Intramolecular silicon-assisted cross-coupling: Total synthesis of (+)-brasilenyne

Article abstract of DOI:10.1021/ja028936q

The first, total synthesis of (+)-brasilenyne (1) has been achieved in 19 steps from l-(S)-malic acid. The key elements of this approach are a highly diastereoselective ring-opening of a 1,3-dioxolanone with bis(trimethylsilyl)acetylene) promoted by TiCl<

Full text of DOI:10.1021/ja028936q

Published on Web 11/27/2002
Intramolecular Silicon-Assisted Cross-Coupling: Total Synthesis of
(+)-Brasilenyne
Scott E. Denmark* and Shyh-Ming Yang
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue,
Urbana, Illinois 61801
Received October 14, 2002
Red algae (and marine organisms that feed on red algae) of the
Laurencia species produce a variety C15 acetogenenins containing
halogenated medium-ring ethers.1 Representative examples, such
as (+)-laurencin and (+)-obtusenyne, have stimulated a significant
level of effort for construction of oxocenes and oxonins.2 (+)-
Brasilenyne (1), an antifeedant isolated from sea hare (Aplysia
brasiliana) by Fenical, et al. in 1979,3 has a novel nine-membered
cyclic ether skeleton containing a 1,3-cis,cis-diene unit which
presents a formidable synthetic challenge.4 A recent disclosure from
these laboratories described the sequential ring-closing metathesis/
silicon-assisted intramolecular cross-coupling for the construction
of medium-sized, carbo- and heterocyclic rings bearing a 1,3-cis,cis-
diene unit.5 By applying this reaction as a key strategic element,
we report herein the first, total synthesis of (+)-brasilenyne.
The retrosynthetic plan is outlined in Scheme 1. Simplification
of the enyne side chain and chloride functionality in (+)-1 reduces
the challenge to the intermediate 2, which was projected to arise
from palladium-catalyzed, silicon-assisted intramolecular cross-
coupling of 3. The hydroxy group liberated in the cross-coupling
is perfectly situated for installation of the chlorine. Alkenylsilyl
ether 3 would arise from diastereoselective allylation of aldehyde
4 and application of ring-closing metathesis (RCM) of a vinyl
alkenylsilyl ether derivative. The aldehyde 4 could be elaborated
from 5 in which the propargylic stereogenic center would be set
by the diastereoselective ring opening of a 1,3-dioxolanone, with
bis(trimethylsilyl)acetylene. Thus, the C(2) and C(8) stereocenters
were to be installed by reactions controlled by the C(9) center from
malic acid.
alcohol with TBSCl and pyridine afforded 6 in 85% yield.7 The
stereogenic center at the propargylic position was introduced by
Lewis-acid-mediated ring opening of 6 with bis(trimethylsilyl)-
acetylene. Orienting experiments employed TiCl4 as the Lewis acid
by a procedure similar to the ring opening of acetal templates
developed by Johnson, et al.8a Gratifyingly, ring opening of
dioxolanone 6 proceeded smoothly to afford the desired compound
5 and ring-opened methyl ester of 5 (after quenching with MeOH).
Furthermore, treatment of the crude mixture with a catalytic amount
of p-TsOH in refluxing benzene gave 5 in 86% yield as a single
diastereomer. The results strongly suggested that (1) the mechanism
of ring opening of the dioxolanone proceeds through an oxocar-
benium ion intermediate and (2) the high diastereoselectivity of
the ring-opening process was controlled by the stereogenic center
of the malic acid residue.9,10
Conversion of the trimethylsilyl alkyne to iodide 7 was efficiently
accomplished by treatment of 5 with N-iodosuccinimide with a
catalytic amount of silver nitrate in DMF.11 Furthermore, cis
reduction of 7 with potassium azodicarboxylate gave the geo-
metrically defined Z-alkenyl iodide 8 in 80% yield.12 Elaboration
of 8 into aldehyde 4 began with the transformation of the lactone
unit into a Weinreb amide.13 Further protection of the hydroxy group
with PMBCl afforded 9 in 82% yield.14 Reduction of 9 with
DIBAL-H at low temperature provided aldehyde 4 in 87% yield.
The next critical stage was to introduce the third stereogenic
center of 1. Diastereoselective allylation of 4 by a nonchelation-
controlled addition afforded only a modest level of stereocontrol.15
The successful generation of homoallylic alcohol 10 was ultimately
achieved by employing a chiral allylborane reagent developed by
Brown, et al.16 Treatment of 4 with allylB(lIpc)2 generated in situ
from (+)-B-chlorodiisopinocampheylborane afforded 10 in 72%
yield with 93/7 diastereoselectivity. Furthermore, an improvement
of yield (89%) and selectivity (>97/3) were secured by use of Mg2+
salt-free conditions at -100 °C.16b
Scheme 1
With 10 in hand, the stage was set for implementation of the
key RCM/cross-coupling sequence. Thus, silylation of 10 with
chlorodimethylvinylsilane provided the vinyl silyl ether, which was
subjected to the RCM reaction with Schrock’s molybdenum
complex as the catalyst.17 By using 5.0 mol % of that catalyst, the
ring-closure went to completion efficiently in 92% yield. The crucial
nine-membered ring-forming reaction was carried out with 7.5 mol
% of [allylPdCl]2 as the catalyst and 10 equiv of TBAF as activator
using syringe-pump addition.5 The intramolecular cross-coupling
proceeded smoothly to afford the corresponding nine-membered
ether 2 in 61% yield.
The synthesis of advanced intermediate 2 began by condensation
of commercially available L-(S)-malic acid6 with propanal promoted
by BF3‚Et2O to afford the 1,3-dioxolanone as a 7/3 mixture of cis
and trans isomers (Scheme 2). Selective reduction of the carboxylic
acid using BH3‚THF at 0 °C followed by protection of the primary
Elaboration of the enyne side chain began by the protection of
the hydroxy group with TBSOTf using pyridine and a catalytic
amount of DMAP (88%). Further, deprotection of the PMB group
* To whom correspondence should be addressed. E-mail: denmark@scs.uiuc.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 15196-15197
10.1021/ja028936q CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
Acknowledgment. Funding for this research was provided by
the National Institutes of Health (GM63167-01A1). We are grateful
to Professor William Fenical (UCSD) for generously providing IR,
1H NMR, and 13C NMR spectra of natural (+)-brasilenyne.
Supporting Information Available: Detailed procedures and full
characterization of all compounds along with 1H and 13C NMR and IR
spectra of synthetic (+)-brasilenyne (PDF). X-ray crystallographic files
in CIF format. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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(4) The parent 2,3,4,9-tetrahydrooxonin ring is unknown.
a Conditions: (a) propanal, BF3‚Et2O, Et2O, -30 °C to rt, 2 h, 85%; (b)
BH3‚THF, THF, 0 °C, 3 h, 82%; (c) TBSCl, pyridine, CH2Cl2, rt, 4 h,
85%; (d) (1) bis(trimethylsilyl)acetylene, TiCl4, CH2Cl2, -73 °C, 3 h then
(2) p-TSA (1 mol %), benzene, Dean-Stark, 1 h, 86%; (e) N-iodosuccin-
imide, AgNO3 (10 mol %), DMF, rt, 10 min, 95%; (f) KO2CNdNCO2K,
AcOH, THF/i-PrOH, rt, 6 h, 80%; (g) MeOMeNH‚HCl, AlMe3, CH2Cl2, 0
°C to rt, 1 h, 93%; (h) PMBCl, Ag2O, CH2Cl2, rt, 24 h, 82%; (i) DIBAL-
H, CH2Cl2, -73 °C, 3 h, 87%; (j) allylB(lIpc)2, Et2O, -100 °C, 2 h, 89%;
(k) chlorodimethylvinylsilane, Et3N, CH2Cl2, 0 °C to rt, 30 min, 91%; (l)
Schrock’s catalyst (5 mol %), benzene, rt, 1 h, 92%; (m) [allylPdCl]2 (7.5
mol %), TBAF, rt, 60 h, 61%. (n) TBSOTf, pyridine, DMAP (10 mol %),
CH2Cl2, 0 °C to rt, 2 h, 88%; (o) DDQ, CH2Cl2/H2O (19/1), rt, 30 min,
84%; (p) Dess-Martin periodinane, CH2Cl2, rt, 2 h, 83%; (q) 1,3-
bis(triisopropylsilyl)propyne, n-BuLi, THF, -74 °C to rt, 8 h, 83% (Z/E )
6/1); (r) TBAF, THF, 0 °C, 1.5 h, 93%; (s) CCl4, (n-Oct)3P, toluene, 60-
65 °C, 12 h, 92%.
(5) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 2102.
(6) L-(S)-Malic acid was purchased from Aldrich and was shown to be of
99% ee by CSP-GLC analysis.
(7) All new compounds have been fully characterized, and all yields
correspond to isolated, analytically pure materials. For detailed experi-
mental procedures, see Supporting Information.
(8) To the best of our knowledge, the ring opening of a 1,3-dioxolanone with
bis(trimethylsilyl)acetylene is unprecedented. Ring opening of acetal
templates with silylacetylenic compounds promoted by Lewis acid have
been reported, see: (a) Johnson, W. S.; Elliott, R.; Elliott, J. D. J. Am.
Chem. Soc. 1983, 105, 2904. (b) Yamamoto, Y., Nishii, S.; Yamada, J.-i.
J. Am. Chem. Soc. 1986, 108, 7116. (c) Rychnovsky, S. D.; Dahanukar,
V. H. J. Org. Chem. 1996, 61, 7648.
(9) Mashraqui, S. H.; Kellogg, R. M. J. Org. Chem. 1984, 49, 2513.
(10) The S-configuration at the propargylic position was confirmed by
conversion of 5 to a hexacarbonyldicobalt complex (with Co2(CO)8),
whose full stereostructure was confirmed by single-crystal X-ray diffrac-
tion. The crystallographic coordinates of the cobalt complex have been
deposited with the Cambridge Crystallographic Data Centre; deposition
no. CCDC-195245.
(11) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994, 485.
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C. A.; Webber, S. E.; Serhan, C. N. J. Org. Chem. 1989, 54, 5527. (b)
Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667.
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(14) Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945.
(15) The diastereoselectivity of allylation of 4 with allyltrimethylsilane was
only 74/26 when promoted by BF3‚Et2O, see: (a) Danishefsky, S. J.;
Deninno, M. P.; Phillips, G. B.; Zelle, R. E. Tetrahedron 1986, 42, 2809.
(b) For addition of allyltributylstannes to R-alkoxy aldehydes, see: Keck,
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(17) Schrock’s molybdenum complex is commercially available (Strem) or can
be prepared according to the reported procedure with consistent purity
and reactivity, see: (a) Fox, H. H.; Yap, K. B.; Robbins, J.; Cai, S.;
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with DDQ18 followed by oxidation with Dess-Martin periodinane19
afforded 11 in 61% overall yield from coupling product 2. Peterson-
type olefination20 was employed to introduce the required Z-enyne
side chain. Treatment of 11 with lithiated 1,3-bis(triisopropyl)-
propyne at low temperature followed by slowly warming the
solution to room temperature produced the enyne in 83% yield as
a ca. 6/1 Z/E mixture of geometrical isomers. Subsequently, removal
of the TBS as well as the TIPS groups with TBAF afforded the
hydroxy enyne 12 in 93% yield. Finally, inversion of 8R-hydroxy
group into the 8S-chloride using CCl4/(n-Oct)3P2f completed the
total synthesis of (+)-brasilenyne 1. The spectroscopic and analyti-
cal data from the synthetic sample were identical in all respects
1
(mp, H NMR, 13C NMR, IR, and [R]24D) to those reported for
natural (+)-brasilenyne.
In conclusion, the first total synthesis of (+)-brasilenyne has been
accomplished in 19 steps (5.1% overall) from L-(S)-malic acid. The
synthesis features the sequential RCM/silicon-assisted intramo-
lecular cross-coupling method for construction of a medium-sized
ring ether bearing a 1,3-cis,cis-diene unit. Extension of this strategy
to the synthesis of other medium-sized ring and macrocyclic
compounds is under active study.
(18) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
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