Sequential coupling of zincated hydrazone, alkenylboronate, and electrophile that creates several contiguous stereogenic centers

Article abstract of DOI:10.1021/ja044878s

A zincated N,N-dimethylhydrazone of a ketone undergoes stereospecific syn addition to E- or Z-alkenylboronate to generate a γ-Zn/B dimetallic intermediate, which reacts with a carbon electrophile to give a γ-borylhydrazone in good yield with excellent dia

Full text of DOI:10.1021/ja044878s

Published on Web 10/16/2004
Sequential Coupling of Zincated Hydrazone, Alkenylboronate, and
Electrophile That Creates Several Contiguous Stereogenic Centers
Masaharu Nakamura,*,†,‡ Takuji Hatakeyama,‡ Kenji Hara,§ Hiroki Fukudome,‡ and
Eiichi Nakamura*,‡
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received August 25, 2004; E-mail: masaharu@chem.s.u-tokyo.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Aldol-type 1,2-addition of a metal enamide to a carbonyl group
stereochemical assignment of other products in Table 1. The
intermediate 2a-2c may be predominantly in Z-geometry in light
of the data in Table 1 (vide infra). The use of the dummy ligand
was mandatory to achieve the high yield. The N-alkyl- and N-aryl
imines that were used in our previous studies3 have been found to
be low-yielding in the present reaction (eq 1).
can diastereoselectively create two stereogenic centers if mutual
face selectivity for the enamide and the carbonyl enantiofaces is
controlled well. Likewise but more interestingly, syn stereoselective1
1,2-addition of a metal enamide to a 1,2-disubstituted olefin can
create three contiguous stereogenic carbon centers at positions R,
â, and γ to the imine carbon atom (cf. hydrazone E in Scheme 1).
In addition, the fourth stereogenic center may be created on the
electrophilic carbon atom in the electrophile E+ upon coupling with
D (cf. Table 1, entry 8). Such a reaction, however, has been difficult
to achieve either because of the low reactivity of 1,2-substituted
olefins toward the enamide or because of the difficulty to trap an
intermediate such as D with an electrophile in a selective man-
ner.2,3a,5 We report here that E- (and Z-) alkenylboronates (C) behave
as good acceptors4 of zincated hydrazones5 (B) and that the overall
coupling reaction take place with up to >99% diastereostereose-
lectivity (ds). The boron group in the product can be converted
stereospecifically to a hydroxy group.
Scheme 1. Stereocontrolled Construction of Multistereogenic
Centers by Addition/Trapping Sequence
Table 1 summarizes the results of the addition/trapping sequence
with various zincated hydrazones, alkenylboronates, and electro-
philes. A zincated hydrazone 5 of likely Z-double bond geometry
(vide infra) prepared from a 1-cyclohexylpropan-1-one hydrazone
reacted with E-propenylboronate 6 (99.3% E) to give a syn adduct
9syn that possesses two stereogenic centers in 93% yield with 99.2%
diastereoselectivity (entry 1). The reactions of 5 with E-octenyl-
boronate 7 and E-styrylboronate 8 also proceeded with 99.5 and
99.6% ds, respectively (entries 2 and 3). The reaction with
Z-propenylboronate 12 (99.1% Z) gave an alternative anti diaste-
reomer 9anti as a major product (82% ds, entry 4).
The reaction of a cycloheptanone hydrazone 13 with the E-bor-
onate 6 gave an anti adduct 14anti with 81% ds at room temperature
(entry 5). On the other hand, the reaction with the Z-borate 12 took
place more rapidly (at 0 °C) to give the syn diastereomer 14syn
with 98.5% ds (entry 6).6 The inversion of the diastereoselectivity
between the acylic (5) and the cyclic (13) hydrazones suggests to
us that the acyclic enamide 5 (and 2a-2c) is in Z-geometry. In
addition, the observed diastereoselectivity suggests a six-centered
boat transition state of the syn carbometalation reaction.3b
We can create one additional (entries 7, 9, and 10) and two
additional stereogenic centers (entry 8) by trapping the B/Zn
intermediate D with a carbon electrophile. The reaction between 5
and 6 followed by treatment with allyl bromide (2.4 equiv) in the
presence of CuCl (1 equiv) in Et2O gave a γ-borylhydrazone 15 in
86% yield with overall 99.2% ds. When THF or HMPA was used
as a solvent, the stereoselectivity eroded to 67% owing to the
epimerization of the carbon center to which the Zn and the B atoms
are bonded (vide infra). The stereochemistry of this third stereogenic
center combined with the syn addition of the first addition reaction
indicates that the electrophilic trapping occurred with overall
retention of the stereochemistry of the B/Zn intermediate (vide
infra). This addition/trapping sequence can be applied for aryl
ketone hydrazone to give adduct 19 with 97.6% ds (entry 10).
Scheme 1 outlines the procedure: A zincated hydrazone B is
prepared from the corresponding hydrazone A by treatment with 2
equiv of tert-butyllithium (1 equiv for deprotonation and another
as a ligand on the zinc atom) followed by addition of 1 equiv of
zinc chloride. The zincated hydrazone B undergoes syn addition at
0 °C to the E- (or Z-) alkenylboronate C in hexane to give the
B/Zn bimetallic species D, which upon electrophilic trapping gives
a γ-borylhydrazone E in good to high overall yield.
We first examined the reaction between E-hexenylboronate 3
and the N,N-dimethylhydrazone of 3-pentanone to investigate the
effect of a nontransferable “dummy” ligand (R) on the zinc atom
(2a-2c). The nature of the dummy ligand has a significant impact
on both the stereoselectivity and the reaction rate. The zincated
hydrazone 2a bearing a tert-butyl ligand gave, reacting at 0 °C for
24 h, the highest proportion of what we call here a “syn” adduct 4
in excess (95.2:4.8) to the alternative “anti” adduct in 88% yield.
The relative stereochemistry of 4 was determined by the method
described in Supporting Information, which also reports on the
† PRESTO, Japan Science and Technology Agency (JST).
‡ The University of Tokyo.
§ Present address: Hokkaido University.
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J. AM. CHEM. SOC. 2004, 126, 14344-14345
10.1021/ja044878s CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
addition of an organocopper compound to cyclohexenone8 (see
Supporting Information).
Table 1. Stereoselective Addition to Alkenylboronate and
Trapping
The B/Zn intermediate D undergoes slow epimerization as to
the C-Zn stereochemistry under the reaction conditions. This is
shown by the production of the compounds possessing the same
â- and γ-stereochemistry (cf. 15 and 17) starting with E- and
Z-alkenylboronate (entries 7 and 9). We noted that the stereose-
lectivity of the product starting with the Z-boronate (entry 9) is
rather condition-dependent, while that with the E-boronate (entries
7, 8, and 10) is constantly high, considering that the relative
configuration of the chelate D starting with the E-alkenylboronate
is thermodynamically more stable than the one starting with the
Z-boronate.
The γ-borylhydrazones such as 17 are amenable to further trans-
formations (eq 2). For instance, hydrolysis of the hydrazone moiety
can be achieved readily (albeit slight stereochemistry erosion), the
ketone group can be reduced stereoselectively with BH3‚THF, and
the boron group was converted stereospecifically to an alcohol (the
terminal double bond was hydrogenated before the reduction to
avoid complication). The diol 21 was obtained with 85% diaste-
reoselectivity among other minor diastereomers accounting for the
rest. Esterification of the diol and recrystallization gave diester 22
with 99% ds, and the stereochemisty was determined by X-ray
crystallography.
Supporting Information Available: Details of the experimental
procedure and characterization and physical data of products (CIF,
PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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VCH: New York, 2000; pp 165-189. (b) Hoveyda, A. H.; Heron, N.
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Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 431-454. (c) Marek, I.;
Normant, J. F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
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(4) (a) Nakamura, M.; Hara, K.; Hatakeyama, T.; Nakamura, E. Org. Lett.
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(5) Nakamura, M.; Hara, K.; Sakata, G.; Nakamura, E. Org. Lett. 1999, 1,
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a Addition reactions were carried out in hexane at 0 °C for 12-48 h.
b Zincated hydrazones were prepared as those in Scheme 1. c 1.05 equiv of
5 or 1.25 equiv of 13 and 18. d BR′2 ) 4,4,5,5-tetramethyl-1,3,2-diox-
aborolanyl. e Electrophilic trappings were carried out in Et2O with 1-2 equiv
of CuCl and 2-4 equiv of electrophile. f Isolated yield. g Diastereomeric
ratios (dr) were determined by GC analyses of a crude product unless
otherwise noted. h Addition reaction was carried out for 48 h at room
temperature. i Percentage of the major isomer over all others determined
1
by H NMR spectra.
The chemistry can be extended to the creation of four stereogenic
centers (entry 8). Thus, starting with 5, a 1,4-addition of the B/Zn
intermediate to 2-cyclohexen-1-one in the presence of Me3SiCl7
and CuCl afforded the three-component coupling product 16 in 69%
overall yield with >95% overall ds. While we defer detailed
discussion, we can understand the stereochemistry of the 1,4-
addition in terms of the reported transition state of the conjugate
(6) Six- and eight-membered ring substrates gave comparable results (data
given in Supporting Information).
(7) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368-3370.
(8) (a) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1997, 119,
4900-4910. (c) Yamanaka, Y.; Nakamura, E. Organometallics 2001, 20,
5675-5681.
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