Synthesis of the tetrahydropyran subunit (C8-C20 Fragment) of (-)-Dactylolide and (-)-Zampanolide

Article abstract of DOI:10.1055/s-0029-1219931

The asymmetric synthesis of the tetrahydropyran containing C8-C20 fragment, a common key subunit of both (-)-dactylolide and (-)-zampanolide, is described. The salient feature of this synthesis is the extension of carbon chains using alkynols followed by the use of an alkyne system to generate the desired functionalities, in particular formation of the embedded pyran via an intramolecular oxa-Michael addition of a β-hydroxyynone. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219931

1536
LETTER
Synthesis of the Tetrahydropyran Subunit (C8–C20 Fragment) of
(–)-Dactylolide and (–)-Zampanolide
Tetrahydropyran
h
Subunit of (–
.
)-Dactylolid
R
e
and (–)-Zampa
a
nolide ji Reddy,* B. Srikanth
Organic Division – I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: rajireddy@iict.res.in
Received 6 March 2010
(–)-zampanolide (1) and (–)-dactylolide (2a). Here we re-
port a new synthetic route for the important pyran-con-
taining subunit, the C8–C20 fragment of these natural
products.
Abstract: The asymmetric synthesis of the tetrahydropyran con-
taining C8–C20 fragment, a common key subunit of both (–)-dactyl-
olide and (–)-zampanolide, is described. The salient feature of this
synthesis is the extension of carbon chains using alkynols followed
by the use of an alkyne system to generate the desired functional-
ities, in particular formation of the embedded pyran via an intramo-
lecular oxa-Michael addition of a b-hydroxyynone.
O
1
O
1
O
OH
H
O
O
O
O
Key words: tetrahydropyran, dactylolide, zampanolide, hydroxy-
ynone, alkyne
N
O
19
H
19
8
8
H
H
O
O
15
11
15
11
(–)-Zampanolide (1) and (+)-dactylolide (2b, Figure 1)
are naturally occurring 20-membered macrolactones iso-
lated in 1996 (by Higa et al.)1 and 2001 (by Riccio et al.),2
respectively, from two different marine sponges. Both of
these cytotoxic natural products have a structurally unique
skeleton which consists of a highly unsaturated 20-mem-
bered macrolactone, a 2,6-cis-disubstituted 4-exomethy-
lene tetrahydropyran, and two trisubstituted olefins.
Compound 1 was shown to exhibit significant cytotoxic
activity against a variety of tumor cell lines.3 It was origi-
nally assumed that 1 and 2b display the same absolute ste-
reochemistry; notably, while 1 was found to be highly
potent, 2b only displayed a modest biological activity.
This suggested that the N-acyl hemiaminal side chain of 1
is important for its significant cytotoxic activity. Howev-
er, it was subsequently shown through synthesis of (–)-
dactylolide (2a) that the enantiomeric relationship is not
the same for the natural (–)-zampanolide (1) and (+)-dac-
tylolide (2b). Interestingly, it could be shown that the po-
tency of (–)-dactylolide (2a) in biological assays was on
the order of the potency observed for its enantiomer (+)-
dactylolide (2b) confirming the importance of the N-acyl
hemiaminal side chain for high potency of 1.4 The unusual
structures of both the macrolides coupled with the inter-
esting biological profiles makes these compounds prime
targets for synthetic studies. The first total synthesis of
both these macrolides was achieved by Smith and co-
workers providing the relative and absolute stereochemi-
cal assignment.5 Since then, a number of total syntheses6
and several formal synthesis7 have appeared in the litera-
ture. Our interest in the synthesis of macrolides and tet-
rahydropyran containing natural products8 impelled us to
pursue the synthesis of the potent cytotoxic compounds
11S,15S,19S: (–)-dactylolide (2a)
11R,15R,19R: (+)-dactylolide (2b)
(–)-zampanolide (1)
Figure 1 Structure of zampanolide and dactylolide
Our disconnection approach of both (–)-zampanolide (1)
and (–)-dactylolide (2a) is shown in Scheme 1. As demon-
strated by Hoye,6c 1 can be obtained from 2a by introduc-
tion of N-acyl hemiaminal side chain 3. Further
disconnection of 2a revealed two fragments, an acid frag-
ment 4 and a tetrahydropyran fragment 5. The latter frag-
ment 5 was envisioned to come from a known compound
6 via hydroxyynone cyclization for the tetrahydropyran
ring formation as the key step. The use of alkynols allows
for the straightforward carbon-chain extension, and the
alkyne provides the necessary functionality for the instal-
lation of the tetrahydropyran during the course of the syn-
thesis.
The synthesis began with the known hydroxy Weinreb
amide (6, Scheme 2) which was obtained in four steps
from L-malic acid following a previously reported proto-
col.9 Initially, the four-carbon extension was achieved by
the addition of homopropargyl benzyl ether (7) using eth-
yl magnesium bromide as a base to Weinreb amide 6,
which gave the desired alkynone 8. Next, the hydroxy-
ynone 8 was subjected to the key cyclization by the treat-
ment with AgOTf in dichloromethane at room
temperature to give the pyranone 9 in 99% yield.10 Unfor-
tunately, reduction of the double bond and the deprotec-
tion of the benzyl ether as a one-pot reaction (10% Pd/C
in EtOAc or 10% Pd/C in EtOH) did not provide satisfac-
tory results, 11 was isolated only in less than 20% yield
along with the reduced benzyl ether 10. Therefore, tet-
rahydropyranone 11 was obtained from compound 9 via a
two-step sequence, reduction of double bond to 10 using
SYNLETT 2010, No. 10, pp 1536–1538
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219931; Art ID: G05910ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Tetrahydropyran Subunit of (–)-Dactylolide and (–)-Zampanolide
1537
O
O
O
19
O
HO
H
8
O
OTBS
(–)-zampanolide
(1)
O
4
+
HO
(–)-dactylolide (2a)
O
+
O
OH
O
TBDPSO
OMe
NH2
N
O
6
3
5
Scheme 1 Retrosynthetic analysis
10% Pd/C and Na2CO3 in EtOAc11 followed by removal accomplished using tetrabutylammonium fluoride to give
of the benzyl ether using DDQ in 81% yield. Oxidation of the alcohol 13 in 92% yield. Oxidation of the alcohol 13
alcohol 11 using SO3×py–DMSO (Parikh–Doering oxida- led to an aldehyde, which was extended to the a,b-unsat-
tion) to the corresponding aldehyde and a subsequent urated ester by Wittig olefination with Ph3P=C(Me)COO-
Wittig olefination of both ketone and aldehyde with meth- Et affording 14 in good yield. The next task was chain
yltriphenylphosphonium iodide provided alkene 12. Des- extension at C18 using a three-carbon unit. Reduction of
ilylation of tert-butyldiphenylsilyl ether 12 was ester 14 with DIBAL-H and subsequent treatment with
OBn
OTBDPS
OBn
(7)
OH
O
OH
O
O
AgOTf
ref. 9
TBDPSO
HO
6
OH
4 steps
EtMgBr
CH2Cl2, r.t.,
0.5 h, 99%
THF, 12 h, 60%
OBn
O
8
O
9
(L)-malic acid
OH
OBn
OTBDPS
O
OTBDPS
O
OTBDPS
O
1) SO3⋅Py, DMSO
CH2Cl2, Et3N, 3 h
DDQ
10% Pd/C, H2, Na2CO3
EtOAc, r.t., 2 h, 96%
CH2Cl2–H2O (19:1)
r.t., 12 h, 85%
2) Ph3P+CH3I–, n-BuLi
THF, 0 °C to reflux
70%
O
O
10
11
12
Br
OEt
OH
1) DIBAL-H, CH2Cl2
0 °C, 1 h, 92%
1) SO3⋅Py, DMSO
O
CH2Cl2, Et3N, 3 h
O
TBAF
O
O
2) Ph3PC(Me)COOEt
CH2Cl2, 12 h, 85%
THF, 0 °C, 90%
2) CBr4, Ph3P, CH2Cl2
0 °C to r.t., 0.5 h, 94%
13
14
15
HO
HO
(–)-DIPT, TBHP
Ti(Oi-Pr)4, 4 Å MS
OH
LiAlH4, THF
5
CH2Cl2, –25 °C,
4 h, 85%
0 °C to r.t., 12 h, 91%
K2CO3, NaI,
CuI, Et3N, acetone
0 °C to r.t., 12 h, 70%
O
O
16
17
Scheme 2 Synthesis of C8–C20 fragment
Synlett 2010, No. 10, 1536–1538 © Thieme Stuttgart · New York

1538
C. R. Reddy, B. Srikanth
LETTER
(10) (a) Wang, C.; Forsyth, C. J. Org. Lett. 2006, 8, 2997.
(b) Nicolaou, K. C.; Cole, K. P.; Frederick, M. O.; Aversa,
R. J.; Denton, R. M. Angew. Chem. Int. Ed. 2007, 46, 8875.
(c) Nicolaou, K. C.; Frederick, M. O.; Burtoloso, A. C. B.;
Denton, R. M.; Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.;
Umezawa, T.; Suzuki, T. J. Am. Chem. Soc. 2008, 130, 7466.
(11) Griggs, N. D.; Phillips, A. J. Org. Lett. 2008, 10, 4955.
(12) Yoshinari, T.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.;
Suzuki, K. Angew. Chem. Int. Ed. 2010, 49, 881.
carbontetrabromide and triphenylphosphine provided the
bromide 15 in 86% yield. At this point the three-carbon
unit was introduced to compound 15 through a CuI/
K2CO3/NaI-mediated coupling reaction to give 16 in 70%
yield.12 Reduction of the alkyne functionality to the de-
sired trans-olefin by LiAlH4 afforded the allylic alcohol
17 in 91% yield. Finally, Sharpless asymmetric epoxida-
tion of 17 gave target compound 5 in 85% yield. This frag-
ment is Hoye’s advanced intermediate in his syntheses of
(–)-dactylolide and (–)-zampanolide. Our spectral data
were in accordance with the reported data.6c,13
(13) Spectral Data for Representative Compounds
(S)-8-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)-2-
hydroxyoct-5-yn-4-one (8)
[a]D31 –8.5 (c 1.0, CHCl3). IR (KBr): nmax = 3442, 2929,
2215, 1670, 1426, 1110, 822, 703 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.65–7.59 (m, 4 H), 7.43–7.21 (m, 11 H), 4.53
(s, 2 H), 4.25–4.16 (m, 1 H), 3.60 (t, J = 2.9 Hz, 2 H), 3.60
(td, J = 10.9, 5.1 Hz, 2 H), 2.74–2.71 (m, 2 H), 2.65 (t,
J = 6.5 Hz, 2 H), 2.03 (br s, 1 H), 1.06 (s, 9 H). 13C NMR (75
MHz, CDCl3): d = 186.0, 137.6, 135.4, 132.9, 129.8, 128.4,
127.7, 127.6, 91.6, 81.4, 73.0, 68.0, 67.0, 66.8, 48.7, 26.8,
20.4, 19.1. ESI-HRMS: m/z calcd for C31H36NaO4Si:
523.2306 [M + Na]+; found: 523.2295.
In summary, we have demonstrated a concise synthesis of
a common tetrahydropyran subunit of (–)-dactylolide and
(–)-zampanolide. The tetrahydropyran ring formation was
achieved by cyclization of a hydroxyynone which through
its simplicity represents a highly efficient strategy which
is based on the extension of carbon chains using alkynols
followed by the use of the newly introduced alkyne sys-
tems to generate the desired functionalities.
(2S,6S)-2-[2-(Benzyloxy)ethyl]-6-[(tert-butyldiphenyl-
silyloxy)methyl]dihydro-2H-pyran-4 (3H)-one (10)
[a]D27 –10 (c 1.0, CHCl3). IR (KBr): nmax = 2928, 2858,
1640, 1463, 1426, 1363, 1111, 701 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.64 (td, J = 7.5, 1.3 Hz, 4 H), 7.44–7.17
(m, 11 H), 4.46 (AB, J = 12.2 Hz 1 H), 4.41 (AB, J = 12.2
Hz, 1 H), 3.83–3.49 (m, 6 H), 2.35 (dd, J = 14.1, 4.5 Hz, 3
H), 2.20 (ddd, J = 14.1, 11.5, 4.5 Hz, 1 H), 1.95–1.73 (m, 2
H), 1.02 (s, 9 H). 13C NMR (75 MHz, CDCl3): d = 207.3,
135.6, 135.5, 133.3, 133.2, 129.6, 128.3, 127.6, 127.5, 77.0,
73.9, 73.0, 66.3, 66.0, 47.7, 44.0, 36.4, 26.7, 19.2. ESI-
HRMS: m/z calcd for C31H38NaO4Si: 525.2437 [M + Na]+;
found: 525.2443.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
B.S. thank the CSIR, New Delhi for financial assistance.
References and Notes
(1) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(2) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.;
Debitus, C.; Gomez-Paloma, L.; Riccio, R. Eur. J. Org.
Chem. 2001, 775.
(3) Field, J. J.; Singh, A. J.; Kanakkaanthara, A.; Halafihi, T.;
Northcote, P. T.; Miller, J. H. J. Med. Chem. 2009, 52, 7328.
(4) Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965.
(5) Smith, A. B. III.; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
Soc. 2001, 123, 12426.
(6) (a) Smith, A. B. III.; Safonov, I. G.; Corbett, R. M. J. Am.
Chem. Soc. 2002, 124, 11102. (b) Smith, A. B. III.;
Safonov, I. G. Org. Lett. 2002, 4, 635. (c) Hoye, T. R.; Hu,
M. J. Am. Chem. Soc. 2003, 125, 9576. (d) Ding, F.;
Jennings, M. P. Org. Lett. 2005, 7, 2321. (e) Sanchez, C.
C.; Keck, G. E. Org. Lett. 2005, 7, 3053. (f) Aubele, D. L.;
Wan, S.; Floreancig, P. E. Angew. Chem. Int. Ed. 2005, 44,
3485. (g) Louis, I.; Hungerford, N. L.; Humphries, E. J.;
McLeod, M. D. Org. Lett. 2006, 8, 1117. (h) Uenishi, J.;
Iwamoto, T.; Tanaka, J. Org. Lett. 2009, 11, 3262.
(i) Sharif, E.; O’Doherty, G. A. Chemtracts 2009, 22, 67.
(7) (a) Loh, T.; Yang, J.; Feng, L.; Zhou, Y. Tetrahedron Lett.
2002, 43, 7193. (b) Troast, D. M.; Yuan, J.; Porco, J. A. Jr.
Adv. Synth. Catal. 2008, 1701. (c) Smitha, A. B. III.; Fox,
R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41, 675.
(8) (a) Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2009, 50,
2478. (b) Reddy, C. R.; Dharmapuri, G.; Rao, N. N. Org.
Lett. 2009, 11, 5730. (c) Reddy, C. R.; Rao, N. N.; Srikanth,
B. Eur. J. Org. Chem. 2010, 345.
(E)-6-[(2S,6S)-6-Allyl-4-methylenetetrahydro-2H-
pyran-2-yl]-5-methylhex-5-en-2-yn-1-ol (16)
[a]D28 –15.3 (c 0.5, CHCl3). IR (KBr): nmax = 3458, 2932,
2853, 2325, 1647, 1427, 1219, 1015, 893, 771 cm–1. 1H
NMR (300 MHz, CDCl3): d = 5.91–5.74 (m, 1 H), 5.48 (dq,
J = 7.1, 1.1 Hz, 1 H), 5.12–5.08 (m, 1 H), 5.08–5.01 (m, 1
H), 4.71 (t, J = 1.5 Hz, 2 H), 4.26 (s, 2 H), 4.00 (ddd,
J = 10.9, 7.9, 2.8 Hz, 1 H), 3.41–3.30 (m, 1 H), 2.93 (s, 2 H),
2.45–2.32 (m, 1 H), 2.29–2.12 (m, 3 H), 2.06 (t, J = 12.8 Hz,
1 H), 1.93 (t, J = 12.8 Hz, 1 H), 1.58 (br s, 1 H), 1.75 (s, 3
H). 13C NMR (75 MHz, CDCl3): d = 143.8, 134.0, 133.3,
126.4, 116.5, 108.3, 82.6, 80.4, 76.1, 75.1, 50.9, 40.2, 39.4,
29.2, 28.3, 16.4. ESI-HRMS: m/z calcd for C16H22NaO2:
269.1512 [M + Na]+; found: 269.151.
[(2R,3R)-3-{(E)-3-[(2S,6S)-6-Allyl-4-methylene-
tetrahydro-2H-pyran-2-yl]-2-methylallyl}oxiran-2-yl]-
methanol (5)
[a]D27 –15.5 (c 1.0, CH2Cl2). IR (KBr): nmax = 3425, 3074,
2980, 2937, 2896, 1649, 1433 cm–1. 1H NMR (300 MHz,
CDCl3): d = 5.92–5.70 (m, 1 H), 5.34 (dq, J = 7.7, 1.0 Hz, 1
H), 5.14–5.10 (m, 1 H), 5.09–5.02 (m, 1 H), 4.74 (t, J = 1.5
Hz, 2 H), 4.04 (ddd, J = 10.8, 7.7, 2.6 Hz, 1 H), 3.98–3.88
(m, 1 H), 3.71–3.60 (m, 1 H), 3.43–3.32 (m, 1 H), 3.07 (ddd,
J = 5.6, 5.6, 2.2 Hz, 1 H), 2.97–2.93 (m, 1 H), 2.41 (dd,
J = 14.1, 6.2 Hz, 1 H), 2.33 (dd, J = 14.5, 6.0 Hz, 1 H), 2.28–
2.14 (m, 4 H), 2.05 (t, J = 12.6 Hz, 1 H), 1.93 (t, J = 12.6 Hz,
1 H), 1.76 (d, J = 1.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3):
d = 144.2, 135.0, 134.4, 128.0, 116.9, 108.7, 77.7, 75.4, 61.4,
58.2, 54.5, 41.5, 40.7, 40.6, 39.8, 17.3. ESI-HRMS: m/z
calcd for C16H24NaO3: 287.1618 [M + Na]+; found:
287.1626.
(9) Shioiri, T.; McFarlane, N.; Hamada, Y. Heterocycles 1998,
47, 73.
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