The true structures of the vannusals, part 2: Total synthesis and revised structure of vannusal b

Full text of DOI:10.1002/anie.200902029

Communications
DOI: 10.1002/anie.200902029
Natural Products (2)
The True Structures of the Vannusals, Part 2: Total Synthesis and
Revised Structure of VannusalB**
K. C. Nicolaou,* Adrian Ortiz, and Hongjun Zhang
In the preceding communication[1] we described our initial
attempts to determine the true structures of the vannusals [A
(1) and B (2), originally assigned structures (Figure 1)].
Herein, we report the total synthesis of the real vannusal B
(i.e. structure 4 in Figure 1) that served not only to render it
available for biological investigations, but also to demystify its
true molecular architecture and that of its sibling, vannusal A.
Our initial intelligence gathering efforts led us to the
conclusion that a) the stereochemical details of the “south-
western” part of the molecule (i.e. rings A and B, C3, C29, C6,
and C7) were most likely correct as reported in the originally
assigned structures 1 and 2, and b) the most likely place for an
error was the very top of the “northeastern” region of those
structures (i.e. ring E, C25 and C21). As we had already
synthesized three of the four possible C25/C21 diastereomers of
the originally assigned structure of vannusal B (2)[2] and found
them to be erroneous, we returned to the remaining
diastereomer, structure 3 (C25-epi-2; Figure 1), as a possible
candidate for the true structure of vannusal B. By virtue of its
trans configuration at C25/C21, structure 3 was abandoned
earlier on the basis of the large coupling constant observed
between H21 and H25 (J = 8.5 Hz) in the trans-substituted C21-
epi-2 isomer (structure 3 in Ref. [1]). This observation led us
to chase several other diastereomers which, as we have seen in
the preceding communication,[1] ended by proving that none
of them represented the true structure of vannusal B.
Figure 1. Originally assigned structures of vannusals A (1) and B (2),
final targeted stereoisomer 3 [C25-epi-2], and revised structure 4.
BOM=benzyloxymethyl, SEM=trimethylsilylethoxymethyl, TIPS=tri-
isopropylsilyl.
With all the evidence in front of us, we were now forced to
reconsider the possibility that the C25-epi-2 structure (i.e. 3,
Figure 1) may accommodate the observed smaller coupling
constant for natural vannusal B (JH25,21 = 1.6 Hz) by virtue of
a special conformation. We therefore decided to pursue the
synthesis of 3 as the possible coveted structure of vannusal B.
The selection of structure 3 as our next favored target defined
compounds 5 and 6 (Figure 1) as the required building blocks
for its construction. Of these two fragments, only 6 needed to
be synthesized, since 5 was already available in enantiopure
form from our previous studies.[2] Its synthesis began with
reduction of racemic 8 [obtained by reaction of the titanium
enolate of diketone (ꢀ )-7 (TiCl4, Et3N) with acetone (ca.
6:1 d.r.)][2] using DIBAL-H, which proceeded stereoselec-
tively from the a face of the molecule and at both carbonyl
sites to afford, upon purification by chromatography, pure
triol 9 in 64% yield over two steps (Scheme 1). The
diastereoselective reduction of (ꢀ )-8 with NaBH4 stands in
contrast to the reduction of its TES-protected counterpart,
which gave the opposite configuration at C25.[2]
[*] Prof. Dr. K. C. Nicolaou, A. Ortiz, Dr. H. Zhang
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
[**] We thank Prof. Graziano Guella for samples and NMR spectra of
vannusals A and B, and for helpful discussions. We thank Dr. D. H.
Huang, Dr. G. Siuzdak, and Dr. R. Chadha for NMR spectroscopic,
mass spectroscopic, and X-ray crystallographic assistance, respec-
tively. Financial support for this work was provided by the NSF
(fellowship to A.O.), the Skaggs Institute for Research, and a grant
from the National Institutes of Health (USA).
Interestingly, triol 9 exhibited a small coupling constant
between H25 and H21 (JH25,21 = 1.0 Hz), which was rather
surprising given the coupling constants between the same
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902029.
protons of its siblings, 9a (JH25,21 = 10.0 Hz),[1] 9b (JH25,21
=
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Figure 2. Key 1H NMR coupling constants for tricyclic intermediates 9
(JH25,21 =1.0 Hz), 9a (JH25,21 =10.0 Hz), 9b (JH25,21 =3.5 Hz), and 9c
(JH25,21 <1.0 Hz) (top), and X-ray crystal structure of tetraol 9d
(bottom; ORTEP: thermal ellipsoids are shown at 30% probabliity).
Bz=benzoyl.
within triol 9. These observations underscored the dangers of
relying on the coupling constants to assign configurations
around five-membered rings, and provided somewhat of an
endorsement of our choice of target 3 as a candidate for the
true structure of vannusal B.
Returning to the main sequence of Scheme 1, installment
of SEM groups on all three hydroxy groups of intermediate 9
required sequential treatment with SEMCl and iPr2NEt
(508C, 24 h) first, and subsequent use of KHMDS and
excess SEMCl to deliver the corresponding tri-SEM deriva-
tive 10 (96% overall yield). The remaining steps to the
targeted fragment (ꢀ )-6 followed the previously chartered
route[1] and proceeded in high overall yield through inter-
mediates 11–13, as summarized in Scheme 1.
Scheme 1. Construction of aldehyde (ꢀ)-6. Reagents and conditions:
a) TiCl4 (1.3 equiv), Et3N (3.0 equiv), acetone (10 equiv), CH2Cl2,
ꢁ928C, 8 h; b) DIBAL-H (5.0 equiv), toluene, ꢁ78!08C, 30 min, 64%
over two steps; c) aq HF/THF (1:4), 258C, 18 h, 83%; d) iPr2NEt
(20 equiv), SEMCl (6.0 equiv), nBu4NI (1.0 equiv), 508C, 24 h; KHMDS
(3.0 equiv), SEMCl (5.0 equiv), Et3N (10 equiv), THF, ꢁ78!258C, 1 h,
96% over two steps; e) O3, py (1.0 equiv), CH2Cl2/MeOH (1:1),
ꢁ788C; then Ph3P (5.0 equiv), ꢁ78!258C, 1 h, 97%; f) KH
(10 equiv), allyl chloride (30 equiv), HMPA (10 equiv), DME, ꢁ10!
258C, 8 h, 95%; g) iPr2NEt (1.0 equiv), 1,2-dichlorobenzene, 2008C
(MW), 20 min; then NaBH4 (10 equiv), MeOH, 1 h, 258C, 88% over
two steps; h) BOMCl (10 equiv), iPr2NEt (30 equiv), nBu4NI
(1.0 equiv), CH2Cl2, 508C 12 h; i) O3, py (1.0 equiv), CH2Cl2/MeOH
(1:1), ꢁ788C; then Ph3P (5.0 equiv), ꢁ78!258C, 1 h, 81% over two
steps; j) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 258C, 12 h; k) O3,
py (1.0 equiv), CH2Cl2/MeOH (1:1), ꢁ788C; then Ph3P (5.0 equiv),
ꢁ78!258C, 1 h, 80% over two steps. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DIBAL-H=diisobutylaluminum hydride, DME=1,2-
dimethoxyethane, HMDS=hexamethyldisilazane, HMPA=hexamethyl-
phosphoramide, py=pyridine, TBS=tert-butyldimethylsilyl.
The coupling of enantiopure vinyl iodide (ꢁ)-5[2] with
racemic aldehyde (ꢀ )-6 (Scheme 2) proceeded smoothly
through the lithio derivative of 5 (tBuLi) to afford, after
removal of the TIPS group (TBAF, 258C), a mixture of
diastereomeric diols 14a and 14b (84% over 2 steps, ca.
1:1 d.r.), which were separated by chromatography. Based on
our previous studies,[4] the undesired diastereomers (such as
14b) had been routinely utilized for reconnaissance studies
regarding late stage transformations, particularly the SmI2-
cyclization and final global deprotection. Consequently, both
coupling products 14a and 14b were separately converted
into cyclization precursors 15a and 15b, respectively, through
the same sequence of reactions involving temporary silylation
of the primary hydroxy group (TESCl, imid), carbonate
3.5 Hz),[1] and 9c (JH25,21 < 1.0 Hz;[2] see Figure 2). Particu-
larly striking was the difference between the two trans com-
pounds 9 (JH25,21 = 1.0 Hz) and 9a (JH25,21 = 10.0 Hz). An X-
ray crystallographic analysis[3] (see ORTEP drawing,
Figure 2) of tetraol 9d (obtained from 9 by desilylation with
aqueous HF as shown in Scheme 1; m.p. 139–1418C, benzene/
MeOH) confirmed the assigned stereochemical relationships
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Scheme 2. Coupling of fragments (ꢁ)-5 and (ꢀ)-6. Reagents and
conditions: a) (ꢁ)-5 (1.3 equiv), tBuLi (2.6 equiv), THF, ꢁ78!ꢁ408C,
40 min; then (ꢀ)-6 (1.0 equiv), ꢁ40!08C, 20 min; b) TBAF (1.0m in
THF, 2.0 equiv), THF, 258C, 8 h, 84% (ca. 1:1 d.r.) over two steps, 14a
and 14b separated by chromatography; c) TESCl (2.0 equiv), imid
(10 equiv), CH2Cl2, 258C, 30 min; d) KHMDS (10 equiv), ClCO2Me
(20 equiv), Et3N (20 equiv), THF, ꢁ78!258C, 30 min; e) HF·py/py
(1:4), 0!258C, 12 h, 89% for sequence 14a!15a, 96% for sequence
14b!15b (over 3 steps); f) PhI(OAc)2 (2.0 equiv), AZADO
(0.1 equiv), CH2Cl2, 258C, 24 h, (96% for 15a, 97% for 15b); g) aq
HF/THF (1:4), 258C, 1.5 h, 81%. imid=imidazole, TBAF=tetra-n-
butylammonium fluoride, TES=triethylsilyl, THF=tetrahydrofuran.
Scheme 3. Synthesis of vannusal B structure 3. Reagents and condi-
tions: a) SmI2 (0.1m in THF, 10 equiv), HMPA (30 equiv), THF,
ꢁ20!258C, 20 min, 67%; b) Ac2O (20 equiv), Et3N (20 equiv), DMAP
(0.2 equiv), CH2Cl2, 258C, 30 min, quant.; c) SEMCl (10 equiv), iPr2NEt
(30 equiv), CH2Cl2, 508C, 18 h; d) DIBAL-H (5.0 equiv), CH2Cl2,
ꢁ788C, 30 min, 83% over two steps; e) NaH (10 equiv), CS2
(3.0 equiv), THF, 0!258C, 30 min; then CH3I (6.0 equiv), 0!258C,
1 h, 79%; then 1858C (MW), 1,2-dichlorobenzene, 15 min, 88%;
f) KHMDS (4.0 equiv), SEMCl (4.0 equiv), Et3N (8.0 equiv), THF,
ꢁ50!258C, 20 min, 78%; g) ThexBH2 (5.0 equiv), THF, ꢁ10!258C,
30 min; then BH3·THF (15 equiv), 258C, 1 h; then 30% H2O2/3n
NaOH (1:1 d.r.), 25!458C, 30 min; 71% (1:1.3 d.r.);
formation at the secondary position (KHMDS, ClCO2Me),
removal of the TES group (HF·py; 89% yield for 14a, 96%
yield for 14b), and oxidation of the liberated primary hydroxy
group [PhI(OAc)2, AZADO (cat.),[5] 96% yield for 15a, 97%
yield for 15b], as summarized in Scheme 2.
First to be advanced from this point was intermediate 15a,
which possessed our favored diastereomeric configuration.
Much to our disappointment, precursor 15a, with its three
SEM groups in place, failed to undergo the desired SmI2-
induced ring closure as several of its previous siblings,[1,2] thus
prompting us to modify its structure as a means to adjust its
reactivity. To this end, 15a was treated with aqueous HF to
afford, cleanly, dihydroxy substrate 16 (81% yield) through
selective cleavage of the SEM groups at C22 and C26
(Scheme 2). Pleasantly, substrate 16 underwent the desired
SmI2-induced cyclization to afford polycyclic structure 17 as
the major product (67% yield), which possessed, however,
the undesired configuration at C10 and C28 as shown in
Scheme 3. The obligatory inversion of the configuration at C10
and C28 of product 17 required a sequence that initially
h) oNO2C6H4SeCN (3.0 equiv), nBu3P (9.0 equiv), py (12 equiv), THF,
258C, 10 min; then 30% H2O2, 25!458C, 30 min, 86%; i) KHMDS
(6.0 equiv), TESCl (4.0 equiv), Et3N (8.0 equiv), THF, ꢁ50!258C,
20 min, 93%; j) LiDBB (excess), THF, ꢁ78!-508C, 30 min, 85%;
k) PhI(OAc)2 (4.0 equiv), TEMPO (2.0 equiv), CH2Cl2, 258C, 15 h, 88%;
l) Ac2O (30 equiv), Et3N (60 equiv), DMAP (2.0 equiv), CH2Cl2, 258C,
24 h, quant.; m) aq HF/THF (1:3), 258C, 6 h, 90%. DMAP=
4-dimethylaminopyridine, LiDBB=lithium di-tert-butylbiphenyl,
TEMPO=2,2,6,6-teramethyl-1-piperidinyloxy (free radical),
Thexy=thexyl.
involved selective temporary acetylation at C28 (Ac2O, Et3N,
DMAP, quantitative yield), installation of a SEM group at C22
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(SEMCl, iPr2NEt), and deacetylation (DIBAL-H) to furnish
diol 19, in 83% yield over two steps. Selective formation of a
xanthate at C28 and subsequent syn elimination [NaH, CS2,
MeI, 79% yield; then microwave (MW) heating, 1858C, 88%
yield] afforded, after protection of the hydroxy group at C26
with an SEM group, conjugate diene 20 (78% yield). The
latter compound was converted into the desired C10/C28
diastereomer 21 through the previously developed sequence
involving hydroboration/oxidation (ThexBH2; BH3; H2O2,
71% yield) and phenylselenenylation/syn elimination
(oNO2C6H4 SeCN, nBu3P; H2O2, 86% yield). Intermediate
21 was then transformed into diol 22 through sequential
silylation (KHMDS, TESCl, 93% yield) and cleavage of the
BOM groups (LiDBB, 85% yield). The final three steps to
structure 3, which involved sequential oxidation of the
primary hydroxy group within 22 (PhI(OAc)2, TEMPO,
88% yield), acetylation of the secondary hydroxy group
(Ac2O, Et3N, DMAP, quantitative yield), and global desily-
lation (aq HF, 90% yield) proceeded smoothly to afford
vannusal B structure 3, but not before the completion of the
synthesis of vannusal B structure 4 (see below), which we will
describe next because of its special significance.
Scheme 4 summarizes the total synthesis of vannusal B
structure 4. As it turned out, this synthesis was shorter and
more efficient than that of vannusal B structure 3. Thus,
remarkably, and in stark contrast to the attempted cyclization
of its diastereomeric counterpart (15a), the SmI2-mediated
ring closure of precursor 15b proceeded smoothly and
efficiently (82% yield) to afford polycyclic compound 24 as
a single diastereomer. Furthermore and much to our delight,
the two newly formed stereogenic centers at C10 and C28
possessed the correct configuration relative to the adjacent
quaternary centers, thus needing no configurational adjust-
ment as previously required. Placement of a TES group on the
hydroxy group at C28 of 24 (KHMDS, TESCl), and subse-
quent removal of the two BOM groups (LiDBB), led to diol
25 in 78% yield over two steps. Selective oxidation of the
primary alcohol within the latter compound was best achieved
through the use of PhI(OAc)2 in the presence of 1-Me-
AZADO[5] as a catalyst to afford aldehyde 26, whose
remaining hydroxy group was acetylated (Ac2O, DMAP) to
give protected vannusal B structure 26 (87% yield over 2
steps). Finally, the coveted structure 4 was generated from 26,
in 85% yield, by exposure to aqueous HF at ambient
temperature.
Scheme 4. Completion of the revised structure of vannusal B (4).
Reagents and conditions: a) SmI2 (0.1m in THF, 10 equiv), HMPA
(30 equiv), THF, ꢁ20!258C, 30 min, 82%; b) KHMDS (5.0 equiv),
TESCl (10 equiv), Et3N (10 equiv), THF, ꢁ78!258C, 20 min, 94%;
c) LiDBB (excess), THF, ꢁ78!-508C, 30 min, 83%; d) PhI(OAc)2
(2.0 equiv), 1-Me-AZADO (0.2 equiv), CH2Cl2, 258C, 18 h; e) Ac2O
(10 equiv), Et3N (20 equiv), DMAP (1.0 equiv), CH2Cl2, 258C, 18 h,
87% over two steps; f) aq HF/THF (1:4!1:3), 258C, 3 h, 85%;
g) NaBH4 (20 equiv), MeOH, 20 min, 90%.
structure, including absolute configuration, of vannusal B as
proven by comparison of its 1H and 13C NMR and CD spectra
1
with those of the natural product. Furthermore, the H and
13C NMR spectroscopic data of the NaBH4 reduction product
of synthetic vannusal B (27; Scheme 4) also matched those of
its counterpart obtained from natural vannusals A and B,[6,7]
thus providing further support of structure 4 as the true
structure of vannsualB. The structure of crystalline synthetic
vannusal B (m.p. > 2008C decomposition, EtOAc/THF) was
ultimately confirmed by X-ray crystallographic analysis[8] (see
ORTEP drawing, Figure 3). The structural differences
between the originally assigned and revised structures of
vannusal B are located mainly in the “eastern” domain of the
molecule (C10, C28, C13, C14, C26, C17, C18, and C21 stereocenters
were inverted), a circumstance that apparently arose from the
difficulty in relating the stereocenters at C7 and C10 in the
original structural studies. This challenge could only be solved
either by X-ray crystallographic analysis, or chemical syn-
thesis. In the end it was done by both, the latter preceding the
former, thereby demonstrating the facilitating nature of total
synthesis in structural elucidation even in this modern era.
The 500 MHz 1H NMR spectrum of synthetic vannusal B
structure 4 appeared excitingly close to the 600 MHz
1H NMR spectrum of natural vannusal B that we had in our
possession,[6] a fact that piqued our enthusiasm for the soon to
be completed structure 3 (see Scheme 3), which still com-
manded our main attention. Our arrival at vannusal B
structure 3 (Scheme 3), however, was met with grief because
1
the 600 MHz H NMR spectrum of this compound did not
match that (also 600 MHz) of the natural product. Thankfully,
our disappointment was short lived this time, for upon
1
obtaining a 600 MHz H NMR spectrum of synthetic struc-
ture 4 (Scheme 4), to which we immediately returned, we
realized that it was identical in every detail to that (600 MHz)
of natural vannusal B! Indeed, structure 4 represents the true
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Communications
[1] K. C. Nicolaou, H. Zhang, A. Ortiz, Angew. Chem. 2009; 121,
5752; Angew. Chem. Int. Ed. 2009, 48, 5642, see the preceding
communication in this issue.
[2] K. C. Nicolaou, H. Zhang, A. Ortiz, P. Dagneau, Angew. Chem.
2008, 120, 8733 – 8738; Angew. Chem. Int. Ed. 2008, 47, 8605 –
8610.
[3] CCDC 726955 (9d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[4] Details of these studies will be reported in the full account of this
work.
[5] M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem.
Soc. 2006, 128, 8412 – 8413.
Figure 3. X-ray crystal structure of vannusal B (4; thermal ellipsoids
are shown at 30% probability).
[6] G. Guella, F. Dini, F. Pietra, Angew. Chem. 1999, 111, 1217 – 1220;
Angew. Chem. Int. Ed. 1999, 38, 1134 – 1136.
[7] We thank Prof. Graziano Guella for samples of vannusals A and
B, 1H and 13C NMR spectra of vannusals A and B as well as their
reduction derivative 27.
[8] CCDC 726954 (4) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
The chemistry described here underscores once again the
indispensable roles of total synthesis in the structural
elucidation of scarce natural products and in rendering
them in sufficient quantities for further investigations in
those cases where their scarcity stymie such studies.
Received: April 15, 2009
Keywords: natural products · NMR spectroscopy ·
.
revised structures · structure elucidation · total synthesis
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