An expedient entry into the fused polycyclic skeleton of vannusal A

Article abstract of DOI:10.1039/b208234a

The synthesis of the fused polycyclic carbon framework of vannusal A is described; key features include inter- and intramolecular aldol reactions, a Mn(III) initiated radical cyclization, and a ring-closing olefin metathesis reaction.

Full text of DOI:10.1039/b208234a

An expedient entry into the fused polycyclic skeleton of vannusal A†‡
K. C. Nicolaou,* Michael P. Jennings and Philippe Dagneau
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry and
Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
E-mail: kcn@scripps.edu
Received (in Cambridge, UK) 22nd August 2002, Accepted 23rd September 2002
First published as an Advance Article on the web 7th October 2002
The synthesis of the fused polycyclic carbon framework of
vannusal A is described; key features include inter- and
intramolecular aldol reactions, a Mn(III) initiated radical
cyclization, and a ring-closing olefin metathesis reaction.
an olefin metathesis reaction, allowed the disassembly of 2 into
key intermediates 3 and 4 as potential precursors. The
convergent strategy suggested by these two disconnections was
advanced further by tracing tricycle 4 to spiro system 5 via a key
radical-induced ring closure. It was anticipated that the
projected cascade radical cyclization of 5 to 4 could be initiated
In 1999, a highly unusual triterpene, termed vannusal A (1,
1
Scheme 1), was reported by the Pietra group. Isolated from the
3
by Mn(OAc) whereas a Mukaiyama-type aldol reaction was
tropical strains of the marine ciliate Euplotes vannus, 1
possesses a 30-carbon backbone comprising seven rings and
thirteen stereogenic centers of which three are quaternary.
Whereas various biosynthetic pathways for the generation of 1
from squalene can be imagined,1 its total synthesis in a
laboratory setting can be considered rather challenging and
most likely requiring special strategies and tactics. Specifically,
the fused polycyclic carbon core of vannusal A was deemed
from the very outset as the most severe hurdle to be overcome
before a total synthesis could be realized. We, therefore,
initially focused our efforts on the construction of model system
reserved for the construction of the required spiro ketone 5.
The highly functionalized and strained norbornane derivative
4 was synthesized as delineated in Scheme 2. The successful
route to this intermediate began with a one-pot, tandem
sequence involving regioselective hydroboration of olefinic
substrate 6 with 9-BBN (for abbreviations of reagents and
protecting groups, see the legends in Schemes 2 and 3) followed
by coupling of the resulting borane under Suzuki conditions
2 2 3
(Pd[dppf]Cl , K CO , 80 °C) with the required iodo-ketone,
2
leading to enone 7 in 84% overall yield. Conjugate addition of
a propenyl group to 7 proceeded by addition of the correspond-
2
(Scheme 1) representing the basic framework of the molecule.
In this communication, we report a facile entry into the fused
polycyclic carbon skeleton of vannusal A by a convergent
strategy featuring a number of selective transformations that
will hopefully pave the way for its eventual total synthesis.
Inspection of structure 2 revealed the strategic bond dis-
connections indicated in Scheme 1 as particularly productive in
unraveling potential starting building blocks for its construc-
tion. Thus, an intermolecular aldol process, in conjunction with
Scheme 2 Preparation of the key keto-aldehyde intermediate 4: (a) 9-BBN
2 2 3
(1.2 equiv.), THF, 75 °C, 2 h; (b) Pd[dppf]Cl (1 mol%), aq. K CO (4.0
equiv.), THF, 80 °C, 4 h, 84%; (c) LiCl (0.2 equiv.), CuI (0.1 equiv.),
TMSCl (1.5 equiv.), THF, 220 °C, 0.5 h; then MeCHNCHMgBr (1.2
equiv.), THF, 220 °C, 2 h; (d) aq. HF (2.0 equiv.), MeCN, 25 °C, 2 h, 71%;
(
e) PCC (1.5 equiv.), CH
MeOH, 50 °C, 2.5 h, 95%; (g) HMDS (1.5 equiv.), CH
TMSI (1.3 equiv.), CH Cl , 1 h, 50%, (h) KH (3.0 equiv.), (MeO)
equiv.), THF, 85 °C, 4 h, 95%, (i) Mn(OAc) (3.0 equiv.) Cu(OAc)
equiv.), HOAc, 80 °C, 1 h, 76%; (j) DIBAL (4.0 equiv.), THF, 278 to 0 °C,
5 h, 91%; (k) BAIB (2.0 equiv.), TEMPO (0.1 equiv.),CH Cl , 25 °C, 12 h,
75%; (l) Ac O (10.0 equiv.), pyridine, 50 °C, 3 h, 71%. 9-BBN =
2
Cl
2
, 25 °C, 1 h, 89%; (f) NH
Cl , 0 °C, 0.5 h; then
CO (20.0
(2.0
4
Cl (0.1 equiv.),
2
2
Scheme 1 Structure of vannusal A (1), fused polycyclic skeleton 2, and
retrosynthetic analysis of the latter (2).
2
2
2
3
2
†
Electronic supplementary information (ESI) available: selected physical
2
2
data for compounds 11 and 2. See http://www.rsc.org/suppdata/cc/b2/
2
b208234a/
9-borabicyclo[3.3.1]nonane, dppf = diphenylphosphino ferrocene, TMS =
trimethylsilyl, DIBAL = diisobutylaluminium hydride, BAIB = [bis(ace-
toxy)iodo]benzene, TEMPO = 2,2,6,6 tetramethyl-1-piperidinyloxyl.
‡
Dedicated to Professor Herbert C. Brown on the occasion of his 90th
birthday.
2
480
CHEM. COMMUN., 2002, 2480–2481
This journal is © The Royal Society of Chemistry 2002

Fig. 1 Key nOe enhancements for diol 14.
isolation of a diastereomerically pure aldol product (14) in 65%
yield (based on 4) whose spectroscopic data were consistent
with the opposite stereochemistry for the hydroxyl group as
required for vannusal A (anti as opposed to the desired syn).
Since this stereochemical outcome could, in principle, be
rectified later on in the sequence through standard chemistry,
we proceeded to the next stage which required protection of the
newly generated hydroxyl group as a TES ether (TESCl,
imidazole, 72% yield) furnishing protected diol 15. Concerned
with potential epimerization and/or elimination problems
during the pending olefination of the cyclopentanone moiety in
Scheme 3 Synthesis of vannusal AAs polycyclic skeleton (2): (a) 3, LiHMDS
2.2 equiv.),THF, 278 °C, 1 h; then 4, 1 h, 278 °C, 65%; (b) TESCl (1.2
equiv.), imidazole (2.5 equiv.), DMAP (0.5 equiv.), DMF, 25 °C, 36 h, 72%;
c) Zn (10.0 equiv.), PbCl (0.01 equiv.), TMSCl (0.1 equiv.), CH (20.0
equiv.), THF, 25 °C, 0.5 h; then TiCl (3.0 equiv.), 5 h, 88%; (d) catalyst 17,
0.3 equiv.) CH Cl , 50 °C, 12 h, 84%; (e) PPTS (0.3 equiv.), MeOH,
CH Cl , 25 °C, 6 h, 91%; LiHMDS = lithium salt of 1,1,1,3,3,3-hexame-
1
5 under the standard Wittig conditions, we turned to a
(
8
modified Takai protocol in which the action of the obligatory
reagents (Zn, CH , and TiCl ) was enhanced by the addition of
catalytic amounts of PbCl and TMSCl. This reaction per-
formed admirably in this instance to afford the desired olefin
16) in 88% yield.9 Pleasantly, exposure of 16 to Grubbs’
2
I
2
4
(
2
2 2
I
2
4
(
2
2
(
2
2
thyldisilazane, TES = triethylsilyl, PPTS = pyridinium p-toluenesulfo-
nate.
second generation catalyst 17 formed the missing cyclohexene
ring and subsequent PPTS promoted desilylation led to the
targeted vannusal skeleton 2 in 76% yield.10 With the complete
fused polycyclic framework in hand, our attention was finally
turned to deducing the global relative stereochemistry of the
synthesized molecule. As shown in Fig. 2, all of the stereogenic
centers of 2‡ correspond, as indicated by the nOe enhance-
ments, to that of 1, except for the free hydroxyl group which
resides in the pseudo-equatorial position.
ing Grignard reagent under modified Kharasch3 conditions
(
CuI–LiCl) to afford the corresponding enolate, which was
4
trapped with TMSCl as the silyl enol ether. Treatment of the
latter product with aq. HF removed both silyl groups and
furnished intermediate 8, with the trans arrangement of the two
appendages on the six-membered ring, as a mixture of
inconsequential geometrical isomers in 71% overall yield.
Oxidation of the primary alcohol in 8 with PCC led to the
corresponding keto-aldehyde (89% yield), whose aldehyde
function was then selectively converted to a dimethoxy acetal 9
4
by treatment with catalytic amounts of NH Cl in refluxing
MeOH (95% yield) thereby setting the stage for the crucial
intramolecular spirocyclization via a Mukaiyama-type aldol
reaction. Gratifyingly, upon exposure of acetal 9 to excess
TMSI in the presence of HMDS, cyclization proceeded to afford
the coveted spiro compound 10 in 50% yield as a single
stereoisomer (except for the olefin geometry which was
Fig. 2 Key nOe enhancements for polycycle 2.
The described synthesis of vannusal A’s fused polycyclic
skeleton represents a novel approach to this natural product and
demonstrates the power of modern synthetic technologies to
construct complex molecular architectures. Efforts toward
implementing this strategy to effect the total synthesis of
vannusal A and B are now under way.
We thank the NIH, the Skaggs Institute for Chemical
Biology, and the George E. Hewitt Foundation (Fellowship to
M. P. J.) for financial support.
5
maintained as a mixture). With the first quaternary center fixed
in intermediate 10, we then turned our attention to the
introduction of the second such motif. Thus, refluxing spiro-
cycle 10 in THF with excess KH and (MeO)
quantitatively, keto-ester 5 as a mixture of two diastereomers
95% total yield). Noteworthy is the fact that, just as in the case
2
CO afforded,
(
of the geometrical isomerism, the stereochemistry of the ester
group in 5 was irrelevant to the stereochemical outcome of the
pending ring closure. Indeed, treatment of the latter compound
3 2
(5) with Mn(OAc) and Cu(OAc) in hot acetic acid (80 °C)
according to the Snider protocol furnished the expected keto-
Notes and references
ester 11 in 76% yield as a single diastereomer via the anticipated
1
G. Guella, F. Dini and F. Pietra, Angew. Chem., Int. Ed., 1999, 38,
134.
6
radical pathway. The next step toward 4 was the reduction of
1
1
1 to the corresponding diol, an objective which was accom-
2
3
B. H. Ridgway and K. A. Woerpel, J. Org. Chem., 1998, 63, 458.
M. S. Kharasch and P. O. Tawney, J. Am. Chem. Soc., 1941, 63,
plished stereoselectively with DIBAL. Much to our delight, the
resulting relative stereochemistry within 12 correlated with the
required configuration of 1 as evidenced by the observed nOe
enhancements (see Fig. 1). The primary hydroxyl of 12 was
2
308.
4 M. T. Reetz and A. Kindler, J. Organomet. Chem., 1995, 502, C5.
5 Y. Tokunaga, M. Yagihashi, M. Ihara and K. Fukumoto, J. Chem. Soc.,
Perkin Trans. 1, 1997, 189.
7
selectively oxidized by the BAIB-TEMPO protocol to furnish
6
7
B. B. Snider, Chem. Rev., 1996, 96, 339.
A. De Mico, R. Margarita, L. Parlanti, A. Vescovi and G. Piancatelli, J.
Org. Chem., 1997, 62, 6974.
aldehyde 13 in 75% overall yield. Subsequent acetylation
2
(Ac O, py) of the free secondary alcohol furnished the protected
aldehyde 4 in 72% yield.
8
9
K. Takai, Y. Hotta, K. Oshima and H. Nozaki, Tetrahedron Lett., 1978,
With the required fragment 4 readily available, attention was
then focused on coupling the two fragments and then executing
the final elaborations to the target structure, as shown in Scheme
1
9, 2417.
K. Takai, T. Kakiuchi, Y. Kataoka and K. Utimoto, J. Org. Chem., 1994,
9, 2688.
5
3
. Thus, treatment of cyclopentanone (3) with excess LiHMDS
10 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
in THF at 278 °C, followed by addition of aldehyde 4, led to the
953.
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