Total synthesis of the nominal didemnaketal A

Article abstract of DOI:10.1002/anie.201203406

False identity: The synthesis of a natural product described by Faulkner and co-workers two decades ago has revealed the need for the revision of some stereochemical assignments. The key steps in this flexible route, which could provide access to stereodefined analogues for biological evaluation, included a Julia coupling, a Suzuki-Miyaura reaction, and Wittig olefination (see scheme; MOM, PMB, and TBS are protecting groups). Copyright

Full text of DOI:10.1002/anie.201203406

Angewandte
Chemie
DOI: 10.1002/anie.201203406
Natural Products
Total Synthesis of the Nominal Didemnaketal A**
Fu-Min Zhang, Lei Peng, Hui Li, Ai-Jun Ma, Jin-Bao Peng, Jing-Jing Guo, Dengtao Yang,
Si-Hua Hou, Yong-Qiang Tu,* and William Kitching
Despite remarkable advances in the treatment
and prophylaxis of the human immunodefi-
ciency virus (HIV), AIDS-related infections
remain a scourge for humankind. In 2010,
approximately 1.8 million people died from
AIDS-related causes, and there were 2.7 mil-
lion new infections (including 0.39 million
children) worldwide.[1] Consequently, the dis-
covery and development of new chemothera-
peutic agents against AIDS is still of great
urgency. One important approach in this area
would be based on structural modification of
natural anti-HIV inhibitors.[2] The synthetic
verification of promising structures could also
lead to the discovery of efficient synthetic
routes to potentially active structures.[3]
Didemnaketal A (1) and B (2; Scheme 1),
isolated from the Ascidian Didemnum Sp. by
Faulkner and co-workers, have been demon-
strated to be effective HIV-1-protease inhib-
itors (IC50 = 2 and 10 mm, respectively).[4] Their
structures and configuration were assigned on
Scheme 1. Synthetic strategy toward the proposed structure of didemnaketal A.
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
the basis of extensive NMR spectroscopic
studies, Mosher chiral-shift methods, and
chemical degradation of a subsequently isolated analogue,
didemnaketal C (3; Scheme 1). It is highly likely that
didemnaketals A and B are produced from didemnaketal C
by oxidation and methanolysis on storage, respectively.[4c] On
this basis, if the absolute configuration deduced by Faulkner
and co-workers for didemnaketal B (portrayed in Scheme 1)
is accepted, didemnaketal A (1) would be the
5S,6S,7R,8R,10S,11S,12S,14S,16R,18R,20S,21R stereoisomer.
Didemnaketal A features a spiroketal moiety and a main
chain containing 23 carbons and 12 stereogenic centers.
Furthermore, there are three different ester groups at C5, C7,
C8, and C11 and a free OH group at C21. Thus, overall, these
compounds have a rare and challenging architecture. The
scarce natural supply, unusual structure, and significant HIV-
1-inhibition properties of the didemnaketals have attracted
the interest of synthetic chemists. Synthetic approaches
toward subunits of didemnaketals were developed by Rich
and co-workers,[5] Ito et al.,[6a] Fuwa et al,[6b] and our research
group.[7] However, there has been no report of a total
synthesis of didemnaketal A.
Such a synthesis presents at least three major challenges:
1) the polymethyl and multioxygenation patterns are
arranged somewhat irregularly on the main chain (unlike
more straightforward 1,3-dimethyl or 1,3-dihydroxy disposi-
tions) and are thus difficult to generate efficiently by
repetitive use of a single reliable method (e.g. aldol reaction
variants); 2) acyclic stereocontrol is more difficult than that in
rigid (cyclic) frameworks; and 3) chemoselective protection/
deprotection and then regioselective esterification of poly-
hydroxy systems are tactically awkward. Herein, we report
the first total synthesis of the proposed structure of didem-
naketal A.
[*] Prof. Dr. F.-M. Zhang, Dr. L. Peng, H. Li, A.-J. Ma, J.-B. Peng,
J.-J. Guo, D. Yang, S.-H. Hou, Prof. Dr. Y.-Q. Tu
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry, Lanzhou University
Lanzhou 730000 (P. R. China)
E-mail: tuyq@lzu.edu.cn
Prof. Dr. W. Kitching
Department of Chemistry, The University of Queensland (Australia)
Our retrosynthetic analysis is outlined in Scheme 1.
Unlocking of the spiroketal moiety furnishes precursor 4
with an elongated carbon chain and reveals two OH groups at
C12 and C20 and a keto group at C16. Importantly, the six OH
groups with the syn configuration at C7–C8, C11–C12, and
C20–C21 in 4 could be stereoselectively installed by the
[**] This research was supported by the NSFC (Nos. 20921120404,
20972059, 21072085, 21272097, and 21290180), the “973” Program
(No. 2010CB833203), and the “111” Program of MOE. We thank
Prof. C.-A. Fan, S.-H. Wang, and Z.-L. Liu for discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203406.
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Sharpless asymmetric dihydroxylation (SAD reaction). The
three methyl-bearing stereogenic centers at C6, C14, and C18
could originate from “chiral pool” components. Furthermore,
Sharpless asymmetric dihydroxylation (SAD)[11] of ether 11
generated the triol 12, and selective TBS protection of the two
secondary hydroxy groups, followed by the elimination of the
tertiary alcohol, gave the terminal olefin 14. Selective
removal of the TBDPS protecting group and the oxidation
of the resulting primary alcohol with Dess–Martin period-
inane[12] furnished the aldehyde segment C (15) in 77% yield
(2 steps). Significantly, only seven linear steps were required
for the preparation of segment C from (S)-citronellol.
ꢀ
ꢀ
ꢀ
the bonds C2 C3, C8 C9, and C16 C17 in 4 could be formed
by Wittig olefination, a Suzuki–Miyaura reaction, and Julia
coupling, respectively. Following these disconnections, the
four simpler segments A, B, C, and D were proposed for the
construction of 4, whereby the segments B, C, and D could be
derived from the alcohol 5, (S)-citronellol (6), and the
aldehyde 7, respectively.
The sulfone segment D (R6 = TBS, R7 = MOM) was
prepared from the aldehyde 7[13] (Scheme 4), which under-
went Wittig olefination[14] and protection of the resulting
Guided by this strategy, we began our synthesis of the
proposed didemnaketal A structure 1 with the preparation of
segment B (R = Me, R1 = PMB). Starting from compound 5
(Scheme 2),[8] removal of the TBS group permitted diol
Scheme 2. Reagents and conditions: a) 1) TBAF, THF, 08C, 90%;
2) 4-methoxybenzaldehyde, CH2Cl2, CSA, room temperature, 99%;
3) DIBAL, CH2Cl2, ꢀ788C, 95%; b) Jones oxidation, acetone, then
CH2N2/Et2O, 68% (2 steps); c) 1) O3, CH2Cl2, ꢀ788C, 93%; 2) CrCl2,
CHI3, THF, 08C!RT, 71%. CSA=camphorsulfonic acid, DIBAL=
diisobutylaluminum hydride, PMB=p-methoxybenzyl, TBAF=tetra-n-
butylammonium fluoride.
=
Scheme 4. Reagents and conditions: a) 1) PPh3 CHCOCH3, CH2Cl2,
558C, 95%; 2) glycol, PPTS, benzene, reflux, 92%; b) AD-mix-a,
CH3SO2NH2, tBuOH/H2O (1:1), 08C, 91%; c) TBSOTf, 2,6-lutidine,
CH2Cl2, ꢀ908C, 72% (based on recovered starting material);
d) MOMCl, NaI, DIPEA, DME, 1008C, 95%; e) 1) NH4F, CH3OH,
reflux, 70%; 2) I2, PPh3, imidazole, toluene, room temperature, 95%;
3) PhSO2Na, DMF, room temperature, 84%. DIPEA=N,N-diisopropyl-
N-ethylamine, DME=1,2-dimethoxyethane, MOM=methoxymethyl,
PPTS=pyridinium p-toluenesulfonate, Tf=trifluoromethanesulfonyl.
protection with 4-methoxybenzaldehyde. Subsequent reduc-
tive opening of the p-methoxyphenyl acetal generated the
alcohol 8, which was oxidized with the Jones reagent and then
esterified with CH2N2 to give the ester 9. Finally, vinyl iodide
10 (segment B) was readily obtained by the ozonolytic
conjugated enone to afford the ketal 16 in 87% yield over two
steps. The stereoselective installation of hydroxy groups at
C20 and C21 by the SAD protocol yielded the diol 17.
Subsequently, selective protection of the hydroxy groups at
C20 and C21 in 17 was studied. The mono-TBS ether at C20
was acquired in 72% yield by the use of TBSOTf and 2,6-
lutidine in CH2Cl2 at ꢀ908C. Further protection of the
hydroxy group at C21 of 18 with MOMI prepared in situ at
1008C afforded the MOM ether 19 in excellent yield.[15]
Selective desilylation of the O-TBDPS ether in 19, followed
by iodination of the resulting alcohol, gave the primary iodide
intermediate, which reacted with sodium benzene sulfinate to
provide the desired sulfone 20 in 56% yield over three steps.
With the three key building blocks B, C, and D available,
our focus shifted to the crucial segment-coupling reactions
(Scheme 5). Formation of the spiroketal moiety would result
in the “internal” protection of the ketodiol unit; therefore, the
Julia coupling[16] of segments C and D was attempted initially
for the formation of the C9–C23 fragment. Under standard
conditions, the reaction provided the anticipated coupling
products, which were oxidized with the Collins reagent to
form the C16 keto group. Subsequent reductive removal of
the sulfone group furnished the C9–C23 fragment 21 in 82%
yield over three steps. Spirocyclization with NH4F·HF as
a promoter afforded the desired spiroketal 22 in 86% yield.
=
cleavage of the C C bond in 9 and a subsequent Takai
reaction.[9]
The aldehyde segment C (R4 = R5 = TBS) was synthesized
from (S)-citronellol (6; Scheme 3). Treatment of 6 with active
[10]
O2
was followed by selective protection of the primary
alcohol to afford the ether 11 in 48% yield over two steps. The
Scheme 3. Reagents and conditions: a) 1) Rose Bengal, O2, hn,
CH3OH; 2) TBDPSCl, imidazole, CH2Cl2, 08C, 48% (2 steps); b) AD-
mix-a, CH3SO2NH2, tBuOH/H2O (1:1), 08C, 85%; c) TBSCl, imidazole,
DMF, 908C, 78%; d) SOCl2, pyridine, 08C, 91%; e) 1) NH4F, MeOH,
reflux, 88%; 2) Dess–Martin periodinane, CH2Cl2, room temperature,
88%. DMF=N,N-dimethylformamide.
2
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Scheme 5. Reagents and conditions: a) 1) nBuLi, THF, ꢀ78!08C, 30 min, then 20; 2) Collins reagent (10 equiv), CH2Cl2, room temperature;
3) SmI2, THF, ꢀ788C, 82% (3 steps); b) NH4F·HF, CH3OH, reflux, 86%; c) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 89%; d) 9-BBN, ꢀ788C!RT,
4 h, then 10, DMF, Cs2CO3, [Pd(dppf)2Cl2], AsPh3, room temperature, 5 h, 77%; e) AD-mix-b, CH3SO2NH2, tBuOH/H2O (1:1), 08C, then CHCl3,
room temperature, 3 days, 45% for 25 and 15% for 25’; f) TESCl, imidazole, DMF, 608C, 89%; g) DIBAL, CH2Cl2, ꢀ788C; h) segment A, CH2Cl2,
558C, 3 days, 95% (2 steps). 9-BBN=9-borabicyclo[3,3,1]nonane, dppf=1,1’-bis(diphenylphosphanyl)ferrocene, TES=triethylsilyl.
Next, our attention was directed to the connection of
segment B with the C9–C23 fragment (Scheme 5). Thus,
reprotection of the free OH group in 22 as the TBS ether gave
the Suzuki–Miyaura precursor 23.[17] Pleasingly, the Suzuki–
Miyaura coupling[18] between vinyl iodide 10 (segment B) and
the hydroboration product derived from 23 proceeded well to
produce fragment 24 (C3–C23) in 77% yield. The desired C10
methyl group was also installed stereoselectively during this
ters as well as the entire chain (C1–C23) with crucially
differentiated protection of the secondary hydroxy groups at
C5, C8, C11, and C21 to enable later sequence-selective
esterification of the corresponding alcohols.
We then considered possible conditions for the selective
installation of three different ester groups at C5, C7, C8, and
C11 (Scheme 6). First, acetylation of the C7 hydroxy group
gave 29. However, the dual removal of the silyl groups at C8
and C11 of 29 to yield the diol 30 proved problematic, because
acetyl migration from C7 to C8 occurred prior to cleavage of
the TBS ether at C11. We therefore carried out the sequence
of reactions in a different order. Under mildly acidic
conditions, selective cleavage of the C8 TES ether of 29
provided the desired product 31; both acetyl migration and
the deprotection of other acid-sensitive groups were avoided.
The free hydroxy group at C8 in 31 was then acylated with
isovaleric anhydride to introduce the C8 isovalerate ester
moiety. We installed the second isovalerate ester at C11 in two
steps: selective removal of the TBS group in 32,[21] followed by
acylation. Next, the PMB group at C5 of 33 was removed,[22]
and acylation with propionic anhydride provided compound
=
process. The E configuration of the C C bond in 24 was
deduced from the coupling constant (J = 16.8 Hz) in the
1
=
H NMR spectrum. Subsequent SAD of the C C bond in 24,
followed by in situ intramolecular trapping of the resulting C7
hydroxy group with the C3 methyl ester, generated the
desired 7R,8R d-lactone 25 in 45% yield, along with the
minor undesired 7S,8S d-lactone 25’.[17] The structure of 25
was assigned by NMR spectroscopic studies, Mosher methods,
and the X-ray crystallographic analysis of its isomer 25’.[19] All
12 stereocenters in 25 had been correctly installed, exactly as
assigned in the proposed stereostructure of didemnaketal A
by Faulkner and co-workers.[4] The formation of the d-lactone
in 25 provided the possibility for tactical discrimination
between the OH groups at C7 and C8. As a result, the C8
hydroxy group could be protected efficiently as the TES ether
to give compound 26. The lactone 26 was reduced to afford
the lactol 27, which was subsequently used without purifica-
tion for a direct Wittig reaction with segment A[20] to furnish
28. This advanced intermediate 28, which was available in 18
steps from the known compound 7, contained all stereocen-
1
34. At this stage, detailed analysis of H NMR, 13C NMR,
COSY, HSQC, and HMBC spectra demonstrated that the
ester groups were located in positions consistent with the
conclusions reported for didemnaketal A.[4] Finally, depro-
tection at C21 and C22 with 40% HF afforded the target
compound 1.
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esters.[4c,23] If the details of the
structural assignment of natural
didemnaketal A by Faulkner et al.
are considered,[24] the current spec-
tral differences might plausibly
arise from some stereochemical
misassignments, in particular for
C5, C6, C7, C8, and C21. On this
basis,
a series of stereodefined
building blocks could be conceived
for further stereochemical modifi-
cations to our constituent frag-
ments in the present synthetic
routes; these studies will be
reported in due course.
In conclusion, we have de-
scribed the first total synthesis of
the proposed structure of didemna-
ketal A in 31 steps for the longest
linear sequence. The key steps
include Julia coupling, a Suzuki–
Miyaura reaction, Sharpless asym-
metric dihydroxylation, and Wittig
olefination. The synthesis gives
a vivid example of selective protec-
tion/deprotection in this polyol
system. This route could provide
convenient access to structurally
diverse analogues for further activ-
ity evaluation.
Scheme 6. Reagents and conditions: a) Ac2O, CH2Cl2, DMAP (cat.), room temperature, 96%;
b) PPTS, C2H5OH, 08C, 97% (based on recovered starting material); c) isovaleric anhydride, CH2Cl2,
DMAP (cat.), room temperature, 99%; d) HF·pyridine, THF–pyridine, room temperature, 3 days,
96%; then isovaleric anhydride, CH2Cl2, DMAP (cat.), room temperature, 97%; e) DDQ, CH2Cl2/
buffer (pH 7; 1:1), room temperature, 96%; then propionic anhydride, CH2Cl2, DMAP (cat.), room
temperature, 89%; f) 40% HF, THF, room temperature, 89%. DMAP=4-dimethylaminopyridine,
DDQ=2,3-dichloro-5,6-dicyanobenzoquinone.
Received: May 3, 2012
Revised: August 28, 2012
Published online: && &&, &&&&
Keywords: antiviral agents ·
esterification · natural products · spiro compounds ·
total synthesis
1
To our disappointment, however, the H and 13C NMR
.
spectra of our synthetic sample 1 were not coincident in all
respects with the data reported by Faulkner and co-workers
for the “natural” didemnaketal A.[4] Significant differences
(Dd > 0.08 ppm) in the 1H NMR chemical shifts were
observed between the synthesized didemnaketal A (1) and
the “natural” compound for the hydrogen atoms at C8, C10,
C14, C19, C20, C21, and C36, and some clear discrepancies
(Dd > 1.0 ppm) were also observed in the 13C NMR chemical
shifts for C7, C8, C10, C20, C23, and C26.[19] The absolute
configuration of the C9–C20 segment in didemnaketal A was
deduced by Faulkner and co-workers on the basis of the
following methods: 1) determination of the relative config-
uration of the C9–C20 unit by X-ray crystallographic analysis
of a chemical-degradation fragment;[4c] 2) assignment of the
absolute configuration at C20 by the use of a chiral aniso-
tropic reagent;[4c] and 3) confirmation of the absolute config-
uration at C11 by the use of an alternative Mosher method.[4c]
Therefore, the assignment of the stereogenic centers between
C9 and C20 could be reliable; however, the absolute
configuration at C5, C6, C7, C8, and C21 was based only on
the analysis of coupling constants, ROSEY correlations, and
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[17] CCDC 872804 (23) and 867474 (25’) contain the supplementary
crystallographic data for this paper. These data can be obtained
[24] For the determination of the constitutional structure of didem-
naketal A through the use of extensive spectroscopic methods,
1
including HRMS, H NMR spectroscopy, 13C NMR spectrosco-
py, NOE analysis, H,H COSY, HMQC, and HMBC, see
Ref. [4a]. For the stereochemical determination of the C9–C20
fragment of didemnaketal A by X-ray crystallographic analysis
further combined with two alternative methods for the assign-
ment of the absolute configuration at C11 and C20, see Ref. [4c].
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Angewandte
Communications
Communications
Natural Products
False identity: The synthesis of a natural
product described by Faulkner and co-
workers two decades ago has revealed the
need for the revision of some stereo-
chemical assignments. The key steps in
this flexible route, which could provide
access to stereodefined analogues for
biological evaluation, included a Julia
coupling, a Suzuki–Miyaura reaction, and
Wittig olefination (see scheme; MOM,
PMB, and TBS are protecting groups).
F.-M. Zhang, L. Peng, H. Li, A.-J. Ma,
J.-B. Peng, J.-J. Guo,
D. Yang
&&&& — &&&&
Total Synthesis of the Nominal
Didemnaketal A
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!