Enantioselective synthesis of 1(R)-hydroxypolygodial

Article abstract of DOI:10.1016/j.tetlet.2005.04.020

Enantioselective preparation of 1(R)-hydroxypolygodial (5) has been achieved starting from α-ionone through a synthetic strategy involving a Corey-Bakshi-Shibata oxazaborolidine-mediated reduction and a stereoselective Diels-Alder reaction as key steps.

Full text of DOI:10.1016/j.tetlet.2005.04.020

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4061–4063
Enantioselective synthesis of 1(R)-hydroxypolygodial
Carmela Della Monica, Giorgio Della Sala, Deborah DꢀUrso,
Irene Izzo and Aldo Spinella*
`
Dipartimento di Chimica, Universita di Salerno, Via S. Allende, 84081 Baronissi (Salerno), Italy
Received 24 February 2005; revised 31 March 2005; accepted 5 April 2005
Available online 20 April 2005
This work is dedicated to the memory of Professor G. Sodano
Abstract—Enantioselective preparation of 1(R)-hydroxypolygodial (5) has been achieved starting from a-ionone through a synthetic
strategy involving a Corey–Bakshi–Shibata oxazaborolidine-mediated reduction and a stereoselective Diels–Alder reaction as key
steps.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Polygodial (1) belongs to a group of terpenoid unsatu-
rated 1,4-dialdehydes, isolated from terrestrial and mar-
ine sources,1 which are known to show a pungent
sensation in the human tongue. Recently, a vanilloid
activity has been reported for some of them.2 Some
years ago, some researchers suggested that biological
activities of these compounds are linked to the dialde-
hyde moiety and to reactivity towards nucleophiles.3
The observation that some bulkier molecules, for exam-
ple, isocopalendial (2) and scalaradial (3), were not hot
tasting, suggested that the size of the molecule was also
important.4 However, the hot taste reported for com-
pound 4,5 a deacetoxy derivative of the tasteless sester-
terpenoid scalaradial, pointed out the influence of an
oxygenated function, such as the acetoxy group, on
the bioactivity of these compounds (Fig. 1). This stimu-
lated a research program directed to vanilloid active
compounds containing the unsaturated 1,4-dialdehyde
moiety and hydroxy or acetoxy groups in their skeleton
and we chose 1(R)-hydroxypolygodial (5) as first target
of our investigation.
CHO
CHO
CHO
CHO
1
2
R
CHO
CHO
3 R=OAc; 4 R=H
Figure 1.
synthetic scheme based on a Diels–Alder reaction start-
ing from dimethylacetylenedicarboxylate (7) and the
hydroxydiene derivative 6 whose preparation involves
a
stereocontrolled Corey–Bakshi–Shibata reduction
(Scheme 1).7
Preparation of hydroxylated drimane compounds
involving a microbial hydroxylation was not considered
as this leads to a mixture of mono and diol derivatives
containing the hydroxyl function in several positions
of the drimane skeleton except at C-1.6 We planned a
OH CHO
OTBS
CO2Me
CHO
Keywords: Total synthesis; Diels–Alder reaction; Terpenoids; Poly-
godial; Vanilloid activity.
CO2Me
5
6
7
*
Corresponding author. Tel.: +39 089 965373; fax: +39 089 965296;
e-mail: spinella@unisa.it
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.020

4062
C. Della Monica et al. / Tetrahedron Letters 46 (2005) 4061–4063
O
TBSO
CO2Me
CO2Me
OH
CO2Me
CO2Me
a
+
b,c
a
O
O
8
9
17
16
16
OH
O
OH
13
TBSO
CO2Me
CO2Me
g
d, e
f
6
b
O
c
11
12
10
Scheme 2. Preparation of hydroxydiene 6. Reagents and conditions:
(a) MCPBA, CH2Cl2, ꢀ78 ꢁC ! 0 ꢁC, 12 h; (b) O3, CH2Cl2, ꢀ78 ꢁC,
4 h then Me2S, CH2Cl2, ꢀ78 ꢁC ! rt, 12 h; (c) pyrrolidine, Et2O, rt,
12 h, 76% (three steps); (d) MeP+Ph3Brꢀ, n-BuLi, THF, 0 ꢁC ! rt, 4 h;
(e) PDC, CH2Cl2, rt, 1 h, 79% (two steps); (f) (S)-MeCBS reagent,
BH3ÆTHF (syringe pump addition: 1.2 mmol/h), THF, 35 ꢁC, 88%,
93% ee; (g) TBSCl, imidazole, CH2Cl2, rt, 12 h, 96%.
18
Scheme 3. Preparation of 16. Reagents and conditions: (a) H2, Pd–C,
HCl and MeOH, 12 h, 16 (27%), 17 (49%); (b) DBU, THF, 40 ꢁC, 4 h,
90%; (c) H2, Pd–C and MeOH, 5 h, 72%.
accessibility to the hydroxyl function. Therefore, we
decided to move to the methodology of Lallemand
and co-workers involving two steps: a base catalyzed
isomerization followed by hydrogenation.12
The first step of the synthesis (Scheme 2) consists of
preparation of epoxide 9 from a-ionone (8).8 Ozonolysis
of 9, followed by reductive work-up, afforded an epoxy-
aldehyde which proved to be quite sensible to purifica-
tion conditions; therefore, the following eliminative
ring opening of the epoxide was performed on the crude
extract obtained after ozonolysis leading to compound
10 (76% yield from 8). The synthesis of ketone 11 was
completed by Wittig reaction of aldehyde 10 with
CH2@PPh3, followed by PDC oxidation (79%, two-step
yield). (R)-2,4,4-Trimethyl-3-vinyl-2-cyclohexene-1-ol
(12) was prepared by enantioselective reduction of
dienone 11 with (S)-Me-Corey–Bakshi–Shibata [(S)-
MeCBS] oxazaborolidine–borane reagent, giving dienol
12 (88% yield and 93% enantiomeric excess)9 which was
then converted into silyl derivative 6 (96%).
DBU catalyzed isomerization13 afforded mainly the con-
jugated diene 18 (90% yield), which was subjected to
hydrogenation (H2, Pd–C and MeOH) affording com-
pound 1614 (72% yield). The stereochemistry of 16 was
1
established via H NMR NOE measurements (Fig. 3).
Irradiation of H-1 (d 3.74 ppm) led to enhancements
of the signals due to H-5 (d 1.17 ppm) and H-9 (d
3.21 ppm).
These experiments indicated that H-1, H-5 and H-9 were
in cis-relationship. Reduction of the ester functionalities
produced diol 19, which was then oxidized using Swern
conditions (C2O2Cl2, DMSO and NEt3) to give dialde-
hyde 20 (87%).
The Diels–Alder reaction of 6 with dimethylacetylenedi-
carboxylate (7) proceeded quite slowly (neat, 110 ꢁC,
48 h) affording compound 1310 as a major product
(40%) together with small amounts of its diastereomer
14 (5%) and triene 15 (8.5%) (Fig. 2). The reaction
was stopped after 48 h, although unreacted diene 6
was still present, because longer reaction time favoured
the increase of triene 15.
Finally, 1(R)-hydroxypolygodial (5)15 was produced by
deprotection of the TBS ether using TBAF (74%)
(Scheme 4).
TBSO
MeO2C
H
CO2Me
The stereoselectivity observed can be rationalized by an
approach of the dienophile to the diene anti to the allylic
substituent. Leyꢀs reductive isomerization procedure for
13 (H2, Pd–C and HCl)11 proved to be unsuitable for
our substrate, causing partial loosing of the protecting
group (Scheme 3). Furthermore, deprotection of 17
proved to be very difficult probably due to the bad
H
H
Figure 3.
TBSO
TBSO
CH2OH
CHO
CH2OH
CHO
TBSO
CO2Me
TBSO
CO2Me
CO2Me
CO2Me
CO2Me
a
b
c
16
5
CO2Me
+
+
20
19
Scheme 4. Synthesis of target 5. Reagents and conditions: (a)
DIBALH, THF, toluene, ꢀ78 ꢁC ! rt, 12 h, 94%; (b) Swern, 1 h,
87%; (c) TBAF, THF, rt, 2 h, 74%.
13
15
14
Figure 2.

C. Della Monica et al. / Tetrahedron Letters 46 (2005) 4061–4063
4063
(3H, s, CH3Si–), 0.89 (9H, s, (CH3)3CSi–), 1.08 (3H, s,
CH3), 1.16 (3H, s, CH3), 1.31 (3H, s, CH3), 1.34 (1H, m,
H-3), 1.47 (1H, ddd, J = 4.5, 4.5, 13.6 Hz, H0-3), 1.73–1.79
(2H, m, H-2 and H0-2), 2.78 (1H, dd, J = 2.1, 22.4 Hz, H-
7), 3.04 (1H, dd, J = 5.8, 22.4 Hz, H0-7), 3.69 (3H, s,
–CO2CH3), 3.78 (3H, s, –CO2CH3), 4.17 (1H, dd, J = 5.8,
8.4 Hz, H-1), 5.70 (1H, dd, J = 2.1, 5.8 Hz, H-6). 13C
NMR (CDCl3, 100 MHz): d ꢀ3.0 (q), ꢀ2.6 (q), 18.9 (s),
21.7 (q), 26.4 (·3) (q), 26.8 (t), 28.5 (t), 31.3 (q), 32.2 (q),
35.4 (s), 36.1 (t), 46.3 (s), 51.9 (q), 52.5 (q), 74.1 (d), 119.0
(d), 126.6 (s), 148.0 (s), 148.8 (s), 166.4 (s), 169.2 (s).
EIMS: m/z 422, 365, 333, 305, 291, 259, 231, 199.
11. Howell, S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc.,
Chem. Commun. 1981, 507–508.
In conclusion, we have completed the synthesis of 1(R)-
hydroxypolygodial (5), starting from a-ionone in 13
steps and 8% overall yield. An investigation on the
vanilloid activity of 5 is now in progress and the results
will be given in due course. This synthetic scheme offers
the possibility of preparing other correlated naturally
occurring dialdehydes, such as those isolated from
Drimys brasiliensis.16
Acknowledgements
The authors acknowledge financial support from Uni-
`
versita di Salerno and from MIUR-COFIN 2002 ꢁTaste
chemoreception: synthesis and structure–activity rela-
12. Jalali-Naini, M.; Guillerm, D.; Lallemand, J.-Y. Tetrahe-
dron 1983, 39, 749–758.
13. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273–281.
tionship of taste active compoundsꢀ.
25
14. Physical data of compound 16: ½aŠ ꢀ39.6 (c 1.0, CHCl3).
1H NMR (CDCl3, 400 MHz): d D0.04 (3H, s, CH3 Si–),
0.09 (3H, s, CH3Si–), 0.85 (3H, s, CH3), 0.90 (9H, s,
(CH3)3CSi–), 0.91 (3H, s, CH3), 0.99 (3H, s, CH3), 1.17
(1H, dd, J = 6.0, 10.6 Hz, H-5), 1.26 (1H, m, H-3), 1.43
(1H, ddd, J = 3.3, 3.3, 13.6 Hz, H0-3), 1.58 (1H, dddd,
J = 3.0, 11.2, 13.4, 13.6 Hz, H-2), 1.71 (1H, dddd, J = 3.3,
4.2, 4.2, 13.4 Hz, H0-2), 2.15–2.28 (2H, m, H-6 and H0-6),
3.21 (1H, m, H-9), 3.61 (3H, s, –CO2CH3), 3.66 (3H, s,
–CO2CH3), 3.74 (1H, dd, J = 4.2, 11.2 Hz, H-1), 7.02 (1H,
m, H-7). 13C NMR (CDCl3, 100 MHz): d ꢀ2.9 (q), ꢀ2.3
(q), 9.2 (q), 18.9 (s), 21.8 (q), 24.5 (t), 26.6 (·3) (q), 28.5
(t), 32.5 (s), 32.6 (q), 39.4 (t), 43.4 (s), 48.1 (d), 51.6 (q),
51.7 (q), 56.6 (d), 80.6 (d), 129.6 (s), 140.3 (d), 167.3 (s),
173.3 (s). EIMS: m/z 424, 367, 335, 205, 171, 157, 145,
References and notes
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131.
31
D
15. Physical data of 1(R)-hydroxypolygodial (5): ½aŠ ꢀ175.1
(c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): d 0.88 (3H, s,
CH3), 0.91 (3H, s, CH3), 0.92 (3H, s, CH3), 1.24 (1H, ddd,
J = 4.0, 13.5, 13.5 Hz, H-3), 1.44 (1H, ddd, J = 3.2, 3.2,
13.5 Hz, H0-3), 1.54 (1H, dd, J = 5.1, 11.5 Hz, H-5), 1.57–
1.72 (2H, m, H-2 and H0-2), 2.24 (1H, br dd, J = 11.5,
20.4 Hz, H-6), 2.51 (1H, ddd, J = 5.1, 5.1, 20.4 Hz, H0-6),
3.63 (1H, dd, J = 4.4, 10.9 Hz, H-1), 3.71 (1H, br s, H-9),
8. Nicolaou, K. C.; Li, W. S. J. Chem. Soc., Chem. Commun.
1985, 421.
7.04 (1H, m, H-7), 9.39 (1H, s, OHCC-8), 9.93 (1H, d,
J = 1.2 Hz, OHCC-9).
13
C NMR (CDCl3, 100 MHz): d
9. The enantiomeric excess was determined by HPLC analy-
sis (Chiralcel OD, 1% 2-propanol in hexane, 1 mL/min, tR
(R): 10.37 min, tR (S): 9.21 min).
15.1 (q), 21.9 (q), 25.5 (t), 27.7 (t), 32.2 (q), 32.4 (s), 39.5 (t),
43.0 (d), 44.0 (s), 54.5 (d), 75.6 (d), 137.9 (s), 152.5 (d),
192.6 (d), 202.8 (d). ESMS: m/z 249 [MꢀH]ꢀ.
25
10. Physical data of compound 13: ½aŠ ꢀ50.7 (c 0.95, CHCl3).
16. Vichnewski, W.; Kulanthaivel, P.; Herz, W. Phytochem-
istry 1986, 25, 1476–1478.
D
1H NMR (CDCl3, 400 MHz): d 0.06 (3H, s, CH3Si–), 0.09