Total synthesis of (±)-ceratopicanol: Application of Pd-catalyzed enediyne cycloreduction

Article abstract of DOI:10.1055/s-2005-917117

Pd-catalyzed cycloreduction of enediyne 3 successfully afforded the linear triquinane skeleton 4. Total synthesis of (±)-ceratopicanol was accomplished using additional eight-step transformations starting from 4. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917117

2694
LETTER
Total Synthesis of ( )-Ceratopicanol: Application of Pd-Catalyzed Enediyne
Cycloreduction
Total
Synthesis
o
h
f
(
)-Ceratop
a
icanol ng Ho Oh,* Chul Yun Rhim, Mira Kim, Dai In Park, Aruna Kumar Gupta
GOS Lab, Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, Korea
Fax +82(2)22990762; E-mail: changho@hanyang.ac.kr
Received 22 August 2005
O
TBSO
HO
Abstract: Pd-catalyzed cycloreduction of enediyne 3 successfully
afforded the linear triquinane skeleton 4. Total synthesis of ( )-cer-
i–v
vi, vii
atopicanol was accomplished using additional eight-step transfor-
mations starting from 4.
1
TIPSO
3
2
TIPSO
Key words: ceratopicanol, palladium, enediyne, cycloreduction,
triquinane
Scheme 1 Preparation of enediyne 3. Reagents and conditions: (i)
DHP, TsOH (cat), CH2Cl2, r.t., 2 h (98%): (ii) n-BuLi, 2,2-dimethyl-
4-pentenal, THF, –78 °C (80%); (iii) (i-Pr)3SiOTf, 2,6-lutidine,
CH2Cl2, r.t., 2 h (92%); (iv) TsOH (cat.), i-PrOH, r.t., 4 h, (88%); (v)
PDC, CH2Cl2, r.t., 10 h (86%); (vi) ethynylmagnesium bromide, THF,
0 °C, 2 h (78%); (vii) t-BuMe2SiCl, imidazole, DMF, r.t., 6 h (90%).
In 1996, we reported Pd-catalyzed cycloreduction of
enediynes affording [m,5,n]-tricyclic compounds
(Equation 1).1 The reaction indeed proceeds with high
levels of chemo- and stereoselectivities and is accompa-
nied by a significant increase in structural complexity. We
have utilized this method to synthesize members of the
triquinane natural products and here wish to report a
highly efficient synthesis of ( )-ceratopicanol.
nesium bromide and again protected its hydroxyl group
with tert-butyldimethylsilyl chloride to give the enediyne
3 in multi-gram scale. The seven-step overall yield from 1
to 3 was 38%. In real syntheses, multi-gram scale prepa-
ration of 3 was accomplished with only one purification
step for the aldehyde 2 during these processes.
R
R
[π-allylPdCl]2 (5 mol%)
The next challenge was to transform enediyne 3 into the
tricycle 4. Pd-catalyzed cycloreduction of 3 under our re-
ported conditions gave a mixture of tricycle 4 in only 35%
yield along with unidentified products.1 This was fair
enough but had to be improved its chemical yield. A ma-
jor problem was found to arise from competitive b-elimi-
nation of the alkylpalladium intermediates A which could
be prone to undergo b-elimination to form the triene 5 as
shown in Scheme 2.7
m
()a
()a
n
HCOOH (1.5 equiv)
a, b = 1, 2; R = H, Me
()b
()b
Equation 1
Ceratopicanol, isolated from the fungus Ceratocystis
piceae Ha 4/82 by Hanssen and Abraham in 1988,2 has an
attractive synthetic challenge due to the uncommon pres-
ence of two vicinal bridgehead quaternary carbons among
the five contiguous chiral centers, on a cis,anti,cis-
triquinane framework.3 Its structure represents evidence
for the biosynthetic generation of hirsutene and related
natural products associated with the humulene cascade.4
By now, six groups reported total syntheses of ceratopi-
canol that span from a low of 7 to a high of 21 synthetic
steps in varying efficiencies.5 Our synthesis of ( )-cer-
atopicanol began with enediyne 3, which was readily pre-
pared from 4-pentyn-1-ol in very common processes
(Scheme 1).
PdOOCH
TBSO
PdOOCH
TBSO
TBSO
Et3SiH
H
TIPSO
TIPSO
TIPSO
A
B
4
TBSO
Transformation of 4-pentyn-1-ol (1) into the aldehyde 2
was conducted: THP-protection of the hydroxyl group,
coupling of its terminal carbon with 2,2-dimethyl-4-pen-
tenal, TIPS-protection of the newly formed hydroxyl
group, deprotection of THP into the alcohol,6 and PDC
oxidation. The aldehyde 2 was coupled with ethynylmag-
TIPSO
5
Scheme 2 Pd-catalyzed cycloreduction of enediyne 3 to 4.
We believe that the intermediate A undergoes two path-
ways: one to thermodynamically stable triene 5 and the
other to kinetically facile cyclopentenylmethyl intermedi-
ate B.1 To facilitate formation of 4, a stronger reductant
was required to cleave the carbon–Pd bond of B. Thus, we
have attempted optimization studies by adding reductants
SYNLETT 2005, No. 17, pp 2694–2696
1
7
.1
0
.2
0
0
5
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917117; Art ID: U26305ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (±)-Ceratopicanol
2695
as well as by changing reaction temperature and solvents. of ceratopicanol. However, the major isomer 7b was
After all, a catalytic mixture of [(p-allyl)PdCl]2 (5 mol%), proven to have a cis,cis,cis configuration by 2D-NOESY
PPh3 (20 mol%), HCOOH (1.0 equiv), and triethylsilane experiments, which was confirmed by X-ray crystal struc-
(10 equiv) in 1,4-dioxane, was found to transform ene- ture of its derivative 12b. In the beginning of this synthe-
diyne 3 to the cycloreduced tricycle 4 in 70–75% yield sis, deoxygenation of 7b was attempted, since we assumed
(a:b ratio of angular H = 1:3) along with only a little that 7b had the correct configuration with that of cera-
amount of 5.8 Although eight racemic products could be topicanol (Scheme 4). Its Wolff–Kishner deoxygenation
formed due to four stereogenic centers, only four tricyclic did not occur.10 Its reduction with sodium borohydride
products were generated with anti-relationship between furnished alcohol 8b (86%) and the following Barton–
TBSO group and the angular methyl group. Gratifyingly, McCombei deoxygenation and desilylation were carried
we were able to obtain 4 in multi-gram quantity from each out successfully to give 11b in 55% yield. Since 1H NMR
trial, which was important in early stage in multi-step data of 11b were different from reported data of cerato-
syntheses.
picanol, we elucidated a structure of 12b, the desilylated
compound of 8b, by X-ray study as shown in Figure 1.
With the tricyclic compound 4 in hand by using our Pd-
catalyzed cycloreduction methodology as a key step, we
could attempt a total synthesis of ( )-ceratopicanol, a
triquinane sesquiterpene as shown in Scheme 3.
TBSO
HO
H
H
Wolff–Kishner reduction
no reaction
H
11β
TBSO
TBSO
TBSO
7β
O
H
H
a
c
NaBH4 86%
i) KH, CS2, then MeI
ii) n-Bu3SnH, AIBN
TIPSO
RO
O
6
3
iii) TBAF
4 (R = OTIPS)
4a (R = H)
b
HO
TBSO
55% overall
HF
H
H
d
TBSO
TBSO
TBSO
H
H
12β
H
8β
HO
HO
f
e
Scheme 4 Conversion of 7b to 11b.
H
H
HO
MeS2CO
7α (26%)
O
9
8
g
i
TBSO
TBSO
HO
H
H
h
H
7β (48%)
O
10
O
Ceratopicanol (11)
Scheme 3 Total synthesis of ( )-ceratopicanol. Reagents and con-
ditions: (a) 5 mol% [(p-allyl)PdCl]2, 20 mol% PPh3, 1.0 equiv
HCOOH, 10 equiv Et3SiH, 1,4-dioxane, 80 °C, 20 h (70%); (b) TB-
AF, THF (83%); (c) (COCl)2, DMSO, then Et3N, CH2Cl2, –78 °C
(88%); (d) Me2CuMgBr, THF,–78 °C to r.t. (74%); (e) DIBAL, THF,
0 °C, 1 h (90%); (f) KH, CS2, then MeI, THF (95 %); (g) n-Bu3SnH,
AIBN (cat.), toluene, reflux, 30 min, then TBAF, THF, reflux, 2 h
(64%); (h) LDA, PhSeCl, –78 °C, then H2O2, CH2Cl2, r.t., 2 h (82%);
(i) Li, NH3, t-BuOH, –78 °C, 20 min (55 %).
Figure 1 X-ray structure of 12b.
A remaining problem was how to utilize 7b in this synthe-
sis. We could convert 7b to the enone 10 by a-selenylation
followed by oxidative elimination in one-pot process.11
Lithium reduction of 10 in liquid ammonia gave the alco-
hol 8 as per Mehta’s synthesis.5f,12 Overall yield from 7b
to 8 was 45%.
Selective deprotection of TIPS group of 4 by using one
equivalent TBAF in THF afforded 4a which was then
oxidized to give a 1:3 diastereomeric mixture of enone 6.
Introduction of a bridgehead quaternary methyl group was
cleanly conducted by using classical magnesium di-
methylcuprate in THF at –78 °C in 74% yield.9 At this Complete synthesis of ceratopicanol from 7a was accom-
stage, we needed to separate two diastereomers, one of plished by deoxygenation using known methods.13
which had to be altered its ring configuration. Based on Reduction of 7a with DIBAL to the alcohol 8 (1:9) and its
2D NMR analysis of related compounds done by us in xanthate formation of 8 to 9 were easily conducted.
1996, the major isomer was believed to have a
Reduction using tributyltin hydride smoothly occurred in
cis,trans,cis ring configuration, which matched with that refluxing toluene in the presence of a catalytic amount of
Synlett 2005, No. 17, 2694–2696 © Thieme Stuttgart · New York

2696
C. H. Oh et al.
LETTER
(5) (a) Paquette, L. A.; Geng, F. J. Am. Chem. Soc. 2002, 124,
9199. (b) Mukai, C.; Kobayashi, M.; Kim, I. J.; Hanaoka, M.
Tetrahedron 2002, 58, 5225. (c) Anger, T.; Graalmann, O.;
Schröder, H.; Gerke, R.; Kaiser, U.; Fitjer, L.; Noltemeyer,
M. Tetrahedron 1998, 54, 10713. (d) Baralotto, C.; Chanon,
M.; Julliard, M. J. Org. Chem. 1996, 61, 3576. (e) Clive, D.
L. J.; Magnuson, S. R. Tetrahedron Lett. 1995, 36, 15.
(f) Metha, G.; Karra, S. R. J. Chem. Soc., Chem. Commun.
1991, 1367.
(6) (a) Almqvist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6,
957. (b) Shenvi, A. B.; Gerlach, H. Helv. Chim. Acta 1980,
63, 2426.
(7) Similar types of alkylpalladium intermediates bearing a b-
hydrogen are prone to undergo elimination to the
corresponding alkenes. For reviews, see: (a) Trost, B. M.
Science 1991, 254, 1471. (b) Trost, B. M. Acc. Chem. Res.
1990, 23, 34. (c) Trost, B. M.; Shi, Y. J. Am. Chem. Soc.
1993, 115, 12491.
(8) For the use of formic acid or formates as a hydrogen donor
in palladium-mediated reactions, see: (a) Tsuji, J.
Palladium Reagents and Catalysts; Wiley: Chichester,
1995. (b) Tsuji, J.; Mandai, T. Synthesis 1996, 1. (c) Trost,
B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625. (d)Oh,C.
H.; Jung, H. H.; Sung, H. R.; Kim, J. D. Tetrahedron 2001,
57, 1723. (e) Oh, C. H.; Park, S. J. Tetrahedron Lett. 2003,
44, 3785.
(9) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 136.
(b) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171.
(10) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126,
5436.
AIBN. Chromatographic purification of TBS-protected
ceratopicanol resulted in failure due to difficulty in re-
moving tributyltin hydride and its derivatives.14 Thus,
upon completion of the reduction, the reaction mixture
was concentrated under reduced pressure, dissolved in
THF, and refluxed in the presence of TBAF. Due to high
affinity between tin and fluoride, this process could afford
pure ( )-ceratopicanol (11) as a colorless oil in 64% yield,
whose 1H NMR data were identical to reported data.15 Fi-
nally, we decided this synthesis using the mixture of 7a
and 7b without separation. About 1:3 mixture of 7a and 7b
was converted to the enone 10 and dissolving metal reduc-
tion to alcohol 8, and the following Barton–McCombie re-
duction and desilylation gave ( )-ceratopicanol in similar
yield based on a mixture of 7a and 7b. Overall, this syn-
thesis based on Pd-catalyzed cycloreduction as a key step
is composed of eight highly efficient steps and furnished
( )-ceratopicanol in overall 13–15% yield based on the
enediyne 3.
In conclusion, we accomplished the total synthesis of
ceratopicanol in eight steps with 14% overall yield based
on readily prepared endiyne 3. Most steps were composed
of highly efficient procedures. Finally, we wish to note
that Pd-catalyzed cycloreduction of enediyne 3, leading to
the key skeleton of the triquinane natural products, made
this synthesis highly efficient and practical method over
the reported syntheses to date.
(11) Piers, E.; Orellana, A. Synthesis 2001, 2138.
(12) Shono, T.; Kise, N.; Fujimoto, T.; Tominga, N.; Morita, H.
J. Org. Chem. 1992, 57, 7175.
(13) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Metha, G.; Umarye, J. D.
Tetrahedron Lett. 2001, 42, 1991. (c) Keller, V. A.; Kim, I.;
Burke, S. D. Org. Lett. 2005, 7, 737.
(14) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968.
(15) All new compounds were fully characterized by 1H NMR,
13C NMR, IR, HRMS (or elemental analysis).
Acknowledgment
We wish to acknowledge the financial support of Korea Research
Foundation (2004-C00197), Korea. A. K. Gupta is grateful for a
Brain-Pool fellowship supported by the KOSEF.
References
Ceratopicanol (11): 1H NMR (400 MHz, CDCl3): d = 3.71
(dd, J = 10.0, 7.2 Hz, 1 H), 2.49 (m, 1 H), 2.34 (ddd,
J = 11.3, 8.3, 8.3 Hz, 1 H), 2.15 (dd, J = 14.0, 9.6 Hz, 1 H),
1.88 (m, 1 H), 1.67 (ddd, J = 13.0, 8.4, 1.2 Hz, 1 H), 1.56 (m,
1 H), 1.50–1.32 (m, 5 H), 1.23 (dd, J = 13.0, 4.8 Hz, 1 H),
1.08 (dd, J = 13.8, 6.8 Hz, 1 H), 1.04 (s, 6 H), 0.88 (s, 3 H),
0.87 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 82.62, 58.80,
54.96, 51.23, 48.77, 44.18, 41.94, 41.68, 40.85, 39.56,
31.54, 30.60, 28.54, 23.66, 21.25. FT-IR (neat): 3310 (–OH,
br s) cm–1.
(1) (a) Oh, C. H.; Rhim, C. Y.; Kang, J. H.; Kim, A.; Park, B. S.;
Seo, Y. Tetrahedron Lett. 1996, 37, 8875. (b) Oh, C. H.;
Rhim, C. Y.; Jung, H. H.; Jung, S. H. Bull. Korean Chem.
Soc. 1999, 20, 643.
(2) Hanssen, H. P.; Abraham, W. R. Tetrahedron 1988, 44,
2175.
(3) For reviews, see: (a) Mehta, G.; Srikrishna, A. Chem. Rev.
1997, 97, 671. (b) Singh, V.; Thomas, B. Tetrahedron 1998,
54, 3647.
Isomer of Ceratopicanol (11b): 1H NMR (400 MHz,
CDCl3): d = 3.88 (m, 1 H), 2.64 (h, J = 8.0 Hz, 1 H), 2.45 (dt,
J = 11.2, 9.6 Hz, 1 H), 2.08 (dtd, J = 13.6, 9.2, 5.6 Hz, 1 H),
1.79 (ddd, J = 11.6, 11.4, 5.6 Hz, 1 H), 1.65–1.54 (m, 2 H),
1.46 (s, 1 H), 1.44 (s, 1 H), 1.38 (ddd, J = 12.8, 8.8, 2.0 Hz,
1 H), 1.31 (d, J = 4.0 Hz, 1 H), 1.28 (m, 1 H), 1.11–1.06 (m,
2 H), 1.04 (s, 3 H), 0.95 (s, 3 H), 0.91 (s, 3 H), 0.79 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 81.16, 59.62, 54.63, 52.27,
49.83, 44.25, 41.44, 40.97, 39.85, 32.81, 30.25, 29.35,
28.15, 23.69, 19.63. FT-IR (neat): 3320 (–OH, br s) cm–1.
HRMS (ES): m/z calcd for C15H26ONa+: 245.1881; found:
245.1872.
(4) (a) Hayano, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T.
Helv. Chim. Acta 1981, 64, 1347. (b) Comer, F. W.;
McCapra, F.; Qureshi, I. H.; Scott, A. I. Tetrahedron 1967,
23, 4761.
Synlett 2005, No. 17, 2694–2696 © Thieme Stuttgart · New York