Angewandte
Chemie
envisaged that the CM of 7 would be more facile than the
competitive RCM, because the latter process has to proceed
through energetically demanding pathway(s). Thus, forma-
tion of a ruthenacyclobutane B by breaking the hydrogen
bonding in A or a conformationally strained ruthenacyclo-
butane C would be necessary for the RCM of 7 to give 13b. In
the event, we were delighted to find that treatment of 7 with
G-II (5 mol%) in methyl acrylate/CH2Cl2 (1:1) at room
temperature afforded (E)-enoate 13a in a gratifying 77%
yield, and the cyclohexene-derivative RCM product 13b was
isolated in only 7% yield (entry 3). Moreover, we could lower
the amount of methyl acrylate used in the reaction without
affecting the product selectivity (entry 4). Therefore, the
intramolecular hydrogen bonding formed within ruthenium
alkylidene A plays a key role in determining the reaction
pathway. Consequently, we were able to reproducibly prepare
13a in good yield.
Completion of the total synthesis of 1 is illustrated in
Scheme 4. Protection of 13a as its BOM ether and subsequent
desilylation provided alcohol 6. The intramolecular oxa-
conjugate addition of 6 was best accomplished by treatment
with DBU in toluene at 1008C which afforded the thermo-
dynamically favored 14 in 73% yield (14/3-epi-14 = > 20:1).
At this stage, the minor C5 diastereoisomer could be
separated by flash chromatography on silica gel.[15] Hydrolysis
of 14 using TMSOK[16] provided acid 4 quantitatively.
Esterification of 4 with alcohol 5[17] under Yamaguchi
conditions[18] delivered ester 3 in 94% yield.
As expected, the construction of the 14-membered macro-
cycle 2 by the RCM of 3 was a significant challenge. After
extensive investigations, we eventually found that treatment
of 3 with G-II (30 mol%) in the presence of 1,4-benzoquino-
ne[7c,19] in toluene at 1008C afforded the 14-membered
macrocycle 15 in 85% yield. As a result of the high reaction
temperature, slow addition of the G-II complex was impor-
tant to achieve a satisfactory conversion.[20] Gratifyingly, 15
was isolated solely as the desired Z isomer, whose hydro-
genation was anticipated to occur from the less hindered
Re face of the molecule to give neopeltolide macrolactone 2
with the desired configuration at C9. This outcome was
suggested by molecular modeling and by a recent related
report by Tu and Floreancig.[4c,21] In the event, the stereose-
Scheme 4. Completion of the total synthesis of 1. a) BOMCl, iPr2NEt,
nBu4NI, 1,2-dichloroethane, 508C; b) TBAF, AcOH, THF, 358C, 90%
(over 2 steps); c) DBU, toluene, 1008C, 73% (d.r. >20:1); d) TMSOK,
Et2O, RT, 100%; e) 2,4,6-Cl3C6H2COCl, Et3N, THF, RT; then 5, DMAP,
toluene, RT, 94%; f) G-II (30 mol%), 1,4-benzoquinone, toluene,
1008C, 85%; g) H2 (0.8 MPa), Pd/C, Pd(OH)2/C, EtOH, RT, 93%.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP=4-dimethylamino-
pyridine, TBAF=tetrabutylammonium fluoride, THF=tetrahydrofuran,
TMS=trimethylsilyl.
pyran-containing macrolide natural products and their ana-
logues.
À
lective hydrogenation of the C8 C9 double bond with
concomitant hydrogenolysis of the BOM group afforded 2
in 93% yield as a single diastereomer, which has previously
been transformed into 1 by us[5] and other research groups.[3b–f]
In conclusion, we have completed a concise total synthesis
of (+)-neopeltolide (1), which proceeded in only 13 steps
(longest linear sequence) from commercially available
(E)-cinnamaldehyde. The present synthesis represents the
shortest asymmetric synthesis of 1 reported to date. High-
lights of the present synthesis are: 1) a highly chemoselective
CM of 7 by exploiting hydrogen bonding, 2) a stereoselective
intramolecular oxa-conjugate addition of 6 under thermody-
namic conditions to forge the 2,4,6-trisubstituted tetrahydro-
pyran subunit, and 3) a macrocyclization of 3 through a
stereoselective RCM/hydrogenation sequence. Significantly,
our newly developed olefin metathesis-based strategy should
be generally applicable to the rapid assembly of tetrahydro-
Received: February 2, 2010
Published online: March 22, 2010
Keywords: chemoselectivity · cyclization · macrolides ·
.
metathesis · natural products
[1] A. E. Wright, J. C. Botelho, E. Guzmꢀn, D. Harmody, P. Linley,
P. J. McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J. Nat. Prod.
[2] O. A. Ulanovskaya, J. Janjic, M. Suzuki, S. S. Sabharwal, P. T.
[3] For the total synthesis of 2, see: a) W. Youngsaye, J. T. Lowe, F.
Angew. Chem. Int. Ed. 2010, 49, 3041 –3044
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3043