Stereoselective synthesis of 2,6-cis-Tetrahydropyrans through a tandem allylic oxidation/oxa-michael reaction promoted by the gem-disubstituent effect: Synthesis of (+)-neopeltolide Macrolactone

Full text of DOI:10.1002/anie.200903690

Angewandte
Chemie
DOI: 10.1002/anie.200903690
Natural Product Synthesis
Stereoselective Synthesis of 2,6-cis-Tetrahydropyrans through a
Tandem Allylic Oxidation/Oxa-Michael Reaction Promoted by the
gem-Disubstituent Effect: Synthesis of (+ )-Neopeltolide
Macrolactone**
Hyoungsu Kim, Yongho Park, and Jiyong Hong*
Structurally complex tetrahydropyrans (THPs) are found in a
wide range of biologically interesting natural products.
Although considerable effort has been devoted to the
development of synthetic routes to THPs,[1] there still exists
a great need for a synthetic approach to these classes of
molecules that enables rapid and easy access to substrates,
proceeds with excellent stereoselectivity in excellent yield,
and requires mild reaction conditions compatible with various
functional groups.
Surprisingly, despite considerable progress in the Michael
reaction of carbon nucleophiles, there has been far less
interest in the analogous Michael reaction of oxygen nucle-
ophiles (oxa-Michael reaction). The slow development of the
oxa-Michael reaction is mainly due to major drawbacks such
as the low reactivity of oxygen nucleophiles and the reversi-
bility issue, as well as a lack of control over stereoselectivity.[2]
Owing to the poor nucleophilicity of oxygen atoms in the oxa-
Michael reaction, alcohols must be deprotonated by strong
bases to enhance their nucleophilicity, or the conjugate
acceptor must be activated by Lewis or Brønsted acids,
amines, or transition-metal complexes.[2–4] These harsh reac-
tion conditions are often incompatible with other functional
groups of the substrate. In particular, as a result of compet-
itive acetal formation, instability, and the enolizability of
aldehydes, the oxa-Michael reaction of alcohols to
a,b-unsaturated aldehydes has been elusive.[5]
promote preorganization of the conformation of a substrate
for an intramolecular oxa-Michael reaction. We also antici-
pated that this structural element could help decrease the
reversibility of the reaction to form the oxa-Michael product.
We hypothesized that a 1,3-dithiane group at the C4 position
of an alcohol nucleophile could satisfy these requirements on
the basis of the gem-disubstituent effect. Furthermore, the
1,3-dithiane group would serve as a latent functional group
for a carbonyl, hydroxy, or olefinic group, or a hydrogen atom.
To test this hypothesis, we prepared substrate 4 for the
oxa-Michael reaction as follows (Scheme 1): The 1,3-dithiane
coupling[6] of 1 with allyl bromide 2,[7] followed by THP
deprotection, provided 3. The coupling of 3 with (ꢀ )-glycidyl
benzyl ether then proceeded smoothly to afford the allylic
alcohol 4. As expected, the chemoselective oxidation of 4 with
MnO2 and subsequent intramolecular oxa-Michael reaction
of the resulting a,b-unsaturated aldehyde 5 provided the
desired 2,6-cis-THP 6a with excellent stereoselectivity
(d.r.>20:1, 93%; tandem allylic oxidation/oxa-Michael reac-
tion).[8–10]
Herein, we report the stereoselective and efficient syn-
thesis of 2,6-cis-THPs through an unprecedented tandem
allylic oxidation/oxa-Michael addition of alcohols to a,b-
unsaturated aldehydes promoted by the gem-disubstituent
effect and its application to the concise synthesis of
(+)-neopeltolide macrolactone.
To overcome the low reactivity of oxygen nucleophiles, we
envisioned the introduction of a structural element that would
[*] Dr. H. Kim, Y. Park, Prof. Dr. J. Hong
Department of Chemistry, Duke University
Durham, NC 27708 (USA)
Fax: (+1)919-660-1605
E-mail: jiyong.hong@duke.edu
[**] This research was supported by Duke University and the Duke
Chemistry Undergraduate Summer Research Program. We
acknowledge the NCBC (Grant No. 2008-IDG-1010) for funding of
NMR instrumentation. Y.P. gratefully acknowledges the North
Carolina section of the American Chemical Society for an NC ACS
Undergraduate Scholarship.
Scheme 1. Synthesis of the 2,6-cis-THP 6a through a tandem allylic
oxidation/oxa-Michael reaction: a) nBuLi, THF, ꢁ788C, 1 h, then 2,
ꢁ788C, 1 h; b) p-toluenesulfonic acid, MeOH, 258C, 12 h, 78% for
two steps; c) tBuLi, HMPA/THF (1:10), ꢁ788C, 5 min, then (ꢀ)-
glycidyl benzyl ether, ꢁ788C, 1 h, 83%; d) MnO2, CH2Cl2, 258C, 24 h,
93%. Bn=benzyl, HMPA=hexamethylphosphoramide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903690.
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Table 1: Scope of the tandem allylic oxidation/oxa-Michael reaction.
The stereochemical outcome of this tandem allylic
oxidation/oxa-Michael reaction can be rationalized on the
basis that the unfavorable 1,3-diaxial interaction of the C6
a,b-unsaturated carbonyl group and the C4 dithiane group in
conformation 5b is larger than that of the C6 hydrogen atom
and the dithiane group in conformation 5a; thus, 6a is formed
preferentially. It is known that a 2,6-cis-THP is thermody-
namically more favorable than a 2,6-trans-THP in equilibri-
um.[11] To identify the origin of the stereoselective formation
of 6a in the tandem reaction, the trans isomer 6b was
subjected to the reaction conditions for the cyclization
(MnO2, CH2Cl2, 258C, 24 h). As no formation of 6a was
observed in this case, we could conclude that the formation of
6a was kinetically controlled (see the Supporting Information
for details).
Encouraged by the preliminary results, we set out to
explore the scope of the tandem allylic oxidation/oxa-Michael
reaction. First, we examined a range of oxidation conditions
for the tandem reaction. The Parikh–Doering oxidation of 4
(SO3·pyridine, Et3N/dimethyl sulfoxide (DMSO)/CH2Cl2
(1:1:4), 258C, 24 h) provided the desired 2,6-cis-THP 6a
with excellent stereoselectivity (d.r. > 20:1, 93%). Other
oxidation conditions (pyridinium chlorochromate, tetrapro-
pylammonium perruthenate, or Dess–Martin periodinane)
also afforded 6a (d.r. > 20:1), but in low to moderate yields
(21–51%) owing to competitive oxidation of the secondary
hydroxy group, decomposition of the aldehyde intermediate,
or possible oxidation of the 1,3-dithiane group. Swern
oxidation of 4 did not provide 6a, but significant decom-
position of the aldehyde intermediate was observed (see the
Supporting Information for details).
Entry
Substrate
Conditions[b]
Product
(yield [%])[a]
(yield [%], d.r.[c])
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
12a (88, >20:1)
12a (87, >20:1)
13a (86, >20:1)
12b (75, >20:1)
12b (87, >20:1)
13b (81, >20:1)
12c (81, >20:1)
12c (75, >20:1)
13c (76, >20:1)
12d (96, >20:1)
12d (94, >20:1)
13d (76, >20:1)
12e (86, NA[d])
12e (87, NA[d])
13e (75, NA[d])
1
2
3
4
5
11a (74)
11b (72)
11c (76)
11d (83)
11e (67)
[a] Yield of isolated 11 from the coupling reaction (tBuLi, HMPA/THF
(1:10), ꢁ788C, 5 min, then 10, ꢁ788C, 0.5–2 h). [b] A) MnO2, CH2Cl2,
258C, 24 h; B) SO3·pyridine, Et3N/DMSO/CH2Cl2 (1:1:4), 258C, 24 h;
C) I MnO2, CH2Cl2, 258C, 1.5 h; II dimethyltriazolium iodide, MnO2,
DBU, MeOH, 4 ꢀ MS, 258C, 23 h. [c] The diastereomeric ratio (2,6-cis-
THP/2,6-trans-THP) was determined by integration of the 1H NMR
spectrum of the crude product. [d] Not applicable.
When 4 was subjected to the conditions for the tandem
reaction in the presence of dimethyltriazolium iodide,[12] the
THP methyl ester 7 was obtained in a single step from 4 in a
one-pot allylic oxidation/oxa-Michael/oxidation reaction
(Scheme 2). This MnO2 oxidation catalyzed by an N-hetero-
conditions examined proceeded smoothly to provide the
corresponding 2,6-cis-THP aldehydes 12a–d or esters 13a–d
with excellent diastereoselectivity (d.r. > 20:1; Table 1,
entries 1–4). Even the sterically hindered tertiary alcohol
11e was converted into the THP aldehyde 12e and ester 13e
in good yield (75–87%) under the mild reaction conditions
(Table 1, entry 5).
We hypothesized that the 1,3-dithiane group would be
critical to overcoming the low reactivity of oxygen nucleo-
philes and the reversibility of the reaction by promoting an
ideal conformation for cyclization through the gem-disub-
stituent effect.[14] To prove this hypothesis, we prepared
substrates 14 and 16 with no or a diminished gem-disubstitu-
ent effect and subjected them to the reaction conditions for
the tandem reaction (Table 2). Although the MnO2 oxidation
of 14 provided the desired 2,6-cis-THP 15a (d.r. 7:1; Table 2,
entry 1), the reaction also produced ketone 15b (15a/15b 3:1)
as a result of a slow oxa-Michael addition step owing to the
absence of the gem-disubstituent effect and the competing
oxidation of the benzylic hydroxy group. Parikh–Doering
oxidation of 14 failed to provide 15a; instead, the exclusive
formation of 15b was observed (Table 2, entry 2). When gem-
dimethyl substitution was introduced in the substrate 14, the
tandem reaction was accelerated (Table 2, entries 3 and 4).
Thus, the reaction of 16 with MnO2 or under Parikh–Doering
conditions provided 17a with good stereoselectivity
Scheme 2. One-pot allylic oxidation/oxa-Michael/oxidation reaction to
give the THP ester 7: I) MnO2, CH2Cl2, 258C, 1.5 h; II) dimethyltriazo-
lium iodide, MnO2, DBU, MeOH, 4 ꢀ MS, 258C, 23 h, 61%.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
cyclic carbene proved to be a reliable method for the
oxidation of aldehydes containing sensitive electron-rich
sulfur atoms to the corresponding carboxylic acids or esters.[13]
To investigate the scope and stereochemical outcome of
the tandem reaction with respect to substituents at the C2
position, we prepared allylic alcohols 11a–e by coupling 3
with the commercially or readily available epoxides 10a–e
and subjected them to MnO2 or Parikh–Doering oxidation, or
MnO2 oxidation in the presence of dimethyltriazolium iodide
(Table 1). The tandem reaction of 11a–d under the reaction
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Table 2: Investigation of the gem-disubstituent effect on reaction rate
and stereoselectivity.
Entry
Substrate
14
Conditions[a]
Product (yield [%],[b] d.r.[c])
1
2
3
4
5
6
A
B
A
B
A
B
15a/15b 3:1 (83, 7:1)
15b only (92, NA[d])
17a/17b 4:1 (94, 10:1)
17a/17b 3:1 (94, 10:1)
12d only (96, >20:1)
12d only (94, >20:1)
16
11d
[a] A) MnO2, CH2Cl2, 258C, 24 h; B) SO3·pyridine, Et3N/DMSO/CH2Cl2
(1:1:4), 258C, 24 h. [b] Combined yield of the isolated THP and ketone.
[c] The diastereomeric ratio (2,6-cis-THP/2,6-trans-THP) was determined
1
by integration of the H NMR spectrum of the crude product. [d] Not
applicable.
(d.r. 10:1). However, competing benzylic oxidation was also
observed (17a/17b 4:1 and 3:1, respectively). The oxidation
of 11d, which contains the 1,3-dithiane group, with MnO2 or
under Parikh–Doering conditions gave 12d with excellent
stereoselectivity (d.r. > 20:1) and did not produce 18 (Table 2,
entries 5 and 6). These results clearly demonstrated that the
gem-disubstituent effect accelerated the intramolecular oxa-
Michael reaction. A more dramatic gem-disubstituent effect
was observed when the Parikh–Doering conditions were used.
Interestingly, an improvement in stereoselectivity was also
observed with the 1,3-dithiane group. This improvement may
be due to the increased 1,3-diaxial interaction/more rigid
chair-like transition state induced by the cyclic dithiane group
compared with the hydrogen atoms or the dimethyl group.
Encouraged by the efficiency and versatility of the tandem
allylic oxidation/oxa-Michael reaction, we embarked on a
stereoselective synthesis of (+)-neopeltolide macrolactone
(21). The marine macrolide (+)-neopeltolide (19) is an
extremely potent inhibitor of tumor-cell proliferation[15] and
has attracted considerable interest from a number of synthetic
research groups.[16–18] We envisioned that the embedded 2,6-
cis-4-hydroxy-THP could be constructed by using the tandem
allylic oxidation/oxa-Michael reaction as the key bond-form-
ing step (Scheme 3).
Scheme 3. Retrosynthesis of (+)-neopeltolide macrolactone (21).
Bz=benzoyl.
oxa-Michael reaction. The allylic oxidation/oxa-Michael
reaction/oxidation of 23 (MnO2, CH2Cl2, 258C, 3 h; then
dimethyl triazolium iodide, MnO2, DBU, MeOH, M.S. (4 ꢀ),
258C, 21 h) afforded the desired 2,6-cis-THP methyl ester 22
with excellent stereoselectivity (d.r. > 20:1, 78%). The
tandem reaction was chemoselective; it did not require any
protection of the three hydroxy groups in 23. The hydrolysis
of 22 under basic conditions, followed by a macrocyclization
reaction of the resulting acid 32 according to the procedure
described by Shiina et al.,[24] proceeded smoothly to give 33.
Final deprotection of the 1,3-dithiane group completed the
synthesis of (+)-neopeltolide macrolactone (21), which
proved identical in all respects to known synthetic
21.[17b,18e,h] Compound 21 was converted into the known
alcohol 34[17b,18a,c,e,f,g] by a stereoselective reduction.[17b] The
synthesis of (+)-neopeltolide (19) could be completed by a
Mitsunobu esterification reaction of 34 with the known acid
20,[18f,25] as described previously.[17b,18a,c,e,f,g]
The synthesis of 21 started with the preparation of the
chiral epoxide 24 for dithiane coupling (Scheme 4). The
coupling of 1 with (R)-5-iodo-4-methylpentene,[19] followed
by the ring opening of (R)-(ꢁ)-epichlorohydrin and concur-
rent epoxide formation, afforded 26. The ring opening of
epoxide 26, deprotection of the 1,3-dithiane group, and
Evans–Tischenko reduction[20] of b-hydroxyketone 28
afforded the desired anti 1,3-diol 29. Methylation of the
secondary hydroxy group,[21] asymmetric dihydroxylation,[22]
and epoxide formation[23] afforded the substrate 24 for the
second 1,3-dithiane coupling.
In summary, we have explored a tandem allylic oxidation/
oxa-Michael reaction for the stereoselective and efficient
synthesis of 2,6-cis-THPs. The reaction required no activation
of the oxygen nucleophile or aldehyde, was applicable to a
broad range of substrates, and proceeded with excellent
stereoselectivity. We also demonstrated that the 1,3-dithiane
group enabled rapid access to substrates, promoted the
intramolecular oxa-Michael reaction through the gem-disub-
stituent effect, and improved the stereoselectivity of the
reaction as a result of the increased 1,3-diaxial interaction.
The chemoselective nature of the tandem allylic oxidation/
oxa-Michael reaction and the efficiency of dithiane coupling
reactions enabled a concise and efficient synthesis of
(+)-neopeltolide macrolactone (21) with minimal use of
The coupling of 3 and 24 proceeded smoothly with
accompanying deprotection of the benzoyl-protected hydroxy
group to set the stage for the key tandem allylic oxidation/
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[3] For examples of intermolecular oxa-Michael reactions made
possible by activation, see: a) T. C. Wabnitz, J. S. Spencer, Org.
Lett. 2003, 5, 2141 – 2144; b) I. C. Stewart, R. G. Bergman, F. D.
Toste, J. Am. Chem. Soc. 2003, 125, 8696 – 8697; c) L. Zu, S.
Zhang, H. Xie, W. Wang, Org. Lett. 2009, 11, 1627 – 1630, and
references therein.
[4] For examples of intramolecular oxa-Michael reactions made
possible by activation, see: a) D. A. Evans, J. A. Gauchet-
Prunet, J. Org. Chem. 1993, 58, 2446 – 2453; b) J. M. Palazꢃn,
M. A. Soler, M. A. Ramirez, V. S. Martin, Tetrahedron Lett.
1993, 34, 5467 – 5470; c) A. Fettes, E. M. Carreira, Angew. Chem.
2002, 114, 4272 – 4275; Angew. Chem. Int. Ed. 2002, 41, 4098 –
4101; d) B. M. Trost, H. Yang, G. Wuitschik, Org. Lett. 2005, 7,
4761 – 4764; e) H. H. Jung, P. E. Floreancig, Org. Lett. 2006, 8,
1949 – 1951, and references therein.
[5] During the preparation of this manuscript, Trost et al. reported a
synthesis of THPs through the [InRu(PPh3)2Cl]-catalyzed redox
isomerization of primary and secondary propargyl alcohols,
followed by a subsequent intramolecular conjugate addition:
B. M. Trost, A. C. Gutierrez, R. C. Livingston, Org. Lett. 2009,
11, 2539 – 2542.
[6] For a review on 1,3-dithiane coupling, see: M. Yus, C. Najera, F.
Foubelo, Tetrahedron 2003, 59, 6147 – 6212.
[7] J. P. Roduit, H. Wyler, Helv. Chim. Acta 1985, 68, 403 – 414.
[8] The configuration of the 2,6-disubstituted THP was determined
to be cis by NMR spectroscopy (see the Supporting Information
for details).
[9] The tandem reaction of 9 (the E isomer of 4), which was
prepared by the coupling of 8 (the E isomer of 3) with (ꢀ )-
glycidyl benzyl ether, under the conditions of MnO2 oxidation
provided 6a (d.r. > 20:1, 87%). Thus, the double-bond geometry
appears to have no effect on the stereoselectivity and conversion
of the reaction (see the Supporting Information for details).
[10] For a review on tandem reactions with MnO2, see: R. J. K.
Taylor, M. Reid, J. Foot, S. A. Raw, Acc. Chem. Res. 2005, 38,
851 – 869.
[11] a) B. Maurer, A. Grieder, W. Thommen, Helv. Chim. Acta 1979,
62, 44 – 47; b) A. J. F. Edmunds, W. Trueb, Tetrahedron Lett.
1997, 38, 1009 – 1012; c) A. Bhattacharjee, O. Soltani, J. K.
De Brabander, Org. Lett. 2002, 4, 481 – 484.
Scheme 4. Stereoselective synthesis of the 2,6-cis-THP 22 and (+)-
neopeltolide macrolactone (21): a) nBuLi, THF, ꢁ78!ꢁ108C, 1 h,
then (R)-5-iodo-4-methylpentene, ꢁ78!ꢁ408C, 4 h, 79%; b) nBuLi,
THF, 258C, 5 min, then (R)-epichlorohydrin, ꢁ788C, 2 h, then 258C,
12 h, 83%; c) EtMgBr, CuI, THF, ꢁ40!ꢁ108C, 3 h, 96%; d) MeI,
CaCO3, CH3CN/H2O (3:1), 258C, 14 h, 87%; e) PhCHO, SmI2, THF,
08C, 3 h, 87%; f) 1,8-bis(dimethylamino)naphthalene, Me3O·BF4,
CH2Cl2, 0–258C, 2 h, 93%; g) AD mix-b, H2O/tBuOH (1:1), 08C, 10 h,
92%, a/b 3:1; h) NaH, N-p-toluenesulfonylimidazole, THF, 0–258C,
1 h, 92%; i) tBuLi, HMPA/THF (1:10), ꢁ788C, 5 min, then 24, ꢁ788C,
3 h, 75%; j) MnO2, CH2Cl2, 258C, 3 h, then dimethyltriazolium iodide,
MnO2, DBU, MeOH, 4 ꢀ MS, 258C, 21 h, 78%; k) 0.1n LiOH, THF/
MeOH (3:1), 258C, 1 h, 99%; l) 2-methyl-6-nitrobenzoic anhydride, 4-
dimethylaminopyridine, CH2Cl2, 24 h, 69%; m) MeI, CaCO3, CH3CN/
H2O (3:1), 258C, 30 h, 89%; n) NaBH4, MeOH, 08C, 1 h, 93%.
[12] B. E. Maki, K. A. Scheidt, Org. Lett. 2008, 10, 4331 – 4334.
[13] A. B. Smith III, D. Lee, C. M. Adams, M. C. Kozlowski, Org.
Lett. 2002, 4, 4539 – 4541.
[14] For a review on the gem-disubstituent effect, see: M. E. Jung, G.
Piizzi, Chem. Rev. 2005, 105, 1735 – 1766.
[15] A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody, P. Linley,
P. J. McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J. Nat. Prod.
2007, 70, 412 – 416.
protecting groups (16 steps to (+)-neopeltolide macrolactone
(21) in 5.2% overall yield from commercially available
(S)-(+)-4-isopropyl-3-propionyl-2-oxazolidinone).[26]
This
[16] For a review on the synthesis of (+)-neopeltolide, see: J. Gallon,
S. Reymond, J. Cossy, C. R. Chim. 2008, 11, 1463 – 1476.
[17] For the first total synthesis of (+)-neopeltolide and revision of its
structure, see: a) W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo,
J. S. Panek, Angew. Chem. 2007, 119, 9371 – 9374; Angew. Chem.
Int. Ed. 2007, 46, 9211 – 9214; b) D. W. Custar, T. P. Zabawa,
K. A. Scheidt, J. Am. Chem. Soc. 2008, 130, 804 – 805.
[18] a) S. K. Woo, M. S. Kwon, E. Lee, Angew. Chem. 2008, 120,
3286 – 3288; Angew. Chem. Int. Ed. 2008, 47, 3242 – 3244; b) V. V.
Vintonyak, M. E. Maier, Org. Lett. 2008, 10, 1239 – 1242; c) H.
Fuwa, S. Naito, T. Goto, M. Sasaki, Angew. Chem. 2008, 120,
4815 – 4817; Angew. Chem. Int. Ed. 2008, 47, 4737 – 4739; d) R.
Kartika, T. R. Gruffi, R. E. Taylor, Org. Lett. 2008, 10, 5047 –
5050; e) I. Paterson, N. A. Miller, Chem. Commun. 2008, 4708 –
4710; f) V. V. Vintonyak, B. Kunze, F. Sasse, M. E. Maier, Chem.
Eur. J. 2008, 14, 11132 – 11140; g) O. A. Ulanovskaya, J. Janjic,
M. Suzuki, S. S. Sabharwal, P. T. Schumacker, S. J. Kron, S. A.
Kozmin, Nat. Chem. Biol. 2008, 4, 418 – 424; h) W. Tu, P. E.
Floreancig, Angew. Chem. 2009, 121, 4637 – 4641; Angew. Chem.
synthetic method would be broadly applicable to the efficient
synthesis of a diverse set of bioactive natural products
containing 2,6-cis-THP rings.
Received: July 6, 2009
Published online: September 8, 2009
Keywords: gem-disubstituent effect · tandem reactions ·
.
natural products · oxa-Michael addition · tetrahydropyrans
[1] For reviews on THP synthesis, see: a) T. L. B. Boivin, Tetrahe-
dron 1987, 43, 3309 – 3362; b) P. A. Clarke, S. Santos, Eur. J. Org.
Chem. 2006, 2045 – 2053; c) I. Larrosa, P. Romea, F. Urpꢁ,
Tetrahedron 2008, 64, 2683 – 2723.
[2] For a recent review on the oxa-Michael reaction, see: C. F.
Nising, S. Brꢂse, Chem. Soc. Rev. 2008, 37, 1218 – 1228.
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Int. Ed. 2009, 48, 4567 – 4571; i) D. W. Custar, T. P. Zabawa, J.
Hines, C. M. Crews, K. A. Scheidt, J. Am. Chem. Soc. 2009, 131,
12406 – 12414.
[23] D. R. Hicks, B. Fraser-Reid, Synthesis 1974, 203.
[24] I. Shiina, H. Fukui, A. Sasaki, Nat. Protoc. 2007, 2, 2312 – 2317.
[25] a) K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am.
Chem. Soc. 2000, 122, 12894 – 12895; b) P. Wipf, T. H. Graham, J.
Org. Chem. 2001, 66, 3242 – 3245; c) L. A. Dakin, N. F. Langille,
J. S. Panek, J. Org. Chem. 2002, 67, 6812 – 6815; d) Y. Wang, J.
Janjic, S. A. Kozmin, J. Am. Chem. Soc. 2002, 124, 13670 – 13671.
[26] a) R. A. Shenvi, D. P. OꢄMalley, P. S. Baran, Acc. Chem. Res.
2009, 42, 530 – 541; b) I. S. Young, P. S. Baran, Nat. Chem. 2009,
1, 193 – 205.
[19] A. B. Smith III, C. M. Adams, S. A. Kozmin, D. V. Paone, J. Am.
Chem. Soc. 2001, 123, 5925 – 5937.
[20] D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112, 6447 –
6449.
[21] D. A. Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, Tetrahedron
Lett. 1994, 35, 7171 – 7172.
[22] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
Angew. Chem. Int. Ed. 2009, 48, 7577 –7581
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