Total synthesis and determination of the absolute configuration of (+)-neoisoprelaurefucin

Article abstract of DOI:10.1016/S0040-4039(03)01667-8

The first total synthesis of the seven-membered ring ether marine natural product (+)-neoisoprelaurefucin (1) has been achieved employing a regioselective internal alkylation of amide 3, a novel sequence for removal of the triethylsilyl group from the resulting triethylsilyloxepene 2, and a bromoetherification of alcohol 16 as key steps. In addition, the absolute stereochemistry of the natural product was assigned.

Full text of DOI:10.1016/S0040-4039(03)01667-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6609–6612
Total synthesis and determination of the absolute configuration
of (+)-neoisoprelaurefucin
Hyunjoo Lee,a Hyoungsu Kim,a Seungyoup Baek,a Sanghee Kimb and Deukjoon Kima,*
aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong,
Kwanak-Gu, Seoul 151-742, Republic of Korea
bNatural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yungun, Jongro-Ku, Seoul 110-460,
Republic of Korea
Received 8 May 2003; revised 27 June 2003; accepted 4 July 2003
Abstract—The first total synthesis of the seven-membered ring ether marine natural product (+)-neoisoprelaurefucin (1) has been
achieved employing a regioselective internal alkylation of amide 3, a novel sequence for removal of the triethylsilyl group from
the resulting triethylsilyloxepene 2, and a bromoetherification of alcohol 16 as key steps. In addition, the absolute stereochemistry
of the natural product was assigned.
© 2003 Published by Elsevier Ltd.
(+)-Neoisoprelaurefucin (1), isolated from Laurencia
nipponica by Suzuki et al. in 1996, is a seven-membered
ring ether marine natural product with a unique 2,7-
dioxabicyclo[4.2.1]nonane skeleton.1 The structure of
(+)-neoisoprelaurefucin was proposed on the basis of
an extensive NMR spectroscopic analysis and biosyn-
thetic considerations although its absolute stereochem-
istry was not determined.1 In this paper, we report the
first asymmetric total synthesis of (+)-neoisoprelaure-
fucin (1), which also led to the assignment of its abso-
lute configuration.2 As shown in our retrosynthetic plan
(Scheme 1), we envisaged that the desired triethylsilyl-
oxepene 2 might be secured regioselectively by internal
alkylation of (E)-allylic chloride 3 using a strategically
placed bulky silyl group to inhibit the otherwise
favored SN2% alkylation. Further analysis suggested key
alkylation substrate 3 should in turn be readily accessi-
ble from vinyl iodide 4 and known epoxy alcohol 5.3
from alcohol 7 in three straightforward steps in 70%
overall yield: (1) O-alkylation of alcohol 7 with 2-
bromo-N,N-dimethylacetamide, (2) removal of THP
protecting group of 8 under standard acidic conditions,
and (3) chlorination of the resulting allylic alcohol 9
with CCl4 and Ph3P.6
To our delight, the crucial intramolecular alkylation of
amide 3 could be effected by treatment with KHMDS
in THF at room temperature to furnish a 3:1 mixture of
the desired triethylsilyloxepene 2 and tetrahydrofuran
derivative 2%.7 Furthermore, the regioselectivity could be
increased to a 6:1 by using toluene as solvent (78% total
yield).8
As shown in Scheme 2, protection of alcohol 5 with
PMB-Cl (88%), followed by regioselective opening of
the resulting epoxide 6 with the vinyl lithium generated
from readily available vinyl iodide 44 by treatment with
t-BuLi, furnished homoallylic alcohol 7 in 71% yield.5
The key internal alkylation substrate 3 was prepared
Keywords: internal alkylation; total synthesis; marine natural
product; seven-membered ether ring.
* Corresponding author. Tel.: +82-2-880-7850; fax: +82-2-888-0649;
e-mail: deukjoon@plaza.snu.ac.kr
Scheme 1. Retrosynthetic plan for (+)-neoisoprelaurefucin
(1).
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01667-8

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H. Lee et al. / Tetrahedron Letters 44 (2003) 6609–6612
Scheme 2. Reagents and conditions: (a) PMBCl, NaH, DMF, 0°C, 2 h, 88%; (b) n-BuLi, Et2O, BF3·Et2O, THF, −78°C, 1 h, 71%;
(c) 2-bromo-N,N-dimethylacetamide, NaH, THF, rt, 24 h, 86%; (d) PTSA, MeOH, rt, 30 min, 94%; (e) Ph3P, CCl4, reflux, 20 min,
87%; (f) KHMDS, PhCH3, rt, 30 min, 67%; (g) NBS, CH3CN, rt, 10 min, 96%; (h) n-Bu3SnH, PhH, reflux, 30 min, 93%; (i)
EtMgBr, THF, 0°C, 30 min; (j) L-Selectride®, THF, −78°C, 2 h, 57% (for two steps); (k) t-BuOK, THF, 0°C, 1.5 h, 70%; (l) CBr4,
1-methyl-cyclohexene, n-Oct3P, PhCH3, 70°C, 3 h, 77%; (m) DDQ, CH2Cl2/pH 7.4 buffer (10:1), 0°C, 1 h, 99%; (n) NBS, CH3CN,
rt, 10 min, 99%; (o) H2, Pd/C, EtOH, rt, 2 h, 95%; (p) Dess–Martin periodinane, CH2Cl2, rt, 30 min, 87%; (q) CBr4, Ph3P,
CH2Cl2, rt, 1 h, 99%; (r) Pd(PPh3)4, n-Bu3SnH, PhCH3, rt, 20 min, 59%; (s) Pd(PPh3)4, Et2NH, CuI, trimethylsilylacetylene, rt,
3 h, 78% after three cycles; (t) TBAF, THF, 0°C, 20 min, 97%.
bromoalkene 21 (59%).14 Finally, Sonogashira
We overcame serious difficulties encountered in
coupling15 of (Z)-bromoalkene 21 with ethynyltri-
removal of the triethylsilyl group from triethylsilylox-
methylsilane (78% after three cycles) and removal of the
TMS group of the resulting TMS-enyne 22 with TBAF
produced (+)-neoisoprelaurefucin (97%). The spectro-
scopic data (1H and 13C NMR, IR) and specific rota-
tion of our synthetic (+)-neoisoprelaurefucin were in
good agreement with those reported for the natural
product ([h]2D3 +17.3 (c 0.15. CHCl3); lit.1 ([h]2D3 +17.2 (c
1.30. CHCl3)).
epene 2 by using a novel five-step sequence leading to
key intermediate 14 as follows: (1) bromolactonization9
of g,d-unsaturated amide 2 with NBS (96%), (2)
stereoselective debromination of bromolactone 10 with
n-Bu3SnH (93%),7 (3) addition of EtMgBr to g-lactone
11, (4) stereoselective L-Selectride® reduction of the
resulting mixture of hemiketal 12 and ketone 12% (3:1)
in a Felkin–Ahn sense (57% for two steps),10 and (5)
Peterson-like elimination of syn-silyl alcohol 13 by
treatment with potassium t-butoxide in THF (70%).7
In conclusion, we have accomplished the first asymmet-
ric total synthesis of the seven-membered ring ether
marine natural product (+)-neoisoprelaurefucin (1). The
approach features an efficient internal alkylation to
form the oxepene skeleton with good regio- and stere-
ocontrol, a novel sequence for removal of a silyl group
from a vinylsilane, and a stereoselective bromoetherifi-
cation step. In addition, the absolute stereochemistry of
the natural product was established to be as shown in
Scheme 1.
With key intermediate 14 in hand, we addressed the
remaining task of construction of the 2,7-dioxabicy-
clo[4.2.1]nonane skeleton and (Z)-enyne unit present in
(+)-neoisoprelaurefucin (1). Bromination of alcohol 14
with inversion of configuration by the procedure of
Murai,10a removal of the PMB protecting group of 15
under conditions of Yonemitsu,11 and stereoselective
bromoetherification of the resulting unsaturated alcohol
16 by the action of NBS provided the desired bicyclic
bromo ether 17 in 76% overall yield for the three steps.7
Introduction of the (Z)-enyne moiety of (1) into 17 was
accomplished employing Sonogashira methodology as a
key step. Thus, hydrogenolysis of the benzyl group of
17 followed by Dess–Martin oxidation12 of the resulting
alcohol 18 gave aldehyde 19 (83% for two steps). Con-
version of aldehyde 19 to the corresponding 1,1-dibro-
moalkene 20 (99%) and subsequent stereoselective
Uenishi’s debromination13 produced the requisite (Z)-
Acknowledgements
This work was supported by 2002 BK21 project for
Medicine, Dentistry and Pharmacy and the Ministry of
Health and Welfare (01-PJ2-PG6-01NA01-0002). We
thank Professor Minoru Suzuki (Hokkaido University)
for providing spectra of natural (+)-neoisoprelaurefucin
(1).

H. Lee et al. / Tetrahedron Letters 44 (2003) 6609–6612
6611
References
J=11.2 Hz, 1H), 4.41–4.47 (m, 3H), 4.09 (ddd, J=5.8,
8.2, 9.7 Hz, 1H), 3.80 (s, 3H), 3.67 (dt, J=2.9, 8.5 Hz,
1H), 3.56–3.60 (m, 1H), 3.48–3.52 (m, 1H), 3.21 (s, 3H),
3.00 (s, 3H), 2.29 (dd, J=10.2, 11.9 Hz, 1H), 2.08 (dd,
J=5.7, 12.0 Hz, 1H), 1.76–1.80 (m, 1H), 1.66–1.71 (m,
1H), 0.97 (t, J=7.9 Hz, 9H), 0.67 (q, J=7.9 Hz, 6H);
13C NMR (100 MHz, CDCl3) l 171.5, 158.9, 143.1,
138.5, 131.5, 129.7, 128.3, 127.8, 127.4, 113.5, 111.1,
83.0, 81.6, 79.4, 72.9, 72.7, 66.9, 55.2, 44.9, 37.8, 35.9,
35.4, 31.9, 8.1, 3.4; IR (neat) 2951, 1656, 1513, 1458,
1401, 1247, 1071, 902, 822, 732 cm−1. For lactone 11:
[h]2D5=−31.6 (c 0.30, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.28–2.39 (m, 5H), 7.20 (d, J=8.6 Hz, 2H),
6.86 (d, J=8.7 Hz, 2H), 5.03 (dd, J=2.4, 7.5 Hz, 1H),
4.43–4.54 (m, 4H), 4.33 (d, J=6.8 Hz, 1H), 4.06 (dd,
J=3.9, 10.1 Hz, 1H), 3.81 (s, 3H), 3.72 (td, J=3.5, 9.7
Hz, 1H), 3.55–3.58 (m, 1H), 2.45 (d, J=14.7 Hz, 1H),
2.34 (td, J=7.3, 14.6 Hz, 1H), 1.97–2.04 (m, 2H), 1.77–
1.83 (m, 2H), 1.64 (tdd, J=4.8, 9.5, 14.3 Hz, 1H), 0.99
(t, J=8.0 Hz, 9H), 0.67 (q, J=7.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) l 176.6, 159.2, 138.6, 130.4, 129.6,
128.3, 127.7, 127.4, 113.7, 82.2, 77.2, 75.5, 72.7, 72.6,
71.0, 66.9, 55.3, 30.3, 29.4, 39.2, 24.5, 7.6, 3.4; IR (neat)
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1
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2954, 1772, 1612, 1513, 1456, 1249, 1107, 948, 740 cm−1
.
1
For oxepene 14: [h]D25=−10.4 (c 1.00, CHCl3); H NMR
(500 MHz, CDCl3) l 7.26–7.35 (m, 5H), 7.21 (d, J=8.6
Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.75 (t, J=4.0 Hz,
2H), 4.42–4.52 (m, 4H), 3.79 (s, 3H), 3.61 (td, J=4.5,
7.9 Hz, 1H), 3.50–3.56 (m, 3H), 3.36–3.40 (m, 1H), 3.18
(ddd, J=1.9, 6.8, 10.0 Hz, 1H), 2.9 (s, 1H), 2.18–2.38
(m, 4H), 1.96 (dtd, J=4.3, 6.9, 14.1 Hz, 1H), 1.78 (tdd,
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(100 MHz, CDCl3) l 159.2, 138.4, 130.4, 129.6, 129.2,
128.6, 128.3, 127.7, 127.5, 113.7, 83.5, 80.9, 78.2, 75.3,
72.9, 72.2, 66.7, 55.2, 33.3, 32.3, 30.4, 26.0, 9.8; IR
(neat) 2869, 1612, 1513, 1457, 1248, 1100, 1033, 821, 698
;
cm−1 HRMS (EI) found 440.2536 [M+; calcd for
C27H36O5: 440.2563]. For bicyclic bromo ether 17:
[h]2D5=0.74 (c 0.35, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.29–7.38 (m, 5H), 4.55 (s, 2H), 4.50 (dd,
J=4.6, 8.4 Hz, 1H), 4.36 (dd, J=3.3, 3.8 Hz, 1H), 4.30
(q, J=3.3 Hz, 1H), 4.04–4.10 (m, 2H), 3.94 (dd, J=3.4,
9.1 Hz, 1H), 3.60–3.68 (m, 2H), 2.78 (d, J=15.1 Hz,
1H), 2.41 (ddd, J=3.6, 9.2, 16.1 Hz, 1H), 2.11–2.19 (m,
3H), 2.03–2.07 (m, 1H), 1.82–1.91 (m, 2H), 1.11 (t, J=
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) l 138.5,
128.3, 127.6, 127.5, 83.9, 80.1, 75.7, 72.8, 71.9, 67.3,
62.5, 51.2, 36.2, 30.4, 29.3, 28.5, 12.5; IR (neat) 2929,
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−32.5 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) l
7.28–7.37 (m, 5H), 7.21 (d, J=8.5 Hz, 2H), 6.86 (d,
J=8.5 Hz, 2H), 6.23 (td, J=3.0, 8.2 Hz, 1H), 4.56 (d,
J=11.1 Hz, 2H), 4.50 (d, J=11.9 Hz, 1H), 4.44 (d,
J=11.9 Hz, 1H), 4.40 (d, J=11.1 Hz, 1H), 4.02 (d,
J=10.3 Hz, 1H), 3.81 (s, 3H), 3.64–3.67 (m, 1H), 3.60
(dd, J=5.0, 7.1 Hz, 2H), 3.40 (dd, J=4.6, 9.6 Hz, 1H),
3.02 (s, 3H), 2.93 (s, 3H), 2.79 (ddd, J=2.1, 10.6, 14.7
Hz, 1H), 2.52 (dd, J=8.6, 16.0 Hz, 1H), 2.44 (d, J=
15.5 Hz, 1H), 2.34 (dd, J=9.8, 15.4 Hz, 1H), 2.03 (dtd,
J=2.6, 7.5, 15.0 Hz, 1H), 1.71 (tdd, J=4.9, 9.9, 14.0
Hz, 1H), 0.94 (t, J=7.9 Hz, 9H), 0.60 (q, J=7.9 Hz,
6H); 13C NMR (100 MHz, CDCl3) l 170.2, 159.1, 141.7,
139.8, 138.5, 130.4, 129.5, 128.2, 127.5, 127.4, 113.6,
79.8, 78.2, 72.6, 72.3, 67.0, 55.1, 37.0, 35.8, 34.8, 32.8,
30.0, 7.4, 2.3; IR (neat) 2951, 1656, 1613, 1513, 1458,
1215, 1250, 1105, 823, 731 cm−1; HRMS (EI) found
567.3387 [M+; calcd for C33H49NO5Si: 567.3380]. For
tetrahydrofuran derivative 2%: [h]2D5=−79.9 (c 1.00,
CHCl3); 1H NMR (500 MHz, CDCl3) l 7.28–7.37 (m,
5H), 7.24 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),
5.79 (dd, J=10.8, 17.4 Hz, 1H), 5.04 (d, J=10.8 Hz,
2H), 5.00 (d, J=17.4 Hz, 1H), 4.93 (s, 1H), 4.70 (d,
2867, 1453, 1365, 1194, 1095, 836, 739, 698, 636 cm−1
;
HRMS (EI) found 382.1137 [(M++H)−Br; calcd for
C19H27O379Br: 382.1144 or M+−HBr; calcd for
C19H25O381Br: 382.1144].
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