Model studies towards the bistramide D tetrahydropyran

Article abstract of DOI:10.1016/j.tetlet.2008.02.123

The synthesis of a model of the bistramide D tetrahydropyran ring is achieved using a selective cross-metathesis and an intramolecular Michael addition under kinetic control.

Full text of DOI:10.1016/j.tetlet.2008.02.123

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2832–2834
Model studies towards the bistramide D tetrahydropyran
Roderick W. Bates *, Kalpana Palani
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
Received 21 December 2007; revised 4 February 2008; accepted 21 February 2008
Available online 4 March 2008
Abstract
The synthesis of a model of the bistramide D tetrahydropyran ring is achieved using a selective cross-metathesis and an intramolecular
Michael addition under kinetic control.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Tetrahydropyran; Michael addition; Cyclisation; Metathesis
The bistramides are a small family of natural products
isolated from an ascidian, Lissoclinum bistratum.1 The mol-
ecules are made up of three units, a tetrahydropyran
(except in the case of bistramide K), an amino acid and a
spiroketal. The bistramides display a range of biological
properties, and have been shown to bind to actin.2 A num-
ber of syntheses of bistramides A and C have been
reported.3 On the other hand, bistramide D 1, reportedly
less toxic than A or C, has only been synthesised from bis-
tramide A.4 We report here our model studies towards the
synthesis of the tetrahydropyran moiety of bistramide D,
utilising a stereoselective kinetic intramolecular Michael
addition.5
The intramolecular Michael addition is a facile method
to construct a heterocyclic ring and has recently been used
for the synthesis of Diospongin A.6 In these syntheses, an
alcohol undergoes nucleophilic addition to an enone moi-
ety. The product, the cis and therefore bis-equatorial iso-
mer, is clearly the more stable of the two, and it appears
likely that the reaction is under thermodynamic control.
On the other hand, Banwell has shown that the corre-
sponding reaction of an alcohol to an a,b-unsaturated
ester, under carefully controlled conditions, yields the
product of kinetic control, the trans-isomer, as the major
product.7 We report here the use of this strategy in model
studies towards the tetrahydropyran moiety 2 of bistramide
D (Scheme 1). The only difference between our target and
the natural target is the absence of the methyl group at
C9 (model 2a: R = H; natural product 2b: R = CH3).
The first challenge was the construction of the syn-1,3-
diol in an expeditious fashion (Scheme 2). We opted to
employ the iodolactonisation procedure of Bartlett8 and
Cardillo.9 Thus, (S)-(+)-epichlorohydrin was first ring-
opened with lithiobutyne in the presence of boron trifluor-
ide etherate. Alcohol 4 was then converted to a t-butyl car-
bonate under mild conditions, and the alkyne was reduced
to the cis-alkene 5. For reliability, the use of P2-nickel,10
prepared from nickel acetate and sodium borohydride,
was preferred over the use of Lindlar’s catalyst. Treatment
of this carbonate with iodine in acetonitrile yielded the
O
OH
NH OH
O
HN
O
O
OH
1
O
*
Corresponding author. Tel.: +65 63168907; fax: +65 67911961.
E-mail address: roderick@ntu.edu.sg (R. W. Bates).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.123

R. W. Bates, K. Palani / Tetrahedron Letters 49 (2008) 2832–2834
2833
BOMO
OH
R
O
CO2Me
BOMO
R
OMe
3a,b
2a R = H
2b R = CH3
O
Scheme 1.
constants. Elimination of the iodine was achieved by treat-
ment with meta-chloroperbenzoic acid (mCPBA), thus
effecting a rarely employed iodoso elimination.11 The prod-
uct of the elimination was exclusively the trans-alkene. At
this point, the carbonate was opened, leading to pro-
tected12 epoxy alcohol 7 as a single diastereoisomer.
As in our synthesis of Diospongin A, it was intended to
introduce the Michael acceptor by ring opening with a
Grignard reagent, followed by cross-metathesis (Scheme
3). Ring opening proceeded smoothly to give diene 8,
provided that THF was used as the solvent. In ether or
ether-THF mixtures products resulting from attack on
the BOM group by the Lewis acidic magnesium were iso-
lated. Initially, cross-metathesis with methyl acrylate in
the presence of Grubbs’ second generation catalyst at room
temperature resulted in the formation of an inseparable
mixture of compounds. It was determined that these were
the desired methyl ester 3a and the corresponding des-
methyl compound 3c. It was apparent that cross-metathesis
with the acrylate had occured exclusively at the terminal
alkene, but some cross-metathesis of the internal alkene
had occured with the ethylene by-product of the first
cross-metathesis, giving rise to 3c. This illustrates the deli-
cate selectivities that can be achieved.13 The solution to the
problem was found by simply passing a stream of nitrogen
over the reaction mixture to sweep away the ethylene as
generated. With this trivial modification, the desired
Michael precursor 3a could be obtained in both pure and
in good yield (76%). Unsurprisingly, no RCM was
observed.
1. Boc2O, DMAP
2. H2, P2 Ni
Li
BF3.OEt2
98%
OH
Cl
O
Cl
91%
4
O
Ot-Boc
O
O
I2, CH3CN
67%
Cl
Cl
5
6
I
1. mCPBA
2. K2CO3, MeOH
3. BOMCl, i-Pr2NEt
BOMO
O
61%
7
Scheme 2.
BOMO
BOMO
OH
O
BrMg
THF
70%
7
8
Grubbs II
CO2Me
BOMO
OH
CO2Me
R'
3a R' = CH3
3c R' = H
Scheme 3. Synthesis of the cyclisation precursor.
iodocarbonate 6. The syn stereochemistry of the two
oxygen atoms was apparent from analysis of the coupling
BOMO
BOMO
OH
NaH, THF
-78°C
CO2Me 2a
CO2Me
O
87%
2a:2c = 7:3
H
H
b
a
3a
BOMO
2c
CO2Me
O
H
H
b
a
Scheme 4. Intramolecular Michael addition.
Table 1
1H NMR chemical shifts of the THP methyne protons (2a and 2c)
trans-Isomer 2a
Bistramide D1
cis-Isomer 2c
CO H
CO H
Ref. 7
2
Ref. 7
2
O
O
Me
Me
Ha Hb
Ha Hb
Ha
Hb
d 3.84
d 4.19
d 3.88
d 4.25
d 3.87
d 4.22
d 3.37
d 3.72
d 3.44
d 3.75

2834
R. W. Bates, K. Palani / Tetrahedron Letters 49 (2008) 2832–2834
B. D.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J. Chem.
The final critical intramolecular Michael addition was
1998, 51, 9.
carried out under the conditions described by Banwell:
treatment of 3a with sodium hydride in THF at ꢀ78 °C
(Scheme 4).7 It was gratifying to find that the major prod-
uct of the reaction was the trans-isomer 2a, accompanied
by some of the cis-isomer 2c, in a ratio of 7:3 and which
were separable by column chromatography. A remarkable
concordance of NMR data was observed and served to
assign the stereochemistry (Table 1).14
8. Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013.
9. Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Chem. Soc., Chem.
Commun. 1981, 465; Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.;
Sandri, S. J. Org. Chem. 1982, 47, 4626.
10. Brown, H. C.; Brown, C. A. J. Am. Chem. Soc. 1963, 85, 1005.
11. Holmes, C. P.; Bartlett, P. A. J. Org. Chem. 1989, 54, 98; For another
example, see: Knapp, S.; Naughton, A. B. J.; Murai Dahr, T. G.
Tetrahedron Lett. 1992, 33, 1025.
In conclusion, we have shown that the combination of
cross-metathesis and intramolecular Michael addition is a
viable pathway to complex tetrahydropyrans, even to pro-
duce the less stable isomer, and also in the presence of
other alkenes.
12. During BOM protection, some opening of the epoxide to a chloro-
hydrin was noted. This could be converted back to the epoxide by
treatment with powdered NaOH in THF.
13. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
14. Compound 2a: 1H NMR (500 MHz, CDCl3) d 7.37–7.28 (5H, m, Ar),
5.67 (1H, dq, J = 15.3, 6.5 Hz, CH3–CH@CH), 5.27 (1H, ddq,
J = 15.3, 8.5, 1.3 Hz, CH3–CH@CH–CH), 4.81 (1H, d, J = 6.9 Hz,
O–CH2–O), 4.68 (1H, d, J = 11.7 Hz, O–CH2–Ar), 4.68 (1H, d,
J = 7.0 Hz, O–CH2–O), 4.54 (1H, d, J = 11.8 Hz, O–CH2–Ar), 4.22–
4.12 (2H, m, CH2–CHb–CH2, @CH–CH–CH2), 3.84 (1H, m, CH2–
CHa–CH2), 3.66 (3H, s, COOCH3), 2.56 (1H, dd, J = 14.8, 8.2 Hz,
CH–CH2–COOMe), 2.44 (1H, dd, J = 14.8, 5.7 Hz, CH–CH2–
COOMe), 2.14 (1H, ddd, J = 13.8, 8.8, 5.0 Hz, CH–CH2–CH), 1.71
(3H, dd, J = 6.5, 1.3 Hz, CH3–CH@CH), 1.68–1.57 (4H, m), 1.47
(1H, ddd, J = 13.6, 8.8, 4.9 Hz, CH–CH2–CH), 1.39–1.31 (2H, m);
13C NMR (75 MHz, CDCl3) d 171.8, 138.2, 130.7, 130.0, 128.3, 127.9,
127.5, 91.6, 74.5, 69.4, 68.4, 67.6, 51.6, 39.5, 38.4, 30.0, 29.5, 18.4,
Acknowledgements
We thank the Singapore Ministry of Education Aca-
demic Research Fund Tier 2 (Grant T206B1220RS) and
Nanyang Technological University for generous support
of this work.
References and notes
26
17.7; ½aꢁD 42:6 (c 0.6, MeOH) HRMS Found 241.1434 (M+-BOM,
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C13H21O4 requires 241.1434); Compound 2c: 1H NMR (500 MHz,
CDCl3) d 7.35–7.27 (5H, m, Ar), 5.65 (1H, dq, J = 15.3, 6.6 Hz, CH3–
CH@CH), 5.26 (1H, ddq, J = 15.4, 8.6, 1.4 Hz, CH3–CH@CH–CH),
4.79 (1H, d, J = 6.9 Hz, O–CH2–O), 4.66 (1H, d, J = 11.9 Hz, O–
CH2–Ar), 4.65 (1H, d, J = 6.6 Hz, O–CH2–O), 4.50 (1H, d,
J = 11.8 Hz, O–CH2–Ar), 4.23–4.19 (1H, m, @CH–CH–CH2), 3.74–
3.69 (1H, m, CH2–CHb–CH2), 3.69 (3H, s, COOCH3), 3.40–3.34 (1H,
m, CH2–CHa–CH2), 2.53 (1H, dd, J = 14.9, 8.3 Hz, CH–CH2–
COOMe), 2.38 (1H, dd, J = 14.8, 5.2 Hz, CH–CH2–COOMe), 1.88
(1H, ddd, J = 13.6, 8.8, 5.2 Hz, CH–CH2–CH), 1.83–1.80 (1H, m),
1.72 (3H, dd, J = 6.5, 1.5 Hz, CH3–CH@CH), 1.62–1.55 (3H, m), 1.50
(1H, ddd, J = 13.5, 8.9, 4.7 Hz, CH–CH2–CH), 1.27–1.19 (2H, m).
Decoupling experiments revealed that both Ha and Hb of this minor
isomer displayed typical axial–axial coupling constants (10.6 and
11.1 Hz, respectively). 13C NMR (100 MHz, CDCl3) d 172.0, 138.1,
130.7, 130.0, 128.3, 127.9, 127.5, 91.4, 74.6, 74.4, 74.2, 69.3, 51.5, 42.0,
41.6, 31.2 (2C), 23.4, 17.8 HRMS Found 241.1434 (M+-BOM,
´
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J. Chem. Soc., Perkin Trans. 1 1996, 967; Banwell, M. G.; Bissett,
C
13H21O4 requires 241.1434).