1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes - a2d 1 synthons via tandem umpolung

Article abstract of DOI:10.1021/jo900347s

(Equation Presented) 1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-alkenes have been developed as an a²d¹ synthon via tandem umpolung. Upon addition of Grignard reagents and further quench by carbonyl compounds, this synthon produces α,α′-

Full text of DOI:10.1021/jo900347s

1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-1-alkenessa2d1 Synthons
via Tandem Umpolung
Yue-Lei Chen*,† and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstraꢀe 40, 48149 Mu¨nster, Germany
chenx506@umn.edu; dhoppe@uni-muenster.de
ReceiVed February 16, 2009
1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-alkenes have been developed as an a2d1 synthon via tandem
umpolung. Upon addition of Grignard reagents and further quench by carbonyl compounds, this synthon
produces R,R′-branched-R′-oxygenated ketones. Strategically, this widely applicable method installs
respectively a carbanion unit and a carbonyl unit formally onto the R-carbon and the carbonyl center of
an aldehyde in one-pot.
1. Introduction
for solving the first problem. Analogously, an umpolung of the
d2 synthon to an a2 synthon on carbonyl structures might be a
potential solution for the second problem. To the best of our
knowledge, this strategy has not been clearly proposed.4
Herein, we would like to present our discovery of a readily
prepared 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkene struc-
ture (1, OR ) N,N-diisopropylcarbamoyloxy (OCb), SO2R1 )
tosyl), which serves as an a2d1 synthon5 via a tandem umpolung.
By this, we wish to extend the solution for the above-mentioned
first problem, and in particular, to address the second problem
A major body of synthetic organic chemistry employs
carbonyl compounds with their inherent reactivity as a1 and d2
synthon (for example when the R-position of a carbonyl
compound is capable of deprotonation) to construct complex
structures.1 However, several problems have long been recog-
nized: some complex structures can not be readily achieved by
applying the a1 synthon directly; synthesis utilizing the d2
synthon is frequently affected by side reactions such as self-
condensation. The umpolung of an a1 synthon to a d1 synthon
by the early stoichiometric dithiane chemistry2 and the recent
catalytic NHC chemistry3 can be considered as breakthrough
(3) (a) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed.
2007, 46, 2988–3000. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV.
2007, 107, 5606–5655.
† Current address: Center for Drug Design, Academic Health Center,
University of Minnesota, 8-125 Weaver Densford Hall, 308 Harvard St. SE,
Minneapolis, MN 55455.
(1) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; WILEY-
VCH: New York, 1995.
(2) (a) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–258. (b) Gro¨bel,
B. T.; Seebach, D. Synthesis 1977, 357–402. (c) Umpoled Synthons. A SurVey
of Sources and Uses in Synthesis; Hase, T. A., Ed.; John Wiley & Sons: New
York, 1987. For some recent applications of dithiane chemistry in organic
synthesis, see: (d) Chen, Y.-L.; Leguijt, R.; Redlich, H. J. Carbohydr. Chem.
2007, 26, 279–303. (e) Chen, Y.-L.; Leguijt, R.; Redlich, H.; Fro¨hlich, R.
Synthesis 2006, 4212–4218. (f) Chen, Y.-L.; Leguijt, R.; Redlich, H. Synthesis
2006, 2242–2250. (g) Chen, Y.-L.; Redlich, H.; Bergander, K.; Fro¨hlich, R. Org.
Biomol. Chem. 2007, 5, 3330–3339.
(4) Some formal substitutions of R-halogenated esters by carbanion sources
were reported: a formal substitution of R-halogenated esters by addition and
rearrangement of Grignard reagent: (a) Hussey, A. S.; Herr, R. R. J. Org. Chem.
1959, 24, 843–845. Using organocadmium reagents for substitution of R-bro-
moesters: (b) Jones, P. R.; Young, J. R. J. Org. Chem. 1968, 33, 1675–1676. (c)
Amano, T.; Yoshikawa, K.; Sano, T.; Ohuchi, Y.; Shiono, M.; Ishiguro, M.;
Fujita, Y. Synth. Commun. 1986, 16, 499–507. Using boron reagents for
substitution of R-bromoesters: (d) Cai, J.; Nemoto, H.; Singaram, B.; Yamamoto,
Y. Tetrahedron Lett. 1996, 37, 3383–3386. Co catalyzed coupling reactions
between Grignard reagents and R-bromoesters: (e) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886–1889. Fe catalyzed coupling
reactions between Grignard reagents and R-bromoesters: (f) Fu¨rstner, A.; Martin,
R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc.
2008, 130, 8773–8787.
4188 J. Org. Chem. 2009, 74, 4188–4194
10.1021/jo900347s CCC: $40.75 2009 American Chemical Society
Published on Web 05/04/2009

a2d1 Synthons Via Tandem Umpolung
withdrawing substituent (sulfonyl group) are rare.10 We believe
that to achieve the success on the catalytic anionic addition to
such substrates, a good electronic balance among the OR group,
the sulfonyl group and the R4M reagent is essential. In the course
of our research, we have discovered that copper-catalyzed
addition of Grignard reagents onto tosylated enol carbamate
derivatives (1, R ) Cb, R1 ) p-tolyl) is a general and high
yielding method for the desired first addition.
SCHEME 1. Proposed One-Pot Tandem Umpolung Leads
to an a2d1 Synthon
To establish a general method, we have synthesized a series
of compounds of structure 1 by varying the sulfone group, and
tested addition of different R4M reagents with several transition
metal catalysts. The OR substitution on structure 1 was chosen
as OCb11 for the reason that they are stable toward various
organometallic reagents, enable good chelation with metal
cations which may facilitate the desired addition, and are readily
removed.
from the aspect of umpolung. As illustrated in Scheme 1, the
C-1 position on structure 1 is regarded as a masked carbonyl
group. When the structure 1 is subjected into transition metal
catalyzed addition reactions, carbanion R4 could be transferred
to the a2 position, which results in a tandem umpolung and
generates a d1 synthon 2. Structure 2 can be further coupled
with another carbonyl center, revealing the masked carbonyl
center (structure 3) after migration of the carbamoyl group and
elimination of the sulfonyl group based on the early findings in
our group.6 Strategically, 1-(N,N-diisopropylcarbamoyloxy)-1-
tosyl-1-alkene 1 serves as an a2d1 synthon via a tandem
umpolung, which, in a highly economic7 fashion (four steps in
one pot), formally installs a carbanion unit and a carbonyl unit
respectively onto the R-carbon and the carbonyl center of an
aldehyde (Scheme 1).
During the further investigation of the first addition in Scheme
1, we have found: (1) The desired addition is promoted by
various Cu(I) or Cu(II) salts with organolithium and Grignard
reagents. Ni(II) leads to a direct substitution of the sulfonyl
group.12 (2) The readily available Grignard reagents as the R4M
reagent gave the best result. They are mild enough to avoid
significant double-bond migration when an allylic proton is
present on the R2 or R3 group, and are compatible with many
functional groups. Organolithium reagents can be used for the
addition reaction,13 but their strong basicity induces frequently
the double bond migration in the presence of the allylic proton,
and tolerates fewer functional groups. Meanwhile, the very mild
and readily prepared organozinc compounds were too unreactive
for the conjugate addition.14 (3) Substituent R1 on structure 1
is preferably p-Tol. When 2-pyridyl or n-C4F9 was used, the
first addition intermediate 2, independent from the metal applied,
is prone to remove the sulfonyl group in situ. (4) Additives such
as TMSCl, BF3 ·Et2O or HMPA failed to accelarate the addition
as they usually do in the Michael type addition.15 Therefore,
the primary focus is on copper-catalyzed Grignard additions of
1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-alkenes.
2. Results and Disscussion
We explored this strategy in two steps: (1) the first addition,
in which intermediate 2 is quenched by hydrolysis and (2) the
in situ second addition/migration/elimination, which completes
the tandem umpolung and reveals the masked carbonyl structure,
leading to structure 3 in one pot.
2.1. Establish the Conditions for the First Addition. The
first addition in Scheme 1 describes the addition of an
organometallic reagent to 1-oxygenated-1-sulfonyl alkenes,
which is strategically new and demanding. It is common to
perform transition metal catalyzed nonanionic addition reactions
(such as hydrogenation8 or aryl transfer9) to inactivated CdC
double bond or CdC double bond with geminal electron-
donating substituent and electron-withdrawing substituent (the
contradictorily operating substituents lead to practically less
activated alkenes). On the contrary, after surveying the liturature,
we noticed that, although it could be very important for organic
synthesis, catalytic anionic addition reactions on CdC bond with
geminal electron-donating substituent (OR group) and electron-
As demonstrated in Scheme 2, enol carbamates 4a-c were
used to prepare the sulfones 5a-d as the a2d1 synthon.
Compound 4a was readily prepared by elimination of HCl from
2-chloroethyl carbamate.6e Compound 4b was prepared by
double bond migration of allylic alcohol carbamate with high
(10) Some conjugate addition of stoichiometrical lithium organocuprate to
R-oxygenated-R,ꢀ-unsatured carbonyl compounds are known: (a) Brehm, M.;
Go¨ckel, V. H; Jarglis, P.; Lichtenthaler, F. W. Tetrahedron: Asymmetry 2008,
19, 358–373. (b) Verdaguer, X.; Vázquez, J.; Fuster, G.; Bernardes-Génisson,
V.; Greene, A. E.; Moyano, A.; Pericás, M. A.; Riera, A. J. Org. Chem. 1998,
63, 7037–7052. (c) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T.
J. Am. Chem. Soc. 1990, 112, 3466–3474. (d) Luengo, J. I.; Koreeda, M. J.
Org. Chem. 1989, 54, 5415–5417. Several copper-catalyzed conjugate addition
reactions to R-oxygenated-R,ꢀ-unsatured carbonyl compounds are known for
certain substrates: (e) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Can.
J. Chem. 1992, 70, 2325–2328. (f) Lander, P. A.; Hegedus, L. S. J. Am. Chem.
Soc. 1994, 116, 8126–8132. (g) Cardillo, G.; Gentilucci, L.; Tolomelli, A.;
Tomasini, C. Tetrahedron 1999, 55, 6231–6242.
(11) According to unpublished results in our group, substituent R on structure
1 can be either Cb or 2,2,4,4-tetramethyl-1,3-oxazolidin-3-carbonyl (Cby).
Generally Cb leads to slightly higher yield for the addition reaction leading to
structure 2.
(12) Ni or Pd catalyzed substitution and reduction of R,ꢀ-unsaturated
sulfone: (a) Fabre, J.-L.; Julia, M. Tetrahedron Lett. 1983, 24, 4311–4314. Ni
catalyzed substitution of R,ꢀ-unsaturated sulfone was reported: (b) Fabre, J. L.;
Julia, M.; Verpeaux, J.-N. Bull. Soc. Chim. Fr 1985, 5, 762–771.
(13) Unpublished results in this group.
(5) Intentions of using ketene dithioacetals as a2d1 synthons were described: (a)
Mikolajczyk, M.; Grzejszczak, S.; Zatorski, A.; Mlotkowska, B.; Gross, H.;
Costisella, B. Tetrahedron 1978, 34, 3081–3088. (b) Thuillier, A. Phosphorus
Sulfur 1985, 23, 253–276.
(6) (a) Reggelin, M.; Tebben, P.; Hoppe, D. Tetrahedron Lett. 1989, 30,
2915–2918. (b) Tebben, P.; Reggelin, M.; Hoppe, D. Tetrahedron Lett. 1989,
30, 2919–2922. (c) Hoppe, D.; Tebben, P.; Reggelin, M.; Bolte, M. Synthesis
1997, 183–190. (d) Zimmermann, M.; Wibbeling, B.; Hoppe, D. Synthesis 2004,
765–774. (e) Siemer, M.; Fro¨hlich, R.; Hoppe, D. Synthesis 2008, 2264–2270.
(7) A recent example demonstrating the efficiency of one-pot reaction for
synthesis of (-)-oseltamivir: Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem.,
Int. Ed. 2009, 48, 1304–1307.
(8) See for example: Brown, J. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds; Springer: Berlin, 1999; Vol. 1,
Chapter 5.1
(9) See for example: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103,
2829–2844. (b) Navarre, L.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2004,
69–73.
(14) For review, see: Alexakis, A.; Ba¨ckvall, J. E; Krause, N.; Pa`mies, O.;
Die´guez, M. Chem. ReV 2008, 108, 2796–2823.
(15) Lipschutz, B. H. In Organometallics in Synthesis - A Manual, 2nd ed.;
Schlosser, M., Ed.; John Wiley & Sons Inc: New York, 2002; pp 666-815.
J. Org. Chem. Vol. 74, No. 11, 2009 4189

Chen and Hoppe
SCHEME 2. Syntheses of the Sulfone Substrates 5a-d
SCHEME 3. General Procedure for the First Addition
prolonged reaction time at higher temperature, further substitu-
tions of the Ts12 and the OCb19 group were observed (Scheme
4, next two reactions).
The above examples have demonstrated a general and efficient
method for the copper-catalyzed addition of Grignard reagents
to 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes (5a-d).
As a new method for catalytic anionic addition to less activated
alkenes, it allows one to perform deprotecting manipulations
on the products 6a-l as well as an in situ second addition/
migration/elimination sequence to complete the tandem umpolung.
2.2. Synthetic Application of the First Addition Products.
Products of the first addition can serve as useful synthetic
intermediates. The OCb and the Ts substitution allow many
potential functional group conversions. We briefly demonstrate
here that the OCb protection and the sulfonyl group on
compounds 6j-l can be removed reductively in one pot to
efficiently offer R-branched alcohols 11a-c (Scheme 5).
Compared to common preparations of those R-branched alcohols
by hydrolysis of alkenes or ring-opening of epoxides, this
method circumvents the regioselectivity problem.
Z-selectivity.16 Compound 4c was produced as an E/Z mixture
via condensation between phenylacetaldehyde and CbCl. The
starting materials 5a-d for the first addition were readily
prepared by lithiation with s-BuLi and condensation with TsF
from compounds 4a-c.17 In the conversion from compound
4b to 5b, no significant E/Z change was observed; while
condensation of the E/Z-4c with TsF yielded double bond
isomers 5c and 5d which are readily separated by silica gel
chromatography. In all the cases, it is essential to add the
lithiated enol carbamates into TsF solution to avoid the conjugate
addition of the lithiated enol carbamates onto the tosylated
products. In general, the wide availability of compounds 4a-c
as well as the reliable lithiation-condensation methods contribute
to a broadly applicable strategy.
2.3. Establish the Conditions for the Second Addition/
Migration/Elimination. Armed with the knowledge from the
first addition, one can proceed to the second addition/migration/
elimination to complete the tandem umpolung by quenching
the magnesiated intermediate 2 with aldehydes or ketones.
After a few initial experiments, it was found that the
magnesiated sulfone intermediate 2 reacts with chloroformates,
aldehydes and simple ketones, but does not react with MeI,
TMSCl, and hindered ketones.13 This indicates a relatively hard
nature20 of the metalated sulfone and its sensitivity toward steric
hindrance.
Further investigation indicated the magnesiated sulfone
intermediate 2 to be a mild base which suffers no significant
R-deprotonation of carbonyl compounds, compared to its
lithiated analogous. This advantage enables many carbonyl
compounds to be applied in the new method, but several
problems were recognized: (1) Upon quenching with aldehydes
or ketones, magnesiated intermediate 2 is less reactive than its
lithiated analogues. Longer reaction time and higher temperature
for improving the yield caused further decomposition of
unreacted intermediate 2. (2) The dsired elimination of the Ts
substituent may not be complete due to many reasons such as
conformations, additives and temperature. (3) As the most
critical factor for tandem reaction, the reaction condition for
the second addition/migration/elimination must be compatible
Virtually all common Grignard reagents gave moderate to
excellent yields for the copper-catalyzed first addition to
substrates 5a-d (Scheme 3 and Table 1). The results with alkyl,
alkenyl, allylic, and aryl Grignad reagents are demonstrated in
Table 1. Less reactive Grignard reagents such as vinylmagne-
sium bromide (Table 1, entries 1 and 8) or less reactive sulfone
substrates such as 5b (Table 1, entries 5 and 7) required higher
temperature or prolonged reaction times. Allylmagnesium
bromide (Table 1, entries 2, 6 and 12) demonstrated high
reactivity and completed the reaction at low temperature or in
short reaction times. Also, the E/Z configuration of the sulfone
substrates has little effect on the yield (Table 1, entries 10-15).
Diethyl ether was found a widely applicable solvent for this
reaction. Generally, the reaction temperature needs to be below
-20 °C to avoid decomposition of intermediate 2. The diaste-
reoselectivity of this reaction is sensitive to the reaction
conditions and is of interest for further investigation.18
During investigation of the first addition, several major side
products were also identified. For less reactive sulfone substrates
such as 5b, the OCb group is prone to reductive cleavage when
an R-proton in the Grignard reagent is present (Scheme 4, the
first reaction). With highly reactive Grignard reagents, or
(16) Hoppe, D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg, F.; van Huelsen, E.
Chem. Ber. 1985, 118, 2822–2851.
(17) For the lithiation of the enol carbamates 4a, b and c, see: (a) Sengupta,
S.; Snieckus, V. J. Org. Chem. 1990, 55, 5680–5683. (b) Peschke, B. Dissertation,
University of Kiel, 1991. (c) Kocienski, P.; Dixon, N. J. Synlett 1989, 52–54.
(d) Kocienski, P.; Barbar, C. Pure Appl. Chem. 1990, 62, 1933–1942.
(18) For discussion of lithiated sulfones and their H/D exchange experiments,
see: Boche, G. Angew. Chem., Int. Ed. 1989, 28, 277–297.
(19) For Ni catalyzed substitution of enol carbamate by Grignard reagent:
see ref 17c.
(20) Chemical Hardness - Applications From Molecules to Solids; Pearson,
R. G., Ed.; Wiley-VCH: Weinheim, 1997.
4190 J. Org. Chem. Vol. 74, No. 11, 2009

a2d1 Synthons Via Tandem Umpolung
TABLE 1. Examples for the First Additiona
entry
starting material/product
R1/R2
Grignard reagent (equiv. to carbamate)
T (°C)/reaction time
yield (%)/drd
1b
5a/6a
5a/6b
5a/6c
5a/6d
5b/6e
5b/6f
5b/6g
5b/6h
5b/6i
5c/6j
5c/6k
5c/6L
5d/6j
5d/6k
5d/6l
H/H
H/H
H/H
H/H
Vinyl-MgBr (1.4)
Allyl-MgBr (1.4)
i-PrMgBr (1.4)
p-Methoxyphenyl-MgBr (1.4)
n-BuMgBr (2)
Allyl-MgBr (2)
PhMgBr (3)
Vinyl-MgBr (2)
1-Methylvinyl-MgBr (2)
p-Methoxyphenyl-MgBr (3)
1-Methylvinyl-MgBr (2)
Allyl-MgBr (1.2)
p-Methoxyphenyl-MgBr (3)
1-Methylvinyl-MgBr (2)
Allyl-MgBr (1.2)
-20 to -25/8 h
-78/15 min
87/-
2b
89/-
3b
-25 to -30/2 h
-25 to -30/2 h
-30 to -35/16 h
-25 to -30/1 h
-30 to -35/16 h
-20 to -25/8 h
-30 to -35/8 h
-30 to -35/16 h
-40 to -45/16 h
-40 to -45/0.5 h
-30 to -35/16 h
-40 to -45/16 h
-40 to -45/0.5 h
79/-
93/-
4b
5c
Me/H
Me/H
Me/H
Me/H
Me/H
Ph/H
Ph/H
Ph/H
H/Ph
H/Ph
H/Ph
55/0.83
57/0.85
47/0.82
71/n.a.
88/0.40
70/0.50
84/0.42
95/1.0
78/0.50
92/2.5
84/0.95
6c
7b
8b
9b
10b
11b
12b
13b
14b
15b
a General procedure: copper source was reacted with Grignard reagent at the indicated reaction temperature, and then a solution of the sulfone 5a-d
in toluene was added. The mixture was stirred at the indicated temperature for the specified time, and was quenched by addition of saturated aqueous
NH4Cl solution. b Using 15% equiv. Cu(OTf)2 as copper source. c Using 15% equiv. CuBr ·Me2S as copper source. d dr was measured by GC.
Stereochemistry of the diastereomeric products 6a-l was not determined.
SCHEME 4. Side Reactions of the First Addition
second addition/migration/elimination (Table 2, entries 1-3),
while sterically hindered pivaldehyde gave moderate yields
(Table 2, entry 7). Using (S)-2-(t-butyldimethylsilyloxy)propa-
nal21 and 2,3-O-isopropylidene-D-glyceraldehyde22 as the quench-
ing reagents gave readily separated enantio-enriched diastere-
oisomers 12 h-k (Table 2, entries 8 and 9). Entry 10 demonstrated
the mild magnesiated sulfone 2 (compared to its lithiated
analogues) and the mild second addition/migration/elimination
condition can be used to produce ꢀ,γ-unsaturated ketones, which
are highly susceptible to double bond migration. More interest-
ingly, entry 11 showed that acetone, with its low reactivity and
six acidic protons, can be used as the quenching reagent. With
the aid of LiBr at the specified temperature and reaction time,
intermediate 2 was able to give a moderate yield of the desired
product 12m. Further deprotection and functional group ma-
nipulations on analogues of 12a-m can be achieved using the
methods developed in our group.6c
SCHEME 5. Preparation of r-Branched Alcohols from the
First Addition Products
As indicated by the above experiments, a general and efficient
procedure has been developed for the second addition/migration/
elimination to complete the desired tandem umpolung on the
a2d1 synthon. Combined with certain additives, the mild
magnesiated sulfone 2 allows various aldehydes and acetone
to be applied in this procedure to generate R, R′-branched-R′-
oxygenated ketones as useful building blocks in moderate to
excellent yields.
SCHEME 6. General Procedure for Utilizing the a2d1
Synthon by the Second Addition/Migration/Elimination
3. Conclusions
In summary, a series of readily prepared 1-(N,N-diisopropyl-
carbamoyloxy)-1-tosyl-1-alkenes was developed as substrates
for copper-catalyzed addition by Grignard reagents. The result-
ing magnesiated sulfones from this first addition can be
hydrolyzed and produce useful synthetic intermediates. More
importantly, the magnesiated sulfone intermediates can be
directly quenched by carbonyl compounds to yield R-branched-
R′-oxygenated ketones. Most types of Grignard reagents as well
as most typical aldehydes can be applied to this tandem reaction
and give moderate to good yields. From the retrosynthetic point
of view, 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes,
upon the first Grignard reagent addition and second carbonyl
with the condition of the first addition. Therefore, the reaction
requires a careful selection of temperatures, reaction time, and
additives.
We found that a procedure of 8 h at -50 to -55 °C for the
second addition, warming to rt slowly, and then 1 h at rt for
completing the migration and elimination, is optimal. Also,
additives are necessary: tetraisopropoxytitanium (TIPT) gener-
ally leads to higher yields, while LiBr significantly decreases
the R-deprotonation of the carbonyl compounds. Following those
conditions, different carbonyl compounds, including aliphatic
aldehydes, aryl aldehydes and acetone can be applied to the
second addition/migration/elimination sequence to give moderate
to excellent yields.
(21) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.; Chobanian,
H. R. Org. Synth. 2005, 81, 157–170.
(22) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6–13.
As demonstrated in Scheme 6 and Table 2, benzaldehyde and
substituted benzaldehydes gave excellent yields of the desired
J. Org. Chem. Vol. 74, No. 11, 2009 4191

Chen and Hoppe
TABLE 2. Examples for Utilizing the a2d1 Synthon by the Second Addition/Migration/Elimination with Different Carbonyl Compounds As
the Quenching Reagentsa
a General procedure: following the general procedure illustrated in Scheme 3 and Scheme 6, upon the end of the first addition, the reaction mixture
was not quenched, but cooled to -50 to -55 °C, and to which additive and the carbonyl compound were added. After being stirred for 8 h, the mixture
was warmed to rt and then quenched by addition of saturated aqueous NH4Cl solution. b With TIPT as an additive. c With LiBr as an additive.
d Stereochemistry of the products was not determined.
Hz, 6H, Cb); 13C NMR (CDCl3, 100 MHz) δ 149.4 (CdO), 145.8
(Ts), 144.6 (Ts(OCb)Cd), 135.1 (Ts), 129.5 (2 C, Ts), 128.9 (2 C,
Ts), 126.3 (CHd), 47.0 (Cb), 46.7 (Cb), 21.6 (Ts), 21.1 (2 C, Cb),
21.0 (2 C, Cb), 11.9 (dCH-CH3); FTIR (CHCl3 cast film
microscope) ν 3065 (m), 2972 (s), 2935 (m), 2878 (m), 1732 (s),
1666 (m), 1597 (m), 1437 (s), 1319 (s), 1280 (s), 1127 (s), 670
(s); HRMS (ESI+) calcd for C17H25NO4SNa+ 362.1397, found
362.1408; Anal. Calcd for C17H25NO4S (339.45) C 60.15, H 7.42,
N 4.14, found C 60.10, H 7.34, N 4.08.
General Procedure for the Copper-Catalyzed Addition of
Grignard Reagents to Sulfone Substrates 5a-d. Copper source
(15 mol%, taken directly from the commercially available materials,
dried under vacuum in situ at rt) and diethyl ether (5 mL, dried
over sodium) was added into a predried Schlenk tube, and cooled
to the described reaction temperature. Grignard reagent (in diethyl
ether or THF, normally as a 0.5-3 M solution) was added dropwise
to the above mixture. The suspension was stirred at this temperature
for 10 min followed by addition of the substrate (normally as a
0.2-0.3 M solution in toluene). The resulting mixture was then
stirred for the described time at the described temperature. For
quenching the reaction, a solution of formic acid in MeOH was
added at the reaction temperature followed by addition of sat. aq.
NH4Cl. The organic phase was then separated and the water phase
was washed several times with diethyl ether. Combined organic
layers were passed through a silica gel pad and evaporated to
dryness. The residue was purified by MPLC (with a standard
program: n-pentane: diethyl ether ) 30:1 to 20:1 to 10:1 to 5:1 to
2:1 to 1:1) to yield the products 6a-l.
compounds addition/migration/elimination, serve as a new a2d1
synthon via an unprecedented tandem umpolung and installs
respectively a carbanion unit and a carbonyl unit formally onto
the R-carbon and the carbonyl center of an aldehyde.
4. Experimental Section
General Procedure for the Preparation of Substrates
5a-d. s-BuLi (40 mL, 1.22 M in n-hexane, 48.8 mmol, 1.2 equiv)
was added dropwise to a solution of TMEDA (7.3 mL, 5.6 g, 48.8
mmol, 1.2 equiv) in 150 mL of diethyl ether at -78 °C. To the
above solution, carbamate substrate (4a-c, neat, 40.5 mmol, 1
equiv) was added dropwise. The resulting light-yellow mixture was
then stirred at -78 °C for 4 h and transferred by a cannular in a
dropwise manner into a solution of TsF (9.0 g, 51.7 mmol, 1.3
equiv) in 100 mL of diethyl ether at -78 °C. After the transfer
being finished, stirring of the resulting mixture was continued for
another hour at -78 °C. The reaction was quenched by addition of
2 N aq. HCl and the water phase was extracted several times by
diethyl ether. Combined organic layers were washed with 2 N HCl,
sat. aq. NaHCO3 and brine in turn and evaporated to dryness. The
residue was purified by MPLC to yield sulfone 5a-d.
(E)-1-Tosylprop-1-enyl N,N-Diisopropylcarbamate (5b). From
compound 4b6e (7.5 g, 40.5 mmol), product 5b (10.7 g, 31.5 mmol,
78%) was produced as a light-yellow oil. Compound 5b was readily
crystallized from diethyl ether to produce a white crystalline solid.
Rf 0.35 (ethyl acetate: cyclohexane, 1/2); mp 100-101 °C (diethyl
ether); tR 20.1 min (HP-5); NMR data were resolved with the aid
1
1
1
of H-1H COSY, H-13C HMQC, and H-13C HMBC methods;
1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J ) 8.2 Hz, 2H, Ts), 7.29
(m, 2H, Ts), 6.84 (q, J ) 7.1 Hz, 1H, CHd), 4.03-3.96 (m, 1H,
Cb), 3.71-3.65 (m, 1H, Cb), 2.41 (s, 3H, Ts), 1.72 (d, J ) 7.2 Hz,
3H, dCH-CH3), 1.21 (d, J ) 6.8 Hz, 6H, Cb), 1.09 (d, J ) 6.8
3-Methyl-1-tosylbutyl N,N-Diisopropylcarbamate (6c). From
compound 5a (200 mg, 0.62 mmol), compound 6c (179 mg, 0.48
mmol, 79%) was produced as a colorless oil. Rf 0.46 (ethyl acetate:
cyclohexane, 1/2); tR 20.3 min (HP-5); NMR data were resolved
with the aid of 1H-1H COSY, 1H-13C HMQC, and 1H-13C HMBC
4192 J. Org. Chem. Vol. 74, No. 11, 2009

a2d1 Synthons Via Tandem Umpolung
methods; 1H NMR (CDCl3, 400 MHz) δ 7.72 (d, J ) 8.3 Hz, 2H,
Ts), 7.24 (d, J ) 7.9 Hz, 2H, Ts), 5.89 (dd, J ) 3.8 Hz, 9.7 Hz,
1H, CH-Ts), 3.94-3.88 (m, 1H, Cb), 3.51-3.44 (m, 1H, Cb), 2.35
(s, 3H, Ts), 1.96-1.84 (m, 2H, CH2), 1.71-1.60 (m, 1H, CH),
1.08 (d, J ) 6.9 Hz, 3H, Cb), 1.06 (d, J ) 6.9 Hz, 3H, Cb), 1.01
(d, J ) 6.8 Hz, 3H, Cb), 0.91 (d, J ) 6.7 Hz, 3H, CH3), 0.87 (d,
J ) 6.8 Hz, 3H, Cb), 0.87 (d, J ) 6.7 Hz, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) δ 151.6 (CdO), 145.0 (Ts), 133.5 (Ts), 129.6
(2 C, Ts), 129.5 (2 C, Ts), 84.5 (Ts), 46.3 (Cb), 46.1 (Cb), 34.9
(CH2), 24.7 (CH), 23.1 (CH3), 21.6 (Ts), 21.5 (CH3), 21.3 (Cb),
20.9 (Cb), 20.1 (Cb), 19.9 (Cb); FTIR (CHCl3 cast film microscope)
ν 2965 (s), 2937 (m), 2898 (m), 2874 (m), 1711 (s), 1598 (m),
1433 (s), 1323 (s), 1283 (s), 1154 (s), 1138 (s), 1078 (s), 1042 (s),
660 (s), 580 (s); HRMS (ESI+) calcd for C19H31NO4SNa+
392.1866, found 392.1870; Anal. Calcd for C19H31NO4S (369.52)
C 61.76, H 8.46, N 3.79, found C 61.44, H 8.48, N 3.63.
C, Ts), 127.4 (Ph), 127.3 (Ph), 127.2 (Ph), 126.4 (Ph), 125.9 (Ph),
113.6 (CH2d), 83.6 (Ts(OCb)CH), 51.5 (Ph(isopropenyl)CH), 45.4
(Cb), 44.4 (Cb), 20.6 (Ts), 19.3 (Cb), 19.2 (CH3), 19.0 (Cb), 18.9
1
(Cb), 18.8 (Cb); NMR of minor isomer: H NMR (CDCl3, 400
MHz) δ 7.46 (d, J ) 8.3 Hz, 2 H, Ts), 7.08 (d, J ) 8.1 Hz, 2 H,
Ts), 7.19-7.13 (m, 5 H, Ph), 6.39 (d, J ) 10.7 Hz, 1 H,
Ts(OCb)CH), 4.91(s, 1 H, CH2d), 4.75 (s, 1 H, CH2d), 4.12 (d, J
) 10.7 Hz, 1 H, Ph(isopropenyl)CH), 4.03-3.93 (m, 1 H, Cb),
3.58-3.51 (m, 1 H, Cb), 2.29 (s, 3 H, Ts), 1.57 (s, 3 H, CH3), 0.95
(d, J ) 6.8 Hz, 3 H, Cb), 1.10-1.06 (m, 9 H, Cb-CH3); 13C NMR
(CDCl3, 100 MHz) δ 150.8 (CdO), 143.3 (Ts), 142.7 (Me-Cd),
136.0 (Ph), 133.9 (Ts), 128.3 (2 C, Ts), 128.0 (2 C, Ts), 127.4
(Ph), 127.3 (Ph), 127.2 (Ph), 126.4 (Ph), 125.9 (Ph), 111.7 (CH2d),
85.2 (Ts(OCb)CH), 51.5 (Ph(isopropenyl)CH), 45.5 (Cb), 45.1 (Cb),
20.5 (Ts), 20.1 (Cb), 19.9 (CH3), 19.8 (Cb), 19.2 (Cb), 19.1 (Cb);
FTIR (CHCl3 cast film microscope) ν 3073 (m), 3030 (m), 2970
(s), 2933 (m), 2878 (m), 1740 (s), 1716 (s), 1649 (m), 1598 (m),
1434 (s), 1371 (s), 1324 (s), 1155 (s), 1097 (m), 1062 (m), 1041
(m), 895 (m), 755 (s), 703 (m), 667 (m); HRMS (ESI+) calcd for
C25H33NO4SNa+ 466.2023, found 466.2017; Anal. Calcd for
C25H33NO4S (443.60) C 67.69, H 7.50, N 3.16, found C 67.47, H
7.62, N 3.11.
General Procedure for One-Pot Reduction of Compounds
6j-l. DIBAL-H (6 mL, 1 M in hexane, 20 equiv.) was added
dropwise into a solution of starting material 6j, 6k or 6l (0.30
mmol) in THF (4 mL) at rt. The mixture was then heated at 80 °C
in a sealed Schlenk tube for 8 h (with interval release of internal
pressure). Afterward sat. aq. potassium sodium tartrate (Rochelle
salt) was added and the mixture was vigorously stirred for 0.5 h.
The organic phase was separated and the water phase was extracted
by diethyl ether several times. Combined organic phases were
evaporated (bath temperature and pressure should be regulated to
avoid loss of product) and the residue was purified by MPLC (with
a standard program: n-pentane: diethyl ether ) 10:1 to 5:1 to 2:1
to 1:1 to 1:2) to yield the products 11a-c.
2,3-Dimethyl-1-tosylbut-3-enyl N,N-Diisopropylcarbamate
(6i). From compound 5b (200 mg, 0.59 mmol), compound 6i (198
mg, 0.52 mmol, 88%) was obtained as a colorless oil. Major isomer:
minor isomer ) 1: 0.4; Rf 0.50 (ethyl acetate: cyclohexane, 1/2);
tR 20.8 min (minor diastereomer), 20.9 min (major diastereomer)
(HP-5); NMR data were recorded from compound 6i as a diaster-
eomeric mixture and resolved below separately, with the aid of
1H-1H COSY, 1H-13C HMQC, and 1H-13C HMBC methods;
NMR of major isomer: 1H NMR (CDCl3, 400 MHz) δ 7.72-7.69
(m, 2H, Ts), 7.23-7.20 (m, 2H, Ts), 5.73 (d, J ) 9.7 Hz, 1H,
Ts(OCb)CH), 4.75 (s, 1H, CH2d), 4.70 (s, 1H, CH2d), 4.04-3.96
(m, 1H, Cb), 3.25-3.18 (m, 1H, Cb), 3.09-3.03 (m, 1H, Me(iso-
propenyl)CH), 2.32 (s, 3H, Ts), 1.58 (s, 3H, )C-CH3), 1.33 (d, J
) 6.9 Hz, 3H, CH3), 1.00 (d, J ) 6.6 Hz, 3H, Cb), 0.94 (d, J )
6.8 Hz, 6H, Cb), 0.76 (d, J ) 6.8 Hz, 3H, Cb); 13C NMR (CDCl3,
100 MHz) δ 150.7 (CdO), 144.8 (Me-Cd), 144.7 (Ts), 134.5
(Ts), 129.54 (Ts), 129.49 (Ts), 129.33 (Ts), 129.31 (Ts), 113.5
(CH2d), 86.7 (Ts(OCb)CH), 46.7 (Cb), 45.2 (Cb), 41.2 (Me(iso-
propenyl)CH), 21.5 (Ts), 20.4 (Cb), 20.2 (Cb), 20.0 (Cb), 19.8 (Cb),
1
18.4 (dC-CH3), 16.5 (CH3); NMR of minor isomer: H NMR
2-(4-Methoxyphenyl)-2-phenylethanol (11a). From compound
6j (153 mg, 0.30 mmol), compound 11a (61 mg, 0.27 mmol, 90%)
was produced as a colorless oil. Rf 0.29 (ethyl acetate: cyclohexane,
1/2); tR 17.3 min (HP-5); NMR data were resolved with the aid of
1H-1H COSY, 1H-13C HMQC, and 1H-13C HMBC methods; 1H
NMR (CDCl3, 400 MHz) δ 7.21-7.09 (m, 5H, Ph), 7.06-7.04
(m, 2H, Ph), 6.77-6.72 (m, 2H, Ph), 4.04-3.95 (m, 3H, CH, CH2),
3.64 (s, 3H, MeO), 1.75 (s, 1H, OH); 13C NMR (CDCl3, 100 MHz)
δ 158.4 (Ph-OMe), 141.9 (Ph), 133.6 (Ph), 129.3 (2 C, Ph), 128.7
(2 C, Ph), 128.3 (2 C, Ph), 126.7 (Ph), 114.1 (2 C, Ph), 66.2 (C-
OH) 55.3 (MeO), 52.8 (C-Ph); FTIR (CHCl3 cast film microscope)
ν 3378 (brs), 3060 (m), 3028 (m), 3001 (m), 2953 (m), 2934 (m),
1611 (m), 1512 (s), 1249 (s), 829 (m); HRMS (ESI+) calcd for
C15H16O2Na+ 251.1048, found 251.1050. Above analyses match
the reported data.23
General Procedure for the Tandem Umpolung Including
the Second Addition/Rearrangement/Elimination. Following the
standard condition for the first addition (normally with 0.5-0.9
mmol carbamate starting material), and before queching the reaction
with protic compounds, the mixture was cooled to -70 °C and
tetraisopropoxytitanium (TIPT, neat, 1 equiv. to the Grignard
reagent) or LiBr (as beads, 1 equiv. to the Grignard reagent) was
added. After 30 min, the aldehyde component (neat, 1.5 equiv to
the Grignard reagent) was added dropwise and the resulting mixture
was stirred at -50 to -55 °C for 8 h before it was gradually
warmed to rt. The mixture was then stirred for another hour at rt
and quenched by a solution of formic acid in MeOH (1 M, 1 equiv
to the Grignard reagent). The quenched mixture was passed through
a silica gel pad which was later washed several times by diethyl
ether. Combined organic layers were evaporated and the residue
(CDCl3, 400 MHz) δ 7.72-7.69 (m, 2H, Ts), 7.23-7.20 (m, 2H,
Ts), 5.85 (d, J ) 4.1 Hz, 1H, Ts(OCb)CH), 4.78 (s, 1H, CH2)),
4.77 (s, 1H, CH2d), 4.04-3.96 (m, 1H, Cb), 3.44-3.38 (m, 1H,
Cb), 3.16-3.11 (m, 1H, Me(isopropenyl)CH), 2.33 (s, 3H, Ts), 1.68
(s, 3H, dC-CH3), 1.24 (d, J ) 7.0 Hz, 3H, CH3), 1.09 (pseudo-t,
J ) 6.5 Hz, 6H, Cb), 1.01 (d, J ) 6.3 Hz, 3H, Cb), 0.85 (d, J )
6.8 Hz, 3H, Cb); 13C NMR (CDCl3, 100 MHz) δ 151.3 (CdO),
145.1 (Me-Cd), 144.9 (Ts), 134.5 (Ts), 129.54 (Ts), 129.49 (Ts),
129.33 (Ts), 129.31 (Ts), 113.0 (CH2d), 86.1 (Ts(OCb)CH), 46.6
(Cb), 45.9 (Cb), 39.2 (Me(isopropenyl)CH), 21.6 (Ts), 20.72 (Cb),
20.65 (Cb), 20.2 (dC-CH3),20.0 (Cb), 19.9 (Cb), 14.4 (CH3); FTIR
(CHCl3 cast film microscope) ν 3074 (m), 2971 (s), 2939 (m), 2879
(m), 1715 (s), 1598 (m), 1433 (s), 1330 (s), 1149 (s), 1067 (s),
1042 (s), 657 (s); HRMS (ESI+) calcd for C20H31NO4SNa+
404.1866, found 404.1861; Anal. Calcd for C20H31NO4S (381.53)
C 62.96, H 8.19, N 3.67; found C 62.81, H 8.19, N 3.54.
3-Methyl-2-phenyl-1-tosylbut-3-enyl N,N-Diisopropylcarbam-
ate (6k). From compound 5c (150 mg, 0.37 mmol), compound 6k
(136 mg, 0.31 mmol, 84%) was obtained as a colorless oil. Major
isomer: minor isomer ) 2.4: 1; Rf 0.41 (ethyl acetate: cyclohexane,
1/2); tR 24.0 min (major isomer), 24.2 min (minor isomer) (HP-5);
NMR data were recorded from compound 6k as a diastereomeric
1
mixture and resolved below separately, with the aid of H-1H
1
1
COSY, H-13C HMQC, and H-13C HMBC methods; NMR of
major isomer: 1H NMR (CDCl3, 400 MHz) δ 7.73 (d, J ) 8.3 Hz,
2H, Ts), 7.22 (d, J ) 7.8 Hz, 2H, Ts), 7.19-7.13 (m, 5H, Ph),
6.43 (d, J ) 10.3 Hz, 1H, Ts(OCb)CH), 5.18 (s, 1H, CH2d), 4.89
(s, 1H, CH2d), 4.24 (d, J ) 10.3 Hz, 1H, Ph(isopropenyl)CH),
3.65-3.60 (m, 1H, Cb), 3.18-3.15 (m, 1H, Cb), 2.33 (s, 3H, Ts),
1.71 (s, 3H, CH3), 0.89 (d, J ) 6.8 Hz, 3H, Cb), 0.75 (d, J ) 6.8
Hz, 3H, Cb), 0.69 (d, J ) 6.8, 3H, Cb), 0.54 (d, J ) 6.8 Hz, 3H,
Cb); 13C NMR (CDCl3, 100 MHz) δ 149.8 (CdO), 143.8 (Ts-),
141.6 (Me-Cd), 137.6 (Ph), 133.4 (Ts), 128.7 (2 C, Ts), 128.2 (2
(23) Taylor, S. K.; Clark, D. L.; Heinz, K. L.; Schramm, S. B.; Westermann,
C. D.; Barnell, K. K. J. Org. Chem. 1983, 48, 592–596.
J. Org. Chem. Vol. 74, No. 11, 2009 4193

Chen and Hoppe
was purified by MPLC (n -pentane: diethyl ether ) 30:1 to 20:1 to
10:1 to 5:1 to 1:1) to yield the products 12a-m.
(CH), 22.8 (CH(CH3)2), 22.6 (CH(CH3)2), 21.7 (Cb), 21.6 (Cb),
20.5 (Cb), 20.4 (Cb), 20.1 (CH3), 17.9 (t-Bu), -4.4 (Si-CH3), -5.1
(Si-CH3); FTIR (CHCl3 cast film microscope) ν 2958 (s), 2932 (s),
2859 (m), 1721 (s), 1694 (s), 1468 (s), 1439 (s), 1368 (s), 1321
(s), 1288 (s), 1256 (s), 1216 (s), 1146 (s), 1094 (s), 1064 (s), 953
(s), 837 (s), 776 (s), 632 (s); [R]D -18.4 (c 1, CHCl3); HRMS
(ESI+) calcd for C21H43NO4SiNa+ 424.2854, found 424.2848; Anal.
Calcd for C21H43NO4Si (401.66) C 62.80, H 10.79, N 3.49, found
C 62.52, H 10.69, N 3.39.
4-Methyl-2-oxo-1-phenylpentyl N,N-Diisopropylcarbamate
(12a). From compound 5a (163 mg, 0.50 mmol), compound 12a
(124 mg, 0.39 mmol, 78%) was obtained as a colorless oil. Rf 0.51
(ethyl acetate: cyclohexane, 1/2); tR 17.2 min (HP-5); NMR data
were resolved with the aid of 1H-1H COSY, 1H-13C HMQC, and
1H-13C HMBC methods; 1H NMR (CDCl3, 400 MHz) δ 7.37-7.22
(m, 5H, Ph), 5.86 (s, 1H, CH-Ph), 4.06-3.90 (brs, 1H, Cb),
3.88-3.70 (brs, 1H, Cb), 2.33-2.28 (m, 1H, CH2), 2.15-2.09 (m,
1H, CH2), 2.07-2.00 (m, 1H, CH), 1.29-1.13 (m, 12H, Cb), 0.77
(d, J ) 6.6 Hz, 3H, CH3), 0.65 (d, J ) 6.5 Hz, 3H, CH3); 13C
NMR (CDCl3, 100 MHz) δ 204.8 (CdO), 154.6 (CdO), 134.0
(Ph), 128.9 (Ph), 128.8 (2 C, Ph), 128.2 (2 C, Ph), 81.3 (CH-O),
47.4 (CH2), 46.6 (Cb), 45.7 (Cb), 23.8 (CH), 22.5 (CH3), 22.2 (CH3),
21.5 (Cb), 21.3 (Cb), 20.52 (Cb), 20.47 (Cb); FTIR (CHCl3 cast
film microscope) ν 3033 (m), 2961 (s), 2935 (m), 2873 (m), 1731
(s), 1691 (s), 1437 (s), 1368 (s), 1299 (s), 1216 (m), 1135 (m),
1046 (s), 701 (s), 633 (s); HRMS (ESI+) calcd for C19H29NO3Na+
342.2040, found 342.2030; Anal. Calcd for C19H29NO3 (319.44) C
71.44, H 9.15, N 4.38, found C 71.40, H 9.38, N 4.25.
3,4-Dimethyl-2-oxo-1-phenylpent-4-enyl N,N-Diisopropylcar-
bamate 12l. From compound 5b (250 mg, 0.74 mmol), compound
12l (198 mg, 0.60 mmol, 81%) was obtained as a colorless oil.
Major isomer: minor isomer ) 1: 0.58; Rf 0.48 (ethyl acetate/
cyclohexane, 1/2); tR 17.4 min (minor diastereomer), 17.5 min
(major diastereomer) (HP-5); NMR data were recorded from
compound 12l as a diastereomeric mixture and resolved below
1
1
separately, with the aid of H-1H COSY, H-13C HMQC, and
1H-13C HMBC methods; NMR of major isomer: 1H NMR (CDCl3,
400 MHz) δ 7.38-7.26 (m, 5H, Ph), 6.03 (s, 1H, Ph(OCb)CH),
4.67 (s, 2H, CH2)), 4.10-3.88 (brs, 1H, Cb), 3.85-3.63 (brs, 1H,
Cb), 3.42 (q, J ) 7.0 Hz, 1H, Me(isopropenyl)CH), 1.19 (s, 3H,
dC-CH3), 1.28-1.09 (m, 12H, Cb), 1.16 (d, J ) 7.0 Hz, 3H,
CH3); 13C NMR (CDCl3, 100 MHz) δ 205.9 (CdO), 154.6 (CdO),
143.2 (Me-Cd), 133.8 (Ph), 128.93 (Ph), 128.90 (Ph), 128.86 (Ph),
128.7 (Ph), 128.6 (Ph), 114.0 (CH2d), 80.0 (Ph(OCb)CH), 51.1
(CH), 46.7 (Cb), 45.7 (Cb), 21.3 (2 C, Cb), 20.4 (2 C, Cb), 19.9
(dC-CH3), 15.6 (CH3); NMR of minor isomer: 1H NMR (CDCl3,
400 MHz) δ 7.38-7.26 (m, 5H, Ph), 6.22 (s, 1H, Ph(OCb)CH),
4.90 (s, 1H, CH2d), 4.81 (s, 1H, CH2)), 4.10-3.88 (brs, 1H, Cb),
3.85-3.63 (br, 1H, Cb), 3.17 (q, J ) 6.8 Hz, 1H, Me(isoprope-
nyl)CH), 1.65 (s, 3H, dC-CH3), 1.28-1.09 (m, 12H, Cb), 0.95
(d, J ) 6.8 Hz, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 205.3
(CdO), 154.4 (CdO), 144.4 (Me-Cd), 134.6 (Ph), 128.93 (Ph),
128.90 (Ph), 128.86 (Ph), 128.7 (Ph), 128.6 (Ph), 114.7 (CH2d),
79.4 (Ph(OCb)CH), 50.3 (CH), 46.7 (Cb), 45.7 (Cb), 21.3 (2 C,
Cb), 20.4 (2 C, Cb), 19.4 (dC-CH3), 14.6 (CH3); FTIR (CHCl3
cast film microscope) ν 3066 (m), 3034 (m), 2973 (s), 2936 (s),
2876 (m), 1731 (s), 1695 (s), 1437 (s), 1370 (s), 1294 (s), 1135
(s), 700 (s); HRMS (ESI+) calcd for C20H29NO3Na+ 354.2040,
found 354.2043; Anal. Calcd for C20H29NO3 (331.45) C72.47, H
8.82, N 4.23, found: C 72.37, H 8.95, N 4.08.
(2S,3R)-2-(tert-Butyldimethylsilyloxy)-6-methyl-4-oxoheptan-
3-yl N,N-Diisopropylcarbamate and (2S,3S)-2-(tert-Butyldim-
ethylsilyloxy)-6-methyl-4-oxoheptan-3-yl N,N-Diisopropylcar-
bamate (12 h, i). From compound 5a (300 mg, 0.92 mmol), TLC
faster moving component (148 mg, 0.36 mmol, 39%) was produced
as a colorless oil. Rf 0.65 (ethyl acetate: cyclohexane, 1/2); tR 17.2
min (HP-5); NMR data were resolved with the aid of 1H-1H COSY,
1
1
1H-13C HMQC, and H-13C HMBC methods; H NMR (CDCl3,
400 MHz) δ 4.79 (d, J ) 4.3 Hz, 1H, CH-O), 4.15-4.09 (m, 1H,
CH-O), 3.93-3.83 (m, 2H, Cb), 2.34 (ddd, J ) 6.7 Hz, 17.8 Hz,
24.0 Hz, 2H, CH2), 2.14-2.04 (m, 1H, CH), 1.26-1.16 (m, 12H,
Cb), 1.14 (d, J ) 6.3 Hz, 3H, CH3), 0.85 (d, J ) 4.6 Hz, 3H,
CH(CH3)2), 0.83 (d, J ) 4.6 Hz, 3H, CH(CH3)2), 0.80 (s, 9H, t-Bu),
0.00 (s, 3H, Si-CH3), -0.01 (s, 3H, Si-CH3); 13C NMR (CDCl3,
100 MHz) δ 207.9 (CdO), 154.6 (CdO), 82.5 (CH-O), 68.7 (CH-
O), 49.7 (CH2), 46.4 (Cb), 45.9 (Cb), 25.7 (3 C, t-Bu), 23.2 (CH),
22.7 (CH(CH3)2), 22.6 (CH(CH3)2), 21.4-20.4 (4 C, Cb), 20.0 (CH3),
17.9 (t-Bu), -4.6 (Si-CH3), -5.0 (Si-CH3); FTIR (CHCl3 cast film
microscope) ν 2958 (s), 2932 (s), 2859 (m), 1730 (s), 1696 (s), 1468
(s), 1435 (s), 1369 (s), 1319 (s), 1289 (s), 1255 (s), 1217 (s), 1145 (s),
1072 (s), 1046 (s), 1005 (s), 832 (s), 776 (s), 668 (s); [R]D +12.4 (c
1, CHCl3); HRMS (ESI+) calcd for C21H43NO4SiNa+ 424.2854, found
424.2852; Anal. Calcd for C21H43NO4Si (401.66) C 62.80, H 10.79,
N 3.49, found C 62.71, H 11.04, N 3.43.
Acknowledgment. Generous support by the Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft
is gratefully acknowledged.
From compound 5a (300 mg, 0.92 mmol), TLC slower moving
component (118 mg, 0.28 mmol, 30%) was produced as a colorless
oil. Rf 0.62 (ethyl acetate: cyclohexane, 1/2); tR 17.3 min (HP-5);
Note Added after ASAP Publication. There was an error
in the abstract and TOC graphic in the version published ASAP
May 4, 2009; the corrected version was published May 8, 2009
then additional typographical errors were corrected on May 13,
2009.
NMR data were resolved with the aid of H-1H COSY, H-13C
HMQC, and 1H-13C HMBC methods; 1H NMR (CDCl3, 400 MHz)
δ 4.89 (d, J ) 2.7 Hz, 1H, CH-O), 4.27 (qd, J ) 2.7 Hz, 6.4 Hz,
1H, CH-O), 4.15-4.02 (m, 1H, Cb), 3.81-3.67 (m, 1H, Cb),
2.41-2.29 (m, 2H, CH2), 2.12-2.02 (m, 1H, CH), 1.30-1.14 (m,
12H, Cb), 1.12 (d, J ) 6.4 Hz, 3H, CH3), 0.85 (d, J ) 1.8 Hz, 3H,
CH(CH3)2), 0.84 (d, J ) 1.7 Hz, 3H, CH(CH3)2), 0.80 (s, 9H, t-Bu),
0.00 (s, 3H, Si-CH3), -0.04 (s, 3H, Si-CH3);13C NMR (CDCl3,
100 MHz) δ 208.0 (CdO), 155.1 (CdO), 82.2 (CH-O), 68.8
(CH-O), 49.5 (CH2), 46.9 (Cb), 45.5 (Cb), 25.7 (3 C, t-Bu), 23.3
1
1
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra for all
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900347S
4194 J. Org. Chem. Vol. 74, No. 11, 2009