Synthesis of the all-cis-trimethyldecalin fragment of unusual terpenes by radical-mediated protonolysis of an alkylboron derivative

Article abstract of DOI:10.1016/j.tetlet.2014.06.075

The synthesis of an enantiopure building-block with a contiguous all-cis-trimethyldecalin motif embedded in unusual terpenes is described. Starting from the Wieland-Miescher ketone, the key step is a one-pot hydroboration of an exocyclic methylene double bond promoted by disiamylborane and radical-mediated protonolysis of the corresponding alkylborane using 4-tert-butylcatechol.

Full text of DOI:10.1016/j.tetlet.2014.06.075

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the all-cis-trimethyldecalin fragment of unusual
terpenes by radical-mediated protonolysis of an alkylboron
derivative
Giorgio Villa , Ben Bradshaw , Cédric Bürki , Josep Bonjoch , Philippe Renaud a,
a
b
a
b,
⇑
⇑
a
Universität Bern, Department of Chemistry and Biochemistry, Freiestrasse 3, CH-3012 Bern, Switzerland
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of an enantiopure building-block with a contiguous all-cis-trimethyldecalin motif
embedded in unusual terpenes is described. Starting from the Wieland–Miescher ketone, the key step
is a one-pot hydroboration of an exocyclic methylene double bond promoted by disiamylborane and
radical-mediated protonolysis of the corresponding alkylborane using 4-tert-butylcatechol.
Ó 2014 Published by Elsevier Ltd.
Received 12 May 2014
Revised 16 June 2014
Accepted 18 June 2014
Available online xxxx
Keywords:
Organoboranes
Protonolysis
Diastereoselectivity
Radical reduction
H-transfer
Terpenes
The 4,5,10-trimethyldecalin backbone (terpene numbering),
whose three methyl groups have an all-cis relationship, involving
a cis-decalin ring fusion, is found in relatively few terpenes. This
stereoparent with three contiguous stereogenic centers, two of
them being all-carbon quaternary stereocenters, occurs in the
OH
O9 CO2H
O
1
4
2
3
1
0
8
7
5
6
1
marine diterpenoid nakamurol, a related diterpenoid possessing
2
a 9-methyladenium moiety in the side chain, the furanosesquit-
nakamurol A
aignopsanoic acid A
(+)-microcionin-1
3
4
erpenes (+)- and (À)-microcionin-1, and in the five marine
5,6
Figure 1. Natural products with an all-cis-trimethyldecalin framework and their
numbering pattern.
aignopsane sesquiterpenoids reported so far (Fig. 1).
In this study we focused our attention on achieving stereocon-
trolled and rapid access to the unreported enantiopure trimethyl-
decalone 1 from the easily available enantiomerically pure
that are not available, at least at an attractive price, in their (S)-
form. Enantiopure dimethyldecalone 3 has been prepared from
S)-(+)-Wieland–Miescher ketone (2) by Paquette and others,
and from (S)-(+)-carvone by De Groot. However, these two
approaches require long reaction sequences. Recently, a novel
approach for the synthesis of rac-1 from Wieland–Miescher ketone
rac-2) was reported (Scheme 1, Eq. 2). The installation of the
methyl substituent at C-10 through a well-established conjugate
addition (2 ? 4) was easy. However, as for the conversion of 2
to 3, transformation of the C-4 carbonyl group of 4 to the corre-
(
S)-(+)-Wieland–Miescher ketone 2.7 The most representative
precedents for achieving the synthesis of the enantiomer of the tar-
12
13
(
1
b
8,9
get ent-1 and of the racemic rac-1 are depicted in Scheme 1.
14
The conversion of dimethyldecalone ent-31
b,10
and rac-3
11
to
ent- and rac-1, respectively, is easily achieved by treatment with
Gilman reagent (Scheme 1, Eq. 1). However, this approach is not
suitable for the preparation of 1 since ent-3 is prepared from (R)-
(
1
0
1b
pulegone or (R)-3-methylcyclohexanone, two building blocks
15
1
2
sponding methyl substituent in
troublesome.
Taking into account the length of previous syntheses of ent- and
rac-1, we decided to examine the reduction of the exocyclic
1 has proven long and
⇑
Corresponding authors. Tel.: +34 934024540; fax: +34 934024539 (J.B.); tel.:
41 31 631 4359 (P.R.).
E-mail addresses: josep.bonjoch@ub.edu (J. Bonjoch), philippe.renaud@dcb.
9
+
unibe.ch (P. Renaud).
http://dx.doi.org/10.1016/j.tetlet.2014.06.075
0
040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Villa, G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.075

2
G. Villa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
(
1)
coming from the olefin either in acetal 5 or in ketone 6
O
Me CuLi
O
2
1
9
(Scheme 3). We conducted a rapid screening of hydroborating
agents to ascertain whether the steric demand around the boron
center influences the diastereoselectivity. Following this approach,
ref. 1b (ent-1)
ref. 8 (rac-1)
ent- or rac-1
ent- or rac-3
we selected the BH
catecholborane for its promising preliminary results, and disi-
amylborane (Sia BH) for its high steric demand. The results are
ÁSMe
2
complex for its low steric demand,
3
1
7
(
2)
2
O
O
summarized in Table 1.
Me2CuLi
ref. 9
5 steps
ref. 9
O
Acetal 5 was always deprotected to the ketone 1/epi-1 during its
organoborane-catechol mediated reduction presumably due to the
acidic properties of catechol. Reduction of the ketone was always
observed during the hydroboration of 6. As the screened hydrobo-
rating agents are known to react faster with terminal olefins than
ketones, this observation suggests that the hydroboration is
unusually slow due to a large steric demand at C-5. When the
hydroborating agent was used in excess, both the ketone and the
exo-methylene group reacted. For substrate 6, the crude interme-
diate alcohol 8 obtained by the hydroboration/radical-mediated
protonolysis was directly oxidized to the trimethyldecalone 1
before analysis and yield determination. The hydroboration with
O
O
rac-4
rac-2 (WMK)
rac-1
Scheme 1. Previous synthesis of ent-1 and rac-1.
methylene in compound 5,9 synthesized in three steps from
2
0
Wieland–Miescher ketone (2), in which the two quaternary car-
bons are formed (Scheme 2). We have previously examined the
direct transformation of the exocyclic methylene in 5 and 6 to
the target 1, but the stereochemical control was not good enough.
The diastereoselectivity in the hydrogenation using several
BH
3
ÁSMe
2
of both substrates 5 and 6 was performed at 0 °C, leading
9
16
to moderate diastereoselectivities (dr 3–5.5:1) and low to moder-
ated yields. Hydroborations with catecholborane require heating
and afford the desired trimethyldecalone in only 44% yield from
conditions and catalysts never exceeded 3:1 for 1/epi-1. All the
preliminary studies were conducted in the racemic series.
Recently, Renaud and co-workers17 reported a mild radical
6
5
as a 5:1 ratio of diastereomers. Starting from dioxolanyl acetal
, only degradation of the substrate was observed. Hydroborations
procedure for the transformation of organoboranes to alkanes (rad-
ical-mediated protonolysis), in which 4-tert-butylcatechol (TBC), a
well-established radical inhibitor and antioxidant, acts as a source
2
with in situ generated Sia BH were slow and had to be performed
at room temperature, but gave the highest diastereomeric ratios
and yields from both 5 and 6 (Table 1, entries 2 and 5). The best
1
8
of hydrogen atoms. An efficient chain reaction is observed due to
the exceptional reactivity of phenoxyl radicals toward alkylbor-
anes. The reaction has been applied to a wide range of organoboron
derivatives such as B-alkylcatecholboranes, trialkylboranes,
pinacolboronates, and alkylboronic acids. We thought that this
methodology, involving a one-pot chain reduction of alkylboron
compounds with catechols, might allow us to take advantage of
the improved stereocontrol provided by the hydroboration and
O
O
O
1) Borane
) TBC, air,
O
+
2
8
0 °C
5
1
epi-1
avoid the multi-step sequence reported for the transformation of
DMP
9
2
to 1 (via 5).
O
Thus, the challenge was to set the all-cis configuration of the
methyl groups in ketone 1 by direct reduction of an organoborane
1) Borane
) TBC, air,
OH
2
8
0 °C
6
8
O
O
O
O
3
steps
10% HCl
ref. 9
DMP = Dess-Martin periodinane
TBC = 4-tert-butylcatechol
O
ref. 9
O
Scheme 3. One-pot hydroboration/radical protonolysis. Reaction conditions: see
Table 1.
2
5
6
O
H2, Pd-C
ref. 9
O
+
O
5
Table 1
Hydroboration and radical mediated alkylborane protonolysisa of exo-methylene
compounds 5 and 6 to trimethyldecalone 1: racemic series
7
(minor)
epi-7 (major)
Entry
Alkene
Borane
Yield (%)b
1/epi-1
1
2
5
5
6
6
6
BH
Sia
BH
3
2
3
ÁSMe
2
2
20c
80
58
44
70
3:1d
9:1
5.5:1
5:1
H2 (30 atm), cat.
O
O
BH
6
+
e
3
ÁSMe
solvent
ref. 9
e
4
Catecholborane
e
5
Sia
2
BH
6.5:1
1
epi-1
a
All reactions performed as two-step one-pot reaction following the general
procedure reported in the experimental section (footnote 21). Diastereoselectivities
as observed in the 1H NMR reaction mixture, based on characteristic chemical shifts
ofba-carbonyl protons.
cat.
solvent
CH2Cl2
C6H6
1/epi-1
1.5:1
2:1
Pd-C (70%)
Isolated yield of the mixture of diastereomers.
(Ph3)3RhCl (1%)
c
Unoptimized yield.
PtO2 (10%)
CH2Cl2
3:1 (95% yield)
d
Diastereoselectivity lower than the one reported in Ref. 9. This point was not
further investigated due to the low yield of the reaction.
e
Yield and diastereomeric ratio were determined after oxidation of initially
Scheme 2. Approach to trimethyldecalone 1 via catalytic hydrogenation according
to Ref. 9 (racemic series).
formed alcohol using Dess–Martin periodinane (DMP) to 1/epi-1.
Please cite this article in press as: Villa, G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.075

G. Villa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
(
+)-Wieland-Miescher ketone (2)
financial support. The group at Barcelona thanks the Spanish
Ministry of Economy and Competitiveness (Project CTQ2010-
O
O
, TsOH; iii) Ph3P=CH2
i) Me2CuLi; ii)
1
4846/BQU) for financial support.
8
0% (over 3 steps); according ref. 9
References and notes
BH3·Me2S (1.5 equiv)
Me
O
O
MeCH=C(Me2) (3 equiv)
ClCH2CH2Cl
1.
Isolation: (a) Shoji, N.; Umeyama, A.; Teranaka, M.; Arihara, S. J. Nat. Prod. 1996,
9, 448–450; Synthesis and determination of the absolute configuration, see:
b) Díaz, S.; Cuesta, J.; González, A.; Bonjoch, J. J. Org. Chem. 2003, 68, 7400–
406.
O
O
Me
5
(
7
BR2
10
5
2
3
.
.
Isolation: Iwagawa, T.; Kaneko, M.; Okamura, H.; Nakatani, M.; van Soest, R. W.
M. J. Nat. Prod. 1998, 61, 1310–1312.
(a) Cimino, G.; De Stefano, S.; Guerriero, A.; Minale, L. Tetrahedron Lett. 1975,
R = 3-methylbut-2-yl
(= siamyl)
OH
OH
1
6, 3723–3726; (b) Cimino, G.; De Rosa, S.; De Stefano, S.; Morrone, R.; Sodano,
Me
O
G. Tetrahedron 1985, 41, 1093–1100; (c) Gaspar, H.; Gavagnin, M.; Calado, G.;
Castelluccio, F.; Mollo, E.; Cimino, G. Tetrahedron 2005, 61, 11032–11037.
Me
Me
(
10 equiv)
4. Gaspar, H.; Santos, S.; Carbone, M.; Rodrigues, A. S.; Rodrigues, A. I.; Uriz, M. J.;
Feio, S. M. S.; Melck, D.; Humanes, M.; Gavagnin, M. J. Nat. Prod. 2008, 71, 2049–
2052.
5. Johnson, T. A.; Amagata, T.; Sashidhara, K. V.; Oliver, A. G.; Tenney, K.;
Matainaho, T.; Ang, K. K.; McKerrow, J. H.; Crews, P. Org. Lett. 2009, 11, 1975–
air
Me (+)-1 (80%, dr 9:1)
ClCH2CH2Cl
1978.
H
Me
6. Johnson, T. A.; Sohn, J.; Inman, W. D.; Estee, S. A.; Loveridge, S. T.; Vervoot, H. C.;
Tenney, K.; Liu, J.; Ang, K. K.-H.; Ratnam, J.; Bray, W. M.; Gassner, N. C.; Shen, Y.
Y.; Lokey, R. C.; McKerrow, J. H.; Boundy-Mills, K.; Nukanto, A.; Kanti, A.;
Jukistiono, H.; Kardono, B. S.; Bjeldanes, L. F.; Crews, P. J. Nat. Prod. 2011, 74,
R2B
Me
O
Me
O
R2B
H
2545–2555.
O
O
7
8
.
.
(a) Bradshaw, B.; Etxebarria-Jardí, Bonjoch J.; Viózquez, S. F.; Guillena, G.;
Nájera, C. Org. Synth. 2011, 88, 330–341; (b) Bradshaw, J.; Bonjoch, J. Synlett
endo (major)
exo (minor)
2011, 337–356.
Cory, R. M.; Burton, L. P. J.; Chan, D. M. T.; McLaren, F. R.; Rastall, M. H.;
Scheme 4. Optimized preparation of enantiopure (+)-1 from (+)-Wieland–Miescher
ketone. Rationale for the diastereoselectivity of the hydroboration step.
Renneboog, R. M. Can. J. Chem. 1984, 62, 1908–1921.
9. Bradshaw, B.; Etxebarria-Jardí, G.; Bonjoch, J. Org. Biomol. Chem. 2008, 6, 772–
78.
7
10. Bian, M.; Wang, Z.; Xiong, X.; Sun, Y.; Matera, C.; Nicolaou, K. C.; Li, A. J. Am.
Chem. Soc. 2012, 134, 8078–8081.
result in terms of yield and diastereoselectivity (80% yield, dr 9:1)
was obtained starting from the acetal protected ketone 5 (Table 1,
entry 2 and Scheme 4). These results demonstrate that the
hydroboration/radical-mediated protonolysis is a useful and viable
procedure to obtain the right selectivity at the stereogenic center
C-5. The selectivity in favor of the desired all-cis diastereoisomer
increases with the steric demand of the hydroborating agent
1
1. For representative routes leading to the racemic 3: (a) Boeckman, R., Jr.; Blum,
D. M.; Ganem, B. Org. Synth. 1978, 58, 158–163; (b) Zoretic, P. A.; Golen, J. A.;
Saltzman, M. D. J. Org. Chem. 1981, 46, 3554–3555.
1
1
2. (a) Paquette, L. A.; Wang, T.-Z.; Phillippo, C. M. G.; Wang, S. J. Am. Chem. Soc.
1994, 116, 3367–3374.
3. (a) Díaz, S.; González, A.; Bradshaw, B.; Cuesta, J.; Bonjoch, J. J. Org. Chem. 2005,
70, 3749–3752; (b) Carneiro, V. M. T.; Ferraz, H. M. C.; Vieira, T. O.; Ishikawa, E.
E., ; Silva, L. F., Jr. J. Org. Chem. 2010, 75, 2877–2882.
1
1
4. Jenniskens, L. H. D.; De Groot, A. Tetrahedron 1998, 54, 5617–5622.
5. (a) Smith, R. A. J.; Hannah, D. J. Tetrahedron 1979, 35, 1183–1189; (b) Vellekoop,
A. S.; Smith, R. A. J. Tetrahedron 1998, 54, 11971–11994; (c) Hirai, G.; Oguri, H.;
Hayashi, M.; Koyama, K.; Koizumi, Y.; Moharram, S. M.; Hirama, M. Bioorg. Med.
Chem. Lett. 2004, 14, 2647–2651; (d) Ref. 9.
(
disiamylborane vs BH
3
ÁSMe
2
) and the protection of the ketone
as an acetal (acetal vs ketone). The stereochemical outcome of this
reaction is best explained by an endo-selective hydroboration
process leading to trialkylborane 10 (Scheme 4). The exo-selective
hydroboration is disfavored by steric interactions between the
borane and the vicinal axial methyl substituent as well as by devel-
oping 1,3-diaxial interactions.
1
6. Hydrogenation of 5 employing Pd/C quantitatively gave the reduced product
but with a 1:3 diastereoselectivity.8 However, a reversed selectivity was found
when ketone 6, obtained by hydrolysis of 5, was used as the substrate The cis–
trans ratio was further improved by using Wilkinson’s catalyst, which resulted
in a 2:1 ratio. The diastereoselectivity was enhanced even more by employing
Adam’s catalyst.
With experimental conditions for the diastereoselective
reduction of the exocyclic double bond in hand, we applied the
overall reaction sequence, starting from the enantiopure (+)-
Wieland–Miescher ketone (>99% ee) synthesized by our reported
17. (a) Villa, G.; Povie, G.; Renaud, P. J. Am. Chem. Soc. 2011, 133, 5913–5920; (b)
Povie, G.; Villa, G.; Ford, L.; Pozzi, D.; Schiesser, C. H.; Renaud, P. Chem.
Commun. 2010, 36, 803–805.
1
8. Trialkylboranes react with 4-tert-butylcatechol to afford the corresponding
alkanes and a boric ester. These products arise from a formal protonolysis of
the trialkylborane. However, from a mechanistic point of view, the reaction is
not an ionic process but involves transient radical species and requires the use
of a radical initiator such as air.
7
a
procedure, to achieve the building block (+)-1 in enantiomeri-
2
1,22
cally pure form
(Scheme 4).
In conclusion, the hydroboration/radical-mediated protonolysis
using disiamylborane represents a useful and viable procedure to
obtain the appropriate selectivity at the stereogenic center C-5
and improve the synthesis of the valuable building-block 1 directly
from acetal 5, since the cleavage of the acetal took place during the
radical-mediated protonolysis. By using this approach, the (S)-(+)-
Wieland–Miescher ketone can be converted into the valuable
enantiopure all-cis building block 1 in only 4 steps and 54% overall
yield (Scheme 4). This compares very favorably with the previously
reported sequence to rac-1 from the racemic Wieland–Miescher
ketone involving eight steps (seven of them to install the methyl
group at C-4).
radical
initiator
t-Bu
OH
2
R3B
+
3
OH
t-Bu
t-Bu
6
R–H
+
O
O
O
O
B O
O
B
t-Bu
19. A high diastereoselectivity is needed considering the extreme difficulty in the
separation of the epimers when are formed in related dimethyldecalin
compounds: see Ref. 11b.
Acknowledgments
20. To verify if the two epimeric alcohols lead to different selectivities, we tried to
reduce ketone 6 with L-selectride at a low temperature before running the
hydroboration. However, the L-selectride ketone reduction afforded a 4:1
mixture of diastereoisomeric alcohols 9. This lack of diastereoselectivity
prevented us to further investigate this approach.
The team at Bern University thanks the Swiss National Science
Foundation (grant 20020_152782) and the University of Bern for
Please cite this article in press as: Villa, G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.075

4
G. Villa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
solvent was removed under reduced pressure. The product was purified by
flash chromatography (pentane/Et 95:5) to give (72 mg, 80%) as
yellowish oily mixture of diastereoisomers (dr 9:1). An analytical pure
O
OH
L-Selectride
78 °C
2
O
1
a
1
-
sample of 1 shows the following data: [
500 MHz, COSY) d 0.84 (s, 3H, Me-C4a), 0.88 (s, 3H, Me-C8a), 0.89 (d,
J = 6.5 Hz, 3H, Me-C5), 1.07 (dm, J = 10.5 Hz, H-8 eq), 1.3–1.4 (m, 1H, H-6),
.50–1.60 (m, 4H, H-8ax, 2H-7, H-6), 1.68 (td, J = 14.5, 4.5 Hz, 1H, H-4ax), 1.69
D 3
a] +28.8 (c 1.14, CHCl ); H NMR
(
6
9 (dr 4:1)
1
2
1. (4aR,5S,8aR)-4a,5,8a-Trimethyl-3,4,4a,5,6,7,8,8a-octahydro-1H-naphthalen-2-one
(dd, J = 14.5, 2.1 Hz, 1H, H-1 eq), 1.89 (ddd, J = 14.5, 6.5, 2.1 Hz, 1H, H-4 eq),
2.14 (dm, J = 12 Hz, 1H, H-5ax), 2.18 (dm, J = 14 Hz,1H, H-3 eq), 2.39 (td,
J = 14.5, 5 Hz, 1H, H-3ax), 3.04 (d, J = 14.5 Hz, 1H, H-1ax); 13C NMR (75 MHz,
HSQC) d 15.3 (5-Me), 16.1 (4a-Me), 21.9 (C-7), 24.6 (8a-Me), 30.4 (C-6), 31.0 (C-
(
1): To a 1 M solution of BH ÁSMe complex (1.5 mL, 1.5 mmol) in 1,2-
3
2
dichloroethane was added 2-methyl-2-butene (0.32 mL, 3 mmol) and the
reaction mixture was stirred for 30 min at 40 °C. The mixture was then cooled
down to 0 °C and 1,2-dichloroethane (2 mL) was added. To this solution was
then added a solution of 5 (110 mg, 0.5 mmol) in 1,2-dichloroethane (1.5 mL)
and the reaction mixture was stirred at 0 °C for 30 min and then allowed to
warm up to rt overnight. 4-tert-Butylcatechol (831 mg, 5 mmol) was added
and the reaction mixture was stirred for 3 h at 80 °C opened to air. The reaction
mixture was finally allowed to cool down to rt, filtered over alox and the
5), 32.2 (C-4), 35.9 (C-8), 37.6 (C-3), 37.9 (C-4a), 41.8 (C-8a), 49.0 (C-1), 213.4
+
(C-2). HRMS calcd for C13
H
23O (MH ) 195.1749, found 195.1753.
22. The absolute configuration of (+)-1 was established not only by considering the
enantiopurity of the starting material (+)-2, but also because we had previously
reported compound (À)-1 (Ref. 1b), although without noting its levorotatory
character.
Please cite this article in press as: Villa, G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.075