10.1002/ejoc.201801117
European Journal of Organic Chemistry
FULL PAPER
acetal Z-14b. We inferred its configuration from NOE interactions between 5–
CH3 and OCH3 [CDCl3/C6D6 (3:2), 400.4 MHz].
Me3SiCl,–78 °C
W. Norin, M. Wennerstal, X. Wu, L. Hagberg (Karo Bio AB), WO 2009012954,
2009: bromination; then cyanation.
[8] The stereodescriptor 2,3trans refers to the orientation of the C3 Me vs. C2 C1’
− −
→ room temp.
(in 3 h)
CH3
LDA, THF,
–78 °C, 1 h;
NOE
O
O
O
O
5
bond in the dioxolane ring of aldols 8, 10 , and 18 (as imposed by induced dia-
OCH3
OCH3
OCH3
O
O
stereocontrol of an aldol addition). The stereodescriptor 2,1’syn – and 2,1’anti
O
OLi
14a
OSiMe3
14b
likewise – describes the orientation of the C2 O vs. the C1’
− −O bond (as imposed
59
Z-
by simple diastereocontrol of an aldol addition) provided these aldols are drawn
as in Scheme 1.
[9] The term “brominating hydrolysis“ describes the overall change of substruc-
[19] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79, 1920–1923.
[20] Examples of axial preferences in Zimmerman-Traxler transition states of
aldol-equivalent additions of
γ,γ-disubstituted allylmetals to aldehydes are
ture C(
this transformation results from a hydrolysis C(
tautomerization C( OH)C=C C(=O)C H, and an
C(=O)C C(=O)C Br.
−Cl)C=C into substructure C(=O)C−C−Br. Formally (not mechanistically!),
summarized in T. Mejuch, N. Gilboa, E. Gayon, H. Wang, K. N. Houk, I. Marek,
Acc. Chem. Res. 2013, 46, 1659–1669.
[21] C. H. Heathcock, S. K. Davidsen, K. T. Hug, L. A. Flippin, J. Org. Chem.
1986, 51, 3027–3037.
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2177–2194. This is a consequence of what is designated as an "endocyclic
restriction" in a broader context (P. Beak, Acc. Chem. Res. 1992, 25, 215–222).
[24] Mukaiyama aldol additions: S. E. Denmark, W. Lee, Chem. Asian J. 2008,
3, 327–341 and literature cited therein.
−Cl)C=C
→
C(−
OH)C=C, a
−
→
−C
−
α-bromination
−C
−H
→
−C−
[10] Selected precedents: a) C.-N. Hsiao, M. R. Leanna, L. Bhagavatula, E. de
Lara, T. M. Zydowsky, B. W. Horrom, H. E. Morton, Synthetic Comm. 1990, 20,
3507–3517: NBS, H2O; b) R. A. Craig, J. L. Roizen, R. C. Smith, A. C. Jones,
B. M. Stoltz, Org. Lett. 2012, 14, 5716–5719: NaOBr, aq. AcOH; c) V. Pace, L.
Castoldi, M. J. Hernáiz, A. R. Alcántara, W. Holzer, Tetrahedron Lett. 2013, 54,
4369–4372: Ca(OBr)2, aq. AcOH.
[11] Ref.[10b]
.
[25] Y. Yang, X. Fu, J. Chen, H. Zhai, Angew. Chem. Int. Ed. 2012, 51, 9825–
9828.
[12] Selected reviews: a) R. Mahrwald (Ed.), Modern Methods in Stereoselective
Aldol Reactions, Wiley-VCH, Weinheim, New York, 2013; b) G. L. Beutner, S.
E. Denmark, Angew. Chem. Int. Ed. 2013, 52, 9086–9096; Angew. Chem. 2013,
9256–9266; c) S. B. J. Kan, K. K. H. Ng, I. Paterson, Angew. Chem. Int. Ed.
2013, 52, 9097–9108; Angew. Chem. 2013, 9267–9279; d) J.-i. Matsuo, M.
Murakami, Angew. Chem. Int. Ed. 2013, 52, 9109–9118; Angew. Chem. 2013,
125, 9280–9289.
[13] a) Preparation including isolation: M. Hatano, T. Mizuno, A. Izumiseki, R.
Usami, T. Asai, M. Akakura, K. Ishihara, Angew. Chem. Int. Ed. 2011, 50,
12189–12192; b) in situ preparation preceding an aldol addition: A. B. Smith, C.
Sfouggatakis, D. B. Gotchev, S. Shirakami, D. Bauer, W. Zhu, V. A. Doughty,
Org. Lett. 2004, 6, 3637–3640.
[14] We also considered installing the phenyl group before the aldol addition by
using the phenyl ketone 55 as the source of the nucleophile instead of the ester
9. In fact, we attempted both an aldol addition of the lithium enolate of ketone
55 and a Mukaiyama aldol addition of the corresponding enol silane 57 yet
employed 2-chlorocrotonaldehyde (15) as the electrophile (cf. below) instead of
2-chloroacrolein (12; cf. Scheme 1):
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7523–7527.
[27] a) Original report: D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–
4156; b) summary of applications: V. V. Zhdankin, J. Org. Chem. 2011, 76,
1185–1197.
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5454–5459; b) application to a similar substrate: J. S. Clark, G. Yang, A. P.
Osnowski, Org. Lett. 2013, 15, 1460–1463.
[29] H. Hoffmann, H. J. Dieter, Angew. Chem. 1964, 76, 944-953; Angew.
Chem., Int. Ed. Engl. 1964, 3, 737-746.
[30] Prior to our work SmI2-induced inter- and intramolecular aldol additions of
α
-haloketones have been used by a) Z. Yang, D. Shannon, V.-L. Truong, P.
Deslongchamps, Org. Lett. 2002, 4, 4693–4696; b) D. Chapdelaine, J. Belzile,
P. Deslongchamps, J. Org. Chem. 2002, 67, 5669–5672; c) B. A. Sparling, R.
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Silverston, C. D. Vanderwal, J. Org. Chem. 2016, 81, 1819–1838.
[31] The cis-orientation of the C1 OTBS and C4
− −OH bonds in compound cis-39
Ph
O
follows from the following cross peaks in the NOESY spectrum (CDCl3, 400.13
MHz):
LDA, THF,
O
O
O
+
O
HO
O
−78 °C → room temp.
Ph
Cl
H
CH3
H
O
Cl
55
15
56
trans,syn-
O
OH
14
4
Ph
O
H
O
1
BF3·OEt2, CH2Cl2,
TBSO
O
O
O
O
+
H
O
cis-39
O
−78 °C → room temp.
Ph
Cl
[32] a) Original report: G. M. Atkins, E. M. Burgess, J. Am. Chem. Soc. 1968,
90, 4744–4745; summaries of applications: b) S. Santra, Synlett 2009, 328–329,
c) M. M. Heravi, T. Ahmadi, A. Fazeli, N. M. Kalkhorani, Curr. Org. Synth. 2015,
12, 328–357.
[33] a) Original report: Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978,
43, 2480–2482; summaries of applications: b) T. T. Tidwell, Synthesis 1990,
857–870; c) T. T. Tidwell, Org. React. 1990, 39, 297–572.
HO
OSiMe3
Cl
57
15
trans,anti-58
These reactions suffered from low reactivity at −78 °C and
a
lack of
chemoselectivity at room temp., delivering nothing or complex mixtures.
Considering 12 more prone to side-reactions than 15 we excluded ketone 55
and enol silane 57 from our planning.
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[15] J. H. Dodd, R. S. Garigipati, S. M. Weinreb, J. Org. Chem. 1982, 47, 4045–
4049.
another position of an
α
-oxygenated side-chain were reported by P. Langer, V.
1599.
[16] Previous additions of Li enolates of type-9 esters to achiral electrophiles: a)
R. Naef, D. Seebach, Angew. Chem. Int. Ed. Eng. 1981, 20, 1030–1031; Angew.
Chem. 1981, 93, 1113–1114; b) W. Ladner, Chem. Ber. 1983, 116, 3413–3426;
c) M. Pohmakotr, T. Junpirom, S. Popuang, P. Tuchinda, V. Reutrakul,
Tetrahedron Lett. 2002, 43, 7385–7387; c) M. S. M. Timmer, B. L. Stocker, P.
H. Seeberger, J. Org. Chem. 2006, 71, 8294–8297; d) E. Bette, A. Otto, T.
Dräger, K. Merzweiler, N. Arnold, L. Wessjohann, B. Westermann, Eur. J. Org.
Chem. 2015, 2357–2365; e) K. C. Nicolaou, Q. Cai, H. Sun, B. Qin, S. Zhu, J.
Am. Chem. Soc. 2016, 138, 3118–3124.
[17] Previous additions of silyl ketene acetals of type-9 esters to achiral electro-
philes: a) D. A. Evans, W. B. Trotter, J. C. Barrow, Tetrahedron 1997, 53, 8779–
8794; b) V. K. Aggarwal, S. J. Masters, H. Adams, S. E. Spey, G. R. Brown, A.
J. Foubister, J. Chem. Soc., Perkin Trans. 1 1999, 155–162; c) Y. Hayashi, M.
Shoji, J. Yamaguchi, K. Sato, S. Yamaguchi, T. Mukaiyama, K. Sakai, Y. Asami,
H. Kakeya, H. Osada, J. Am. Chem. Soc. 2002, 124, 12078–12079.
Köhler, Org. Lett. 2000, 2, 1597
−
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4538; b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7287.
[37] J. Suffert, J. Org. Chem. 1989, 54, 509-510.
[38] Due to the instability and volatility of 2-chloroacrolein (12), the distillation
was performed quickly at a temperature as low as possible. The resulting small
temperature gradient in the condenser and the high vapor pressure of 12 led to
partial substance loss. The receiving flasks were cooled with dry ice.
[39] J. Kadota, S. Komori, Y. Fukumoto, S. Murai, J. Org. Chem. 1999, 64,
7523–7527.
[40] The SmI2 solution was titrated according to A. Dahlén, G. Hilmersson, Eur.
J. Inorg. Chem. 2004, 3020–3024.
[41] The C4-configurations in both isomers were not assigned.
[18] Deprotonating the related ester 59 under the same conditions (LDA, THF,
−78 °C, 1 h) and quenching with Me3SiCl furnished the Z-configured silyl ketene
19
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