Cascade- and orthoamide-type overman rearrangements of allylic vicinal diols

Article abstract of DOI:10.1002/chem.201301216

This article describes the details of two new types of Overman rearrangement from allylic vicinal diols. Starting from identical diols, both bis(imidate)s and cyclic orthoamides were selectively synthesized by simply changing the reaction conditions. Whil

Full text of DOI:10.1002/chem.201301216

DOI: 10.1002/chem.201301216
Cascade- and Orthoamide-Type Overman Rearrangements of Allylic Vicinal
Diols
Yasuaki Nakayama, Ruriko Sekiya, Hiroki Oishi, Naoto Hama, Miki Yamazaki,
Takaaki Sato,* and Noritaka Chida*[a]
Abstract: This article describes the de-
tails of two new types of Overman re-
arrangement from allylic vicinal diols.
Starting from identical diols, both bis-
ACHTUNGTRENNUNG(imidate)s and cyclic orthoamides were
selectively synthesized by simply
changing the reaction conditions.
Whilst exposure of the bisACTHNUTRGNE(NUG imidate)s to
thermal conditions initiated the double
Overman rearrangement to introduce
of cyclic orthoamides resulted in a
single rearrangement (the orthoamide-
type Overman rearrangement). The
newly generated allylic alcohols from
the orthoamide-type reaction can po-
tentially undergo a variety of further
transformations. For instance, we dem-
onstrated an Overman/Claisen se-
quence in one pot. The most conspicu-
ous feature of this method is that it
offers precise control over the number
of Overman rearrangements from the
same allylic vicinal diols. This method
also excludes the tedious protecting-
group manipulations of the homoallylic
alcohols, which are necessary in con-
ventional Overman rearrangements.
All of the performed rearrangements
proceeded in a completely diastereose-
Keywords: allylic compounds · dia-
stereoselectivity · diols · domino re-
actions · rearrangement
two identical nitrogen groups in
a
single operation (the cascade-type
Overman rearrangement), the reaction
lective fashion through
transition state.
a chair-like
Introduction
sulting in the formation of a doubly rearranged product (4,
cascade-type Overman rearrangement).[5a,b,7] On the other
hand, cyclic orthoamide 5 gives the singly rearranged prod-
uct (7) through a-hydroxyimidate 6.[5c,8] This method with
The allylic trichloroacetimidate rearrangement (Overman
rearrangement)[1] has been widely used as one of the most
practical [3,3]-sigmatropic rearrangements[2] in organic syn-
thesis. This reaction is extremely powerful and even pro-
ceeds with densely functionalized molecules. When imidates
that are derived from chiral secondary or tertiary alcohols
are employed, a chirality-transfer reaction[3] takes place
through a well-defined chair-like transition state to provide
enantiopure allylic amides.[1] The Overman rearrangement
has been applied to a number of total syntheses of biologi-
cally active natural alkaloids.[4,5,6c,d] However, although most
examples of the Overman rearrangement have been applied
to allylic alcohols, the rearrangement of allylic vicinal diol 1
had been overlooked until our recent reports (Scheme 1).[5,6]
Allylic vicinal diol 1 can give either a bis
cyclic orthoamide (5) upon treatment with CCl3CN and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU). Under thermal con-
ditions, bis(imidate) 2 undergoes the first Overman rear-
ACHTUNGTREN(NGNU imidate) (2) or a
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
rangement to provide compound 3, which readily undergoes
a second rearrangement in a single operation, thereby re-
[a] Y. Nakayama, R. Sekiya, H. Oishi, N. Hama, M. Yamazaki,
Dr. T. Sato, Prof. Dr. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology, Keio University, 3-14-1
Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
Scheme 1. Two types of Overman rearrangements of allylic vicinal diols
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301216.
(cascade-type and orthoamide-type) and their applications. DBU=1,8-
diazabicycloACTHNUTRGNEUNG[5.4.0]undec-7-ene. Ac=acetyl.
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FULL PAPER
Table 1. Selective formation of bisACTHNUTRGNE(UNG imidate)s (12) and cyclic orthoamides
allylic vicinal diols has a number of salient synthetic fea-
tures: First of all, enantiopure allylic vicinal diol 1 is readily
available from naturally occurring polyols, such as carbohy-
drates, and Sharpless asymmetric dihydroxylation.[9] Second,
the number of rearrangements can be precisely controlled
(13) from syn-vicinal diols (11).[a]
by the selective formation of either bisACTHNUTRGNEUNG(imidate) 2 or cyclic
orthoamide 5. The classical method for the synthesis of com-
pounds 4 and 7 from allylic vicinal diol 1 requires the pro-
tection of the homoallylic alcohol group in compound 1
prior to the first rearrangement, with the second reaction
performed after deprotection. However, our method can
preclude extra protecting-group manipulations. One of the
most practical advantages of this method is that it offers
predictable stereochemical outcomes. That is, the stereo-
chemistry can be engineered from considering the chair-like
six-membered transition state and an appropriate combina-
tion of the stereochemistry of the two secondary alcohols
and the geometry of the olefin. For example, as shown in
Scheme 2, although the cascade-type Overman rearrange-
Entry
syn-11
Method
Yield [%][b]
d.r.[c]
1:1
1
2
A
B
82 (12a)
96 (13a)
3
4
A
B
84 (12b)
89 (13b)
1:1
1:1
5
6
A
B
86 (12c)
91 (13c)
[a] Method A: compound syn-11 (100 mmol), DBU (2.2 equiv), CH2Cl2
(0.2m), À208C, 15 min, then CCl3CN (20 equiv), À208C, 1 h. Method B:
compound syn-11 (150 mmol), CCl3CN (1.3 equiv), CH2Cl2 (0.05m), 08C,
15 min, then DBU (0.1 equiv), 08C, 4 h. [b] Yield of isolated product
after purification by column chromatography on silica gel. [c] Diastereo-
meric ratio was determined by 1H NMR spectroscopy. Bn=benzyl,
MPM=p-methoxybenzyl.
droxyimidate, although we have no evidence for which alco-
hol reacts first. If the second intermolecular reaction with
CCl3CN is faster than the intramolecular cyclization reaction
Scheme 2. The stereochemical relationship between the allylic vicinal
diols (1) and the products (4) in the cascade-type Overman rearrange-
ment.
to form syn-cyclic orthoamide 13, syn-bisACHTNUTRGNEUNG(imidate) 12 can be
selectively generated. Indeed, when excess CCl3CN
(20 equiv) was quickly added to a vigorously stirring solu-
tion of diols 11a–11c, DBU (2.2 equiv), and CH2Cl2 (0.2m)
ment of both (Z)-syn-1 and (E)-anti-1 would both give anti-
4, the reactions of both (E)-syn-1 and (Z)-anti-1 would
result in the formation of syn-4. This method is highly prac-
tical and has enabled the enantioselective total synthesis of
various biologically active compounds: A-315675 (8)[5a] and
(À)-agelastatin A (9)[5b] through cascade-type Overman re-
arrangements, and broussonetine F (10)[5c] through ortho-
amide-type Overman rearrangements. Herein, we now pro-
vide full details of our investigations on these new Overman
rearrangements of allylic vicinal diols.
at À208C, bis
ACHTUNGTREN(NUNG imidate)s 12a–12c were selectively obtained
in high yields, irrespective of the structure of the olefin
(Table 1, method A, entries 1, 3, and 5). On the other hand,
when the intramolecular cyclization of the a-hydroxyimidate
dominates the second intermolecular reaction with CCl3CN,
syn-cyclic orthoamide 13 can be generated. The addition of
a catalytic amount of DBU (10 mol%) to a solution of com-
pounds 11a–11c, CCl3CN (1.3 equiv), and CH2Cl2 (0.05m) at
08C resulted in the selective formation of cyclic orthoamides
13a–13c as a 1:1 mixture of two diastereomers (Table 1,
method B, entries 2, 4, and 6).
Results and Discussion
Compared with syn-diol 11, the reaction of anti-diol 11[10]
was more prone to the formation of bisACHTNUTRGNEUNG(imidate) 12 over
Precise control over the number of Overman rearrange-
ments from identical allylic vicinal diols requires flexible re-
cyclic orthoamide 13, owing to steric repulsion between the
two substituents in the five-membered cyclic orthoamide
action conditions to form either bis
G
(13, Table 2). Therefore, the formation of anti-bisACTHNGURETNNUG(imidate)
thoamides. Our investigation to find such conditions com-
menced with optimization by using syn-diol 11[10] (Table 1).
Mechanistically, the treatment of syn-diol 11 with CCl3CN
in the presence of DBU initiates the formation of the a-hy-
12 required less of the reagents (DBU (1.0 equiv) and
CCl3CN (8 equiv)) and afforded a higher yield than syn-bis-
AHCTUNGTRENNUNG
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T. Sato, N. Chida et al.
Table 2. Selective formation of bis
(imidate)s (12) and cyclic orthoamides
Table 3. Cascade-type Overman rearrangement.[a]
(13) from anti-vicinal diols (11).[a]
Entry
1
12
14
Yield
[%][b]
95
Entry
anti-11
Method
Yield
[%][b]
d.r.
2
3
89
90
1
2
C
D
91 (12d)
83 (13d)
single
3
4
C
D
90 (12e)
84 (13e)
4
73
single
single
5
6
C
D
96 (12 f)
81 (13 f)
5
6
95
81
[a] Method C: compound anti-11 (100 mmol), DBU (1.0 equiv), CH2Cl2
(0.2m), À208C, 15 min, then CCl3CN (8.0 equiv), À208C, 30 min. Meth-
od D: compound anti-11 (300 mmol), CCl3CN (1.3 equiv), ZnCl2
(0.2 equiv), CH2Cl2 (0.05m), 08C, 15 min, then DBU (0.3–0.7 equiv), 08C,
4 days. [b] Yield of isolated product after purification by column chroma-
tography on silica gel.
[a] Compound 12 (60 mmol), Na2CO3 (0.4 equiv), tBuPh (0.03m) in a
sealed tube, 2008C, 30–60 min. [b] Yield of isolated product after purifi-
cation by column chromatography on silica gel.
not trivial. Application of method B, which was originally
developed for syn-diol 11, to anti-diol 11 resulted in the gen-
Having successfully developed the cascade-type reaction,
we turned our attention to the more challenging ortho-
amide-type Overman rearrangement. When we started this
program, only two reports relating to the orthoamide-type
reaction had been documented, despite its synthetic utility
(Scheme 3): Vyas et al. reported that the rearrangement of
seven-membered cyclic orthoamide 15 gave compound 17 in
68% yield,[8a] whilst Danishefsky’s group attempted the or-
thoamide-type Overman rearrangement of cyclic 1,2-diol 18
eration of
(imidate) 12. For example, the reaction of diol 11e gave
cyclic orthoamide 13e in 45% yield, along with bis(imidate)
a significant amount of undesired anti-bis-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
12e in 44% yield. After extensive investigations, we found
that the addition of a catalytic amount of ZnCl2 (20 mol%)
dramatically suppressed the formation of bisACTHUNRTGNEUNG(imidate)s 12d–
12 f, thus giving cyclic orthoamides 13d–13 f in high yields as
single diastereomers (Table 2, method D, entries 2, 4, and 6).
With both syn- and anti-bis
ACHTUNGTNER(NUNG imidate)s 12 in hand, we then
investigated the cascade-type Overman rearrangement
(Table 3). A solution of (Z)-syn-bisACTHNUTRGNEUNG(imidate) 12a and tert-
[11]
butylbenzene in the presence of Na2CO3
was heated at
2008C in a sealed tube, thus giving anti-bisAHCTUNGTERNGN(UN amide) 14a in
95% yield (Table 3, entry 1). The reaction proceeded with
complete diastereoselectivity. The reaction of (E)-syn-bis-
ACHTUNGTRENNUNG(imidate) 12b also exhibited a high yield and high diastereo-
selectivity (Table 3, entry 2). Considering that both enan-
tiomers of diols 12a and 12b are easily available,[10] all four
possible stereoisomers of compound 14 can be synthesized
as single diastereomers. The cascade reaction of trisubstitut-
ed olefin 12c proceeded in 90% yield, thereby leading to
the construction of two continuous stereocenters, including
sterically hindered a-trisubstituted amines (Table 3, entry 3).
These conditions were also applicable to anti-bis
12 (Table 3, entries 4–6).
ACHTUNGTRENUN(NG imidate)s
Scheme 3. Precedents for the orthoamide-type Overman rearrangement.
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Overman Rearrangements of Allylic Vicinal Diols
FULL PAPER
in the total synthesis of (Æ)-pancratistatin.[8b] They reported
that two diastereomers that were derived from the ortho-
amide group underwent equilibration upon thermolysis.
However, no rearranged product (20) was produced. They
proposed that one possible explanation for this result was
that cyclic orthoamide 18 could open up to afford a-hydrox-
yimidate 19, but that the rate of reclosure to afford com-
pound 18 was much faster than the rearrangement step. We
observed a similar phenomenon to Danishefsky’s report
(Table 4). A 1:1 diastereomeric mixture of cyclic orthoamide
22a in 56% yield (77% yield based on recovered starting
material; Table 4, entry 6).
With optimized conditions in hand, we investigated the
scope of the reaction with a range of substrates (Table 5). In
contrast to the cascade-type reaction, the yield of the or-
Table 5. Substrate scope in the orthoamide-type Overman rearrange-
AHCTUNGTRENNUNG
ment.[a]
Table 4. Optimization of the reaction conditions in the orthoamide-type
Overman rearrangement.[a]
Entry
13
22
Yield
[%][b]
1
2
3
56
67
34
Entry
Additive
Yield [%][b]
22a
13a
4
5
6
63
72
27
1
2
3
4
5
6
none
K2CO3
Na2CO3
17
8
32
48
19
56
0
54
31
28
43
27
4 ꢁ M.S.
BHT (100 mol%)
BHT (5 mol%)
[a] Compound 13a (50 mmol), additive, tBuPh (0.03m) in a sealed tube,
1808C, 1 d. [b] Yield of isolated product after purification by column
chromatography on silica gel. BHT=2,6-di-tert-butylhydroxytoluene.
[a] Compound 13 (50 mmol), BHT (5 mol%), tBuPh (0.03m) in a sealed
tube, 1808C. [b] Yield of isolated product after purification by column
chromatography on silica gel.
13a was separable by HPLC and an equilibrium was
reached between two diastereomers in the same ratio after a
few days at room temperature through a-hydroxyimidate
21a. Indeed, the realization of the rearrangement was not
trivial. After extensive investigation, we isolated rearranged
product 22a in only 17% yield after heating at 1808C in a
sealed tube for 1 day. However, cyclic orthoamide 13a had
significantly decomposed, owing to the prolonged reaction
time (Table 4, entry 1). Then, the effects of standard basic
thoamide-type rearrangement depended on the structure of
the substrates. The E olefins showed slightly higher yields
than the Z olefins (Table 5, entry 1 vs. entry 2, and entry 4
vs. entry 5). The anti-cyclic orthoamides 13d and 13e exhib-
ited better results than syn-orthoamides 13a and 13b, proba-
bly because anti-orthoamides 13d and 13e were prone to
open up into the a-hydroxyimidates, as shown in Table 2
(Table 5, entry 1 vs. entry 4, and entry 2 vs. entry 5). Disap-
pointingly, the reaction of trisubstituted olefins resulted in a
significant decrease in yield because of the large degree of
steric hindrance (Table 5, entries 3 and 6). Notably, all of
the orthoamides that were tested (13) provided their corre-
sponding stereoisomers (22) as a single product.
[12]
additives, such as K2CO3 and Na2CO3,[11] on the Overman
rearrangement were investigated (Table 4, entries 2 and 3).
Whilst the addition of K2CO3 led to a low yield, the less
basic Na2CO3 had some positive effects in preventing the
decomposition pathway. The addition of 500 wt.% 4 ꢁ M.S.
(molecular sieves) led to an increase in the yield (Table 4,
entry 4). Finally, we found that BHT (2,6-di-tert-butylhy-
droxytoluene)[13,14] prevented the decomposition reaction to
give compound 22a in 19% yield, together with recovery of
the starting material (13a) in 43% yield (Table 4, entry 5).
Because large amounts of BHT suppressed the rate of the
rearrangement itself, we found that the addition of 5 mol%
BHT was the optimal amount, thus providing compound
The orthoamide-type Overman rearrangement of com-
À
pound 5 can lead to the construction of a carbon nitrogen
bond, along with the generation of a new allylic alcohol,
which has the potential to undergo another [3,3]-sigmatropic
rearrangement, such as the Claisen rearrangement
(Scheme 4).[15] Namely, the orthoamide-type reaction would
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T. Sato, N. Chida et al.
Table 7. Sequential one-pot Overman/Claisen rearrangement.
Entry
13
25
Yield
[%]
Scheme 4. One-pot sequential Overman/Claisen rearrangement.
1
2
3
45
54
54
enable us to perform two different rearrangements in one
pot. If the Overman/Claisen sequence were successful,
highly useful chiral building blocks 23 could be obtained
from simple cyclic orthoamide 5.
Although our final goal was the execution of two different
rearrangements in a one-pot process, we first surveyed opti-
mal conditions for the second Claisen rearrangement from
allylic alcohol 22a (Table 6). The reaction was performed
4
55
Table 6. Optimization of the reaction conditions in the Claisen rear-
rangement.
[a] Compound 13 (50 mmol), BHT (5 mol%), tBuPh (0.03m) in a sealed
tube, 1808C, 1–2 d, then MeC(OEt)3 (16 equiv), pivalic acid (1.0 equiv),
AHCTUNGTRENNUNG
BHT (10 mol%), tBuPh (0.03m) in a sealed tube, 1408C. [b] Yield of iso-
lated product after purification by column chromatography on silica gel.
orthoamides 13a–13e smoothly took place, irrespective of
the structure of the orthoamides (Table 7, entries 1–4). Here
again, all of the products were obtained as single diastereo-
mers. Thus, we accomplished the sequential stereoselective
Entry
Reagents
MeC(OMe)2NMe2
MeC(OEt)3, 2-nitrophenol
MeC(OEt)3, propionic acid
MeC(OEt)3, pivalic acid
MeCACHTUNGTRENNUNG(OEt)3, pivalic acid, BHT (10 mol%)
Yield [%]
1
2
3
4
5
G
44 (24a)
69 (25a)
53 (25a)
71 (25a)
77 (25a)
AHCTUNGTRENNUNG
À
À
installation of carbon nitrogen and carbon carbon bonds in
a one-pot reaction.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
The stereochemistries of the newly generated carbon cen-
ters were unambiguously determined through their conver-
sion into cyclic compounds. An example that was derived
from (Z)-allylic syn-diol 11a is shown in Scheme 5. The anti-
[a] Compound 22a (30 mmol), MeCACHTUNGTRENNUG(OMe)2NMe2 or MeCACHUTNGTREN(NUGN OEt)3
(16 equiv), acid (1.0 equiv), tBuPh (0.03m) in a sealed tube, 1408C.
[b] Yield of isolated product after purification by column chromatogra-
phy on silica gel.
bisACTHUNRTGNEUNG(amide) 14a, which was produced by the cascade-type
Overman rearrangement of compound 12a, was treated
with Cs2CO3 in DMF at 1008C[17] to afford cyclic urea 26a in
48% yield. The stereochemistry of the resulting urea (26a)
was convincingly confirmed by a NOESY experiment, which
showed that the cascade-type Overman rearrangement
indeed proceeded through a six-membered chair-like transi-
tion state. Singly rearranged product 22a from cyclic ortho-
with identical solvent and reaction vessels as for the ortho-
ACHTUNGTRENNUNGamide-type Overman rearrangement. The use of Eschen-
moser’s conditions resulted in a low yield of the product
(Table 6, entry 1) and so Johnson’s conditions were em-
ployed in the presence of a variety of Brønsted acids,[16] thus
revealing that pivalic acid was the best choice (Table 6, en-
tries 2–4). A combination of pivalic acid and 10 mol% BHT,
which was used in the orthoamide-type Overman rearrange-
ment, resulted in a slight improvement in yield (Table 6,
entry 5).
With the reaction conditions for the Claisen rearrange-
ment established, we then implemented two different rear-
rangements in one pot (Table 7). After the completion of
the first Overman rearrangement of cyclic orthoamides
13a–13e at 1808C, the reaction mixture was cooled to
amide 13a was converted into anti-bisACTHNUTRGNEUNG(amide) 14a upon ex-
posure to the reaction conditions of the conventional Over-
man rearrangement. On the other hand, compound 25a,
which was synthesized by the sequential Overman/Claisen
rearrangement of compound 13a, was converted into g-
lactam 27a. The treatment of compound 25a with a 5m
aqueous solution of KOH and tBuOH at 70–1108C gave
64% yield of g-lactam 27a, the NOESY spectrum of which
clearly indicated that the rearrangement took place in a
highly stereoselective manner, as expected.
1408C and MeC
ACHTUNGTRENNUNG(OEt)3, pivalic acid, and 10 mol% BHT
were added. Gratifyingly, the one-pot sequential reaction of
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Overman Rearrangements of Allylic Vicinal Diols
FULL PAPER
pot. The second Claisen rearrangement proceeded without
isolation of the product of the first orthoamide-type Over-
man rearrangement, thus affording the installation of two
different functional groups (Scheme 5).
Acknowledgements
We thank Prof. Takeshi Noda and Ms. Yuka Shibaoka (Kanagawa Insti-
tute of Technology) for their assistance with the mass spectrometry anal-
ysis.
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[6] We have reported the cascade-type Claisen rearrangement of allylic
vicinal diols in the total synthesis of (À)-morphine, see: a) H. Tani-
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ments in the orthoamide-type Claisen rearrangement and its appli-
cation to the total synthesis of (À)-kainic acid; see: c) K. Kitamoto,
Scheme 5. An example of the stereochemical determination of the re-
ACHTUNGTRENNUNGarranged products that were derived from (Z)-allylic syn-diol 11a.
Conclusion
We have developed two new types of Overman rearrange-
ments of allylic vicinal diols. Both bis(imidate)s and cyclic
AHCTUNGTRENNUNG
orthoamides were selectively synthesized from common al-
lylic vicinal diols; the resulting intermediates underwent
either cascade-type or orthoamide-type Overman rearrange-
ments, respectively. Whereas the rearrangement of the bis-
À
ACHTUNGTRENNUNG(imidate)s established two contiguous carbon nitrogen
bonds in a single operation, the orthoamide-type rearrange-
ment gave the singly rearranged products. The conspicuous
features of our method are: 1) the ease of preparation of
the chiral allylic vicinal diols; 2) precise control over the
number of rearrangements from the same starting diols;
3) complete diastereoselectivity and predictable stereochem-
ical outcomes; and 4) exclusion of the need for protecting-
group manipulations on the homoallylic alcohol, which is a
requisite in conventional Overman rearrangements. Further-
more, the newly generated allylic alcohols by the orthoa-
mide-type rearrangements can undergo versatile transforma-
tions. As an example, we demonstrated the sequential Over-
man/Claisen rearrangement of cyclic orthoamides in one
Chem. Eur. J. 2013, 19, 12052 – 12058
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12057

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Received: March 30, 2013
Published online: July 19, 2013
12058
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Chem. Eur. J. 2013, 19, 12052 – 12058