Asymmetric total synthesis of (-)-amphidinolide v through effective combinations of catalytic transformations

Article abstract of DOI:10.1021/ja401717b

An asymmetric total synthesis of (-)-amphidinolide V was accomplished. The synthesis features a base-catalyzed alkynyl silane alcoholysis/ring-closing enyne metathesis sequence for facile construction of a 1,3-diene motif. A diene RCM followed by a ring-c

Full text of DOI:10.1021/ja401717b

Communication
pubs.acs.org/JACS
Asymmetric Total Synthesis of (−)-Amphidinolide V through
Effective Combinations of Catalytic Transformations
Ivan Volchkov and Daesung Lee*
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor Street, Chicago, Illinois, 60607, United States
S
* Supporting Information
and an unsaturated side chain. The relative configurations of its
ABSTRACT: An asymmetric total synthesis of (−)-am-
phidinolide V was accomplished. The synthesis features a
base-catalyzed alkynyl silane alcoholysis/ring-closing
enyne metathesis sequence for facile construction of a
1,3-diene motif. A diene RCM followed by a ring-
contractive allylic transposition of cyclic silyl ethers was
incorporated for the stereoselective installation of a
functionalized 1,5-diene subunit. An efficient proline-
mediated direct cross-aldol condensation of two advanced
aldehyde intermediates was utilized for the construction of
a key α,β-unsaturated epoxyaldehyde. This total synthesis
demonstrates the prowess of metal-catalyzed transforma-
tions in complex molecule synthesis.
four stereogenic centers (C8−C10 and C13) were deduced from
1H−1H coupling constants and NOESY data.2 This assignment
was later unambiguously confirmed by Furstner et al. through the
̈
first total synthesis of (−)-amphidinolide V and its analogues.3a
The absolute configuration was later determined by comparison
of the synthetic material with an authentic sample along with
structure-activity relationship studies.3b
One of the most distinctive structural features of amphidino-
lide V is its densely arrayed alkene moieties, two pairs of which
are 1,3-dienes. Based on the connectivity patterns we envisioned
that these 1,3-diene subunits could be effectively installed by
enyne metathesis. This would allow a highly flexible approach for
the synthesis of not only the natural amphidinolide V but also
many congeners thereof. Herein, we describe a conceptually
novel synthesis of amphidinolide V relying on several transition
metal-catalyzed reactions and a proline-mediated cross-con-
densation of two advanced aldehyde intermediates as enabling
tools.
Our strategy toward the synthesis of (−)-amphidinolide V (1)
is outlined in Scheme 1. To minimize protecting group
manipulations, we planned to introduce the allylic alcohol
functionality after macrolactonization of seco-acid 2. This
postlactonization-functionalization is highly meritorious consid-
ering the complications in stereoselective alkylations of
epoxyaldehydes4 or syn-selective reductions of epoxyketones.5
The seco-acid 2 is envisaged to be accessed through a cross-aldol
condensation of epoxyaldehyde 3 and donor aldehyde 4. The
1,3-diene functionality of 4 would be installed by enyne cross-
metathesis (CM) between the corresponding internal alkyne and
ethylene gas. The acceptor aldehyde 3, containing a siloxane
moiety, could be derived from a ring contraction6 of 8-membered
silacyclodiene 5 via a Re-catalyzed allylic 1,3-transposition. The
intermediate 5 would be prepared from secondary alcohol 6 and
silane 7 via a metal-catalyzed silane alcoholysis followed by ring-
closing metathesis (RCM). The trimethylsilyl-substituted 1,3-
diene moiety of 6 could be constructed by enyne RCM with
alkynylsilyl ether 8 and subsequent ring cleavage via methyl-
lithium addition.
mphidinolides belong to the structurally diverse family of
Asecondary metabolites isolated from symbiotic dinoflagel-
lates Amphidinium sp.1 (+)-Amphidinolide V was extracted from
Amphidinium strain Y-5 along with 14 other members of this
family. The marine plankton was separated from the inside of the
cell of a flatworm Amphiscolops sp. collected off Chatan beach,
Okinawa. This scarce (0.00005% of the wet weight) natural
metabolite exhibited cytotoxicity against murine lymphoma
L1210 (IC50, 3.2 μg/mL) and human epidermoid carcinoma KB
cells (IC50, 7 μg/mL) in vitro. Amphidinolide V (Scheme 1) is a
14-membered macrolactone possessing a syn-epoxyalcohol
subunit, three isolated and two vicinal exo-methylene groups,
Scheme 1. Retrosynthetic Analysis
The preparation of enyne 8 commenced with a base-induced
alcoholysis of alkynylsilane 97 with enantiomerically enriched
homoallylic alcohol 108 as previously reported9 (Scheme 2). The
silyl ether 8 was converted to cyclic siloxene 11 by enyne RCM10
with Grubbs first-generation (GI) catalyst. Ring opening of
silacycle 11 with methyllithium delivered secondary alcohol 6 via
Received: February 16, 2013
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja401717b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Preparation of Substrates for Allylic Transposition
Precursor (5)
Scheme 3. Preparation of Acceptor Aldehyde (3)
a
a
a
Reagents and conditions: (a) NaH (10 mol %), hexanes-THF (12:1),
Reagents and conditions: (a) (Xantphos)CuCl (5 mol %), t-BuOLi
rt, 12 h, 96%; (b) GI (15 mol %), H2C=CH2, DCM (0.01 M), 55 °C,
12 h, 88%; (c) MeLi, THF, −50 °C, 1.5 h, 80%; (d) n-BuLi, THF, −30
°C to rt, 5 h, 84%; (e) PhOH, Ph3PAuCl (1 mol %), AgSbF6 (1 mol
%), DCE, rt, 10 min, 82%; (e) Red-Al (3 equiv), Et2O, 0 °C, 0.5 h,
89%.
(0.7 equiv, slow addition), PhMe, 85 °C, 5.5 h, 97%; (b) GII (5 mol
%), BQ (20 mol %), DCM (0.005 M), 40 °C, 12 h, 96%; (c) Re2O7
(10 mol %), Et2O, 0 °C, 16 h, 85%, (E/Z = 85:15); (d) CAN (3
equiv), 2-methyl-2-butene (20 equiv), acetone-H2O (9:1), 0 °C, 0.5 h,
54% (64% BORSM); (e) IBX, DMSO, rt, 1 h; (f) (EtO)2P(O)-
CH2CO2Et, NaHMDS, THF, −78 °C to 0 °C, 3 h, 79% (2 steps); (g)
DIBAL-H, THF, −50 °C, 1.5 h, 91%; (h) Ti(i-PrO)4 (10 mol %),
(−)-D-DIPT (15 mol %), t-BuOOH, MS (4 Å), DCM, −20 °C, 12 h,
dr = 88:12; (i) SO3·Py, DMSO, Et3N, DCM 10 °C, 3 h, 94% (2 steps).
Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, BQ =
1,4-benzoquinone, NaHMDS = sodium bis(trimethylsilyl)amide,
DIBAL-H = diisobutylaluminum hydride, (−)-D-DIPT = (−)-diiso-
propyl D-tartrate.
the concomitant unmasking of the hydroxyl group and the
trimethylsilyl-substituted 1,3-diene subunit. The trimethylsilyl
group plays a critical role in effectively protecting the 1,3-diene
moiety from unwanted metathesis and other side reactions along
the synthetic sequence. The preparation of silane counterpart 7
was initiated by the merger of lithiated p-methoxyphenyl (PMP)
ether 12 and methoxysilane 13,6 affording alkynyl allylsilane 14.
Unfortunately, the initially planned gold-catalyzed intramolecu-
lar allylation11 of 14 in the presence of allylic alcohol 6 to directly
form 16 was preempted by the facile dehydration of 6 to form a
conjugated tetraene under the Lewis acidic conditions. Thus,
phenoxysilane 15 was prepared instead, and after several
attempts, the Si−O bond in 1512 could be efficiently reduced
with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al)
to provide silane 7 in 89% yield.
With coupling partners 6 and 7 both in hand, we next turned to
their dehydrogenative coupling (Scheme 3). After many failures,
we found that silyl ether 16 could be obtained in 87% yield with a
catalytic amount of (Xantphos)CuCl and a substoichiometric
amount of t-BuOLi at 85 °C, a modified conditions of Ito and
Sawamura.13 RCM14 of 16 catalyzed by Grubbs second-
generation (GII) catalyst in the presence of benzoquinone15
provided allylic 1,3-transposition6,16 precursor 5. Importantly,
the trimethylsilyl substituent of the 1,3-diene moiety directed the
RCM to occur selectively with the styryl group. Under previously
reported conditions6 (Re2O7, Et2O) compound 5 underwent a
1,3-allylic transposition at 0 °C delivering siloxene 17 as an
inseparable mixture of E/Z-isomers (85:15). Notably, more
soluble Ph3SiOReO3 afforded the rearranged product as a 1:1
mixture of E/Z-isomers even at lower temperatures. The PMP
group of 17 was then cleaved with ammonium cerium(IV)
nitrate (CAN) in the presence of 2-methyl-2-butene as a proton
scavenger to give free alcohol 18 in 54% yield together with
unreacted starting material.17 Subsequent elaboration of 18 via 2-
iodoxybenzoic acid (IBX)-mediated oxidation, Horner-Wads-
worth-Emmons homologation, and DIBAL-H reduction fol-
lowed by Sharpless asymmetric epoxidation18 delivered epox-
yalcohol 19 as an inseparable mixture of diastereomers (dr =
88:12). The formation of the observed diastereomers of 19
should primarily be the consequence of partial racemization6 of
17 during the allylic transposition.7 Oxidation of epoxyalcohol 19
was best achieved under the Parikh-Doering conditions19
providing epoxyaldehyde 3 in 94% combined yield over two
steps.
Once the aldol condensation acceptor aldehyde 3 was secured,
we searched for a route to access the relatively simple donor
aldehyde 4, which commenced with monosaponification of the
known symmetric diester 20 (Scheme 4).7 Treatment of 20 with
1 equiv of potassium hydroxide in MeOH-H2O solution afforded
monoacid 21 in 54% yield together with equal amounts of diacid
and unreacted starting material 20, which was recycled. Acid 21
a
Scheme 4. Preparation of Donor Aldehyde (4)
a
Reagents and conditions: (a) KOH (1 equiv), MeOH-H2O (2:1), 12
h, 54%, (77% BORSM); (b) BOP (1.1 equiv), i-Pr2NEt 0.5 h, then
NaBH4, 94%; (c) H2C=CH2 (2 atm), GII (10 mol %), BQ (20 mol
%), DCM, 50 °C, 12 h, 76%; (d) SO3·Py, DMSO, Et3N, DCM, 0 °C
to rt, 2 h, 79%. BORSM = based on recovered starting material.
B
dx.doi.org/10.1021/ja401717b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 5. Cross-Aldol Condensation and Completion of the Synthesis
a
Reagents and conditions: (a) L-proline (1 equiv), MS (4 Å), DMF, 0 °C, slow addition of 4 over 24 h, 66%, (E/Z = 12.5:1), 60% E; (b) AgF (4
equiv), Et3N·3HF, THF, rt, 0.5 h, 77%; (c) Me3SnOH (10 equiv), DCE, 100 °C, 2.5 h, quantitative; (d) Cl3C6H2COCl, i-Pr2NEt, THF, 2 h, then
DMAP, PhMe (0.002 M), 61%, (50% of 26); e) NaBH4, MeOH, 0 °C, 91%; (f) Ti(i-PrO)4 (10 mol %), (−)-D-DIPT (15 mol %), t-BuOOH, MS (4
Å), DCM, −20 °C, 12 h; (g) I2, PPh3, imidazole, DCM, rt, 1.5 h, 85% (2 steps); (h) t-BuLi, Et2O (0.002 M), −120 °C, 80%, (i) AgF (5 equiv) THF-
MeOH-H2O (10:9:1), rt, 3 h, 62%.
was then reduced to alcohol 22 with NaBH4 through its
hydroxybenzotriazole ester.20 Enyne CM10 of 22 with ethylene in
the presence of benzoquinone delivered diene 23, which was
subsequently oxidized to provide donor aldehyde 4 using the
Parikh-Doering protocol.
quantitatively obtained seco-acid 2 was then subjected to the
Yamaguchi macrolactonization27 conditions affording 61%
combined yield of macrocyclic epimers along with 6% of a
dimeric product. The undesired C13 epimer was separated at this
stage affording macrocycle 26 as a single isomer in 50% yield.
After reduction of 26 with NaBH4 in MeOH, asymmetric
epoxydation of allylic alcohol 27 delivered diepoxide 28 as a
single diastereomer. Exposure of 28 to I2/PPh3 provided iodide
29, the reductive opening of which was examined under various
conditions.28 Gratifyingly, we found that addition of t-BuLi to a
dilute solution (0.002 M) of 29 in Et2O at −120 °C afforded
epoxyalcohol 30 in 80% yield.29 However, addition of t-BuLi to a
more concentrated solution of iodide 29 delivered the desired
product 30 in much reduced yield due to the reaction of t-BuLi
with the lactone moiety. The final removal of the trimethylsilyl
group was accomplished with AgF in a solvent mixture of THF-
MeOH-H2O,30 furnishing (−)-amphidinolide V (1). The
spectroscopic data of the synthetic material are identical to
those reported.3
In conclusion, an asymmetric total synthesis of (−)-amphidi-
nolide V has been accomplished in a longest linear sequence of
22 steps from commercially available starting materials with 3.3%
overall yield. This approach illustrates the prowess of the silicon-
tethered ring-closing enyne and diene metathesis as well as the
allylic transposition of silyl ethers to enable stereoselective
construction of 1,3- and 1,5-diene motifs. Moreover, the silicon
tethers were utilized as efficient protecting groups along the
synthesis whereby the number of unnecessary protecting group
manipulations was reduced. Another salient future of this
synthesis is the direct proline-mediated cross-aldol condensation
of two nonequivalent advanced aldehydes, which allowed for
rapid construction of a complex synthetic intermediate.
Investigations directed toward the development of catalytic
cross-aldol condensation and its application to the synthesis of
chiral building blocks and other natural products will be reported
in due course.
With both the acceptor and donor aldehydes in hand, we
optimized conditions for their cross-aldol condensation.
Although the direct organocatalytic cross-aldol reaction of two
nonequivalent aldehydes is known,21 the direct cross-condensa-
tion to form the corresponding α,β-unsaturated aldehyde is
limited to the reaction with formaldehyde.22 It is well-known that
H2O plays an important role in the proline-catalyzed aldol
reaction assisting hydrolysis of oxazolidinone intermediates
formed in the catalytic cycle.23,24 Aldol condensations mediated
by a secondary amine proceed via Knoevenagel-Mannich-type
mechanism with second-order dependence of the reaction rate
on the catalyst concentration.22b,25 Therefore, removal of H2O
from the reaction medium should increase the amount of
iminium ion intermediate or the corresponding oxazolidinone
form, thus facilitating the condensation process. Based on this
reasoning, we examined the reaction between aldehydes 3 and 4
in the presence of 4 Å molecular sieves (MS) with increased
loading of L-proline (Scheme 5). We found that the addition of 4
Å MS had a dramatic effect on the ratio between cross-aldol and
cross-condensation products. Thus, a slow addition of donor
aldehyde 4 to epoxyaldehyde 3 and 10 mol % of proline in the
absence of MS afforded aldol reaction products with only a small
amount of condensation product 24. However, inclusion of 4 Å
MS under otherwise identical conditions significantly increased
the formation of 24, rendering it the predominant product.
Ultimately, with 100 mol % of proline and 4 Å MS, the
condensation product 24 was produced as the sole product in
66% isolated yield (E/Z = 12.5:1). Notably, self-condensation of
4 was not observed under these conditions.
After separation of E/Z-isomers, the C13 hydroxyl group of 24
was liberated by the selective removal of diphenylsilyl group with
silver fluoride and Et3N·3HF to generate 25. The trimethylsilyl
group, an array of double bonds, and the epoxyaldehyde moiety
remained unchanged under these conditions. At this point
saponification of the methyl ester in the presence of these
sensitive functionalities was achieved by heating 25 with 10 equiv
of Me3SnOH26 in dichloroethane at 100 °C for 2.5 h. The
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ja401717b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Lee, D. J. Am. Chem. Soc. 2006, 128, 8142. (g) Yun, S. Y.; Hansen, E. C.;
Volchkov, I.; Cho, E. J.; Lo, W. Y.; Lee, D. Angew. Chem., Int. Ed. 2010,
49, 4261. (h) Herrmann, A. T.; Saito, T.; Stivala, C. E.; Tom, J.;
Zakarian, A. J. Am. Chem. Soc. 2010, 132, 5962. (i) Xie, Y.; Floreancig, P.
E. Chem. Sci. 2011, 2, 2423. (j) Xie, Y.; Floreancig, P. E. Angew. Chem.,
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Cheong, P. H.-Y. J. Am. Chem. Soc. 2013, 135, 1471.
AUTHOR INFORMATION
Corresponding Author
dsunglee@uic.edu
Notes
■
The authors declare no competing financial interest.
(17) Exposure of 17 to other tested oxidants, such as DDQ, PIFA, or
Ag(II) picolinate resulted in substrate decomposition.
(18) (a) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(b) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
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ACKNOWLEDGMENTS
■
Financial support from UIC through the Dean’s Scholar Award
to I.V. is greatly acknowledged. We thank Prof. Hyun-soon
Chong at the Illinois Institute of Technology for use of their
polarimeter. The Mass Spectrometry Laboratory at the
University of Illinois at Urbana-Champaign is greatly acknowl-
edged for acquisition of HRMS data.
(21) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798. (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152. (c) Mangion, I. K.;
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