Formal total syntheses of (+)-prelaureatin and (+)-laurallene by diastereoselective brook rearrangement-mediated [3 + 4] annulation

Article abstract of DOI:10.1021/jo100708n

Figure presented The formal syntheses of (+)-prelaureatin (1) and (+)-laurallene (2), halogenated eight-membered-ring ethers, are described. The key step of our strategy relies on diastereoselective construction of a trans-α,α′-disubstituted oxocene structure through a Brook rearrangement-mediated [3 + 4] annulation with acryloylsilane 9 and 6-oxa-2-cycloheptenone derivative 22′.

Full text of DOI:10.1021/jo100708n

pubs.acs.org/joc
probably because of the difficulty in establishing a trans-R,
Formal Total Syntheses of (þ)-Prelaureatin
and (þ)-Laurallene by Diastereoselective Brook
Rearrangement-Mediated [3 þ 4] Annulation
R0-disubstituted oxocene structure originating from its kin-
etic and thermodynamic instability compared to the cis-
isomer.7 That is in contrast to extensive studies on the syn-
thesis of another subclass, the lauthisan-type represented by
laurencin (3),8 that involves a cis-R,R0-disubstituted pattern
at the ether oxygen.
Michiko Sasaki, Kazuhisa Oyamada, and Kei Takeda*
Department of Synthetic Organic Chemistry, Graduate
School of Medical Sciences, Hiroshima University, 1-2-3
Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
The first total syntheses of 1 and 2 were reported by
Crimmins and co-workers, who used an asymmetric glyco-
late aldol addition (4 f 5) and ring-closing metathesis (6 f 7)
for construction of the trans-R,R0-disubstitution pattern and
the oxocene core, respectively (Scheme 1).5a
We have recently reported the synthesis of Crimmins’s
intermediate 7, in which diastereoselective Brook rearrange-
ment-mediated [3 þ 4] annulation was used for construction
of the eight-membered ether system.9 Here, we report an-
other formal total synthesis of prelaureatin (1) and laurallene
(2) via advanced Crimmins’s intermediate 8 using a similar
but more efficient strategy.
takedak@hiroshima-u.ac.jp
Received April 14, 2010
Scheme 2 provides an outline of the previously reported
synthesis of 7. Although this synthesis features the stereo-
selective construction of trans-R,R0-substitution by taking
advantage of the stereospecificity of the [3 þ 4] annulation
that we have developed, that presents some drawbacks. The
major one is that 7 is a relatively early intermediate in
Crimmins’s synthesis and that this synthesis requires many
more steps than his approach. One of the causes for the
lengthy pathway in our synthesis is the reduction-oxidation
sequence of the formyl group in 12, which was derived from
[3 þ 4] annulation (9 þ 10 f 11) followed by oxidative
cleavage of the two-carbon tether. These steps were required
to avoid an epimerization at the 2-position in 16, which
would be expected if the enone system was introduced prior
to cleavage of the tether (11 f 12).
The formal syntheses of (þ)-prelaureatin (1) and (þ)-
laurallene (2), halogenated eight-membered-ring ethers,
are described. The key step of our strategy relies on
diastereoselective construction of a trans-R,R0-disubsti-
tuted oxocene structure through a Brook rearrangement-
mediated [3 þ 4] annulation with acryloylsilane 9 and
6-oxa-2-cycloheptenone derivative 220.
In an attempt to overcome this problem, we examined an
alternative synthetic route that would allow more efficient
synthesis of an advanced intermediate 8. The plan is based on
the use of oxacycloheptenone enolate 17 bearing the substitu-
tion pattern required for 8 as a four-carbon unit in the
[3 þ 4] annulation and based on the introduction of the enone
system at an earlier stage in the synthesis (Scheme 3). Toward
the latter end, the enone carbonyl group in 18 (Y=OH) should
be chemo- and stereoselectively reduced and protected prior to
cleavage of the two-carbon tether to convert to 19 (Y=OH).
The formyl group resulting from the cleavage can be used for a
shift of the double bond, after which the group can be removed.
Prelaureatin (1)1 (Figure 1) is a biogenetic precursor2 of
several members of the laurenan structural subclass such as
laurallene (2),3 which is one of two basic structural types of
halogenated eight-membered-ring ethers isolated from red
algae of the genus Laurencia.4 Although much attention has
been focused on the synthesis of 1 and 2 due to their unique
structural features, few syntheses have been reported,5,6
(1) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32,
5597–5598.
(2) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa, A.;
Murai, A. Tetrahedron 1997, 53, 8371–8382.
(3) Fukuzawa, A.; Kurosawa, E Tetrahedron Lett. 1979, 20, 2797–2800.
(4) (a) Irie, T.; Izawa, H.; Kurosawa, E. Tetrahedron 1970, 26, 851–870.
(b) Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 9, 2735–2738.
(c) Irie, T.; Izawa, M.; Kurosawa, E. Tetrahedron Lett. 1968, 9, 2091–2096.
(5) (a) Crimmins, M. T.; Elie, A. T. J. Am. Chem. Soc. 2000, 122, 5473–
5476. (b) Fujiwara, K.; Souma, S.; Mishima, H.; Murai, A. Synlett 2002,
1493–1495.
(6) (a) Ishihara, J.; Shimada, Y.; Kanoh, N.; Takasugi, Y.; Fukuzawa, A.;
Murai, A. Tetrahedron 1997, 53, 8371–8382. (b) Saitoh, T.; Suzuki, T.;
Sugimoto, M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44, 3175–
3178.
(8) (a) Adsool, V. A.; Pansare, S. V. Org. Biomol. Chem. 2008, 6, 2011–
2015. (b) Fujiwara, K. In Topics in Heterocyclic Chemistry; Kiyota, H., Ed.;
Springer: Berlin Germany, 2006; Vol. 5, pp 97-148. (c) Fujiwara, K.; Yoshimoto,
S.; Takizawa, A.; Souma, S.; Mishima, H.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 6819–6822. (d) Baek, S.; Jo, H.; Kim, H.; Kim, H.;
Kim, S.; Kim, D. Org. Lett. 2005, 7, 75–77. (e) Crimmins, M. T.; Choy, A. L.
J. Am. Chem. Soc. 1999, 121, 5653–5660. (f) Kr€uger, J.; Hoffmann, R. W. J. Am.
Chem. Soc. 1997, 119, 7499–7504. (g) Burton, J. W.; Clark, J. S.; Derrer, S.;
Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483–
7498. (h) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem.
Soc. 1995, 117, 5958–5966. (i) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992,
33, 4345–4348.
(7) (a) Fujiwara, K.; Souma, S.; Mishima, H.; Murai, A. Synlett 2002,
1493–1495. (b) Fujiwara, K. J. Synth. Org. Chem. Jpn. 2007, 65, 502–510. (c)
Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007, 129,
2269–2274. (d) Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hoshi, T. Tetra-
hedron Lett. 2007, 48, 1109–1112. (e) Ortega, N.; Martı
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Eur. J. Org. Chem. 2009, 554–563.
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(9) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata, M.; Yamaguchi,
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DOI: 10.1021/jo100708n
r
Published on Web 05/12/2010
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2010 American Chemical Society

Sasaki et al.
JOCNote
FIGURE 2. Structures 20 and 21.
SCHEME 4. Synthesis of 22
FIGURE 1. Structures of prelaureatin (1), laurallene (2), and laur-
encin (3).
SCHEME 1. Crimmins’s Synthesis of Prelaureatin (1) and
Laurallene (2)
both cases mixtures of diol derivatives and the starting
materials were formed (Figure 2).
In light of this result, we set out to slightly modify our
strategy so that two carbonyl groups in 18 can be dist-
inguished. Attempted [3 þ 4] annulation10,11 with 9 and
sodium enolate of 22, prepared from known epoxy alcohol
2312 as shown in Scheme 4,13 followed by hydroxylation by
Davis’ reagent14 in a one-pot operation proved less reward-
ing in terms of yield in this case. We therefore focused on R-
hydroxylation of 18 (Y=H) via oxidation of the correspond-
ing silyl enol ether, which would also enable us to distinguish
the two carbonyl groups in 18 (Y =H).
SCHEME 2. Our Previous Formal Synthesis of 1 and 2
[3þ4] annulation of 9 and sodium enolate 220 proceeded in
a highly diastereoselective manner to afford exclusively 24 in
80% yield (Scheme 5).15 The observed excellent selectivity
could be explained in terms of the approach of the acryloyl-
silane from the same side as the C-7 substituent in 220 that is
sterically less hindered because of pseudoequatorial disposi-
tion of the substituent on the seven-membered ring. Further-
more, ab initio calculations16 of the ground state of 220
suggested that the PMB group efficiently blocks the face
through a chelation involving the methoxy group and the
sodium atom (Figure 3). Treatment of 24 with NBS followed
by TBAF afforded enone 25 in 69% yield, which was
converted to silyl enol ether 26 in 95% yield by exposure to
(10) Sawada, Y.; Sasaki, M.; Takeda, K. Org. Lett. 2004, 6, 2277–2279.
(11) For the construction of eight-membered carbocycles, see: (a) Take-
da, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031–1033. For the original
Brook rearrangement-mediated [3þ4] annulation protocol for seven-mem-
bered carbocycles, see: (b) Takeda, K.; Takeda, M.; Nakajima, A.; Yoshii, E.
J. Am. Chem. Soc. 1995, 117, 6400–6401. (c) Takeda, K.; Nakajima, A.;
Yoshii, E. Synlett 1996, 753–754. (d) Takeda, K.; Nakajima, A.; Takeda, M.;
Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M.
J. Am. Chem. Soc. 1998, 120, 4947–4959. (e) Takeda, K.; Nakajima, A.;
Takeda, M.; Yoshii, E.; Zhang, J.; Boeckman, R. K., Jr. Org. Synth. 1999,
76, 199–213. (f) Takeda, K.; Ohtani, Y. Org. Lett. 1999, 1, 677–679.
(g) Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905.
(h) Nakai, Y., Kawahata, M., Yamaguchi, K., Takeda, K. J. Org. Chem. 2007, 70,
1379-1387.
SCHEME 3. Synthetic Plan for 8
(12) Beckman, R. K., Jr.; Liu, X. Synthesis 2002, 2138–2142.
(13) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett. 2002, 43, 7263–
7266.
(14) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
Chem. 1984, 49, 3241–3243.
(15) The stereostructure of 24 was assigned by spectral comparison with
structurally related compounds9 and confirmed by conversion into 8.
(16) Calculations were performed with the Spartan’06 program. Spar-
tan’06 (Ver. 1.0.1 for Mac); Wavefunction, Inc: Irvine, CA.
To test the feasibility of this approach, we first attempted
selective reduction of model substrates 20 and 21,9 but in
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Sasaki et al.
JOCNote
SCHEME 5. Synthesis of 8
FIGURE 3. Structure of 220 at RI-MP2/6-31þG*.
In summary, we have demonstrated the usefulness of our
Brook rearrangement-mediated [3 þ 4] annulation, which
allows the one-pot construction of highly functionalized
eight-membered oxygen heterocycles.
Experimental Section
(1R,3R,5R,6S)-8-(tert-Butyldimethylsilyloxy)-6-(dimethyl-
(phenyl)silyl)-3-((R)-1-(4-methoxybenzyloxy)propyl)-2-oxabicy-
clo[3.3.2]-dec-7-en-9-one (24). To a cooled (-80 °C) solution of
NaHMDS (1.66 M in THF, 1.37 mL, 2.27 mmol) in THF
(30 mL) was added a solution of 9 (692 mg, 2.27 mmol) in
THF (8 mL) over 8 min and then the solution was stirred at the
same temperature for 15 min. To this solution was added a
solution of 22 (600 mg, 2.27 mmol) in THF (8 mL) over 5 min
and the mixture was allowed to warm to -15 °C over 30 min.
The reaction mixture was poured into 10% aqueous NH4Cl
solution (30 mL) and extracted with Et2O (3 ꢀ 20 mL). Com-
bined organic phases were washed with saturated brine (30 mL),
dried, and concentrated. The residual oil was subjected to
column chromatography (silica gel, 50 g, elution with hexane/
AcOEt = 4:1) to give 24 (982 mg, 80%) as a pale yellow oil: Rf
0.39 (hexane/AcOEt = 5:1), [R]25 107.2 (c 1.00, CHCl3); IR
D
(film) 1707, 1252 cm-1; 1H NMR (C6D6) δ 0.19 and 0.19 (each
3H, s), 0.27 (6H, s), 0.98 (9H, s), 1.03 (3H, t, J = 7.3 Hz),
1.50-1.58 (1H, m), 1.69 (1H, dd, J=12.8, 12.8 Hz), 1.73-1.78
(1H, m), 1.92-1.97 (1H, m), 2.04-2.06 (1H, br m), 2.16-2.18
(1H, br m), 2.25 (1H, dd, J = 19.5, 4.1 Hz), 2.63 (1H, dd, J =
19.5, 3.4 Hz), 3.35 (3H, s), 3.38-3.42 (1H, m), 3.79-3.83 (1H,
m), 4.46 (1H, d, J=11.5 Hz), 4.51 (1H, d, J=11.5 Hz), 5.02 (1H,
s), 5.24 (1H, dd, J = 4.6, 1.4 Hz), 6.85 (2H, d, J = 8.5 Hz),
7.24-7.25 (m), 7.29 (2H, d, J = 8.5 Hz), 7.42-7.44 (m); 13C
NMR (C6D6) δ -4.4, -4.2, -3.8, -3.5, 10.9 18.1 23.2, 25.8,
26.9, 36.3, 36.8, 43.5, 54.7, 72.8, 74.3, 83.0, 89.3, 111.3, 114.0,
128.3, 129.4, 129.6, 131.8, 134.0, 137.5, 147.6, 159.7, 203.0;
HRMS calcd for C34H50O5Si2 594.3197, found 594.3186. This
reaction can be performed on a multigram scale.
NaHMDS and TBSCl. The ketone in 26 could be stereo-
selectively reduced by DIBAL to give 27. Treatment of 27
with mCPBA followed by TBAF produced diol 28, which
was converted to 29 by selective protection.
Oxidative cleavage of the two-carbon tether in 29 was
conducted by Pb(OAc)4 to give 30, whose double bond was
shifted by exposure to DBU to afford 31 in 78% overall yield.
Decarbonylation of 31 by refluxing in toluene with Wilk-
inson’s catalyst was unsuccessful, resulting in decomposition
of the starting material. With Tsuji’s catalyst [IrCl(cod)]2 and
PPh317 under modified conditions, however, 32 was obtained
in 80% yield. Transformation of 32 to Crimmins’s inter-
mediate 8 was accomplished by a three-step sequence invol-
ving removal of the PMB group, bromination of the resulting
alcohol, and DIBAL reduction of ester to alcohol. The
spectral data of 8 were consistent with the literature data.
Since compound 8 has been transformed into prelaureatin
(1) and laurallene (2) by seven and six steps, respectively, by
Crimmins et al., formal total syntheses of them were thus
achieved.18
Acknowledgment. This research was partially supported
by a Grant-in-Aid for Scientific Research (B) 19390006 (KT)
and a Grant-in-Aid for Young Scientists (B) 20790011 (MS)
from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT). We thank the Research Center
for Molecular Medicine, Faculty of Medicine, Hiroshima
University, and N-BARD, Hiroshima University for the use
of their facilities.
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, 6251–6215.
(18) The overall yields of the present, our previous, and Crimmins’s
syntheses from 23 and (R)-1-(benzyloxy)pent-4-en-2-ol to 8 are 7.3% (18
steps), 3.2% (22 steps), and 21.3% (13 steps), respectively.
J. Org. Chem. Vol. 75, No. 11, 2010 3943