, 1350, 1336, 1249, 1103. 1H NMR
(400 MHz, CDCl3) δ: 7.07 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0
Hz, 2H), 5.16 (s, 1H, OH), 4.66−4.59 (m, 1 H), 3.04 (dd, J = 16.4,
10.4 Hz, 1H), 2.81 (t, J = 8.0 Hz, 2H), 2.66−2.60 (m, 3H), 2.00 (br,
OH) 1.72−1.68 (m, 1 H), 1.58−1.50 (m, 1H), 1.25 (m, 22H), 0.88
(t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 154.7, 143.4,
132.0, 129.6 (2C), 115.5 (2C), 98.8, 82.2, 71.0, 43.1, 35.0, 33.6, 32.0,
29.8−29.5 (br, 8C), 25.4, 22.8, 22.1, 14.2. HRMS (CI-TOF) m/z calcd
for C26H40NO2 [M + H]+ 398.3059, found 398.3063. To a solution of
desilylated isoxazoline (3.18 g, 8.01 mmol) obtained above in
anhydrous and degassed THF (200 mL) at 0 °C was added SmI2
(288 mL, 0.1 M in THF, 28.8 mmol) slowly, maintaining a dark blue
color throughout the reaction. The reaction mixture was stirred for
additional 30 min at 0 °C and then was quenched by bubbling a stream
of oxygen to give a yellow solution, which was poured into B(OH)3
(7.2 g) solution in H2O (400 mL). The mixture was stirred for 30 min
at room temperature and diluted with Et2O (50 mL). The organic
layer was collected, and the aqueous phase was extracted with Et2O
(3 × 400 mL). The combined organic fractions were washed with
brine (2 × 50 mL), dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 2:1) to afford the
desired β-hydroxylalkynone ( )-10 (2.31 g, 71.4% yield) as a light
yellow oil. IR (neat, cm−1): 3338, 2923, 2853, 2211, 1659, 1515, 1456,
To a solution of alkyne 11 (9.88 g, 38.0 mmol) in THF
(100 mL) at −78 °C was added nBuLi (24.7 mL, 2.0 M in hex-
anes,49.4 mmol) dropwise. After 1 h of stirring, dry DMF (4.4 mL,
57.0 mmol) was added at −78 °C. The reaction mixture was stirred
at −78 °C for 1 h and then quenched with saturated aqueous
NH4Cl solution. The organic layer was collected, and the aqueous
layer was extracted with Et2O (3 × 100 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, and con-
centrated under reduced pressure. The resulting residue was purified
by flash column chromatography on silica gel (hexane/EtOAc =
10:1) to afford the desired aldehyde 12 (8.75 g, 80% yield) as
a yellow oil. IR (neat, cm−1): 3037, 2954, 2931, 2890, 2857, 2361,
2337, 2198, 1667, 1608, 1510, 1467, 1254, 1132. 1H NMR
(400 MHz, CDCl3) δ: 9.16 (s, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.78
(d, J = 8.0 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H),
0.98 (s, 9H), 0.19 (s, 6H). 13C NMR (100 MHz, CDCl3) δ: 177.3, 154.6,
132.3, 129.4 (2C), 120.3 (2C), 98.4, 82.2, 33.2, 25.8 (3C), 21.7, 18.3, −4.3
(2C). HRMS (CI-TOF) m/z calcd for C17H25O2Si [M + H]+ 289.1624,
found 289.1624.
To
a solution of α,β-unsaturated aldehyde 12 (6.19 g,
21.5 mmol) in EtOH (96%, 170 mL) at room temperature were
added NH2OH-HCl (2.24 g, 32.3 mmol) and pyridine (Py, 6.9 mL).
The mixture was stirred at room temperature for 2 h and sub-
sequently concentrated under reduced pressure. To the resul-
ting residue were added EtOAc (50 mL) and water (10 mL), and
the organic layer was collected. The organic fractions were washed
with water (2 × 5 mL) and brine, dried over Na2SO4, and con-
centrated under reduced pressure. To a solution of the crude
oximes, Et3N (6 mL), and pentadecene (11.8 mL, 43 mmol) in
Et2O (250 mL) at −78 °C was added tBuOCl (5.0 mL, 43.0 mmol)
dropwise under a nitrogen atmosphere. The resulting reaction
mixture was allowed to warm to room temperature and stirred
overnight. The reaction was quenched with water (20 mL). The
organic layer was collected, and aqueous phase was extracted with
Et2O (3 × 20 mL). The combined organic fractions were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 5:1) to afford the desired isoxazoline ( )-9
as a light yellow oil (4.85 g, 45% yield over two steps). IR (neat, cm−1):
2927, 2855, 2360, 1609, 1510, 1349, 1257, 1130, 1100. 1H NMR
(400 MHz, CDCl3) δ: 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz,
2H), 4.66−4.58 (m, 1H), 3.03 (dd, J = 16.8, 10.4 Hz, 1H), 2.81 (t, J =
8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 3H), 1.72−1.69 (m, 1H), 1.55−
1.49 (m, 1H), 1.26 (m, 22H), 0.98 (s, 9H), 0.88 (t, J = 6.4 Hz, 3H),
0.19 (s, 6H). 13C NMR (100 MHz, CDCl3) δ: 154.3, 143.1, 132.9,
129.4 (2C), 120.1 (2C), 98.3, 82.0, 71.2, 43.2, 35.1, 33.7, 32.0, 29.8−
29.5 (br, 8C), 25.8 (3C), 25.4, 22.8, 22.1, 18.3, 14.2, −4.4 (2C).
HRMS (CI-TOF) m/z calcd for C32H54NO2Si [M + H]+ 512.3924,
found 512.3918.
1
1244, 1170, 826, 670. H NMR (400 MHz, CDCl3) δ: 7.05 (d, J =
8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 6.07 (s, 1H, OH), 4.11−4.06
(m, 1H), 2.80 (t, J = 7.2 Hz, 2H), 2.69−2.59 (m, 4H), 1.45−1.37
(m, 2H), 1.28−1.22 (m, 22H), 0.88 (t, J = 6.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 188.1, 154.8, 131.5, 129.6 (2C), 115.6 (2C),
95.2, 81.6, 68.0, 52.3, 36.5, 33.1, 32.0, 29.8−29.5 (br, 8C), 25.5, 22.8,
21.6, 14.2. HRMS (CI-TOF) m/z calcd for C26H40O3 [M]− 400.2977,
found 400.2972.
To a suspension of tin(II) triflate (Sn(OTf)2, 4.51 g, 10.8 mmol) in
CH2Cl2 (40 mL) was added N-ethylpiperidine (1.48 mL, 10.8 mmol)
at −78 °C. (−)-14 (1.82 g, 8.98 mmol) in CH2Cl2 (8 mL) was added to
the cold reaction mixture via a cannula. The reaction mixture was allowed
to warm to −40 °C and stirred for 4 h before cooling back to −78 °C.
Aldehyde 15 (2.00 g, 9.85 mmol) in CH2Cl2 (8 mL) was added via a
syringe pump to the enolate solution over 40 min. After being stirred for
an additional 5 h at −78 °C, the reaction mixture was quenched with pH
7.0 phosphate buffer (50 mL). The organic layer was collected, and the
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aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic fractions were washed with saturated aqueous NaHCO3 solution,
dried over Na2SO4, and concentrated under reduced pressure. The residue
was used for the subsequent silylation reaction without purification. To a
solution of the crude aldol product (3.73 g, 8.98 mmol) in dry CH2Cl2
(50 mL) were added triethylamine (Et3N, 4.1 mL, 29.6 mmol) and
4-dimethylamino pyridine (DMAP, 0.24 g, 1.97 mmol). The resulting
solution was cooled to 0 °C with an ice−water bath, and then triethylsilyl
chloride (TESCl, 2.5 mL, 14.8 mmol) was added dropwise. After
complete consumption of the starting material as indicated by TLC, the
mixture was quenched by addition of saturated aqueous NaHCO3 solution
(15 mL). The organic layer was collected, and the aqueous phase was
extracted with CH2Cl2 (3 × 15 mL). The combined organic fractions
were washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 50:1) to afford (−)-16 as
a yellow oil (1.95 g, 41% yield over two steps). [α]D = −217.0 (c 1.0,
CHCl3). IR (neat, cm−1): 2955, 2925, 2875, 2854, 1699, 1462, 1369,
1311, 1239, 1166, 1091, 1041, 1008. 1H NMR (400 MHz, CDCl3) δ: 5.05
(t, J = 7.2 Hz, 1H), 4.32−4.27 (m, 1H), 3.55−3.45 (m, 2H), 3.16 (dd, J =
16.8, 4.0 Hz, 1H), 3.02 (d, J = 11.2 Hz, 1H), 2.41−2.36 (m, 1H), 1.53−
1.48 (m, 2H), 1.25 (m, 22H), 1.06 (d, J = 6.8 Hz, 3H), 0.98 (d, J =
6.8 Hz, 3H), 0.93 (t, J = 8.0 Hz, 9H), 0.88 (t, J = 6.8 Hz, 3H), 0.59 (q, J =
8.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ: 203.0, 172.3, 71.8, 69.1,
45.8, 38.0, 32.1, 31.1, 31.0, 29.9−29.5 (br, 8C), 25.4, 22.8, 19.3, 18.0, 14.3,
7.1 (3C), 5.2 (3C). HRMS (CI-TOF) m/z calcd for C28H55NO2S2Si
[M]− 529.3443, found 529.3438.
quenched with saturated aqueous NH4Cl solution and diluted with
Et2O (10 mL). The organic layer was collected, and the aqueous layer
was extracted with Et2O (3 × 10 mL). The combined organic fractions
were washed with water and brine, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 50:1) to afford
a mixture of diastereomers (1.17 g, 71% yield, dr 0.8:1) as a colorless
oil. To a solution of diastereomers (0.855 g, 1.35 mmol) obtained
above in dry CH2Cl2 (6.7 mL) at 0 °C were added pyridine (Py, 0.4
mL, 4.86 mmol) and Dess−Martin periodinane (DMP, 686 mg, 1.62
mmol). After vigorous stirring for 30 min at 0 °C, the cold bath was
removed, and the reaction mixture was stirred at room temperature
for 12 h until TLC indicated complete consumption of the starting
material. The reaction mixture was diluted with Et2O (10 mL) and
poured into saturated aqueous NaHCO3 solution containing excess
Na2S2O3. The mixture was stirred until the solid was completely
dissolved. The organic phase was collected, washed sequentially with
saturated aqueous NaHCO3 solution, water, and brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (hexane/
EtOAc = 20:1) to afford the ketone (−)-18 (0.653 g, 77% yield) as a
colorless oil. [α]D = −3.8 (c 1.0, CHCl3). IR (neat, cm−1): 2955, 2927,
1
2855, 2213, 1677, 1510, 1463, 1255, 1100, 1007, 915, 840. H NMR
(400 MHz, CDCl3) δ: 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz,
2H), 4.28−4.22 (m, 1H), 2.81 (t, J = 7.2 Hz, 2H), 2.72−2.56 (m, 4H),
1.48−1.45 (m, 2H), 1.33−1.27 (m, 22H), 0.99−0.94 (m, 18H), 0.89
(t, J = 7.2 Hz, 3H), 0.60 (q, J = 8.0 Hz, 6H), 0.19 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ: 186.2, 154.4, 132.4, 129.3 (2C), 120.1 (2C),
93.4, 82.0, 68.8, 53.4, 37.9, 33.3, 32.0, 29.8−29.4 (br, 8C), 25.7 (3C),
25.1, 22.8, 21.4, 18.2, 14.2, 6.9 (3C), 5.0 (3C), −4.4 (2C). HRMS (CI-
TOF) m/z calcd for C38H68O3Si2 [M]− 628.4707, found 628.4712.
To a solution of (−)-16 (1.54 g, 2.88 mmol) in CH2Cl2/hexane (28
mL, 1:1 v/v solution) was added DIBALH (5.76 mL, 1.0 M in hexanes,
5.76 mmol) at −78 °C, and the mixture was allowed to stir at the same
temperature until no yellow color was observed. Then the reaction was
quenched by addition of ethyl acetate (2 mL) at −78 °C and then
saturated aqueous sodium potassium tartrate solution (20 mL). The
mixture was allowed to warm to room temperature and stirred for 2 h.
The organic layer was collected, and the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic fractions were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel (hexane/EtOAc = 50:1) to afford aldehyde
(−)-17 (1.01 g, 94% yield) as a colorless oil. [α]D = −2.5 (c 1.0,
CHCl3). IR (neat, cm−1): 2956, 2925, 2876, 2855, 1728, 1465, 1415,
To a solution of (−)-18 (0.315 g, 0.502 mmol) in CH3CN/THF (5
mL, 10:1 v/v solution) at 0 °C were added pyridine (Py, 0.75 mL) and
HF-pyridine complex (0.75 mL). After 3 h, the reaction was quenched
with saturated aqueous NaHCO3 solution. The organic layer was
collected, and the aqueous layer was extracted with EtOAc (3 × 5 mL).
The combined organic fractions were washed with saturated aqueous
CuSO4 solution and brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel (hexane/EtOAc = 2:1) to afford the desired
phenol (−)-10 (0.200 g, 99% yield) as a light yellow oil. [α]D = −7.4
(c 1.0, CHCl3). IR (neat, cm−1): 3369, 2924, 2853, 2212, 1663, 1515,
1
1377, 1239, 1104, 1009. H NMR (400 MHz, CDCl3) δ: 9.81 (t, J =
2.4 Hz, 1H), 4.21−4.15 (m, 1H), 2.52 (dd, J = 6.0, 2.4 Hz, 2H), 1.55−
1.49 (m, 2H), 1.25−1.21 (m, 22H), 0.95 (t, J = 8.0 Hz, 9H), 0.88 (t,
J = 6.4 Hz, 3H), 0.59 (q, J = 8.0 Hz, 6H). 13C NMR (100 MHz,
CDCl3) δ: 202.6, 68.4, 51.1, 38.1, 32.1, 29.8−29.5 (br, 8C), 25.4, 22.8,
14.3, 7.0 (3C), 5.1 (3C). HRMS (CI-TOF) m/z calcd for C22H47O2Si
[M + H]+ 371.3345, found 371.3348.
1
1461, 1246, 1171, 826. H NMR (400 MHz, CDCl3) δ: 7.05 (d, J =
8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 5.60 (br, OH), 4.10−4.06
(m, 1H), 2.81 (t, J = 7.2 Hz, 2H), 2.70 (br, OH), 2.69−2.60 (m, 4H),
1.42−1.33 (m, 2H), 1.28−1.25 (m, 22H), 0.88 (t, J = 6.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ: 188.0, 154.8, 131.6, 129.6 (2C), 115.6
(2C), 95.1, 81.7, 67.9, 52.3, 36.5, 33.1, 32.0, 29.8−29.5 (br, 8C), 25.5,
22.8, 21.6, 14.2. HRMS (CI-TOF) m/z calcd for C26H40O3 [M]−
400.2977, found 400.2982.
To a solution of alkyne 11 (0.898 g, 3.42 mmol) in THF (19 mL) at
−78 °C was added nBuLi (1.56 mL, 2.0 M in hexanes, 3.12 mmol).
The reaction mixture was stirred for 0.5 h. Aldehyde (−)-17 (0.974 g,
2.63 mmol) in THF (15 mL) was added to the mixture at −78 °C, and
then the reaction was stirred for 1 h. The reaction mixture was
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The Journal of Organic Chemistry
Note
enantiomerically pure (−)-aculeatin A with 48.5% yield from ketone
(−)-7.
To a solution of phenol ( )-10 (100 mg, 0.250 mmol) in acetone/
water (7.5 mL, 5:1 v/v solution) at 0 °C was added phenyliodine
bis(trifluoroacetate) (PIFA, 160 mg, 0.400 mmol) in one portion. After
the mixture protected from light was stirred for 30 min, Na2SO4 and
NaHCO3 were added, and the mixture was stirred for another 10 min
before filtration through a short pad of Celite. The filtrate was
concentrated under reduced pressure to afford the crude product
( )-8, which was used without purification for the double intra-
molecular oxa-Michael addition. To a solution of the crude alkynone
( )-8 in CH2Cl2 (5 mL), (1R)-(−)-10-camphorsulfonic acid (CSA,
115 mg, 0.500 mmol) was added in one portion. After complete
consumption of the starting material ( )-8 as indicated by TLC, the
reaction was quenched with saturated aqueous NaHCO3 solution
(5 mL). The organic layer was collected, and the aqueous layer was
extracted with Et2O (5 × 5 mL). The combined organic fractions were
washed with brine (2 mL), dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to afford the
desired diketone ( )-7 (76.6 mg) as a light yellow oil in 74% yield
over two steps. These procedures were repeated five times to obtain
383 mg of ( )-7 for subsequent reduction studies. The identical
procedure was used to prepare the enantiomerically pure (−)-7 with
the 74.5% overall yield from (−)-10. Spectroscopic data for the
synthetic 7 was in good agreement with those reported in ref 19. Data
for 8: IR (neat, cm−1): 3409, 2925, 2854, 2214, 1670, 1626, 1463,
1380, 1171. 1H NMR (400 MHz, CDCl3) δ: 6.85 (d, J = 10.0 Hz, 2H),
6.19 (d, J = 10.0 Hz, 2H), 4.10−4.06 (m, 1H), 3.24 (br, 2H, OH),
2.71−2.58 (m, 2H), 2.43 (t, J = 8.0 Hz, 2H), 2.02 (t, J = 8.0 Hz, 2H),
1.39−1.23 (m, 24H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 187.6, 185.5, 150.4, 128.8, 93.6, 81.5, 68.9, 67.8, 52.3, 37.8,
36.5, 32.0, 29.8−29.4 (br, 8C), 25.5, 22.8, 14.2, 14.0. HRMS (CI-
TOF) m/z calcd for C26H40O4 [M]− 416.2927, found 416.2928. Data
Method B. To a solution of ketone ( )-7 (20 mg, 0.050 mmol) in
CH2Cl2 (0.5 mL) were added RuCl(p-cymene)[(S,S)-Ts-DPEN]
(0.10 mg, 0.5 mol %), HCO2H (19 μL, 0.50 mmol), and Et3N (28 μL,
0.20 mmol). The reaction mixture was stirred for 20 h at room
temperature. After being diluted with water (1 mL), the organic layer
was collected, and the aqueous layer was extracted with EtOAc
(3 × 1 mL). The combined organic fractions were washed with
saturated aqueous NaHCO3 solution (0.5 mL) and brine (0.2 mL),
dried over Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 5:1 to 2:1) to afford ( )-aculeatin A as a
colorless oil (13.2 mg, 66% yield, 10% ee) and ( )-6-epi-aculeatin D as
a colorless oil (3.4 mg, 17% yield) in 83% total yield with diastereomeric
ratio of 3.8:1. The identical procedure was used to prepare the
enantiomerically pure (−)-aculeatin A with the 66% yield from ketone
(−)-7. (−)-Aculeatin A: 99% ee (HPLC analysis conditions for aculeatin A:
Daicel CHIRALPAK AD-H column; 5% i-PrOH in hexanes; 1.0 mL/min;
tR: 6.25 and 7.19 min). Aculeatin A: [α]D = −6.2 (c 0.2, CHCl3), lit. [α]D =
−5.3 (c 0.9, CHCl3).1 IR (neat, cm−1): 3558, 2925, 2854, 1673, 1462, 1099.
1H NMR (400 MHz, CDCl3) δ: 6.85 (dd, J = 10.0, 2.8 Hz, 1H), 6.75 (dd,
J = 10.0, 2.8 Hz, 1H), 6.15−6.09 (m, 2H), 4.13−4.10 (m, 2H), 3.35 (br
1H, OH), 2.40−2.32 (m, 1H), 2.25−2.20 (m, 1H), 2.05−2.00 (m, 3H),
1.92 (br d, J = 14.0 Hz, 1H), 1.79 (br d, J = 12.0 Hz, 1H), 1.58−1.39 (m,
5H), 1.39−1.19 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 185.3, 150.9, 148.7, 127.4, 127.1, 109.1, 79.7, 65.3, 64.8, 39.1
(2C), 37.9, 35.9, 34.1, 31.9, 29.7−29.5 (br, 8C), 25.6, 22.6, 14.1. HRMS
(CI-TOF) m/z calcd for C26H42O4 [M]− 418.3083, found 418.3085.
1
for (−)-7: [α]D = −5.4 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3)
( )-6-epi-Aculeatin D. IR (neat, cm−1): 3432, 2925, 2854, 1672,
1462, 1127. 1H NMR (400 MHz, C6D6) δ: 6.68 (dd, J = 10.0, 3.2 Hz,
1H), 6.15−6.10 (m, 2H), 6.02 (dd, J = 10.0, 2.0 Hz, 1H), 3.92−3.89
(m, 1H), 3.73−3.67 (m, 1H), 2.06−1.98 (m, 1H), 1.90−1.83 (m, 2H),
1.66−1.62 (m, 1H), 1.55−1.20 (m, 27H), 1.07 (q, J = 12.0 Hz, 1H),
0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, C6D6) δ: 185.2, 151.4,
149.4, 128.1, 127.7, 109.6, 79.8, 69.8, 65.8, 44.1, 41.8, 39.4, 37.0, 35.5,
32.9, 30.8−30.5 (br, 8C), 26.7, 23.7, 15.0. HRMS (CI-TOF) m/z calcd
for C26H42O4 [M]− 418.3083, found 418.3077.
δ: 6.75 (ddd, J = 20.8, 9.6, 2.8 Hz, 2H), 6.13−6.07 (m, 2H), 4.14−4.09
(m, 1H), 2.75 (d, J = 14.4 Hz, 1H), 2.53 (d, J = 14.4 Hz, 1H), 2.41−
2.38 (m, 3H), 2.25−2.18 (m, 1H), 2.09−2.04 (m, 2H), 1.67−1.62 (m,
1H), 1.53−1.47 (m, 1H), 1.40−1.16 (m, 22H), 0.86 (t, J = 6.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 204.7, 185.4, 150.5, 148.7,
127.7, 127.3, 109.7, 79.8, 69.8, 49.9, 46.9, 38.8, 36.2, 34.9, 32.0, 29.8−
29.5 (br, 8C), 25.6, 22.8, 14.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables of comparison of NMR data of our synthetic aculeatin A
and 6-epi-aculeatin D with those reported and copies of 1H and
13C NMR of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Method A. To a solution of ketone ( )-7 (20 mg, 0.050 mmol) in
THF (1 mL) was added a solution of K-Selectride (0.12 mL, 1.0 M in
THF, 0.120 mmol) at −78 °C. After 20 min of stirring at −78 °C, the
reaction was quenched by addition of saturated aqueous NaHCO3
solution (1 mL), EtOAc (2 mL), and water (0.5 mL). The organic
layer was collected, and the aqueous layer was extracted with EtOAc
(2 × 1 mL). The combined organic fractions were washed with water
(0.5 mL) and brine (2 × 0.2 mL), dried over Na2SO4, and concen-
trated under reduced pressure. The resulting residue was used for the
subsequent oxidation without further purification. To the crude diol
in CH2Cl2 (1.0 mL) was added MnO2 (activated powder, 88 mg,
1.0 mmol). After 1 h the mixture was filtered through a short pad of Celite
and concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc =
2:1) to afford ( )-aculeatin A as a colorless oil (9.6 mg, 48% yield over
two steps). The identical procedure was also used to prepare the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rtong@ust.hk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by The Hong Kong
University of Science and Technology (HKUST R9309) and
Research Grant Council of Hong Kong (GRF ECS 605912 and
GRF 605113).
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The Journal of Organic Chemistry
Note
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Soc. 1953, 75, 5930. (b) Gritter, R. J.; Wallace, T. J. J. Org. Chem. 1959,
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