Total synthesis of pseudodehydrothyrsiferol

Article abstract of DOI:10.1021/ol802600n

(Chemical Equation Presented) An enantioselectlve total synthesis of pseudodehydrothyrsiferol has been accomplished. The synthetic sequence highlights formation of the highly strained tetrahydropyran C-ring by a Mitsunobu-type S_N2 reaction with

Full text of DOI:10.1021/ol802600n

ORGANIC
LETTERS
2009
Vol. 11, No. 3
579-582
Total Synthesis of
Pseudodehydrothyrsiferol
Hideaki Hioki,* Masatoshi Motosue, Yasuhiko Mizutani, Akira Noda,
Tomoaki Shimoda, Miwa Kubo, Kenichi Harada, Yoshiyasu Fukuyama, and
Mitsuaki Kodama
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
hioki@ph.bunri-u.ac.jp
Received November 11, 2008
ABSTRACT
An enantioselective total synthesis of pseudodehydrothyrsiferol has been accomplished. The synthetic sequence highlights formation of the
highly strained tetrahydropyran C-ring by a Mitsunobu-type SN2 reaction with an oxygen nucleophile.
Pseudodehydrothyrsiferol (1), belonging to the thyrsiferol
family, was isolated along with other related compounds from
the red alga Laurencia Viridis by Ferna´ndez et al.1 Several
members of the thyrsiferol family exhibit a potent and
specific inhibitory effect on protein phosphatases 2A2 and
strong cytotoxic activity.3 This family has attracted synthetic
attention because of their unique structures of squalene-
derived polyether combined with interesting biological
activities. The characteristic structural feature of this family
includes the strained tetrahydropyran C-ring adopting a twist-
boat conformation to avoid an unfavorable 1,3-diaxial
interaction between the angular methyl group and the side
chain (Figure 1). Three groups have already completed the
syntheses of thyrsiferol, thyrsiferol 23-acetate, and venusta-
Figure 1. Structure of pseudodehydrothyrsiferol (1) and twist-boat
conformation of C-ring in 1.
triol among this family.4 The key step in their syntheses
was how to construct the strained tetrahydropyran C-ring.
Herein we report the first enantioselective total synthesis of
(1) Manr´ıquez, C. P.; Souto, M. L.; Gav´ın, J. A.; Norte, M.; Ferna´ndez,
J. J. Tetrahedron 2001, 57, 3117–3123.
(2) (a) Matsuzawa, S.; Suzuki, T.; Suzuki, M.; Matsuda, A.; Kawamura,
T.; Mizuno, Y.; Kikuchi, K. FEBS Lett. 1994, 356, 272–274. (b) Souto,
M. L.; Manr´ıquez, C. P.; Norte, M.; Leira, F.; Ferna´ndez, J. J. Bioorg. Med.
Chem. Lett. 2003, 13, 1261–1264.
(4) (a) Corey, E. J.; Ha, D. C. Tetrahedron Lett. 1988, 29, 3171–3174.
(b) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. J. Org. Chem. 1990, 55, 5088–5107. (c) Gonza´lez, I. C.;
Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099–9108.
(3) Ferna´ndez, J. J.; Souto, M. L.; Norte, M. Nat. Prod. Rep. 2000, 17,
235–246.
10.1021/ol802600n CCC: $40.75
Published on Web 12/29/2008
2009 American Chemical Society

Scheme 1
.
Retrosynthesis of Pseudodehydrothyrsiferol (1).
Scheme 2. Synthesis of Segment A
be favored over 5-exo product 7 because the terminal vinyl
group can assist cleavage of next C-O bond.7 The epoxy
alcohol was easily cyclized even in the presence of a small
amount of acid in CDCl3. However, endo-exo ratio was low
(6/7 ) 2:1). The ratio was improved to 4.3:1 when the
reaction was performed at -78 °C in the presence of 0.2
equiv of 10-camphorsulfonic acid. TBS protection of the
tertiary alcohol in 6 completed the synthesis of the segment
A (8).
pseudodehydrothyrsiferol (1) featuring unique C-ring closure
by a Mitsunobu-type SN2 reaction.
Our retrosynthetic analysis is illustrated in Scheme 1.
Disconnection of the target molecule at the central part leads
to C16 segment A and C14 segment B, both of which have a
1,3-trans tetrahydrofuran ring with different configuration.
They would be connected by Suzuki-Miyaura coupling. We
envisioned that the key cyclization to form the C-ring would
be realized by ring closure with an oxygen nucleophile.
Segment A with tetrahydropyran ring would be synthesized
from C15 unit C by oxidation and C1 elongation. On the other
hand, segment B would be synthesized from C15 unit E,
which is the antipode of C, by oxidation of the primary
hydroxy group. The carboxylic acid D would be converted
to segment B by a stereospecific Hunsdiecker-type reaction.
Preparation of the segments A and B began with the 1,3-
trans tetrahydrofuran derivative 2 and its enantiomer 9, which
were prepared from the same precursor as reported previ-
ously.5 A synthetic scheme for the segment A is shown in
Scheme 2. After protection of two hydroxy groups in 2 as
TBS ethers, the terminal acetate was hydrolyzed. The
resulting allylic alcohol 3 was converted into epoxide 4 (77%
de) by Sharpless asymmetric epoxidation using diethyl L-(+)-
tartrate.6 The primary alcohol in 4 was oxidized followed
by Wittig methylenation to afford allyl epoxide 5. After
deprotection of the secondary TBS group in 5, the resulting
epoxy alcohol was subjected to cyclization under acidic
conditions. 6-endo Cyclization product 6 was expected to
Scheme 3. Synthesis of Segment B
Segment B was synthesized according to the following
procedure shown in Scheme 3. Starting from 9, the secondary
hydroxy group was acetylated and then terminal acetate was
selectively hydrolyzed. The resulting allylic alcohol was
oxidized to carboxylic acid 10 in further two steps. After
bromination of 10, the resulting dibromide was subjected to
microwave assisted stereospecific decarboxylation along with
debromination according to Tokuda’s procedure.8 (Z)-vinyl
(5) Hioki, H.; Kanehara, C.; Ohnishi, Y.; Umemori, Y.; Sakai, H.;
(7) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K.
J. Am. Chem. Soc. 1989, 111, 5330–5334. (b) Matsukura, H.; Morimoto,
M.; Koshino, H.; Nakata, T. Tetrahedron Lett. 1997, 38, 5545–5548.
(8) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron Lett. 2001, 42,
3893–3896.
Yoshio, S.; Matsushita, M.; Kodama, M. Angew. Chem., Int. Ed. 2000, 39,
2552–2554.
(6) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
580
Org. Lett., Vol. 11, No. 3, 2009

Scheme 4. Syntheses of Pseudodehydrothyrsiferol (1) and Its C-14 Epimer (19)
bromide 11 was mainly obtained with 20:1 stereoselectivtiy
with regard to the olefin geometry.9
this stage. The major isomer was assigned to be 14S by
Kusumi’s method11 after converting 14a to (R)- and (S)-
MTPA esters. Walden inversion at C-14 in 14a is required
to lead pseudodehydrothyrsiferol 1. Tsunoda et al. reported
a dehydrative cyclization of 1,5-diol to tetrahydropyran by
phosphorane-type Mitsunobu reagents (Tsunoda reagent).12
We applied this method to 1, although they only reported
nucleophilic substitution at primary carbon. The least
hindered allyl alcohol at C-14 in 15a expected to be
phosphorylated among five hydroxy groups at first and
subsequent intramolecular nucleophilic substitution at C-14
would take place with the inversion of configuration. A
hydroxy group at C-10 is necessary to attack on C-14 for
The total synthesis of 1 was achieved as shown in Scheme
4. After hydroboration of the segment A (8) with 9-BBN,
microwave-assisted Suzuki-Miyaura cross-coupling10 with
the segment B (11) was carried out to give 12 in good yield.
Terminal hydroxy group in 12 was protected as TBS ether
and then trisubstituted alkene was converted to epoxides 13
as a 2:1 mixture of inseparable diastreomers by treatment
with m-CPBA. This mixture was subjected to Al(O-i-Pr)4-
catalyzed isomerization to give allyl alcohols 14a and 14b,
accompanied by deprotection of the acetate. Two diastere-
omers were separable by simple column chromatography at
(9) Unexpectedly, the reaction proceeded without the aid of microwave
heating; however, the selectivity was slightly reduced (10:1).
(10) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem.
2004, 69, 3173–3180.
(11) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(12) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto,
H.; Itoˆ, S. Tetrahedron Lett. 1996, 37, 2463–2466.
Org. Lett., Vol. 11, No. 3, 2009
581

leading to 1, even in the presence of another oxygen
nucleophile. Upon treatment of 15a with CMMP 20,13 the
most reactive Tsunoda reagent, in benzene at 80 °C for 24 h,
the desired pseudodehydrothyrsiferol 1 was obtained in 45%
yield, along with 20% of isomer 18a formed by an undesired
nucleophilic substitution with a hydroxy group at C-18. The
reaction proceeded with the complete inversion of config-
with a twist-boat conformation occurred more easily than
less-strained C-ring with chair conformation. Shirahama et
al. reported adverse results in case of intramolecular cy-
clization of epoxy alcohol.4b The striking difference is
intriguing but ambiguous at this stage.
In summary, the first total synthesis of pseudodehydroth-
yrsiferol (1) has been completed. The present synthesis
emphasizes the effective formation of the strained tetrahy-
dropyran C-ring, which is the crucial issue in the synthesis
of thyrsiferols. Dehydrative cyclization between secondary
and tertiary 1,5-diol to form a strained tetrahydropyran C-ring
was successfully achieved along with complete Walden
inversion at C-14 utilizing the Tsunoda reagent. Our synthesis
exemplifies a new approach to form highly strained cyclic
ethers. It would be applicable to various hindered diols.
1
uration at C-14. The H and 13C NMR spectra of synthetic
compound 1 were in agreement with those of the natural
product 1. The synthetic sample showed negative optical
rotation in accordance with the natural compound, however
the value was much smaller than that of the natural product.
([R]25 -2.7, lit.1 [R]25 -13.1). Interestingly, when C-14
D
D
epimer 15b was applied to the same cyclization condition,
14-epi-pseudohydrothyrsiferol (19) was not obtained but
isomer 18b in 62% yield. The secondary alcohol at C-18 in
both isomers 15a and 15b was protected by an acetyl group
in two steps to avoid the undesired cyclization by the C-18
oxygen nucleophile. The yield of the cyclization for 16a was
improved to 66% as expected. On the other hand, the reaction
of 16b did not proceed smoothly. 17b was obtained in only
10% yield along with 55% of stating material. Pseudode-
hydrothyrsiferol (1) and 14-epi-pseudodehydrothyrsiferol (19)
were synthesized by hydrolysis of the acetate in 17a and
17b. In these cyclizations, ring closure to strained C-ring
Acknowledgment. We thank Prof. Ferna´ndez (Univer-
sidad de La Laguna) for sending us the NMR spectra of
natural pseudodehydrothyrsiferol for comparison. We further
thank Prof. Tsunoda (Tokushima Bunri University) for a gift
of Tsunoda reagent and direction for the synthesis.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Sakamoto, I.; Kaku, H.; Tsunoda, T. Chem. Pharm. Bull. 2003,
51, 474–476.
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