Radical cyclizations leading to the bicyclo[2.2.1]heptane framework: A new radical approach to (±)-(Z)-β-santalol

Article abstract of DOI:10.1055/s-2005-864825

Tandem radical cyclizations of acyclic iodides, including [3-(2-iodoethyl)-6,10-dimethyl-undeca-5,9-dien-1-ynyl]-dimethylphenylsilane lead in good yields to bicyclo[2.2.1]heptane derivatives. The cascade relies on two sequential radical-mediated 5-exo-cyclizations. The radical approach is illustrated with the total synthesis of racemic-(Z)-β-santalol. The results are remarkable, two fused rings and one stereogenic center are formed in a single operation. A new 'coordinated' hydride appeared to be useful in the cascade.

Full text of DOI:10.1055/s-2005-864825

900
LETTER
Radical Cyclizations Leading to the Bicyclo[2.2.1]heptane Framework:
A New Radical Approach to ( )-(Z)-b-Santalol
Radical
Cycliza
b
tions
L
eadin
i
g
to the
g
Bicyclo[2.2
n
.1]heptane
F
i
rame
w
e
ork w Pianowski,a Leszek Rupnicki,a Piotr Cmoch,b Krzysztof Staliꢀski*b
a
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
b
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: stalinsk@icho.edu.pl
Received 28 August 2004
8
1
11
9
Abstract: Tandem radical cyclizations of acyclic iodides, including
[3-(2-iodoethyl)-6,10-dimethyl-undeca-5,9-dien-1-ynyl]-dimethyl-
phenylsilane lead in good yields to bicyclo[2.2.1]heptane deriva-
tives. The cascade relies on two sequential radical-mediated 5-exo-
cyclizations. The radical approach is illustrated with the total
synthesis of racemic-(Z)-b-santalol. The results are remarkable, two
fused rings and one stereogenic center are formed in a single oper-
ation. A new ‘coordinated’ hydride appeared to be useful in the
cascade.
4
6
5
12
10
2
13
7
3
HO
HO
1
2
3
Figure 1 Important components of the sandalwood oil
edge a direct radical approach to b-santalene or its
derivatives has not been reported so far. In the course of
our studies into the preparation of natural products con-
taining the bicyclo[2.2.1]heptane framework we proposed
that two sequential 5-exo-cyclizations of appropriate
acyclic precursors could lead to the bicyclo[2.2.1]heptane
derivatives. The synthetic potential of the radical transfor-
mation was then explored, and we report herein an appli-
cation of the tandem process to the racemic synthesis of
(Z)-b-santalol (Scheme 1).
Key words: bicyclic compounds, domino reactions, hydrides,
natural products, radicals
Introduction
One of the most powerful methods in the construction of
carbon-carbon bonds is radical cyclization. A large num-
ber of natural products has been prepared using radical cy-
clization methods.1 Tandem radical reactions are ideal for
construction of polycyclic systems.2 Starting from linear
acyclic precursors ‘zipper’, macrocyclization/transannu-
lar cyclizations3 and ‘round trip’4 strategies have been
applied successfully.
R2
R1
R2
R1
R2
I
I
R1
The bicyclo[2.2.1]heptane framework can be found in
various natural products, including terpenes. However, so
far relatively little information has been available regard-
ing radical transformations to this class of compounds. In
the early 80’s Beckwith and co-workers reported that 1,5-
closure of 1- or 3-substituted hex-5-enyl radicals gave cis-
disubstituted cyclic products, whereas 2- or 4-substituted
radicals gave mainly trans-products.5 The significance of
this stereoselectivity was demonstrated in the formation
of bicyclic systems from acyclic precursors.
Scheme 1 The retrosynthetic pathway
Synthesis of Iodides 4–9
For the preparation of precursors two synthetic approach-
es were investigated. Schemes 2 and 3 illustrate the sim-
plicity with which the requisite substrates for the radical
cyclizations are available from commercial materials.
Radical precursors 4–8 were obtained via alkylation of 10
with the corresponding bromide followed by a routine
three-step exchange of the tetrahydropyranyl group into
iodine.9 Unfortunately, the same procedure was not appli-
cable in the case of compound 9. This precursor was pre-
pared in good yields in seven steps from commercially
available geranyl bromide and g-butyrolactone. The cor-
responding lactol was prepared by the reaction of g-buty-
rolactone with geranyl bromide followed by reduction of
the lactone with DIBALH. A sequence of reactions start-
ing from a Wittig-type condensation of the lactol with the
ylide derived from dibromomethyltriphenylphosphonium
bromide10 followed by the elimination of HBr and the re-
duction of the corresponding dibromoalkene 11 gave
East Indian sandalwood oil, obtained by steam distillation
from the heartwood of Santalum album Linn is highly
prized in perfumery.6 Its sweet woody fragrance is mainly
due to the two major components: (–)-(Z)-b-santalol (1,
20–25%) and (+)-(Z)-a-santalol (2, 50–60%; Figure 1).7
Numerous minor components, including (–)-b-santalene,
also contribute to the characteristic overall odor character.
Concerning total syntheses, work so far has mainly con-
centrated on b-santalene (3).8 To the best of our knowl-
SYNLETT 2005, No. 6, pp 0900–0904
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864825; Art ID: D25804ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Radical Cyclizations Leading to the Bicyclo[2.2.1]heptane Framework
901
alkyne 12.11 This was in turn sequentially tosylated, silyl-
ated on the triple bond and substituted to furnish iodide 9.
Despite a longer synthesis the commercial availability and
cheapness of the starting materials allow the preparation
of 9 on a gram scale. The PhMe2Si group was introduced
to ease separation of the reaction mixture after radical
cyclizations by means of HPLC (UV detection), as it ren-
dered the products less volatile. Additionally, silane
groups are known to accelerate radical cyclizations by
activation of the unsaturated partner.2
OH
i
+
Br
11
O
Br
O
Br
I
OH
iii
ii
9
12
SiMe2Ph
Scheme 3 Synthesis of the acyclic precursors. Reagents and condi-
tions: i) LDA, THF, –78 °C, 62%; DIBALH, CH2Cl2, –40 °C, 96%;
Ph3PCHBr2, n-BuLi, THF, –40 °C, 84%; ii) n-BuLi, THF, –78 °C to
r.t., 90%; iii) TsCl/Et3N, CH2Cl2, r.t., 84%; PhMe2SiCl/n-BuLi, THF,
–78 °C, 75%; KI, acetone, reflux, 98%.
R2
OTHP
ii
I
I
OH
R1
i
SiMe2Ph
SiMe2Ph
SiMe2Ph
R
1 = R2 = H
R1 = H, R2 = Me
R1 = R2 = Me
R1 = R2 = Ph
10
8
tributyl tin hydride/AIBN-initiated reactions of iodides 6
at 80 °C gave a mixture of mono- and bicylic products
(15, 20).
4
5
6
7
The former were isolated as an inseparable mixture of cis/
Scheme 2 Synthesis of the acyclic precursors. Reagents and condi- trans isomers. The latter were obtained in the form of E/Z
vinyl isomers.12 Better results were obtained at higher
temperatures (>110 °C) with ACCN as an initiator. Pre-
tions: i) THP, p-TsOH, CH2Cl2, r.t., 99%; n-BuLi, PhMe2SiCl, THF,
–78 °C, 90%; ii) n-BuLi/t-BuLi, TMEDA, THF, –30 °C to –78 °C,
allylic bromide, ca. 60%; p-TsOH, MeOH, r.t., 98%; MsCl/Et3N,
sumably, raising the temperature enhances the equilibra-
CH2Cl2, 0 °C then KI in acetone, reflux, 95%.
tion rate and population of the conformer leading to the
bicyclic products. In the course of the above studies it was
found that the concentration of the hydride should be in
the range 0.008–0.015 M. When the reaction of 7 was car-
Radical Cyclizations of the Acyclic Iodides 4–8 and 9
ried out at room temperature with Et3B/O2 the only isolat-
ed products appeared to be ketones 16 (cis/trans = 3:1;
With the precursors in hand, we conducted several radical
cyclizations under different reaction conditions (Table 1).
Scheme 4). Apparently, too low temperature and/or sus-
Initial investigations revealed that the first cyclization oc-
ceptibility of the intermediate radicals towards oxygen
curred quantitatively. We were not able to detect any
traces of directly reduced acyclic products. The second
were factors in their formation.
In the case of iodide 8 the bicyclic product 24 was formed
in 30% yield reflecting the preference of the first 6-endo-
over 5-exo-cyclization (Scheme 5). Such preference is
cyclization appeared to be less efficient presumably due to
an energy penalty, which must be paid in cyclization to
the strained bicyclo[2.2.1]heptane framework. Initial
Table 1 The Radical Cyclizations of Iodides 4–9
Iodide
T (°C)
[n-Bu3SnH]
Yields (%)
Monocyclica
Bicyclicb
4
5
6
110
110
0.009
0.009
13
14
15
20c
27c
18
19
20
74 (1.0:1.4)
69 (1.0:1.3)d
110
110
0.008
0.032
30
41
65 (1.0:2.7)
41 (1.0:2.7)
7
8
9
20
110
110
0.010e
0.009
0.009
16
23
17
62
58
42
–
24
30 (1.0:1.5)
21
22
40 (1.0:1.4)
4 (1.0:1.4)
a Mixture of cis/trans isomers.
b E/Z ratios in parentheses.
c Only trans.
d Exo/endo = 2.8:1.0.
e Et3B/O2, r.t.
Synlett 2005, No. 6, 900–904 © Thieme Stuttgart · New York

902
Z. Pianowski et al.
LETTER
R2
R1
R2
I
i
1,5-H
R1
H
H
R1
H
H
+
PhMe2Si
PhMe2Si
R2
PhMe2Si
SiMe2Ph
SiMe2Ph
4
5
6
7
9
R1 = R2 = H
13 R1 = R2 = H
18 R1 = R2 = H
19 R1 = H, R2 = Me
20 R1 = R2 = Me
n-Bu3SnH
R1 = H, R2 = Me
R1 = R2 = Me
14 R1 = H, R2 = Me
15 R1 = R2 = Me
16 R1 = O, R2 = Ph
H
H
R1 = H, R2 = Ph
21 R1
22 R1
=
=
R2 = Me
R2 = Me
PhMe2Si
PhMe2Si
22
R1
=
R2 = Me 17 R1
=
R2 = Me
Scheme 6 Formation of compound 22
Scheme 4 Radical cyclizations of iodides 4–9; Reagents and condi-
tions: i) 4–6, 9: n-Bu3SnH/AIBN in PhH at 80 °C or n-BuSnH/ACCN
in PhMe at 110 °C; 7: Et3B/O2 in PhH at r.t.
O
O
I
Sn N
Sn
N
H
known to be influenced by substituents on the double
bond.13 Having been successful with these substrates, we
chose to study the synthesis of the b-santalol from iodide
9. In radical cyclizations of the iodide we were not able to
detect any traces of directly reduced acyclic products. The
second cyclization is less efficient than in other cases, but
the overall result is remarkable because the second closure
seems to be highly sterically demanding.
n-Bu n-Bu
n-Bu n-Bu
25
26
Figure 2 Tin compounds with the intramolecular Sn–N
coordination
The reductive cyclization of 9 with hydride 25 was as ef-
fective as the standard one with n-Bu3SnH (17 45%, 21
39%). The reaction was much cleaner but incomplete;
however the remaining iodide (ca. 10%) was easily sepa-
rated by column chromatography on silica gel. We ob-
served only traces of compound 22. As expected, all the
tin impurities were distinctly more polar. The iodide 26
was isolated in 84% yield and could be quantitatively con-
verted into the starting hydride. Although the stereochem-
istry of the bicyclic product 21 could not be determined at
this stage, subsequent transformations: removal of the
dimethylphenylsilyl group19 followed by regioselective
allylic oxidation20 of one of the methyl groups in 21 gave
the final alcohol 1. The product displayed the characteris-
tic sandalwood scent; identical to that of the natural prod-
uct. Our spectroscopic analyses are in agreement with the
data obtained previously by Krotz and Helmchen and con-
firm the structure of (Z)-b-santalol (1).21 Moreover, the
comparison of GC retention times22 for the synthetic ma-
terial with the commercially available Sandalwood oil
from Santalum album L. showed that the synthetic mate-
rial contained at least 95% of (Z)-b-santalol and less than
5% of unknown impurities. Since hydride 25 contained a
chiral ligand, it was of interest to measure ee in 1. How-
ever, the product appeared to be fully racemic.
SiMe2Ph
I
n-Bu3SnH, ACCN
PhMe, 110 °C
+
SiMe2Ph
SiMe2Ph
24 30 %
8
23 58 %
Scheme 5 The preference of the first 6-endo- over 5-exo-cyclization
In addition to compound 21 minor amounts of 22 were
also isolated. In the latter, migration of the double bond
presumably took place via a mechanism involving hydro-
gen transfer. The bulky silyl protecting group might pre-
vent the approach of the hydride to the vinyl radical and
so permitted the 1,5-H transfer to occur (Scheme 6).
While the bicyclic compound 21 was formed in satisfac-
torily yields its purification was somewhat troublesome
because of non-polar tin impurities. Difficulties in remov-
ing tin species from the products of stannane-mediated
radical reactions are well known. A number of methods
has been developed to facilitate product isolation,14 in-
cluding fluorous tin reagents in an effort to make organo-
tin chemistry more practical and user friendly.15 A recent
synthesis of gymnomitrene ketone demonstrates the ad-
vantage of use of fluorous tin hydrides.4 To solve the iso-
lation problem we used hydride 2516 for the preparative
radical cyclization of 9, assuming that by-products from
this hydride should be more polar and consequently easier
for removal (Figure 2). Hydride 25 can be considered as a
member of tin compounds in which the tin is intramolec-
ularly coordinated to heteroatom(s), particularly nitro-
gen.17 The use of this class of hydrides in radical
chemistry is still in its infancy. Nevertheless, promising
results especially with hydrides possessing chirality on
the tin have been reported.18
In summary, we have described a reasonably short radical
route to the derivatives of the bicyclo[2.2.1]heptane, in-
cluding ( )-(Z)-b-santalol from readily accessible com-
pounds using two sequential radical-mediated 5-exo-
cyclizations. The results are remarkable, two fused rings
and one quaternary stereogenic center are formed in a
‘single’ operation. A new coordinated hydride reagent ap-
peared to be useful in the cascade. Further radical cascade
studies are now in progress in our laboratory.
Synlett 2005, No. 6, 900–904 © Thieme Stuttgart · New York

LETTER
Radical Cyclizations Leading to the Bicyclo[2.2.1]heptane Framework
903
Radical Cyclizations of Iodides 4–8
rator to give the product (79 mg, ~100%), which was treated with
SeO2 (63 mg, 0.57 mmol) and EtOH and refluxed for 4 h. The reac-
tion mixture was allowed to reach r.t. and after treatment with
NaBH4 (50 mg) stirred overnight. After working up the reaction
mixture, b-santalol (68 mg, 80%) was obtained after chromatogra-
phy.
The iodide (0.50 mmol) was dissolved in dry and degassed PhMe at
r.t. The amount of PhMe was calculated according to 0.009 M con-
centration of n-Bu3SnH. The hydride (146 mL, 0.55 mmol), ACCN
(ca. 5% mol) was added and the solution was refluxed. The progress
was monitored by TLC. After evaporation of the solvent the mixture
was filtered through a pad of silica gel (hexane) and subjected to
HPLC (hexanes–EtOAc, 99:1) to give the products.
IR (film): 3321, 3067, 2963, 2872, 1653, 1455, 1373, 1002, 877,
1
817 cm–1. H NMR (CDCl3): d = 5.30–5.26 (1 H, t, J = 7.3 Hz,
H11), 4.73 (1 H, s, H3b), 4.56 (1 H, s, H3a), 4.14 (2 H, s, H13 pro-
tons), 2.67–2.66 (1 H, br d, J = 4.0 Hz, H1), 2.10–2.09 (1 H, br d,
J = 3.5 Hz, H5) 2.12–1.98 (2 H, m, H9 protons), 1.78 (3 H, d,
J = 1.5 Hz, protons of CH3 at C12), 1.70–1.60 (3 H, m, one of the
H8 protons, one of the H6 and one of the H7 protons), 1.45–1.37 (2
H, m, one of the H7 protons, one of the H6 and one of the H10 pro-
tons), 1.26–1.20 (2 H, m, one of the H6 or H7 protons and one of
the H10 protons), 1.18 (1 H, m, one of the H8 protons), 1.17 (1 H,
Representative Spectroscopic Data
Compound 18: IR (film): 3068, 3049, 2957, 2869, 1631, 1427,
1247, 1113, 851, 831 cm–1. MS (EI): m/z (%) = 242 (33) [M+], 227
(87), 199 (5), 148 (100), 135 (27), 121 (38). HRMS (EI): m/z calcd
1
for C16H22Si: 242.1491; found: 242.1501. Major isomer (Z): H
NMR: d = 7.59–7.33 (5 H, m), 5.47–5.45 (1 H, t, J = 2.5 Hz), 2.71–
2.68 (1 H, d, J = 3.9 Hz), 2.36–2.32 (1 H, m), 2.10–2.04 (1 H, m),
1.84–1.79 (1 H, dt, J = 16.3, 2.6 Hz), 1.70–1.20 (6 H, m), 0.34 and
0.33 (6 H, 2 × s) ppm. 13C NMR: d = 167.3, 140.5, 133.8, 128.6,
127.6, 113.0, 44.4, 42.4, 39.5, 36.2, 29.2, 28.3, –0.7, –1.3 ppm. Mi-
nor isomer (E): 1H NMR: d = 7.59–7.33 (5 H, m), 5.26–5.24 (1 H,
t, J = 1.9 Hz), 2.78 (1 H, br s), 2.36–2.32 (1 H, m), 2.30–2.24 (1 H,
m), 1.99–1.94 (1 H, ddd, J = 16.1, 3.2, 1.8 Hz), 1.70–1.20 (6 H, m),
0.38 and 0.36 (6 H, 2 × s) ppm. 13C NMR: d = 167.6, 140.2, 133.7,
128.6, 127.6, 112.1, 50.0, 39.3, 38.8, 37.2, 29.8, 28.3, –0.7, –1.3
ppm.
br s, OH group), 1.04 (3 H, s, protons of CH3 group at C4) ppm. 13
C
NMR (CDCl3): d = 161.1 (C2), 134.0 (C12), 129.0 (C11), 99.7
(C3), 61.6 (C13), 46.8 (C1), 44.8 (C4), 44.7 (C5), 41.5 (C10), 37.1
(C8), 23.7 and 29.7 (C6 and C7), 23.2 (C9), 22.6 (CH3 at C4), 21.2
(CH3 at C12). 1H NMR (C6D6): d = 5.30–5.26 (1 H, t, J = 7.4 Hz),
4.94 (1 H, s), 4.65 (1 H, s), 4.06 (2 H, s), 2.72–2.69 (1 H, d, J = 4.1
Hz), 2.16–1.95 (3 H, m), 1.84 (3 H, d, J = 1.1 Hz), 1.74–1.71 (1 H,
m), 1.70–1.63 (2 H, m), 1.56–1.49 (1 H, m), 1.41–1.33 (3 H, m),
1.14–1.11 (1 H, m), 1.10 (3 H, s) ppm. 13C NMR (C6D6): d = 165.9,
134.8, 128.3, 100.3, 61.4, 47.2, 45.0, 44.9, 41.9, 37.3, 30.0, 24.0,
23.5, 22.7, 21.3 ppm. MS (EI): m/z (%) = 220 (<1) [M+], 189 (5),
161 (4), 122 (50), 94 (100). HRMS (EI): m/z calcd for C15H24O:
220.1827; found: 220.1816.
Compound 21: IR (film): 3068, 3048, 2962, 2924, 2871, 1650,
1463, 1427, 1246, 1112, 833 cm–1. MS (EI): m/z (%) = 337 (7)
[M+ – H], 323 (15), 279 (7), 255 (20), 201 (28), 135 (100). HRMS
(EI): m/z calcd for C23H34Si: 338.2430; found: 338.2445.
Compound 22: IR (film): 3067, 3049, 2957, 2925, 2869, 1623,
1463, 1246, 1111, 832 cm–1. MS (EI): m/z (%) = 337 (8) [M+], 323
(1), 279 (7), 295 (6), 255 (81), 202 (7), 175 (20), 135 (100). HRMS
(EI): m/z calcd for C23H34Si: 338.2430; found: 338.2434. Major iso-
mer (Z): 1H NMR: d = 7.54–7.32 (5 H, m), 5.45–5.30 (2 H, m), 5.11
(1 H, m), 2.78–2.76 (1 H, d, J = 4.6 Hz), 2.30–2.23 (1 H, sextet,
J = 6.7 Hz), 2.10–1.98 (3 H, m), 1.69–1.54 (3 H, m), 1.40–1.34 (1
H, m), 1.18–1.09 (2 H, m), 0.99–0.97 (9 H, m), 0.35 and 0.33 (6 H,
2 × s) ppm. 13C NMR: d = 177.5, 140.7, 140.2, 133.8, 128.5, 127.6,
124.0, 109.2, 47.2, 45.6, 44.7, 41.9, 37.0, 31.2, 28.3, 25.4, 23.7,
22.8, 22.7, –0.6, –0.7 ppm. Minor isomer (E): 1H NMR: d = 7.54–
7.32 (5 H, m), 5.45–5.30 (2 H, m), 5.09 (1 H, m), 2.75–2.73 (1 H, d,
J = 4.3 Hz), 2.30–2.23 (1 H, sextet, J = 6.7 Hz), 2.10–1.98 (3 H, m),
1.69–1.54 (3 H, m), 1.40–1.34 (1 H, m), 1.18–1.09 (2 H, m), 0.99–
0.97 (9 H, m), 0.35 and 0.32 (6 H, 2 × s) ppm. 13C NMR: d = 177.1,
140.7, 140.2, 133.8, 128.5, 127.6, 123.7, 109.5, 47.2, 45.5, 44.0,
43.9, 36.8, 31.2, 29.1, 23.6, 22.9, 22.7 (2×), –0.6, –0.7.
Acknowledgment
Financial support by the Institute of Organic Chemistry, Polish
Academy of Sciences and the Polish State Committee for Scientific
Research (Grant No. 4 T09A 063 25) is gratefully acknowledged.
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Preparative Radical Cyclizations of 9 with Hydride 25
The iodide (464 mg, 1.0 mmol) was dissolved in dry and strictly de-
gassed PhMe at r.t. The amount of PhMe was calculated to afford
0.009 M concentration of hydride 25. The hydride (507 mg, 1.2
mmol), ACCN (ca. 5% mol) was added and the solution was re-
fluxed. The progress was monitored by TLC. After evaporation of
the solvent the mixture was filtered through a pad of silica gel (hex-
ane and then EtOAc) and the hexane extract was purified by column
chromatography followed by HPLC (hexanes–EtOAc, 99:1) to give
compounds 17 (152 mg, 45%), and 21 (132 mg, 39%). The EtOAc
extract contained almost pure bromide 26 (552 mg, 84%).
( )-(Z)-b-Santalol (1)
A mixture of concentrated HI (0.86 mmol), compound 22 (132 mg,
0.39 mmol) was heated for 5 h and then cooled to r.t. The mixture
was neutralized with sat. aq Na2CO3 and the crude product was ex-
tracted with hexane. The solvent was removed with a rotary evapo-
Synlett 2005, No. 6, 900–904 © Thieme Stuttgart · New York

904
Z. Pianowski et al.
LETTER
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