Synthesis of Methylenebicyclo[3.2.1]octanol by a Sm(II)-Induced 1,2-Rearrangement Reaction with Ring Expansion of Methylenebicyclo[4.2.0]octanone

Article abstract of DOI:10.1021/acs.orglett.7b01604

Direct conversion of methylenebicyclo[4.2.0]octanone to methylenebicyclo[3.2.1]octanol by a Sm(II)-induced 1,2-rearrangement with ring expansion of the methylenecyclobutane is described. Three conditions were optimized to allow the adaptation of this approach to various substrates. A rearrangement mechanism is proposed involving the generation of a ketyl radical and cyclopentanation by ketyl-olefin cyclization, followed by radical fragmentation and subsequent protonation.

Full text of DOI:10.1021/acs.orglett.7b01604

Letter
pubs.acs.org/OrgLett
Synthesis of Methylenebicyclo[3.2.1]octanol by a Sm(II)-Induced 1,2-
Rearrangement Reaction with Ring Expansion of
Methylenebicyclo[4.2.0]octanone
Kazuhiko Takatori,* Shoya Ota, Kenta Tendo, Kazuma Matsunaga, Kokoro Nagasawa, Shinya Watanabe,
Atsushi Kishida, Hiroshi Kogen, and Hiroto Nagaoka
Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
S
* Supporting Information
ABSTRACT: Direct conversion of methylenebicyclo[4.2.0]-
octanone to methylenebicyclo[3.2.1]octanol by a Sm(II)-induced
1,2-rearrangement with ring expansion of the methylene-
cyclobutane is described. Three conditions were optimized to
allow the adaptation of this approach to various substrates. A
rearrangement mechanism is proposed involving the generation
of a ketyl radical and cyclopentanation by ketyl−olefin cyclization,
followed by radical fragmentation and subsequent protonation.
Scheme 1. Conversion of Bicyclo[4.2.0]octane to
Bicyclo[3.2.1]octane
icyclo[3.2.1]octane is a common framework found in
Bbiologically important natural products such as gibberellins
and kauranoids.1 Some of these compounds have common
characteristic functional groups in the bicyclic system. For
example, the C/D ring system of gibberellins A1, A3, and steviol
is functionalized bicyclo[3.2.1]octanol 1, with a methylene
group in the cyclopentane and a hydroxyl group at the
bridgehead carbon (Figure 1).2 Many methods for the synthesis
of bicyclo[3.2.1]octane have recently been developed,1,3 and
excellent stereoselective syntheses of those diterpenoids have
been reported.2a,4
Meerwein rearrangement or related reactions, but these
approaches do not provide the required hydroxyl group at
the bridgehead carbon in the product 5 (eq 3).8 A very efficient
skeletal transformation of bicyclo[4.2.0]octanone 2 to bicyclo-
[3.2.1]octanol 1 could be realized by 1,2-rearrangement of the
methylene carbon to the carbonyl group in 2, accompanied by
ring expansion of the cyclobutane in one step (eq 2). Kakiuchi
et al. reported a radical ring-opening reaction of the
cyclobutane at the carbonyl α-position of bicyclo[4.2.0]-
octanones with SmI2.9 SmI2 is an effective reagent for
generating ketyl radicals as key intermediates for a variety of
reactions involving carbonyl groups.10 Therefore, the use of
SmI2 should be effective for generating ketyl radical 6, thereby
initiating 1,2-rearrangement with ring expansion of the
Figure 1. Structures of methylenebicyclo[3.2.1]octanol and related
natural products.
The conversion of bicyclo[4.2.0]octanone 2 to bicyclo-
[3.2.1]octanol 1 is an effective approach for synthesizing the
functionalized C/D ring system of gibberellins and kauranoids
(Scheme 1). The bicyclo[4.2.0]octanone 2 is easily obtained by
[2 + 2] photocycloaddition of allene to cyclohexenone.
However, this conversion requires a multistep sequence (eq
1).6 Treatment of ketone 2 with Lewis acid affords products
with other ring systems rather than 1.7 One-step conversion of
4 to the bicyclo[3.2.1]octane system is possible by Wagner−
Received: May 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclobutane. Herein we report a Sm(II)-induced novel 1,2-
rearrangement for the one-step conversion of bicyclo[4.2.0]-
octanone 2 to methylenebicyclo[3.2.1]octanol 1.
Table 3. Optimization of the Reaction Conditions for 2c
Our initial investigation of the 1,2-rearrangement involved
dropwise addition of a solution of SmI2 (3 equiv) in THF to a
solution of 2a or 2b in THF.11 The reaction of 2a did not go to
completion in the absence of additives and afforded undesired
coupling product 7 (Table 1, entry 1). However, the addition of
a
SmI2
time yield (%), ratio
entry (equiv) additive (equiv)
temp
rt
(h)
1c:9
1
3
HMPA (12)
t-BuOH (1)
0.5
ND
Table 1. Optimization of the Reaction Conditions for 2a
2
3
LiCl (6)
t-BuOH (1)
rt
0.5
98, >1:25
3
4
5
6
3
4
4
4
LiCl (6)
rt
0.5
3
97, 1:25
98, >1:25
93, 1:1
TBACl (8)
TBABr (8)
TBABr (8)
HMPA (16)
reflux
reflux
reflux
12
0.5
88, 11:1
a
yield (%)
a
entry
additive (equiv)
time
24 h
1
7
1
The ratio 1c:9 was determined from the H NMR spectrum of the
b
1
none
0
41
12
4
mixture because the compounds were difficult to separate.
b
2
HMPA (12)
20 h
63
90
b
3
HMPA (12), t-BuOH (1)
30 min
15 min
c
4
LiCl (6), t-BuOH (1)
trace
72
a
b
form a complex mixture containing bicyclo[6.3.0]undecanes,
similar to the formation of 8 from 2b (Table 3, entry 1).
Furthermore, the use of LiCl/t-BuOH afforded only reduced
product 9 (entry 2). Removal of the proton source was vital to
suppress reduction, and the reaction using only dried LiCl as an
additive gave a small amount of 1c (entry 3). It is difficult to
remove all moisture from the lithium salt, and thus we tried
using ammonium salt. Tetrabutylammonium chloride (TBACl)
is insoluble in THF and yielded poor results (entry 4);
however, use of tetrabutylammonium bromide (TBABr), which
is soluble in THF, to form SmBr2 in situ, provided 1c and
reduced product 9 (entry 5).12 Furthermore, when HMPA was
added to enhance the reduction,13 the reaction proceeded
rapidly and the yield of 1c was satisfactory (entry 6), but the
reaction gave almost exclusively 9 upon further addition of t-
BuOH. Entry 6 shows the optimum conditions for substrates
lacking a substituent at the angular position.
Isolated yield. A solution of SmI2 in THF was added dropwise to a
c
stirred solution of the substrate and additives in THF. A solution of
the substrate and additives in THF was added dropwise to a stirred
solution of SmI2 in THF.
HMPA was effective in preventing the formation of 7 (entry 2),
and subsequent addition of t-BuOH accelerated the reaction
and gave the desired rearrangement product 1a in good yield
(entry 3). In contrast, the addition of LiCl afforded 7 (entry 4).
The reaction of substrate 2b in the absence of additives did not
proceed (Table 2, entry 1). The addition of HMPA and t-
Table 2. Optimization of the Reaction Conditions for 2b
Next, the 1,2-rearrangement reaction with ring expansion of
bicyclo[4.2.0]octanones 2d−r was examined under the three
optimized conditions (Scheme 2). Bicyclo[4.2.0]octanones
2d−f with an ester carbonyl group at the angular position
were rearranged to the corresponding bicyclo[3.2.1]octanols
1d−f in high yield using SmI2/HMPA/t-BuOH (condition A).
Reaction of 2d−f with SmI2/LiCl/t-BuOH (condition B)
afforded the products of coupling between two carbonyl groups
such as 7. Reaction condition A was optimal even for 2g, which
has an oxygen functional group at the angular position and gave
1g in satisfactory yield. For substrates 2h−l, which have a
methyl or methylene group at the angular position, condition B
gave results comparable to that obtained with the reaction of
2b. The reactions of 2j and 2k under condition B did not
require t-BuOH because the hydroxyl group acted as an internal
proton source. The use of SmI2/TBABr/HMPA (condition C)
also gave good results for 2k. Condition C was superior for
substrates 2m−o, in which R2 and R3 are not connected by a
tether, and for substrates 2p−r, which lack a substituent at
angular position R1. These substrates gave only alcohols
produced by reduction of the carbonyl group under condition
A. Condition B provided the target products, but the major
products were the corresponding reduced alcohols. Therefore,
by selecting the most appropriate of the three conditions, it was
possible to conduct the desired 1,2-rearrangement reaction with
a
entry
additive (equiv)
temp
time
12 h
yield (%) of 1b
b
1
none
rt
NR
36
b
2
HMPA (12), t-BuOH (1)
HMPA (12), t-BuOH (1)
rt
20 min
20 min
20 min
c
3
rt
61
c
4
LiCl (6), t-BuOH (1)
reflux
91
a
b
Isolated yield. A solution of SmI2 in THF was added dropwise to a
stirred solution of the substrate and additives in THF. A solution of
the substrate and additives in THF was added dropwise to a stirred
solution of SmI2 in THF.
c
BuOH was effective for producing 1b, but the major product
was a derivative of bicyclo[6.4.0]dodecane 8 formed by
cleavage of the fusion bond in the cyclobutane (entry 2).
Dropwise addition of 2b, HMPA, and t-BuOH in THF to a
solution of SmI2 in THF improved the yield of 1b (entry 3).
The addition of LiCl instead of HMPA dramatically increased
the yield of 1b, and reproducibility was increased under reflux
conditions (entry 4).
Quite different results were obtained using substrate 2c, in
which the angular position is unsubstituted and corresponds to
the gibberellin C/D ring (Table 3). Under the conditions
optimized for 2a and 2b (Table 1 entry 3 and Table 2 entry 4),
no desired rearrangement product 1c was obtained, and
HMPA/t-BuOH mainly caused cleavage of the cyclobutane to
B
DOI: 10.1021/acs.orglett.7b01604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the 1,2-Rearrangement with Ring
a b c
, ,
Expansion Strategy
Figure 2. ORTEP drawing of 10.
Based on these findings, we propose the following
mechanism (Scheme 4). The ketyl radical 11 is generated by
Scheme 4. Proposed Mechanism
single-electron reduction of the carbonyl group in 2 with
Sm(II), and a cyclopropane is formed by ketyl−olefin
cyclization.14 The resulting tetracyclic system 12 rearranges to
the bicyclo[3.2.1] system 13 by fragmentation of the
cyclopropane due to distortion, resulting in reformation of
the exo-olefin.15 At the same time, the generated radical is
reduced by Sm(II), yielding Sm Grignard reagent 13.16 Finally,
protonation of 13 completes the rearrangement with ring
expansion, giving 1. This mechanism is consistent with radical
kinetic studies. The rate constants for the reduction of primary
a
Substrates 2 were prepared by [2 + 2] photocycloaddition of the
b
corresponding cyclohexenones and allene. Reaction conditions: A:
SmI2 in THF (0.1 M, 3 equiv), HMPA (12 equiv), t-BuOH (1 equiv)
for 30 min at rt; B: SmI2 in THF (0.1 M, 3 equiv), LiCl (6 equiv), t-
BuOH (1 equiv) for 30 min under reflux; C: SmI2 in THF (0.1 M, 4
equiv), TBABr (8 equiv), HMPA (16 equiv) for 30 min under reflux.
c
d
6
radicals, such as 12, with SmI2 are on the order of 105 to 10
Yield of isolated product. The reaction was carried out for 45 min
e
f
s−1 and are 107 s−1 for the fragmentation of cyclopropylmethyl
radicals similar to 12.17 For substrates with a bulky substituent
at the angular position (R = Me or CO2Me), cyclopropanation
proceeds rapidly (e.g., 11 to 12) because the ketyl radical
carbon and the olefin carbon are in conformational proximity.
In contrast, in the absence of a bulky substituent (R = H),
cyclopropanation proceeds slowly because of the large distance
between the reaction points. Therefore, in the latter case, the
ketyl radical is protonated in the presence of t-BuOH to give
the corresponding alcohol (such as 9) under conditions A and
B. The electron-withdrawing group at the angular position in
substrates 2a,d−g seems to prevent the radical formation by
cleavage of the fusion bond in the cyclobutane, similar to the
formation of 8 from 2b. However, the cleavage is concomitant
under condition A for substrates without an electron-with-
drawing group. Coordination of sterically congested (HMPA)n
to ketyl 11 (X = I) interferes slightly with cyclopropanation,18
and less hindered (THF)n does not prevent cyclopropanation
under condition B (X = Cl), although pinacol coupling is
promoted for esters 2a,d−f.12d Under condition C (X = Br),
the cyclopropanation may proceed with a complex in which the
coordination number of HMPA to SmBr2 is smaller than
SmI2;13 thus, the cleavage does not occur.
under reflux. The reaction was conducted without t-BuOH. Reaction
g
time was 3 h. Starting material 2l was recovered in 12% yield.
h
i
j
Reaction time was 1 h. Reaction time was 2 h. Reaction time was 12
h and starting material 2q was recovered in 21% yield.
ring expansion for various types of substrates, and bicyclo-
[3.2.1]octanols were obtained in excellent yield.
We conducted a deuteration experiment to analyze the
reaction mechanism (Scheme 3). CD3OD was used as a proton
Scheme 3. Deuteration Experiment Using 2a
source instead of t-BuOH in the rearrangement of 2b under
condition B, and the product 1b(D) was labeled stereo-
selectively with deuterium with a high labeling ratio at the
carbon originating from the carbonyl α-carbon fused with the
cyclobutane in 2b. On the other hand, rearrangement of 2k
under condition B at room temperature (Scheme 2) provided
trace amounts of unknown colorless crystals together with
product 1k as a white solid. Surprisingly, X-ray crystallographic
analysis of the crystals revealed that the compound was the
rather unusual tetracyclo[7.2.1.0.1,6010,12]dodecane 10 contain-
ing a cyclopropane (Figure 2).
In conclusion, we developed a ring expansion rearrangement
reaction for converting methylenebicyclo[4.2.0]octanones to
methylenebicyclo[3.2.1]octanols using Sm(II), and optimized
three conditions. This method is applicable to a wide range of
[2 + 2] photocycloadducts of cyclohexenones and allene and
C
DOI: 10.1021/acs.orglett.7b01604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307−
338. (b) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic
Synthesis Using Samarium Diiodide: A Practical Guide; RSC Publishing:
UK, 2010. (c) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev.
2004, 104, 3371−3404. (d) Szostak, M.; Fazakerley, N. J.; Parmar, D.;
Procter, D. J. Chem. Rev. 2014, 114, 5959−6039. (e) Just-Baringo, X.;
Yalavac, I.; Procter, D. Organomet.Chem. 2015, 40, 1−32.
(11) All substrates were prepared by [2 + 2] photocycloaddition of
allene to the corresponding enone. See Supporting Information.
(12) For other preparation methods for SmBr2, see: (a) Selwood, P.
W. J. Am. Chem. Soc. 1934, 56, 2392−2394. (b) Lebrun, A.; Namy, J.-
L.; Kagan, H. B. Tetrahedron Lett. 1993, 34, 2311−2314. (c) Fuchs, J.
R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II Tetrahedron Lett.
1997, 38, 8157−8158. (d) Miller, R. S.; Sealy, J. M.; Shabangi, M.;
Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II J. Am. Chem. Soc. 2000,
provides a new and efficient pathway to the synthesis of
gibberellins, kauranoids, and other natural products containing
the bicyclo[3.2.1]octane framework with an oxygen functional
group at the bridgehead carbon.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01604.
X-ray data for 10 (CIF)
Experimental procedures and spectral data for the
synthesized compounds (PDF)
122, 7718−7722. (e) Hel
́
ion, F.; Lannou, M.-I.; Namy, J.-L.
Tetrahedron Lett. 2003, 44, 5507−5510. (f) Dahlen
́
, A.; Hilmersson,
AUTHOR INFORMATION
G. Eur. J. Inorg. Chem. 2004, 2004, 3020−3024. (g) Sun, L.; Mellah, M.
Organometallics 2014, 33, 4625−4628.
■
Corresponding Author
*E-mail: takatori@my-pharm.ac.jp.
ORCID
(13) Knettle, B. W.; Flowers, R. A., II Org. Lett. 2001, 3, 2321−2324.
(14) Martin-Fontecha, M.; Agarrabeitia, A. R.; Ortiz, M. J.; Armesto,
D. Org. Lett. 2010, 12, 4082−4085.
(15) Underwood, J. J.; Hollingworth, G. J.; Horton, P. N.;
Hursthouse, M. B.; Kilburn, J. D. Tetrahedron Lett. 2004, 45, 2223−
2225.
Kazuhiko Takatori: 0000-0003-1273-6122
Notes
(16) (a) Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114,
6050−6058. (b) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben,
M. J. Synlett 1992, 1992, 943−961.
(17) (a) Hasegawa, E.; Curran, D. P. Tetrahedron Lett. 1993, 34,
1717−1720. (b) Newcomb, M. Radical Kinetics and Clocks. In
Encyclopedia of Radicals in Chemistry, Biology and Materials;
Chatgilialoglu, C., Studer, A., Eds.; John Wiley & Sons Ltd.:
Chichester, 2012; pp 1−18.
(18) (a) Sadasivam, D. V.; Antharjanam, P. S.; Prasad, E.; Flowers, R.
A., II J. Am. Chem. Soc. 2008, 130, 7228−7229. (b) For steric
influence of the coordination of HMPA on ketyl−olefin cyclization,
see: Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132−3139.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) from Japan Society for the Promotion of Science
(No. 23590022) and partially by a grant from the Dementia
Drug Resource Development Center Project S1511016, the
Ministry of Education, Culture, Sports Science and Technology
(MEXT), Japan.
REFERENCES
■
(1) Presset, M.; Coquerel, Y.; Rodriguez, J. Chem. Rev. 2013, 113,
525−595.
(2) (a) Mander, L. N. Chem. Rev. 1992, 92, 573−612. (b) MacMillan,
J. Nat. Prod. Rep. 1997, 14, 221−243. (c) Mander, L. N. Nat. Prod. Rep.
2003, 20, 49−69. (d) García, P. A.; de Oliveira, A. B.; Batista, R.
Molecules 2007, 12, 455−483.
(3) (a) Filippini, M.-H.; Rodriguez, J. Chem. Rev. 1999, 99, 27−76.
(b) Zhao, W. Chem. Rev. 2010, 110, 1706−1745.
(4) (a) Zhu, L.; Huang, S.-H.; Yu, J.; Hong, R. Tetrahedron Lett.
2015, 56, 23−31. (b) Riehl, P. S.; DePorre, Y. C.; Armaly, A. M.;
Groso, E. J.; Schindler, C. S. Tetrahedron 2015, 71, 6629−6650.
(5) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev.
2010, 39, 783−816. (b) Crimmins, Michael T.; Reinhold, Tracy, L.
Enone Olefin [2 + 2] Photochemical Cycloadditions. In Organic
Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1993;
Vol. 44, pp 297−588.
(6) (a) Nagaoka, H.; Shimano, M.; Yamada, Y. Tetrahedron Lett.
1989, 30, 971−974. (b) Synthetic example requiring multistep
conversion for the stereochemistry of photocycloaddition. See:
Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed.
2013, 52, 9019−9022.
(7) (a) Kakiuchi, K.; Nakamura, I.; Matsuo, F.; Nakata, M.; Ogura,
M.; Tobe, Y.; Kurosawa, H. J. Org. Chem. 1995, 60, 3318−3333.
(b) Kakiuchi, K.; Morimoto, T.; Horiguchi, T.; Yamada, K.; Tsutsumi,
K.; Kurosawa, H. Synthesis 2004, 2004, 753−756.
(8) (a) Duc, D. K. M.; Fet
́
izon, M.; Hanna, I.; Olesker, A.; Pascard,
T. J. Chem. Soc., Chem. Commun. 1980, 1209−1210.
C.; Prange,
́
(b) Ue, M.; Kobiro, K.; Kakiuchi, K.; Tobe, Y.; Odaira, Y. Chem. Lett.
1987, 16, 1903−1904. (c) Corey, E. J.; Liu, K. Tetrahedron Lett. 1997,
38, 7491−7494.
(9) Kakiuchi, K.; Minato, K.; Tsutsumi, K.; Morimoto, T.; Kurosawa,
H. Tetrahedron Lett. 2003, 44, 1963−1966.
D
DOI: 10.1021/acs.orglett.7b01604
Org. Lett. XXXX, XXX, XXX−XXX