Development of diastereoselective birch reduction-alkylation reactions of bi- and tricyclic β-alkoxy-α,β-unsaturated ketones

Article abstract of DOI:10.1021/jo901094x

(Chemical Equation Presented) Diastereoselective Birch reduction-alkylation reactions of bicyclic β-alkoxy-α,β-unsaturated carbonyl compounds and tricyclic analogues were investigated. Although the relative configuration of the product was altered accordi

Full text of DOI:10.1021/jo901094x

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Development of Diastereoselective Birch Reduction-Alkylation
Reactions of Bi- and Tricyclic β-Alkoxy-r,β-unsaturated Ketones
Kou Hiroya,*,† Yusuke Ichihashi, Ai Furutono, Kiyofumi Inamoto, Takao Sakamoto, and
Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aza Aoba, Aoba-ku, Sendai
980-8578 Japan †Tel.: +81-22-795-6867. Fax: +81-22-795-6864.
hiroya@mail.tains.tohoku.ac.jp
Received May 25, 2009
Diastereoselective Birch reduction-alkylation reactions of bicyclic β-alkoxy-R,β-unsaturated car-
bonyl compounds and tricyclic analogues were investigated. Although the relative configuration of
the product was altered according to the structure of the starting material, stereoselectivity of the
reaction could be accounted for by similar reaction pathways. The product from the tricyclic
β-alkoxy-R,β-unsaturated carbonyl compound corresponded to the trichothecene skeleton.
Introduction
Wieland-Miescher-type ketone.2,3 When the substituent
group (R) is a methyl group, the bicyclic compound could
be obtained with high optical purity.2a,f,h,i However, if the R
is another group, a serious decrease in optical purity is
observed, and sometimes a stoichiometric amount of proline
must be used to complete the reaction.2d,g
In the course of our continuous investigation to establish a
general method for constructing an asymmetric quaternary
carbon center, we previously published the strong Brønsted
acid promoted cyclization reaction of the acetal 1 to
β-alkoxy-R,β-unsaturated ketone 2a, followed by the intro-
duction of an allyl group at the angular position in the
corresponding TBS (tert-butyldimethylsilyl) ether 2b by a
diastereoselective Birch reduction-alkylation reaction.4,5
Moreover, we succeeded in the synthesis of two diastereo-
Chiral quaternary carbon centers at the angular position,
which frequently occur in alkaloids or terpenoids, are gen-
erally difficult to construct with high optical purity.1 Because
such compounds are known to possess unique biological
activities, there is currently a critical need in organic chem-
istry to develop a general and efficient method for preparing
chiral quaternary carbon centers, especially at the angular
position. The most famous procedure for preparing com-
pounds having an asymmetric center at the angular position
is a chiral amino acid catalyzed cyclization reaction
of prochiral 1,3-cyclohexanedione derivatives to give a
(1) For recent reviews about the stereoselective formation of quaternary
carbon centers, see: (a) Bella, M; Gasperi, T. Synthesis 2009, 1583–1614. (b)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–
5367. (c) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146. (d)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401.
(2) Recent references for proline or its analogue-catalyzed synthesis: (a)
(3) Recent references for the other amino acid or its analogue-catalyzed
synthesis: (a) Nagamine, T.; Inomata, K.; Endo, Y. Heterocycles 2008, 76,
1191–1204. (b) Nagamine, T.; Inomata, K.; Endo, Y. Chem. Pharm. Bull.
2007, 55, 1710–1712. (c) Nozawa, M.; Akita, T.; Hoshi, T.; Suzuki, T.;
Hagiwara, H. Synlett 2007, 661–663. (d) Nagamine, T.; Inomata, K.; Endo,
Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123–131. (e) Inomata, K.;
ꢀ
ꢀ
ꢀ
ꢀ
de Arriba, A. L. F.; Simon, L.; Raposo, C.; Alcazar, V.; Moran, J. R.
Tetrahedron 2009, 65, 4841–4845. (b) Ramachary, D. B.; Sakthidevi, R. Org.
Biomol. Chem. 2008, 6, 2488–2492. (c) Zhang, X.-M.; Wang, M.; Tu, Y.-Q.;
Fan, C.-A.; Jiang, Y.-J.; Zhang, S.-Y.; Zhang, F.-M. Synlett 2008, 2831–
2835. (d) Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056-5068 and
references cited therein. (e) Rajagopal, D.; Narayanan, R.; Swaminathan, S.
Tetrahedron Lett. 2001, 42, 4887–4890. (f) Bui, T.; Barbas, C. F. III Tetrahedron
Lett. 2000, 41, 6951–6954. (g) Hanselmann, R.; Benn, M. Synth. Commun.
1996, 26, 945–961. (h) Tietze, L. F.; Utecht, J. Synthesis 1993, 957–958.
(i) Buchschacher, P.; F€urst, A.; Gutzwiller, J. Org. Synth. 1990, 7, 368–372.
ꢀ
Barrague, M.; Paquette, L. A. J. Org. Chem. 2005, 70, 533–539.
(4) A recent review for the synthesis of 1-oxadecalins: Tang, Y.; Oppenheimer,
J.; Song, Z.; You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785–
10813.
(5) Hiroya, K.; Takahashi, T.; Shimomae, K.; Sakamoto, T. Chem.
Pharm. Bull. 2005, 53, 207–213.
DOI: 10.1021/jo901094x
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Published on Web 08/06/2009
J. Org. Chem. 2009, 74, 6623–6630 6623
2009 American Chemical Society

Hiroya et al.
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SCHEME 1. Diastereoselective Birch Reduction-Alkylation
Reaction and Its Application
SCHEME 2. Previous Examples of Birch Reduction-Alkyl-
ation Reactions
mers, (7aS)-4 and (7aR)-5, whose absolute configurations at
the angular position were opposite to each other, from 3 as a
common intermediate (Scheme 1).5
The sequential Birch reduction-alkylation reaction was
originally developed by Stork et al. in 1961,6 and it has been
applied to synthesize many natural products.7 However,
only two kinds of substrates can be found in the literature
for the reduction-alkylation reaction of a β-alkoxy-R,
β-unsaturated carbonyl compound. The first one is the
reaction of N,N-dialkyl-3-furamide derivatives as sub-
strates,8 and the latter example is enantioselective reductive
alkylation of chiral 2-alkoxybenzamide derivatives.9 Both
examples contain aromatic rings (furan and benzene), and
applications of the reduction-alkylation reaction to β-alk-
oxy-R,β-unsaturated carbonyl compounds, which do not
contain aromatic ring(s), have not been reported yet to the
best of our knowledge.10
using tricyclic substrate 8 was reported by Mukherjee in
198411b (Scheme 2B), and an exclusively cis-controlled reac-
tion of 10 was performed at a later time11c-f,12 (Scheme 2C).
In the case of our substrate shown in Scheme 1, not only
did we observe a cis configuration between cyclohexanone
and tetrahydropyran rings, but we also observed high dia-
stereoselectivity between the side chain (-CH2OTBS) and
the incorporated allyl group. This result prompted us to
investigate the generality of this reaction for different kinds
of substrates. In this article, we report the full details of the
reduction-alkylation reaction and the results of reactions of
compounds having different ring sizes, 2b, 12b, and 13b and
more rigid structure 14, which correspond to the synthesis of
the trichothecene skeleton (Figure 1).
Stork et al. reported the isolation of two compounds, cis-7
and trans-7, in an approximate 3:1 ratio by a Birch reduc-
tion-alkylation reaction of 3,4,5,6,7,8-hexahydro-2H-
naphthalen-1-one (6)11a (Scheme 2A). An identical result
Results and Discussion
1. Synthesis of the Starting Materials. We planned the
synthesis of bicyclic β-alkoxy-R,β-unsaturated ketone deri-
vatives 12b from 1,3-cyclopentanedione (17) with 19 and 13b
from 1,3-cyclohexanedione (18) with 20 via 2-alkyl-1,3-cy-
cloalkanediones 15 and 16, respectively (Figure 2). It is well-
known that the Knoevenagel reaction between 18 and an
aldehyde gives the dimerized compound 21 as a major product.
The difficulty in forming 22 was reported as well.2d,13 There-
fore, we focused on the ingenious Knoevenagel hydrogenation
reaction published by Ramachary and Kishor to synthesize 15
and 16, respectively.2d,14
(6) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83,
2965–2966.
(7) (a) d’Anjelo, J. Tetrahedron 1976, 32, 2979–2990. (b) From the result of
a citation search by Web of Science, refs 6 and 11a have been cited 87 and 264
times, respectively (a point of July 2009).
(8) Kinoshita, T.; Ichinari, D.; Sinya, J. J. Heterocycl. Chem. 1996, 33,
1313–1317.
(9) (a) Paul, T.; Malachowski, W. P.; Lee, J. J. Org. Chem. 2007, 72, 930–
937. (b) Schultz, A. G. Chem. Commun. 1999, 1263-1271 and references cited
therein.
(10) Double reduction of β-keto ester methoxymethyl enol ethers with or
without alkylation reaction has been reported: (a) Ling, T.; Chowdhury, C.;
Kramer, B. A.; Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org.
Chem. 2001, 66, 8843–8853. (b) Coates, R. M.; Shaw, J. E. J. Org. Chem.
1970, 35, 2601–2605. (c) Coates, R. M.; Shaw, J. E. J. Org. Chem. 1970, 35,
2597–2601.
(11) (a) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J.
J. Am. Chem. Soc. 1965, 87, 275–286. (b) Basu, B.; Bhattacharyya, S.;
Mukherjee, D. Tetrahedron Lett. 1984, 25, 1195–1196. (c) Gupta, P. D.;
Pal, A.; Mukherjee, D. Indian J. Chem. 2001, 40B, 1033–1035. (d) Saha, A.
K.; Das, S.; Mukherjee, D. Synth. Commun. 1993, 23, 1821–1828. (e) Ghosal,
M.; Karpha, T. K.; Mukherjee, D. Indian J. Chem. 1992, 31B, 524–525. (f)
Bhattacharyya, S.; Ghosal, M.; Mukherjee, D. Tetrahedron Lett. 1987, 28,
2431–2432.
(12) Production of a trans-fused product or a mixture of the diastereo-
mers was reported by Birch reduction of a similar type of compound: (a)
Claeys, S.; Van Haver, D.; De Clercq, P. J.; Milanesio, M.; Viterbo, D. Eur. J.
Org. Chem. 2002, 1051–1062. (b) Piers, E.; Llinas-Brunet, M.; Oballa, R. M.
Can. J. Chem. 1993, 71, 1484–1494. (c) Van Royen, L. A.; Mijngheer, R.;
De Clercq, P. J. Tetrahedron 1985, 41, 4667–4680.
The aldehyde 1915 was subjected to the Knoevenagel hydro-
genation reaction with 1,3-cyclopentanedione (17) in the pre-
sence of dihydropyridine 23, and a catalytic amount of
L-proline2d gave an almost quantitative yield of 2-substituted
(13) (a) Kennedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A.
J. Org. Chem. 2008, 75, 5151–5154. (b) Liu, G.; Wang, Z. Chem. Commun.
1999, 1129–1130. (c) Fuchs, K.; Paquette, L. A. J. Org. Chem. 1994, 59, 528–
532. (d) Nagarajan, K.; Shenoy, S. J. Indian J. Chem. 1992, 31B, 73–87. (e)
Hobel, K.; Margaretha, P. Helv. Chim. Acta 1989, 72, 975–979. (f) Bolte, M.
L.; Crow, W. D.; Yoshida, S. Aust. J. Chem. 1982, 35, 1421–1429.
(14) The other methods to avoid dimerization have been published. See
refs 13a and 13c.
(15) Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.;
Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935–10946.
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FIGURE 1. Bi- and tricyclic β-alkoxy-R,β-unsaturated carbonyl compounds.
FIGURE 2. Retrosynthetic analysis of 12b and 13b.
SCHEME 3. Synthesis of 12b and 13b
Namely, both ethyl iodide and 2-iodopropane did not react
at all with the enolate derived from 2b, and only protonated
compounds (two diastereomers) were observed together with
inseparable decomposed compounds in quite low yield
(entries 6 and 7). Furthermore, desired alkylated compounds
24f, 24g, and 24h could not be obtained in the reactions with
the reagents having high reactivity (BOMCl, MOMCl, and
TMSCH2Cl), while compound 24i, whose stereochemistry
between angular positions is cis, was isolated in good yield
[entries 8 (67%), 9 (70%), and 10 (74%)]. Although the
exact reason for the protonation has not been clear yet, one
possible way might be considered as follows: the halide
reacted with ammonia much faster than with the enolate,
followed by protonation of the enolate, which was proceeded
by the resulting ammonium cation. From the results
shown above, we concluded that the halides, which can be
used for the reduction-alkylation reaction of bicyclic
β-alkoxy-R,β-unsaturated ketone derivatives, have to satisfy
the following requirements: (1) they must not have a sp3
β-carbon with hydrogen, and (2) they must have enough
reactivity but must not be activated so as to react with
ammonia.
ketone 15. The acetal of 15 was hydrolyzed by treatment with
HCl in methanol,16 and the desired product 12b was formed
with a yield of 76% by protection of the primary alcohol by the
TBS group. In almost the same procedure, 13b was synthesized
from 1,3-cyclohexanedione (18) and the aldehyde 2017 via 13a
with good overall yield (Scheme 3).
2. Stereoselective Birch Reduction-Alkylation Reaction.
The results of a Birch reduction-alkylation reaction with
three different substrates are summarized in Table 1. In most
cases, the addition of isoprene to oxidize the excess amount
of lithium was effective in obtaining the product in good
yield [e.g., entry 1 (36%) vs 3 (61%) and entry 2 (45%) vs 4
(70%)]. The alkylated compounds 24a, 24b, and 24c were
isolated from 2b by treatment with allyl bromide [entries 1
(36%) and 3 (61%)], methyl iodide [entries 2 (45%) and 4
(70%)], and benzyl bromide [entry 5 (53%)] as the sole pro-
ducts, respectively. Unfortunately, it was also noted that the
reduction-alkylation reaction of 2b has serious limitations.
Although the alkyl halides are limited, the alkylated
compounds 25a, 25b, 26a, and 26b were isolated as single
compounds by treatment with allyl bromide [entries 11
(58%) and 13 (52%)] or methyl iodide [entries 12 (68%)
and 14 (25%)] with 12b or 13b, respectively, and reasonable
yields were observed with the recovery of the starting mate-
rials in some cases (entries 11, 12, and 14).
The determination of the configuration of 24a was des-
cribed in our previous paper.5 The structures of 24b, 24c, 25b,
and 26b were estimated by analogy to the 1H and 13C NMR
spectra of 24a, 25a, and 26a, respectively. The stereochemis-
tries of 24i, 25a, and 26a were determined by careful analysis
1
of their H NMR spectra and NOESY experiments, which
are shown in Figure 3.
H4R and H4β in 24i were distinguishable because the
chemical shift of H4R was observed at low field (2.35-
2.44 ppm), which was caused by the deshielding effect of
(16) Khan, A. T.; Mondal, E. Synlett 2003, 694–698.
(17) Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric.
Biol. Chem. 1984, 48, 1841–1844.
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TABLE 1. Diastereoselective Birch Reduction-Alkylation Reactions of 2b, 12b, and 13ba
entry
substrate
RX
time
isoprene
product
yield of the product (%)
recovery of the starting material (%)
1b
2
3
4
5
6
7
8
2b
allyl bromide
methyl iodide
allyl bromide
methyl iodide
benzyl bromide
ethyl iodide
2-iodopropane
BOMCl d
50 min
50 min
1.5 h
40 min
1 h
1.5 h
1.5 h
1 h
1.5 h
1.25 h
1.5 h
1.5 h
1.5 h
1.5 h
-
-
þ
þ
þ
þ
þ
þ
þ
þ
-
-
þ
-
24a
24b
24a
24b
24c
24d
24e
24i
24i
24i
25a
25b
26a
26b
36
45
61
70
53
0
0
67
70
74
0
0
0
0
0
0
0
0
0
0
6
7
0
35
9
MOMCl
10
11
12
13
14
TMSCH2Cl
allyl bromide
methyl iodide
allyl bromide
methyl iodide
12b
13b
58 (62) c
68 (73) c
52
25 (38) c
aAll products shown in the above figure were isolated as a single diastereomer. bThe yield of 24a is from ref 5. cThe numbers in parentheses are the
yields of the product based on the consumed starting material 12b or 13b. dBOM is (benzyloxy)methyl.
FIGURE 3. Selected data of 1H NMR spectra and observed NOE in 24i (A), 25a (B), and 26a (C).
the carbonyl group. The relationship between H2, H4β, H4a,
and H7a can be determined as all cis by observation of the
nuclear Overhauser effect (NOE; Figure 3A).
On the other hand, the stereochemistry in 26a was deter-
mined by clearly observed NOE (Figure 3C). It is noteworthy
that the stereochemistry between the TBS-oxymethyl group
and the allyl group at C4a in 25a was the trans configuration,
whereas that in 26a was cis. We discuss an explanation for
this difference and a plausible mechanism for both substrates
in section 2.4.
The configuration between H7a and H2 in 25a was deter-
mined as cis by observation of the NOE, and that between
H7a and the allyl group was also estimated as cis by the
chemical shift of H3R observed at unusually high field (0.99
ppm), which was caused by the shielding effect of the
carbonyl group (Figure 3B).
3. Application to the Synthesis of a Trichothecene Skeleton.
Trichothecenes belong to the sesquiterpene family, and some
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FIGURE 4. (A) Trichothecene skeleton 27 and its synthetic precursor 28. (B) Structure of the target molecules 29a and 29b and their pre-
cursor 14.
TABLE 2. Diastereoselective Birch Reduction-Akylation Reaction of 14a
entry
alkyl halide
solvent
alkylation conditions
yield (%)
1
2
3
4
allyl bromide
allyl iodide
THF
THF
Et2O
THF
-78 °C, 40 min, and then -33 °C, 4 h
-78 °C, 1.5 h
44 (29a)
49 (29a)
49 (29a)
45 (29b)
-78 °C, 2.3 h
methyl iodide
-78 °C, 1.5 h
a29a and 29b were isolated as a single diastereomer.
of them are known to possess antitumor activity.18 The key
structural feature of the trichothecene skeleton 27 is having a
tricyclic structure, in which the stereochemistries of the three
rings are all in the cis configuration (Figure 4). One fre-
quently found strategy for the synthesis of trichothecenes is
A and C ring formation with stereoselective functionaliza-
tion (e.g., 28), followed by ring closure to construct the B ring
(Figure 4A).19
SCHEME 4. Synthesis of 14 from 18 and 30
For application of the reductive-alkylation reaction des-
cribed above, we assumed the compounds 29a and 29b to be
the trichothecene skeleton, which could be synthesized from
tricyclic β-alkoxy-R,β-unsaturated ketone 14 (Figure 4B).
The key features in our approach are that (i) there are no
published studies using reductive-alkylation for construct-
ing a trichothecene skeleton to our knowledge and (ii) the
correct stereochemistry for the trichothecene skeleton may
be obtained by use of the reductive-alkylation method for
more rigid substrates than the previously examined com-
pounds like 2b, 12b, and 13b.
The synthesis of 14 was started from 1,3-cyclohexanedione
(18) and 2-cyclopentenone (30). The Michael addition reac-
tion of 18 to 30 in the presence of t-BuOK in t-BuOH,
followed by protection of the enol with the MOM group
under standard conditions, provided the desired 31 at a yield
of 84% (two steps). The use of t-BuOK in t-BuOH is superior
to that of NaH in N,N-dimethylformamide (DMF) in terms
of reproducibility. The reduction of the ketone on the
cyclopentane ring was conducted by NaBH4 in methanol
at -78 °C, which gave the alcohol 32 as the sole product.
Acid treatment of 32 in toluene at room temperature gave 14
at a yield of 85% from 31 (Scheme 4). Expectedly, the
hydride attack to the ketone 31 would occur from the less
hindered β-face to give a cis configuration between C1-OH
and the C3 substitutent. The stereochemistry was confirmed
by the result of the formation of tricyclic 14 by acidic
treatment.
The results of the reductive-alkylation reaction of 14 are
summarized in Table 2. In all cases, isoprene was added to
quench the excess amount of lithium before treatment with
an alkyl halide. In the case of 14, allyl iodide gave slightly
better yields than allyl bromide [Table 2, entries 1 (44%) vs
2 (49%)], and the methyl group could also be introduced at
the angular position [Table 2, entry 4 (45%)]. The solvent
did not affect the yield of the product [Table 2, entries 2
(49%) vs 3 (49%)]. Although all of the yields in Table 2 are
moderate because of the production of some unidentified
byproduct, the isolable alkylated product was obtained as a
single diastereomer. The stereochemistry of 29a was deter-
mined by a NOE experiment, as shown in Figure 5, and that
of 29b was confirmed by analogy with the 1H NMR
spectrum.
(18) (a) Fraga, B. M. Nat. Prod. Rep. 2007, 24, 1350–1381. (b) Fraga, B. M.
Nat. Prod. Rep. 2004, 21, 669-693. Recent report for the isolation of cytotoxic
trichothecenes: (c) Loukaci, A.; Kayser, O.; Bindseil, K.-U.; Siems, K.; Frevert,
J.; Abreu, P. M. J. Nat. Prod. 2000, 63, 52–56.
(19) For examples, see: (a) Miyata, J.; Nemoto, H.; Ihara, M. J. Org. Chem.
2000, 65, 504-512 and references cited therein. (b) Nemoto, H.; Takahashi, E.;
Ihara, M. Org. Lett. 1999, 1, 517–519. (c) Pearson, A. J.; O'Brien, M. K. J. Org.
Chem. 1989, 54, 4663–4673. (d) Hua, D. H.; Venkataraman, S.; Chan-Yu-King,
R.; Paukstelis, J. V. J. Am. Chem. Soc. 1988, 110, 4741–4748. (e) Tamm, C.;
Jeker, N. Tetrahedron 1989, 45, 2385-2415 and references cited therein.
J. Org. Chem. Vol. 74, No. 17, 2009 6627

Hiroya et al.
JOCArticle
origin of the predominance of 34b over 34a is not yet clear, but
one possible reason may be the stabilizing effect of the C-O
antibonding orbital by ligation of the enolate π orbital
(Scheme 5).
For the reactions of 12b and 13b, reaction pathways
similar to that of Scheme 5 can be considered. These are
shown in Scheme 6.
The dianiones 35a and 37a, which are the most stable
among the possible conformers, e.g., 35b or 37b, protonate to
produce the enolates 36a and 38a. These enolates flip to 36b
and 38b in order to create a parallel C-O bond with the π
bond of the enolate. The alkylation occurs from the axial
direction, i.e., from the β face for 36b and from the R face for
38b, to give 25 and 26, respectively (Scheme 6). Although the
relative stereochemistry between the TBS-oxymethyl group
and the introduced alkyl group is trans for 25 and cis for 26,
these difference can be reasonably accounted for by the
plausible mechanism described above.
FIGURE 5. Selected data of the 1H NMR spectrum and observed
NOE in 29a.
4. Plausible Mechanism for the Diastereoselective Reduc-
tive-Alkylation of Bi- and Tricyclic β-Alkoxy-r,β-unsatu-
rated Ketone Derivatives. In our previous article, we proposed
a possible mechanism for the expression of diastereoselectivity
in the reductive-alkylation reaction of 2b.5 Namely, proton-
ation may proceed from the dianione 33, which might be the
most stable conformer among the four possible structures, to
produce the enolate. From the observed stereochemistry of 24,
one possible way for the alkylation to proceed is by approach-
ing the allyl bromide from the equatorial direction in 34a.
However, we expect that this possibility is quite unlikely when
we consider the stereoelectronic effect. Thus, we speculate that
alkylation occurs after a flipping of the conformation from 34a
to 34b and then proceeds from the β face (axial direction). The
Furthermore, the diastereoselective production of 29 from
14 can be reasonably explained by the similar mechanism,
including the conformational change from 40a to 40b
(Scheme 7).
Conclusion
We were able to demonstrate diastereoselective Birch re-
duction-alkylation reactions by the bicyclic β-alkoxy-R,
SCHEME 5. Plausible Mechanism for the Diastereoselective Reductive-Alkylation Reaction of 2b
SCHEME 6. Plausible Mechanism for Diastereoselective Reductive-Alkylation Reactions of 12b and 13b
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Hiroya et al.
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SCHEME 7. Plausible Mechanism for the Diastereoselective Reductive-Alkylation Reaction of 14
β-unsaturated carbonyl compounds 2b, 12b, and 13b and
tricyclic analogue 14. Although the diastereoselectivity
varied depending on the structures of the substrates, i.e., 2b
and 12b gave the trans configuration between the TBS-
oxymethyl group and the substituent at the angular position
and 13b gave the cis configuration, the selectivity could be
accounted for by the same reaction pathways. Namely, the
stereochemistry at the β position of β-alkoxy-R,β-unsaturated
carbonyl compounds is induced by the stereochemistry of the
TBS-oxymethyl group and that at the R position is controlled
as cis to the β position for all starting materials. The product
from 14 corresponds to the trichothecene skeleton. Applica-
tion of this methodology to the synthesis of biologically active
compounds is underway in our laboratory.
(2S,4aR,8aS)-4a-Benzyl-2-(tert-butyldimethylsilanyloxyme-
thyl)octahydrochromen-5-one (24c; Table 1, Entry 5). Accord-
ing to the general procedure, reduction of 2b (19.6 mg, 66.1
μmol) was performed by lithium (4.3 mg, 0.620 mmol) in liquid
NH3 (5 mL) and anhydrous THF (1 mL). After the addition of
isoprene (0.1 mL, 1.00 mmol), benzyl bromide (0.1 mL, 0.841
mmol) was reacted at -78 °C for 1 h. The crude product upon
workup was purified by silica gel column chromatography
[ethyl acetate-hexane (1:39)] to afford 24c (13.7 mg, 53%) as
a colorless oil: [R]26D -53.6 (c=0.69, CHCl3); IR ν (neat, cm-1
)
1
1707, 1128, 1088, 837; H NMR (600 MHz, CDCl3) δ 0.018
(3H, s), 0.021 (3H, s), 0.86 (9H, s), 1.08 (1H, td, J=13.0, 4.2
Hz), 1.21 (1H, td, J=13.0, 4.2 Hz), 1.43 (1H, ddt, J = 13.0, 4.2,
2.3 Hz), 1.90-1.96 (2H, m), 2.06 (1H, dt, J = 13.0, 4.2 Hz), 2.21
(1H, qt, J=13.4, 4.5 Hz), 2.26-2.33 (1H, m), 2.38-2.43 (1H,
m), 2.67 (1H, d, J = 13.8 Hz), 2.79 (1H, ddd, J=14.7, 13.4, 6.6
Hz), 3.09 (1H, d, J=13.8 Hz), 3.30-3.36 (1H, m), 3.41 (1H, dd,
J=10.7, 5.1 Hz), 3.56 (1H, dd, J = 10.7, 6.0 Hz), 3.77 (1H, br s),
6.98-7.00 (2H, m), 7.19-7.27 (3H, m); 13C NMR (150 MHz,
CDCl3) δ -5.3, -5.2, 18.4, 21.3, 25.1, 25.9, 26.6, 28.8, 38.6,
43.0, 52.5, 66.7, 78.7, 82.3, 126.8, 128.1, 129.8, 135.8, 212.8; MS
m/z 373 (Mþ - Me, 2%), 331 (Mþ - t-Bu, 100%), 313 (9%),
247 (30%), 197 (31%), 91 (90%). HRMS. Calcd for
C19H27O3Si: 331.1730. Found: 331.1732.
Experimental Section
General Procedure for the Birch Reduction-Alkylation Reac-
tion. Under an argon atmosphere, lithium wire was added to
liquid NH3 at -78 °C, which was distilled over sodium. After
stirring for 10-30 min at -78 °C, a solution of the substrate in
anhydrous tetrahydrofuran (THF) or diethyl ether was added to
the mixture. For entries 3-10 and 13 in Table 1 and all entries in
Table 2, isoprene was added to the mixture. Alkyl halide was
added to the mixture, and the stirring was continued for the time
listed in Tables 1 and 2 at -78 °C. A saturated aqueous NH4Cl
solution was added to the mixture, and NH3 was evaporated at
40 °C. The aqueous layer was extracted with ethyl acetate for
reactions in Table 1 or diethyl ether in all entries in Table 2.
The combined organic solution was washed with a saturated
aqueous NaCl solution, dried over MgSO4, and concentrated
under reduced pressure to afford the crude product.
(2S,4aS,8aS)-2-(tert-Butyldimethylsilanyloxymethyl)-4a-methyl-
octahydrochromen-5-one (24b; Table 1, Entry 4). According to the
general procedure, 2b (26.7 mg, 90.1 μmol) was reduced by lithium
(3.6 mg, 0.519 mmol) in liquid NH3 (5 mL) and anhydrous THF (1
mL). After the addition of isoprene (0.2 mL, 2.00 mmol), methyl
iodide (0.1 mL, 1.61 mmol) was reacted at -78 °C for 40 min. The
crude product upon workup was chromatographed on silica gel
[ethyl acetate-hexane (1:39)] to afford 24b (19.8 mg, 70%) as a
colorless oil: [R]27D -37.1 (c=1.03, CHCl3);IRν(neat, cm-1) 1711,
1462, 1254, 1134, 1092, 837; 1H NMR (600 MHz, CDCl3) δ 0.008
(3H, s), 0.010 (3H, s), 0.85 (9H, s), 1.04 (1H, td, J = 13.5, 4.3 Hz),
1.08 (3H, s), 1.27 (1H, tdd, J=13.5, 11.5, 4.0 Hz), 1.45 (1H, ddt, J=
13.5, 4.3, 2.6 Hz), 1.76-1.86 (2H, m), 2.03 (1H, tdd, J=13.6, 4.2, 2.4
Hz), 2.10 (1H, qt, J=13.6, 4.3 Hz), 2.24 (1H, ddt, J=15.3, 4.3, 2.2
Hz), 2.36 (1H, ddd, J=13.5, 4.0, 2.6 Hz), 2.50 (1H, ddd, J = 15.3,
13.6, 6.6 Hz), 3.37 (1H, dddd, J=11.5, 6.2, 5.2, 2.6 Hz), 3.42 (1H,
dd, J=10.5, 5.2 Hz), 3.56 (1H, dd, J = 10.5, 6.2 Hz), 3.61 (1H, t, J=
2.4 Hz); 13C NMR (150 MHz, CDCl3) δ -5.3, -5.1, 18.4, 20.9,
24.4, 25.6, 25.9, 26.6, 31.9, 37.9, 48.2, 66.8, 78.9, 83.0, 214.3; MS m/z
297 (Mþ - Me, 1%), 255 (Mþ - t-Bu, 65%), 171 (100%). HRMS.
Calcd for C13H23O3Si: 255.1416. Found: 255.1404.
(2S,4aR,7aS)-4a-Allyl-2-(tert-butyldimethylsilanyloxymethyl)-
hexahydrocyclopenta[b]pyran-5-one (25a; Table 1, Entry 11). Ac-
cording to the general procedure, reduction of 12b (92 mg, 0.326
mmol) was performed by lithium (9.4 mg, 1.35 mmol) in liquid
NH3 (5 mL) and anhydrous THF (1 mL). Allyl bromide (0.58
mL, 6.72 mmol) was reacted at -78 °C for 1.5 h. The crude
product upon workup was purified by silica gel column chroma-
tography [ethyl acetate-hexane (1:4z)] to afford 25a (63 mg,
58%) as a colorless oil, and 12b (6 mg, 6%) was recovered from
the later fractions. 25a: [R]27D = þ22.2 (c = 0.46, CHCl3); IR ν
(neat, cm-1) 1742, 1094, 837; 1H NMR (600 MHz, CDCl3) δ 0.03
(6H, s), 0.87 (9H, s), 0.99 (1H, qd, J=14.0, 4.5 Hz), 1.48 (1H, td,
J = 13.8, 4.8 Hz), 1.55 (1H, ddd, J=14.0, 4.4, 2.3 Hz), 1.97-2.04
(3H, m), 2.10-2.13 (1H, m), 2.14-2.19 (1H, m), 2.33 (1H, dd,
J = 19.2, 10.2 Hz), 2.41 (1H, dd, J = 19.2, 10.2 Hz), 3.24 (1H, m),
3.41 (1H, dd, J=10.8, 4.8 Hz), 3.58 (1H, dd, J = 10.8, 6.0 Hz),
3.94 (1H, d, J=4.2 Hz), 5.04 (1H, d, J = 16.8 Hz), 5.10 (1H, d,
J = 10.2 Hz), 5.68 (1H, ddd, J = 16.8, 10.2, 7.2 Hz); 13C NMR
(150 MHz, CDCl3) δ -5.3, -5.2, 18.3, 25.2, 25.6, 25.8, 25.9, 33.8,
38.7, 52.4, 66.5, 76.6, 81.1, 118.6, 132.1, 219.0; MS m/z 267 (Mþ
- t-Bu, 100%). HRMS. Calcd for C14H23O3Si: 267.1416. Found:
267.1413.
(2S,4aS,7aS)-2-(tert-Butyldimethylsilanyloxymethyl)-4a-meth-
ylhexahydrocyclopenta[b]pyran-5-one (25b; Table 1, Entry 12).
According to the general procedure, 12b (95 mg, 0.336 mmol)
was reduced by lithium (9.1 mg, 1.30 mmol) in liquid NH3
(5 mL) and anhydrous THF (1 mL). Methyl iodide (0.65 mL,
6.51 mmol) was reacted at -78 °C for 1.5 h. The crude product
upon workup was purified by preparative TLC developed with
ethyl acetate-hexane (1:4) to afford 25b (66 mg, 68%) as a
J. Org. Chem. Vol. 74, No. 17, 2009 6629

Hiroya et al.
JOCArticle
colorless oil, and 12b (7 mg, 7%) was recovered. 25b: [R]26
=
83.1, 213.5; MS m/z 298 (Mþ, 2%), 241 (Mþ - t-Bu, 11%), 117
(100%). HRMS. Calcd for C16H30O3Si: 298.1964. Found:
298.1988. Calcd for C12H21O3Si: 241.1260. Found: 241.1255.
(1S*,2R*,7R*,9R*)-2-Allyl-8-oxatricyclo[7.2.1.02,7]dodecan-3-
one (29a;Table2, Entry 2). According tothegeneralprocedure, 14
(26.9 mg, 0.151 mmol) was reduced by lithium (4.2 mg, 0.604
mmol) in liquid NH3 (5 mL) and anhydrous THF (2 mL). After
the addition of isoprene(0.151mL, 1.51 mmol), allyl iodide (0.276
mL, 3.02 mmol) was reacted at -78 °C for 1.5 h. The crude
product upon workup was purified by silica gel column chroma-
tography [ethyl acetate-hexane (1:19)] to afford 29a (16.3 mg,
49%) as a colorless solid: mp 87-89 °C (colorless needles from
hexane); IRν (neat, cm-1) 1699, 1614, 1454, 1069, 1007; 1H NMR
(600 MHz, CDCl3) δ 1.31 (1H, ddd, J = 12.5, 5.5, 2.5 Hz), 1.59-
1.80 (6H, m), 1.82-1.88 (1H, m), 1.98 (1H, tt, J = 13.8, 3.5 Hz),
2.08 (1H, qt, J =13.8, 4.4Hz), 2.20 (1H, dd, J=14.7, 8.0 Hz), 2.32
(1H, dd, J = 14.7, 6.5 Hz), 2.34-2.42 (2H, m), 2.73 (1H, t, J=5.5
Hz), 3.87 (1H, br s), 4.27 (1H, br s), 4.97 (1H, dd, J=17.0, 1.0 Hz),
5.03 (1H, dt, J = 9.9, 1.0 Hz), 5.50 (1H, dddd, J = 17.0, 9.9, 8.0,
6.5 Hz); 13C NMR (150 MHz, CDCl3) δ 20.1, 22.6, 26.8, 28.9,
36.4, 36.8, 37.9, 39.4, 55.1, 74.7, 76.3, 118.0, 131.7, 212.8; MS m/z
220 (Mþ, 24%), 192 (7%), 178 (100%), 163 (11%), 149 (33%).
HRMS. Calcd for C14H20O2: 220.1464. Found: 220.1462. Anal.
Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.24; H, 9.14.
(1S*,2R*,7R*,9R*)-2-Methyl-8-oxatricyclo[7.2.1.02,7]dodecan-
3-one (29b; Table 2, Entry 4). According to the general procedure,
14 (98.3 mg, 0.552 mmol) was reduced by lithium (15.3 mg, 2.21
mmol) in liquid NH3 (15 mL) and anhydrous THF (6 mL). After
the addition of isoprene (0.552 mL, 5.52 mmol), methyl iodide
(0.685 mL, 11.0 mmol) was reacted at -78 °C for 1.5 h. The crude
product upon workup was purified by silica gel column chroma-
tography [ethyl acetate-hexane (1:19)] to afford a mixture of 29b
(48.2 mg, 45%) as a colorless oil: IR ν (neat, cm-1) 1705, 1456,
1202, 1080, 1061, 1013; 1H NMR (400 MHz, CDCl3) δ 1.03 (3H,
s), 1.29 (1H, ddd, J = 14.0, 6.8, 3.2 Hz), 1.61-1.98 (8H, m), 2.01-
2.14 (1H, m), 2.33 (1H, ddt, J = 15.9, 4.6, 2.3 Hz), 2.46 (1H, ddd,
J=15.9, 13.6, 6.0 Hz), 2.61 (1H, br t, J = 4.8 Hz), 3.83 (1H, br t,
J=3.0 Hz), 4.28 (1H, br t, J=3.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 19.7, 22.6, 23.2, 26.7, 29.0, 37.3, 38.7, 40.5, 51.4, 74.6,
76.3, 215.1; MS m/z 194 (Mþ, 100%), 179 (7%), 166 (13%), 150
(22%), 138 (49%), 123 (96%). HRMS. Calcd for C12H18O2:
194.1307. Found: 194.1295.
D
þ39.3 (c = 0.40, CHCl3); IR ν (neat, cm-1) 1744, 1097, 837; 1H
NMR (600 MHz, CDCl3) δ 0.03 (3H, s), 0.04 (3H, s), 0.88 (9H,
s), 0.92 (3H, s), 0.94-1.02 (1H, m), 1.40 (1H, td, J=13.2, 4.8
Hz), 1.52 (1H, dt, J = 13.2, 2.4 Hz), 2.01 (1H, ddd, J = 13.8, 9.0,
2.4 Hz), 2.15 (1H, m), 2.20 (1H, ddd, J=13.8, 4.2, 2.4 Hz), 2.31-
2.42 (2H, m), 3.28 (1H, m), 3.42 (1H, dd, J = 10.8, 5.4 Hz), 3.59
(1H, dd, J = 10.8, 5.4 Hz), 3.85 (1H, d, J=3.6 Hz); 13C NMR
(150 MHz, CDCl3) δ -5.3, -5.2, 18.4, 21.6, 25.5, 25.8, 25.9,
28.8, 33.8, 49.1, 66.6, 76.8, 82.8, 220.3; MS m/z 283 (Mþ - Me,
2%), 241 (Mþ - t-Bu, 100%), 223 (26%), 149 (39%). HRMS.
Calcd for C15H27O3Si: 283.1729. Found: 283.1726. Calcd for
C12H21O3Si: 241.1260. Found: 241.1243.
(2S,3aR,7aR)-3a-Allyl-2-(tert-butyldimethylsilanyloxymethyl)-
hexahydrobenzofuran-4-one (26a; Table 1, Entry 13). According
to the general procedure, reduction of 13b (88 mg, 0.312 mmol)
was performed by lithium (8.7 mg, 1.25 mmol) in liquid NH3
(5 mL) and anhydrous THF (1 mL). After the addition of
isoprene (0.65 mL, 6.51 mmol), allyl bromide (0.54 mL, 6.24
mmol) was reacted at -78 °C for 1.5 h. The crude product upon
workup was purified by preparative TLC developed with ethyl
acetate-hexane (1:9) to afford 26a (53 mg, 52%) as a colorless
oil: [R]23D=-44.9 (c = 1.06, CHCl3); IR ν (neat, cm-1) 1708,
1099, 85, 837, 775; 1H NMR (600 MHz, CDCl3) δ 0.08 (3H, s),
0.11 (3H, s), 0.89 (9H, s), 0.99 (1H, t, J=12.0 Hz), 1.86 (2H, m),
2.05-2.12 (2H, m), 2.19 (1H, dd, J=13.8, 7.8 Hz), 2.27-2.30 (1H,
m), 2.44 (1H, dd, J=13.8, 7.8 Hz), 2.46-2.52 (1H, m), 2.55 (1H,
dd, J = 12.0, 4.8 Hz), 3.01 (1H, t, J=10.2 Hz), 3.59 (1H, br s), 3.76
(1H, ddt, J=12.0, 10.2, 4.8 Hz), 3.80-3.85 (1H, m), 5.06 (1H, d,
J = 16.8 Hz), 5.08 (1H, d, J = 10.2 Hz), 5.59 (1H, ddt,
J= 16.8, 10.2, 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ -4.8,
-4.6, 18.1, 21.1, 25.9, 26.0, 38.2, 38.6, 41.5, 53.6, 64.2, 73.1, 81.7,
118.8, 131.4, 212.2; MS m/z 267 (Mþ - t-Bu, 52%), 131 (29%),
117 (100%). HRMS. Calcd for C14H23O3Si: 267.1416. Found:
267.1426.
(2S,3aR,7aS)-2-(tert-Butyldimethylsilanyloxymethyl)-3a-meth-
yloctahydroinden-4-one (26b; Table 1, Entry 14). According to the
general procedure, 13b (46 mg, 0.16 mmol) was reduced by
lithium (4.6 mg, 0.65 mmol) in liquid NH3 (5 mL) and anhydrous
THF (0.5 mL). Methyl iodide (0.32 mL, 3.26 mmol) was reacted
at -78 °C for 1.5 h. The crude product upon workup was purified
by preparative TLC developed with ethyl acetate-hexane (1:4) to
afford 26b (12 mg, 25%) as a colorless wax, and 13b (16 mg, 35%)
was recovered. 26b: [R]26D = -54.8 (c = 0.3, CHCl3); IR ν (neat,
cm-1) 1713, 1096, 1070, 837, 775; 1H NMR (600 MHz, CDCl3) δ
0.08 (3H, s), 0.11 (3H, s), 0.89 (9H, s), 0.98 (1H, dd, J = 12.6, 10.8
Hz), 1.14 (3H, s), 1.81-1.89 (2H, m), 2.02-2.09 (2H, m), 2.25-
2.28 (1H, m), 2.55 (2H, ddd, J=12.6, 4.8, 2.4 Hz), 3.03 (1H, t, J=
10.8 Hz), 3.52 (1H, s), 3.75 (1H, ddd, J=15.0, 10.2, 4.8 Hz), 3.84
(1H, ddd, J=10.8, 5.4, 2.4 Hz); 13C NMR (150 MHz, CDCl3) δ
-4.8, -4.7, 18.1, 21.1, 24.4, 25.9, 26.3, 37.7, 41.7, 50.0, 64.0, 73.3,
Supporting Information Available: Experimental proce-
dures, compound characterization, and analytical data
(specific rotation, 1H and 13C NMR, MS, and HRMS) for
compounds 12b, 13a, 13b, 14, 15, 24a, 24i, and 31, copies of
1H and 13C NMR spectra of all new compounds and 24a,
and copies of NOESY spectra of 24i, 25a, 26a, and 29a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
6630 J. Org. Chem. Vol. 74, No. 17, 2009