Synthesis of the methylene bis-tetrahydropyran motif of (-)-exiguolide

Article abstract of DOI:10.1016/j.tetlet.2010.09.005

A chiral-pool approach for the construction of methylene bis-tetrahydropyran subunit, C₁-C₁₆ fragment, of (-)-exiguolide is described. The synthesis was efficiently accomplished starting from l-glutamic acid and l-aspartic acid invol

Full text of DOI:10.1016/j.tetlet.2010.09.005

Tetrahedron Letters 51 (2010) 5840–5842
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Tetrahedron Letters
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Synthesis of the methylene bis-tetrahydropyran motif of (ꢀ)-exiguolide
⇑
Ch. Raji Reddy , N. Narsimha Rao
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiral-pool approach for the construction of methylene bis-tetrahydropyran subunit, C1–C16 fragment,
Received 10 August 2010
Revised 31 August 2010
Accepted 2 September 2010
Available online 8 September 2010
of (ꢀ)-exiguolide is described. The synthesis was efficiently accomplished starting from
and -aspartic acid involving oxa-Michael reaction and an aldol-driven-reductive etherification as key
steps for the formation of tetrahydropyran ring.
L-glutamic acid
L
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyran
Amino acid
oxa-Michael reaction
Aldol reaction
Reductive etherification
Exiguolide
(ꢀ)-Exiguolide (1) is a 20-membered macrolide isolated from
the methanol extract of the marine sponge Geodia exigua Thiele
(order Astrophorida, Family Geodiidae) by Ohta and co-workers.1
The macrolide 1 prevents the fertilization of the sea urchin (Hemi-
centrotus pulcherrimus) gametes. Structurally, exiguolide consists
of a methylene bis-tetrahydropyran (THP) subunit, five C–C double
bonds, and seven asymmetric carbons. Further, one of the THP
rings contains methoxycarbonyl methylidene group, a less com-
monly found structural feature.2 The biological activity and com-
plex structure of 1 are features that make it a fascinating target.
In 2008, Lee and co-workers have reported the total synthesis of
(+)-exiguolide, enantiomer of 1, and unambiguously determined
the absolute stereochemistry.3 Recently, the total syntheses of
(ꢀ)-exiguolide (1) were reported by Roulland and Fuwa research
groups, independently.4 In continuation of our interest in synthesis
of macrolides and THP-containing molecules,5 herein, we report
the synthesis of methylene bis-tetrahydropyran subunit (C1–C16
fragment) of (ꢀ)-exiguolide. Our retrosynthetic analysis of 1 sim-
plified the structure into two major subunits by the disconnection
of lactone bond and C16–C17 bond. The lactone can be formed using
Yamaguchi conditions and C16–C17 double bond can be achieved
either by ring-closing metathesis or by Julia olefination. In this Let-
ter, we describe the synthesis of bis-THP subunit 2, which was
envisioned from the THP–ketone 3 and aldehyde 4 via an aldol-dri-
ven-reductive etherification. Further, ketone 3 can be derived from
The synthesis of THP-ketone 3 (Scheme 2) was began with the
known protected (4S)-hydroxymethyl-4-butanolide 5, obtained
from L
-glutamic acid.6 In the first step, stereoselective methylation
of 5 was carried out with the use of LDA/MeI at ꢀ78 °C to afford 6
in 78% yield that established the C-15 methyl stereo center.7 The
reduction of lactone 6 using LiBH4 provided the 1,4-diol 7 in 99%
yield, which was protected as a seven-membered acetonide 8
under 2,2-DMP/CSA reaction conditions (90% yield). Then, tert-
butyldiphenylsilyl group of 8 was deprotected to alcohol 9 using
TBAF (91% yield) and subsequent tosylation of 9 (TsCl/Py) provided
the tosylate 10 in 96% yield. The next step involved the four-carbon
chain extension by employing Schlosser copper-catalyzed Grignard
coupling reaction8 on tosylate 10. In the presence of dilithium tet-
rachloro cuprate, compound 10 was readily reacted with 3-butenyl
magnesium bromide to give 11 in 88% yield. The compound 11 was
further used for the pyran ring formation. Hence, olefin 11 was
subjected to ozonolysis followed by a Wittig olefination (PPh3@
CHCOMe) to provide enone 12 in 84% yield (over two steps).
Hydrolysis of acetonide 12 and consequent oxa-Michael addition
were accomplished through a p-TSA-catalyzed one-pot reaction
to afford pyran 13 in 89% yield.9 The relative syn-relationship of
2,6-disubstituted tetrahydropyran 13 was confirmed by NOE effect
between H-9 and H-13 (2D NOESY). The protection of free-hydro-
xyl group of 13 as TBS ether (TBSCl/imidazole, 95% yield) provided
the THP–ketone fragment 3.
L-glutamic acid using oxa-Michael reaction and aldehyde 4 can be
In the approach to aldehyde 4 (Scheme 3), epoxide 14 was
obtained from
L
-aspartic acid (Scheme 1).
prepared in three steps from commercially available L-aspartic acid
using literature methods.10 Ring opening of epoxide 14 with vinyl
magnesium bromide afforded the homoallylic alcohol 15 in 89%
yield.11 Protection of the alcohol 15 as TBS ether 16 with TBSCl/
⇑
Corresponding author. Tel.: +91 40 27191885; fax: +91 40 27160512.
E-mail address: rajireddy@iict.res.in (C.R. Reddy).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.005

C. R. Reddy, N. N. Rao / Tetrahedron Letters 51 (2010) 5840–5842
5841
31
O
32
19
OTBS
HO
L-Glutamic aci
d
16
OPMB
O
O
1
30
O
O
MeO2C
27
3
13
3
O
O
O
9
OTBS
29
MeO2C
O
L-Aspartic acid
7
PMBO
O
28
4
1
2
Scheme 1. Retrosynthetic analysis of (ꢀ)-exiguolide.
O
O
a
OH
c
ref . 6
b
f
O
O
L-Glutamic acid
TBDPSO
OH
TBDPSO
TBDPSO
5
7
6
O
O
O
O
e
d
g
O
O
O
O
11
TBDPSO
HO
h
TsO
8
9
10
nOe
H
H
O
O
i
OH
O
O
13
3
9
O
12
13
Scheme 2. Reagents and conditions: (a) LDA, MeI, THF, ꢀ78 °C, 1 h, 78%; (b) LiBH4, THF, MeOH, 0 °C, 1 h, 99%; (c) 2,2-DMP, CSA (cat.), CH2Cl2, 0 °C to rt, 30 min, 90%; (d) TBAF
(1 M in THF), THF, 0 °C to rt, 1 h, 91%; (e) TsCl, Py, 0 °C, 12 h, 96%; (f) n-C4H7MgBr, Li2CuCl4, THF, ꢀ30 °C to rt, 12 h, 88%; (g) (i) O3, CH2Cl2, NaHCO3, ꢀ78 °C, 30 min, (ii)
Ph3P@CHCOMe, THF, reflux, 10 h, 84% (over two steps); (h) p-TsOHꢁH2O, CH2Cl2, 0 °C to rt, 3 h, 89%; (i) TBDMSCl, DMF, 0 °C to rt, 1 h, 95%.
was successfully employed in our previous Letter.5e Thus, treatment
ref. 10
a
O
L-Aspartic acid
of aldehyde 4 with the lithiated enolate, derived from 3 using LDA,
produced an aldol product as a inseparable mixture of diastereo-
mers. This mixture was treated with Dess–Martin periodinane to
give b-diketone 17 (71% yield over two steps), which entirely existed
as the enol form (confirmed by 1H NMR). The exposure 17 to HF (40%
aq solution) in CH3CN led to the formation of cyclodehydrated prod-
uct 18 in 86% yield.13 Finally, hydrogenation of 18 was proceeded
(91% yield) with the exclusive formation of a tetrahydropyranone
ring14,5e that completed the synthesis of 2.15 Compound 2 was fully
characterized by IR, 1H, 13C NMR, MS, and the syn-relationship of
both the THP rings was confirmed by 2D NOESY experiments.16
In summary, we have successfully demonstrated the synthesis
of methylene bis-THP motif of (ꢀ)-exiguolide using a chiral-pool-
based approach. The strategy used is efficient and scalable from
commercially available natural amino acids. The present route
exhibits the applicability of oxa-Michael reaction and an aldol-dri-
ven-reductive etherification in the synthesis of THP-containing tar-
gets. Ongoing efforts toward the completion of (ꢀ)-exiguolide are
currently underway and will be reported in due course.
PMBO
b
14
OH
OTBS
c
4
PMBO
PMBO
15
16
Scheme 3. Reagents and conditions: (a) vinyl magnesium bromide, CuI, THF, 0 °C,
2 h, 89%; (b) TBDMSCl, imidazole, CH2Cl2, 0 °C to rt, 24 h, 95%; (c) (i) OsO4, NMO,
acetone–H2O (3:1), rt, 4 h, (ii) NaIO4, NaHCO3, THF–H2O (4:1), 0 °C, 1 h, 84%.
a
PMBO
OPMB
O
OTBS
3
4
O
O
TBSO
HO
17
c
b
2
O
O
Acknowledgment
O
N.N.R. thanks CSIR-New Delhi for the award of research
fellowship.
18
Scheme 4. Reagents and conditions: (a) (i) LDA, THF, ꢀ78 °C, 1 h; (ii) Dess–Martin
periodinane, NaHCO3, CH2Cl2, rt, 30 min (71% over two steps); (b) HF (40% aq),
CH3CN, 0 °C to rt, 4 h, 86%; (c) H2, 10% Pd/C, Na2CO3, EtOAC, rt, 10 h, 91%.
References and notes
1. Ohta, S.; Uy, M. M.; Yanai, M.; Ohta, E.; Hirata, T.; Ikegami, S. Tetrahedron Lett.
2006, 47, 1957–1960.
2. (a) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold, E.; Clardy, J. J.
Am. Chem. Soc. 1982, 104, 6846–6848; (b) Cossy, J. C. R. Chimie 2008, 11, 1477–
1482.
3. Kwon, M. S.; Woo, S. K.; Na, S. W.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 1733–
imidazole (95% yield) followed by oxidative cleavage of terminal
olefin afforded the aldehyde 4 in 84% yield.12
Havingboth the fragments3 and 4 in hand, we next proceeded for
the synthesis of methylene bis-tetrahydropyran subunit 2, using an
aldol-driven-reductive etherification strategy (Scheme 4), which
1735.

5842
C. R. Reddy, N. N. Rao / Tetrahedron Letters 51 (2010) 5840–5842
4. (a) Fuwa, H.; Sasaki, M. Org. Lett. 2010, 12, 584–587; (b) Cook, C.; Guinchard, X.;
Liron, F.; Roulland, E. Org. Lett. 2010, 12, 744–747.
3.44–3.30 (m, 3H), 2.64 (dd, J = 15.1, 7.8 Hz, 1H), 2.35 (dd, J = 15.1, 4.8 Hz, 1H),
2.15 (s, 3H), 1.88–1.65 (m, 2H), 1.64–1.49 (m, 2H), 1.47–1.37 (m, 1H), 1.33–
1.06 (m, 4H), 0.9 (m, 12H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3): d 207.7, 76.4,
74.3, 67.7, 50.3, 39.8, 32.3, 31.9, 31.5, 31.4, 31.0, 25.9, 23.5, 17.5; HRMS: calcd
for C18H36O3SiNa (M+Na)+ 351.2326; found 351.2325.
5. (a) Reddy, Ch. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478–2480; (b) Reddy,
Ch. R.; Dharmapuri, G.; Rao, N. N. Org. Lett. 2009, 11, 5730–5733; (c) Reddy, Ch.
R.; Srikanth, B. Synlett 2010, 1536–1538; (d) Reddy, Ch. R.; Madhavi, P. P.;
Chandrashekar, S. Tetrahedron: Asymmetry 2010, 21, 103–105; (e) Reddy, Ch. R.;
Rao, N. N.; Srikanth, B. Eur. J. Org. Chem. 2010, 345–351.
6. Shiro, Y.; Kato, K.; Fujii, M.; Ida, Y.; Akita, H. Tetrahedron 2006, 62, 8687–8695.
7. Hanessian, S.; Roy, R. J.; Petrini, M.; Hodges, P. J.; Di Fabio, R.; Carganico, G. J. J.
Org. Chem. 1990, 55, 5766–5777.
8. Fouquet, C.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 82–83.
9. Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121–6123.
10. Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.; Rapoport, H. Synthesis 1992,
7, 621–623.
11. Mohapatra, D. K.; Das, P. P.; Reddy, D. S.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
5941–5944.
(R)-6-(tert-Butyldimethylsilyloxy)-1-((2S,6S)-6-((R)-3-(tert-butyldimethylsilyloxy)-2
-methylpropyl)tetrahydro-2H-pyran-2-yl)-8-(4-methoxybenzyloxy)octane-2,4-dione
(17): Rf = 0.40 (10% EtOAc in Hexanes); IR (KBr): vmax 2928, 2855, 1729, 1612,
1513, 1462, 1248, 1089, 834, 774 cmꢀ1; Optical Rotation: ½a 2D8
ꢀ7.7 (c = 1.05,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.20 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz,
2H), 5.55 (s, 1H), 4.41 (AB, J = 11.3 Hz, 1H, B of AB), 4.35 (AB, J = 11.3 Hz, 1H, A
of AB), 4.30–4.20 (m, 1H), 3.80 (s, 3H), 3.72–3.62 (m, 1H), 3.47 (t, J = 6.8 Hz,
2H), 3.39 (d, J = 6.0 Hz, 2H), 3.38–3.29 (m, 1H), 2.48 (dd, J = 14.3, 6.7 Hz, 1H),
2.38 (d, J = 6.8 Hz, 2H), 2.28 (dd, J = 14.3, 6.0 Hz, 1H), 1.88–1.67 (m, 4H), 1.64–
1.36 (m, 4H), 1.30–1.06 (m, 3H), 0.9 (s, 9H), 0.85 (m, 12H), 0.04 (s, 3H), 0.02 (s,
6H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3): d 192.6, 190.6, 159.1, 130.4, 129.2,
113.7, 102.1, 76.6, 74.6, 72.6, 67.8, 67.2, 66.2, 55.2, 46.5, 45.7, 39.7, 37.4, 32.4,
31.5, 31.4, 25.9, 25.8, 23.5, 17.4, ꢀ4.7, ꢀ5.3; HRMS: calcd for C37H66O7Si2Na
(M+Na)+ 701.4239; found 701.4234.
12. Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2002,
124, 3245–3253.
13. (a) Newton, R. F.; Reynolds, D. P. Tetrahedron Lett. 1979, 20, 3981–3982; (b) Le,
D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.;
Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185–1204.
(2S,6R)-2-(((2S,6S)-6-((R)-3-Hydroxy-2-methylpropyl) tetrahydro-2H-pyran-2-
yl)methyl)-6-(2-(4-methoxy-benzyloxy)ethyl)dihydro-2H-pyran-4(3H)-one (2):
Rf = 0.40 (50% EtOAc in Hexanes); IR (KBr): vmax 3433, 2931, 2859, 1716,
14. Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066–2067.
15. Spectroscopic data for representative compounds: (E)-7-((4R,6R)-2,2,6-Trimethyl-
1,3-dioxepan-4-yl)hept-3-en-2-one (12): Rf = 0.50 (20% EtOAc in Hexanes);
1606, 1512, 1253, 1088, 1033, 751 cmꢀ1; Optical Rotation: ½a 2D8
ꢂ
+ 8.9 (c = 1.3,
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.18 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz,
2H), 4.39 (s, 2H), 3.80 (s, 3H), 3.78–3.68 (m, 2H), 3.57–3.37 (m, 6H), 2.36 (t,
J = 13.1 Hz, 2H), 2.21 (td, J = 13.1, 5.4 Hz, 2H), 1.99–1.72 (m, 5H), 1.60–1.35 (m,
5H), 1.31–1.16 (m, 3H), 0.90 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
207.8, 159.3, 130.4, 129.3, 113.9, 75.7, 74.5, 74.3, 74.0, 72.9, 67.7, 66.0, 55.4,
48.0, 47.7, 42.4, 40.5, 36.5, 32.3, 31.5, 31.2, 29.8, 23.7, 17.6; HRMS: calcd for
Optical Rotation: ½a D26
ꢂ
+2.6 (c = 1.05, CHCl3); IR (KBr): vmax 2931, 2864, 1712,
1673, 1358, 1218, 1072, 1039 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 6.74 (dt,
J = 15.8, 6.8 Hz, 1H), 6.03 (dt, J = 15.8, 1.4 Hz, 1H), 3.85 (dd, J = 12.0, 1.5 Hz, 1H),
3.82–3.72 (m, 1H), 3.31 (dt, J = 12.0, 2.3 Hz, 1H), 2.28–2.17 (m, 2H), 2.22 (s, 3H),
1.83–1.70 (m, 1H), 1.71–1.32 (m, 6H), 1.30 (s, 3H), 1.27 (s, 3H), 1.02 (d,
J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 198.6, 148.2, 131.3, 100.3, 67.6,
65.7, 41.7, 36.2, 32.4, 31.1, 26.8, 25.1, 25.0, 24.9, 17.1; HRMS: calcd for
C
25H38O6Na (M+Na)+ 457.2561; found 457.2571.
16. The NOE effect between H3–H7 and H9–H13 confirmed the cis-relationship in
both the 2,6-disubstituted THP rings.
C
15H26O3Na (M+Na)+ 277.1774; found 277.1776.
1-((2S,6R)-6-((R)-3-Hydroxy-2-methylpropyl)tetrahydro-2H-pyran-2-yl)propan-
2-one (13): Rf = 0.40 (40% EtOAc in Hexanes); Optical Rotation: ½a D28
ꢂ
ꢀ3.3
(c = 0.90, CHCl3); IR (KBr): vmax 3433, 2927, 1709, 1361, 1195, 1037 cmꢀ1
;
1H
nOe
PMBO
H
NMR (300 MHz, CDCl3): d 3.85–3.74 (m, 1H), 3.57–3.48 (m, 1H), 3.46 (dd,
J = 10.5, 5.3 Hz, 1H), 3.34 (dd, J = 10.5, 6.8 Hz, 1H), 2.67 (dd, J = 15.8, 7.5 Hz, 1H),
2.39 (dd, J = 15.8, 5.3 Hz, 1H), 2.15 (s, 3H), 1.93–1.78 (m, 2H), 1.65–1.37 (m,
5H), 1.31–1.12 (m, 3H), 0.9 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
207.3, 75.5, 73.9, 67.6, 49.8, 40.1, 32.0, 31.1, 31.0, 30.9, 23.3, 17.2; HRMS: calcd
for C12H22O3Na (M+Na)+ 237.1461; found 237.1463.
9
O
H
3
H
7
O
13
H
nOe
1-((2S,6R)-6-((R)-3-(tert-Butyldimethylsilyloxy)-2-methylpropyl)tetrahydro-2H-
pyran-2-yl)propan-2-one (3): Rf = 0.50 (20% EtOAc in Hexanes); Optical
OH
Rotation: ½a 2D7
ꢂ
ꢀ3.2 (c = 1.20, CHCl3); IR (KBr): vmax 2930, 2856, 1717, 1360,
1H NMR (300 MHz, CDCl3): d 3.77–3.65 (m, 1H),
O
1252, 1086, 839, 775 cmꢀ1
;