Total synthesis and structural revision of vannusals A and B: Synthesis of the originally assigned structure of vannusal B

Article abstract of DOI:10.1021/ja100740t

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI₂-mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI ₂-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (±)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and aldehyde (±)-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and (+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally occurring substance. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Full text of DOI:10.1021/ja100740t

Published on Web 05/05/2010
Total Synthesis and Structural Revision of Vannusals A and B:
Synthesis of the Originally Assigned Structure of Vannusal B
K. C. Nicolaou,* Adrian Ortiz, Hongjun Zhang, Philippe Dagneau, Andreas Lanver,
Michael P. Jennings, Stellios Arseniyadis, Raffaella Faraoni, and Dimitrios E. Lizos
Department of Chemistry and the Skaggs Insitute 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 January 27, 2010; E-mail: kcn@scripps.edu
Abstract: The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer
(d-2) are described. Initial forays into these structures with model systems revealed the viability of a
metathesis-based approach and a SmI2-mediated strategy for the key cyclization to forge the central region
of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized
substrates failed to enter the cyclization process. The successful, devised convergent strategy based on
the SmI2-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (()-86 as key building
blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in
Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal
B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported
for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and
aldehyde (()-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and
(+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown
in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally
occurring substance. These investigations led to the discovery and development of a number of new synthetic
technologies that set the stage for the solution of the vannusal structural conundrum.
Introduction
structures, we began to contemplate their total synthesis, being
cognizant of the difficulties ahead, given the unprecedented
In 1999, Guella, Dini, and Pietra disclosed the structures of
vannusals A (1) and B (2) (Figure 1), two secondary metabolites
isolated from strains of the interstitial marine ciliate Euplotes
Vannus (Si121 and BUN3).1 Somewhat reminiscent of steroidal
structures, but more complex, these striking molecular archi-
tectures include 6 rings and 13 stereocenters (three of the latter
are all-carbon quaternary centers). Their structures were assigned
on the basis of mass spectrometric, NMR spectroscopic, and
limited chemical transformation studies. The vannusals possess
a C30 molecular framework, a realization that prompted the
isolation chemists to propose a biosynthetic hypothesis that
postulated squalene (3) as their precursor, but very little
information beyond that (Scheme 1a).1 Guella and co-workers
later proposed a second biosynthetic hypothesis that relied on
the isolation of a natural product from cultures of the E. Vannus
(strain TB6), possessing half of the carbon framework of the
vannusals and appropriately named hemivannusal (4, Scheme
1b).2 These investigators suggested a dimerization of this
monomeric unit (double aldol reaction) as the key step, followed
by an intramolecular aldol/dehydration process and several more
transformations for the vannusal biosynthesis (4 f 5 f 6 f
vannusals A and B, see Scheme 1b). Intrigued by the vannusal
synthetic challenge posed by these molecules. What we were
not expecting, however, were the many twists and turns that
this project had in store for us, and the new challenges that it
would bring on the way. It was not until 2009, 10 years after
the report of their isolation, that the vannusals would yield to
our advances that led not only to their total synthesis but also
(1) Guella, G.; Dini, F.; Pietra, F. Angew. Chem., Int. Ed. 1999, 38, 1134–
1136.
(2) Guella, G.; Callone, E.; Di Giuseppe, G.; Frassanito, R.; Frontini, F. P.;
Mancini, I.; Dini, F. Eur. J. Org. Chem. 2007, 5226–5234.
Figure 1. Originally assigned structures of vannusals A (1) and B (2).
9
7138 J. AM. CHEM. SOC. 2010, 132, 7138–7152
10.1021/ja100740t  2010 American Chemical Society

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Scheme 1. Biosynthetic Hypotheses for Vannusals A and B
Scheme 2. Ring-Closing Metathesis-Based Strategy to Vannusal
Model System 7
Scheme 3. Samarium Diiodide Cyclization-Based Strategy to
Vannusal Model System 11
to their structural revision.3-5 In this and the following article,6
we detail the investigations that culminated in the total synthesis
of vannusals A and B and the demystification of what became
a central puzzle, their true molecular structures.
Results and Discussion
Initial Forays Toward the Vannusal Structures. Inspection
of the structures of vannusals A (1) and B (2) as synthetic targets
quickly led to ring C as a site for retrosynthetic disconnection
in order to devise a convergent strategy, indeed a desirable goal
given the complexity of the molecules. Our first instinct was to
apply a ring-closing metathesis to forge the final ring of the
vannusals (ring C), an idea that was tested successfully with
model system 7 (generated from bisolefin 8 in the presence of
Grubbs II cat. in 86% yield, see Scheme 2).7 Precursor 8 was
prepared from aldehyde 9 and cyclopentanone (10) through aldol
chemistry.7 Aldehyde 9 was efficiently synthesized either in
racemic form from 2-iodocyclohexene-1-one,7 or enantiomeri-
cally enriched (96% ee) from cyclohexenone through a rhodium-
catalyzed, three-component asymmetric reaction developed in
these laboratories.8 However, despite the initial euphoria gener-
ated by this success, complications with more advanced
substrates led us to abandon the metathesis approach in favor
of a samarium diiodide-based strategy. Scheme 3 depicts
retrosynthetically the samarium-based approach to model system
11.9 Thus, 11 was envisioned to arise from aldehyde carbonate
12 through a SmI2-mediated ring closure/ꢀ-elimination. Discon-
nection of precursor 12 through a Shapiro reaction then led to
aldehyde 13 and hydrazone 14 as the required fragments. The
synthesis of aldehyde (()-13 commenced with diol (()-157,9
and proceeded as shown in Scheme 4. Demethylation of (()-
15 required the use of bromocatechol borane that resulted in
clean reaction, as opposed to the more commonly employed
boron trihalides (i.e., BCl3 and BBr3), which led to several
byproducts. The resulting triol was exposed to acetonide
(3) Nicolaou, K. C.; Zhang, H.; Ortiz, A.; Dagneau, P. Angew. Chem.,
Int. Ed. 2008, 47, 8605–8610.
(4) Nicolaou, K. C.; Zhang, H.; Ortiz, A. Angew. Chem., Int. Ed. 2009,
48, 5642–5647.
(5) Nicolaou, K. C.; Ortiz, A.; Zhang, H. Angew. Chem., Int. Ed. 2009,
48, 5648–5652.
(6) Nicolaou, K. C.; Ortiz, A.; Zhang, H.; Guella, G. J. Am. Chem. Soc.
2010, 132; DOI: 10.1021/ja100742b, related article.
(7) Nicolaou, K. C.; Jennings, M. P.; Dagneau, P. Chem. Commun. 2002,
2480–2481.
(8) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R. Angew. Chem.,
Int. Ed. 2005, 44, 3874–3879.
(9) Dagneau, P. Ph.D. Thesis, The Scripps Research Institute, 2006.
9
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A R T I C L E S
Nicolaou et al.
Scheme 4. Construction of Model Aldehyde (()-13a
Scheme 5. Synthesis of Vannusal Model System (()-11 Through
Shapiro Coupling and SmI2-Mediated Cyclizationa
a Reagents and conditions: (a) bromocatecholborane (3.5 equiv), CH2Cl2,
50 °C, 3 h; (b) PPTS (1.0 equiv), 2,2-dimethoxypropane/DMF (1:1), 50
°C, 12 h, 84% for the two steps; (c) TBDPSCl (1.5 equiv), imidazole (3.0
equiv), CH2Cl2, 25 °C, 6 h, 92%; (d) O3, py (1.0 equiv), CH2Cl2/MeOH
(1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 82%; (e) KH (10
equiv), allyl chloride (30 equiv), HMPA (10 equiv), DME, 25 °C, 12 h,
85%; (f) 1,2-dichlorobenzene, 200 °C (µ-wave), 20 min; then NaBH4 (10
equiv), MeOH, 1 h, 25 °C, 82% for the two steps; (g) BOMCl (5.0 equiv),
i-Pr2NEt (15 equiv), n-Bu4NI (1.0 equiv), CH2Cl2, 50 °C, 12 h; (h) 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; (i) TBSCl (10 equiv), DBU (20 equiv),
CH2Cl2, 25 °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.
a Reagents and conditions: (a) 14 (2.0 equiv), n-BuLi (2.5 M hexanes,
4.0 equiv), THF, -78 f -20 °C, 30 min; then (()-13 (1.0 equiv), THF,
-40 f 0 °C, 20 min; (b) TBAF (1.0 M in THF), THF, 25 °C, 12 h, 88%
for the two steps; (c) TESCl (2.0 equiv), imidazole (5.0 equiv), CH2Cl2, 25
°C, 1 h; (d) KHMDS (0.5 M in toluene, 5.0 equiv), ClCO2Me (10 equiv),
Et3N (10 equiv), THF, -78 f 25 °C, 20 min; (e) PPTS (1.0 equiv), MeOH,
25 °C, 6 h, 90% for the three steps; (f) PhI(OAc)2 (2.0 equiv), TEMPO
(1.0 equiv), CH2Cl2, 25 °C, 16 h, 90%; (g) SmI2 (0.1 M in THF, 5.0 equiv),
HMPA (15 equiv), THF, 25 °C, 0.5 h, 33%; (h) Ac2O (10 equiv), 4-DMAP
(1.0 equiv), Et3N (10 equiv), CH2Cl2, 5 h, 92%.
formation conditions [(MeO)2CMe2, PPTS] to furnish hydroxy
acetonide (()-16 in 84% overall yield for the two steps.
Protection of (()-16 (TBDBSCl, imid., 92% yield) followed
by ozonolytic cleavage of the terminal olefin (O3; Ph3P, 82%
yield) led to aldehyde (()-17. In preparation for the pending
Claisen rearrangement, aldehyde (()-17 was converted to allyl
enol ether (()-18 (85% yield) through the use of KH and allyl
chloride in the presence of HMPA, the latter being essential
for the desired O- versus C-allylation.10 The expected E-
geometry (on steric grounds) of the resulting enol ether [(()-
18] was confirmed by NOE studies that revealed an NOE
between H12 and one of the H28 protons (see drawing in Scheme
4). The crucial Claisen rearrangement of (()-18 proceeded
smoothly upon microwave heating (200 °C) to afford, after
NaBH4 reduction, the desired hydroxy olefin (()-19 in 82%
overall yield from (()-17. The targeted aldehyde [(()-13] was
then accessed from the latter intermediate through a four-step
sequence involving: (1) BOM ether formation (BOMCl,
i-Pr2NEt); (2) ozonolysis (O3; Ph3P, 81% yield for the two steps);
(3) silyl enol ether formation (TBSCl, DBU); and (4) ozonolytic
cleavage (O3; Ph3P, 80% for the two steps).
With ample quantities of aldehdye (()-13 in hand, we
proceeded to test the construction of vannusal model system
(()-11 through the proposed Shapiro coupling11 and samarium
diiodide-mediated ring closure.12 To this end, Tris-hydrazone
1413 was converted to the corresponding vinyl lithium reagent
by treatment with n-BuLi (-78 f -30 °C) and reacted with
aldehyde (()-13 to afford, after desilylation with TBAF, diol
(()-20 in 88% yield (see Scheme 5). Preparation of the required
(11) For the use of the Shapiro reaction in organic synthesis, see: (a)
Shapiro, R. H. Org. React. 1976, 23, 405–506. (b) Shapiro, R. H.;
Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735. (c) Adlington,
R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 116, 55–59. (d)
Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Nantermet, P. G.; Claiborne,
C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995,
117, 645–652.
(12) For selected reviews on the use of samarium diiodide in chemical
synthesis, see: (a) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew.
Chem., Int. Ed. 2009, 48, 7140–7165. (b) Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. ReV. 2004, 104, 3371–3403. (c) Kagan, H. B.
Tetrahedron 2003, 59, 10351–10372. (d) Molander, G. A.; Harris,
C. R. Chem. ReV. 1996, 96, 307–338.
(10) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5th ed.; John Wiley and Sons:
New York, 2001; pp 340-341.
(13) Mislankar, D. G.; Mugrage, B.; Darling, S. D. Tetrahedron Lett. 1981,
22, 4619–4622.
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7140 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Scheme 6. Retrosynthetic Analysis of the Originally Assigned
Structure of Vannusal B (2) and Its Diastereomer (d-2)
cyclization precursor (()-12 then proceeded along a path
involving temporary silylation (TESCl, imid.), methyl carbonate
formation (KHMDS, ClCO2Me, Et3N), desilylation (MeOH,
PPTS, 90% yield for the three steps), and oxidation [PhI(OAc)2,
TEMPO, 90% yield]. Gratifyingly, reaction of carbonate alde-
hyde (()-12 with SmI2 in THF at 25 °C in the presence of
HMPA proceeded as planned, presumably through ketyl radical
21 and anion carbonate 22 (sequential single electron transfer
reactions), to furnish polycyclic system (()-11 in 33% yield as
a single diastereoisomer possessing the correct relative C10/C28
stereochemistry. Support for the desired C10/C28 configurations
within (()-11 was provided from NOE studies with the
corresponding acetate derivative [(()-23, Ac2O, 4-DMAP, 92%
yield] (H10/H27, see drawing in Scheme 5) and the relatively
small coupling constant between H10 (ax) and H28 (eq) (JH10,28
) 1.8 Hz).14 Pleasantly, this coupling constant matched precisely
that reported for natural vannusal B.1 With these encouraging
preliminary results, we proceeded to apply the developed
synthetic technologies to the real task, that of synthesizing the
reported vannusal B structure (2).
Retrosynthetic Analysis of Vannusal B. On the basis of the
results of our initial forays toward the vannusal structure, we
devised the synthetic strategy shown retrosynthetically in
Scheme 6 for the total synthesis of vannusal B (2) (and as it
happens, its diastereomer d-2). The disassembly of the vannusal
B structure began with the SmI2-based disconnection at C10/
C28, which by necessity demanded further functional group
transformations in order to reveal diastereomeric allylic alcohols
24 and 25 as potential precursors to 2 and d-2, respectively.
Both intermediates 24 and 25 were then converted retrosyn-
thetically to building blocks 26 (enantiopure) and 27 (racemic
or enantiopure), respectively, through the crucial lithium-
mediated, carbon-carbon bond formation and appropriate
functional group transformations as shown (Scheme 6). Further
simplification of vinyl iodide 26 through Shapiro reaction,
regioselective epoxide opening, and enzymatic desymmetriza-
tion15 led to meso-diol 28, whose origin was traced back to diene
29 through an envisioned regio- and stereoselective hydrobo-
ration reaction. On the other hand, further analysis of aldehyde
27, initially through a Claisen rearrangement and subsequently
through a sequential MnIII-mediated radical cyclization16 and a
Mukaiyama aldol17 reaction, led to olefinic cyclohexanones 32
(racemic) and 33 (enantioenriched) as potential precursors to
the racemic and enantioenriched series of intermediates, re-
spectively. This plan served well as a useful roadmap for our
subsequent synthetic endeavors toward the originally assigned
structure of vannusal B.
Construction of Racemic and Enantiopure “Right” Fragment
(DE Ring System) of Vannusal B. The synthesis of the required
racemic and enantiopure aldehyde building blocks (()/(+)-27
proceeded from diols (()-15 and (+)-34 through olefinic
diketones (()-37 and (+)-38, respectively, as shown in Schemes
7 and 8. It was only after considerable experimentation that we
discovered that the most expedient method to install the requisite
tertiary alcohol-containing side chain in the growing molecule
was through a ketone-ketone aldol reaction, a process that also
provided excellent diastereoselection. Thus, starting with meth-
oxy diol (()-157,9 and methoxy diol (+)-34,8,9 TIPS diols (()-
35 and (+)-36 were prepared [bromocatecholborane; TIPSCl,
imid., 70% yield for (()-35; 85% yield for (+)-36; the lower
yield for (()-35 reflects difficulties with its rather insoluble
demethylated triol precursor] and subjected to IBX oxidation
in DMSO to afford diketones (()-37 (90% yield) and (+)-38
(81% yield), respectively. It is noteworthy to point out that,
while IBX in DMSO performed well in this reaction, other
oxidants such as PCC, DMP and TPAP-NMO resulted in little
or no conversion, presumably due to the lack of reactivity of
the diol in the solvents employed (i.e., CH2Cl2 or CH2Cl2/MeCN
(14) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric
Identification of Organic Compounds; John Wiley and Sons: Hoboken,
2005; pp 172-173.
(15) For selected reviews on enzymatic desymmetrization in organic
synthesis, see: (a) Garcia-Urdiales, E.; Alfoso, I.; Gotor, V. Chem.
ReV. 2005, 105, 313–354. (b) Hartung, I. V.; Hoffmann, H. M. R.
Angew. Chem., Int. Ed. 2004, 43, 1934–1949.
(16) Snyder, B. B. Chem. ReV. 1996, 96, 339–364.
(17) Tokunaga, Y.; Yagihashi, M.; Ihara, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 189–190.
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A R T I C L E S
Nicolaou et al.
Scheme 7. Stereoselective Installation of the C21 Stereocenter
Through a Ketone-Ketone Aldol Reactiona
Scheme 8. Construction of the Completed “Northeastern”
Fragment of the Originally Assigned Structure of Vannusal B in
Racemic [(()-27] and Enantiopure [(+)-27] Formsa
a Reagents and conditions: (a) Br-catecholborane (3.5 equiv), CH2Cl2,
50 °C, 3 h; (b) TIPSCl (2.0 equiv), imidazole (6.0 equiv), DMF, 25 °C,
(()-35: 70% for the two steps, (+)-36: 85% for the two steps; (c) IBX (3.0
equiv), DMSO, 50 °C, 4 h, (()-37: 90%, (+)-38: 81%; (d) TiCl4 (1.0 M in
CH2Cl2, 1.2 equiv), Et3N (3.0 equiv), CH2Cl2, -78 f -30 °C, 30 min;
then acetone (10 equiv), -92 °C, 12 h (9:1 dr); (e) TESOTf (3.0 equiv),
2,6-lut. (5.0 equiv), -78 f -40 °C, 1 h, (()-39: 81% for the two steps,
(+)-40: 73% for the two steps.
mixtures) as a result of strong intramolecular H-bonding.
Apparently, the combination of IBX/DMSO results in the
breakdown of this, prohibiting H-bonding and rapid oxidation
to the diketone with no observable accumulation of the singly
oxidized intermediates (by TLC or NMR spectroscopic analysis).
With diketones (()-37 and (+)-38 in hand, we then attempted
the intended carbon-carbon bond formation through the aldol
reaction with acetone. The ketone-ketone aldol coupling
reaction is used less frequently in synthesis as opposed to its
more commonly employed ketone-aldehyde counterpart, due
to the less reactive nature of the ketone functionality as an
electrophile and the propensity of the aldol product to undergo
retro-aldol and/or ꢀ-elimination. We improvised against these
possible predicaments by choosing to employ a titanium enolate
(which is known to possess high nucleophilicity and low
basicity18), prepared from diketone (()-37 or (+)-38 with TiCl4
and Et3N in CH2Cl2 at -78 °C, in conjunction with a large
excess of acetone (10 equiv) at very low temperatures (-92
°C). Indeed, under these conditions, we were pleased to observe
the formation of the desired aldol products, as their TES
derivatives (TESOTf, 2,6-lut.), in good yield and diastereose-
lectivity [(()-39, 81% yield for the two steps, dr ≈ 9:1; (+)-
40, 73% yield for the two steps, dr ≈ 9:1].
a Reagents and conditions: (a) NaBH4 (20 equiv), THF/MeOH (1:1), -10
f 25 °C, 4 h; (b) PPTS (0.2 equiv), EtOH, 25 °C, 2 h, (()-41: 85% for
the two steps, (+)-42: 71% for the two steps; (c) 2-methoxypropene (20
equiv), CSA (0.1 equiv), CH2Cl2, -78 f -40 °C, 2 h, (()-43: 82%, (+)-
44: 91%; (d) SEMCl (3.0 equiv), i-Pr2NEt (10 equiv), n-Bu4NI (1.0 equiv),
CH2Cl2, 50 °C, 24 h; (e) O3, py (1.0 equiv), CH2Cl2/MeOH (1:1), -78 °C;
then Ph3P (5.0 equiv), -78 f 25 °C, 1 h, 88% for the two steps; (f) KH
(10 equiv), allyl chloride (20 equiv), HMPA (5.0 equiv), DME, -10 f 25
°C, 5 h, 88%; (g) i-Pr2NEt (1.0 equiv), 1,2-dichlorobenzene, 200 °C (µ-
waves), 20 min; then NaBH4 (20 equiv), MeOH, 1 h, 25 °C, 91% for the
two steps; (h) BOMCl (10 equiv), i-Pr2NEt (20 equiv), n-Bu4NI (1.0 equiv),
CH2Cl2, 50 °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, 78% for the two steps; (j) TBSCl
(7.0 equiv), DBU (14 equiv), CH2Cl2, 25 °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,
95% for the two steps.
(85% yield for the two steps) and (+)-42 (71% yield for the
two steps), respectively. Crystalline triol (()-41 (mp 86-89
°C, EtOAc/hexanes) yielded to X-ray crystallographic analysis
(see ORTEP, Figure 2),19 providing unambiguous confirmation
of the assigned stereochemical configurations of these interme-
diates. The observed diastereoselectivity in the NaBH4 reduction
of diketones (()-39 and (+)-40 is primarily due to steric control,
as will be discussed more fully and in the context of similar
reductions of related substrates in the following article.6
Having secured the desired stereochemical relationships of
all stereogenic centers within the DE fragment, we were poised
to introduce the appropriate protecting groups to prepare for
the installation of the third quaternary carbon center, and the
final drive toward the targeted aldehyde. Thus, exposure of triols
(()-41 and (+)-42 to 2-methoxypropene in the presence of CSA
With the C21 stereocenter set, we turned our attention to
establishing the C25 and C26 hydroxyl groups in their correct
stereochemical configurations. This was accomplished through
a rather simple protocol conducted as depicted in Scheme 8.
Indeed, we were gratified to discover that simple treatment of
TES-protected aldol products (()-39 and (+)-40 with NaBH4
in MeOH/THF (1:1) at -10 °C resulted, upon selective
desilylation (PPTS, EtOH), in the formation of triols (()-41
(18) For selected examples of the titanium-mediated ketone-ketone aldol
reaction in organic synthesis, see: (a) Tanabe, Y.; Matsumoto, N.;
Higashi, T.; Misaki, T.; Itoh, T.; Yamamoto, M.; Mitarai, K.; Nishii,
Y. Tetrahedron 2002, 58, 8269–8280. (b) Yoshida, Y.; Hayashi, R.;
Sumihara, H.; Tanabe, Y. Tetrahedron Lett. 1997, 38, 8727–8730.
(c) Yoshida, Y.; Matsumoto, N.; Hamasaki, R.; Tanabe, Y. Tetrahe-
dron Lett. 1999, 40, 4227–4230.
(19) CCDC-698624 contains the supplementary crystallographic data for
triol (()-41 and is available from The Cambridge Crystallographic
Data Centre free of charge via www.ccdc.cam.ac.uk/data_request/cif.
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Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Scheme 9. Construction of Enantiopure Hydroxy Acetate (-)-50a
Figure 2. X-ray derived ORTEP of triol (()-41.
(cat.) resulted in the formation of acetonides (()-43 (82% yield)
and (+)-44 (91% yield), respectively, as show in Scheme 8.
The remaining hydroxyl group within these intermediates was
then capped with a SEM group (SEMCl, n-Bu4NI, i-Pr2NEt),
and the resulting products were subjected to ozonolytic cleavage
(O3; Ph3P) to afford the corresponding aldehydes (88% yield
for the two steps), whose enolates (KH) were trapped with allyl
chloride in the presence of HMPA to form the desired enol
ethers (()-45 and (+)-45, respectively, in 88% yield and as
single geometric isomers, presumed to be the Z-isomers as
shown in structures (()-45 and (+)-45. Gratifyingly, microwave
irradiation of enol ethers (()-45 and (+)-45 at 200 °C, followed
by NaBH4 reduction, led to primary alcohols (()-46 and (-)-
46, respectively, in 91% yield for the two steps. The hydroxyl
group of the latter [(()-46 and (-)-46] was then protected
(BOMCl, n-Bu4NI, i-Pr2NEt), and the resulting BOM ethers
were subjected to ozonolytic cleavage (O3; Ph3P, 78% yield for
the two steps) and truncation by one carbon (TBSCl, DBU,
followed by O3; Ph3P, 95% yield for two steps) to furnish the
targeted aldehydes [(()-27 and (+)-27, respectively].
Construction of the “Southwestern” Framework (AB Ring
System) of Vannusal B, Vinyl Iodide (-)-26. After several failed
attempts to develop an efficient route to the desired “south-
western” fragment of vannusal B (AB ring system), we focused
our attention on a desymmetrization-based strategy involving a
meso-diol derived from the commercially available diol 47, as
shown in Scheme 9. Double dehydration of this diol was
efficiently carried out with POCl3 in pyridine at 90 °C to afford
the rather volatile conjugated diene 29 (97% yield).20 The
subsequent hydroboration reaction of this diene was initially
carried out with ThexBH2, but the latter was eventually replaced
with CyBH2, a less expensive and higher-yielding alternative.
The reaction was presumed to proceed through the intermediacy
of the cyclic trialkyl borane 48 which, upon oxidative workup
(H2O2, NaOH, 50 °C), afforded meso-diol 28 in 51% yield. An
investigation into the possibility of desymmetrizing this diol
led to the development of a highly effective sequence to that
effect. Thus, while attempts to employ Amano Lipase PS to
carry out a selective monoacetylation of meso-28 failed (mainly
due to insolubility problems in the required media), we quickly
realized that the corresponding bis-acetate 49 (prepared in
quantitative yield from 28, Ac2O and 4-DMAP in pyridine) was
a suitable candidate for enzymatic desymmetrization because
of its excellent solubility in the required aqueous-acetone
medium. To this end, we first employed pancreatic porcine lipase
(an inexpensive commercially available enzyme) which, unfor-
tunately, led to disappointing mixtures of products. However,
when AMANO Lipase PS was used, we were delighted to
a Reagents and conditions: (a) POCl3 (2.2 equiv), py, 90 °C, 2 h, 97%;
(b) BH3 ·THF (2.5 equiv), cyclohexene (2.5 equiv), -40 f 0 °C, 2 h; then
29, -40 f 25 °C, 12 h; then 50 °C, 30 min; then 30% H2O2/aq 3 N NaOH
(1:1 v/v), 25 f 50 °C, 12 h, 51%; (c) Ac2O (3.0 equiv), 4-DMAP (0.02
equiv), py, 25 °C, 3 h, quant.; (d) AMANO Lipase PS (100 wt %), acetone:
phosphate buffer pH ) 7 (2:1), 25 °C, 48 h, quant., 99% ee; (e) (S)-MPT-
Cl (1.2 equiv), py, 25 °C, 18 h, 91%.
observe, after 48 h, essentially complete monodeacetylation of
meso-49 with formation of hydroxy acetate (-)-50 in quantita-
tive yield and g99% ee [determined by NMR spectroscopic
analysis of Mosher ester (+)-51, prepared by treatment of (-)-
50 with (S)-MTP-Cl (g99% ee), in pyridine, 91% yield].
With multigram quantities of the appropriately functionalized
enantiopure AB system hydroxy acetate (-)-50 in hand, the
next task became the introduction of the required isopropenyl
side chain. Scheme 10 summarizes how this task was ac-
complished stereoselectively. Thus, hydroxy acetate (-)-50 was
silylated (TBDPSCl, imid., 93% yield), and the acetate group
was removed (DIBAL-H, -78 °C, 98% yield) to afford hydroxy
silyl ether (+)-52. The use of DIBAL-H at low temperature
was a precautionary measure against possible migration of the
silyl group in the deacetylation step that could cause erosion of
the ee. Indeed, Mosher ester formation [(+)-52 f (-)-53, (S)-
MTP-Cl, py, 83%] and NMR spectroscopic analysis of the
resulting derivative revealed no such erosion at this step.
Intermediate (+)-52 was then dehydrated to produce the
disubstituted olefin (-)-54 through two different pathways. The
first, and most direct, involved reaction with Martin’s sulfurane21
in the presence of Et3N (91% yield). Efficient as it was, this
method suffered from the high cost of the reagent, and therefore,
a second, less expensive process for the conversion of (+)-52
to (-)-54 was developed. The latter involved oxidation of (+)-
52 [NMO, TPAP (cat.), 96%],22 regioselective enol triflate
formation [KHMDS, PhNTf2] and reductive cleavage of the
(21) 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.
(22) Ley, S. V.; Norman, J.; William, G. P.; Marsden, S. P. Synthesis 1994,
639–666.
(20) Greidinger, D. S.; Ginsburg, D. J. Org. Chem. 1957, 22, 1406–1410.
9
J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7143

A R T I C L E S
Nicolaou et al.
Scheme 10. Construction of Hydroxy Olefin (+)-56 and X-ray-
Derived ORTEP of Carbamate (-)-57a
involved reaction of the olefin with NIS in the presence of H2O,
followed by treatment with K2CO3, and resulted in the stereo-
selective formation of epoxide (+)-55 in 91% yield (∼9:1 dr).
Scheme 11 provides a plausible mechanistic rationale for this
diastereoselective process. Key to this postulated explanation
is the reversibility of the formation of the two possible iodonium
species, 59 and 60, and the slow trapping of one of them (i.e.,
59), as opposed to the fast trapping of the other (i.e., 60, method
B) by H2O. From the results with m-CPBA epoxidation (∼1:1
ratio of products, method A), it appears that the initial
electrophilic addition to the olefin proceeds with no diastereo-
facial selectivity, a fact that has little, if any, effect on the
iodohydrin-mediated procedure, since the rate-determining step
is likely to be the interception of the iodonium species by H2O.
Subsequent treatment of the generated iodohydrins led to
epoxides (+)-55 and 58 in ∼9:1 diastereoselectivity with the
ꢀ-epoxide [(+)-55] predominating as shown in Scheme 11.
Proceeding with the synthesis, the intended introduction of
the isopropenyl group required reaction of epoxide (+)-55 with
2-lithiopropene at -78 °C in the presence of BF3 ·Et2O (Scheme
10), a reaction that performed splendidly (in contrast to many
other protocols) to afford the desired hydroxy olefin (+)-56,
regio- and stereoselectively, and in 83% yield. In order to
confirm unambiguously the structure of this newly formed
intermediate, p-bromophenyl carbamate (-)-57 (mp 136-138,
EtOAc/hexanes) was prepared (p-BrC6H4NCO, 4-DMAP; TBAF,
74% for the two steps) and subjected to X-ray crystallographic
analysis (see ORTEP, Scheme 10),23 which indeed provided
the sought structural assurance. As productive as it was, the
described sequence thus far left the free hydroxyl group (C29
vannusal numbering) of (+)-56 with the wrong configuration,
necessitating its inversion. This configurational correction was
carried out through a Mitsunobu reaction (p-NO2C6H4COOH,
Ph3P, DEAD, 94% yield),24 followed by ester cleavage (DIBAL-
H, -78 °C, 96% yield), to afford the desired hydroxy compound
(+)-63 as shown in Scheme 12. With the completion of ring
A, and in preparation for appropriate functionalization of ring
B, a protecting group switch within (+)-63 was necessary. This
was accomplished through the use of BOMCl and i-Pr2NEt
(toluene, 90 °C), followed by treatment with TBAF (1.0 M in
THF, 70 °C), to afford hydroxy compound (-)-64 in 97%
overall yield. The rather forcing conditions (elevated temper-
ature) employed in the latter two reactions were both interesting
and necessary. After oxidation of (-)-64 to ketone (-)-65
[NMO, TPAP (cat.)] the stage was set for the generation of the
corresponding Tris-hydrazone in preparation for the intended
Shapiro reaction. This seemingly simple operation proved more
adventurous than anticipated as seen from the optimization
attempts listed in Table 1. Thus, initial experiments using MeOH
as solvent (entry 1) proved disappointing, providing Tris-
hydrazone (-)-66 in low conversion and an unacceptable degree
of epimerization at C7 (dr ≈ 1:1). However, it was quickly
discovered that by switching to THF as solvent and decreasing
the reaction time diminished the degree of epimerization,
although the conversion remained unsatisfactory (entries 2-4).
Finally, use of Na2SO4 as a dehydrating reagent resulted in the
formation of (-)-66 in excellent yield (90%) and diastereose-
lectivity (dr > 10:1) with the desired product predominating
a Reagents and conditions: (a) TBDPSCl (1.2 equiv), imidazole (3.0
equiv), CH2Cl2, 25 °C, 12 h, 93%; (b) DIBAL-H (1.0 M in hexanes, 2.5
equiv), CH2Cl2, -78 °C, 30 min, 98%; (c) (S)-MTP-Cl (1.5 equiv), py, 25
°C, 18 h, 83%; (d) Martin’s sulfurane (1.3 equiv), Et3N (3.0 equiv), CH2Cl2,
25 °C, 12 h, 91%; (e) NMO (1.5 equiv), TPAP (0.03 equiv), CH2Cl2/MeCN
(9:1), 25 °C, 12 h, 96%; (f) KHMDS (0.5 M in toluene, 1.5 equiv), PhNTf2
(1.25 equiv), THF, -78 f -40 °C, 30 min; (g) Et3SiH (2.5 equiv),
Pd(Ph3P)4 (0.02 equiv), DMF, 50 °C, 3 h, 95% for the two steps; (h) NIS
(1.5 equiv), THF/H2O (4:1), 0 f 25 °C, 1.5 h; then K2CO3 (2.5 equiv),
MeOH, 25 °C, 18 h, 91%; (i) 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; (+)-55, -78 f -20 °C, 30 min, 83%; (j) p-BrC6H4NCO (4.0 equiv),
Et3N (6.0 equiv), 25 °C; (k) TBAF (8.0 equiv), THF, 25 °C, 12 h, 74% for
the two steps.
triflate moiety [Et3SiH, Pd(Ph3P)4 (cat.), 95% for the two steps].
m-CPBA epoxidation of olefin (-)-54 resulted in 93% yield of
a 1:1 mixture of R- and ꢀ-epoxides (see Scheme 11). To
circumvent this rather disappointing outcome, a two-step
procedure was developed for the preparation of the desired
ꢀ-epoxide [(+)-55] from (-)-54. Proceeding through iodohydrin
formation (see 61 and 62, Scheme 11), this two-step procedure
(23) CCDC-698602 contains the supplementary crystallographic data for
p-bromophenyl carbamate (-)-57 and is available from The Cambridge
Crystallographic Data Centre free of charge via www.ccdc.cam.ac.uk/
data_request/cif.
(24) Martin, S. F.; Dodge, J. F. Tetrahedron Lett. 1991, 32, 3017–3020.
9
7144 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Scheme 11. Mechanistic Rationale for the Stereoselective Epoxidation of Olefin (-)-54 Through Iodohydrin Formation
Scheme 12. Construction of Vinyl Iodide (-)-26a
Table 1. Optimization of the Formation of Tris-Hydrazone (-)-66a
drc
(C-7)
temp time Tris-NHNH2 conc
(equiv)
yield
(%)
entry solvent (°C) (h)
(M)
additive
1
2
3
4
5
MeOH 25
16
16
16
1
1.2
1.2
1.0
1.0
1.5
0.1 none
0.1 none
0.1 pH 7 buffer 50 5:1
0.2 none
0.2 Na2SO4
66 1:1
85 1:1
THF
THF
THF
THF
25
25
25
25
53 >10:1
90 >10:1
b
4
a Reactions were run on a 0.1-0.3 mmol scale. b Reaction was run
up to 13.0 mmol scale. c dr was determined by 1H NMR spectroscopic
analysis; temp ) temperature; conc ) concentration.
alternative route to vinyl iodide (-)-26 from ketone (-)-65,
involving a three-step sequence [KHMDS, PhNTf2; Me3Sn-
SnMe3, PdCl2(dppf)2 (cat.); NIS, 50% overall yield] and
proceeding through the corresponding vinyl triflate [(-)-67,
Scheme 12] and the corresponding vinyl trimethyl tin derivative
(not shown), proved less effective and, therefore, was abandoned
in favor of the direct two-step procedure previously described.
Coupling of Vinyl Iodide (-)-26 and Aldehyde (()-27 and
First Approach to the Originally Assigned Structure of
Vannusal B. With multigram quantities of enantiopure vinyl
iodide (-)-26 available we were now in a position to address
its coupling with the equally readily available racemic aldehyde
(()-27 and its enantiopure counterpart [(+)-27]. The coupling
of vinyl iodide (-)-26 with aldehyde (()-27 proceeded through
the intermediacy of the corresponding vinyl lithium species
generated from the former upon treatment with two equivalents
of t-BuLi at -78 f -40 °C (see Scheme 13). When enantiopure
aldehyde (+)-27 was employed, allylic alcohol (-)-69 was
formed in 80% yield and as a single product, whereas when
racemic aldehyde (()-27 was used, two diastereomers, (-)-69
(more polar, 40% yield) and (+)-70 (less polar, 40% yield),
were obtained as expected. In both cases, the product(s) obtained
was of the same relative stereochemical configuration at the
newly generated center (C12). In order to provide a mechanistic
rationale for this exclusive diastereoselectivity, we presumed
that the coupling reaction proceeds through the chelation-
controlled transition state (68-TS) shown in Scheme 13. In this
mode of addition, the oxygen of the aldehyde moiety is fixed
in a six-membered chelate, whose “front” (Si) face is blocked
by the bulky TIPS group, leaving the “back” (Re) face open
a Reagents and conditions: (a) p-NO2C6H4CO2H (1.5 equiv), DEAD (1.5
equiv), Ph3P (1.8 equiv), benzene, 0 f 25 °C, 18 h, 94%; (b) DIBAL-H
(1.0 M in hexanes, 2.5 equiv), CH2Cl2, -78 °C, 30 min, 96%; (c) BOMCl
(3.0 equiv), i-Pr2NEt (10 equiv), toluene, 90 °C, 12 h; (d) TBAF (1.0 M in
THF, 10 equiv), 70 °C, 8 h, 97% over the two steps; (e) NMO (1.5 equiv),
TPAP (0.03 equiv), CH2Cl2/MeCN (9:1), 12 h, 96%; (f) Tris-NHNH2 (1.5
equiv), Na2SO4 (100 wt %), THF, 4 h, 90%; (g) n-BuLi (2.5 M in hexanes,
2.1 equiv), THF, -78 f -25 °C, 20 min; then I2 (2.0 equiv), -78 f -25
°C, 20 min, 90%; (h) KHMDS (0.5 M in toluene, 1.5 equiv), PhNTf2 (1.5
equiv), THF, -78 f - 40 °C, 30 min, 94%; (i) Me3SnSnMe3 (2.0 equiv),
LiCl (10 equiv), PdCl2(dppf)2 (0.1 equiv), dioxane, 60 °C, 12 h; (j) NIS
(1.5 equiv), THF, -50 °C, 50% for the two steps.
(entry 5, Table 1, Scheme 12). Our experience with Tris-
hydrazone (-)-66 (e.g., hygroscopic, rather labile, irreproducible
Shapiro coupling reaction results), however, forced us to convert
it to vinyl iodide (-)-26, whose chemical stability and reactivity
properties proved much superior to those of its precursor.
This conversion was carried out most efficiently through the
treatment of (-)-66 with n-BuLi (2.2 equiv, -78 f -20 °C)
to generate, initially, the corresponding dianion, and, eventually,
the corresponding vinyl lithium, followed by quenching with
I2 to afford (-)-26 (90% yield) as shown in Scheme 12. The
9
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A R T I C L E S
Nicolaou et al.
Scheme 13. Coupling of Vinyl Iodide (-)-26 with Aldehydes (+)-27
and (()-27 and Preparation of γ-Lactones (-)-71 and (+)-72a
Scheme 14. Synthesis of Aldehyde Carbonate (-)-73 and Initial
SmI2-Mediated Cyclization Resultsa
a Reagents and conditions: (a) TESCl (2.0 equiv), imidazole (5.0 equiv),
CH2Cl2, 25 °C, 0.5 h, 97%; (b) KHMDS (0.5 M in toluene, 2.5 equiv),
ClCO2Me (4.0 equiv), Et3N (4.0 equiv), THF, -78 f 25 °C, 1 h; (c) HF ·py/
py (1:4), 0 f 25 °C, 12 h, 78% for the two steps; (d) PhI(OAc)2 (5.0 equiv),
TEMPO (1.0 equiv), CH2Cl2, 25 °C, 24 h, 98%; (e) SmI2 (0.1 M in THF,
5.0 equiv), HMPA (15 equiv), THF, -10 f 25 °C, 30 min, ∼20%.
yield as summarized in Scheme 13] exhibited the aforemen-
tioned NOEs (between H12 and H27R or H27ꢀ), thus supporting
(albeit not with absolute certainty) the anti relationship between
H12 and the C27 in these structures. Racemic aldehyde (()-27 was
preferred in the coupling reaction with vinyl iodide (-)-26 because
of its easier accessibility and lower cost as compared to its
enantiopure counterpart (this choice turned out to be of major
importance as we shall see by the end of the vannusal story).
In this and all other coupling reactions of vinyl iodide (-)-26
with various aldehyde partners, the more polar spot (silica, TLC)
corresponded to the “desired” diastereomeric product, and the
less polar spot, to the “undesired” product. Furthermore, the
“desired” (more polar) product exhibited consistently and
invariably a 1H NMR spectroscopic δ value downfield shift (for
H7) relative to its undesired (less polar) counterpart (∆δ ≈
0.5-1.0 ppm), thus allowing easy identification of the two
diastereomers.
Satisfied (to an extent) with this structural analysis, we pressed
forward with diol (-)-24 [the one derived from the presumed
“correct” enantiomer of aldehyde (()-27] in order to set the
stage for the crucial SmI2-induced cyclization. To this end, and
as shown in Scheme 14, diol (-)-24 was converted to aldehyde
carbonate (-)-73 through a four-step sequence involving
temporary installation of a TES group at the primary alcohol
(TESCl, imid., 97%), carbonate formation at the secondary
a Reagents and conditions: (a) (-)-26 (1.3 equiv), t-BuLi (2.6 equiv),
THF, -78 f -40 °C, 30 min; then (+)-27 or (()-27 (1.0 equiv), -40 f
0 °C, 20 min, (-)-69: 80% or (-)-69: 40%; (+)-70: 40%; (b) TBAF
(1.0 M in THF, 4.0 equiv), THF, 25 °C, 5 h, (-)-24: 86%; (+)-25:
97%; (c) PhI(OAc)2 (5.0 equiv), TEMPO (0.5 equiv), CH2Cl2, 25 °C,
48 h, (-)-71: 80%; (+)-72: 80%.
for attack (red dotted arrow). In order to confirm this hypothesis,
we sought to secure the configuration of the newly generated
C12 stereocenter (this was also important since the orientation
of this center may have consequences on the outcome of the
pending SmI2-mediated ring closure). From inspection of manual
molecular models of the corresponding γ-lactones [i.e., (-)-71
and (+)-72, see Scheme 13], we surmised that NOE studies on
these intermediates may provide the answer to the configuration
at C12, since the shown diastereomers (Scheme 13) were not
expected to exhibit NOEs between H12 and H27, as opposed to
their diastereomeric counterparts (not shown), which were
expected to exhibit strong NOEs due to the proximity of these
protons (syn relationship of H12 and C27). Indeed, neither of the
γ-lactones (-)-71 or (+)-72 [prepared from the corresponding
allylic alcohols (-)-69 and (+)-70 by treatment with TBAF
followed by oxidation with PhI(OAc)2-TEMPO in 80% overall
9
7146 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Table 2. Optimization of the SmI2-Mediated Cyclization of
Aldehyde Carbonate (-)-73a
Scheme 15. Preparation of Crystalline p-Bromophenyl Carbamate
(-)-81 and Its X-ray-Derived ORTEPa
entry additive (equiv)
temp (°C)
solvent yield [(-)-77 + (+)-78] (% combined)
1
2
3
4
5
6
7
none
25
25
50
THF
THF
THF
0
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
10c
<10b
<10b
<10b
20c
-78 to 25 THF
-40 to 25 THF
30
30
MeCN
THF
30c
a Reactions were run on 0.01-0.10 mmol scale using 5.0 equiv of
SmI2 (0.1 M in THF). b Yield estimated by 1H NMR spectroscopic
analysis. c Isolated yield.
alcohol (KHMDS, ClCO2Me, Et3N), desilylation (HF ·py, 78%
overall yield for the two steps), and oxidation with
PhI(OAc)2-TEMPO (98% yield). With precursor aldehyde
carbonate (-)-73 readily available, experimentation for its SmI2-
mediated cyclization to the vannusal skeleton began in earnest.
Unfortunately, as shown in Scheme 14, our initial attempts to
cyclize this precursor in THF at room temperature failed to
produce any cyclized product. Instead, we isolated trace amounts
of diene aldehyde 76. The structure of this rather unexpected
product was discerned from its mass spectrometric and NMR
spectroscopic data. Its formation may be explained by a
mechanism involving intermediate species 74 and 75 as shown
in Scheme 14. Thus, it is postulated that the initially formed
samarium-bound ketyl radical species is capable of assuming a
conformation in which the radical orbital is anti-parallel to the
C13-C14 bond, thereby allowing a Grob-type fragmentation that
leads to the observed dienealdehyde 76 (an alternate pathway
to aldehyde 76 may involve anionic Grob-type fragmentation
following prior SET reaction). However, further experimentation
as summarized in Table 2 led to conditions under which two
cyclized products could be obtained [(-)-77 and (+)-78, entries
2, 6, and 7]. Unfortunately, none of these products possessed
the desired stereochemical configuration at C10; they differed
with respect to their configurations at C28. Moreover, the
maximum combined yield of (-)-77 and (+)-78 was 30%
[(-)-77:(+)-78 ∼1:2, entry 7, Table 2], a discouraging result
considering the undesired stereochemical outcome of the
reaction and the several steps that still remained to complete
the total synthesis. Faced with the failure to improve further
the reaction conditions for this and a number of other related
substrates, we turned our attention to a different tactic, but not
before obtaining an X-ray crystallographic structure of a
crystalline derivative of the major cyclization product [(+)-78].
This fortunate result became possible by serendipity, as a
consequence of our attempt to invert the stereochemistry of the
C28 hydroxyl group of (+)-78 through a Mitsunobu reaction as
shown in Scheme 15. Thus, reaction of this compound with
p-NO2C6H4CO2H, Ph3P, and DEAD in benzene at 70 °C led to
the isolation of tetrahydrofuran-containing polycycle (-)-80,
presumably through activated intermediate 79, whose intramo-
lecular collapse as shown precludes external displacement of
the O-PPh3 leaving group by the nucleophile (p-NO2C6-
a Reagents and conditions: (a) DEAD (10 equiv), Ph3P (10 equiv),
p-NO2C6H4CO2H (10 equiv), benzene, 70 °C, 2 h, 88% based on recovered
starting material (40%); (b) LiDBB, THF, -78 f -50 °C; 0.5 h, 90%; (c)
HF·py/THF, 25 °C, 4 h, 93%; (d) p-BrC6H4NCO (10 equiv), py, 40 °C,
12 h, 84%.
H4COO-). The combination of severe steric congestion for the
desired nucleophilic attack and proximity/rigidity effects is
apparently overwhelmingly in favor of the observed intramo-
lecular reaction. Sequential removal of the BOM (LiDBB, 90%
yield) and SEM (HF ·py, 93% yield) groups followed by
selective installation of a bromophenyl carbamate group at C29
(p-BrC6H4NCO, py, 84% yield) then led to crystalline derivative
(-)-81 (mp 180-182 °C, EtOAc/hexanes). X-ray crystal-
lographic analysis of the latter compound (see ORTEP, Scheme
15)25 unambiguously confirmed its vannusal-like structure and,
by extension, those of its precursors, (+)-78 and (-)-80.
Second Approach to the Originally Assigned Structure of
Vannusal B. The failure to optimize the yield of cyclization of
substrate (-)-73 prompted us to consider placing a chelating
group at the ꢀ-position of the aldehyde functionality. This
modification was considered to be favorable for the desired
SmI2-induced ring closure by virtue of its potential to restrict
the ketyl radical intermediate from assuming the antiperiplanar
arrangement required for the nonproductive carbon-carbon
bond cleavage (see structure 74, Scheme 14). The orthogonality
(25) CCDC-698624 contains the supplementary crystallographic data for
p-bromophenyl carbamate (-)-81. This data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
9
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A R T I C L E S
Nicolaou et al.
Scheme 16. Synthesis of Aldehyde (()-86a
Scheme 17. Coupling of Vinyl Iodide (-)-26 and Aldehyde (()-86
and Synthesis of Polycyclic Hydroxy Olefins (-)-90 and (+)-91a
a Reagents and conditions: (a) Ac2O (30 equiv), 4-DMAP (0.1 equiv),
Et3N (40 equiv), CH2Cl2, 25 °C, 18 h, 79%; (b) 2-methoxypropene (20
equiv), CSA (1.0 equiv), CH2Cl2, -78 f -30 °C, 3 h, 82%; (c) MeMgBr
(50 equiv), toluene, 50 °C, 8 h, 94%; (d) SEMCl (10 equiv), i-Pr2NEt (30
equiv), n-Bu4NI (1.0 equiv), CH2Cl2, 50 °C, 48 h, 96%; (e) O3, py (1.0
equiv), CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78 f 25
°C, 1 h, 96%; (f) KH (10 equiv), allyl chloride (20 equiv), HMPA (5.0
equiv), DME, -10 f 25 °C, 3 h, 92%; (g) i-Pr2NEt (1.0 equiv),
1,2-dichlorobenzene, 200 °C (µ-waves), 20 min; then NaBH4 (20 equiv),
MeOH, 1 h, 25 °C, 88% for the two steps; (h) BOMCl (6.0 equiv), i-Pr2NEt
(15 equiv), CH2Cl2, 50 °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, 85% for the two
steps; (j) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 36 h; (k) O3,
py (1.0 equiv), CH2Cl2/MeOH (1:1), -78 °C; then Ph3P (5.0 equiv), -78
f 25 °C, 1 h, 97% for the two steps.
a Reagents and conditions: (a) (-)-26 (1.3 equiv), t-BuLi (2.6 equiv),
THF, -78 f -40 °C, 30 min; then (()-86 (1.0 equiv), - 40 f 0 °C, 20
min, 80%; (b) TBAF (1.0 M in THF, 5.0 equiv), THF, 25 °C, 1 h, 98%; (c)
TESCl (1.5 equiv), imidazole (5.0 equiv), CH2Cl2, 25 °C, 1 h, 99%; (d)
KHMDS (0.5 M in toluene, 3.0 equiv), ClCO2Me (5.0 equiv), Et3N (5.0
equiv), THF, -78 f 25 °C, 2 h; (e) HF ·py/py (1:4), 0 f 25 °C, 12 h,
88% for the two steps; (f) PhI(OAc)2 (3.0 equiv), TEMPO (1.0 equiv),
CH2Cl2, 25 °C, 24 h, 98%; (g) SmI2 (0.1 M in THF, 5.0 equiv), HMPA (15
equiv), THF, -10 f 25 °C, 30 min, 80% [(-)-90: 28%; (+)-91: 52%].
allylic alcohols [(+)-87 and (-)-88] in 80% combined yield
(Scheme 17). The desired SmI2-mediated cyclization precursor
(-)-89 was accessed from allylic alcohol (-)-88 (perceived to
be the “correct” diastereoisomer) through a five-step sequence
involving: (i) removal of the TIPS group (TBAF, THF, 98%
yield); (ii) TES protection of the primary hydroxyl group
(TESCl, imid, 99% yield); (iii) carbonate formation at the
secondary hydroxyl (KHMDS, ClCO2Me,Et3N); (iv) selective
removal of the TES group (HF ·py/py, 88% yield for the two
steps); and (v) oxidation of the newly liberated primary alcohol
to the corresponding aldehyde [PhI(OAc)2, TEMPO, (-)-89,
98%]. With aldehyde carbonate (-)-89 in hand, we were primed
to test our hypothesis regarding the neighboring group effect
of the chelating OSEM group on the cyclization reaction. Indeed,
treatment of (-)-89 with SmI2-HMPA at -10 °C resulted in
the formation of the desired cyclization product as a mixture
of diastereomers and in high yield [(-)-90, 28%; (+)-91, 52%].
This remarkable result was a turning point in the project, both
from a morale standpoint and logistical perspective, in that it
allowed the preparation of relatively large quantities of these
advanced intermediates for further explorations and elaboration.
The next task at hand was to develop a method for the obligatory
configurational adjustments at C10 and C28. To this end, it was
speculated that dehydration of these two diastereomers would
merge them into a single conjugated diene substrate [see
structure (+)-93, Scheme 18] that could be susceptible, in
principle, to a regioselective rehydration through hydroboration
chemistry. Furthermore, molecular modeling of diene (+)-93
of the SEM and acetonide protecting groups was also of
importance as it was anticipated to facilitate the eventual
construction of vannusal A from vannusal B. This maneuver
required the construction of a new aldehyde partner for coupling
with vinyl iodide (-)-26. We chose the SEM group as a suitable
chelator at the C26 position with an acetonide group blocking
the C25 and C22 sites, design elements that defined aldehyde
(()-86 as our next target (Scheme 16). Its synthesis commenced
with triol (()-41 (see Scheme 8 for its preparation), which
remarkably underwent selective acetylation (Ac2O, 4-DMAP,
Et3N) to afford monoacetate (()-82 in 79% yield. This fortuitous
event allowed us to introduce the acetonide group at the C25/
C22 location [(2-methoxypropene, CSA (cat.), 82% yield],
remove the acetate group (MeMgBr, 50 °C, 96%), and install
the SEM group at the C26 position (SEMCl, i-Pr2NEt, n-Bu4I,
96% yield) as required, affording fully protected intermediate
(()-83. The remaining steps from (()-83 to aldehyde (()-86
proceeded through intermediates (()-84 and (()-85 [and
followed the same route previously discussed in Scheme 8 for
the synthesis of aldehyde (()-27] as summarized in Scheme
16.
Following our previously described fragment coupling pro-
tocol (see Scheme 13), vinyl iodide (-)-26 was smoothly united
with aldehyde (()-86, affording the expected 1:1 mixture of
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7148 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Scheme 18. Total Synthesis of the Originally Assigned Structure of
Vannusal B (2)a
Figure 3. NOEs observed for compounds (+)-95 and (+)-98.
diastereoisomer (+)-91 required a syn type elimination for its
conversion to diene (+)-93. For this operation, we resorted to
the rarely employed xanthate formation/Chugaev elimination,26
which, in this instance, worked beautifully (NaH, CS2, CH3I;
µ-wave irradiation, 185 °C) to deliver the desired diene [(+)-
93], in 92% overall yield, through xanthate intermediate (+)-
92. With the coveted diene in hand, we were now poised to
test the viability of the expected regio- and stereoselective
hydroboration pathway to the desired C10/C28 diastereomeric
alcohol. This rather delicate operation was successfully con-
ducted by initial reaction of diene (+)-93 with ThexBH2, which
reacted effortlessly with the C3-appended terminal olefin (0f25
°C, 1 h) as conveniently monitored by TLC analysis. Subsequent
addition of BH3 ·THF to the reaction mixture accomplished the
desired hydroboration of the diene, affording, after the usual
oxidative workup (NaOH, H2O2), a mixture of C2 diastereomeric
diols (ca. 1:1.3, 65% combined yield). This mixture was then
subjected to o-nitrophenyl selenide formation (o-NO2C6H4SeCN,
n-Bu3P), and the resulting primary selenides were oxidized
(H2O2) to generate the corresponding selenoxides, whose
spontaneous syn elimination furnished hydroxy olefin (+)-94
in 67% overall yield as a single compound.27 The desired C10/
C28 configurations within the newly obtained hydroxy olefin (+)-
94 were confirmed by NOE studies with the corresponding
acetate derivative (+)-95 (Ac2O, 4-DMAP, 96% yield, Scheme
18), which revealed the expected through space interactions
between H7/H10 and H10/H27 as shown in Figure 3.
Having reached intermediate (+)-94 with all stereocenters
in their proper configurations, only a short path separated us
from the targeted molecule (i.e., 2, Scheme 18). Thus, the
requisite aldehyde and acetate functionalities of the molecule
were installed through a four-step sequence involving selective
functional group manipulations [(i) KHMDS, TESCl, quant.;
(ii) LiDBB, THF, -78 f -50 °C, 84% yield; (iii) PhI(OAc)2,
TEMPO, 88% yield; and (iv) Ac2O, 4-DMAP, Et3N, quant.].
Finally, global deprotection through sequential treatment with
HF·py and aq HCl in the same pot furnished the coveted
vannusal B structure 2 in 80% overall yield. It was with much
disappointment and dismay, however, that we came to realize
that the NMR spectroscopic data of our synthetic material,
although similar, did not match those reported for natural
vannusal B1 (see following article for differences).6
a Reagents and conditions: (a) POCl3 (60 equiv), py, 60 °C, 3 h, 81%;
(b) CS2 (8.0 equiv), NaH (6.0 equiv), THF, 0 f 25 °C, 30 min; then MeI
(12 equiv), 0 f 25 °C, 3 h; then 185 °C (µ-waves), 1,2-dichlorobenzene,
15 min, 92%; (c) ThexBH2 (5.0 equiv), THF, -10 f 25 °C, 1 h; then
BH3 ·THF (15 equiv), 0 f 25 °C, 30 min; then 30% H2O2/3 N aq NaOH
(1:1), 25 f 40 °C, 1 h; 65% overall yield (∼1:1.3 dr); (d) o-NO2C6H4SeCN
(2.0 equiv), n-Bu3P (6.0 equiv), py (12 equiv), THF, 25 °C, 10 min; then
30% H2O2, 0 f 25 °C, 12 h, 67%; (e) Ac2O (20 equiv), Et3N (20 equiv),
4-DMAP (1.0 equiv), CH2Cl2, 24 h, 96%; (f) KHMDS (0.5 M in toluene,
5.0 equiv), TESCl (5.0 equiv), Et3N (8.0 equiv), THF, -78 f 25 °C, 30
min, 94%; (g) LiDBB (excess), THF, -78 f -50 °C, 30 min, 84%; (h)
PhI(OAc)2 (3.0 equiv), TEMPO (1.0 equiv), CH2Cl2, 25 °C, 24 h, 88%; (i)
Ac2O (30 equiv), Et3N (30 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 25 °C,
12 h, quant.; (j) HF ·py/THF (1:4), 25 °C, 3 h; then 3 N aq HCl/THF (1:3),
25 °C, 6 h, 80%.
revealed a large diastereofacial bias between the R (bottom)
and ꢀ (top) faces of the diene, with the sterically larger C15/C16
bridgehead moiety blocking the latter face. Evidence of the
severe steric hindrance at the C12 site was already available from
the rather forcing alkoxide-mediated conditions needed to install
the carbonate moiety at this position at a previous stage [step
d, (-)-88f(-)-89, Scheme 17].
With these encouraging signs, we proceeded to convert
hydroxy olefins (-)-90 and (+)-91 to diene (+)-93 as shown
in Scheme 18. Thus, the C10/C28 anti diastereomer (-)-90 was
dehydrated with a standard trans elimination reaction employing
POCl3 (py, 70 °C) that led smoothly to the desired diene [(+)-93]
in 81% yield. By virtue of its syn C10/C28 configuration,
In our early investigations, the “wrong” diastereoisomer (+)-
25 (see Scheme 13), arising from the union of vinyl iodide (-)-
(26) Chugaev, L. Chem. Ber. 1899, 32, 3332–3335. For selected examples
of the Chugaev elimination (xanthate thermolysis) 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.
(27) Grieco, P. A.; Nishizawa, M. J. J. Org. Chem. 1977, 42, 1717–1720.
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A R T I C L E S
Nicolaou et al.
Scheme 19. Total Synthesis of Vannusal B Structure (+)-d-2a
products (see Scheme 17). The structural assignment of the
newly obtained polycyclic system (+)-98 was based on NOE
experiments (see Figure 3) that detected the syn relationship
between H10 and H27 (NOE observed) and suggested the anti
relationship between H10 and H7 (no NOE observed). Even more
intriguing was the realization that the stereochemical configura-
tions at C10 and C28 (relative to the DE ring domain) were
exactly the same as those observed for the model system (()-
29 as described above (see Scheme 5). A possible explanation
for the stereochemical outcomes of these SmI2-mediated ring
closures will be discussed in a separate section below.
Pressing forward with the synthesis, the path to the final
product was short and swift as it was based on the chemistry
already developed for the related advanced intermediate (+)-
94 (see Scheme 18). Thus, as shown in Scheme 19, (+)-98 was
converted to aldehyde acetate (-)-100 via diol (+)-99 through
a four-step sequence involving: (i) TES protection of the C28
hydroxyl group (KHMDS, TESCl); (ii) removal of the BOM
groups (LiDBB, 92% yield for the two steps); (iii) PhI(OAc)2-
TEMPO oxidation of the primary alcohol (89% yield); and (iv)
acetylation of the C29 hydroxyl group (Ac2O, 4-DMAP, Et3N,
99% yield). Finally, global deprotection of precursor (-)-100
through sequential treatment with HF ·py (89% yield) and aq
HCl (92% overall yield) led to the targeted vannusal B structure
(+)-d-2 [C10, C13, C14, C17, C18, C21, C25, C26, C28-epi-2] through
the corresponding dihydroxy acetonide (not shown). As we
expected (rightly or wrongly, as it finally turned out), the NMR
spectroscopic data of this structure did not match those of the
natural product.1
Mechanistic Considerations of the SmI2-Mediated Cycliza-
tions. During this research program we had the opportunity to
observe a number of interesting substrate effects on the
efficiency and stereoselectivity of the SmI2-mediated cyclization
to generate vannusal-type structures. While the anticipated
improved yield of this reaction upon substitution of the rigid
acetonide group with a SEM group [a more flexible and
powerful chelating moiety (see substrate (-)-89, Scheme 17)]
has already been briefly mentioned and rationalized, the diverse
stereochemical results obtained with the various cyclization
substrates warrant further discussion. Below we offer some
speculations regarding these intriguing stereochemical observa-
tions based solely on molecular models.
Figure 4 depicts the four possible transition states (ketyl
radicals 12-TSa-d) of the SmI2-mediated cyclization of alde-
hyde carbonate (()-12 that afforded product (()-11 (see Scheme
5) in 33% yield, apparently through 12-TSa, a transition state
relatively free of steric interactions as compared to the other
three (12-TSb-d), all of which suffer from some sort of
unfavorable steric interaction (see Figure 4). Their respective
products are, therefore, not observed.
Figure 5 includes the four possible transition states (73-
TSa-d) for the SmI2-mediated cyclization of the more elaborate
precursor (-)-73 which gave a mixture of products [(-)-77,
10% yield and (+)-78, 20% yield, see Table 2]. Inspection of
manual molecular models of these transition states reveals the
indicated steric interactions (A, B, and C), with C being the
most severe, followed by B, and then A. Apparently only 73-
TSc and 73-TSd are viable, leading to the observed products
[(-)-77 and (+)-78, respectively], both of which have the
opposite C10 configuration (relative to the C15-C16 bridge) from
that of product (()-11 (Figure 4).
a Reagents and conditions: (a) TESCl (2.0 equiv), imidazole (6.0 equiv),
CH2Cl2, 25 °C, 30 min, quant.; (b) KHMDS (0.5 M in toluene, 2.5 equiv),
ClCO2Me (4.0 equiv), Et3N (4.0 equiv), THF, -78 f 25 °C, 2 h; (c) HF ·py/
py (1:4), 0 f 25 °C, 12 h, 77% for the two steps; (d) PhI(OAc)2 (5.0 equiv),
TEMPO (1.0 equiv), CH2Cl2, 25 °C, 24 h, 98%; (e) SmI2 (0.1 M in THF,
5.0 equiv), HMPA (15 equiv), THF, -10 f 25 °C, 30 min, 73%; (f) TESCl
(2.0 equiv), imidazole (6.0 equiv), CH2Cl2, 5 h; (g) LiDBB (excess), THF,
-78 f -50 °C, 30 min, 92% for the two steps; (h) PhI(OAc)2 (5.0 equiv),
TEMPO (2.0 equiv), CH2Cl2, 25 °C, 36 h, 89%; (i) Ac2O (20 equiv), Et3N
(30 equiv), 4-DMAP (2.0 equiv), CH2Cl2, 25 °C, 12 h, 99%; (j) HF ·py/
THF (1:4), 25 °C, 0.5 h, 89%; (k) 3 N aq HCl/THF (1:3), 25 °C, 12 h,
92%.
26 and aldehyde (()-27, was employed as a “model” system
in order to scout the chemistry that lay ahead prior to committing
the “more precious” diastereoisomers [i.e., (-)-24, Scheme 13,
and later on, (-)-88, Scheme 17] to further elaboration. As the
campaign for the search of the true structures of the vannusals
intensified, this practice became even more important and
provided a greater level of thoroughness. It was for these reasons
that we carried diasteroisomer (+)-25 to the end product,
vannusal B structure d-2 [C10, C13, C14, C17, C18, C21, C25, C26,
C28-epi-2], through a similar, albeit, as it turned out, shorter
route. Scheme 19 summarizes the pathway to d-2 from (+)-25
[obtained from (+)-70 by exposure to TBAF (as shown in
Scheme 13)]. Thus, conversion of diol (+)-25 to the cyclization
precursor, aldehyde carbonate (-)-97, proceeded through the
same four-steps and in similar yields as those described for its
congener [compound (-)-24, Scheme 14] as summarized in
Scheme 19. Interestingly, however, when aldehyde carbonate
(-)-97 was exposed to the same SmI2-mediated conditions as
those previously employed in the case of (-)-89 (Scheme 17)
(SmI2, HMPA, THF, -10 °C), hydroxy olefin (+)-98 was
formed in 73% yield and as a single diastereoisomer. This result
is in contrast to the cyclization of the diastereomeric counterpart
of this substrate, precursor (-)-89, which led to diastereomeric
Inspection of Figure 6, which depicts the transition states
89-TSa-d for the cyclization precursor (-)-89 leading to
9
7150 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Vannusal B: Synthesis of Assigned Structure
A R T I C L E S
Figure 4. Stereocontrolling steric interactions within transition states 12-TSa-d leading from substrate (()-12 to cyclization product (()-11 on exposure
to SmI2 (see Scheme 5).
Figure 5. Stereocontrolling steric interactions within transition states (73-TSa-d) from cyclization precursor (-)-73 leading to formation of products
(-)-77 and (+)-78 (see Table 2).
Figure 6. Stereocontrolling steric interactions within transition states 89-TSa-d leading to products (-)-90 and (+)-91 from cyclization precursor (-)-89
on exposure to SmI2 (see Scheme 17).
products (-)-90 and (+)-91 (see Scheme 17), reveals severe
steric interactions [C in 89-TSa and A and C in 89-TSb].
These prohibitive effects explain the absence of the corre-
sponding products, whereas the less severe interactions in
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A R T I C L E S
Nicolaou et al.
Figure 7. Stereocontrolling steric interactions within transition states 97-TSa-d leading from cyclization precursor (-)-97 to cyclization product (+)-98
on exposure to SmI2 (see Scheme 19).
89-TSc (B) and 89-TSd (A) allow the formation of the
observed products [i.e., (-)-90 and (+)-91, respectively]. The
ability of the strategically placed (at C26) SEM group, and
possibly the overall conformational changes imparted by it
on substrate (-)-89, as well as the potential inductive effect
of the chelating oxygen atom,28 are the likely reasons for
the significant increase in yield (80% total) of this ring closure
as opposed to that observed for substrate (-)-73 (30%
combined yield, see Figure 5 and Table 2).
Finally, Figure 7 depicts the four transition states (97-TSa-d)
for the cyclization of precursor aldehyde carbonate (-)-97,
which leads to the single product (+)-98 in 73% yield (see
Scheme 19). In this case, it is 97-TSa that is relatively free of
steric interactions as compared to the other three (97-TSb, 97-
TSc, and 97-TSd) transition states. Although we have not
performed the experiment, it is interesting to speculate whether
placing a SEM group at the C26 hydroxyl group of substrate
(-)-97 would lead to an increase of cyclization efficiency as it
did in the previous case [i.e., with substrate (-)-73 vs substrate
(-)-89, Figures 5 and 6, respectively].
B (and its congener, vannusal A). As expected, this undertaking
resulted in the development of several synthetic strategies and
technologies that would prove valuable in the next phase of
the program and eventually lead to the revision of the structures
and the total synthesis of both vannusals A and B. These
included efficient synthetic routes that made readily available,
and in multigram quantities, the required building blocks, their
efficient coupling, the crucial SmI2-mediated cyclization reaction
that forged the final ring of the vannusal skeleton, and the
impressively regio- and stereoselective hydroboration of the
conjugated diene system to install the correct stereochemical
configurations at C10 and C28. The application of these enabling
technologies and the interplay between chemical synthesis, NMR
spectroscopy, and molecular design that led to the completion
of this project are described in the following article.6
Acknowledgment. We thank Professor Graziano Guella for a
sample of natural vannusal B and 1H NMR spectra of vannusals A
and B, and for helpful discussions. We thank Drs. D. H. Huang,
G. Siuzdak, and R. Chadha for NMR spectroscopic, mass spectro-
metric, and X-ray crystallographic assistance, respectively. Financial
support for this work was provided by the Skaggs Institute for
Research, as well as fellowships from the NSF (to A.O.), The
George E. Hewitt Foundation for Medical Research (to M.P.J.),
the Association pour la Recherche sur le Cancer (to S.A.), and the
Swiss National Science Foundation (to R. Faraoni), and grants from
the National Institutes of Health (USA) (GM063752 and
CA100101).
Conclusion
In this article we described our endeavors that led to the total
synthesis of the originally assigned structure (2) of vannusal
B. This success, however, only proved that this structure was
erroneously assigned to the natural product, thereby defining a
new challengesthat of deciphering the true structure of vannusal
(28) (a) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6357–
6361. (b) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem.
Soc. 1987, 109, 453–463. (c) Kawatsura, K.; Dekura, F.; Shirahama,
H.; Matsuda, F. Synlett 1996, 373–376. (d) Keck, G. E.; Wager, C. A.;
Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64, 2172–2173. (e)
Kawatsura, M.; Hosaka, K.; Matsuda, F.; Shirhama, H. Synlett 1995,
729–732.
Supporting Information Available: Experimental procedures
and full compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org
JA100740T
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7152 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010