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reported for the natural product (Table 1). However, the full
NOE data for this compound supports the structure 2b, rather
than the originally proposed structure 1b. Crucially, the
Table 1: Selected physical properties for 2a and 2b.
2a: Rf =0.62 (silica gel, hexane/EtOAc 2:1); [a]2D5 =À126.6 (c=0.08,
CHCl3); IR (thin film): n˜ =2923, 1792, 1742, 1104. 1H NMR (600 MHz,
CDCl3): d=7.34–7.27 (m, 5H), 5.46 (m, 1H), 5.22 (dd, J=17.4, 10.8 Hz,
1H), 5.08 (br.t, J=6.6 Hz, 1H), 4.78 (d, J=10.8 Hz, 1H), 4.72 (d,
J=9.0 Hz, 1H), 4.60 (d, J=17.4 Hz, 1H), 3.98 (d, J=8.4 Hz, 1H), 3.44
(d, J=8.4 Hz, 1H), 3.19 (dd, J=6.0, 1.2 Hz, 1H), 3.12 (ddd, J=8.4, 5.4,
5.4 Hz, 1H), 2.19 (m, 1H), 2.03 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H),
1.69 (d, J=1.2 Hz, 3H), 1.67 (m, 1H), 1.60 (s, 3H), 1.46–1.37 (m, 2H),
1.31 (s, 3H), 1.16 (m, 1H), 1.00 (s, 3H), 0.91 ppm (d, J=7.2 Hz, 3H).
13C NMR (150 MHz, CDCl3): d=209.5, 171.7, 139.6, 134.5, 131.5, 131.4,
127.7, 127.7, 125.9, 124.6, 123.6, 118.4, 93.1, 89.6, 73.7, 51.7, 50.1, 49.0,
38.8, 35.5, 34.9, 34.6, 25.7, 25.5, 22.7, 21.7, 20.1, 17.8, 17.3 ppm. HRMS
(ESI-TOF): m/z calcd for C31H38O4Na+, 497.2662; found 497.2657.
2b: Rf =0.62 (silica gel, hexane/EtOAc 2:1); [a]2D5 =À256.6 (c=0.80,
CHCl3); [lit.,[1] [a]D25 =À240.0 (c=0.50, CHCl3)]; IR (thin film): n˜ =2926,
1792, 1743, 1173 cmÀ1; 1H NMR (600 MHz, CDCl3) d=7.37–7.26 (m,
5H), 5.46 (m, 1H), 5.22 (dd, J=17.6, 11.2 Hz, 1H), 5.11 (br.t,
J=6.8 Hz, 1H), 4.80 (d, J=11.2 Hz, 1H), 4.71 (d, J=8.8 Hz, 1H), 4.61
(d, J=17.6 Hz, 1H), 3.99 (d, J=8.4 Hz, 1H), 3.48 (d, J=8.4 Hz, 1H),
3.16 (d, J=6.0, 1.2 Hz, 1H), 3.02 (ddd, J=8.4, 6.0, 6.0 Hz, 1H), 2.09 (m,
1H), 2.02 (m, 1H), 1.99 (m, 1H), 1.94 (m, 1H), 1.73 (m , 1H), 1.70 (s,
3H), 1.61 (s, 3H), 1.46 (m, 1H), 1.44 (m, 1H), 1.31 (s, 3H), 1.20 (m,
1H), 1.02 (s, 3H), 0.82 ppm (d, J=6.8 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d=209.6, 171.6, 139.6, 134.5, 131.4, 131.4, 127.7, 127.7, 125.9,
124.5, 123.8, 118.4, 93.0, 89.7, 73.6, 51.8, 50.3, 49.0, 38.7, 35.9, 35.0,
34.9, 25.8, 25.7, 23.4, 21.7, 20.1, 17.7, 16.8 ppm. HRMS (ESI-TOF): m/z
calcd for C31H39O4+, 475.2843; found 475.2845.
Figure 2. ORTEP views of a) 11a and b) 12 with thermal ellipsoids set
at the 30% level. Bn=benzyl.
ethylene group of the tertiary carbon) as in IX and X, from
which palladium is extruded to form spirolactone 12.
The pure stereoisomer of 12, was then converted into
hyperolactone C (4) by a three-step sequence that involved
debenzylation (BBr3), selenation, and oxidation/syn elimina-
tion (79% overall yield).
With the required fragments in hand, the stage was now
set to investigate the key [2+2] photoinduced cycloaddition
reaction.[10] Irradiation of a mixture of 4 and 3a (24S) or 3b
(24R) in the presence of 2’-acetonapthone as a triplet
sensitizer and in a quartz cell (> 320 nm filters) as a reaction
vessel, led to rapid chemo-, regio-, and stereoselective
cyclobutane formation through hetero-coupling to give 2a
(24S) or 2b (24R), of which 2b proved to be the natural
product.[11] The reaction was carried out in concentrated
CH2Cl2 solution with a fourfold excess of the less valuable
terpene added in portions (Scheme 4).
absence of a strong NOE interaction between H18 and the
closest protons on the aromatic ring eliminates the proposed
structures 1a and 1b.[12] The confusion apparently arose from
the assumption that the NOE interaction observed between
H6 and H17 is indicative of a syn arrangement between these
protons, whereas this is not necessarily the case. Furthermore,
the observed NOE interaction between H6 and H22 is
indicative of anti, rather than syn arrangement, as these
hydrogen atoms are in closer proximity within the anti
structures 2a or 2b, than they are within the syn structures
1a or 1b.
In conclusion, a 12-step total synthesis of biyouyanagin A
has been accomplished and led to the stereochemical
reassignment of the natural product from 1a or 1b, to 2b.
In addition to the structural revision, the described chemistry
renders the natural substance readily available for further
biological investigations and opens the way to design
analogues for studies for structure-activity relationships. It
should also be noted that terpenoid 3a similarly reacted with
4 under the same photolytic conditions to afford (24S)-epi-
biyouyanagin A (2a); a substance that may occur naturally as
well.
Scheme 4. Completion of the total synthesis of biyouyanagin A (2b).
Reagents and conditions: a) 4 (1.0 equiv), 3b (4.0 equiv), 2’-aceto-
naphthone (1.0 equiv), CH2Cl2, 258C, 5 h, 46%.
The spectroscopic data (1H and 13C NMR, MS, IR data)
and optical rotation of this product were consistent with those
Received: April 9, 2007
4710
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 4708 –4711