Total synthesis of (-)-HM-3 and (-)-HM-4 utilizing a palladium-catalyzed addition of an arylboronic acid to an allenic alcohol followed by eschenmoser-claisen rearrangement

Article abstract of DOI:10.1055/s-0033-1341059

The first asymmetric total synthesis of (-)-HM-3 and (-)-HM-4, aromatic sesquiterpenes isolated from the phytopathogenic fungus Helicobasidium mompa, has been achieved. Highlight of the synthesis is an enantiospecific construction of the quaternary carbon stereocenter utilizing a palladium-catalyzed addition of arylboronic acid to the allenic alcohol followed by Eschenmoser-Claisen rearrangement. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341059

1160▌
LETTER
letter
Total Synthesis of (–)-HM-3 and (–)-HM-4 Utilizing a Palladium-Catalyzed
Addition of an Arylboronic Acid to an Allenic Alcohol Followed by
Eschenmoser–Claisen Rearrangement
First Asymmetric Total Synthesis of (–)-HM-3 and (–)-HM-4
Masahiro Yoshida,* Tomoyo Kasai, Tomotaka Mizuguchi, Kosuke Namba
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337294; E-mail: yoshi@tokushima-u.ac.jp
Received: 14.02.2014; Accepted: 03.03.2014
total synthesis of 1 and 2, utilizing a palladium-catalyzed
Abstract: The first asymmetric total synthesis of (–)-HM-3 and
addition of an arylboronic acid to an allene followed by
(–)-HM-4, aromatic sesquiterpenes isolated from the phytopatho-
Eschenmoser–Claisen rearrangement.
genic fungus Helicobasidium mompa, has been achieved. Highlight
of the synthesis is an enantiospecific construction of the quaternary
carbon stereocenter utilizing a palladium-catalyzed addition of aryl-
boronic acid to the allenic alcohol followed by Eschenmoser–
Claisen rearrangement.
OH
X
.
O
Claisen-type
rearrangement
R
Pd-catalyzed
addition
*
OH
*
+
Key words: allenes, boron, Claisen rearrangement, natural prod-
ucts, palladium, total synthesis
R
Ar
R
Ar
*
ArB(OH)2
Scheme 1 Palladium-catalyzed addition of an arylboronic acid to an
allenic alcohol followed by Claisen-type rearrangement
(–)-HM-3 (1) and (–)-HM-4 (2) are aromatic sesquiter-
penes that were isolated from the phytopathogenic fungus
Helicobasidium mompa by Takahashi and Nohara in
1989.1 The structure of (–)-HM-3 was originally proposed
as 1′, which was revised to 1 based upon comparison with
a synthetic compound by Srikrishna in 2006 (Figure 1).2
Because of the sterically congested structure of 1 and 2
which contain a quaternary carbon stereocenter at the ben-
zylic position, considerable synthetic interest has been
stimulated.
Retrosynthetic analysis of (–)-HM-3 (1) and (–)-HM-4 (2)
is shown in Scheme 2. We expected that 1 and 2 could be
synthesized from the cyclopentenone 3 via the functional
transformation on the cyclopentane ring. Compound 3
would be produced by the construction of a five-mem-
bered ring from the amide 4, which may be obtained from
the optically active allenic alcohol 5 and the arylboronic
acid 6 by a sequential palladium-catalyzed addition–
Eschenmoser–Claisen rearrangement.
OH
OH
O
OR
OH
OMe
OR
OMe
AcO
HM-3 (1) R = Ac
HM-4 (2) R = H
1'
HM-3 (1) R = Ac
HM-4 (2) R = H
3
Figure 1 Structure of HM-3 (1) and HM-4 (2)
OH
We have previously reported a palladium-catalyzed addi-
tion of arylboronic acids to allenic alcohols, in which aryl-
substituted allylic alcohols having an E geometry were
produced in regio- and stereoselective manner.3 In addi-
tion, a quaternary carbon stereocenter can be created ste-
reospecifically by the Claisen-type rearrangement of the
resulting allylic alcohol (Scheme 1).4 Since this method-
ology is useful for the synthesis of natural products having
a quaternary carbon stereocenter at the benzylic position,5
we planned to apply it for the synthesis of (–)-HM-3 (1)
NMe2
OMe
.
O
Ph
5
OMe
Ph
+
OMe
(HO)2B
OMe
4
6
and (–)-HM-4 (2). Herein, we report the first asymmetric Scheme 2 Retrosynthetic analysis of HM-3 (1) and HM-4 (2)
The key sequence toward the intermediate 4 is outlined in
SYNLETT 2014, 25, 1160–1162
Scheme 3. When the optically active allenic alcohol 55a
(96% ee) and the arylboronic acid 6 were treated with 5
Advanced online publication: 03.04.2014
DOI: 10.1055/s-0033-1341059; Art ID: ST-2014-U0123-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
First Asymmetric Total Synthesis of (–)-HM-3 and (–)-HM-4
1161
6
NMe2
mol% of [Pd2(OH)2(PPh3)4][BF4]2 and five equivalents
of Et3N in dioxane–H2O (20:1) at 80 ºC, the desired aryl-
substituted allylic alcohol 7 was obtained together with an
inseparable unidentified by-product. The resulting mix-
ture of 7 was further subjected to the Eschenmoser–
Claisen rearrangement to afford the corresponding amide
4 having a quaternary asymmetric center in 58% yield in
two steps. The enantiomeric excess of 4 was determined
as 95%, which indicates that a highly enantiospecific
[3,3]-sigmatropic rearrangement via the cyclic transition
state 8 had proceeded.7
O
O
OMe
OMe
MeLi
OMe
OMe
Ph
Ph
Et2O, r.t.
81%
4
9
O
O3; Ph3P
OMe
K2CO3
H
OMe
CH2Cl2-MeOH
–78 °C to r.t.
t-BuOH, reflux
96%
O
85%
10
OMe
[Pd(OH)2(PPh3)4][BF4]2
(5 mol%)
OH
O
O
(HO)2B
OMe
.
+
OMe
OMe
OMe
NaH, MeI
Ph
Et3N (5 equiv)
dioxane–H2O (20:1)
80 °C
OMe
THF–DMF
65%
6
5 (96% ee)
3
11
OH
OMe
O
Me2NC(Me)(OMe)2
xylene, reflux
O
OMe
Ar
Ph
Ph
OMe
H2, Pd/C
Me2N
OMe
EtOH
99%
7
8
NMe2
O
12
OMe
OMe
Scheme 4 Synthesis of the cyclopentanone 12
Ph
of the methyl ether in 14 by the treatment with BBr3 pro-
vided (–)-HM-4 (2) in 55% yield. Furthermore, (–)-HM-3
(1) was obtained in 81% yield by the regioselective acet-
ylation of 2 using Ac2O. Spectral data of synthetic (–)-
HM-3 (1)8 and (–)-HM-4 (2)9 were in good agreement
with those derived from the natural products.10
4 58% (95% ee)
(2 steps)
Scheme 3 Synthesis of the intermediate 4
The reaction of the amide 4 with MeLi afforded the meth-
yl ketone 9 (81%), which was converted into the ketoalde-
hyde 10 by the oxidative cleavage of the double bond in
85% yield (Scheme 4). Then construction of the cyclopen-
tane ring by the intramolecular aldol condensation of 10
using K2CO3 was successfully accomplished to produce
the cyclopentenone 3 in 96% yield. After α-dimethylation
of 3 using NaH and MeI (65%), the resulting product 11
was hydrogenated to give the cyclopentanone 12 in 99%
yield.
HO
O
NaBH4
OMe
OMe
OMe
MeOH, 0 °C
91%
OMe
13
12
1) NaH, CS2, MeI
THF
OMe
BBr3
The final stage of the synthesis involves a reductive deox-
ygenation of the ketone moiety in 12 (Scheme 5). In the
synthesis of racemic HM-3 and HM-4 by Srikrishna, it
was reported that the sequential thioacetalization–reduc-
tive desulfurization of 12 successfully proceeded. We ini-
tially examined the reactions according to the reported
procedure, but this method did not give reproducible
yield, unfortunately. After several attempts, it was found
that Barton–McCombie radical deoxygenation protocol is
more effective in our case. Thus, after the reduction of the
ketone 12 with NaBH4 (91% yield), the Barton–
McCombie deoxygenation for the resulting alcohol 13 af-
forded the desired product 14 in moderate yield. Cleavage
OMe
CH2Cl2, –40 °C
55%
2) AIBN, n-Bu3SnH
benzene, reflux
47% (2 steps)
14
OH
OH
OH
Ac2O, pyridine
OAc
CH2Cl2
81%
HM-3 (1)
HM-4 (2)
Scheme 5 Completion of the total synthesis of (–)-HM-3 (1) and
(–)-HM-4 (2)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1160–1162

1162
M. Yoshida et al.
LETTER
min, the solvent was removed in vacuo. The residue was
In conclusion, the first asymmetric total synthesis of
(–)-HM-3 (1) and (–)-HM-4 (2) has been achieved. The
key elements of the synthesis include the enantiospecific
construction of the quaternary carbon stereocenter using
a palladium-catalyzed addition of the arylboronic acid
to the optically active allenic alcohol followed by
Eschenmoser–Claisen rearrangement. Application of this
process to the synthesis of other natural products is now in
progress.
chromatographed on silica gel with hexane–EtOAc (70:30)
as eluent to give amide 4 (289.9 mg, 58% in 2 steps, 95% ee)
as a yellow oil; [α]D33 –9.6 (c = 1.00, CHCl3). IR (KBr):
3023, 2936, 1643, 1492, 1458, 1401, 1275, 1052, 1021 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.69 (s, 3 H), 2.24 (s, 3 H),
2.85 (s, 3 H), 2.93 (s, 3 H), 3.04 (d, J = 14.8 Hz, 1 H), 3.10
(d, J = 14.8 Hz, 1 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 6.25 (d, J
= 16.4 Hz, 1 H), 6.82 (d, J = 16.4 Hz, 1 H), 6.85 (d, J = 8.0
Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H),
7.28 (t, J = 7.6 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 15.6 (Me), 26.4 (Me), 35.4 (Me),
37.7 (Me), 42.4 (CH2), 42.7 (Cq), 59.3 (Me), 60.0 (Me),
122.5 (CH), 124.7 (CH), 126.0 (CH), 126.0 (CH), 126.8
(CH), 128.4 (CH), 130.9 (Cq), 137.9 (Cq), 138.1 (Cq), 139.8
(CH), 151.6 (Cq), 151.7 (Cq), 171.3 (Cq). HRMS (ESI): m/z
[M + H]+ calcd for C23H30NO3: 368.2226; found: 368.2226.
Enantiomeric excess was determined by HPLC analysis
[CHIRALCEL AS-H column, 10% isopropanol–hexane,
flow rate = 0.3 mL/min, λ = 254 nm, tR = 24.6 min (S), tR =
26.6 min (R)].
Acknowledgment
This study was supported in part by a Grant-in-Aid for Scientific
Technique Research Promotion Program for Agriculture, Forestry,
Fisheries and Food Industry from the Ministry of Agriculture, Fore-
stry and Fisheries.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(8) Data for 1: mp 137.8–140.5 °C (recrystallized from EtOAc–
hexane); [α]D29 –33.3 (c = 0.44, CHCl3). IR (KBr): 3339,
2924, 2361, 1736, 1421, 1373, 1281, 1239, 1191 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 0.74 (s, 3 H), 1.15 (s, 3 H),
1.40 (s, 3 H), 1.49–1.79 (m, 5 H), 2.11 (s, 3 H), 2.37 (s, 3 H),
2.53–2.61 (s, 1 H), 5.14 (s, 1 H), 6.69 (d, J = 8.0 Hz, 1 H),
7.08 (d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ =
16.0 (Me), 20.5 (CH2), 20.6 (Me), 22.9 (Me), 25.5 (Me),
26.9 (Me), 39.4 (CH2), 41.2 (CH2), 44.9 (Cq), 51.3 (Cq),
121.1 (CH), 126.3 (CH), 128.2 (Cq), 133.0 (Cq), 138.0 (Cq),
146.5 (Cq), 168.5 (Cq). HRMS (ESI): m/z [M + Na]+ calcd
for C17H24O3Na: 299.1623; found: 299.1618.
References and Notes
(1) Kajimoto, T.; Yamashita, M.; Imamura, Y.; Takahashi, K.;
Nohara, T.; Shibata, M. Chem. Lett. 1989, 18, 527.
(2) Srikrishna, A.; Ravikumar, P. C. Tetrahedron 2006, 62,
9393.
(3) Yoshida, M.; Matsuda, K.; Shoji, Y.; Gotou, T.; Ihara, M.;
Shishido, K. Org. Lett. 2008, 10, 5183.
(4) (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (b) Martín
Castro, A. M. Chem. Rev. 2004, 104, 2939.
(9) Data for 2: mp 104.5–106.9 °C (recrystallized from EtOAc–
hexane); [α]D33 –24.6 (c = 0.16, CHCl3). IR (KBr): 2926,
1715, 1507, 1457, 1373, 1294 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 0.76 (s, 3 H), 1.18 (s, 3 H), 1.41 (s, 3 H), 1.51–
1.80 (m, 5 H), 2.22 (s, 3 H), 2.55–2.64 (m, 1 H), 4.88 (s, 1
H), 5.55 (s, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 8.4
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 15.2 (Me), 20.2
(CH2), 22.9 (Me), 25.3 (Me), 26.7 (Me), 39.2 (CH2), 40.9
(CH2), 44.9 (Cq), 51.0 (Cq), 120.6 (CH), 120.8 (CH), 121.1
(Cq), 131.2 (Cq), 142.1 (Cq), 143.1 (Cq). HRMS (ESI): m/z
[M + Na]+ calcd for C15H22O2Na: 257.1517; found:
257.1516.
(5) (a) Yoshida, M.; Shoji, Y.; Shishido, K. Org. Lett. 2009, 11,
1441. (b) Yoshida, M.; Shoji, Y.; Shishido, K. Tetrahedron
2010, 66, 5053.
(6) Bushnell, G. W.; Dixon, K. R.; Hunter, R. G.; McFarland, J.
J. Can. J. Chem. 1972, 50, 3694.
(7) To a stirred solution of allenic alcohol 5 (200 mg, 1.37
mmol) in dioxane–H2O (20:1; 13.7 mL) were added
arylboronic acid 6 (537 mg, 2.74 mmol), Et3N (0.95 mL,
6.85 mmol), and [Pd2(OH)2(PPh3)4][BF4]2 (100.6 mg, 0.069
mmol) at r.t. After stirring was continued for 90 min at 80
°C, the reaction mixture was diluted with EtOAc and filtered
through a pad of silica gel. The residue upon evaporation of
the solvent was chromatographed on silica gel with hexane–
EtOAc (95:5) as eluent to give allylic alcohol 7 as a mixture,
which was used in the next reaction without further
purification. To a stirred solution of allylic alcohol 7 (1.37
mmol) in p-xylene (29.1 mL) was added N,N-dimethyl-
acetamide dimethylacetal (2.01 mL, 13.7 mmol) at r.t. After
the stirring was continued under reflux conditions for 30
(10) 1H NMR and 13C NMR spectral data of 1 and 2 were in
complete agreement with those reported for the natural and
synthetic products (ref. 1 and 2). Although the reason is not
clear, the optical rotations of our synthetic samples were
different from the values reported for the natural products1
[1: [α]D −8.1 (CHCl3); 2: [α]D −57.4 (CHCl3)].
Synlett 2014, 25, 1160–1162
© Georg Thieme Verlag Stuttgart · New York

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