Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks

Article abstract of DOI:10.1021/acs.orglett.8b01358

Diastereoselective fluorination of N-Boc (R)- and (S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure (S,S)- and (R,S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.

Full text of DOI:10.1021/acs.orglett.8b01358

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Generating Stereodiversity: Diastereoselective Fluorination and
Highly Diastereoselective Epimerization of α‑Amino Acid Building
Blocks
Wei Wei,†,‡,¶ Rama Kanwar Khangarot,†,¶ Lothar Stahl,§ Cristina Veresmortean,† Padmanava Pradhan,†
Lijia Yang,† and Barbara Zajc*,†,‡
†Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031,
United States
‡The Ph.D. Program in Chemistry, The Graduate Center, City University of New York, New York, New York 10016, United States
§Department of Chemistry, University of North Dakota, Abbott Hall Room 425, 151 Cornell Street Stop 9024, Grand Forks, North
Dakota 58202-9024, United States
S
* Supporting Information
ABSTRACT: Diastereoselective fluorination of N-Boc (R)- and (S)-2,2-
dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown
diastereoselective epimerization at the fluorine-bearing carbon atom α to the
sulfone was realized. Diastereoselectivities of both reactions were excellent for
benzothiazolyl sulfones, allowing access to two enantiomerically pure
diastereomers from one chiral precursor. To demonstrate synthetic utility,
the benzothiazolyl sulfones were converted to diastereomerically pure (S,S)-
and (R,S)-benzyl sulfones via sulfinate salts and to amino acids. To understand
the diastereoselectivities, DFT analysis was performed.
product was synthesized by desilylation−fluorination of an
allylsilane derivative.9
luoroorganic chemistry has been a focus of intense
Fresearch in the past decade due to the interesting
properties of fluoroorganic compounds, making them desirable
candidates as pharmaceuticals, materials, and agrochemicals, to
name a few.1 Diastereoselective introduction of fluorine atom
into a molecule by asymmetric induction via an existing
stereogenic center, either as part of the molecule or by a
removable chiral auxiliary, has been extensively studied in
electrophilic fluorinations α to a carbonyl moiety.2a However,
diastereoselective C−F bond formation α to a sulfone has
received scarce attention.2 We have been involved in the
electrophilic fluorination of heteroaryl sulfones,3,4 and this
prompted our interest in exploring the effect of a stereogenic
center on diastereoselectivity of fluorination α to a sulfone
moiety. As a chiral entity, we chose the 2,2-dimethyloxazolidine
unit, which can be further converted to various derivatives,
including unnatural amino acids.5 In this context, several
sulfone-derived amino acids have shown biological activity, such
as S-aryl cysteine S,S-dioxides that inhibit mammalian
kynureninase6a,b and α-amino β-sulfone hydroxamates that
were shown to be potent inhibitors of MMP enzymes.6c,d
Asymmetric induction by a 2,2-dimethyloxazolidine unit has
been explored in reactions of Garner’s aldehyde,7 but there are
limited reports of fluorination α to its stereogenic center.
Deoxofluorination with DAST α to the stereogenic center of a
2,2-dimethyloxazolidine moiety has been reported, but only
one diastereoisomer could be synthesized via this route.8
Alternatively, a 1:1 diastereoisomeric mixture of fluorinated
We initially focused on a 1,3-benzothiazol-2-yl sulfone, N-
Boc-protected (R)-4-((benzo[d]thiazol-2-ylsulfonyl)methyl)-
2,2-dimethyloxazolidine. Synthesis commenced from either
(R)-Garner aldehyde or from D-serine (Scheme 1, also see
the Supporting Information (SI)), to give the common
intermediate (S)-4-(hydroxymethyl)-2,2-dimethyloxazolidine.
A reaction of this intermediate with benzo[d]thiazole-2-thiol
under Mitsunobu conditions gave sulfide (R)-1a that was
oxidized to sulfone (R)-2a with (NH4)2Mo7O24·4H2O/H2O2.
Fluorination under heterogeneous conditions previously
reported by us3,4 (LDA, solid NFSI addition, PhMe) resulted
in a highly diastereoselective reaction, with a product ratio
≥97:3 (yield of 60%, 65% based upon recovered starting
material). To unequivocally determine configuration at the new
stereogenic center, 3a was crystallized (EtOH) and analyzed
crystallographically. This showed the major diastereoisomer to
be (R,R)-3a. Similarly, (S)-2a, synthesized from L-serine, upon
fluorination gave (S,S)-3a (X-ray structure shown in Scheme
1), along with a trace of (S,R)-3a. In several repetitions, the
isolated yields ranged from 56 to 64%, with some recovered
starting. The amounts of the minor diastereomer were trace to
1
3% and barely detectable by H NMR.
Next, the influence of base on the diastereomer ratio in the
fluorination of (S)-2a was studied (Table 1).
Received: April 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Highly Diastereoselective Fluorination of N-Boc-
Protected (R)- and (S)-4-((Benzo[d]thiazol-2-
ylsulfonyl)methyl)-2,2-dimethyloxazolidine and X-ray
a
Structures of the Products
Figure 1. Products from the epimerization of (R,R)-3a to (R,S)-3a
(top) and of (S,S)-3a to (S,R)-3a (thermal ellipsoids are at the 50%
probability level). N: blue; S: yellow; O: red; F: green.
To assess the effect of the aryl moiety on the
diastereoselectivity of the fluorination and epimerization, a
series of sulfones was synthesized and subjected to fluorination
(Scheme 2 and Table 2). Yields of the fluorination step were
moderate to excellent.
Scheme 2. Synthesis and Fluorination of N-Boc-Protected
(S)-4-((Arylsulfonyl)methyl)-2,2-dimethyloxazolidines
a
Thermal ellipsoid are at the 50% probability level. N: blue; S: yellow;
O: red; F: green.
a
Table 1. Effect of Base on the Fluorination of (S)-2a
mono 3a/difluoro product (S,S)-3a/(S,R)-3a isomer
b
b
entry
base
LDA
ratio
ratio
c
1
2
3
4
5
6
no difluoro
74:26
≥97:3
88:12
45:55
22:78
16:84
15:85
d
d
e
f
LHMDS
NaHMDS
MDA
72:28
no difluoro
no difluoro
no difluoro
MDA
g
MDA
Fluorination proceeded diastereoselectively in all cases
(Table 2, entries 1−7, vide infra). Diastereoselectivity
depended on the aryl moiety: excellent for benzothiazolyl
(3a) and for phenyl (3d), good for 2- and 4-pyridyl (3b and
3c), and moderate for N-methyl-2-imidazolyl (3e).
a
Reactions were performed in PhMe, base (1.2 equiv) was added to
(S)-2a at −78 °C, after 12 min solid NFSI was added (1.4 equiv); −
b
78 C 1.5 h, then rt 1.5 h. Determined by 19F NMR of the crude
̊
c
reaction mixture. In several repetitions, the amount of (S,R)-3a
ranged from 3% to trace amounts. Product not isolated. Isolated
d
e
f
Epimerization of fluorinated substrates 3 was also tested by
exposure of diastereomeric mixtures, isolated in the fluorination
reaction, to NaHMDS in PhMe (Table 2, entries 1−5).
Epimerization with NaHMDS gave (S,R)-3 as the major
diastereoisomer in all cases, with high diastereoselectivities for
3a−d (entries 1−4 in Table 2). The lowest distereoselectivity
was observed for the epimerization of 3e, with a (S,S)-3e/
(S,R)-3e dr = 17:83 (entry 5). Because diastereoselectivity in
the initial fluorination reaction depended on the counterion,
with the highest diastereoselectivity observed with Li bases, we
also tested epimerization reactions of 3a and 3e with LHMDS
(Table 2, entries 6−8). Indeed, with LHMDS instead of
NaHMDS, a higher diastereoselectivity was observed for the
epimerization of the (S,S)-3a + (S,R)-3a mixture (dr = ≥97:3),
resulting in a (S,S)-3a + (S,R)-3a mixture with dr = 2:98
(compare entry 6 to entry 1). Isomerization of the (S,S)-3e +
(S,R)-3e mixture (dr = 62:38) with LHMDS also resulted in an
increased diastereoselectivity, as compared to epimerization
with NaHMDS (compare entry 7 to entry 5). Repeated
epimerization of the (S,S)-3e + (S,R)-3e mixture (dr = 17:83)
with LHMDS gave a (S,S)-3e + (S,R)-3e mixture with dr =
4:96 (entry 8). Finally, exposure of epimerized mixture (S,S)-3a
yield of 3a was 27% and of (S)-2a was 45%. To (S)-2a at −78 °C,
MDA was added, after 1 h 15 min NFSI was added; − 78 °C 1.5 h,
g
then rt 1.5 h. Isolated yield of 3a was 30% and of (S)-2a was 46%. To
(S)-2a at −50 °C, MDA was added, after 1 h 15 min NFSI was added;
− 50 °C 1.5 h, then rt 1.5 h. Isolated yield of 3a was 27% and of (S)-2a
was 42%.
From Table 1, certain observations emerge. Whereas
competing difluorination was not observed with LDA and
iPr2NMg (MDA), it was seen with LHMDS and NaHMDS.
Diastereoselectivity of the fluorination depended on the metal
ion, with Li as a counterion favoring (S,S)-3a as the major
isomer.
We then assessed whether epimerization at the new
stereogenic center could be accomplished under basic
conditions. With LDA or n-BuLi, in PhMe, decomposition of
3a occurred. However, when the (R,R)-3a and the (S,S)-3a
were independently exposed to NaHMDS in PhMe, a mixture
of diastereomers resulted from each; (R,R)-3a/(R,S)-3a = 1:10
and (S,S)-3a/(S,R)-3a = 1:9, respectively. The stereochemistry
at the epimerized stereogenic carbon was confirmed by X-ray
crystallography (Figure 1, crystals from EtOH).
B
DOI: 10.1021/acs.orglett.8b01358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Diastereoselectivities and Yields in the
Scheme 3. Conversion of 3a to Benzyl Sulfones (S,S)-4 and
(S,R)-4 via Sulfinate Salts and to Amino Acids
Fluorination and Subsequent Epimerization Reactions
b
fluorination: F-
isomers dr (S,S)-/
(S,R)-3
c
epimerization of (S,S)-3 + (S,R)-3:
base, % yield, dr (S,S)-/(S,R)-3
entry Het/Ph
1
2
2a: BT
≥97:3
78:22
NaHMDS, 76, 10:90
NaHMDS, 87, 6:94
2b: 2-
Py
3
2c: 4-
Py
88:12
NaHMDS, 85, 4:96
4
5
2d: Ph
96:4
NaHMDS, 63, 8:92
NaHMDS, 83, 17:83
2e: N-
Me-
Im
62:38
6
7
2a: BT
≥97:3
62:38
LHMDS, 89, 2:98
LHMDS, 84, 10:90
2e: N-
Me-
Im
synthetic building blocks. As a proof of principle, sulfones
(S,S)- and (S,R)-4 were converted to N-Boc amino acids 6 (see
the SI for details).
d
8
2e: N-
Me-
Im
17:83
LHMDS, 81, 4:96
To gain some insight into the highly diastereoselective
fluorination and epimerization reactions, we performed
preliminary DFT computations on the Li carbanions derived
from (R)-2a, (R,R)-3a, and its epimer (R,S)-3a at the B3LYP/
6-311++g(2d,2p) level (Figure 2).
d
9
2a: BT
2:98
NaHMDS, 65, 10:90
NaHMDS, 76, 15:85
d
10
2e: N-
Me-
Im
4:96
a
Determined by 19F NMR of the crude reaction mixture.
Fluorinations were performed in PhMe, base (1.2 equiv) was
b
added to (S)-2 at −78 °C, after 12 min solid NFSI was added (1.4
c
equiv); −78 °C 1.5 h, then rt 1.5 h. Epimerization of mixtures of 3 (dr
shown in column 3): base (1.5 equiv) was added to 3 at −78 °C, −78
d
°C, 6.5 h, −78 °C → −20 °C in 20 min, then quench. Diastereomer
mixture of F-isomers was obtained in the epimerization.
+ (S,R)-3a (dr = 2:98) to NaHMDS (entry 9) gave a product
mixture with dr = 10:90, comparable to the result in entry 1.
Similarly, upon exposure to NaHMDS, the (S,S)-3e + (S,R)-3e
mixture (dr = 4:96, obtained by epimerization with LHMDS)
reverted to a (S,S)-3e + (S,R)-3e mixture with dr = 15:85,
(compare entry 10 to entry 5).
To assess whether any loss of chirality occurred at the initial
stereogenic center upon fluorination, the four stereoisomers of
3a were isolated and shown to separate on Chiralpak IC-3 (see
the SI). Fluorination of (S)-2a afforded a crude mixture of
(S,S)-3a/(S,R)-3a that was purified by column chromatog-
raphy. Both diastereomers were collected together in order to
prevent any potential loss of enantiomers via self-disproportio-
nation.10 The HPLC trace did not show the presence of (R,R)-
3a. Similarly, (R,R)-3a was subjected to epimerization to (R,S)-
3a by NaHMDS, and HPLC analysis of the crude mixture did
not show presence of (S,R)-3a.
As the highest diastereoselectivity was achieved with
benzothiazole-derived sulfones 3a, we wanted to gain some
preliminary insight into potential further transformations.
Benzothiazole sulfones have been originally described as
protected sulfinate salts11 and have gained renewed attention
recently.12,13 Therefore, we subjected (S,S)- and (S,R)-3a to
reaction with NaBH4, and the crude sulfinate salts were
converted to diastereomerically pure sulfones (S,S)-4 and
(S,R)-4 (Scheme 3). No chirality erosion at the fluorine-bearing
stereogenic center was observed by 19F NMR, indicating the
potential use of the isomers of 3a as versatile, chirally defined,
Figure 2. Li carbanions: generated from (R)-2a, upper figures;
generated from (R,R)-3a and its epimer (R,S)-3a, lower figures. Li:
purple; N: blue; S: yellow; O: red; F: green.
The difference in stability of the two Li carbanions, I and II,
generated by proton abstraction from (R)-2a, is 19.3 kcal/mol,
whereas that for carbanion III generated by proton abstraction
from (R,R)-3a and IV generated from (R,S)-3a is 19.1 kcal/
mol. Models of more stable carbanions I and III show close
proximity of Li to the benzothiazole nitrogen atom, the
carbanion, and the carbonyl oxygen atom of the Boc group
(Figure 2). Intramolecular chelation of Li in carbanions α to a
sulfone functionality, containing a preexisting stereogenic
center, has previously been shown to result in diastereoselective
alkylations by favoring one mode of attack via a less-hindered
approach of the electrophile.14−17 In the present case, it is
plausible that the electrophile approach to the more stable
carbanion I, with lithium chelated by the benzothiazole
nitrogen atom and the Boc oxygen atom, is not favored from
the sterically congested, concave side, and attack occurs
C
DOI: 10.1021/acs.orglett.8b01358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
preferentially from a less-hindered side, anti to large
benzothiazole moiety and syn to sulfone oxygen atoms.18
This would explain the highly diastereoselective fluorination.
Isomerization of the newly formed fluorinated stereogenic
center in (R,R)-3a could plausibly be rationalized in a similar
manner. Capture of a proton by carbanion III generated from
(R,R)-3a (showing Li chelation to the benzothiazole nitrogen
and Boc oxygen atoms, Figure 2), from a less-hindered side,
would result in inversion at the fluorine-bearing stereogenic
center, to give (R,S)-3a.19
In summary, metalation−electrophilic fluorination α to a
sulfone moiety in chiral N-Boc-protected (R)- and (S)-2,2-
dimethyl-4-((arylsulfonyl)methyl)oxazolidines proceeded with
good to excellent diastereoselectivity. Diastereoselectivities
depend on the base used and on the aryl/heteroaryl moiety
and were best with LDA and benzothiazolyl-derived sulfones.
Previously unknown base-induced epimerization at the fluorine-
bearing stereogenic center α to a sulfone proceeded with good
to excellent diastereoselectivity and was the highest for
benzothiazolyl sulfones. This chemistry allows for stereo-
diversity in that from a single chiral precursor either of the two
fluorinated, enantiomerically pure diastereomers can be
synthesized. No chirality scrambling occurs at the original
stereocenter in the fluorination or epimerization steps. Utility
of these chiral, benzothiazole sulfone building blocks was
shown by their conversion to benzyl sulfones, via intermediate
sulfinate salts, without erosion of chirality at the fluorine-
bearing carbon atom. Diastereomeric benzyl sulfones were
further converted to N-Boc-protected amino acids. On the basis
of computational models of the carbanions derived from
benzothiazolyl sulfones, chelation of Li by benzothiazole N and
the Boc O atoms could plausibly account for the
diastereoselectivities observed in metalation−fluorination and
in the base-induced epimerization by approach of the
electrophile from a less-hindered side.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this work by NSF Grant No. CHE-1565754 and
PSC CUNY awards to B.Z. is gratefully acknowledged.
Infrastructural support at CCNY was provided by NIH Grant
No. G12MD007603 from the NIMHD. We thank Dr. Andrew
Poss (Honeywell) for a sample of NFSI and Dr. Michelle Neary
(The CUNY X-ray Facility, Hunter College) for X-ray analysis
of (S,S)-3a. We are grateful to the CUNY HPCC at the CSI
funded by NSF Grant Nos. CNS-0958379, CNS-0855217, and
ACI 1126113.
REFERENCES
■
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH
Verlag: Weinheim, 2004. (b) Laali, K. K., Ed. Modern Organofluorine
Chemistry−Synthetic Aspects; Bentham Science Publishers: San
́ ́
Francisco, 2006; Vol. 2. (c) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic
and Medicinal Chemistry of Fluorine; John Wiley & Sons, Inc.:
Hoboken, NJ, 2008. (d) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−
319. (e) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.
2013, 52, 8214−8264. (f) Gillis, E. P.; Eastman, K. J.; Hill, M. D.;
Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−8359.
(g) Thematic issue on organofluorine chemistry: Chem. Rev. 2015,
115, 563−1306.
(2) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1−PR43.
(b) Iwasaki, Y.; Shimizu, M.; Hirosawa, T.; Yamada, S. Tetrahedron
Lett. 1996, 37, 6753−6754.
(3) Zajc, B.; Kumar, R. Synthesis 2010, 2010, 1822−1836.
(4) Recent examples: (a) Kumar, R.; Pradhan, P.; Zajc, B. Chem.
Commun. 2011, 47, 3891−3893. (b) Mandal, S. K.; Ghosh, A. K.;
Kumar, R.; Zajc, B. Org. Biomol. Chem. 2012, 10, 3164−3167.
(c) Kumar, R.; Zajc, B. J. Org. Chem. 2012, 77, 8417−8427.
(d) Kumar, R.; Singh, G.; Todaro, L. J.; Yang, L.; Zajc, B. Org.
Biomol. Chem. 2015, 13, 1536−1549. (e) Banerjee, S.; Sinha, S.;
Pradhan, P.; Caruso, A.; Liebowitz, D.; Parrish, D.; Rossi, M.; Zajc, B.
J. Org. Chem. 2016, 81, 3983−3993.
ASSOCIATED CONTENT
■
(5) (a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60,
6711−6745. (b) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 2011,
3261−3278.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01358.
(6) (a) Dua, R. K.; Taylor, E. W.; Phillips, R. S. J. Am. Chem. Soc.
1993, 115, 1264−1270. (b) Drysdale, M. J.; Reinhard, J. F. Bioorg.
Med. Chem. Lett. 1998, 8, 133−138. (c) Becker, D. P.; DeCrescenzo,
G.; Freskos, J.; Getman, D. P.; Hockerman, S. L.; Li, M.; Mehta, P.;
Munie, G. E.; Swearingen, C. Bioorg. Med. Chem. Lett. 2001, 11, 2723−
2725. (d) Becker, D. P.; Barta, T. E.; Bedell, L.; DeCrescenzo, G.;
Freskos, J.; Getman, D. P.; Hockerman, S. L.; Li, M.; Mehta, P.;
Mischke, B.; Munie, G. E.; Swearingen, C.; Villamil, C. I. Bioorg. Med.
Chem. Lett. 2001, 11, 2719−2722.
1
Experimental details, compound data, and H and 13C
spectra (PDF)
Accession Codes
CCDC 1586437−1586440 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) (a) Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. I
2001, 2136−2157. (b) Passiniemi, M.; Koskinen, A. M. P. Beilstein J.
Org. Chem. 2013, 9, 2641−2659.
(8) De Jonghe, S.; Van Overmeire, I.; Van Calenbergh, S.; Hendrix,
C.; Busson, R.; De Keukeleire, D.; Herdewijn, P. Eur. J. Org. Chem.
2000, 2000, 3177−3183.
(9) Teare, H.; Huguet, F.; Tredwell, M.; Thibaudeau, S.; Luthra, S.;
Gouverneur, V. ARKIVOC 2007, No. x, 232−244.
(10) Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766−769.
(11) Ueno, Y.; Kojima, A.; Okawara, M. Chem. Lett. 1984, 13, 2125−
2128.
(12) Aziz, J.; Messaoudi, S.; Alami, M.; Hamze, A. Org. Biomol. Chem.
2014, 12, 9743−9759.
(13) (a) Prakash, G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A.
Angew. Chem., Int. Ed. 2011, 50, 2559−2563. (b) Zhou, Q.; Ruffoni,
A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S.
Angew. Chem., Int. Ed. 2013, 52, 3949−3952. (c) He, Z.; Tan, P.; Ni,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bzajc@ccny.cuny.edu.
ORCID
Lothar Stahl: 0000-0003-4482-9673
Barbara Zajc: 0000-0002-3885-0241
Author Contributions
¶W.W. and R.K.K. contributed equally to this work.
D
DOI: 10.1021/acs.orglett.8b01358
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C.; Hu, J. Org. Lett. 2015, 17, 1838−1841. (d) Day, J. J.; Neill, D. L.;
Xu, S.; Xian, M. Org. Lett. 2017, 19, 3819−3822.
(14) Dehmlow, E. V.; Pieper, S.; Neumann, B.; Stammler, H.-G.
Liebigs Ann./Recueil 1997, 1997, 1013−1018.
(15) Enders, D.; Muller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org.
̈
Chem. 2000, 2000, 879−892.
(16) Gais, H.-J. In Organosulfur Chemistry in Asymmetric Synthesis;
Toru, T., Bolm, C., Eds.; Wiley: Weinheim, 2008; pp 375−398.
(17) Hellmann, G.; Hack, A.; Thiemermann, E.; Luche, O.; Raabe,
G.; Gais, H.-J. Chem. - Eur. J. 2013, 19, 3869−3897.
(18) Approach of electrophile anti to a bulky substituent and syn to
sulfone oxygens in carbanions α to sulfone has been reported; see refs
16 and 17.
(19) Substitution reactions of organolithiums with electrophiles were
reported to proceed more commonly with retention of configuration;
however, inversion has been observed as well. (a) Clayden, J.
Stereoselective and Stereospecific Substitution Reactions of Organo-
lithiums. In Organolithiums: Selectivity for Synthesis; Baldwin, J. E.,
Williams, R. M., Eds.; Tetrahedron Organic Chemistry Series; Elsevier
Science Ltd.: Oxford, UK, 2002; Vol. 23, pp 241−271. (b) Gawley, R.
E. Tetrahedron Lett. 1999, 40, 4297−4300.
E
DOI: 10.1021/acs.orglett.8b01358
Org. Lett. XXXX, XXX, XXX−XXX