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T. Hoshino, Y. Sakai / Tetrahedron Letters 42 (2001) 7319–7323
the trimethylcyclohexanone ring has remained unre-
solved. The chemical shifts of the cyclohexanone ring of
9 were compared with those of 198 having the
2R,3S,4R-stereochemistry,11 which is available from the
chemical synthesis from ( )-1 by using the Lewis acid
SnCl4.11 A careful comparison of the NOESY spectrum
of 9 with that of 19 showed that a strong NOE between
Me-25 and H-2 was observed for 9, whereas there was
no NOE between them for 19 (Scheme 3). Detailed
NOE analyses allowed us to propose the structure 9
(Fig. 1 and Scheme 3). Compound 19 is produced from
(3S)-1 via chair-formed 18, which is then subjected to
the 1,2-rearrangement reactions of the hydride and the
methyl in an antiparallel concerted manner.11 On the
other hand, it is likely that the formation of 9 proceeds
from (3R)-6 via twist boat-formed 17 and that the
rearrangement reactions proceed as shown in Scheme 3,
taking into consideration the stereochemistry
(2S,3R,4R) of the trimethylcyclohexanone ring of 9.
The deprotonation from the OH group, formed after
the epoxide ring-opening, could give ketone 9. Forma-
tion of 9 led to a surprising and important question,
because lanosterol synthase is believed to be active only
to (3S)-1, but inert to (3R)-1. One possible explanation
of this paradox may be that the larger steric bulk size of
the ethyl group may have induced incorrect placement
of the (3R)-epoxide at the catalytic site intrinsic to the
(3S)-epoxide, where (3R)-6 had been constrained to
fold with a boat form in the enzyme cavity. Despite the
occurrence of looser binding around the A/B-ring for-
mation site, the cyclase had still a binding ability to
(3S)-6 which enabled it to form the chair structure,
leading to the production of 8 and to further cyclization
to form 11 and 13; the yield (31%) of 8, 11 and 13 from
(3S)-6 was higher than that (7.7%) of 9 from (3R)-6.
(No.13660150) from the Ministry of Education, Sci-
ence, Sports and Culture, Japan.
References
1. (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev.
1993, 93, 2189–2206; (b) For a recent review, see: Wendt,
K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew.
Chem., Int. Ed. Engl. 2000, 39, 2812–2833.
2. Medina, J. C.; Guajardo, R.; Kyler, K. J. Am. Chem.
Soc. 1989, 111, 2310–2311.
3. van Tamlene, E. E. J. Am. Chem. Soc. 1968, 90, 3284–
3285.
4. (a) Corey, E. J.; Virgil, S. C.; Liu, D. R.; Sarsha, S. J.
Am. Chem. Soc. 1992, 114, 1524–1525; (b) Corey, E. J.;
Cheng, H. Tetrahedron Lett. 1996, 37, 2709–2712.
5. Hoshino, T.; Ishibashi, E.; Kaneko, K. J. Chem. Soc.,
Chem. Commun. 1995, 2401–2402.
6. Hoshino, T.; Sakai, Y. J. Chem. Soc., Chem. Commun.
1998, 1591–1592.
7. Hoshino, T.; Williams, H. J.; Shishido, K.; Scott, A. I. J.
Labelled Compd. Radiopharm. 1990, 28, 1283–1292.
8. NMR data for 8, 9, 11, 13 and 19. 1H NMR (600.13
MHz) and 13C NMR (150.9 MHz) in C6D6, ppm relative
to 7.28 and 128.0 ppm of the solvent peak.
Compound 8: (analog of Achilleol A), lH: 0.92 (3H, s,
H-25), 1.13 (3H, s, H-24), 1.14 (3H, t, J=7.6 Hz, H-31),
1.48 (1H, m, H-6ax), 1.68 (3H, s, H-30), 1.72 (1H, m,
H-6eq), 1.73 and 1.74 (3H each, s, H-28 and H-29), 1.77
(1H, t, J=6.3 Hz, H-3), 1.80 (3H, s, H-23), 1.85 (2H, bt,
J=7.7 Hz), 1.98 (1H, m, H-5ax), 2.02 (1H, m, H-8), 2.22
(2H, q, J=7.6 Hz, H-27), 2.22 (4H, t, J=7.7 Hz, H-15
and 19), 2.30 (8H, m, H-11, 12, 16, 20), 2.38 (1H, m,
H-5eq), 2.41 (1H, m, H-8), 3.24 (1H, dd, J=13.8, 6.6
Hz), 4.84 (1H, s, H-26), 5.02 (1H, s, H-26), 5.37 (1H, bt,
J=6.8 Hz), 5.43 (3H, m, H-10, 13, 17). lC: 13.6 (C-31),
16.1 (C-28 and C-29), 16.2 (C-25), 17.7 (C-30), 23.6
(C-27), 24.7 (C-7), 25.3 (C-23), 26.3 (C-24), 27.1 and 27.2
(C-16 and C-20), 28.4 (C-12), 29.05 (C-11), 32.6 (2C, C-5
and C-6), 35.9 (C-8), 40.2 (C-15 and C-19), 40.6 (C-2),
51.8 (C-3), 76.7 (C-1), 108.6 (C-26), 124.3 (C-10), 124.9
(C-13, 17 and 21), 131.1 (C-22), 134.9 and 135.1 (C-14
and C-18), 141.7 (C-9), 148.0 (C-4). [h]2D5 (EtOH) −7.8
(c=0.08).
Compound 9: lH: 0.784 (3H, s, H-26), 0.903 (3H, d, J=7
Hz, H-25), 1.069 (3H, d, J=6.9 Hz, H-24), 1.146 (3H, t,
J=7.5, H-31), 1.38 (1H, m, H-5eq), 1.72 (m, H-5 ax),
1.45 (2H, m, H-7), 1.60 (1H, m, H-4), 1.69 (3H, s, H-30),
1.75 and 1.73 (3H each, s, H-28 and H-29), 1.80 (3H, s,
H-23), 2.01 (2H, m, H-8), 2.17 (1H, m, H-6ax), 2.20 (2H,
q, J=7.5 Hz, H-27), 2.20–2.35 (6H, m, H-11, 12, 15 and
16), 2.25 (1H, m, H-6eq), 2.31 (1H, q, J=6.9 Hz, H-2),
5.36 (1H, bt, J=6.9 Hz, H-21), 5.40 (3H, m, H-10, 13,
17). lC: 9.23 (C-24), 13.60 (C-31), 14.05 (C-25), 16.09 and
16.20 (C-28 and -29), 17.71 (C-30), 21.05 (C-26), 24.12
(C-27), 27.11 and 27.22 (C-16 and -20), 28.98 (C-12),
29.45 (C-11), 30.32 (C-8), 34.65 (C-4), 36.25 (C-7), 36.93
(C-6), 42.45 (C-3), 50.07 (C-2), 124.4 (C-10), 124.75,
124.77 and 124.92 (C-10, 13 and 17), 130.88 (C-22), 135.0
and 135.3 (C-14 and 18), 141.85 (C-9) and 211.03 (C-1).
Selected lH in CDCl3 relative to the solvent peak (7.26
In conclusion, this is the first report that a triterpene
having a trimethylcyclohexanone ring was produced by
mammalian cyclase. It is quite interesting from the
aspect of molecular evolution that the same cyclohex-
anone skeleton is also constructed by the squalene
cyclase of a protozoa T. pyriformis. This supports the
idea that triterpenoid cyclases should have evolved
from a common ancestor cyclase; that is, a variety of
natural triterpene skeletons may have been created by
subtle changes in the active sites.12 This study also gave
further evidence that lanosterol is biosynthesized via the
ring-expansion process of the five-membered C-ring as
shown in Scheme 1. It is noteworthy that the ethyl
group migrates in a similar way to the methyl of natural
1. Kyler et al. reported that the vinyl appendage (the
same C2 unit as ethyl group) at C-10 had no influence
on the cyclization as for Baker’s yeast cyclase, leading
to the complete polycyclization to give a lanosterol
homolog without any abortive cyclization products
having been trapped.2 The specificity for squalene
analogs is different between pig liver and Baker’s
yeast.5,6
Acknowledgements
This work was supported by a Grant-in-Aid to T.H.