A connective approach to the tetrahydropyran subunit of polycavernoside a via a novel 1,1-dianion equivalent

Article abstract of DOI:10.1016/j.tetlet.2005.05.054

Racemic tetrahydropyran 3 was efficiently synthesised from allylsilane 6 and aldehyde 7 via an intramolecular Sakurai cyclisation. In a single step, the relative configuration of three chiral centres was established. Allylsilane 6 was readily assembled fr

Full text of DOI:10.1016/j.tetlet.2005.05.054

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4887–4890
A connective approach to the tetrahydropyran subunit of
polycavernoside A via a novel 1,1-dianion equivalent
*
´ ´ ´
Carlos Perez-Balado and Istvan E. Marko
´ ´
Universite catholique de Louvain, Departement de Chimie, Unite de Chimie Organique et Medicinale,
Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
´
´
ˆ
Received 29 March 2005; revised 3 May 2005; accepted 12 May 2005
Available online 6 June 2005
Abstract—Racemic tetrahydropyran 3 was efficiently synthesised from allylsilane 6 and aldehyde 7 via an intramolecular Sakurai
cyclisation. In a single step, the relative configuration of three chiral centres was established. Allylsilane 6 was readily assembled
from 1-iodo-1-selenopropene 10, a synthetic equivalent of a propene 1,1-dianion.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Polycavernoside A 1 is the major component of a small
SOPh
family of novel and structurally unique macrolide disac-
charides(polycavernosides). Isolated in 1993 by Yasu-
moto et al. from the red alga Polycavernosa tsudai,
polycavernoside A was identified as the toxin respon-
sible for the fatal human intoxication that occurred in
the island of Guam, in 1991.1 Since the elucidation of
its planar structure, this powerful marine toxin became
the target of several synthetic groups, undoubtedly at-
tracted by its challenging architectural and biological
features. Polycavernoside A 1 possesses an unusual 13-
membered keto-lactone ring and an interesting five-
membered hemiketal function adjacent to the ketone
group. Moreover, a labile triene moiety is linked to C-
15 (Fig. 1). In 1998, Murai and co-workers published
the first total synthesis of 1,2 establishing at the same
time its absolute stereochemistry. Two other total syn-
theses have been reported to date.3
O
O
O
O
O
5
OH
4
O
13
15
HO 10 O
O
O
1
9
O
O
5
S
S MeO
O
O
O
MeO
O
O
O
OMe
OMe
OMe
Our retrosynthetic analysis is depicted in Figure 1. Dis-
connection of the C1–O and C9–C10 bonds leads to
three fragments of approximately the same molecular
complexity. The northern subunit consists of the five-
membered lactone 4, bearing the trienyl side chain,
and the southern moiety 2 embodies a tetrasubstituted
1
OH
OH
2
Polycavernoside A
S
S
OH
O
Keywords: Allylsilanes; Polycavernoside A; 1-Iodo-1-selenoalkenes;
Sakurai cyclisation.
3
*
Corresponding author. Tel.: +32 10 47 87 73; fax: +32 10 47 27 88;
e-mail: marko@chim.ucl.ac.be
Figure 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.054

´ ´
C. Perez-Balado, I. E. Marko / Tetrahedron Letters 46 (2005) 4887–4890
4888
tetrahydropyran core. The disaccharide residue has
already been efficiently prepared by Murai and co-
workers.4 In a previous letter, we have reported an
expedient synthesis of 4 from the readily available c-
butyrolactone subunit 5.5 As a continuation of our
endeavours towards a flexible and versatile construction
of 1, we wish to report a concise and stereocontrolled
approach to the tetrahydropyran subunit 2, utilising
an intramolecular Sakurai cyclisation (IMSC) as the
key step. This reaction has proved to be a powerful tool
for the assembly of tri- and tetrasubstituted tetrahydro-
pyrans, with excellent control of their relative and abso-
lute stereochemistry. This methodology has already
been successfully applied in our laboratory to the syn-
thesis of pseudomonic acid B, milbemycin b3 and the
middle core of amphidinols.6
C@C bond (Scheme 1). The relative configuration of
the three stereogenic centres in the final product is gov-
erned by the preference of the substituents to occupy
pseudoequatorial positions in the chair-like transition-
state during the ring closure step.7 An important para-
meter in the control of the relative orientation of the
substituents in the final adduct is the geometry of the
C@C bond of the allylsilane. According to this model,
the Z-allylsilane 6 is required to obtain the tetrahydro-
pyran possessing the correct stereochemistry as present
in polycavernoside A.
Despite the number of procedures described in the liter-
ature for the synthesis of alkenes, there are few, simple
and general methodologies that allow the preparation
of trisubstituted allylsilanes with good stereocontrol of
the double bond geometry.8 In order to explore new
strategies in this field, we decided to prepare allylsilane
6 from a synthetic equivalent of an alkene 1,1-dianion.
Several reports describe the synthesis of alkene 1,1-di-
anions.9 Unfortunately, most of these species were found
to suffer from serious shortcomings, such as lack of reac-
tivity, difficulty in handling and, often, tedious prepara-
tion. In the event, it was found that 1,1-iodoselenoalkene
10 was an interesting and versatile intermediate that
could readily be transformed into a variety of di- and
tri-substituted olefins. In the preceding letter,10 we have
disclosed some of our preliminary results on the efficient
preparation of these 1,1-iodoselenoalkenes. Sequential
functionalisation of both heteroatom positions should
lead stereoselectively to the desired allysilane 6.
Following our strategy, the southern subunit 2 could be
derived from the tetrahydropyran 3 by a few functional
group transformations. Thus, the preparation of rac-3
became our prime objective. Our antithetic analysis of
rac-3 is shown in Figure 2. Application of the IMSC ret-
ron to rac-3 leads to the generation of two simple frag-
ments: the allylsilane 6 and the protected b-hydroxy
aldehyde 7. The condensation of these two fragments
should afford stereoselectively the requisite exo-methyl-
ene tetrahydropyran rac-3. The intramolecular Sakurai
cyclisation is believed to proceed via a two-step mecha-
nism. The coupling between an allylsilane such as 6 and
an aldehyde, in the presence of a Lewis acid, generates
initially an oxocarbenium cation intermediate, which
undergoes subsequent ring closure by intramolecular
nucleophilic addition of the pendant allylsilane function,
to give a tetrahydropyran ring possessing an exocyclic
1-Iodo-1-selenoalkene 10 was prepared in two steps
from propyne. Deprotonation of 8 with n-BuLi gener-
ated the corresponding acetylide, which was subse-
quently reacted with 2,4,6-triisopropylphenylselenyl
bromide, affording the 1-selenoalkyne 9 (87% yield).
Hydroalumination of 9 with DIBAL-H led to the quan-
titative formation of a (Z)-1,1-alumino-selenoalkene
intermediate, which was quenched with I2 under care-
fully controlled conditions to give selectively, and with
retention of configuration of the C@C bond, the 1,1-
iodo-selenoalkene 10 in 92% yield. The use of the steri-
cally hindered 2,4,6-triisopropylphenyl (TIPP) group on
selenium proved mandatory to prevent the competitive
(sp)C–Se bond cleavage during the hydroalumination
step.10
S
S
OH
S
S
OTBDMS
O
O
OH
+
H
7
(H3C)3Si
6
rac-3
I
10
Opening of the dithianylmethyl oxirane 11 by the vinylic
anion derived from 10, by I/Li exchange with n-BuLi, in
the presence of BF3ÆOEt2, resulted in the formation of
SeTIPP
Figure 2.
S
OH
S
H1
H5
HO
TMS
Si(CH )
3 3
6
TBDMSO
BF .OEt
H4
3
2
O
H2
O
S
91%
+
CH Cl ,
2 2
-78°C to rt
S
H3
S
S
O
J1-2=9.6 Hz
J3-5=10 Hz J4-5=3 Hz
19
H
OTBDMS
7
rac-3
Scheme 1.

´ ´
C. Perez-Balado, I. E. Marko / Tetrahedron Letters 46 (2005) 4887–4890
4889
the homoallylic alcohol 12 in 50% yield based upon 10
(100% based upon oxirane 11). In the absence of a Lewis
acid, this vinyl lithium species proved to be rather unre-
active towards oxirane 11. The moderate yield in the
presence of BF3ÆOEt2 is due to the concomitant forma-
tion of an unreactive vinyl fluoroborate intermediate,11
which consumes 50% of the vinyl lithium reagent. By
employing 2 equiv of vinylselenide 10, a quantitative
yield of adduct 12 could be reached.
of the coupling constants in adduct rac-3 (Scheme 3),
indicating that the transformation of 10 to 6 took place
with retention of configuration.
With a ready supply of allylsilane 6 in hand, we next
turned our attention to the crucial intramolecular Saku-
rai cyclisation. We were delighted to observe that the
tetrahydropyran rac-3 was readily obtained, in 91%
yield, when 6 and aldehyde 7 were treated with 1 equiv
of BF3ÆOEt2, at low temperature. Interestingly, we
found that a smooth deprotection of the TBDMS group
occurred when the reaction mixture was allowed to
warm up to room temperature, affording in a single
operation, the free alcohol.14 The relative stereochemis-
try of rac-3 was unambiguously established by careful
analysis of its 1H NMR spectrum. The coupling constant
values of 9.6 and 10 Hz for the H1–H2 and H5–
H3 hydrogen pairs clearly indicate that the three substit-
uents occupy equatorial positions on the tetrahydropy-
ran ring system (Scheme 1).
After treatment of 12 with methylmagnesium bromide,
in order to deprotonate the homoallylic hydroxy func-
tion, the alkenyl C–Se bond was reductively cleaved with
LDBB (lithium 4,40-di-t-butylbiphenylide),12 generating
the carbanion 15 and lithium selenoate 17 (Scheme 2).
Whilst it is reasonable to assume that the lithium salt
15 is initially formed under these reductive conditions,
it is quite plausible that metal exchange might take place
under the reaction conditions, leading either to 16 or an
equilibrating mixture of 15 and 16, with the latter reagent
being the active species in the subsequent coupling step.
In this regard, using n-BuLi to perform the deprotona-
tion of alcohol 12, followed by LDDB treatment, led
to significant erosion in the yields of 13. Attempts to re-
act these organometallic derivatives with various alkylat-
ing agents, in order to introduce the CH2TMS moiety,
failed probably owing to the lack of reactivity of these si-
lyl-containing electrophiles. Quenching of the intermedi-
ates 15/16 with I2 led to the vinyl iodide 13 in excellent
yield.13 Cross-coupling of 13 with trimethylsilylmethyl
magnesium chloride, catalysed by Pd(PPh3)4, ultimately
generated the requisite allylsilane 6 in 55% overall yield
from 12. It is noteworthy that 1 equiv of MeI had to be
added to the lithiated species 15/16, before the iodine
quench, in order to obtain good yields of 13. In this case,
MeI rapidly and chemoselectively traps the lithium sele-
noate 17, generated during the reductive cleavage of
vinyl selenide 12. In the absence of MeI, 17 reacts
competitively with I2, leading to the formation of numer-
ous, undesired products. The Z configuration of the
C@C bond of the allylsilane 6 was established by NOE
experiments and subsequently confirmed by the analysis
The relative stereochemistry of adduct rac-3 can be eas-
ily rationalised by examining the transition state in-
voked in the final cyclisation of the allylsilane residue
onto the oxocarbenium cation 19. In order to minimise
steric interactions, the substituents occupy pseudoequa-
torial positions. The geometry of the allylsilane double
bond controls the C2 configuration.
In summary, we have shown that racemic tetrahydropy-
ran 3 could be synthesised efficiently from allylsilane 6
and aldehyde 7 using the IMSC condensation as a key
step. By the judicious control of the allylsilane C@C
double bond, the relative stereochemistry of three chiral
centres could be established in a single operation. We
have also demonstrated that 1-iodo-1-selenoalkenes
are useful precursors for the synthesis of stereo-
defined trisubstituted allylsilanes. These interesting
vinylselenides can be considered as alkene-1,1-dianion
a
b
SeTIPP
87%
92%
8
9
O
SeTIPP
SeTIPP
Li
MgBr
S
11
1. CH3MgBr (1eq),
THF, 0°C
SeTIPP
I
S
or
HO
S
c, 100%
HO
S
S
BrMgO
LiO
16
2. LDBB (2 eq),
-78°C
10
12
15
S
+
12
LiSeTiPP
17
H3C
H
Si(CH3)3
I
ClMg
Si(CH3)3
d
14
81%
e, 68%
H
OH
HO
S
S
I
3.1%
2%
H
1. MeI (1 eq),
-78°C
S
N.O.E.
13
S
HO
13 (81%)
S
S
6
2. I2 (2.5 eq),
-78°C
Scheme 3. Reagents and conditions: (a) n-BuLi, THF, ꢀ40 ꢁC then
2,4,6-triisopropylphenylselenyl bromide, C6H6, 0 ꢁC to rt, 5 h; (b)
DIBAL-H, hexane, 0 ꢁC to rt, 3 h, then I2, THF, ꢀ78 ꢁC to rt, 2 h; (c)
n-BuLi, THF, ꢀ78 ꢁC, 30 min, BF3ÆOEt2, then ( )-11, THF, ꢀ78 ꢁC,
1 h; (d) CH3MgBr, THF, 0 ꢁC, 15 min, LDBB, ꢀ78 ꢁC, 30 min, MeI,
ꢀ78 ꢁC, 15 min, then I2, ꢀ78 ꢁC, 1 h; (e) 14, Pd(PPh3)4, THF, rt, 9 h.
+
MeSeTiPP
18 (86%)
Scheme 2.

´ ´
C. Perez-Balado, I. E. Marko / Tetrahedron Letters 46 (2005) 4887–4890
4890
12. For synthetic applications of LDBB see: Yus, M. Chem.
Soc. Rev. 1996, 25, 155.
equivalents. Current efforts are now being directed
towards delineating the scope and applications of sele-
noalkenes such as 10, establishing an enantioselective
synthesis of tetrahydropyran 3 and completing the total
synthesis of polycavernoside A. The results of these
investigations will be reported in due course.
13. Experimental procedure for the preparation of vinyl iodide
13: To a solution of selenide 12 (130 mg, 0.26 mmol) in
THF at 0 ꢁC and under argon, was added dropwise
CH3MgBr (130 lL, 0.39 mmol and 3.0 M in Et2O). After
stirring for 15 min at 0 ꢁC, this solution was added, via
syringe, to a LDBB solution (2.5 mL, 0.3 M in THF)
maintained at ꢀ78 ꢁC. At the end of the addition, the
solution colour changed from dark green to clear red. The
mixture was stirred for 30 min at ꢀ78 ꢁC and neat MeI
(16 lL, 0.26 mmol) was added. Stirring was continued for
another 10 min. The solution became colourless. A solu-
tion of I2 (165 mg, 0.65 mmol) in THF (2 mL) was added
dropwise and the mixture stirred for 1 h at ꢀ78 ꢁC. The
reaction was quenched by addition of ethanol (2 mL) at
ꢀ78 ꢁC and the solution was allowed to reach room
temperature. It was diluted with petroleum ether (5 mL),
washed with a satd aq solution of Na2S2O3 (5 mL) and
extracted several times with petroleum ether. The com-
bined organic layers were dried over MgSO4 and the
solvents were evaporated under reduced pressure. The
crude material was purified by flash chromatography
(petroleum ether/Et2O, 1/1) to afford 73 mg (81% yield) of
the title compound as a yellow oil. 1H NMR (CDCl3,
300 MHz): dH (ppm): 5.73 (1H, qt, J = 6.3, 1.1 Hz), 4.28
(1H, dd, J = 8.4, 6.0 Hz), 4.35–4.20 (1H, m), 2.99–2.80
(4H, m), 2.62 (2H, d, J = 6.5 Hz), 2.25–1.80 (4H, m), 1.77
(3H, d, J = 6.3 Hz); 13C NMR (75 MHz, CDCl3): dC
(ppm): 128.4, 106.3, 67.3, 53.3, 44.7, 42.4, 30.6, 30.2, 26.4,
22.5. IR (neat): 3348, 2938, 2900, 1647, 1422, 1243,
1115 cmꢀ1. MS (EI) m/z (%): 219 [M+ꢀI] (15), 205 (29),
188 (22).
Acknowledgements
Financial support of this work by Chirotech Technology
´
Ltd, Cambridge, UK and the Universite catholique de
Louvain is gratefully acknowledged.
References and notes
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J. Am. Chem. Soc. 1993, 115, 1147; (b) Haddock, R. L.;
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Wardrop, D. J. J. Am. Chem. Soc. 2001, 123, 8593.
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855; For another synthesis of the sugar part of polycav-
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Tetrahedron Lett. 1995, 36, 4341.
´
5. (a) Dumeunier, R.; Marko, I. E. Tetrahedron Lett. 2000,
41, 10219; (b) Dumeunier, R. Ph.D. Dissertation, Univer-
14. Experimental procedure for the preparation of tetrahydro-
pyran rac-3: To a solution of allylsilane 6 (65 mg,
0.21 mmol) and aldehyde 7 (60 lL, 0.32 mmol) in CH2Cl2
(2 mL) at ꢀ78 ꢁC, under argon, was added BF3ÆOEt2
(41 lL, 0.32 mmol) dropwise. The reaction mixture was
allowed to warm slowly to ꢀ30 ꢁC, and the disappearance
of the starting material was monitored by TLC. After
completion of the reaction, the solution was allowed to
reach rt, poured over a saturated aqueous solution of
NaHCO3 (5 mL) and extracted with CH2Cl2 (4 · 5 mL).
The combined organic layers were dried over MgSO4 and
the solvents were removed under reduced pressure. The
crude material was purified by chromatography on silica
gel (petroleum ether/Et2O, 2/1) affording 55 mg (91%
´
site catholique de Louvain, Belgium, 2004.
´
6. (a) For pseudomonic acids see: Marko, I. E.; Plancher, J.
M. Tetrahedron Lett. 1999, 40, 5259; For milbemycin b3
´
see: (b) Marko, I. E.; Murphy, F.; Dolan, S. Tetrahedron
1996, 37, 2507; For amphinols see: (c) Leroy, B.; Marko, I.
´
´
E. J. Org. Chem. 2002, 67, 8744; (d) Leroy, B.; Marko, I.
E. Tetrahedron Lett. 2000, 41, 7225.
´
7. (a) Marko, I. E.; Dumeunier, R.; Leclercq, C.; Leroy, B.;
Plancher, J. M.; Mekhalfia, A.; Bayston, D. J. Synthesis
´
2002, 958; (b) Marko, I. E.; Bayston, D. J. Tetrahedron
Lett. 1993, 34, 6595.
8. For some selected reviews see: (a) Sarkar, T. K. In Science
of Synthesis: Houben–Weyl Methods of Molecular trans-
formations; George Thieme: Stuttgart, 2002; Vol. 4, 837;
(b) Sarkar, T. K. Synthesis 1990, 969, and 1101.
9. For some selected reviews see: (a) Chinkov, N.; Chechik,
H.; Majumdar, S.; Liard, A.; Marek, I. Synthesis 2002,
2473; (b) Marek, I. Chem. Rev. 2000, 100, 2887.
1
yield) of the title compound as a colourless oil. H NMR
(CDCl3, 300 MHz): dH (ppm): 4.80 (1H, d, J = 1.5 Hz),
4.73 (1H, d, J = 1.5 Hz), 4.23 (1H, dd, J = 9.3, 4.8 Hz),
3.92–3.82 (2H, m), 3.62 (1H, tt, J = 10, 3 Hz), 3.18 (1H, td,
J = 9.6, 3 Hz), 3.00–2.66 (4H, m), 2.30–1.60 (9H, m), 1.99
(3H, d, J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz): dC
(ppm): 148.3, 107.3, 83.2, 75.2, 60.9, 44.4, 42.5, 41.5, 41.4,
35.6, 30.8, 30.5, 26.1, 12.7. IR (neat): 3332, 3046, 2935,
2899, 1647, 1423, 1056, 1027. MS (EI) m/z (%): 288 [M+]
(89), 214 (34), 145 (78). Anal. Calcd for C14H24O2S2: C,
58.29; H, 8.39. Found C, 57.54; H, 8.35.
´
10. Preceding article. Perez-Balado, C.; Lucaccioni, F.;
Marko, I. E. Tetrahedron Lett. 2005, 46, doi:10.1016/
´
j.tetlet.2005.05.052.
11. Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Org. Chem. 1984,
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