Total synthesis and structural revision of vannusals A and B: Synthesis of the true structures of vannusals A and B

Article abstract of DOI:10.1021/ja100742b

Having determined through total synthesis that the originally assigned structure of vannusals A and B were incorrect, we set out to uncover the identity of the true structures of these novel marine natural products. Our search was based on intelligence gathered by NMR spectroscopy and chemical synthesis and took us through the total synthesis of eight diastereomeric vannusal B structures [2, d-2, 3, d-3, 4, d-4, 5, and d-5, Figure 2]. The true structures of vannusals A and B were finally determined to be d-5 and d-1, respectively. Their total synthesis was based on a highly convergent and efficient strategy that involved fragments vinyl iodide (-)-6 and aldehyde (±)-94, and featured a stereoselective lithium-mediated coupling reaction and a samarium-induced cyclization process that forged the final ring of the carbon framework. The synthetic strategies and technologies developed in these investigations expand the scope of chemical synthesis and render these compounds readily available for biological evaluation, while the NMR spectroscopic insights gained should prove useful in future structural determination endeavors.

Full text of DOI:10.1021/ja100742b

Published on Web 05/05/2010
Total Synthesis and Structural Revision of Vannusals A and
B: Synthesis of the True Structures of Vannusals A and B
K. C. Nicolaou,* Adrian Ortiz, Hongjun Zhang, and Graziano Guella†
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and the Department of
Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received February 1, 2010; E-mail: kcn@scripps.edu
Abstract: Having determined through total synthesis that the originally assigned structure of vannusals A
and B were incorrect, we set out to uncover the identity of the true structures of these novel marine natural
products. Our search was based on intelligence gathered by NMR spectroscopy and chemical synthesis
and took us through the total synthesis of eight diastereomeric vannusal B structures [2, d-2, 3, d-3, 4,
d-4, 5, and d-5, Figure 2]. The true structures of vannusals A and B were finally determined to be d-5 and
d-1, respectively. Their total synthesis was based on a highly convergent and efficient strategy that involved
fragments vinyl iodide (-)-6 and aldehyde (()-94, and featured a stereoselective lithium-mediated coupling
reaction and a samarium-induced cyclization process that forged the final ring of the carbon framework.
The synthetic strategies and technologies developed in these investigations expand the scope of chemical
synthesis and render these compounds readily available for biological evaluation, while the NMR
spectroscopic insights gained should prove useful in future structural determination endeavors.
Introduction
In the preceding article1 we described the total synthesis of
the originally assigned structure of vannusal B, one of two
marine natural products whose isolation and structural assign-
ment [structures 1 (vannusal A) and 2 (vannusal B), Figure 1]
were reported in 1999, by Guella, Dini, and Pietra.2 Comparison
of the NMR spectral data of synthetic 2 and natural vannusal B
revealed the nonidentity of the originally assigned structure (2)
to the true structure of vannusal B, precipitating a structural
puzzle whose solution was exacerbated by the scarcity of the
natural products. In this article, we present a detailed account
of our work that led to the demystification of this conundrum
and, at the same time, the total synthesis of vannusals A and B
and several of their analogues.
Figure 1. Originally assigned structures of vannusals A (1) and B (2).
5.7-3.5 ppm) of the 1H NMR spectra of the synthetic, originally
assigned, vannusal B structure [(+)-2] (top) and natural vannusal
B (bottom). As seen from comparing the two spectral regions,
the most dramatic discrepancy lay with H26 (∆δ +0.485 ppm).
Panels a and b of Figure 4 depict the 1H and 13C NMR chemical
shift differences, respectively, between the synthetic, originally
assigned, vannusal B structure (+)-2 (blue bars) and natural
vannusal B (set to zero).
Results and Discussion
Despite its failure to prove the structure of vannusal B, our
total synthesis of the originally assigned structure (+)-21,3
provided a wealth of information in terms of synthetic technol-
ogy and NMR spectroscopic intelligence that proved invaluable
in our campaign to elucidate the true structures of the vannusals,
a campaign that required the total synthesis of eight vannusal
B diastereoisomers (2, d-2, 3, d-3, 4, d-4, 5, and d-5, Figure
2). Figure 3 shows the well-resolved and diagnostic region (δ
While the 1H NMR comparison (Figure 4a, blue bars) reveals
several chemical shift differences, two stand out: those of H26
(mentioned above and seen in Figures 3 and 4a) and H16right
(seen in Figure 4a) (∆δ -0.413). The fact that both these protons
were located in the “northeastern” domain of the molecule,
together with the realization that most differences resided in
the same region, pointed to the vicinity around rings D and E
as the problematic site of the structure. This assumption was
further supported by similarly large differences in the 13C NMR
chemical shifts (Figure 4b, blue bars), most notably for C21 (∆δ
-11.54 ppm), C25 (∆δ +3.91 ppm), and C27 (∆δ +3.00 ppm).
Interestingly, the synthetic diastereomeric structure (+)-d-2
exhibited less drastic differences both in its 1H (Figure 4a, red
bars) and 13C NMR (Figure 4b, red bars) spectra from natural
† Faculty of Science, Bioorganic Chemistry Lab, University of Trent, Italy.
(1) Nicolaou, K. C.; Ortiz, A.; Zhang, H.; Dagneau, P.; Lanver, A.;
Jennings, M. P.; Arseniyadis, S.; Faraoni, R.; Lizos, D. E. J. Am. Chem.
Soc. 2010, 132, DOI: 10.1021/ja100740t (preceding article).
(2) Guella, G.; Dini, F.; Pietra, F. Angew. Chem., Int. Ed. 1999, 38, 1134–
1136.
(3) Nicolaou, K. C.; Zhang, H.; Ortiz, A.; Dagneau, P. Angew. Chem.,
Int. Ed. 2008, 47, 8605–8610, see also ref 1.
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A R T I C L E S
Nicolaou et al.
Figure 2. Vannusal B structures (2, d-2, 3, d-3, 4, d-4, 5, and d-5) synthesized as part of the campaign to elucidate the true structures of the vannusals.
Figure 3. 1H NMR spectral comparison (δ 5.7-3.5 ppm, d4-MeOH, 4600 MHz) of the originally assigned structure [(+)-2, top] and natural vannusal B
(bottom).
vannusal B. Having convinced ourselves of the general vicinity
of the problem and that the originally assigned overall skeleton
of the molecule was correct, we then attempted to pinpoint the
correct configuration(s) of the stereocenter(s) within the “north-
eastern” region of the vannusal B structure. For this we relied
on the NMR spectroscopic evidence shown in Figure 5, which
included: (a) a revealing w-J coupling between H26 and H15left
present in both synthetic and natural vannusal B (w-JH26,15left
) 1.6 Hz); (b) NOEs between H26 and H27, and H26 and H19R;
and (c) NOE between H25 and H16right. The first two observations
(a and b) provided evidence for the correctness of the initial
configurational assignment at C26, whereas the latter observation
(c) supported the originally assigned configuration of the C18
stereocenter.2
Faced with this evidence we focused our search on a
possible configurational error at C25 and/or C21. Indeed, the
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Vannusals A and B: Synthesis of True Structures
A R T I C L E S
1
Figure 4. (a) Graphically depicted H chemical shift differences (∆δ, ppm, d4-MeOH, 600 MHz) between the originally assigned structures [(+)-2: blue
and (+)-d-2: red] and natural vannusal B (set to zero). r ) right; l ) left. (b) Graphically depicted 13C chemical shift differences (∆δ, ppm, d4-MeOH, 600
MHz) between the originally assigned structures [(+)-2: blue and (+)-d-2: red] and natural vannusal B (set to zero).
spectroscopic evidence upon which the original configura-
tional assignment at these stereocenters relied was incom-
plete.2 The fact that these stereocenters resided on a
cyclopentane ring made their assignment even more treacher-
ous, as revealed from the observation of seemingly conflicting
coupling constants for natural vannusals A [JH25,21 ) 6.6
Hz (d4-MeOH) or 8.3 Hz (d6-benzene)] and B [JH25,21 ) 2.0
Hz (d4-MeOH)].2 Our synthetic vannusal B structure (+)-2
exhibited JH25,21 ) 3.0 Hz (d4-MeOH). In deciding which
one of the three remaining C25/C21 diastereoisomers of the
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Figure 7. Retrosynthetic analysis of vannusal B structure (+)-3 [C21-epi-2].
1
Figure 5. Key H NMR coupling constants and NOEs exhibited by both
the originally assigned structure [(+)-2] and natural vannusal B.
Therefore, a short detour was necessary to reach the desired
dihydroxy nitrile intermediate. Reasoning that the side reaction
was occurring through initial formation of an R-OAlEt2 species
followed by intramolecular delivery of an Et group, we
proceeded to block the free hydroxyl with an acetate group
(Ac2O, Et3N, 4-DMAP, 90%) to generate acetate epoxide (()-
11, whose reaction with Et2AlCN occurred as anticipated in 81%
yield to afford the expected hydroxy acetate (()-12. Removal
of the now superfluous acetate group (K2CO3, MeOH, quant.)
from this hydroxy acetate furnished the targeted dihydroxy
nitrile (()-13 as a single compound. Acetonide formation
[(MeO)2CMe2, PPTS] then led to crystalline acetonide nitrile
(()-14 (mp 87-88 °C, hexanes, 89% yield). X-ray crystal-
lographic analysis of the latter compound provided unambiguous
confirmation of its structure (see ORTEP, Scheme 1, bottom).7
The required aldehyde fragment (()-7 was synthesized from
nitrile acetonide (()-14 as summarized in Scheme 2. To this
end, the nitrile group of (()-14 was converted to the desired
tertiary alcohol moiety through a high-yielding, four-step
procedure involving (a) aldehyde generation (DIBAL-H), (b)
MeMgBr addition, (c) oxidation [NMO, TPAP, (cat.)],8 and (d)
a second MeMgBr addition to afford intermediate (()-15 in
80% overall yield. The latter was then protected with SEMCl
in the presence of i-Pr2NEt and n-Bu4NI to give the correspond-
ing SEM ether acetonide, whose terminal olefin was cleaved
(O3; Ph3P), furnishing the expected aldehyde (91% over the two
steps). The latter reacted with allyl chloride in the presence of
KH to afford the desired allyl enol ether (()-16 (95% yield,
E:Z ∼6:1). Heating of this enol ether under microwave
conditions (200 °C) induced the expected Claisen rearrangement,
furnishing upon NaBH4 reduction primary alcohol (()-17 (97%
overall yield). With the last quaternary center installed, protec-
tion of the hydroxyl group within the latter compound as a BOM
ether (BOMCl, i-Pr2NEt, n-Bu4NI), followed by ozonolytic
cleavage (O3; Ph3P, 80% yield for the two steps) of the terminal
olefin, led to aldehyde (()-18, which was then truncated to the
desired aldehyde (()-7 through a two-step sequence involving
originally assigned vannusal B structure [(+)-2] to be the
next synthesized, we were influenced by the hemi-vannusal
biosynthetic hypothesis proposed by Guella et al. and
summarized in Figure 6.4
Thus, assuming that two molecules of the same absolute
configuration of hemivannusal are joined and processed to
vannusal B, and that no epimerization takes place along the
biosynthetic pathway, then the C21 absolute configuration of the
product should be the same as its C3 absolute configuration
[3(S)], namely 21(S) (see Figure 6). It was on the basis of this
hypothesis that we chose structure (+)-3 [C21-epi-2] as our next
synthetic target, hoping that it would be the true structure of
vannusal B.
Total Synthesis of Vannusal B Structure (+)-3 [C21-epi-2].
The synthetic strategy employed to synthesize vannusal B
structure (+)-3 [C21-epi-2] was based on the same retrosynthetic
analysis that was used to design the total synthesis of the
originally assigned structure (+)-2.1,3 In this case, this analysis
defined vinyl iodide (-)-6 and aldehyde fragment (()-7 as the
required building blocks (see Figure 7). Since the vinyl iodide
[(-)-6] was already available through a previously developed
route,1,3 the immediate goal for this synthesis was to develop a
process for the construction of aldehyde (()-7. To this end,
and after a few scouting expeditions, we devised a diastereo-
selective synthesis of nitrile acetonide (()-14 (Scheme 1) which
served as a precursor to the desired aldehyde (()-7 (Scheme
2). Thus, Martin’s sulfurane-induced dehydration of diol (()-
85 led to hydroxy olefin (()-9 (87% yield, Scheme 1), which
was subjected to vanadium-catalyzed epoxidation [t-BuOOH,
VO(acac)2 (cat.)]6 to afford regio- and diastereoselectively
epoxide (()-10 (90% yield, single diastereomer). Postulated
transition state 9-TS explains the selectivity of this reaction
(homoallylic assistance). Reaction of hydroxy epoxide (()-10
with the Nagata reagent (Et2AlCN) failed to produce the desired
dihydroxy nitrile (()-13 in satisfactory yield, instead leading
to a dihydroxy ethyl-containing compound as a major product.
Figure 6. Guella biosynthetic hypothesis for the vannusals providing impetus for targeting vannusal B structure (+)-3 [C21-epi-2].4
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A R T I C L E S
Scheme 1. Construction of Nitrile Acetonide (()-14 (top) and Its
Scheme 2. Construction of Aldehyde (()-7a
X-ray Derived ORTEP (bottom)a
a Reagents and conditions: (a) DIBAL-H (1.5 M in toluene, 1.15 equiv),
toluene, -78 f -20 °C, 1 h; then 0.1 N aq HCl, 25 °C, 30 min; (b)
MeMgBr (5.0 equiv), THF, 0 °C, 1 h; (c) NMO (2.0 equiv), TPAP (0.05
equiv), CH2Cl2; MeCN (9:1), 25 °C, 1 h; (d) MeMgBr (5.0 equiv), THF,
-10 °C, 1 h, 80% for the four steps; (e) n-Bu4NI (1.0 equiv), SEMCl (5.0
equiv), i-Pr2NEt (20 equiv), 12 h; (f) O3, py (1.0 equiv), CH2Cl2/MeOH
(1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 91%; (g) KH (10
equiv), allyl chloride (20 equiv), HMPA (10 equiv), DME, -10 f 25 °C,
8 h, 95% (E:Z ∼6:1); (h) i-Pr2NEt (1.0 equiv), o-dichlorobenzene, 200 °C
(µ-waves), 20 min; then NaBH4 (10 equiv), MeOH, 2 h, 25 °C, 97% for
the two steps; (i) BOMCl (10 equiv), i-Pr2NEt (30 equiv), n-Bu4NI (1.0
equiv), CH2Cl2, 50 °C 12 h; (j) O3, py (1.0 equiv), CH2Cl2/MeOH (1:1),
-78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 80% for the two steps;
(k) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 24 h; (l) O3, py
(1.0 equiv), CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78 f
25 °C, 1 h, 86% for the two steps.
a Reagents and conditions: (a) Martin’s sulfurane (1.1 equiv), Et3N (10
equiv), CH2Cl2, 25 °C, 5 h, 87%; (b) t-BuOOH (3.0 equiv), VO(acac)2 (0.2
equiv), benzene, 25 °C, 6 h, 90%; (c) Ac2O (10 equiv), Et3N (30 equiv),
4-DMAP (1.0 equiv), CH2Cl2, 4 h, 25 °C, 90%; (d) Et2AlCN (10 equiv),
toluene, -78 f -20 °C, 19 h, 81%; (e) K2CO3 (1.0 equiv), MeOH, 25 °C,
2 h, quant.; (f) DMF/2,2-dimethoxypropane (1:1), PPTS (1.0 equiv), 24 h,
89%.
-78f25 °C); (iii) selective desilylation (HF ·py/py, 0 f 25
°C, 90% overall yield); and (iv) oxidation [PhI(OAc)2, TEMPO,
87%]. Disappointingly, however, the much anticipated cycliza-
tion of aldehyde carbonate (-)-21 under the standard SmI2-
conditions failed to produce either of the expected polycyclic
systems (23r/ꢀ). Interestingly, when the diastereomeric alde-
hyde carbonate (-)-22 [prepared through the same sequence
as (-)-20 as shown in Scheme 3] was subjected to the same
cyclization conditions (SmI2, HMPA, -10 f 25 °C), the
reaction proceeded well, furnishing polycyclic system (-)-24
in 76% yield and as a single diastereomer. Despite this rather
intriguing observation, we failed to derive any insightful
information from it at this stage and returned to our objective
of elaborating what we perceived at the time to be the correct
diastereomeric coupling product [i.e., (-)-19] to the desired
polycyclic structures through a more favorable cyclization
substrate. In retrospect, as we shall see later, a subtle clue was
hidden within these observations; specifically, we refer to the
meaning of the failure of (-)-21 to undergo ring closure and
the facility by which (-)-22 cyclized readily to form the desired
product with correct configurations at both newly generated
stereocenters.
enol ether formation (TBSCl, DBU) and ozonolytic cleavage
(O3; Ph3P, 86% overall yield).
With both fragments, vinyl iodide (-)-6 and aldehyde (()-7
available, their union became the next task. Thus, and as shown
in Scheme 3, lithiation of vinyl iodide (-)-6 (t-BuLi, -78 f
-40 °C) followed by addition of aldehyde (()-7 led to the
expected coupling products (∼1:1 dr), which after desilylation
with TBAF were chromatographically separated to afford pure
diastereomers (-)-19 (35% yield) and (-)-20 (30% yield). The
conversion of diastereomer (-)-19 to cyclization precursor (-)-
21 required four steps, namely: (i) temporary silylation (TESCl,
imid.); (ii) carbonate formation (KHMDS, ClCO2Me, Et3N,
(4) Guella, G.; Callone, E.; Di Giuseppe, G.; Frassanito, R.; Frontini, F. P.;
Mancini, I.; Dini, F. Eur. J. Org. Chem. 2007, 5226–5234.
(5) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 4997–5003.
Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003–5010.
(6) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981,
103, 7690–7692.
Our return to the drawing board soon led to the adoption of
a plan to modify the cyclization substrate so as to take advantage
of our previous findings in connection with the synthesis of the
(7) CCDC-726953 contains the supplementary crystallographic data for
(()-14 and is available free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(8) Ley, S. V.; Norman, J.; William, G. P.; Marsden, S. P. Synthesis 1994,
639–666.
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Scheme 3. Construction of Aldehyde Carbonates (-)-21 and
(-)-22 and Results of Their SmI2-Induced Cyclizationsa
Scheme 4. Construction of Tri-SEM Protected Aldehyde (()-27
and Its Elaboration to Hydroxy Olefins (-)-31 and (-)-32a
a Reagents and conditions: (a) (-)-6 (1.3 equiv), t-BuLi (2.6 equiv), THF,
-78 f - 40 °C, 30 min; then (()-7 (1.0 equiv), -40 f 0 °C, 20 min; (b)
TBAF (3.0 equiv) THF, 25 °C, 2 h, (-)-19: 35%, (-)-20: 30%; (c) TESCl
(2.0 equiv), imidazole (6.0 equiv), CH2Cl2, 25 °C, 1 h; (d) KHMDS (0.5
M in toluene, 2.5 equiv), ClCO2Me (5.0 equiv), Et3N (6.0 equiv), THF,
-78 f 25 °C, 1 h; (e) HF ·py/py (1:4), 0 f 25 °C, 12 h, 90% yield for the
(-)-19 route, 87% for the (-)-20 route; (f) PhI(OAc)2 (2.0 equiv), TEMPO
(1.0 equiv), CH2Cl2, 25 °C, 24 h, (-)-21: 87%, (-)-22: 97%; (g) SmI2 (0.1
M in THF, 5.0 equiv), HMPA (15 equiv), THF, -10 f 25 °C, 30 min,
(-)-24: 76%.
a Reagents and conditions: (a) SEMCl (10 equiv), i-Pr2NEt (30 equiv),
CH2Cl2, 50 °C, 48 h, 90%; (b) DIBAL-H (1.1 equiv), toluene, -78 f 30
°C, 1 h; then 0.1 N aq HCl, 25 °C, 20 min; (c) MeMgBr (10 equiv), THF,
0 °C, 30 min; (d) NMO (2.0 equiv), TPAP (0.05 equiv), CH2Cl2/MeCN
(7:1), 25 °C, 3 h; (e) MeMgBr (10 equiv), THF, -10 °C, 20 min, 72% for
the four steps; (f) (-)-6 (1.3 equiv), t-BuLi (2.6 equiv), THF, -78 f -40
°C, 30 min; then (()-27 (1.0 equiv), -40 f 0 °C, 20 min; (g) TBAF (3.0
equiv) THF, 25 °C, 6 h, (-)-28: 41%, (+)-29: 42%; (h) TESCl (2.0 equiv),
imidazole (10 equiv), CH2Cl2, 25 °C, 5 h; (i) KHMDS (0.5 M in toluene,
5.0 equiv), ClCO2Me (10 equiv), Et3N (10 equiv), THF, -78 f 25 °C,
1 h; (j) HF ·py/py (1:4), 0 f 25 °C, 36 h, 79% for the three steps; (k)
PhI(OAc)2 (2.0 equiv), AZADO (0.1 equiv), CH2Cl2, 25 °C, 24 h, 95%; (l)
SmI2 (0.1 M in THF, 4.0 equiv), HMPA (12 equiv), THF, -20 f 25 °C,
3.5 h, (-)-31, 33% yield, (-)-32, 21%.
originally assigned structure of vannusal B.1 This plan dictated
the installment of a SEM moiety a C26 of the cyclization
precursor as a facilitating group for the desired ring closure.1,3
Since the C21/C25 trans relationship of the substituents precluded
the use of the acetonide group as a means to engage these
positions, we chose the tri-SEM aldehyde (()-27 (see Scheme
4) as the subtarget “northeastern” fragment for our next attempt
to construct the desired skeletal framework of vannusal B. The
synthesis of this substrate commenced from dihydroxy nitrile
(()-13 and proceeded along the path shown in Scheme 4. Thus,
SEM protection of (()-13 (SEMCl, i-Pr2NEt, n-Bu4NI, 90%
yield) afforded bis-SEM ether nitrile (()-25, whose conversion
to bis-SEM tertiary alcohol (()-26 proceeded through the
standard sequence of reduction (DIBAL-H)/methylation (MeMg-
Br)/oxidation (NMO, TPAP cat.)8/methylation (MeMgBr) as
summarized in Scheme 4 and discussed earlier in connection
with the synthesis of (()-15 from (()-14 (Scheme 2). The rest
of the chemistry to aldehyde (()-27 and coupling products (-)-
28 and (+)-29 followed similar lines and proceeded through
analogous intermediates as shown in Schemes 2 and 3 (see
Scheme 4 for details and yields). The desired diastereoisomer
from the two coupling products, intermediate (-)-28 (perceived
to be the correct isomer), was then taken forward to the targeted
cyclization substrate aldehyde carbonate (-)-30 through the
previously developed four-step sequence [temporary TES mono-
protection, carbonate formation, selective desilylation, and
oxidation, this time employing the newly reported AZADO9
system instead of TEMPO as a catalyst] as summarized in
Scheme 4.
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A R T I C L E S
Scheme 5. Total Synthesis of Vannusal B Structure (+)-3
The completion of the synthesis of precursor (-)-30 set the
stage for the much anticipated radical/anion-mediated cycliza-
tion, intended to forge the elusive skeleton of our targeted
molecule. Pleasantly, the C26sSEM group proved cooperative
in this instance, facilitating the desired ring closure (SmI2,
HMPA, THF, -20 f 25 °C) to afford a mixture of diastere-
omeric products (at C28) which were chromatographically
separated [(-)-31, 33% yield, and (-)-32, 21% yield]. As
demonstrated previously in the case of the originally assigned
structure of vannusal B,1,3 both diastereoisomers could be
processed through separate pathways, to the same diene
intermediate, as a prelude to installing the proper configurations
at C10 and C28 (see Scheme 5). Thus, treatment of the
diastereomer possessing the anti C10/C28 H/OH stereochemical
relationship [(-)-32] with POCl3 in pyridine at 60 °C caused
dehydration, furnishing conjugated diene (+)-34 in 72% yield,
while conversion of the syn H/OH diastereomer [(-)-31] to the
same diene required initial formation of the corresponding
xanthate [(-)-33, NaH, CS2; MeI] followed by Chugaev
elimination10 (microwave heating, 185 °C, 86% yield for the
two steps). Conjugated diene (+)-34 was converted to the
desired alcohol (-)-35, possessing the correct C10/C28 config-
uration through a sequence involving hydroboration (first with
ThexBH2 and then with BH3 ·THF), followed by oxidation
(H2O2, aq NaOH), to afford the corresponding diol (mixture of
diastereomers at C2, single diastereomer at C10 and C28), selective
aryl selenation at the primary OH-bearing position (o-
NO2C6H4SeCN, n-Bu3P), and oxidation (H2O2, syn-elimination
of the corresponding aryl selenoxide, 68% overall yield).11
Having installed all stereocenters in their desired configuration
in structure (-)-35, the conversion of the latter compound to
the targeted vannusal B structure (+)-3 proceeded smoothly and
in high overall yield as shown in Scheme 5. Thus, the free
hydroxyl group of (+)-35 was first protected, as its TES ether
(TESCl, KHMDS, Et3N, 89% yield) and the BOM groups were
removed (LiDBB), to reveal the corresponding diol (-)-36,
whose primary hydroxyl group was selectively oxidized to the
corresponding aldehyde with PhI(OAc)2 and 1-Me-AZADO
(cat.),9 leaving the secondary alcohol exposed to the obligatory
acetylation (Ac2O, Et3N, 4-DMAP, 87% yield for the two steps)
to afford the protected vannusal B structure (+)-37. Finally,
global desilylation through the action of aq HF in THF led to
structure (+)-3 [C21-epi-2] in 77% yield.
[C21-epi-2]a
a Reagents and conditions: (a) POCl3, py, 60 °C, 1 h, 72% (b) NaH (15
equiv), CS2 (30 equiv), THF, 0 f 25 °C, 30 min; then MeI (45 equiv), 25
°C, 24 h; then 185 °C (µ-waves), o-dichlorobenzene, 15 min, 86% for the
two steps; (c) ThexBH2 (5.0 equiv), THF, -10 f 25 °C, 0.5 h; then
BH3 ·THF (15 equiv), 25 °C, 1 h; then 30% H2O2/3 N aq NaOH (1:1), 0 f
45 °C, 1 h; 70%; (d) o-NO2C6H4SeCN (3.0 equiv), n-Bu3P (9.0 equiv), py
(12 equiv), THF, 25 °C; then 30% H2O2, 0 f 45 °C, 68%; (e) KHMDS
(6.0 equiv), TESCl (4.0 equiv), Et3N (8.0 equiv), THF, -50 f 25 °C, 30
min, 89%; (f) LiDBB (excess), THF, -78 f -50 °C, 1 h, 83%; (g)
PhI(OAc)2 (2.0 equiv), 1-Me-AZADO (0.2 equiv), CH2Cl2, 25 °C, 22 h;
(h) Ac2O (30 equiv), Et3N (90 equiv), 4-DMAP (2.0 equiv), CH2Cl2, 25
°C, 36 h, 87% for the two steps; (i) 48% aq HF/THF (1:3), 25 °C, 7 h,
77%.
For the sake of completeness, we also processed intermediate
(-)-24, possessing the opposite relative stereochemistry of the
two domains of the molecule (obtained as discussed above,
Scheme 3). Scheme 6 summarizes the sequence employed for
the conversion of (-)-24 to the corresponding vannusal B
structure (+)-d-3 [C21-epi-d-2], which was considerably shorter
than the one used to convert its counterparts [(-)-31/(-)-32)]
to vannusal B structure (+)-3 due to the fact that the configura-
tions at C10 and C28 did not require inversion. The sequence
began with temporary engagement of the free hydroxyl group
within (-)-24 (TESCl, imid., 83% yield), followed by removal
of the BOM group (LiDBB, 84% yield), to afford diol (+)-38.
Intermediate (+)-39 was then prepared from the latter compound
through selective oxidation of the primary alcohol [PhI(OAc)2,
TEMPO, 77% yield], acetylation of the secondary alcohol
(Ac2O, 4-DMAP, Et3N), and desilylation (HF ·py, THF, 94%
for the two steps). Finally, exposure of (+)-39 to aq HCl caused
acetonide cleavage to afford targeted vannusal B structure (+)-
d-3 [C21-epi-d-2].
(9) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem.
Soc. 2006, 128, 84128413. We thank Professor Iwabuchi and Nissan
Chemical Industries, Ltd., for generous gifts of AZADO and 1-Me-
AZADO catalysts.
(10) Chugaev, L. Chem. Ber. 1899, 32, 3332–3335. For examples of the
Chugaev elimination (xanthate pyrolysis) used in organic synthesis,
see: (a) Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen,
B. J. M.; de Groot, A. J. J. Org. Chem. 1999, 64, 9178–9188. (b)
Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001,
42, 4523–4526. (c) Padwa, A.; Zhang, H. J. Org. Chem. 2007, 72,
2570–2582.
The spectroscopic data of synthetic vannusal B structure (+)-3
were consistent with its structure, but again, disappointingly,
did not match those of natural vannusal B,2 and neither did those
(11) Grieco, P. A.; Nishizawa, M. J. J. Org. Chem. 1977, 42, 1717–1720.
9
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A R T I C L E S
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Scheme 6. Total Synthesis of Vannusal B Structure (+)-d-3
[C21-epi-d-2]a
B were path pointing. A cursory inspection of the diagnostic
region (δ 5.7-3.5 ppm) of the H NMR spectra of synthetic
1
vannusal B structure (+)-3 and natural vannusal B (see Figure
8) was sufficient to spot their significant differences. These were
the chemical shifts for H26 [red, δ ) 3.96 ppm for natural
vannusal B vs δ ) 4.42 ppm for (+)-3, ∆δ ) 0.473 ppm] and
H25 [blue, δ ) 4.37 ppm for natural vannusal B vs δ ) 3.96
ppm for (+)-3, ∆δ ) 0.41 ppm] and the distinctly different
coupling constant between H21 and H25 [JH21,25 ) 2.0 Hz for
natural vannusal B vs 8.5 Hz for (+)-3]. Panels a and b of Figure
9 respectively depict the 1H and 13C NMR chemical shift
differences (∆δ, ppm) for each proton and carbon of synthetic
vannusal B structure (+)-3 (red) and its congener (+)-d-3 (blue)
and natural vannusal B (set to zero). In comparing these graphs
with those corresponding to the originally assigned structure
[(+)-2] and its congener (+)-d-2 (panels a and b of Figure 4),
it became clear that the spectral differences between synthetic
(+)-3 and natural vannusal B (set to zero) remained substantial,
and for certain signals were even more dramatic in the C21-epi
compound than the original structures. Furthermore, the major
differences appeared in the “northeastern” region of the molecule
and to the “right” side of the C15-C16 bridgehead. Interestingly,
structure (+)-d-3 was spectrally closer to the natural vannusal B
than our “favored” structure (+)-3, an observation whose signifi-
cance we also failed to recognize at the time, as we had for
structures (+)-2 and (+)-d-2. It was also interesting to note at this
stage that structure (+)-d-3 exhibited an identical coupling constant
to that exhibited by the natural product between H10 and H28 (JH10,28
a Reagents and conditions: (a) TESCl (2.0 equiv), imidazole (10 equiv)
CH2Cl2, 3 h, 83%; (b) LiDBB (excess), THF, -78 f -50 °C, 30 min,
84%; (c) PhI(OAc)2 (10 equiv), TEMPO (2.0 equiv), CH2Cl2, 25 °C, 24 h,
77%; (d) Ac2O (40 equiv), Et3N (40 equiv), 4-DMAP (2.0 equiv), CH2Cl2,
25 °C, 12 h; (e) HF ·py/THF (1:4), 25 °C, 30 min, 94% for the two steps;
(f) 3 N aq HCl/THF (1:3), 25 °C, 12 h, 88% after two cycles.
of its congener (+)-d-3, a fact that, at the time, was not
surprising given our fixation on the originally assigned relative
configuration between the two domains of the vannusal mol-
ecule. Despite being disappointing, the spectral comparisons
between synthetic vannusal structure (+)-3 and natural vannusal
Figure 8. 1H NMR spectral comparison (δ 5.7-3.5 ppm) of synthetic vannusal B structure (+)-3 (top, d4-MeOH, 500 MHz) and natural vannusal B
(bottom, d4-MeOH, 600 MHz).
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Vannusals A and B: Synthesis of True Structures
A R T I C L E S
Figure 9. a. Graphically depicted 1H chemical shift differences (∆δ, ppm) between synthetic vannusal B structures (+)-3 (blue, d4-MeOH, 500 MHz) and
(+)-d-3 (red, d4-MeOH, 600 MHz) and natural vannusal B (600 MHz, set to zero). r ) right; l ) left. b. Graphically depicted 13C chemical shift differences
(∆δ, ppm) between synthetic vannusal B structures (+)-3 (blue, 150 MHz) and (+)-d-3 (red, 150 MHz) and natural vannusal B (set to zero). r ) right; l
) left.
) 1.8 Hz), whereas our favored congener structure (+)-3 exhibited
a larger coupling constant between these protons (JH10,28 ) 3.0
Hz). The importance of this observation also went unnoticed at
the time, and it was only later that its significance became clear.
To be sure, however, we remained convinced that the
structural problem was one of stereochemical configuration
and that it resided around ring E.
Total Synthesis of Vannusal B Structure (+)-4 [C25-epi,
C21-epi-2] and (+)-d-4 [C25-epi, C21-epi-d-2]. With the failure
of the spectral properties of (+)-3 and (+)-d-3 to match those
9
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A R T I C L E S
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Scheme 7. Construction of Aldehyde (()-40a
Figure 10. Retrosynthetic analysis of vannusal B structure (+)-4 [C25-
epi, C21-epi-2].
Table 1. Ti- and Li-Mediated Aldol Reactions of Diketone (()-41
with Acetonea
entry
enolate
reagents
temp (°C)
product ratiob 42a:42c
1
2
3
4
5
Ti
Ti
Ti
Li
Li
TiCl4, Et3N
TiCl4, Et3N
TiCl4, Et3N
LDA
-40
2:1
6:1
9:1
1:1
1:3
-78
-92
-78
-40 to 0
LDA
a Reactions were conducted on 0.1-10.0 mmol scale. b TESOTf,
c
1
2,6-lut. Product ratio determined by H NMR spectroscopic analysis.
of natural vannusal B and the intelligence we gathered from
the spectroscopic analysis of the synthesized vannusal structures,
we proceeded to contemplate and define the next synthetic target
of our quest for the true structure of the natural product. The
relative coupling constant between H25 and H21 (JH25,21 ) 8.5
Hz) exhibited by the trans isomer (+)-3 in comparison to the
much smaller value (JH25,21 ) 2.0 Hz) for the same coupling
constant exhibited by natural vannusal B2 pointed to the
remaining E-ring cis isomer (+)-4 (see Figure 10) as the likely
structure and so it was that we embarked on the total synthesis
of this isomer [and its diastereoisomer (+)-d-4, see later, Scheme
10].
According to our developed synthetic strategy toward these
targets, aldehyde (()-40 was needed in addition to the already
available enantiopure vinyl iodide (-)-6 (see Figure 10). The
specific protecting group design within (()-40 was based on
our previous findings that an OSEM group at C26 facilitates the
SmI2-induced ring closure and our expectation that the syn
relationship of the C25/C21 isomer would accommodate an
acetonide moiety. The required aldehyde fragment (()-40 was
constructed as summarized in Scheme 7. Recalling that the
opposite cis C25/C21 isomer of this aldehyde was secured through
a route involving a Ti-mediated aldol reaction between diketone
(()-41 and acetone (see Table 1),1,3 we sought modified
conditions to favor the desired configuration in the aldol product.
Table 1 summarizes the results with the titanium (entries 1-3)
and lithium (entries 4 and 5) enolates of substrate (()-41. As
shown in entry 5, and much to our delight, the lithium enolate
of (()-41 as generated with LDA (i-Pr2NH, n-BuLi in hexanes,
THF, -78 f -40 °C) reacted with acetone at -40 f 0 °C to
afford the desired C21 ꢀ-aldol isomer as the major product, which
was reacted with TESOTf in the presence of 2,6-lutidine to give
TES ether (()-42 (66% yield for the two steps), together with
a Reagents and conditions: (a) LDA [generated from i-Pr2NH (5.0 equiv),
n-BuLi (2.5 M in hexanes, 5.0 equiv)], THF, -78 f - 40 °C; then acetone
(20 equiv), -40 f 0 °C, 1 h, (3:1 dr); (b) TESOTf (2.0 equiv), 2,6-lutidine
(5.0 equiv), -78 f -40 °C, 1 h, 66% for the two steps; (c) NaBH4 (20
equiv), THF/MeOH (1:1), -10 f 25 °C, 4 h; (d) EtOH, PPTS (0.25 equiv),
25 °C, 2 h, 91% for the two steps; (e) (MeO)2CMe2/DMF (1:1), PPTS (1.0
equiv), 40 °C, 6 h, quant.; (f) SEMCl (5.0 equiv), i-Pr2NEt (15 equiv),
n-Bu4NI (1.0 equiv), CH2Cl2, 50 °C, 24 h, 97%; (g) O3, py (1.0 equiv),
CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h,
94%; (h) KH (10 equiv), allyl chloride (20 equiv), HMPA (10 equiv), DME,
-10 f 25 °C, 3 h, 88%; (i) i-Pr2NEt (1.0 equiv), o-dichlorobenzene,
µ-waves, 200 °C, 20 min; then NaBH4 (10 equiv), MeOH, 2 h, 25 °C, 82%
for the two steps; (j) BOMCl (3.0 equiv), i-Pr2NEt (10 equiv), n-Bu4NI
(1.0 equiv), CH2Cl2, 50 °C 12 h; (k) O3, py (1.0 equiv), CH2Cl2/MeOH
(1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 94% for the two
steps; (l) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 24 h; (m) O3,
py (1.0 equiv), CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78
f 25 °C, 1 h, 95% for the two steps.
its minor C21 R-isomer [(()-42a, 21% yield for the two steps].
The diastereoselectivity of this reaction (∼3:1) was eroded when
it was carried out at -78 °C (Table 1, entry 4) to ∼1:1,
indicating that, perhaps, it is under thermodynamic control with
an equilibrium being established between the two products
through retroaldol. Figure 11 provides a postulated mechanistic
rationale for the titanium and lithium enolate aldol reactions
leading to (()-42a ad (()-42, respectively, as the major
products. Thus, we propose the low-temperature (-92 °C)
titanium-mediated aldol reaction of 41 to be under kinetic
control, with chelation of the titanium enolate to both reacting
partners (see 41-TSa and 41-TSb) favoring the formation of
the C21-R epimer 42a. In contrast, the LDA-mediated aldol
reaction of 41 may be reversible at the higher reaction
temperatures employed (-40 f 0 °C). Therefore, a thermody-
namic equilibrium between adducts 41-TSc and 41-TSd likely
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Vannusals A and B: Synthesis of True Structures
A R T I C L E S
Figure 11. (a) A low-temperature titanium-mediated aldol reaction provides kinetic product (()-42a. (b) A reversible LDA-mediated aldol reaction provides
thermodynamic product (()-42.
45, whose conversion to the desired aldehyde fragment [(()-
40] followed a similar pathway as previously delineated [through
intermediates (()-46 and (()-47, see Scheme 7 for details].
With ample quantities of both “southwestern” [(-)-6] and
“northeastern” [(()-40] fragments in hand, the drive toward the
targeted structures (+)-4 and (+)-d-4 became feasible (see
Scheme 8). Thus, as previously demonstrated, the coupling of
enantiopure vinyl iodide (-)-6 with racemic aldehyde (()-40
proceeded smoothly through the lithium derivative of (-)-6 (t-
BuLi) to afford, after removal of the TIPS group (TBAF, 25
°C), a mixture of diastereomeric diols (-)-48 and (-)-49 (72%
combined yield for the two steps, ∼1:1 dr), which were
chromatographically separated. Coupling products (-)-48 and
(-)-49 were individually converted to cyclization precursors
(-)-50 and (+)-51, respectively, through the same sequence of
reactions as previously described, involving temporary silylation
of the primary hydroxyl group (TESCl, imid.), carbonate
formation at the secondary position (KHMDS, ClCO2Me),
removal of the TES group [HF ·py, 84% overall yield from (-)-
48; 80% overall yield for (-)-49], and oxidation of the liberated
primary hydroxyl group [PhI(OAc)2, AZADO (cat.),9 95% yield
for (-)-50, 97% yield for (+)-51] as summarized in Scheme 8.
When aldehyde carbonate (-)-50 was exposed to the
SmI2sHMPA conditions (-10 f 25 °C), the desired ring
closure took place, leading to polycyclic product (-)-52 in 74%
yield as a single diastereoisomer, but possessing the undesired
C10/C28 configurations in relation to the “northeastern” part of
the molecule. However, when its diastereomeric congener (+)-
51 was exposed to the same conditions, hydroxy olefin (+)-53
was formed in 84% yield and, again, as a single diastereomer,
except that this time both newly generated stereocenters (C10/
C28) were of the desired relative configuration with regards to
the “northeastern” domain.
Figure 12. X-ray derived ORTEP of hydroxy acetonide (()-44.
is established, leading to the modest selectivity observed for
the C21-ꢀ epimer (()-42.
Returning to the construction of the targeted aldehyde (()-
40 (see Scheme 7), diketone TES ether (()-42 was diastereo-
selectively reduced with NaBH4 in MeOH/THF (1:1) at -10
°C to afford, upon desilylation [EtOH, PPTS (cat.)], triol (()-
43 in 91% overall yield as a single diastereomer. Treatment of
the latter with (MeO)2CMe2 in the presence of PPTS at ambient
temperature led to the isolation of the crystalline hydroxy
acetonide (()-44 (mp 77-78 °C, EtOAc/hexanes) in quantita-
tive yield. X-ray crystallographic analysis of this compound (see
ORTEP, Figure 12)12 unambiguously confirmed its structure and
those of its progenitors [i.e., (()-43 and (+)-42]. Installment
of a SEM group (SEMCl, i-Pr2NEt, n-Bu4NI, 97% yield) at the
free hydroxyl group of (()-44, followed by ozonolytic cleavage
of its olefinic bond (O3; Ph3P, 94% yield), led to aldehyde (()-
First to be advanced from this point was hydroxy olefin (-)-
52, which underwent xanthate formation at C28 (NaH, CS2; MeI)
and, upon heating under microwave conditions (185 °C), syn
elimination to afford conjugated diene (+)-54 (89% overall
yield) as shown in Scheme 9. The latter compound was
converted to the desired C10/C28 diastereomer hydroxy olefin
(-)-55 through the previously developed sequence involving
hydroboration/oxidation (ThexBH2; BH3 ·THF; H2O2/NaOH,
70% overall yield) and arylselenylation/syn elimination (o-
NO2C6H4SeCN, n-Bu3P; H2O2, 70% overall yield).11 Intermedi-
(12) CCDC-757085 contains the supplementary crystallographic data for
hydroxy acetonide (()-44. This data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
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A R T I C L E S
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Scheme 8. Construction of Hydroxy Olefins (-)-52 and (+)-53a
Scheme 9. Total Synthesis of Vannusal B Structure (+)-4 [C25-epi,
C21-epi-2]a
a Reagents and conditions: (a) NaH (8.0 equiv), CS2 (8.0 equiv), THF,
0 f 25 °C, 20 min; then MeI (12 equiv), 25 °C, 24 h; (b) µ-waves, 185
°C, o-dichlorobenzene, 15 min, 89% for the two steps; (c) ThexBH2 (5.0
equiv), THF, -10 f 25 °C, 0.5 h; then BH3 ·THF (15 equiv), 25 °C, 1 h;
then 30% H2O2/3 N aq NaOH (1:1), 0 f 45 °C, 1 h; 70%; (d)
o-NO2C6H4SeCN (3.0 equiv), n-Bu3P (9.0 equiv), py (12 equiv), THF, 25
°C; then 30% H2O2, 0 f 45 °C, 70%; (e) KHMDS (6.0 equiv), TESCl (4.0
equiv), Et3N (8.0 equiv), THF, -50 f 25 °C, 30 min, 94%; (f) LiDBB
(excess), THF, -78 f -50 °C, 1 h, 82%; (g) PhI(OAc)2 (3.0 equiv),
TEMPO (1.0 equiv), CH2Cl2, 25 °C, 24 h, 92%; (h) Ac2O (30 equiv), Et3N
(90 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 25 °C, 12 h, quant.; (i) 48% aq
HF/THF (1:3), 25 °C, 7 h, 75%.
a Reagents and conditions: (a) (-)-6 (1.3 equiv), t-BuLi (2.6 equiv), THF,
-78 f -40 °C, 30 min; then (()-40 (1.0 equiv), -40 f 0 °C, 20 min;
(b) TBAF (4.0 equiv) THF, 25 °C, 30 min, (-)-48: 36%, (-)-49: 36%. (c)
TESCl (2.0 equiv), imidazole (4.0 equiv), CH2Cl2, 25 °C, 30 min; (d) KHMDS
(0.5 M in toluene, 2.5 equiv), ClCO2Me (3.0 equiv), Et3N (3.0 equiv), THF,
-78 f 25 °C, 1 h; (e) HF ·py/py (1:4), 0 f 25 °C, 12 h; (f) PhI(OAc)2 (3.0
equiv), AZADO (0.1 equiv), CH2Cl2, 25 °C, 24 h, (-)-50: 80% for the four
steps, (+)-51: 78% for the four steps; (g) SmI2 (0.1 M in THF, 5.0 equiv),
HMPA (15 equiv), THF, -10 f 25 °C, 30 min, (-)-52: 74%, (+)-53: 84%.
Scheme 10. Total Synthesis of Vannusal B Structure (+)-d-4
[C25-epi, C21-epi-d-2]a
ate (-)-55 was then transformed to diol (+)-56 through
sequential silylation (KHMDS, TESCl, 94% yield) and cleavage
of the BOM groups (LiDBB, 82% yield). The final three steps
to structure (+)-4, involving sequential oxidation of the primary
hydroxyl group within (-)-55 [PhI(OAc)2, TEMPO, 92% yield],
acetylation of the secondary hydroxyl group (Ac2O, Et3N,
4-DMAP, quant.), and global deprotection (aq HF, 75% yield),
proceeded smoothly as it had previously. However, and again
much to our chagrin, the 1H and 13C NMR spectra of synthetic
(+)-4 did not match those of the natural product.
The conversion of the other diastereomeric polycycle inter-
mediate (+)-53 to diastereomeric vannusal B structure (+)-d-4
is summarized in Scheme 10. Thus, following the previously
developed short sequence, involving silylation (KHMDS, TESCl)
and cleavage of the BOM groups (LiDBB) to afford diol (+)-
58 (77% for the two steps), sequential oxidation of the primary
hydroxyl group within the latter compound [PhI(OAc)2, TEMPO,
85% yield], and acetylation of the secondary hydroxyl group
(Ac2O, Et3N, 4-DMAP, quant.), furnished precursor (+)-59,
a Reagents and conditions: (a) KHMDS (0.5 M toluene, 4.0 equiv),
TESCl (8.0 equiv), Et3N (10 equiv), THF, 20 min; (b) LiDBB (excess),
THF, -78 f -50 °C, 30 min, 77% for the two steps; (c) PhI(OAc)2 (2.0
equiv), TEMPO (1.0 equiv), CH2Cl2, 25 °C, 48 h; (d) Ac2O (20 equiv),
Et3N (30 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 25 °C, 12 h, 85% for the
two steps; (e) aq HF/THF (1:3), 25 °C, 7 h, 77%.
whose global desilylation (aq HF, 77% yield) proceeded
smoothly to unveil vannusal B structure (+)-d-4.
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Vannusals A and B: Synthesis of True Structures
A R T I C L E S
Figure 13. 1H NMR spectral comparison (δ 5.7-3.5 ppm, d4-MeOH, 600 MHz) of synthetic vannusal B structure (+)-4 (top) and natural vannusal B
(bottom).
In examining the diagnostic regions of synthetic vannusal B
structure (+)-4 and natural vannusal B (see Figure 13), we
noticed with interest some striking similarities between them
as opposed to our previous comparisons. For the first time in
our search for the right structure, the corresponding H25, H26,
and H28 signals for the two, still nonidentical structures converge
to close proximity with each other. Most encouraging was the
∆δ ∼0.1 ppm shift of the H26 signal of (+)-4 (δ 4.054 ppm)
which, until then, had remained relatively downfield (e.g., 2: δ
4.438 ppm; 3: δ 4.424 ppm) from the position of the corre-
sponding signal of the natural product (δ ) 3.953 ppm).
Furthermore, we were pleased to see the restoration of a
relatively small coupling constant between H25 and H21 (JH25,21
) 3.0 Hz) in structure (+)-4, suggesting that we were on the
right track with the cis C25/C21 stereorelationship.
sassignment to the vannusals was rooted not just in its
“northeastern” region, but also in its “southwestern” domain
(i.e., A/B ring system).
Model AB Ring System Studies. Having assured ourselves
(as it turned out, incorrectly) of the correctness of the “north-
eastern” domain of the vannusal molecule, we turned our
attention to its “southwestern” region. The original configura-
tional assignments around the AB ring system of the vannusals
1
were based on H/1H NMR coupling constants (J-values; red)
and nuclear overhauser effects (NOEs; blue), as summarized
in Figure 15, for vannusal A.2 Specifically, the relatively large
coupling constant between H6 and H7 (JH6,7 ) 10.0 Hz)
supported the anti periplanar relationship between these protons,
while the shared, relatively small coupling constant between
H29 and H3 and H6 [JH29,3 (eq, ax) ) JH29,6 (eq, ax) ) 3.5 Hz]
suggested the all-cis relationship of these protons, a conclusion
further supported by the NOEs observed between H3 and H29,
and H29 and H6. Interestingly, no NOE between H3 and H6 (that
would have revealed a true 1,3-diaxial interaction between them)
was reported. Additionally, NOEs were observed around the
flanks of the A ring (i.e., between H29 and H8ꢀ, and H5R and
H12, see Figure 15), which led to the placement of its C3 and
C29 substituents as shown (cis). Finally, an observed NOE
between H7 and H10 was the only evidence pointing to the
assigned configuration of the important C7 stereocenter with
respect to the “northeastern” domain of the molecule.2
A more thorough comparison of the 1H and 13C NMR
chemical shift differences between (+)-4 (blue) and (+)-d-4
(red) with natural vannusal B (set to zero) is graphically depicted
in panels a and b, respectively, of Figure 14. Among the many
discrepancies, the most striking difference centered on C21 [1H
∆δ +0.295 ppm, Figure 14a; 13C ∆δ -10.73 ppm, Figure 14b].
Additionally, we began noticing a curious trend in the incongru-
ity of the left-half fragment (A/B-ring domain; C1-C12) of our
diastereomers thus far prepared as compared to the natural
product.2 The recognition of the persistent NMR spectroscopic
discrepancies in the “southwestern” region, despite the positive
response of the structural adjustments in the “northeastern” site
of the molecule in terms of chemical shifts (especially in the
diagnostic region), led us to wonder whether the initial mis-
Despite this supporting spectroscopic evidence for the
originally assigned structure of the AB region of the
vannusals, and because of the rather unreliable nature of
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Nicolaou et al.
Figure 14. (a) Graphically depicted 1H chemical shift differences (∆δ, ppm, d4-MeOH, 600 MHz) between vannusal B structures (+)-4 (blue) and (+)-d-4
(red) and natural vannusal B. r ) right; l ) left. (b) Graphically depicted 13C chemical shift differences (∆δ, ppm, 150 MHz) between synthetic vannusal
B structures (+)-4 (blue) and (+)-d-4 (red) and natural vannusal B (set to zero).
NMR spectroscopic information for stereochemical assign-
ments around five-membered rings15 as we had already
experienced, we decided to prepare all eight diastereomers
of the AB ring system (see Figure 16) and study their NMR
spectra in order to derive useful information regarding the
true structures of the vannusals. We reasoned that such an
investigation could also prove to be useful in solving other
stereochemical problems involving five-membered rings
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(+)-70, respectively, Ac2O, 4-DMAP, 96% yield], which were
obtained from epoxide (+)-68 as previously described.1,3 The
previously synthesized1 diastereomeric mixture of epoxides
68a/b (∼1:1 dr) was converted to alcohols (+)-71 and (+)-69
through the action of 2-lithiopropene in the presence of
BF3 ·Et2O in 80% combined yield (∼1:1 dr). Chromatographic
separation of the two diastereomers allowed conversion of pure
(+)-71 to acetates (+)-62 (Ac2O, 4-DMAP, Et3N, 92% yield)
and (+)-63 [(i) Ph3P, p-NO2C6H4CO2H, DEAD; (ii) DIBAL-
H; (iii) Ac2O, 4-DMAP, Et3N, 11% yield for the three steps,
unoptimized].
The synthesis of the other four diastereomeric acetates
(64-67) required initial epimerization of the previously syn-
thesized ketone (+)-73,1 an objective that was met by refluxing
the latter in benzene in the presence of DBU (Scheme 12). Under
these conditions, a favorable equilibrium between the desired
epimeric ketone (-)-74 and the starting C6 epimer (+)-73 [(-)-
74/(-)-73, ∼2:1 dr, 98% combined yield] was established.
Chromatographic separation of ketone (-)-74 allowed its further
elaboration to olefin (+)-75 [KHMDS, PhNTf2; Et3SiH,
Pd(Ph3P)4 (cat.), 91% overall yield]. Epoxidation of the latter
with m-CPBA resulted in the formation of a mixture of the two
epimeric epoxides 76a/b (86% yield ∼1:1 dr), whose opening
with 2-lithiopropene (prepared from 2-bromopropene and t-
BuLi) in the presence of BF3 ·Et2O led to diastereomeric alcohols
(-)-77 (22% yield) and (-)-78 (28% yield), together with
recovered starting material 76a/b (28%). Acetylation of hydroxy
1
Figure 15. Key H/1H couplings (red, J-value) and NOEs (blue) used to
assign the original structure of vannusal A.2
beyond the vannusals conundrum. The syntheses of model
systems 60-67 were based, for the most part, on the
chemistry developed in our quest for vinyl iodide (-)-6
discussed previously.1,3 Schemes 11 and 12 summarize the
devised routes to these compounds, starting with epoxides
(+)-68 and 68a/b and ketone (-)-74.
Thus, acetates (+)-60 and (+)-61 were prepared (as shown
in Scheme 11) from the corresponding alcohols [(+)-69 and
Figure 16. Structures of targeted AB model systems 60-67.
Scheme 11. Construction of Model Compounds (+)-60, (+)-61, (+)-62, and (+)-63a
a Reagents and conditions: (a) Ac2O (5.0 equiv), Et3N (5.0 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 0.5-8 h, (+)-60 (96%), (+)-61 (96%), (+)-62 (92%),
(+)-63 [11% overall yield from (+)-71, unoptimized]; (b) 2-bromopropene (4.5 equiv), t-BuLi (1.7 M in pentane, 8.0 equiv), THF, -78 °C, 5 min; then
BF3 ·Et2O (2.0 equiv), 2 min; then 68a/68b (∼1:1 dr), -78 f -20 °C, 30 min, 80% [(+)-69/(+)-71 ∼1:1 dr]; (c) p-NO2C6H4CO2H (3.0 equiv), DEAD (3.0
equiv), Ph3P (3.0 equiv), benzene, 25 °C, 18 h; (d) DIBAL-H (1.0 M in CH2Cl2, 2.5 equiv), CH2Cl2, -78 °C, 30 min.
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Scheme 12. Synthesis of AB Model Systems (-)-64, (-)-65, (-)-66, and (-)-67a
a Reagents and conditions: (a) DBU (1.0 equiv), benzene, 90 °C, 12 h, [2:1, (-)-74/(+)-73, ∼2:1], 98% combined yield, chromatographic separation; (b)
KHMDS (0.5 M in toluene, 1.5 equiv), PhNTf2 (1.5 equiv), THF, -78 f -40 °C, 30 min; (c) Et3SiH (2.0 equiv), Pd(Ph3P)4 (0.05 equiv), DMF, 50 °C, 3 h,
91% for the two steps; (d) m-CPBA (2.0 equiv), CH2Cl2, -10 f 25 °C, 12 h, 86% (∼1:1 dr); (e) 2-bromopropene (4.5 equiv), t-BuLi (1.7 M in pentane,
8.0 equiv), THF, -78 °C, 5 min; then BF3 ·Et2O (2.0 equiv), 2 min; then 76a/b, -78 f -20 °C, 30 min, (-)-77: 22% yield, (-)-78: 28% yield, recovered
starting material (28%); (f) Ac2O (5.0 equiv), Et3N (5.0 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 25 °C, 4-6 h, (-)-65 (86%), (-)-66 (86%), (-)-64 (94%),
(-)-81 (71% for the two steps); (g) p-NO2C6H4CO2H (1.5 equiv), DEAD (1.5 equiv), Ph3P (1.8 equiv), benzene, 0 f 25 °C, 18 h, 39%; (h) DIBAL-H (1.0
M in CH2Cl2, 2.5 equiv), CH2Cl2, -78 °C, 30 min, 81%; (i) TiCl4 (1.2 equiv), Et3N (3.0 equiv), acetone (20 equiv), CH2Cl2, -78 °C, 30 min, 92%; (j)
NaBH4 (10 equiv), THF/MeOH (1:1), 0 °C, 1 h (∼6:1 dr), see (f) for yield; (k) Burgess reagent (10 equiv), benzene, 80 °C, 1 h, 50%.
olefin (-)-78 under standard conditions furnished acetate model
system (-)-66 (86% yield), whereas Mitsunobu inversion
([Ph3P, p-NO2C6H4CO2H, DEAD, 39% yield; DIBAL-H) gave
diastereomeric hydroxy olefin (-)-79, whose acetylation, as
before, led to the desired diastereomeric acetate (-)-64 (76%
yield for the two steps). Similarly, acetylation of alcohol (-)-
77 proceeded smoothly to afford the next diastereomeric acetate
[(-)-66, 86% yield]. The intended Mitsunobu reaction of this
alcohol [(-)-77] as the shortest route to acetate (-)-67 proved
unsuccessful, presumably due to severe steric hindrance.
Therefore, an alternative approach to this AB model system
acetate (-)-67 was sought and found in a sequence starting with
cyclopentanone (-)-74 (Scheme 12). Thus, aldol reaction of
(-)-74 with acetone through titanium enolate formation (TiCl4,
Et3N, CH2Cl2, -78 °C) furnished, exclusively, tertiary alcohol
(-)-80 (92% yield), possessing the expected anti stereochemical
arrangement between the two substituents flanking its carbonyl
group. Stereoselective reduction of this hydroxy ketone with
NaBH4 (∼6:1 dr) followed by selective monoacetylation of the
resulting diol then furnished hydroxy acetate (-)-81 (71% yield
for the two steps), whose regioselective dehydration with
Burgess reagent afforded the desired acetate model system (-)-
67 in 50% yield.
With all eight AB model systems available (60-67), we were
in a position to proceed with the acquisition and analysis of
their one-dimensional and two-dimensional NMR spectra. Figure
17 summarizes the crucial coupling constants (J-values) and
NOEs observed for these compounds. Thus, (+)-60, (+)-61,
(+)-62, (-)-64, (-)-65, and (-)-67 exhibited relatively large
coupling constants for H6/H7 (JH6,7 ) 9.6-11.0 Hz), supporting
the anti periplanar relationship within these structures [for (+)-
63 and (-)-66 this coupling constant was not discernible due
to signal overlap]. A cursory inspection of the model systems
on the left side of Figure 16 (e.g., 60-64) reveals striking
similarities between model system (+)-60 and natural vannusal
A. Thus, the coupling constants between H6/H7, H3/H29, and
H29/H6 were the same in the two compounds [JH6,7 ) 9.6 Hz;
JH3,29 ) JH29,6 ) 3.5 Hz (t) for both (+)-60 and natural vannusal
A], and so was the chemical shift for H29 (δ 5.43 ppm). In
addition, model system (+)-60 exhibited the same NOEs as the
natural product. On the other hand, model system (+)-61
exhibited the diagnostic H29 1H NMR signal as a triplet (δ 5.22
ppm) with a relatively large coupling constant (JH29 ) 7.8 Hz),
the latter being composed of two identical vicinal axial-axial
coupling constants JH29,3 and JH29,6, an occurrence which was
further supported by a weak NOE between H3 and H6 (1,3-
diaxial relationship). Model compounds (+)-62 and (+)-63
exhibited significantly different J-values for H29 [(+)-62: dd, J
) 4.5, 2.0 Hz; (+)-63: dd, J ) 5.4, 1.8 Hz] and, thus, along
with (+)-61, were excluded as representatives of the true
structure of the vannusals. Interestingly, all structures in this
series showed one or both of the expected NOEs between H29
and H8R/H8ꢀ, an observation that was in line with the original
report of such an effect within natural vannusal A.2
Shifting our attention to the “right side” series (epimeric at
C6, Figure 17), we noticed a consistent trend among the A-ring
J-values for H29 and H6/H7 (JH3,29, JH29,6, and JH6,7) when
compared to their “left side” counterparts (see Figure 17). This
observation indicated that, despite being diastereoisomers
(epimeric at C6), the structures on the “right side” underwent
very little change in the A-ring bond angles/conformation in
comparison to those of the “left side” series. We, therefore, felt
reasonably comfortable eliminating compounds (-)-65 (t, JH29,3
/
H29,6 ) 9.0 Hz; JH6,7 ) 9.0 Hz), (-)-66 (dd, JH29,3/H29,6 ) 6.0,
3.6 Hz), and (-)-67 (dd, JH29,3/H29,6 ) 5.5, 2.5 Hz, JH6,7 ) 9.6
Hz) on the basis of their diagnostic JH29 coupling constants.
Interestingly, model compound (-)-64 was spectroscopically
virtually identical to (+)-60 and the originally assigned structure
of vannusal A (see Figure 17) with respect to these coupling
constants (although it differed in other aspects of the spectrum).
Despite these similarities, (-)-64, along with all other members
of this series (“right side”, Figure 17), lacked the key NOE
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Vannusals A and B: Synthesis of True Structures
A R T I C L E S
Figure 17. 1H J-coupling constants (red) and NOEs (blue) observed for AB model systems 60-67.
between H29 with H8ꢀ, and was consequently eliminated as a
suspected representative of the true structure of the vannusals.
We had, at this point, removed all of the model compounds of
this study from further consideration, with the exception of (+)-
60 (representing the originally assigned structure of the van-
nusals). While the preceding in-depth spectroscopic analysis led
us essentially back to where we had begun (namely the original
A-/B-ring structural assignment) it had, nonetheless, laid to rest
any further suspicions surrounding this region of the structure
of the vannusals.
Total Synthesis of the True Structure of Vannusal B. Having
convinced ourselves of the correctness of the “southwestern”
domain (i.e., original stereochemical assignments at C3, C29, C6,
and C7; rings A and B) through chemical synthesis and
spectroscopic analysis, we returned to the “northeastern” region
of the vannusal B molecule. Our previous modifications of the
vannusal structure pointed to the stereocenters on the E-ring
(i.e., C25 and C21) as the most likely site of an error, and since
we had already synthesized three of the four possible diaster-
eomers of this region of the molecule [i.e., (()-84, (()-83, and
(()-43; see Figure 20] and found them not to lead to the true
structure of natural vannusal B, the remaining diastereomer [i.e.,
(()-82, ꢀ-C25-OH/R-C21-CMe2OH, Figure 18] became our
next subtarget for the now obligatory NMR spectroscopic
analysis. This structure was tentatively rejected earlier as a
possible candidate representing the true structure of the natural
product on the basis of the rather large coupling constant (JH25,21
) 10.0 Hz) exhibited by its opposite counterpart [i.e., (()-83,
R-C25-OH/ꢀ-C21-CMe2OH, Figure 18, and the JH25,21 ) 8.5
Hz exhibited by synthetic vannusal structure B (+)-3].
The total synthesis of vannusal B structure (+)-5 [C25-epi-2]
required, in addition to vinyl iodide (-)-6, aldehyde (()-94 as a
building block containing the “northeastern” domain of the vannusal
molecule. The latter precursor could be generated from intermediate
(()-82, which was defined as our needed model system for
spectroscopic comparison with the other model systems shown in
Figure 18 [i.e., (()-84, (()-83, and (()-43]. The syntheses of
model system (()-82 and aldehyde (()-94 are shown in Schemes
13 and 14, respectively. Thus, as already discussed above (see Table
1), diketone (()-41 was converted to hydroxy diketone (()-85
(∼6:1 dr) and subjected to DIBAL-H reduction to afford diaste-
reoselectively triol (()-82 (64% yield for the two steps, plus 12%
yield of its chromatographically separable C21 diastereomer,
Scheme 13). Desilylation of (()-82 (aq HF, 83% yield) gave
crystalline tetraol (()-86 (mp 139-141 °C, methanol/benzene),
whose X-ray crystallographic analysis (see ORTEP representation,
Figure 19)13 provided unambiguous proof of its structure, and,
thereby, its precursor (()-82. The selectivity of the DIBAL-H
reduction of hydroxy diketone (()-85 (see Scheme 13 and Figure
20) is interesting, especially when compared to the reduction of
its TES-protected counterpart [(()-87]1,3 (see Figure 20) that led
to the opposite C25 configuration (see Figure 20)1,3 and C21
diastereomer [(()-42, see Scheme 7 and Figure 20]. To explain
these observations, as well as the reduction of the TES-protected
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Figure 18. Comparison of the JH21,25 coupling constants of DE model systems (()-82, (()-83, (()-43, and (()-84.
Scheme 13. Construction of Triol (()-82 and Tetraol (()-86a
Scheme 14. Construction of Aldehyde (()-94a
a Reagents and conditions: (a) TiCl4 (1.0 M in CH2Cl2, 1.2 equiv), Et3N
(3.0 equiv), CH2Cl2, -78 f -30 °C, 30 min; then acetone (10 equiv),
-78 °C, 8 h (∼6:1 dr); (b) DIBAL-H (5.0 equiv), toluene, -78 f °C, 30
min, 64% for the two steps; (c) aq HF/THF (1:4), 25 °C, 18 h, 83%.
version of (()-85 (i.e., compound (()-87, see refs 1 and 3 and
Figure 20), we postulate hypothetical transition states 85-TS, 42-
TS, and 87-TS, respectively. Thus, while the reduction of the C26
carbonyl group occurs in all three cases from the opposite side of
the C15/C16 bridgehead, purely on steric grounds (as expected), the
diastereoselectivity of the reduction of the C25 carbonyl varies with
the substrate/reagent combinations. With substrate (()-87 and
NaBH4, this reduction occurs from the opposite side of the bulky
C21 substituent [(()-87 f 87-TS f 84-TES f (()-84, see Figure
20a], as is the case for substrate (()-42 [(()-42 f 42-TS f 43-
TES f (()-43, see Figure 20b]. To explain the opposite diaste-
reoselectivity of the reduction of hydroxy diketone (()-85, we
called upon likely dimeric aggregates of DIBAL-H in nonpolar
(noncoordinative) media14 and initial aluminate formation at the
hydroxyl group to form transition 85-TS (Figure 20c). Intramo-
a Reagents and conditions (a) i-Pr2NEt (20 equiv), SEMCl (6.0 equiv),
n-Bu4NI (1.0 equiv), 50 °C, 24 h; (b) KHMDS (2.0 equiv), SEMCl (5.0 equiv),
Et3N (10 equiv), THF, -78 f 25 °C, 1 h, 96% for the two steps; (c) O3, py
(1.0 equiv), CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25
°C, 1 h, 97%; (d) KH (10 equiv), allyl chloride (30 equiv), HMPA (10 equiv),
DME, -10 f 25 °C, 8 h, 95%; (e) i-Pr2NEt (1.0 equiv), 1,2-dichlorobenzene,
µ-waves, 200 °C, 20 min; then NaBH4 (10 equiv), MeOH, 1 h, 25 °C, 88%
for the two steps; (f) BOMCl (10 equiv), i-Pr2NEt (30 equiv), n-Bu4NI (1.0
equiv), CH2Cl2, 50 °C 12 h; (g) O3, py (1.0 equiv), CH2Cl2/MeOH (1:1), -78
°C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 81% for the two steps; (h)
TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 12 h; (i) O3, py (1.0 equiv),
CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 80%
for the two steps.
(13) CCDC-726955 contains the supplementary crystallographic data for
tetraol (()-86. This data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(14) DIBAL-H is known to exist in dimeric and forms in benzene, see: (a)
Clark, G. M.; Zweifel, G. J. Am. Chem. Soc. 1971, 93, 527–528. (b)
Ziegler, K.; Kroll, W. R.; Larbig, W. Justus Liebigs Ann. Chem 1960,
629, 222.
(15) (a) Kock, M. J.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem.,
Int. Ed. 2007, 46, 6586–6594. (b) Smith, S. G.; Paton, R. S.; Burton,
J. W.; Goodman, J. M. J. Org. Chem. 2008, 73, 4053–4062. (c) Wu,
A.; Cremer, D. Int. J. Mol. Sci 2003, 4, 158–192. (d) Sheldrake, H. M.;
Jamieson, H. M.; Burton, J. W. Angew. Chem., Int. Ed. 2006, 45, 7199–
7202.
lecular delivery of hydride from the R-face is then possible to
generate 82-i-Bu2Al, whose hydrolysis would lead to the observed
diastereomeric triol (()-82.
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Vannusals A and B: Synthesis of True Structures
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fragment (()-94. As shown in Scheme 14, our attempt to
prepare the next intermediate, tris-SEM ether (()-89, under the
standard conditions (SEMCl, i-Pr2NEt, n-Bu4NI, 50 °C) slowed
down at the bis-SEM ether (()-88 stage [79% yield, plus 20%
yield of (()-89] and had to be pushed forward by resubjecting
the chromatographically separable bis-SEM ether to further
reaction under more forcing conditions (KHMDS, SEMCl, -78
f 25 °C, (()-89, 96% total yield from (()-82]. The remaining
steps from (()-89 to aldehyde (()-94 proceeded along the
previously devised route and through intermediates (()-90-(()-
93 as summarized in Scheme 14.
With both fragments [(-)-6 and (()-94] readily available,
their union and further elaboration proceeded as shown in
Scheme 15. Thus, lithiation of (-)-6 (t-BuLi, THF, -78 f -40
°C), followed by addition of aldehyde (()-94 (-40 f 0 °C),
led, upon desilylation (TBAF), to chromatographically separable
diastereomeric adducts (-)-95 and (+)-96 in 84% total yield
(∼1:1 ratio). Each diastereomer [(-)-95 and (+)-96] was then
converted separately to the desired cyclization precursor [(-)-
99 and (+)-100, respectively] through the corresponding
intermediate hydroxy carbonate [(-)-97 and (+)-98, respec-
tively] by the high-yielding, four-step sequence previously
developed and as summarized in Scheme 15 [(i) temporary
silylation of the primary alcohol (TESCl, imid.); (ii) carbonate
formation at the secondary hydroxyl position (KHMDS,
ClCO2Me, Et3N); (iii) removal of the TES group (HF ·py, (-)-
97: 89% overall yield; (+)-98: 96% overall yield); and (iv)
oxidation [PhI(OAc)2, AZADO (cat.), (-)-99, 96% yield; (+)-
100, 97% yield].
Figure 19. X-ray-derived ORTEP of tetraol (()-86.
1H NMR spectroscopic analysis of the DE ring systems (()-
82, (()-43, (()-83, and (()-84 revealed interesting coupling
constants for H25 and H21 (JH25,21) as shown in Figure 18. Thus,
while the two cis compounds [(()-43 and (()-84] exhibited
relatively small coupling constants for these protons [(()-43: JH25,21
) 3.5 Hz; (()-84: JH25,21 < 1.0 Hz], the two trans isomers [(()-
82 and (()-83] differed drastically in their JH25,21 coupling
constants, with the latter exhibiting a relatively large value [(()-
83: JH25,21 ) 10.0 Hz] and the former a very small value [(()-82:
JH25,21 ) 1.0 Hz]. The dramatic difference in these coupling
constants, although surprising at first, could be understood from
the dihedral angles for H25/H21 within tetraol (()-86 (106.0°) as
revealed by X-ray crystallographic analysis of this compound (see
ORTEP, Figure 19)13 and the calculated dihedral angle (177.1°)16
corresponding to compound (()-83. It also underscored once again
the difficulties in determining stereochemical relationships of
substituents situated on cyclopentane rings.15
Our attempts to advance aldehyde carbonate (-)-99 through
the SmI2-induced cyclization step (see Scheme 16) were
thwarted by its resistance to undergo the desired reaction, thus
Returning to the mainstream synthetic route, the now plentiful
triol (()-82 served well as a precursor to the targeted aldehyde,
Figure 20. Mechanistic rationale for the diastereoselectivities observed in the reductions of diketones (()-42 (a), (()-87 (b), and (()-85 (c).
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Scheme 15. Synthesis of Aldehyde Carbonates (-)-99 and
(+)-100a
Scheme 16. Samarium Diiodide Cyclization Results for Aldehyde
Carbonates (-)-99 and (-)-101a
a Reagents and conditions: (a) aq HF/THF (1:4), 25 °C, 1.5 h, 81%; (b)
SmI2 (0.1 M in THF, 10 equiv), HMPA (30 equiv), THF, -20 f 25 °C, 20
min, 67%.
however, the reaction proceeded well, furnishing polycyclic
product (-)-102 in 67% yield as a single diastereomer.
Having secured polycyclic intermediate (-)-102 we then turned
our attention to its conversion to the targeted vannusal B structure
5 (Scheme 17). The first task was the inversion of the configurations
at C10 and C28 through the previously developed procedure
involving xanthate formation followed by Chugaev elimination.
To this end, selective acetylation of (-)-102 (Ac2O, 4-DMAP,
Et3N, quant.) led to monoacetate (-)-103, whose exposure to
standard SEM ether-forming conditions (SEMCl, i-Pr2NEt, CH2Cl2,
50 °C) resulted in reaction at the C22 hydroxyl, but not the
apparently less reactive C26 hydroxyl group, to afford the corre-
sponding bis-SEM derivative from which the acetate group was
removed through the action of DIBAL-H leading to diol (-)-104
(83% yield for the two steps). The observed relatively large
coupling constant between H10 and H28 (JH10,28 ) 7.5 Hz) in (-)-
103 confirmed the trans (axial-axial) relationship of these protons
within this structure, thus providing support for the structures of
both (-)-103 and (-)-102. Reaction of compound (-)-104 with
NaH, first in the presence of CS2 and then MeI, resulted in selective
xanthate formation at C28 in 79% yield. Heating of this xanthate
at 185 °C (microwave conditions) led to the corresponding
conjugated diene (88% yield),10 whose remaining hydroxyl group
was capped with a SEM group under the more forcing conditions
of KHMDS-SEMClsEt3N (78% yield) to afford tri-SEM deriva-
tive (+)-105. Sequential hydroboration/oxidation of the latter
(ThexBH2; BH3; H2O2, NaOH, 71% yield), followed by selective
aryl selenylation of the resulting diol (o-NO2C6H4SeCN, n-Bu3P)
and oxidation/syn-elimination (H2O2, 86% overall yield for the two
steps),11 gave the desired hydroxy compound (-)-106, possessing
the correct configuration at both C10 and C28. TES protection of
(-)-106 (TESCl, KHMDS, 93% yield) followed by cleavage of
the BOM groups (LiDBB, 85% yield) furnished diol (-)-107,
whose primary hydroxyl moiety was selectively oxidized with
PhI(OAc)2 in the presence of TEMPO to afford the corresponding
hydroxy aldehyde in 88% yield. Subsequent acetylation of the latter
(Ac2O, 4-DMAP, quant.) led to aldehyde acetate (+)-108. Finally,
exposure of (+)-108 to aq HF caused cleavage of all four silicon
groups, leading to vannusal B structure (+)-5. The total synthesis
of this coveted structure was completed shortly after we arrived at
a Reagents and conditions: (a) (-)-6 (1.3 equiv), t-BuLi (2.6 equiv), THF,
-78 f -40 °C, 40 min; then (()-94 (1.0 equiv), -40 f 0 °C, 20 min; (b)
TBAF (1.0 M in THF, 2.0 equiv), THF, 25 °C, 8 h, 84% (∼1:1 dr) for the two
steps, (-)-95 and (+)-96 chromatographically separated; c) TESCl (2.0 equiv),
imidazole (10 equiv), CH2Cl2, 25 °C, 30 min; (d) KHMDS (10 equiv),
ClCO2Me (20 equiv), Et3N (20 equiv), THF, -78 f 25 °C, 30 min; (e) HF·py/
py (1:4), 0 f 25 °C, 12 h, 89% for sequence (-)-95 f (-)-97; 96% for
sequence (+)-96 f (+)-98 over the three steps; (f) PhI(OAc)2 (2.0 equiv),
AZADO (0.1 equiv), CH2Cl2, 25 °C, 24 h, 96% for (-)-99, 97% for (+)-100.
forcing us to deviate slightly from our plans. Suspecting steric
congestion with this particular substrate, we explored the
removal of one or more of its SEM groups. To this end, we
treated (-)-99 with aq HF in THF, and much to our delight
observed selective removal of two of its SEM groups to afford
cleanly dihydroxy SEM derivative (-)-101, in which the lone
1
SEM group resided on the C25 oxygen as determined by H
NMR spectroscopic analysis (that revealed an NOE between
H25 and one of the methylene acetal protons of the SEM group).
It was with some trepidation that we exposed the newly prepared
cyclization precursor to the SmI2 conditions (due to the presence
of the two hydroxyl groups and the absence of the C26sSEM
group that proved beneficial in previous occasions). Pleasantly,
(16) Frisch, M. J.; et al.; Gaussian 03; Gaussian, Inc.: Wallingford CT,
2004.
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Scheme 17. Total Synthesis of Vannusal B Structure (+)-5
[C25-epi-2]a
Scheme 18. Total Synthesis of Vannusal B Structure (+)-d-5
[C25-epi-d-2]a
a Reagents and conditions: (a) SmI2 (0.1 M in THF, 10 equiv), HMPA (30
equiv), THF, -20 f 25 °C, 30 min, 82%; (b) KHMDS (5.0 equiv), TESCl
(10 equiv), Et3N (10 equiv), THF, -78 f 25 °C, 20 min, 94%; (c) LiDBB
(excess), THF, -78 f -50 °C, 30 min, 83%; (d) PhI(OAc)2 (2.0 equiv), 1-Me-
AZADO (0.2 equiv), CH2Cl2, 25 °C, 18 h; (e) Ac2O (10 equiv), Et3N (20 equiv),
4-DMAP (1.0 equiv), CH2Cl2, 25 °C, 18 h, 87% for the two steps; (f) aq HF/
THF (1:3), 25 °C, 3 h, 85%.
diastereomeric product (+)-109 and in 82% yield (see Scheme
18). Equally pleasing was the realization that this product
possessed the correct configuration at C10/C28 relative to the rest
of the “northeastern” (but not to the “southwestern”) region of
the molecule and, as such, needed no further configurational
adjustments, as its diastereomer (i.e., (+)-5 Scheme 17) did.
Consequently, only a five-step sequence was standing between
intermediate (+)-109 and the final product, vannusal B structure
(+)-d-5. Thus, TES installment at the C28 hydroxyl group
(TESCl, KHMDS, 94%) followed by LiDBB-induced removal
of the BOM groups led to diol (+)-110 (83% yield), whose
selective oxidation [PhI(OAc)2, 1-Me-AZADO (cat.)]9 of the
primary hydroxyl group furnished hydroxy aldehyde (+)-111.
Subsequent acetylation of the remaining secondary hydroxyl
group within the latter intermediate afforded polysilylated
acetoxy aldehyde (+)-112 (87% for the two steps), whose
desilylation with aq HF led to vannusal B structure (+)-d-5 in
85% yield.
a Reagents and conditions: (a) Ac2O (20 equiv), Et3N (20 equiv), 4-DMAP
(0.2 equiv), CH2Cl2, 25 °C, 30 min, quant.; (b) SEMCl (10 equiv), i-Pr2NEt
(30 equiv), CH2Cl2, 50 °C, 18 h; (c) DIBAL-H (5.0 equiv), CH2Cl2, -78 °C,
30 min, 83% for the two steps; (d) NaH (4.0 equiv), CS2 (2.3 equiv), THF, 0
f 25 °C, 30 min; then MeI (4.6 equiv), 0 f 25 °C, 1 h, 79%; then µ-waves,
185 °C, 1,2-dichlorobenzene, 15 min, 88%; (e) KHMDS (4.0 equiv), SEMCl
(4.0 equiv), Et3N (8.0 equiv), THF, -50 f 25 °C, 20 min, 78%; (f) ThexBH2
(5.0 equiv), THF, -10 f 25 °C, 30 min; then BH3 ·THF (15 equiv), 25 °C,
1 h; then 30% H2O2/3 N aq NaOH (1:1), 25 f 45 °C, 30 min; 71% (1:1.3 dr);
(g) o-NO2C6H4SeCN (3.0 equiv), n-Bu3P (9.0 equiv), py (12 equiv), THF, 25
°C, 10 min; then 30% H2O2, 25 f 45 °C, 30 min, 86%; (h) KHMDS (6.0
equiv), TESCl (4.0 equiv), Et3N (8.0 equiv), THF, -50 f 25 °C, 20 min,
93%; (i) LiDBB (excess), THF, -78 f -50 °C, 30 min, 85%; (j) PhI(OAc)2
(4.0 equiv), TEMPO (2.0 equiv), CH2Cl2, 25 °C, 15 h, 88%; (k) Ac2O (30
equiv), Et3N (60 equiv), 4-DMAP (2.0 equiv), CH2Cl2, 25 °C, 24 h, quant.; (l)
aq HF/THF (1:3), 25 °C, 6 h, 90%.
1
The 500 MHz H NMR spectrum of synthetic (+)-d-5 was
consistent with its structure, but even more pleasing was its
remarkable similarity to that of natural vannusal B, which
happened to be a 600 MHz spectrum.2 Reasoning that this
favorable comparison meant that we were getting closer to the
real structure of the vannusals, our anticipation for synthetic
vannusal B structure (+)-5 was heightened. Our excitement,
however, was abruptly quenched shortly thereafter when we
arrived at the latter, whose 600 MHz NMR spectrum, although
its diastereomer d-5, whose total synthesis from diastereomeric
aldehyde carbonate (+)-100 we describe next (see Scheme 18).
As events transpired, the total synthesis of vannusal B
structure (+)-d-5 turned out to be considerably shorter than the
one leading to the initially targeted vannusal B structure (+)-5.
Thus, reaction of (+)-100 with SmI2 in THF in the presence of
HMPA at -20 f 25 °C furnished, much to our delight, a single
1
consistent with its structure, did not match the 600 MHz H
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A R T I C L E S
Nicolaou et al.
Figure 21. (a) Graphically depicted 1H NMR chemical shift differences (∆δ, ppm, d4-MeOH, 600 MHz) between vannusal B structure [(+)-5] and natural
vannusal B (set to zero). (b) Graphically depicted 13C NMR chemical shift differences (∆δ, ppm, d4-MeOH, 600 MHz) between vannusal B structure [(+)-5]
and natural vannusal B (set to zero).
NMR spectrum of natural vannusal B.2 Panels a and b of Figure
21 respectively demonstrate the 1H and 13C NMR chemical shift
differences between vannusal B structure (+)-5 (red bars) and
natural vannusal B (set to zero). Interestingly, the majority of
easily rationalized when comparing the structure of (+)-5 with
the revised structure of vannusal B revealed below).
Thankfully, our disappointment was only short-lived, for it
was almost immediately that we returned to structure (+)-d-5,
this time securing its 600 MHz NMR spectrum for a more
reliable comparison with the corresponding spectrum of the
1
the H and 13C NMR inconsistencies are located in the ABC
ring (“southwestern”) segment (an occurrence that can be more
9
7174 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusals A and B: Synthesis of True Structures
A R T I C L E S
Figure 22. 1H NMR spectral comparison (δ 5.7-3.5 ppm, d4-MeOH, 600 MHz) of synthetic vannusal B structure [(+)-d-5] (a) and natural vannusal B (b).
originally assigned structure (1) was safely revised to structure
d-1 in accordance with the revised structure of its closely related
congener, vannusal B [(+)-d-5]. Our confidence for the skeletal
and configurational identity of the two vannusals (A and B)
was based on the similarity of their NMR spectral data and their
previous conversion to the same pentaol derivative [(+)-113)]
by Guella, Pietra, and Dini2 by NaBH4 reduction, an observation
that we confirmed with synthetic vannusal B structure [(+)-d-
5, see Scheme 19]. The spectral data of synthetic pentaol (+)-
113 were identical to those reported in ref 2.
Total Synthesis of the Revised Structure of Vannusal A.
Focusing on the synthesis of vannusal A [(-)-d-1)] from
vannusal B [(+)-d-5], we initially attempted direct acetylation
of the latter, but unfortunately we observed no useful selectivity.
Nevertheless, these experiments revealed that the most reactive
of the four hydroxyl groups within [(+)-d-5] was that situated
at C28 (see Scheme 20). This realization led us to construct the
C28/C25/C22 tris-TES derivative of vannusal B, but again the
attempt to acetylate the remaining hydroxyl group (C26) was
thwarted by the resistance of this, apparently crowded, position
to undergo the desired acetylation. Faced with this predicament,
we reasoned that tethering the C25 and C22 hydroxyl groups
together through a benzylidene-type bridge (e.g., PMP acetal)
may result in pulling the tertiary alcohol away from the vicinity
of the C26 hydroxyl group [see structure (+)-115, Scheme 20],
thereby increasing the reactivity of the latter moiety. Thus,
treatment of vannusal B [(+)-d-5] with PMB(OMe)2 and PPTS
resulted in the formation of the desired PMP acetal (+)-115
(60% yield), together with the overprotected mixed acetal (+)-
114, which could be recycled through acid-induced (aq HCl,
Figure 23. X-ray derived ORTEP of synthetic vannusal B [(+)-d-5)].
natural product.2 Indeed, the two spectra were identical in all
respects (see Figure 22 for the diagnostic region δ 5.7-3.5
ppm), and so were its other physical properties including its
13C NMR and MS spectra. The CD spectrum of synthetic (+)-
d-5 [λ [nm] ) 229 (+20.15), 308 (-12.03)] was identical to
that reported for natural vannusal B [λ [nm] ) 229 (+5.4), 308
(-3.1)], thus confirming the absolute configuration of natural
vannusal B as presented in structure (+)-d-5.2 Delightfully,
synthetic vannusal B crystallized from EtOAc/THF in beautiful
needles (mp >200 °C dec) that yielded to X-ray crystallographic
analysis (see ORTEP, Figure 23),17 providing the ultimate
structural proof of this intriguing natural product. With the true
structure and total synthesis of vannusal B [(+)-d-5)] secured,
our next task became the total synthesis of vannusal A, whose
(17) CCDC-726954 contains the supplementary crystallographic data for
vannusal B [(+)-d-5] and is available from The Cambridge Crystal-
lographic Data Centre free of charge via www.ccdc.cam.ac.uk/
data_request/cif.
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A R T I C L E S
Nicolaou et al.
Scheme 19. Synthesis of Pentaol (+)-113a
Figure 24. Conformational differences between vannusal B [(+)-d-5] and
its C25/C22-PMP acetal [(+)-115].
117 ∼1.5:1 ratio]. Exposure of this mixture to aq HCl at ambient
temperature furnished, after chromatographic separation, van-
nusal A [(-)-d-1] in 43% overall yield for the three steps. The
physical properties of synthetic [(-)-d-1] (1H NMR, 13C NMR,
[R]25D, and MS) matched those reported for the natural vannusal
A.2 Thus, the true structure of vannusal A was revealed and
secured unambiguously as d-1 (Scheme 20).
a Reagent and conditions: (a) NaBH4 (20 equiv), MeOH, 25 °C, 20 min,
90%.
Scheme 20. Total Synthesis of Vannusal A [(-)-d-1]a
Conclusion
Culminating in the total synthesis and structural revision of
vannusals A and B, the chemistry described in this and the
preceding article1 demonstrate the power of chemical synthesis
to reach complex molecular architectures and its indispensable
role in structure elucidation, despite the impressive advances
in analytical techniques and instrumentation witnessed in recent
times. The employed convergent synthetic strategy to these
structures relies on a stereoselective lithium-mediated coupling
of a vinyl iodide and an aldehyde, and a SmI2-induced ring
closure involving a formal SN2′ type displacement that expands
the scope of this powerful reagent in organic synthesis. As a
result of these investigations, these scarce marine natural
products and several of their diastereomers are now readily
available in their enantiomerically pure forms and in sufficient
quantities for biological investigations. Furthermore, the NMR
spectroscopic insights gained in these studies underscore the
difficulties in relying on coupling constants to assign stereo-
chemical configurations around five-membered rings and pro-
vide clues as to how to approach such stereochemical problems.
Finally, the strategies and tactics developed in these studies may
find useful applications in future chemical synthesis endeavors.
a Reagents and conditions: (a) PMPCH(OMe)2 (10 equiv), PPTS (1.0 equiv),
DMF, 50 °C, 12 h, (+)-115: 60%, (+)-114: 22%; (b) 3 N aq HCl, THF, 25
°C, 30 min, 91%; (c) TESCl (10 equiv), imidazole (20 equiv), CH2Cl2, 25 °C,
8 h; (d) Ac2O (20 equiv), 4-DMAP (1.0 equiv), py, 25 °C, 12 h; (e) THF/H2O
(4:1), 12 N aq HCl, 25 °C, 1 h, 43% for the three steps.
Acknowledgment. We thank Drs. D. H. Huang, G. Siuzdak,
and R. Chadha for NMR spectroscopic, mass spectrometric, and
X-ray crystallographic assistance, respectively. Financial support
for this work was provided by the NSF (fellowship to A.O.), the
Skaggs Institute for Research, and grants from the National Institutes
of Health (U.S.A.) (GM063752 and CA100101).
91% yield) conversion back to vannusal B [(+)-d-5]. Indeed,
the predicted conformational change in going from vannusal B
to its C25/C22 acetal structure was confirmed by the relatively
large coupling constant between H25 and H21 (JH25,21 ) 12.0
Hz) for acetal (+)-115 as opposed to the small coupling constant
between H25 and H21 (JH25,21 ) 2.0 Hz) for vannusal B [(+)-
d-5] (see Figure 24). As expected, the reactivity of the C26
hydroxyl group of diol acetal (+)-115 increased considerably
(as compared to vannusal B), as treatment of the former with
TESCl and imidazole followed by acetylation led to a mixture
of TES-acetate derivatives (+)-116 and (+)-117 [(+)-116/(+)-
Supporting Information Available: Experimental procedures
and full compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA100742B
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7176 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010