Stereoselective substrate-controlled asymmetric syntheses of both 2,5-cis- and 2,5-trans-tetrahydrofuranoid oxylipids: Stereodivergent intramolecular amide enolate alkylation

Article abstract of DOI:10.1002/anie.201600637

The concise, highly stereoselective, substrate-controlled asymmetric total syntheses of both 2,5-cis- and 2,5-trans-tetrahydrofuranoid nematocidal oxylipids from the Australian brown algae Notheia anomala have been accomplished in a stereodivergent fashion. The highly stereoselective intramolecular amide enolate alkylation strategy provides access to both stereoisomers of the 3-hydroxy-2,5-disubstituted tetrahydrofuran core of these marine natural products through chelate and nonchelate control, which is driven by the C3-hydroxy protecting group. This approach offers an optional and highly stereoelective access to any of the eight possible stereoisomers of the 2,5-disubstituted-3-oxygenated tetrahydrofuran skeleton, an important structural feature which is present in many biologically active natural products. Two from one: The title reaction leads to both isomers of the tetrahydrofuranoid nematocidal oxylipids in a stereodivergent fashion from a common intermediate. Each of the stereoisomers results from exploiting either chelate or nonchelate control in the reaction. PMB=para-methoxybenzyl, TIPS=triisopropylsilyl.

Full text of DOI:10.1002/anie.201600637

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600637
German Edition: DOI: 10.1002/ange.201600637
Total Synthesis
Stereoselective Substrate-Controlled Asymmetric Syntheses of both
2,5-cis- and 2,5-trans-Tetrahydrofuranoid Oxylipids: Stereodivergent
Intramolecular Amide Enolate Alkylation
Hongjun Jang+, Iljin Shin+, Dongjoo Lee, Hyoungsu Kim,* and Deukjoon Kim
Dedicated to Professor Steven M. Weinreb on the occasion of his 75th birthday
Abstract: The concise, highly stereoselective, substrate-con-
trolled asymmetric total syntheses of both 2,5-cis- and 2,5-
trans-tetrahydrofuranoid nematocidal oxylipids from the Aus-
tralian brown algae Notheia anomala have been accomplished
in a stereodivergent fashion. The highly stereoselective intra-
molecular amide enolate alkylation strategy provides access to
both stereoisomers of the 3-hydroxy-2,5-disubstituted tetrahy-
drofuran core of these marine natural products through chelate
and nonchelate control, which is driven by the C3-hydroxy
protecting group. This approach offers an optional and highly
stereoelective access to any of the eight possible stereoisomers
of the 2,5-disubstituted-3-oxygenated tetrahydrofuran skeleton,
an important structural feature which is present in many
biologically active natural products.
T
he marine C19 oxylipid 1b, which possesses a 2,5-trans-
disubstituted tetrahydrofuran (THF) skeleton as shown in
Scheme 1, was first isolated from the Australian brown algae
Notheia anomala in 1980 by Warren et al.[1] The relative and
absolute stereochemistry of 1b was established by single-
crystal X-ray analysis on the C18–C19 dihydro derivative, and
application of the Horeau method to the C10 monoacetate,
respectively. Extensive reinvestigation of the same species by
Capon and co-workers in 1998 led to the identification of the
diastereomeric 2,5-cis-disubstituted oxylipid 1a.[2] Both 1a
and 1b possess nematocidal activities.[2]
Scheme 1. Retrosynthetic plan for the oxylipds 1a and 1b. IAEA=
intramolecular amide enolate alkylation, PMB=p-methoxybenzyl,
TIPS=triisoproylsilyl.
carbon–carbon bond formation, the elegant pathways
attempted to date include the use of a Prins-type cyclization,
a Mukaiyama-type reaction, [3+2] cycloaddition, or radical
addition, and predominantly generate the 2,5-cis-disubsti-
tuted THF system.[4m,5]
Since the first synthesis of 1b by Williams and co-workers
in 1984,[3] these oxylipids have served as a testing ground to
evaluate strategies for stereoselective construction of the 2,5-
disubstituted-3-oxygenated THF motif, which is present as an
important structural feature in many biologically active
natural products.[4] However, relatively few of the many
hitherto published approaches to construct this critical
structural unit utilized a carbon–carbon bond-forming cycli-
zation reaction as the key step. Of the approaches involving
We describe herein our concise, highly stereoselective,
substrate-controlled asymmetric total syntheses of both 1a
and 1b, which contain 3-hydroxy-2,5-cis- and 3-hydroxy-2,5-
trans-disubstituted THF units, respectively, from a common
intermediate based on a stereodivergent intramolecular
amide enolate alkylation (IAEA) strategy.[6] This novel
strategy was derived from the insights garnered during
development of our protecting-group-dependent intermolec-
ular amide enolate alkylation/RCM protocols for the syn-
thesis of medium-ring-ether natural products.[7] We wish to
emphasize that our versatile approach offers stereoselective
access to any of the eight possible stereoisomers of the 2,5-
disubstituted-3-oxygenated THF skeleton.
[*] H. Jang,[+] I. Shin,[+] Prof. Dr. D. Lee, Prof. Dr. H. Kim
College of Pharmacy, Ajou University
Suwon 16499 (Korea)
E-mail: hkimajou@ajou.ac.kr
Prof. Dr. D. Kim
College of Pharmacy, Seoul National University
As depicted in our retrosynthetic plan (Scheme 1), we
were confident that 1a and 1b could be obtained by
application of our direct ketone synthesis/l-Selectride reduc-
tion protocol[7a,b,d–h,8] to tetrahydrofuranyl a-alkoxy amides 2a
Seoul 08826 (Korea)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600637.
Angew. Chem. Int. Ed. 2016, 55, 6497 –6501
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6497

Angewandte
Communications
Chemie
and 2b, respectively. We were intrigued by the possibility that
the key 2a and 2b intermediates might be secured in
a stereodivergent fashion by, respectively employing a che-
late- and nonchelate-controlled IAEA reaction of the corre-
sponding w-bromo a-alkoxy amides 3a and 3b. These amides
3a and 3b have a C7-hydroxy function protected with
a chelating (i.e., PMB) and non-chelating protecting group
(i.e., TIPS), respectively. We envisioned that 3a and 3b could
be synthesized from the common hydroxybromoamide inter-
mediate 4 through appropriate protection of the OH group,
and 4 in turn could be elaborated from the known epoxy
alcohol 5.[9a]
prepared from commercially available (E)-oct-2-en-1-ol by
a three-step sequence (chlorination,[10] Sharpless asymmetric
dihydroxylation,[11] epoxide formation), was subjected to
Williamson O-alkylation with N,N-dimethyl chloroacetamide
to deliver the desired epoxy a-alkoxy amide 6 in 98% yield.
Regioselective opening of 6 with (nBu)4NBr in the presence
of Mg(NO3)2·6H2O furnished 4 in good yield (90%).[12]
Protection of the hydroxy group in 4 as either the PMB or
TIPS ether using the reaction conditions reported by the
groups of Bundle[13] and Corey,[14] respectively, afforded the
corresponding 3a and 3b in good yields.
With 3a and 3b in hand, we first investigated the desired
chelate-controlled IAEA reaction of 3a for the synthesis of
1a. In the event, treatment of 3a with LiHMDS in THF at
À788C for 1 hour led to exclusive formation of the desired
6,9-cis-THF 2a in 91% yield (entry 2 in Scheme 3), presum-
ably via a chelated transition state geometry (A).[1b] The ROE
(rotating-frame Overhauser effect) interaction between pro-
tons on C6 and C9 in 2a was supportive of the assigned
cis relative stereochemistry. As shown in the table in
Scheme 3, neither the solvent (entries 6 and 7) nor the
cation of the base used (entries 2, 4, and 6) seemed to affect
the yield and diastereoselectivity in a significant manner.
Meanwhile, a lower reaction temperature was found to
improve the yield appreciably (0 versus À788C; entries 3
and 5 versus 4 and 6, respectively).
Our asymmetric synthesis of 1a and 1b commenced with
the preparation of the common synthetic intermediate 4
(Scheme 2). Thus, known the threo-epoxy alcohol 5,[9a]
Having accomplished a highly stereoselective synthesis of
2a, we next turned our attention to construction of 2b for the
synthesis of 1b. Thus, subjection of 3b, with a TIPS-protected
alkoxy group at C7, to KHMDS in THF at À788C for 1 hour
gave rise to 2b as the major isomer (cis/trans = 1:71) in
excellent yield (95%; entry 10 in Scheme 3). The TIPS-
protected alkoxy group is known to be a poor coordinating
Scheme 2. Synthesis of the IAEA substrates 3a and 3b. BRSM=based
on recovered starting material, Tf =trifluoromethanesulfonyl.
Scheme 3. Intramolecular amide enolate alkylation of 6,7-syn-bromoamides. HMDS=hexamethyldisilazide, TBS=tert-butyldimethylsilyl, TES=
triethylsilyl, TMS=trimethylsilyl.
6498 www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 6497 –6501

Angewandte
Communications
Chemie
group for steric and electronic reasons,[7a,b,d,g,h,15e,h,i,k] and the
(over three steps; d.r.: 18:1) by using a pathway similar to the
observed stereoselectivity could be rationalized by invoking
a nonchelated transition-state geometry (B2) which mini-
mizes steric repulsions present, between the bulky TIPS-
protected alkoxy group and the amide enolate moiety, in the
alternative nonchelated transition-state (B1). Diminished
diastereoselectivity was obtained when smaller silyl groups
were used. Thus, upon treatment with KHMDS in THF at
À788C, the cis/trans diastereoselectivity for the TIPS-, TBS-,
and TES-protected cyclization substrates was 1:71, 1:13, and
1:1, respectively (entries 10, 12, and 13). This trend is
consistent with a strong steric effect of the silyl group. In
the case of the least bulky TMS protecting group, however,
a 10:1 mixture of desilylated products was obtained in favor of
the cis isomer after acid treatment, albeit in low total yield
(42%).[16a] This reversal of stereoselectivity is in accord with
observations by Reetz and Hüllmann in their study of
nucleophilic addition to a-silyoxyketones. They reported
that the TMS-protected alkoxy group led to a surprising
degree of chelation-control, thus suggesting that steric factors
appear to be more important than any electronic effect
because of the silyl group.[15b] It is interesting to note that
unlike the intramolecular alkylation of 3a, that of 3b
exhibited better trans/cis diastereoselectivity (entries 10 and
11) in more polar solvent, which would favor a nonchelated
species. Upon exposure of 3b to KHMDS at À788C, the trans/
cis diastereoselectivity observed in THF and toluene was 71:1
and 3:1, respectively. Likewise, bases with larger cations
showed superior trans/cis selectivity (entry 8–10). With 3b in
THF at À788C, the trans/cis diastereoselectivity observed for
KHMDS, NaHMDS, and LiHMDS was 71:1, 7:1, and 4:1,
respectively.[16b]
above-described sequence for 1a, except that the TIPS
protecting group in 7b was removed by exposure to TBAF.
The spectral data and optical rotations of our synthetic 1a and
1b were in good agreement with those reported for the
natural products as well as other synthetic materials. We draw
attention to the fact that the diastereoselectivity observed in
our direct ketone synthesis/l-Selectride reduction sequence
(26:1 for the 6,9-cis series; 18:1 for the 6,9-trans) is far
superior to that reported in previous syntheses for alternative
=
procedures employing the Grignard addition of CH2 CH-
(CH2)7MgBr to tetrahydrofuranyl aldehydes (3:1 to 5.5:1 for
the cis series with a free hydroxy group at C7;[3o–q] and 2.5:1 to
6:1 for trans[3a,b,d,f,g,l–q]).
To further demonstrate the potential of our IAEA
approach, we embarked upon the synthesis of the 6,9-cis-
and 6,9-trans-THF skeletons with the complementary 6,7-
trans relative stereochemistry, as summarized in Scheme 5. In
For the completion of the synthesis, application of our
direct ketone synthesis protocol[7a,b,d–h,8] to 2a with CH2
=
CH(CH2)7MgBr, followed by stereoselective l-Selectride
reduction[7a,b,d–h,8,17] of the resulting ketone in a Felkin–Anh
sense, afforded the desired secondary alcohol 7a in 76%
overall yield for the two steps (d.r.: 26:1; Scheme 4). Finally,
removal of the PMB group in 7a by treatment with DDQ in
wet CH2Cl2 under the Yonemitsu conditions[18] delivered the
oxylipid 1a in 82% yield. The TIPS-protected 2b could be
elaborated to deliver the oxylipid 1b in 50% overall yield
Scheme 5. Intramolecular amide enolate alkylation of 6,7-anti-bromo-
amides.
the event, we were pleased to find that the IAEA reaction of
the PMB- (3c) and TIPS-protected (3d) 6,7-anti-bromo a-
alkoxy amides, derived from the known erythro-epoxy alcohol
5’[19] using a protocol similar to the above-described sequence
for 5, led to the corresponding 6,7-trans-6,9-trans- (2c) and
6,7-trans-6,9-cis-THF (2d) products through chelate and
nonchelate control, respectively, with high stereoselectivity
in good yield. Since both enantiomers of the threo- (5) and
erythro-epoxy (5’) alcohols are readily accessible through
asymmetric dihydroxylation[9a,4n] and Sharpless kinetic reso-
lution,[19] respectively, the present IAEA reactions of 6,7-anti-
bromo a-alkoxy amides, coupled with those of 6,7-syn-amides
(Scheme 3), provide optional access to any of the eight
Scheme 4. Completion of the synthesis. DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, TBAF=tetra-n-butylammonium fluoride.
Angew. Chem. Int. Ed. 2016, 55, 6497 –6501
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6499

Angewandte
Communications
Chemie
Org. Chem. 2001, 66, 9046 – 9051; j) H. Yoda, K. Maruyama, K.
Takabe, Tetrahedron: Asymmetry 2001, 12, 1403 – 1406; k) C.
García, T. Martín, V. S. Martín, J. Org. Chem. 2001, 66, 1420 –
1428; l) R. Fernµndez de la Pradilla, A. Castellanos, Tetrahedron
Lett. 2007, 48, 6500 – 6504; m) C. L. Nesbitt, C. S. P. McErlean,
Tetrahedron Lett. 2009, 50, 6318 – 6320; n) R. Fernµndez de la P-
radilla, A. Castellanos, I. Osante, I. Colomer, M. I. Sµnchez, J.
Org. Chem. 2009, 74, 170 – 181; o) B. Kang, J. Mowat, T. Pinter,
R. Britton, Org. Lett. 2009, 11, 1717 – 1720; p) C. L. Nesbitt,
C. S. P. McErlean, Org. Biomol. Chem. 2011, 9, 2198 – 2208; q) S.
Roy, C. D. Spilling, Org. Lett. 2012, 14, 2230 – 2233; r) L. Li, X.
Ye, Y. Wu, L. Gao, Z. Song, Z. Yin, Y. Xu, Org. Lett. 2013, 15,
1068 – 1071.
possible 2,5-disubstituted-3-oxygenated THF stereoisomers
in a highly stereoselective fashion. It is worth mentioning that
the application of a deprotection/Mitsunobu sequence on 2a
and 2b also proceeded without incident to give the corre-
sponding Mitsunobu products, which were then further
converted into 2d and 2c, respectively, for structure correla-
tion purposes (see the Supporting Information for details).[20]
In conclusion, we have accomplished concise, highly
stereoselective substrate-controlled asymmetric total synthe-
ses of both nematocidal oxylipids 1a and 1b which contain the
3-hydroxy-2,5-cis- and 3-hydroxy-2,5-trans-disubstituted THF
unit, respectively, in a stereodivergent fashion from the
common intermediate 4. These routes, which proceed in
seven steps from known epoxy alcohol 5, provide stereose-
lective access to both 2,5-cis- (2a) and 2,5-trans-THF (2b)
stereoisomers by a highly efficient intramolecular amide
enolate alkylation of 3a and 3b, respectively, through
corresponding chelate and nonchelate control. To the best
of our knowledge, our approach holds the distinction of being
the only extant synthesis in which the respective 2,5-cis and
2,5-trans relative stereochemistry in the THF core of 1a and
1b was established with high stereoselectivity through
a carbon–carbon bond-forming cyclization in a stereodiver-
gent fashion from a common intermediate. Furthermore, our
IAEA-based approach offers optional, highly stereoselective
access to any of the eight possible 2,5-disubstituted-3-oxy-
genated THF stereoisomers.
[4] For recent reviews on the synthesis of THF-containing natural
products, see: a) R. D. Norcrosst, I. Paterson, Chem. Rev. 1995,
95, 2041 – 2114; b) A. Bermejo, B. Figad›re, M.-C. Zafra-Polo, I.
Barrachina, E. Estornell, D. Cortes, Nat. Prod. Rep. 2005, 22,
269 – 303; c) E. J. Kang, E. Lee, Chem. Rev. 2005, 105, 4348 –
4378; d) J. P. Wolfe, M. B. Hay, Tetrahedron 2007, 63, 261 – 290;
e) G. Jalce, X. Franck, B. Figad›re, Tetrahedron: Asymmetry
2009, 20, 2537 – 2581; f) I. B. Spurr, R. C. D. Brown, Molecules
2010, 15, 460 – 501; g) B.-G. Wang, J. B. Gloer, N.-Y. Ji, J.-C.
Zhao, Chem. Rev. 2013, 113, 3632 – 3685; h) A. Lorente, J.
Lamariano-Merketegi, F. Albericio, M. lvarez, Chem. Rev.
2013, 113, 4567 – 4610; i) N. S. Sheikh, Org. Biomol. Chem. 2014,
12, 9492 – 9504; for recent examples of the synthesis of THF-
containing natural products, see: j) D. J. Shepherd, P. A. Broad-
with, B. S. Dyson, R. S. Paton, J. W. Burton, Chem. Eur. J. 2013,
19, 12644 – 12648; k) M. T. Holmes, R. Britton, Chem. Eur. J.
2013, 19, 12649 – 12652; l) T. Umezawa, Y. Oguri, H. Matsuura,
S. Yamazaki, M. Suzuki, E. Yoshimura, T. Furuta, Y. Nogata, Y.
Serisawa, K. Matsuyama-Serisawa, T. Abe, F. Matsuda, M.
Suzuki, T. Okino, Angew. Chem. Int. Ed. 2014, 53, 3909 – 3912;
Angew. Chem. 2014, 126, 3990 – 3993; m) J. Lee, J. S. Panek, J.
Org. Chem. 2015, 80, 2959 – 2971; n) A. Boyer, J. Org. Chem.
2015, 80, 4771 – 4775; o) M. Yamakawa, T. Kurachi, Y. Yoshi-
kawa, M. Arisawa, Y. Okino, K. Suzuki, H. Fujioka, J. Org.
Chem. 2015, 80, 10261 – 10277; p) S. Gahalawat, Y. Garg, S. K.
Pandey, Asian J. Org. Chem. 2015, 4, 1025 – 1029; q) M. Holmes,
D. Kwon, M. Taron, R. Britton, Org. Lett. 2015, 17, 3868 – 3871;
r) V. Mullapudi, C. V. Ramana, Tetrahedron Lett. 2015, 56, 3933 –
3935; s) U. Nookaraju, P. Kumar, RSC Adv. 2015, 5, 63311 –
63317.
Acknowledgments
This work was supported by Basic Science Research Program
through National Research Foundation of Korea, funded by
the Ministry of Science, ICT & Future Planning (NRF-
2014R1A1A2056603).
Keywords: alkylations · cyclizations · heterocycles ·
natural products · total synthesis
[5] For selected examples of 2,5-disubstituted-3-oxygenated THF
À
syntheses by C C bond-forming cyclization, see: a) M. J. Brown,
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6497–6501
Angew. Chem. 2016, 128, 6607–6611
T. Harrison, L. E. Overman, J. Am. Chem. Soc. 1991, 113, 5378 –
5384; b) E. Lee, S.-K. Yoo, H. Choo, H. Y. Song, Tetrahedron
Lett. 1998, 39, 317 – 318; c) P. A. Evans, V. S. Murthy, J. D.
Roseman, A. L. Rheingold, Angew. Chem. Int. Ed. 1999, 38,
3175 – 3177; Angew. Chem. 1999, 111, 3370 – 3372; d) T.-P. Loh,
Q.-Y. Hu, K.-T. Tan, H.-S. Cheng, Org. Lett. 2001, 3, 2669 – 2672;
e) L. E. Overman, L. D. Pennington, J. Org. Chem. 2003, 68,
7143 – 7157; f) J. H. Jung, Y. W. Kim, M. A. Kim, S. Y. Choi,
Y. K. Chung, T.-R. Kim, S. Shin, E. Lee, Org. Lett. 2007, 9, 3225 –
3228; g) S. Kollmann, R. Frçhlich, D. Hoppe, Synthesis 2007,
883 – 892; h) S. N. Chavre, H. Choo, J. K. Lee, A. N. Pae, Y. Kim,
Y. S. Cho, J. Org. Chem. 2008, 73, 7467 – 7471; i) S.-H. Kim, S.-J.
Oh, P. -S. Ho, S.-C. Kang, K.-J. O, C.-M. Yu, Org. Lett. 2008, 10,
265 – 268; j) P. D. Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li,
J. S. Johnson, J. Am. Chem. Soc. 2008, 130, 8642 – 8650.
[1] a) R. G. Warren, R. J. Wells, J. F. Blount, Aust. J. Chem. 1980, 33,
891 – 898; b) the numbering used to describe the key structural
unit is 2,5-trans and 2,5-cis, while a different numbering scheme
that corresponds to the natural product structure is used when
referring to compounds as a whole.
[2] R. J. Capon, R. A. Barrow, S. Rochfort, M. Jobling, C. Skene, E.
Lacey, J. H. Gill, T. Friedel, D. Wadsworth, Tetrahedron 1998, 54,
2227 – 2242.
[3] a) D. R. Williams, Y. Harigaya, J. L. Moore, A. D’sa, J. Am.
Chem. Soc. 1984, 106, 2641 – 2644; b) S. Hatakeyama, K.
Sakurai, K. Saijo, S. Takano, Tetrahedron Lett. 1985, 26, 1333 –
1336; c) M. K. Gurjar, P. S. Mainkar, Heterocycles 1990, 31, 407 –
410; d) H. Chikashita, Y. Nakamura, H. Uemura, K. Itoh, Chem.
Lett. 1993, 477 – 480; e) R. J. Capon, R. A. Barrow, C. Skene, S.
Rochfort, Tetrahedron Lett. 1997, 38, 7609 – 7612; f) Z. M. Wang,
M. Shen, J. Org. Chem. 1998, 63, 1414 – 1418; g) Y. Mori, T.
Sawada, H. Furukawa, Tetrahedron Lett. 1999, 40, 731 – 734;
h) C. García, M. A. Soler, V. S. Martín, Tetrahedron Lett. 2000,
41, 4127 – 4130; i) R. R. Gadikota, C. S. Callam, T. L. Lowary, J.
[6] For a recent review of intramolecular enolate alkylation, see:
a) D. Kim, Synlett 2014, 25, 35 – 57; For examples of tetrahy-
dropyran ring synthesis by intramolecular glycolate alkylation,
see: b) T. Fujisawa, Y. Okumura, K. Morita, Y. Ukaji, Bull.
Chem. Soc. Jpn. 1992, 65, 3487 – 3489; c) H. Ohrui, M. Morita, H.
Meguro, Carbohydr. Res. 1992, 224, 319 – 325; d) S. Knapp, V. V.
Thakur, M. R. Madduru, K. Malolanarasimhan, G. J. Morriello,
6500 www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 6497 –6501

Angewandte
Communications
Chemie
G. A. Doss, Org. Lett. 2006, 8, 1335 – 1337; e) M. Latif, J. I. Yun,
K. Seshadri, H. R. Kim, C. H. Park, H. Park, H. Kim, J. Lee, J.
Org. Chem. 2015, 80, 3315 – 3320.
[13] T. Iversen, D. R. Bundle, J. Chem. Soc. Chem. Commun. 1981,
1240 – 1241.
˝
[14] E. J. Corey, H. Cho, C. Rucker, D. H. Hua, Tetrahedron Lett.
1981, 22, 3455 – 3458.
[7] a) H. Lee, H. Kim, T. Yoon, B. Kim, S. Kim, H.-D. Kim, D. Kim,
J. Org. Chem. 2005, 70, 8723 – 8729; b) J. Park, B. Kim, H. Kim, S.
Kim, D. Kim, Angew. Chem. Int. Ed. 2007, 46, 4726 – 4728;
Angew. Chem. 2007, 119, 4810 – 4812; c) B. Kim, G. Cheon, J.
Park, H. Lee, H. Kim, S. Kim, D. Kim, Heterocycles 2007, 74,
171 – 175; d) W. Jeong, M. J. Kim, H. Kim, S. Kim, D. Kim, K. J.
Shin, Angew. Chem. Int. Ed. 2010, 49, 752 – 756; Angew. Chem.
2010, 122, 764 – 768; e) B. Kim, T. Sohn, S. Kim, D. Kim, J. Lee,
Heterocycles 2011, 82, 1113 – 1118; f) B. S. Dyson, J. W. Burton,
T. Sohn, B. Kim, H. Bae, D. Kim, J. Am. Chem. Soc. 2012, 134,
11781 – 11790; g) M. J. Kim, T. Sohn, D. Kim, R. S. Paton, J. Am.
Chem. Soc. 2012, 134, 20178 – 20188; h) T. Sohn, D. Kim, R. S.
Paton, Chem. Eur. J. 2015, 21, 15988 – 15997; for application of
the asymmetric alkylation/RCM strategy in the synthesis of
medium-ring ether natural products, see: i) M. T. Crimmins,
E. A. Tabet, J. Am. Chem. Soc. 2000, 122, 5473 – 5476 and
references therein.
[15] For the effect of silyl protecting groups on chelation, see:
a) M. T. Reetz, Angew. Chem. Int. Ed. Engl. 1984, 23, 556 – 569;
˝
Angew. Chem. 1984, 96, 542 – 555; b) M. T. Reetz, M. Hullmann,
J. Chem. Soc. Chem. Commun. 1986, 1600 – 1602; c) S. D. Kahn,
G. E. Keck, W. J. Hehre, Tetrahedron Lett. 1987, 28, 279 – 280;
d) G. E. Keck, S. Castellino, Tetrahedron Lett. 1987, 28, 281 –
284; e) S. V. Frye, E. L. Eliel, R. Cloux, J. Am. Chem. Soc. 1987,
109, 1862 – 1863; f) A. J. Stern, J. S. Swenton, J. Org. Chem. 1989,
54, 2953 – 2958; g) S. Shambayati, J. F. Blake, S. G. Wierschke,
W. L. Jorgensen, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112,
697 – 703; h) X. Chen, E. R. Hortelano, E. L. Eliel, S. V. Frye, J.
Am. Chem. Soc. 1990, 112, 6130 – 6131; i) X. Chen, E. R.
Hortelano, E. L. Eliel, S. V. Frye, J. Am. Chem. Soc. 1992, 114,
1778 – 1784; j) D. A. Evans, J. L. Duffy, M. J. Dart, Tetrahedron
Lett. 1994, 35, 8537 – 8540; k) G. R. Stanton, C. N. Johnson, P. J.
Walsh, J. Am. Chem. Soc. 2010, 132, 4399 – 4408.
[8] a) H. Kim, W. J. Choi, J. Jung, S. Kim, D. Kim, J. Am. Chem. Soc.
2003, 125, 10238 – 10240 and references therein; b) H. Lee, H.
Kim, S. Baek, S. Kim, D. Kim, Tetrahedron Lett. 2003, 44, 6609 –
6612; c) S. Baek, H. Jo, H. Kim, H. Kim, S. Kim, D. Kim, Org.
Lett. 2005, 7, 75 – 77.
[9] a) Z.-B. Zhang, Z.-M. Wang, Y.-X. Wang, H.-Q. Liu, G.-X. Lei,
M. Shi, J. Chem. Soc. Perkin Trans. 1 2000, 53 – 57; b) the
enantiomeric excess for 5 (> 91% ee) was determined by
1H NMR analysis of the corresponding Mosher esters following
standard protocols (see J. A. Dale, D. L. Dull, H. S. Mosher, J.
Org. Chem. 1969, 34, 2543 – 2549; J. A. Dale, H. S. Mosher, J.
Am. Chem. Soc. 1973, 95, 512 – 519); details are found the
Supporting Information; c) for synthesis of the antipode of 5,
see: Ref. [4n].
[16] a) The TMS group was removed to simplify product analysis
because varying amounts of desilylated products were also
obtained from the alkylation; b) in the experiments with
LiHMDS and NaHMDS (entries 8 and 9 in Scheme 3), the
reaction did not proceed beyond 45 and 40% conversion,
respectively.
[17] a) H. Iida, N. Yamazaki, C. Kibayashi, J. Org. Chem. 1986, 51,
3769 – 3771; b) J. S. Clark, A. B. Holmes, Tetrahedron Lett. 1988,
29, 4333 – 4336; c) K. Tsushima, A. Murai, Tetrahedron Lett.
1992, 33, 4345 – 4348.
[18] Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982,
23, 885 – 888.
[19] H. Wang, I. D. Kozekov, T. M. Harris, C. J. Rizzo, J. Am. Chem.
Soc. 2003, 125, 5687 – 5700 and references therein.
[10] S. M. Glueck, W. M. F. Fabian, K. Faber, S. F. Mayer, Chem. Eur.
J. 2004, 10, 3467 – 3478.
[20] O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380 –
2382.
[11] K. P. M. Vanhesschel, Z.-M. Wang, K. B. Sharpless, Tetrahedron
Lett. 1994, 35, 3469 – 3472.
[12] a) Y.-G. Suh, B.-A. Koo, J.-A. Ko, Y.-S. Cho, Chem. Lett. 1993,
22, 1907 – 1910; b) difficulties encountered in the opening of
epoxy amide 8 using chloride and iodide prevented us from
investigating internal alkylation of the corresponding halo a-
alkoxy amides.
Received: January 20, 2016
Revised: March 10, 2016
Published online: April 21, 2016
Angew. Chem. Int. Ed. 2016, 55, 6497 –6501
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6501