A total synthesis of (+)-isolaurepan

Article abstract of DOI:10.1016/j.tetlet.2008.09.134

A versatile and efficient method for the enantioselective synthesis of 2,7-cis-disubstituted oxepane 1c, (+)-isolaurepan, using oxidative resolution of a secondary alcohol and highly diastereoselective Et₃SiH/TMSOTf-promoted reductive cyclizati

Full text of DOI:10.1016/j.tetlet.2008.09.134

Tetrahedron Letters 49 (2008) 7012–7014
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A total synthesis of (+)-isolaurepan
*
Divya Tripathi, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Revised 16 September 2008
Accepted 22 September 2008
Available online 26 September 2008
A versatile and efficient method for the enantioselective synthesis of 2,7-cis-disubstituted oxepane 1c,
(+)-isolaurepan, using oxidative resolution of a secondary alcohol and highly diastereoselective Et3SiH/
TMSOTf-promoted reductive cyclization of a hydroxy ketone is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative resolution of secondary alcohols
Cis-selective cyclization
Cyclic ethers
Oxepanes
Isolaurepan
Seven-, eight- and nine-membered medium ring ethers are
encountered as common structural motifs of many ladder ether
marine toxins and simpler Laurencia acetogenin metabolites.1
However, their synthesis is generally difficult via standard cycliza-
tion methodologies.2 Nevertheless, the challenge in their efficient
construction has led to the development of several strategies for
their synthesis,1,3 mainly in racemic form.
In view of the increasing number of biologically active marine
natural products containing medium and large sized cyclic ether
derivatives,4 much attention has been focussed on efficient
approaches towards these systems. (+)-Isolaurepinnacin 1a and
(+)-neoisoprelaurefucin 1b (Fig. 1) containing a 2,7-disubstituted
oxepane core unit were mainly isolated from the genus Laurencia,
and have been synthetic targets of considerable interest. (+)-Iso-
laurepan 1c is a fully saturated analogue of the core of 1a and other
chiral oxepane derivatives.5
Br
O
H
O
O
H
H
H
H
Br
Cl
Br
(+)-isolaurepinnacin
(1a)
(1b)
(+)-neoisoprelaurefucin
O
H
H
(+)-isolaurepan (1c)
Figure 1. Structures of various 2,7-cis-disubstituted oxepanes.
Kotsuki et al. reported the first total synthesis of (+)-isolaurepan
via cis-selective reduction mediated by triethylsilane/TiCl4.6 A few
more groups have described its formal synthesis by different
approaches.7 Although there have been a number of reports on
the stereoselective construction of racemic cis-2,7-disubstituted
oxepanes, literature describing synthetic strategies for its non race-
mic derivatives is rather scarce. Thus, a general strategy for the
enantioselective synthesis of the functionalized medium ring ether
skeleton present in many Laurencia non-terpenoid metabolites is
highly desirable.
As part of our research on the asymmetric synthesis of bioactive
molecules,8 we became interested in developing a general route to
an intermediate which could be useful in the synthesis of a wide
variety of functionalized non-racemic 2,7-cis-disubstituted cyclic
ether-based molecules. Herein, we report the synthesis of (+)-iso-
laurepan (1c) starting from 1,6-hexanediol using oxidative resolu-
tion of a secondary alcohol and cis-selective reduction with
triethylsilane as the key steps.
The synthesis of (+)-isolaurepan 1c started from commercially
available 1,6-hexanediol 2 as illustrated in Scheme 1. Thus,
selective mono hydroxyl protection of 2 with p-methoxybenzyl
bromide in the presence of NaH gave the monoprotected diol 3
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.134

D. Tripathi, P. Kumar / Tetrahedron Letters 49 (2008) 7012–7014
OH
7013
a
b
OPMB
HO
OH
HO
4
4
OPMB
4
5
2
4
3
OH
O
c
+
OPMB
OPMB
4
5
4
5
(S)-4
5
O
OH
d
OPMB
OPMB
4
4
5
5
5
4
Scheme 1. Reagents and conditions: (a) p-CH3OC6H4CH2Br, NaH, dry DMF, cat. TBAI, 0 °C to rt, 1 h, 85%; (b) (i) (COCl)2, DMSO, Et3N, dry CH2Cl2, ꢀ78 °C, 2 h; (ii) n-C6H13MgBr,
THF, 0 °C to rt, 1 h, 91%; (c) (S,S)-Salen–Mn III(Cl) (0.02 equiv), KBr (0.8 equiv), PhI(OAc)2 (0.7 equiv), H2O/CH2Cl2 2:1, rt, 30 min, 45% for (S)-4 and 43% for 5; (d) NaBH4, MeOH,
4 h, 89%.
As shown in Scheme 2, hydroxyl protection of (S)-4 with tert-
butyldimethylsilyl triflate in the presence of a catalytic amount
H
N
H
N
of DMAP and 2,6-lutidine afforded the silyl ether 6 in 85% yield.
Subsequent p-methoxybenzyl deprotection of the primary alcohol
was carried out with DDQ in DCM/H2O (18:1) to give the required
alcohol 7 in 94% yield. Alcohol 7 was oxidized to the aldehyde with
IBX followed by Grignard reaction with 1-bromopropane and Mg in
THF at 0 °C to give the desired compound 8 in 62% yield. The newly
formed secondary alcohol was oxidized using IBX to give ketone
913 which on treatment with p-TSA in methanol afforded the
required deprotected precursor 10.
Mn
Cl
O
O
Figure 2. (S,S)-Salen–MnIIICl complex.
In order to generate the cis-disubstituted cyclic ether, ketone 10
was treated with Et3SiH and TMSOTf which promoted reductive
cyclization6 to give exclusively the cis disubstituted cyclic 7-mem-
bered ether, isolaurepan 1c,14 in 84% yield. The configuration of the
newly generated centres in 1c can be deduced by 1H-NMR and NOE
experiments.6 The physical and spectroscopic data of 1c were iden-
tical with those reported.6
In conclusion, we have developed a short approach to cis- disub-
stituted oxepanes with high enantiomeric excess using (S,S)-Salen–
MnIII(Cl) as the catalyst. The R and S configurations of the cis ring
can be manipulated simply by changing the catalyst in the resolu-
tion step. The synthetic strategy described here has significant
potential for stereochemical variations and further extension to
eight- and nine-membered rings and analogues. Currently, studies
are in progress in this direction.
in 85% yield. This was then oxidized to the corresponding aldehyde
under Swern conditions9 and subsequently treated with the Grig-
nard reagent derived from 1-bromohexane and Mg in THF at 0 °C
to furnish the racemic alcohol 4 in 91% yield.
With substantial amounts of racemic alcohol 4 in hand, our next
aim was to resolve this alcohol to obtain enantiomerically pure (S)-
4. As illustrated in Scheme 1, the racemic alcohol 4 was subjected
to oxidative resolution10 using (S,S)-Salen–MnIIICl as catalyst
(Fig. 2) to give the required optically active alcohol (S)-411 in 45%
yield and 93% ee12 along with the oxidized compound 5 in 43%
yield which was easily isolated from the polar alcohol (S)-4 using
silica gel chromatography. Ketone 5 was recycled by conversion
into the racemic alcohol 4 in 89% yield by reduction with NaBH4
in MeOH.
OTBS
OTBS
OH
a
b
OPMB
OPMB
OH
4
e
4
4
5
5
5
(S)-4
6
7
OTBS OH
OTBS
O
d
c
5
5
4
4
9
8
O
OH
5
f
4
O
10
1c
Scheme 2. Reagents and conditions: (a) TBS-OTf, 2,6-lutidine, cat. DMAP, dry CH2Cl2, 3 h, 0 °C, 85%; (b) DDQ, CH2Cl2/H2O (18:1), rt, 1 h, 94%; (c) (i) IBX, EtOAc, 80 °C, 90%; (ii)
n-C3H7MgBr, THF, 0 °C to rt, 1 h, 62%; (d) IBX, EtOAc, 80 °C; (e) p-TSA, MeOH, rt, 30 min; (f) Et3SiH, TMSOTf, CH2Cl2, 0 °C, 1 h, 84%.

7014
D. Tripathi, P. Kumar / Tetrahedron Letters 49 (2008) 7012–7014
8. (a) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70, 4207; (b) Kumar, P.; Naidu, S.
Acknowledgements
V.; Gupta, P. J. Org. Chem. 2005, 70, 2843; (c) Kumar, P.; Gupta, P.; Naidu, S. V.
Chem. Eur. J. 2006, 12, 1397; (d) Kumar, P.; Naidu, S. V. J. Org. Chem. 2006, 71,
3935; (e) Gupta, P.; Kumar, P. Eur. J. Org. Chem. 2008, 1195; (f) Pandey, S. K.;
Pandey, M.; Kumar, P. Tetrahedron Lett. 2008, 49, 2397 and references cited
therein.
Divya Tripathi thanks UGC, New Delhi, for the award of Senior
Research Fellowship. Financial support for funding of the project
(Grant No. SR/SI/OC-40/2003) from the Department of Science &
Technology, New Delhi, is gratefully acknowledged. This is NCL
communication No. 6710.
9. For reviews on the Swern oxidation, see: (a) Tidwell, T. T. Synthesis 1990, 857;
(b) Tidwell, T. T. Org. React. 1990, 39, 297.
10. For oxidative resolution of secondary alcohols, see: (a) Sun, W.; Wang, H. W.;
Xia, C. G.; Li, J. W.; Zhao, P. Q. Angew. Chem., Int. Ed. 2003, 42, 1042; (b) Li, Z.;
Tang, Z. H.; Hu, X. X.; Xia, C. G. Chem. Eur. J. 2005, 11, 1210.
11. The spectal data of (S)-4: Pale yellow oil. ½a D25
ꢁ
+2.35 (c 1.7, CHCl3); IR (CHCl3):
m
References and notes
3443, 2932, 2400, 1646, 1463, 1215, 1049, 759 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 0.89 (t, J = 6.7 Hz, 3H), 1.22–1.61 (m, 18H), 3.44 (t, J = 6.4 Hz, 2H), 3.57
(m, 1H) 3.80 (s, 3H), 4.43 (s, 2H), 6.90 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H);
13C NMR (50 MHz, CHCl3): d 14.0, 22.5, 25.4, 25.6, 26.2, 29.3, 29.6, 31.8, 37.4,
55.2, 55.2, 69.9, 71.8, 72.4, 113.6, 127.1, 129.2, 130.6, 158.9. Anal. Calcd for
C20H34O3 (322.48): C, 74.49; H, 10.63. Found: C, 74.26; H, 10.85.
1. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Rep. 2003, 20, 1 and earlier reviews in the same series.
2. Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
3. General reviews: (a) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 85, 2301
and earlier reviews in the same series; (b) Yet, L. Chem. Rev. 2000, 100, 2963; (c)
Hoberg, J. O. Tetrahedron 1998, 54, 12631.
4. (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J., Ed.; Academic: New
York, 1978; Vol. 1, Chapter 2; (b) Erickson, K. K. In Marine Natural Products;
Scheuer, P. J., Ed.; Academic: New York, 1983; Vol. 5, p 131; (c) Faulkner, D. J.
Nat. Prod. Rep. 1984, 1, 251; 1986, 3, 1; 1988, 5, 613.
5. (a) Yuasa, Y.; Sato, W.; Shibuya, S. Synth. Commun. 1997, 27, 573; (b) Mujica, M.
T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. J. Org. Chem. 1998, 63, 9728; (c)
Matsumura, R.; Suzuki, T.; Sato, K.; Inotsume, T.; Hagiwara, H.; Hoshi, T.;
Kamat, V. P.; Ando, M. Tetrahedron Lett. 2000, 41, 7697.
6. Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989, 54, 5153.
7. (a) Carreno, M. C.; Mazery, R. D.; Urbano, A.; Colobert, F.; Solladie, G. Org. Lett.
2004, 6, 297; (b) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2007, 18,
1419; (c) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1
1992, 75, 83.
12. The ee was measured by HPLC using a Chiralcel OD column (isopropyl alcohol/
petroleum ether = 1:99); flow, 1.0 ml/min.
13. The spectral data of 9: Colourless oil. ½a D25
ꢁ
+6.0 (c 0.97, CHCl3); IR (CHCl3)
;
m
= 2932, 2400, 1710, 1215, 1051, 759 cmꢀ1 1H NMR (400 MHz, CDCl3): d
0.03 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9H), 0.92 (t, J = 7.4 Hz, 6H), 1.27–1.30 (m,
10H), 1.39–1.41 (m, 4H), 1.59–1.61 (m, 4H), 2.36–2.39 (m, 4H), 3.60, (m, 1H);
13C NMR (50 MHz, CHCl3): d 0.5, 18.6, 18.9, 22.2, 23.0, 27.5, 28.9, 29.9, 30.1,
30.8, 34.4, 36.8, 41.7, 41.9, 47.7, 49.6, 81.6, 81.8, 82.1, 216.3; Anal. Calcd for
C21H44O2Si (356.66): C, 70.72; H, 12.43. Found: C, 70.58; H, 12.61.
14. The spectral data of 1c: Colourless oil ½a D25
ꢁ
+1.5 (c 0.97, CHCl3); lit.6 a 2D4
½ ꢁ +1.5 (c
0.97, CHCl3); IR (CHCl3)
m = 2950, 2920, 2850, 1465, 1455, 1375, 1340, 1140,
1100; 1H NMR (400 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H), 0.90 (t, J = 7.0 Hz,
3H), 1.26–1.44 (m, 10H), 1.47–1.55 (m, 8H), 1.65–1.73 (m, 4H), 3.37–3.39 (m,
2H); 13C NMR (50 MHz, CHCl3): d 14.0, 19.4, 22.6, 25.3, 26.2, 29.3, 31.8, 36.8,
36.9, 37.4, 39.6, 80.0, 80.3.