Synthesis of (-)-hamigeran B

Article abstract of DOI:10.1021/jo8010683

(Chemical Equation Presented) The synthesis of (-)-hamigeran B has been achieved, based on a new approach to cyclopentane construction, the rhodium-mediated intramolecular C-H insertion of α-aryl-α- diazoketones. The endo- isopropyl group was installed by selective hydrogenation of a cyclopropylidene substituent.

Full text of DOI:10.1021/jo8010683

Synthesis of (-)-Hamigeran B
Douglass F. Taber* and Weiwei Tian
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed May 16, 2008
The synthesis of (-)-hamigeran B has been achieved, based on a new approach to cyclopentane
construction, the rhodium-mediated intramolecular C-H insertion of R-aryl-R-diazoketones. The endo-
isopropyl group was installed by selective hydrogenation of a cyclopropylidene substituent.
Introduction
(-)-Hamigeran B 1 is one of a family of eight hamigerans
(Figure 1) isolated1 in 2000 from the poecilosclerid sponge
Hamigera tarangaensis, collected from the Hen and Chicken
Islands east of New Zealand. Hamigeran B was the only one of
the family to show antiviral activity, effecting complete inhibi-
tion of both herpes and polio viruses at low concentration and
with only slight cytotoxicity.
A central concern in the total synthesis of the hamigerans is
the construction of the cyclic quaternary center, from which
the other two stereocenters may evolve. Three independent
approaches to this problem have been described. Nicolaou2 first
reported an asymmetric synthesis utilizing a [4 + 2] photocy-
cloaddition. This route started from an enantiomerically pure
epoxide, obtained via the Jacobsen hydrolytic kinetic resolution.
Clive3 described a synthesis in which the chiral quaternary center
was constructed using Meyers’ chiral auxiliary. Trost4 installed
the quaternary stereogenic center by Pd-catalyzed asymmetric
allylic alkylation of a preformed cyclopentanone.
We envisioned that the key intermediate 12(Scheme 1) could
be assembled by convergent coupling of 9 with the enantio-
(1) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R. J.
Nat. Prod. 2000, 63, 79.
FIGURE 1. Structures of hamigerans.
(2) (a) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed. 2001, 40,
3675. (b) Nicolaou, K. C.; Gray, D.; Tae, J. Angew Chem., Int. Ed. 2001, 40,
3679. (c) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126,
613.
(3) (a) Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed. 2003, 42, 3406. (b)
Clive, D. L. J.; Wang, J. Tetrahedron Lett. 2003, 44, 7731. (c) Clive, D. L. J.;
Wang, J. J. Org. Chem. 2004, 69, 2773.
(4) (a) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am.
Chem. Soc. 2004, 126, 4480. (b) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.
Chem.sEur. J. 2005, 11, 951.
merically pure citronellol derivative 10.5,6 Rh-mediated in-
tramolecular C-H insertion,7 proceeding with retention of
absolute configuration,8 would then complete the cyclopentane
(5) For a review of natural products synthesized from citronellal, see:
Lenardao, E. J.; Botteselle, G. V.; Azambuja, F.; Perin, G.; Jacob, R. G.
Tetrahedron 2007, 63, 6671.
(6) Overman, L. E.; Jacobsen, E. J. J. Am. Chem. Soc. 1982, 104, 7225.
7560 J. Org. Chem. 2008, 73, 7560–7564
10.1021/jo8010683 CCC: $40.75 2008 American Chemical Society
Published on Web 09/05/2008

Synthesis of (-)-Hamigeran B
SCHEME 1
SCHEME 2
SCHEME 3
assembly while at the same time securing the enantiomerically
pure quaternary center of 12. Our enthusiasm for this approach
was, however, tempered by the earlier report9 that the R-aryl-R-
diazoketone 13 could not be induced to cyclize to 14.10
Results and Discussion
Construction and Cyclization of r-Aryl-r-Diazoketones: In
order to develop this approach to cyclopropane construction,
two challenges (Scheme 2) had to be overcome.11 The first
challenge was to optimize the base, solvent, and sulfonyl azide
for the diazo transfer reaction on an R-arylketone. Overall, we
found that 2,4,6-triisopropylbenzenesulfonyl azide (TIBSA) was
better than benzenesulfonyl azide, methanesulfonyl azide,
4-acetamidobenzenesulfonyl azide, or p-nitrobenzenesulfonyl
azide, especially on substrates with an electron-rich aromatic
ring. As the solvent, toluene was better than dichloromethane
or acetonitrile. In combination with DBU, TIBSA gave con-
sistently high yields of R-aryl-R-diazoketones.
The next challenge was the Rh-mediated intramolecular C-H
insertion. Because of the electron-donating aromatic substituent,
dimer formation was always the main side reaction competing
with C-H insertion. By altering the temperature, the solvent,
the addition sequence, and the rhodium catalyst, the yields of
the C-H insertion could be improved. Under the optimized
conditions (toluene as the solvent, rapid addition of the
diazoketone into rhodium catalyst Rh2(pttl)4)12 at room tem-
perature), the diazoketone 16 cyclized efficiently. We were
pleased to observe that, under these conditions, even 13 could
be induced to cyclize to 14, albeit in modest yield.
Synthesis of the Tricyclic Ketone 21: The known aldehyde
106 (Scheme 3) was derived from (R)-citronellol in two steps.
Direct benzylic deprotonation of 3,5-dimethylanisole 9 by 1
equiv of “super base”13 in THF followed by addition of the
aldehyde 10 at low temperature led to the alcohol 18 as a
mixture of two diastereomers. Phenethyl alcohols such as 18
are sometimes difficult to oxidize, and several reagents were
ineffective. Fortunately, the PCC-catalyzed oxidation with
periodic acid14 worked well.
(7) For the first reports of Rh-mediated intramolecular C-H insertion, see:
(a) Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; da Silva, R. R.;
Shulman, S.; Warnet, R. J.; Ceccherelli, P.; Curini, M.; Pellicciari, R. J. Org.
Chem. 1982, 47, 3242. (b) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47,
4808. For a review of natural products synthesized by Rh-mediated intramolecular
C-H insertion reaction, see: (c) Taber, D. F.; Stiriba, S. E. Chem.sEur. J. 1998,
4, 990. For a recent example, see: (d) Taber, D. F.; Frankowski, K. J. J. Org.
Chem. 2005, 70, 6417.
(8) Taber, D. F.; Petty, E. H.; Raman, K. J. Am. Chem. Soc. 1985, 107, 196.
(9) Mateos, A. F.; Coca, G. P.; Alonso, J. J. P.; Gonza´lez, R. R.; Herna´ndez,
C. T. Synlett 1996, 1134.
With the ketone 19 in hand, we could bring to bear our earlier
experience developing the cyclization protocol. Diazo transfer
(10) For the first report of intermolecular Rh-mediated C-H insertion using
R-aryl-R-diazo esters, see: (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc.
1997, 119, 9075. For recent reviews, see: (b) Davies, H. M. L.; Beckwith, R. E. J.
Chem. ReV. 2003, 103, 2861. (c) Davies, H. M. L.; Nikolai, J. Org. Biomol.
Chem. 2005, 3, 4176.
(12) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79. Rh2(Pttl)4 is
dirhodium(II) tetrakis [N-phthaloyl-(S)-t-leucinate.
(13) Guggisberg, Y.; Faigl, F.; Schlosser, M. J. Organomet. Chem. 1991,
415, l.
(11) Taber, D. F.; Tian, W. J. Org. Chem. 2007, 72, 3207.
(14) Hunsen, M. Tetrahedron Lett. 2005, 46, 1651.
J. Org. Chem. Vol. 73, No. 19, 2008 7561

Taber and Tian
SCHEME 4
diastereoselectivity of the hydrogenation of the cyclopropy-
lidene. The propensity of the alkene to move into and around
the ring was exacerbated by hydrogenation catalysts. Ir black
was finally tried because it was known to minimize such alkene
migrations.4,17 The reduction was successful, delivering es-
sentially a single diastereomer. We were pleased to observe that
the strained cyclopropylidene could be hydrogenated without
concomitant reduction of the benzylic alkene.
Upjohn dihydroxylation3,18 of the alkene 24 led to the diol
25 as a mixture of diastereomers. Hydrogenolytic cleavage7b,19
of the cyclopropane ring at 50 °C by PtO2/AcOH established
the isopropyl group and also removed the benzylic alcohol.
Fortunately, oxidation of 26 with TBAP/NMO20 led directly to
the diketone 27, presumably by the oxidation of the enol form
of the initially generated ketone. Demethylation and bromination
following the literature precedent3,4 then led to (-)-hamigeran
B 1, identical (1H NMR, 13C NMR, [R]D) with natural and
previously synthesized material.1-4
Conclusion
We have developed a general route to the 6,6,5-tricyclic
skeleton of (-)-hamigeran B based on C-H insertion of an
R-aryl-R-diazoketone followed by Friedel-Crafts cyclization.
The installation of the endo-isopropyl group was achieved by
selective hydrogenation of a cyclopropylidene substituent. We
expect that Rh-mediated intramolecular C-H insertion of
R-aryl-R-diazoketones will be a powerful tool for the synthesis
of natural products of biological interest.
Experimental Section
reaction by TIBSA and DBU in toluene was high yielding,
delivering 11. The diazoketone 11 was unusually unstable and
light sensitive. A quick chromatography of 11 and immediate
processing were required.
(5R)-7-(Benzyloxy)-1-(3-methoxy-5-methylphenyl)-5-methyl-
1-diazoheptan-2-one (11). To 300 mL of toluene were added the
ketone 19 (10.0 g, 28.2 mmol), DBU (8.6 g, 56.5 mmol), and 2,4,6-
triisopropylbenzenesulfonylazide (10.5 g, 33.9 mmol) sequentially
at 0 °C.11 The reaction mixture was maintained in darkness and
stirred at rt for 4 h. The reaction mixture was directly chromato-
graphed to afford the diazoketone 11 as a yellow oil (9.66 g, 25.4
We were pleased to find, based on our previous optimization,
that Rh-mediated C-H insertion to form the cyclopentane also
proceeded efficiently. The product was a mixture of two
diastereomers at the R position, as expected. The two diaster-
eomers could be separated by column chromatography, but
interconverted on storage, so we carried the mixture on.
Removal of the benzyl protecting group by hydrogenation
followed by oxidation with the Dess-Martin reagent gave the
aldehyde 21, still as a mixture of R-diastereomers. Under acid
catalysis, the two diastereomers of the aldehyde 21 readily
interconverted. The cis isomer of 21 could easily participate in
the intramolecular Friedel-Crafts reaction to form the cyclized
benzylic alcohol. In situ, the alcohol underwent dehydration to
give the alkene 22.15
Synthesis of (-)-Hamigeran B: Wittig reagents did not
convert ketone 22 into the corresponding alkene, perhaps
because 22 was quite acidic. The Petasis reagent,16 known to
be nonbasic, was successful, delivering alkene 23 in 60% yield
(Scheme 4). The strained alkene was unstable under the reaction
condition (55 °C), easily isomerizing to the endocyclic cyclo-
pentene during the reaction. We found that inclusion of NaHCO3
in the reaction mixture prevented the isomerization.
mmol, 90% yield): TLC Rf (PE/MTBE ) 8/2) ) 0.50; [R]20
)
D
+3.93 (c 2.80, CH2Cl2); 1H NMR δ 0.90 (3H, d, J ) 6.8 Hz), 1.60
(5H, m), 2.31 (3H, s), 2.55 (2H, m), 3.49 (2H, m), 3.77 (3H, s),
4.47 (2H, s), 6.60 (1H, s), 6.82 (1H, s), 6.97 (1H, s), 7.27 (5H, m);
13C NMR δ u21 31.6, 36.5, 36.9, 68.4, 72.1, 73.0, 126.6, 138.6,
140.0, 160.1, 193.0; d 19.4, 21.7, 29.7, 55.2, 108.6, 113.6, 118.6,
127.5, 127.6, 128.3; IR (film, cm-1) 2927, 2073, 1649, 1592, 1240;
HRMS calcd for C23H28O3 (M - N2) 352.2038, obsd 352.2041.
(3S)-3-(2-(Benzyloxy)ethyl)-2-(3-methoxy-5-methylphenyl)-3-
12
methylcyclopentanone (12). Rh2(R-pttl)4 (5 mg) was dissolved
in 2 mL of toluene. To this solution was added a solution of the
diazoketone 11 (140 mg, 0.368 mmol) in 2.0 mL of toluene at rt
within 1 min. The reaction was continued for an additional 15 min
at rt. Then the reaction mixture was concentrated and chromato-
graphed to afford the ketone 12 as a mixture of two diastereomers
(108 mg, 0.305 mmol, 83% yield): TLC Rf (PE/MTBE ) 8/2) )
1
0.22; H NMR δ 0.79 (1.2H, s), 1.18 (1.8H, s), 1.50 (1.0H, m),
1.67 (1.0H, m), 1.83 (1.0H, m), 1.94 (1.0H, m), 2.31 (1.0H, m),
(17) (a) Nishimura, S.; Mochizuki, F.; Kobayakawa, S. Bull. Chem. Soc. Jpn.
1970, 43, 1919. (b) Nishimura, S.; Sakamoto, H.; Ozawa, T. Chem. Lett. 1973,
855.
With the diene 23 in hand, we were again faced with two
challenges, differentiating the two alkenes, and controlling the
(18) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.
(19) Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583.
(20) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
(15) Node, M.; Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide,
K.; Fuji, K. Heterocycles 1996, 42, 811.
(16) (a) Petasis, N. A.; Bzowel, E. I. Tetrahedron Lett. 1993, 43, 943. (b)
Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(21) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d” and
for methylene and quaternary carbons as “u”.
7562 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of (-)-Hamigeran B
2.34 (3.0H, s), 2.42 (1.0H, m), 3.11 (0.6H, s), 3.24 (0.4H, s),
3.4-3.6 (2.0H, m), 3.74 (1.2H, s), 3.75 (1.8H, s), 4.41 (1.2H, s),
4.49 (0.8H, s), 6.43 (2.0H, m), 6.62 (1.0H, s), 7.28 (5H, m); 13C
NMR δ u 32.3, 33.2, 33.8, 35.9, 36.1, 40.8, 43.2, 43.3, 67.0, 67.2,
73.2, 73.3, 135.9, 136.2, 138.3, 139.0, 139.1, 159.3, 159.4, 217.6,
217.9; d 20.7, 21.7, 21.8, 26.1, 55.2, 67.4, 68.9, 113.2, 113.3, 113.4,
113.6, 123.5, 123.9, 127.7, 128.5; IR (film, cm-1) 2959, 1724, 1173,
1068; HRMS calcd for C23H28O3 (M+) 352.2038, obsd 352.2023.
(3S)-3-(2-Hydroxyethyl)-2-(3-methoxy-5-methylphenyl)-3-me-
thylcyclopentanone (20). The ketone 12 (6.03 g, 17.1 mmol) was
dissolved in 50 mL of THF and 1 mL of water; 5% Pd/C (1.0 g)
was added at rt. The reaction container was then filled with
hydrogen gas (1 atm) and stirred vigorously overnight. The mixture
was passed through a pad of Celite then dried (Na2SO4), and
concentrated in vacuo. The residue was chromatographed to afford
the alcohol 20 as a mixture of two diastereomers (4.41 g, 16.8
mmol, 98% yield): TLC Rf (PE/MTBE ) 6/4) ) 0.10; 1H NMR δ
0.80 (1.8H, s), 1.19 (1.2H, s), 1.2-1.4 (1H, m), 1.7-1.9 (3H, m),
2.17 (1H, m), 2.30 (3H, s), 2.47 (1H, m), 3.11 (0.4H, s), 3.20 (0.6H,
s), 3.6 (1H, m), 3.7 (2H, m), 3.75 (3H, s), 6.42 (2H, m), 6.63 (1H,
s); 13C NMR δ u 32.1, 33.3, 35.8, 35.9, 36.8, 43.1, 43.2, 43.7, 59.2,
59.4, 135.9, 136.1, 139.0, 139.1, 159.3, 159.4, 217.6, 217.9; d 20.4,
21.7, 26.0, 55.2, 67.5, 68.8, 113.2, 113.2, 113.4, 113.6, 123.4, 123.8;
IR (film, cm-1) 3428, 2952, 1733, 1595, 1459; HRMS calcd for
C16H22O3 (M+) 262.1569, obsd 262.1557.
(1S)-2-(2-(3-Methoxy-5-methylphenyl)-1-methyl-3-oxocyclo-
pentyl)acetaldehyde (21). Dess-Martin periodinane (7.42 g, 17.5
mmol) was added into the solution of the alcohol 20 (3.06 g, 11.7
mmol) in 100 mL of DCM at rt. The reaction continued for 30
min. The mixture was diluted with 300 mL of ether and passed
through a pad of silica gel. The eluant was concentrated in vacuo.
The residue was chromatographed to afford the ketone 21 as a
mixture of two diastereomers (2.90 g, 11.1 mmol, 95% yield): TLC
Rf (PE/MTBE ) 6/4) ) 0.29; 1H NMR δ 0.94 (0.6H, s), 1.40 (2.4H,
s), 1.90 (1H, m), 2.14 (2H, m), 2.23 (1.0H, m), 2.32 (3H, s), 2.50
(2H, m), 3.19 (0.8H, s), 3.41 (0.2H, s), 3.77 (3H, s), 6.39 (1H, s),
6.43 (1H, s), 6.65 (1H, s), 9.59 (0.8H, t, J ) 2.4 Hz), 9.83 (0.2H,
t, J ) 2.4 Hz); 13C NMR δ u 33.0, 33.1, 35.8, 36.2, 43.3, 43.7,
48.9, 54.4, 135.6, 135.9, 139.7, 140.1, 159.9, 160.1, 216.4, 217.4;
d 21.6, 22.1, 26.7, 55.6, 66.7, 68.3, 113.7, 113.9, 114.0, 123.5,
124.0, 202.3, 202.4; IR (film, cm-1) 2958, 2739, 1735, 1597, 1287;
HRMS calcd for C16H20O3 (M+) 260.1412, obsd 260.1408.
(3aS,9bS)-6-Methoxy-3a,8-dimethyl-3,3a-dihydro-2H-
cyclopenta[r]naphthalen-1(9ꢀH)-one (22). The aldehyde 21
(0.407 g, 1.56 mmol) was dissolved in 15 mL of diethyl ether at
rt. BF3 ·OEt2 (5 mL) was added at once. The reaction mixture turned
blue right after the addition. The mixture was stirred for 1 h before
quenching by water. The mixture was partitioned between MTBE
and, sequentially, water, saturated aqueous NaHCO3, and brine. The
combined organic extract was dried (Na2SO4) and concentrated in
vacuo. The residue was chromatographed to afford the alkene 22
as a colorless oil (0.138 g, 0.570 mmol, 37% yield): TLC Rf (PE/
MTBE ) 8/2) ) 0.33; [R]20D ) -109.8 (c 1.90, CH2Cl2); 1H NMR
δ 1.12 (3H, s), 1.81 (1H, m), 2.02 (2H, m), 2.29 (3H, s), 2.47 (1H,
m), 2.83 (1H, s), 3.72 (3H, s), 5.48 (1H, dd, J ) 1.2, 9.6 Hz), 6.52
(1H, s), 6.57 (1H, s), 6.70 (1H, d, J ) 10 Hz); 13C NMR δ u 35.5,
38.8, 41.8, 117.4, 131.1, 138.3, 154.9, 217.6; d 21.9, 25.7, 55.5,
60.1, 110.8, 121.8, 123.5, 132.4; IR (film, cm-1) 2951, 1742, 1460,
1270, 1104; HRMS calcd for C16H18O2 (M+) 242.1307, obsd
242.1296.
0.87 (1H, m), 1.10 (3H, s), 1.75 (1H, m), 1.90 (1H, m), 2.30 (1H,
m), 2.33 (3H, s), 2.50 (1H, m), 3.29 (1H, br s), 3.78 (3H, s), 5.51
(1H, d, J ) 9.6 Hz), 6.52 (1H, s), 6.69 (1H, s), 6.70 (1H, d, J )
10 Hz); 13C NMR δ u 1.0, 2.7, 32.4, 39.8, 44.1, 113.0, 117.4, 136.6,
136.7, 154.6; d 21.8, 24.8, 54.1, 55.3, 109.3, 119.9, 124.0, 134.4;
IR (film, cm-1) 2919, 2837, 1571, 1459, 1324, 1095; HRMS calcd
for C19H22O (M+) 266.1671, obsd 266.1660.
(1R,3aS,9bS)-1-Cyclopropyl-6-methoxy-3a,8-dimethyl-2,3,3a,9b-
tetrahydro-1H-cyclopenta[r]naphthalene (24). The alkene 23
(0.36 g, 1.35 mmol) and Ir black4 (50 mg) were mixed with 10
mL of EtOH at rt. The mixture was then placed in a Parr reactor
filled with H2 (1100 psi). The reaction was monitored by GC-MS.
After about 4-8 h, the reaction mixture was diluted with diethyl
ether (100 mL) and passed through a pad of Celite. The eluant
was concentrated and chromatographed to afford 24 as a colorless
oil (0.201 g, 0.749 mmol, 55% yield, 80% yield based on starting
material not recovered). Starting material was recovered (0.11 g,
31% yield, TLC Rf (PE/DCM ) 8.5/1.5) ) 0.29): TLC Rf (PE/
DCM ) 8.5/1.5) ) 0.43; [R]20 ) +10.1 (c 6.22, CH2Cl2); H
1
D
NMR δ -0.39 (1H, m), -0.21 (1H, m), -0.14 (1H, m), 0.06 (1H,
m), 0.23 (1H, m), 1.04 (3H, s), 1.36 (1H, m), 1.49 (1H, m), 1.58
(1H, m), 1.85 (2H, m), 2.31 (3H, s), 2.85 (1H, d, J ) 10 Hz), 3.80
(3H, s), 5.56 (1H, d, J ) 10 Hz), 6.50 (1H, s), 6.54 (1H, s), 6.66
(1H, d, J ) 10 Hz); 13C NMR δ u 2.4, 5.4, 32.6, 41.1, 43.0, 119.3,
136.5, 136.9, 154.4; 13C NMR δ 13.6, 21.7, 26.9, 52.2, 52.5, 55.4,
109.0, 118.8, 124.0, 135.9; IR (film, cm-1) 2942, 2861, 1575, 1458,
1100; HRMS calcd for C19H24O (M+) 268.1827, obsd 268.1824.
(1R,3aR,9bR)-1-Cyclopropyl-6-methoxy-3a,8-dimethyl-
2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[r]naphthalene-4,5-di-
ol (25). The alkene 24 (200 mg, 0.745 mmol) was combined with
CCl4 (4 mL), water (1 mL), acetone (8 mL), and t-BuOH (4 mL)
at rt. Potassium osmium(VI) oxide dihydrate (14 mg, 5% mol) and
N-methylmorpholine-N-oxide (0.41 g, 3.50 mmol) were added at
once.3,18 The reaction mixture was stirred vigorously at rt for 2
days, then partitioned between MTBE and, sequentially, saturated
aqueous NH4Cl and brine. The combined organic extract was dried
(Na2SO4) and concentrated in vacuo. The residue was chromato-
graphed to afford the diol 25 as a mixture of diastereomers (96
mg, 0.317 mmol, 43% yield, 60% yield based on starting material
not recovered). Starting material was recovered (55 mg, 28% yield,
TLC Rf (PE/MTBE ) 6/4) ) 0.80): TLC Rf (PE/MTBE ) 6/4) )
1
0.29; H NMR δ -0.20-0.40 (4H, m), 0.54 (1H, m), 1.17 (1.5H,
s), 1.19 (1.5H, s), 1.25 (3H, s), 1.53 (6 H, m), 1.88 (1 H, m), 2.09
(1 H, m), 2.18 (1 H, s), 2.32 (3 H, s), 2.40 (1 H, m), 2.63 (1H, s),
2.96 (1 H, d, J ) 8.0 Hz), 3.05 (1 H, d, J ) 9.2 Hz), 3.60 (1 H, d,
J ) 4.0 Hz), 3.85 (1.5 H, s), 3.87 (1.5 H, s), 3.93 (1 H, m), 5.06
(1 H, dd, J ) 4.4, 8.0 Hz), 6.54 (1 H, s), 6.68 (0.5H, s), 6.82 (0.5
H, s); 13C NMR δ u 2.99, 3.76, 5.67, 6.09, 29.9, 31.3, 33.7, 36.9,
43.6, 44.4, 121.6, 122.0, 137.0, 137.1, 137.3, 138.0, 157.1, 157.3;
d 12.2, 14.0, 21.2, 21.3, 28.8, 29.8, 49.2, 51.5, 53.1, 53.7, 54.8,
54.9, 65.0, 65.9, 71.4, 74.4, 107.8, 108.0, 123.7, 124.1; IR (film,
cm-1) 2955, 1709, 1677, 1459, 1107; HRMS calcd for C19H26O3Na
(M + Na) 325.1780, obsd 325.1772.
(1R,3aR,9bR)-1-Isopropyl-6-methoxy-3a,8-dimethyl-2,3,3a,4,5,9b-
hexahydro-1H-cyclopenta[r]naphthalen-4-ol (26). The diol 25 (36
mg, 0.12 mmol) and PtO2 (10 mg) were mixed in AcOH (2.5 mL)
at rt. H2 (1 atm) was bubbled through the mixture as it was
maintained in an oil bath (50 °C).7b,19 The reaction was monitored
by TLC. When the reaction completed (about 1 h), it was diluted
with 20 mL of Et2O and passed through a pad of Celite. The eluant
was concentrated and chromatographed to afford the alcohol 26 as
a colorless oil (23 mg, 0.079 mmol, 67% yield): TLC Rf (PE/MTBE
(3aS,9bR)-1-Cyclopropylidene-6-methoxy-3a,8-dimethyl-
2,3,3a,9b-tetrahydro-1H-cyclopenta[r]naphthalene (23). The
ketone 22 (0.185 g, 0.763 mmol) and NaHCO3 (12 mg) were added
to 5 mL of toluene. Petasis reagent16 (6.5 mL, 0.7 M in toluene,
4.58 mmol) was added at rt. The reaction mixture was maintained
at 55-60 °C for 2 days, then chromatographed directly. The alkene
23 was isolated as yellow oil (0.120 g, 0.45 mmol, 60% yield):
1
) 8/2) ) 0.25; H NMR (360 MHz) δ 0.66 (3H, d, J ) 6.5 Hz),
0.96 (1H, m), 1.09 (3H, d, J ) 6.5 Hz), 1.13 (1H, m), 1.30 (3H, s),
1.48 (1H, m), 1.61 (1H, m), 1.86 (1H, m), 2.11 (1H, m), 2.30 (3H,
s), 2.38 (1H, m), 3.01 (2H, m), 3.55 (1H, dd, J ) 4.3, 11.5 Hz),
3.79 (3H, s), 6.51 (1H, s), 6.60 (1H, s); 13C NMR (90 MHz) δ u
28.3, 29.7, 31.9, 45.7, 122.5, 135.0, 138.2, 156.3; d 21.5, 21.7,
TLC Rf (PE/MTBE ) 8/2) ) 0.80; [R]20 ) +103.8 (c 6.26,
D
1
CH2Cl2); H NMR δ 0.49 (1H, m), 0.69 (1H, m), 0.76 (1H, m),
23.9, 26.4, 29.6, 53.3, 53.9, 55.3,75.7, 108.2, 122.7; IR (film, cm-1
)
J. Org. Chem. Vol. 73, No. 19, 2008 7563

Taber and Tian
2924, 2855, 1458, 1264; HRMS calcd for C19H28O2 (M+) 288.2089,
obsd 288.2088.
(1H, s); 13C NMR δ u 27.1, 34.0, 57.0, 116.9, 144.3, 150.9, 164.8,
184.5, 200.2; d 20.0, 22.7, 23.3, 24.6, 28.3, 51.6, 56.7, 116.4, 123.5.
(-)-Hamigeran B (1). Following Trost’s procedure,4 1 was
isolated as a yellow solid (81% yield). The product was recrystal-
lized from hexanes before it was characterized: mp ) 155 - 160
°C (lit.1-4 mp 154-167 °C); TLC Rf (PE/MTBE/MeOH ) 90/10/
1) ) 0.47; [R]20D ) -200 (c 0.14, CH2Cl2) (lit.1-4 [R]D ) -151.1
(1R,3aR,9bR)-1-Isopropyl-6-methoxy-3a,8-dimethyl-1,2,3,3a-
tetrahydro-9bH-cyclopenta[r]naphthalene-4,5-dione (27). The
alcohol 26 (68 mg, 0.236 mmol), powdered 4 Å molecular sieve
(0.65 g), N-methylmorpholine-N-oxide (272 mg, 2.32 mmol), and
TBAP (tetra-n-butylammonium perruthenate)20 (10 mg) were mixed
in DCM (3 mL) at rt. The reaction was monitored by TLC. After
about 3 h, it was chromatographed directly to afford the known3
diketone 27 as a yellow oil (38 mg, 0.127 mmol, 54% yield): TLC
1
to -211); H NMR δ 0.45 (3H, d, J ) 6.4 Hz), 0.54 (3H, d, J )
6.8 Hz), 1.20 (1H, m), 1.30 (3H, s), 1.54 (1H, m), 1.68 (1H, m),
1.80 (1H, m), 2.30 (1H, m), 2.51 (3H, s), 2.64 (1H, m), 3.38 (1H,
d, J ) 9.2 Hz), 6.83 (1H, s), 12.63 (s, 1 H); 13C NMR δ u 26.9,
34.0, 57.1, 111.8, 116.4, 142.9, 150.4, 161.0, 184.6, 199.2; d 19.9,
23.5, 24.5, 24.6, 28.3, 51.5, 56.4, 124.4.
Rf (PE/MTBE ) 8/2) ) 0.08; [R]20 ) -345.9 (c 0.74, CH2Cl2);
D
1H NMR (360 MHz) δ 0.44 (3H, d, J ) 6.5 Hz), 0.57 (3H, d, J )
6.5 Hz), 1.20 (1H, m), 1.28 (3H, s), 1.55 (2H, m), 1.79 (1H, m),
2.25 (1H, m), 2.43 (3H, s), 2.50 (1H, m), 3.35 (1H, d, J ) 9.7 Hz),
3.95 (3H, s), 6.71 (1H, s), 6.78 (1H, s); 13C NMR (90 MHz) δ u
28.2, 35.6, 55.3, 120.8, 146.1, 147.4, 161.6, 181.0, 201.9; d 20.5,
22.6, 23.3, 24.3, 28.7, 52.0, 56.2, 56.2, 111.1, 124.5.
Acknowledgment. We thank John Dykins for high-resolution
mass spectra under the financial support by NSF 0541775. This
work was supported by the National Institutes of Health (GM
060287).
(1R,3aR,9bR)-6-Hydroxy-1-isopropyl-3a,8-dimethyl-1,2,3,3a-
tetrahydro-9bH-cyclopenta[r]naphthalene-4,5-dione (28). Fol-
lowing Clive’s procedure,3 the phenol 28 was isolated as a yellow
solid (88% yield): TLC Rf (PE/MTBE ) 8/2) ) 0.46; [R]20
)
Supporting Information Available: Experimental generals
and spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
D
1
-225.8 (c 0.62, CH2Cl2); H NMR δ 0.43 (3H, d, J ) 6.8 Hz),
0.54 (3H, d, J ) 6.8 Hz), 1.22 (1H, m), 1.30 (3H, s), 1.55 (1H, m),
1.67 (1H, m), 1.79 (1H, m), 2.26 (1H, m), 2.39 (3H, s), 2.64 (1H,
m), 3.40 (1H, d, J ) 9.2 Hz), 6.70 (1H, s), 6.73 (1H, s), 11.90
JO8010683
7564 J. Org. Chem. Vol. 73, No. 19, 2008