Dual stereoselectivity in the dialkylzinc reaction using (-)-β-pinene derived amino alcohol chiral auxiliaries

Article abstract of DOI:10.1021/jo802371z

(+)-Nopinone, prepared from naturally occurring (-)-β-pinene, was converted to the two regioisomeric amino alcohols 3-MAP and 2-MAP in very good yield and excellent isomeric purity. Amino alcohol 3-MAP was synthesized by converting (+)-nopinone to the corresponding α-ketooxime. This was reduced to the primary amino alcohol and was converted to the morpholino group through a simple substitution reaction. 3-MAP was characterized by X-ray crystallography, which displayed the rigidity of the pinane framework. Amino alcohol 2-MAP was prepared from its trans isomer 2, which in tum was synthesized via hydroboration/ oxidation of the morpholine enamine of (+)-nopinone. Two-dimensional NMR was used to characterize amino alcohol 2-MAP, and NOE was used to confirm its relative stereochemistry. These amino alcohols were employed as chiral auxiliaries in the addition of diethylzinc to benzaldehyde to obtain near-quantitative asymmetric induction in the products. The use of 3-MAP yielded (S)-phenylpropanol in 99% ee, and its regioisomer 2-MAP gave the opposite enantiomer, (R)-phenylpropanol, also in 99% ee. Other aromatic, aliphatic, and α,β-unsaturated aldehydes were implemented in this method, affording secondary alcohols in high yield and enantiomeric excess. Amino alcohols 2-MAP and 3-MAP were also found to be useful in the dimethylzinc addition reaction, both catalyzing the addition to benzaldehyde with nearly quantitative ee. Regioisomeric amino alcohols 2-MAP and 3-MAP, even though they were prepared from one enantiomer of nopinone, provide antipodal enantiofacial selectivity in the dialkylzinc addition reaction. This circumvents the necessity to synthesize amino alcohols derived from (-)-nopinone, which in tum requires the unnatural (+)-β-pinene. Possible mechanistic insights are offered to explain the dual stereoselectivity observed in the diethylzinc addition reaction involving regioisomeric, pseudo-enantiomeric amino alcohols 3-MAP and 2-MAP.

Full text of DOI:10.1021/jo802371z

Dual Stereoselectivity in the Dialkylzinc Reaction Using
(-)-ꢀ-Pinene Derived Amino Alcohol Chiral Auxiliaries
Caitlin M. Binder,† April Bautista,† Marek Zaidlewicz,‡ Marek P. Krzemin´ski,*,‡
Allen Oliver,† and Bakthan Singaram*,†
Department of Chemistry and Biochemistry, UniVersity of California, Santa Cruz, 1156 High Street, Santa Cruz,
California 95064, and Department of Chemistry, Nicolaus Copernicus UniVersity, 87-100 Torun´, Poland
singaram@chemistry.ucsc.edu; mkrzem@chem.umk.pl
ReceiVed October 22, 2008
(+)-Nopinone, prepared from naturally occurring (-)-ꢀ-pinene, was converted to the two regioisomeric amino
alcohols 3-MAP and 2-MAP in very good yield and excellent isomeric purity. Amino alcohol 3-MAP was
synthesized by converting (+)-nopinone to the corresponding R-ketooxime. This was reduced to the primary
amino alcohol and was converted to the morpholino group through a simple substitution reaction. 3-MAP
was characterized by X-ray crystallography, which displayed the rigidity of the pinane framework. Amino
alcohol 2-MAP was prepared from its trans isomer 2, which in turn was synthesized via hydroboration/
oxidation of the morpholine enamine of (+)-nopinone. Two-dimensional NMR was used to characterize amino
alcohol 2-MAP, and NOE was used to confirm its relative stereochemistry. These amino alcohols were
employed as chiral auxiliaries in the addition of diethylzinc to benzaldehyde to obtain near-quantitative
asymmetric induction in the products. The use of 3-MAP yielded (S)-phenylpropanol in 99% ee, and its
regioisomer 2-MAP gave the opposite enantiomer, (R)-phenylpropanol, also in 99% ee. Other aromatic,
aliphatic, and R,ꢀ-unsaturated aldehydes were implemented in this method, affording secondary alcohols in
high yield and enantiomeric excess. Amino alcohols 2-MAP and 3-MAP were also found to be useful in the
dimethylzinc addition reaction, both catalyzing the addition to benzaldehyde with nearly quantitative ee.
Regioisomeric amino alcohols 2-MAP and 3-MAP, even though they were prepared from one enantiomer of
nopinone, provide antipodal enantiofacial selectivity in the dialkylzinc addition reaction. This circumvents the
necessity to synthesize amino alcohols derived from (-)-nopinone, which in turn requires the unnatural (+)-
ꢀ-pinene. Possible mechanistic insights are offered to explain the dual stereoselectivity observed in the
diethylzinc addition reaction involving regioisomeric, pseudo-enantiomeric amino alcohols 3-MAP and 2-MAP.
Introduction
employed terpene-based amino alcohols, including camphor-
derived DAIB and MIB ligands, to impart excellent facial
selectivity in the addition of diethylzinc to aldehydes and
ketones.3 However, these methods require both enantiomers of
the chiral director to access both enantiomers of the product
The asymmetric addition of dialkylzinc to aldehydes is a
commonly used method for synthesizing chiral secondary
alcohols.1 This is largely because organozinc reagents are mild
reagents and chemoselective compared to analogous organo-
lithium and Grignard reagents.2 Early work in this field
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994. (b) Soai, K.; Shibata, T. In Organozinc Reagents; Knochel, P., Jones,
P., Eds.; Oxford University Press: New York, 1999; pp 245-258. (c) Lurain,
A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70, 1262–1268. (d) Nugent,
W. A. Org. Lett. 2002, 4, 2133–2136.
† University of California, Santa Cruz.
‡ Nicolaus Copernicus University.
10.1021/jo802371z CCC: $40.75
Published on Web 02/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2337–2343 2337

Binder et al.
alcohol. Unfortunately, (-)-camphor is over 150 times more
expensive than naturally occurring (+)-camphor, the precursor
for both DAIB and MIB. This is a general trend for many
terpenes, amino acids, and other natural products, which are
often used as chiral directors,4 where only one enantiomer is
naturally occurring and/or commercially available.
Optically active ꢀ-amino alcohols derived from pinenes have
served as chiral auxiliaries in a wide variety of organic reactions,
including the asymmetric reduction of ketones5 and the asym-
metric addition of organozinc reagents to aldehydes.6 Although
both enantiomers of R-pinene are readily available, (-)-ꢀ-pinene
is the only natural product. However, (+)-nopinone obtained
from (-)-ꢀ-pinene is an excellent precursor for amino alcohols
that are promising as chiral directors in asymmetric reductions
and organometallic addition reactions. Recently, amino alcohols
derived from (-)-R-pinene7 and (-)-ꢀ-pinene5a were used to
synthesize chiral oxazaborolidines that were employed in the
asymmetric reduction of ketones with excellent enantioselec-
tivities. While trans-amino alcohols containing pinane frame-
work were used with limited success as chiral auxiliaries in
diethylzinc additions,6a the corresponding cis-amino alcohols
have never been used for this purpose. This prompted us to
synthesize cis-amino alcohols from (+)-nopinone and to evalu-
ate these amino alcohols in the asymmetric dialkylzinc reaction.
Even though only (+)-nopinone is easily accessible, we wanted
to explore the possibility of producing dual chiral directors by
synthesizing pseudo-enantiomeric amino alcohols starting from
this single enantiomer of nopinone.
FIGURE 1. Amino alcohols synthesized from (-)-ꢀ-pinene.
catalysis utilizing amino alcohol chiral directors.11 Herein, we
report the preparation of pseudo-enantiomeric cis-amino alcohols
from a single enantiomer of nopinone and the achievement of
dual enantioselective control in the dialkylzinc reaction with
aldehydes.
Results and Discussion
The dual chiral directors derived from (+)-nopinone, includ-
ing (1R,2S,3R,5R)-3-dialkylamino-6,6-dimethylbicyclo[3.1.1]-
heptan-2-ols 3-MAP and 1a,b (3-amino-2-ols), (1R,2S,3R,5R)-
2-dialkylamino-6,6-dimethylbicyclo[3.1.1]heptan-3-ol 2-MAP,
and (1R,2S,3S,5R)-2-dialkylamino-6,6-dimethylbicyclo[3.1.1]-
heptan-3-ol 2 (2-amino-3-ols), are shown in Figure 1.
(+)-Nopinone, needed for our work, was synthesized by
ozonolysis of (-)-ꢀ-pinene in high yield.12 Because ozonolysis
is not safe to perform on a large scale, we also oxidatively
cleaved (-)-ꢀ-pinene using a RuCl3/NaIO4 system.13 (+)-
Nopinone, thus obtained, was treated with a strong base and
iso-pentyl nitrite to afford R-ketooxime 3. Stereoselective
reduction of 3 with lithium aluminum hydride (LiAlH4) afforded
the unsubstituted amino alcohol 4 in 60% yield over three steps
(Scheme 1).14
Primary amino alcohol 4 was treated with a mild base and
the corresponding dibromo compound to afford the morpholino,
pyrrolidino, and piperidino alcohols 3-MAP, 1a, and 1b,
respectively (Scheme 2). X-ray crystallography was used to
confirm the structure and stereochemistry of each of these novel
compounds based on the known absolute configuration of the
pinane ring (Figure 2).15 The bicyclic ring provides rigidity that
keeps the morpholine pseudoequatorial and the hydroxy in a
pseudoaxial position, with both these groups and the gem-
dimethyl group on the same face of the molecule (Scheme 2).
The regioisomeric amino alcohol 2-MAP was synthesized
through the intermediate formation of its trans-isomer 2. This
“Dual enantioselective control” using chiral directors derived
from a single enantiomeric precursor has been sparsely re-
ported.8 Recently, “effective chirality switching” was reported
in the diethylzinc addition reaction by simply changing the
metal-to-ligand ratio in the preparation of the nickel catalyst.9
Pseudo-enantiomeric iminolactones, derived from a single
enantiomer of camphor quinone, have been reported to serve
as stoichiometric, covalently bound chiral auxiliaries for dias-
tereoselective R-alkylations of amino acids.10 This newly
growing field of dual stereoselectivity is of great interest as it
has the potential to reach a myriad of applications in asymmetric
(2) (a) Nakamura, E. In Organometallics in Synthesis, a Manual; Schlosser,
M., Ed.; Wiley: New York, 2002; p 579. (b) Soai, K.; Niwa, S. Chem. ReV.
1992, 92, 833–856.
(3) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
49–69. (b) Nugent, W. A Chem. Comm. 1999, 15, 1369–1370. See also ref 1b.
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Koovsk, P. Org. Lett. 2005, 7, 3219–3222. (b) Spino, C.; Godbout, C.; Beaulieu,
C.; Harter, M.; Mwene-Mbeja, T. M.; Boisvert, L. J. Am. Chem. Soc. 2004,
126, 13312–13319. (c) Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J.
Org. Chem. 2007, 72, 123–131. (d) Mhadgut, S. C.; Toeroek, M.; Esquibel, J.;
Toeroek, B. J. Catal. 2006, 238, 441–448.
(5) (a) Krzeminski, M. P.; Wojtczak, A. Tetrahedron Lett. 2005, 46, 8299–
8302. (b) Cho, B. T. Tetrahedron 2006, 62, 7621–7643. (c) Corey, E. J.; Helal,
C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012. (d) Brown, H. C.;
Ramachandran, P. V.; Chandrasekharan, J. Heteroat. Chem. 1995, 6, 117–131.
(e) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. J. Org. Chem. 1996, 61,
95–99.
(10) (a) Xu, P.-F.; Lu, T.-J. J. Org. Chem. 2003, 68, 658–661. (b) Xu, P.-F.;
Li, S.; Lu, T.-J.; Wu, C.-C.; Fan, B.; Golfis, G. J. Org. Chem. 2006, 71, 4364–
4373.
(6) (a) Goralski, C. T.; Chrisman, W.; Hasha, D. L.; Nicholson, L. W.; Rudolf,
P. R.; Zakett, D.; Singaram, B. Tetrahedron: Asymmetry 1997, 8, 3863–3871.
(b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757–824. (c) Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–6072. See also
refs 1 and 2.
(7) (a) Hobuss, D.; Baro, A.; Laschat, S.; Frey, W. Tetrahedron 2008, 64,
1635–1640. (b) Masui, M.; Shioiri, T. Synlett 1997, 3, 273–274.
(8) (a) Kim, Y. H. Acc. Chem. Res. 2001, 34, 955–962. (b) Martens, J.;
Dauelsberg, C.; Behnen, W.; Wallbaum, S. Tetrahedron: Asymmetry. 1992, 3,
347–350. (c) Kim, S. M.; Byun, I. S.; Kim, Y. H. Angew. Chem., Int. Ed. 2000,
39, 728–731.
(11) For reviews on amino alcohols as chiral auxiliaries in organic synthesis,
see: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835–875.
(b) Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 17, 2699–2715. (c) Vicario,
J. L.; Badia, D.; Carrillo, L.; Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005,
9, 219–235.
(12) Grimshaw, J.; Grimshaw, J. T.; Juneja, H. R. J. Chem. Soc., Perkin
Trans. 1 1972, 50.
(13) (a) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936. (b) Rousset, C. J.; Iyer, S.; Negishi, E.-i. Tetrahedron:
Asymmetry 1997, 8, 3921–3926.
(14) Compound 4 and its regioisomer are excellent chiral auxiliaries for the
asymmetric reduction of prochiral ketones, giving enantiomeric product alcohols.
Krzemin´ski, M. P., personal communication.
(9) Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem.,
Int. Ed. 2007, 46, 9002–9005.
2338 J. Org. Chem. Vol. 74, No. 6, 2009

Dialkylzinc Reaction Using Amino Alcohol Chiral Auxiliaries
SCHEME 1. Synthesis of Primary 3-Amino-2-ol from
(-)-ꢀ-Pinene
FIGURE 2. ORTEP diagram of 3-MAP-HCl.
SCHEME 2. Synthesis of 3-Amino-2-ols
FIGURE 3. Proposed models for selectivity in the R-amino ketone
reduction: (a) reaction of ketone 6 with LAB reagent; (b) reaction of
ketone 6 with LAB reagent and Et3B.
SCHEME 3. Synthesis of Chiral Auxiliary 2-MAP
trans-amino alcohol was in turn prepared from the corresponding
enamine. Conversion to enamine 5 was accomplished by
refluxing the common precursor (+)-nopinone with an in situ
generated titanium-morpholine complex. Literature procedures
for making hindered enamines reported the use of 9 equiv of
secondary amine and a slight excess of TiCl4 to drive the
reaction to completion.16 While only 1 equiv of amine is needed
to form the enamine, the other 2 equiv are used to scavenge
the HCl formed when TiCl4 reacts with water produced during
the reaction (eq 1).
ization via Swern oxidation.19 We envisioned that the steric
requirement of the morpholine moiety and the gem-dimethyl
group were substantial enough to block the ꢀ-face of the
molecule for stereospecific hydride delivery. However, the
reduction of R-amino ketone 6 was more problematic than
initially anticipated. Sodium borohydride (NaBH4) reduction
resulted in a 2:1 cis/trans mixture. The result using lithium
diisopropylaminoborane (Li[H3BN(i-Pr)2], LAB reagent)20 was
identical, indicating that the LAB reagent has steric requirements
similar to that of NaBH4. We found the addition of triethylbo-
rane (Et3B) to the LAB reagent greatly improved the stereose-
lectivity of this reduction. It is known that the reaction of a 1:1
mixture of LAB reagent with Et3B generates lithium triethyl-
borohydride in situ.21 This sterically more demanding reagent
preferentially adds from the R-face of the ring, resulting in a
separable mixture of diastereomers, with 2-MAP being the
major product (Figure 3, Scheme 3).
RCH2COR' + 3HNR2′′ + 0.5 TiCl4 f
RCHdC[NR2′′]R' + 2R2′′NH2Cl + 0.5 TiO2 (1)
We reasoned that some of the secondary amine could be
replaced with a volatile tertiary amine, which would not complex
with titanium but rather serve only to sequester HCl (eq 2).
RCH2COR' + 1.5 HNR2′′ + 1.5 NEt3 +
0.5 TiCl4 f RCHdC[NR2′′]R' + 0.5 R2′′NH2Cl +
1.5 NEt3HCl + 0.5 TiO2 (2)
Additionally, we were able to reduce TiCl4 to a substoichio-
metric quantity, which is similar to other reports of TiCl4-
mediated enamine syntheses.17 These adjustments not only
decreased the amounts of reagents needed but also reduced the
solid byproduct, allowing greater recovery of the product
enamine 5.
Relative stereochemistry of 2-MAP was determined by NOE
correlations. It was possible that epimerization of the R-center
Enamine hydroboration followed by methanolysis and then
oxidation afforded 2 in 85% isolated yield.18 Oxidation to
R-morpholino ketone 6 was accomplished with minimal epimer-
(16) (a) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213. (b)
Carlson, R.; Nilsson, A. Acta Chem. Scand. B 1984, 38, 49–53.
(17) (a) De Paulis, T.; Betts, C. R.; Smith, H. E.; Mobley, P. L.; Manier,
D. H.; Sulser, F. J. Med. Chem. 1981, 24, 1021–1026. (b) Palee`ek, J.; Paleta, O.
Synthesis 2004, 521–524.
(15) (a) See Supporting Information for 1a and 1b. (b) Crystal data for
C13H24ClNO2: Mr ) 261.78; monoclinic; space group P21; a ) 6.0276(10) Å; b
) 19.160(3) Å; c ) 6.0924(10) Å; R ) 90°; ꢀ ) 106.163(2)°; γ ) 90°; V )
675.78(19) Å; Z ) 2; T ) 150(2) K; λ(Mo KR) ) 0.71073 Å; µ(Mo KR) )
0.274 mm-; dcalc ) 1.287g ·cm-1; 7607 reflections collected; 3302 unique (Rint
) 0.0307); giving R1 ) 0.0356, wR2 ) 0.0739 for 2940 data with [I > 2σ(I)]
and R1 ) 0.0434, wR2 ) 0.0769 for all 3302 data. Residual electron density
(e- · Å-3) max/min: 0.232/-0.191.
(18) Fisher, G. B.; Goralski, C. T.; Nicholson, L. W.; Hasha, D. L.; Zakett,
D.; Singaram, B. J. Org. Chem. 1995, 60, 2026–2034.
(19) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(20) (a) Brown, H. C.; Sharp, R. L. J. Am. Chem. Soc. 1968, 90, 2915–
2927. (b) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt,
E. R.; Goralski, C. T.; Singaram, B. J. Org. Chem. 1994, 59, 6378–6385.
(21) Harrison, J.; Alvarez, S. G.; Godjoian, G.; Singaram, B. J. Org. Chem.
1994, 59, 7193–7194.
J. Org. Chem. Vol. 74, No. 6, 2009 2339

Binder et al.
FIGURE 4. Key NOE correlations in 2-MAP.29
TABLE 1. Amino Alcohol Screening and Optimization of the
Diethylzinc Reaction
FIGURE 5. Correlation of % ee in the addition of diethylzinc to
benzaldehyde with varying ratios of the cis/trans diastereomers 2-MAP
and 2. Reactions carried out with 1 mmol benzaldehyde, 1.2 mmol
Et2Zn, and 0.05 mmol amino alcohol at -15 °C with the following
results (% 2-MAP, % ee): (0, 71), (19, 89), (45, 92), (57, 92), (80,
93), (100, 99). The yields were near-quantitative in each reaction.
entry
amino alcohol (mol %)
temp (°C)
yield (%)a
ee (%)b
1
1a (10)
1b (10)
0
0
0
99
99
99
99
98
92
97
89
99
94
84 (S)
87 (S)
86 (S)
97 (S)
97 (S)
99 (S)
96 (S)
58 (R)
95 (R)
99 (R)
2c
3c
4c
5
3-MAP (10)
3-MAP (10)
3-MAP (8)
3-MAP (5)
3-MAP (1)
2 (10)
ee is followed by a gradual increase from 92% to 99% ee over
45% to 100% of 2-MAP in the cis/trans mixture.
-15 to 0
-15 to 0
-15 to 0
-15 to 0
0
-15 to 0
-15 to 0
6c
7
Whereas the diastereomers 2 and 2-MAP both favored the
production of (R)-phenylpropanol, the latter provided far
superior asymmetric induction (Table 1, entries 8 and 9). This
is likely due to the chiral space of the tricoordinate alkylzinc
aminoalkoxide (Figure 6).23 This zinc complex formed with 2
is likely to occur in the plane of the ring or partially below,
where influence from the sterically demanding gem-dimethyl
group is minimal. The complexation of diethylzinc with 2-MAP,
however, is expected to take place above the plane of the ring,
allowing greater interaction with the gem-dimethyl group and
directing ethyl group delivery to the re face of benzaldehyde
(Figure 6b and c).24 In a 1:1 diastereomeric mixture, it is possible
that the heterodimer formed between diethylzinc, 2, and 2-MAP
could be held in a trans conformation, which would be more
stable and less likely to catalyze an alkyl addition. On the other
hand, an excess of 2-MAP in the cis/trans mixture would create
both hetero- and homodimers, the latter of which is more
reactive and therefore responsible for the high induction obtained
for the product alcohol.25 However, this explanation does not
account for the high asymmetric induction obtained for the cis/
trans mixture containing 19% and 45% of 2-MAP. Apparently,
the rates of diethylzinc reaction catalyzed by 2 and 2-MAP are
not the same, allowing a [EtZn:2-MAP] homodimer to pre-
dominate the catalyst mixture. This finding makes the synthesis
of 2-MAP more practical, as the cis/trans mixture obtained from
a NaBH4 reduction of 6 gives results comparable to those of
pure 2-MAP.26
8c
9c,d
10c
2:2-MAP (10)
2-MAP (5)
a Isolated yield. b Determined by chiral GC, corrected for the 92%
optical purity of (-)-ꢀ-pinene. Uncorrected values represented in
Supporting Information. c Results reported as an average of at least 2
trials. d 1:2 mixture of 2:2-MAP.
of ketone 6 could have occurred before reduction, yielding the
diastereomeric cis-alcohol. We therefore found it necessary to
look for through-space couplings of Ha to other protons known
to be on the R-face of the ring. Irradiation of the signal for
proton Hb showed correlation to protons Ha, Hc, and Hd,
indicating that these protons reside on the same face of the ring.
This was given further evidence by the correlation of Hd to the
equatorial methyl group, as well as its correlation back to Hb.
The proximity of the fixed stereocenters of the pinane ring
allowed for the confirmation of absolute configuration (Figure
4). From this data, it was clear that the Swern oxidation was
mild enough to prevent epimerization.
Amino alcohols 3-MAP, 1a,b, 2, and 2-MAP were screened
in the reaction of diethylzinc with benzaldehyde. Of the
3-amino-2-ols, chiral ligand 3-MAP bearing the morpholino
group provided good induction of (S)-phenylpropanol and was
chosen for further optimization (Table 1, entries 1-3).22
Lowering the temperature to -15 °C then gradually increasing
to 0 °C drastically increased the asymmetric induction (Table
1, entry 4). It was also found that the catalyst loading could be
decreased to 5 mol % and still maintain near-quantitative
asymmetric induction in the product (Table 1, entries 5-7).
These optimized conditions were chosen for further investigation.
We were surprised to find that the 2:1 cis/trans mixture of
amino alcohols obtained from the sodium borohydride reduction
of R-amino ketone 6 gave results comparable to those of pure
2-MAP in the diethylzinc reaction (Table 1, entry 9). This
suggests that diastereomeric purity of the ligand was not crucial
for obtaining secondary alcohol products in high enantiomeric
excess. Intrigued by this finding, we set out to further investigate
the apparent asymmetric amplification in mixtures of these cis/
trans diastereomers using the optimized conditions. Spiking the
trans-amino alcohol 2 with only 19% of 2-MAP increases the
% ee from 71% to 89% (Figure 5). This significant increase in
Switching the amino and alcohol positions switches the facial
preference for the reaction. In the reaction of benzaldehyde with
diethylzinc catalyzed by 3-MAP, the ethyl group is situated on
the si face of benzaldehyde (Figure 6d). Experimental observa-
tions clearly show that this pseudo-enantiomeric amino alcohol
(22) The morpholino group has been previously shown to enhance enantio-
meric excess in the diethylzinc addition reaction: Steiner, D.; Sethofer, S. G.;
Goralski, C. T.; Singaram, B Tetrahedron: Asymmetry 2002, 13, 1477–1483.
See also ref 3b.
(23) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl.
Chem. 1988, 60, 1597.
(24) Soai, K.; Yokoyama, S.; Hayasaka, T. J. J. Org. Chem. 1991, 56, 4264–
4268.
(25) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 4832–4842.
(26) A similar observation has been made regarding the use of diastereomeric
mixtures of catalysts in the diethylzinc reaction: Bolm, C.; Mun˜iz, K.; Hildebrand,
J. P Org. Lett. 1999, 1, 491–494.
2340 J. Org. Chem. Vol. 74, No. 6, 2009

Dialkylzinc Reaction Using Amino Alcohol Chiral Auxiliaries
FIGURE 6. Proposed models for diethylzinc complexation with (a) 2 and (b) 2-MAP; proposed transition states in the reaction of diethylzinc and
benzaldehyde in the presence of (c) 2-MAP and (d) 3-MAP.
TABLE 2. Addition of Diethylzinc to Aromatic and Aliphatic
Aldehydes
SCHEME 4. Asymmetric Dimethylzinc Addition with
2-MAP and 3-MAPa
a Reactions were carried out using 1 mmol benzaldehyde, 1.5 equiv of
Me2Zn (2M in toluene), and 0.05 mmol amino alcohol at -15 °C for 18 h.
observed in the reactions of 2,2-dimethyl-4-pentenal and 2-eth-
ylbutyraldehyde (Table 2, entries 7 and 8).
We were delighted to find that the oxidative cleavage product
of (-)-limonene oxide 727 was converted to the secondary
alcohol in high diastereomeric excess while leaving the methyl
ketone intact. This demonstrates reaction chemoselectivity as
well as the ability to deliver an ethyl group with high facial
selectivity, distinguishing between a proton and a ꢀ-branched
group. Additionally, amino alcohols 2-MAP and 3-MAP were
equally effective as chiral directors in the essentially quantitative
asymmetric addition of the less reactive dimethylzinc to
benzaldehyde (Scheme 4).
Conclusion
A pseudo-enantiomeric pair of amino alcohols was synthe-
sized from naturally occurring (-)-ꢀ-pinene through the com-
mon intermediate (+)-nopinone. These bicyclic amino alcohols
were used as chiral directors in the addition of dimethyl- and
diethylzinc to various aldehydes. By virtue of the position of
the amino and alcohol groups, ligands 3-MAP and 2-MAP
promote opposite enantiofacial selectivity in the ethyl group
delivery to the aldehyde. This circumvents the problem with
using the more expensive and unnatural (+)-ꢀ-pinene for the
synthesis of the enantiomer of 3-MAP. To the best of our
knowledge, this is the first report of regioisomeric, noncovalently
bound chiral directors promoting dual stereoselectivity. The
apparent complementarity with which amino alcohols 3-MAP
and 2-MAP bind to the metal center suggests that these directors
have potential applications toward other organozinc or perhaps
other organometallic addition reactions.
a Isolated yield. b Determined by chiral GC, corrected for 92% optical
purity of commercially available (-)-ꢀ-pinene. Absolute configuration
determined by comparison of optical rotation to literature values.
c Results are reported as an average of at least two trials d Product
referred to as 8b in Supporting Information. e de determined by
integration of 1H NMR signals; absolute configuration not assigned.
f Product referred to as 8a in Supporting Information.
pair permits access to both enantiomers of the diethylzinc
addition product in excellent enantiomeric excess and quantita-
tive yields.
A substrate study was carried out to demonstrate the
versatility of this reaction and compatibility with other functional
groups. The two chiral auxiliaries 3-MAP and 2-MAP consis-
tently provided good induction in the diethylzinc addition to
aromatic aldehydes (Table 2, entries 1-5). In addition, we
demonstrated the ability to alkylate R,ꢀ-unsaturated as well as
aliphatic aldehydes with good ee (Table 2, entries 6-10). As
expected, a higher degree of substitution at the R-center
increased asymmetric induction in the aliphatic substrates. This
is exemplified by the nearly quantitative asymmetric induction
Experimental Section
The following experimental details and characterizations are for
compounds that are not previously reported in the literature. For
experimental details and characterization of all other compounds,
see Supporting Information.
(1R,2S,3R,5R)-6,6-Dimethyl-3-morpholinobicyclo[3.1.1]heptan-
2-ol (3-MAP). To a 50-mL round-bottom flask were added 4 (310
(27) Binder, C. M.; Dixon, D. D.; Almaraz, E.; Tius, M. A.; Singaram, B.
Tetrahedron Lett. 2008, 49, 2764–2767.
J. Org. Chem. Vol. 74, No. 6, 2009 2341

Binder et al.
mg, 2 mmol), K2CO3 (558 mg, 4 mmol), bis(2-bromoethyl)ether
(0.3 mL, 2.4 mmol), and CH3CN (16 mL). The flask was fitted
with a water-cooled reflux condenser and drying tube (CaCl2) and
the reaction mixture was heated to reflux for 18 h. After the mixture
had cooled to room temperature, the solids were filtered off and
rinsed with CH3CN. The organic liquid was concentrated in vacuo.
The remaining oil was acidified with concd HCl (0.4 mL) and
extracted with Et2O (3 × 10 mL). The remaining white solid was
dissolved in water (1 mL) and 2:1 Et2O/THF (15 mL) and then
neutralized with solid NaOH (200 mg). The aqueous layer was
extracted with 2:1 Et2O/THF (3 × 15 mL). The combined organic
layers were concentrated in vacuo, leaving 420 mg of 3-MAP as
MHz) δ (ppm): 3.69 (tdd, J ) 11.0 Hz, J ) 6.0 Hz, J ) 3.0 Hz,
2H), 3.66 (tdd, J ) 11.0 Hz, J ) 6.0 Hz, J ) 3.0 Hz, 2H), 2.87
(brs, 1H), 2.81 (brs, 2H), 2.74 (dt, J ) 19.0 Hz, J ) 3.0 Hz, 1H),
2.63 (dtd, J ) 11.0 Hz, J ) 6.5 Hz, J ) 3.5 Hz, 1H), 2.49 (m,
4H), 2.09 (septet, J ) 3.0 Hz, 1H), 1.31 (s, 3H), 1.08 (d, J ) 11.0
Hz, 1H), 1.06 (s, 3H). 13C NMR (CDCl3, 500 MHz) δ (ppm): 218.3,
71.9, 67.3, 50.6, 44.4, 39.9, 37.9, 29.7, 29.4, 26.6, 19.9. Bp 126
°C (10 mmHg), IR (neat) 1716 cm-1. ESITOFMS m/z [M + H]+
224.1644 (calcd for C13H22NO2 224.1645).
(1R,2S,3R,5R)-6,6-Dimethyl-2-morpholinobicyclo[3.1.1]heptan-
3-ol (2-MAP). To a 25-mL round-bottom flask containing 6 (226
mg, 1 mmol) was added a stir bar and THF (1 mL), which was
then cooled to 0 °C. A 1 M solution of Et3B in THF (1 mmol) was
added followed by the dropwise addition of Li[H3BN(i-Pr)2] reagent
(1 M in THF, 1.25 mmol), which was synthesized by literature
procedures.28 This solution was allowed to stir overnight (18 h)
while gradually warming to room temperature. The reaction was
quenched at 0 °C by the slow addition of water (1 mL), followed
by 3 M HCl (2 mL). The aqueous fraction was washed with Et2O
(2 × 25 mL) and then treated with solid NaOH (25 mmol, 1 g).
The aqueous fraction was extracted with Et2O (3 × 15 mL). The
combined organic extracts were washed with water (2 × 5 mL),
dried (MgSO4), filtered, and concentrated in vacuo to give a clear
oil (220 mg). The oil was loaded onto a silica gel column (10 mL
SiO2) and the desired product was eluted with 0.5% MeOH in DCM
to give a clear oil, which solidified upon standing (121 mg, 67%
1
a white solid (95% yield). H NMR (CDCl3, 600 MHz) δ (ppm):
4.23 (dd, J ) 6.6 Hz, J ) 7.2 Hz, 1H), 3.77 (ddd, J ) 15.0 Hz, J
) 11.4 Hz, J ) 3.0 Hz, 2H), 3.75 (ddd, J ) 15.0 Hz, J ) 11.4 Hz,
J ) 3.0 Hz, 2H), 2.76 (td, J ) 8.4 Hz, J ) 7.2 Hz, 1H), 2.67 (brs,
2H), 2.58 (brs, 2H), 2.35 (q, J ) 5.4 Hz, 1H), 2.10 (dt, J ) 10.8
Hz, J ) 5.4 Hz, 1H), 1.98 (qd, J ) 5.4 Hz, J ) 0.6 Hz, 1H), 1.94
(dt, J ) 12.6 Hz, J ) 5.4 Hz, 1H), 1.89 (td, J ) 12.6 Hz, J ) 10.8
Hz, 1H), 1.57 (brs, OH, 1H), 1.35 (d, J ) 10.8 Hz), 1.22 (s, 3H),
1.03 (s, 3H). 13C NMR (CDCl3, 500 MHz) δ (ppm): 69.8, 67.3,
58.4, 45.9, 40.5, 38.9, 30.4, 27.5, 27.1, 23.5, 22.7. Mp 78 °C, [R]20
-5.9 (c 4, MeOH), IR (DCM, HCl salt) 3400, 3255 cm-1D
.
ESITOFMS m/z [M + H]+ 226.1821 (calcd for C13H24NO2
226.1802).
4-[(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl]morpho-
line (5). An oven-dried 250-mL flask with sidearm was equipped
with a stir bar and water-cooled condenser fitted with a rubber
septum connected to an argon bubbler. The assembly was cooled
under argon and the flask was charged with cyclohexane (50 mL),
morpholine (4.7 mL, 54 mmol), and Et3N (7.3 mL, 54 mmol) and
then cooled to 0 °C in an ice bath. The rubber septum was replaced
with a drying tube (CaCl2). A 1 M solution of TiCl4 in toluene
(13.4 mmol) was added dropwise over 45 min, creating large
amounts of a dark green precipitate. (+)-Nopinone (2.5 g, 18 mmol)
was added in one portion and the solution was refluxed for 4 h,
during which time the flask contents changed from dark green to
dark red to light brown. The contents were cooled to room
temperature and filtered through celite under Schlenk conditions.
The solids were washed with 200 mL of cyclohexane and the
organic extracts were concentrated in vacuo, yielding the desired
1
yield). H NMR (CDCl3, 600 MHz) δ (ppm): 4.13 (ddd, J ) 9.0
Hz, J ) 2.4 Hz, 1H), 3.77 (brs, 2H), 2.93 (dd, J ) 9.0 Hz, J ) 3.0
Hz, 1H), 2.64 (brs, 2H), 2.46 (ddd, J ) 14.4 Hz, J ) 9.6 Hz, J )
4.0 Hz, 1H), 2.42 (brs, 2H), 2.37 (dtd, J ) 9.6 Hz, J ) 6.0 Hz, J
) 2.4 Hz, 1H), 2.32 (ddd, J ) 9.0 Hz, J ) 6.0 Hz, J ) 3.0 Hz,
1H), 1.99 (dq, J ) 14.4 Hz, J ) 2.4 Hz, 1H), 1.89 (dddd, J ) 9.0
Hz, J ) 6.0 Hz, J ) 4.0 Hz, J ) 2.4 Hz, 1H), 1.19 (s, 3H), 1.034
(s, 3H), 0.89 (d, J ) 9.6 Hz, 1H). 13C NMR (CDCl3, 500 MHz) δ
(ppm): 68.8, 67.1, 59.3, 53.0, 42.6, 41.0, 38.4, 36.2, 30.8, 27.4,
21.9. Mp 42-44 °C, [R]20 +28.7 (c 4, MeOH), IR (DCM) 3254
D
cm-1. ESITOFMS m/z [M + H]+ 226.1808 (calcd for C13H24NO2
226.1802).
General Procedure for Dimethyl- and Diethylzinc
Addition to Aldehydes. A 25-mL round-bottom flask and magnetic
stir bar were oven-dried, fitted with a rubber septum, and cooled
under argon. Amino alcohol (0.05 mmol, 11.3 mg) was added and
the flask was purged with argon for 5 min. Et2Zn (1.2 mmol, 1 M
in hexane) or Me2Zn (1.5 mmol, 2 M in toluene) was added to the
flask and the mixture was stirred at -15 °C for 15 min. Aldehyde
(1 mmol) was added dropwise (neat or as a 10 M solution in
anhydrous DCM) and a bright yellow color was observed for
aromatic substrates. The reaction was allowed to stir at -15 °C
for 1 h and then kept at 0 °C. The reaction was quenched with satd
NH4Cl (2 mL) and diluted with Et2O (5 mL). The aqueous layer
was separated and the organic fraction was washed with 3 M HCl
(5 mL) followed by 1 M HCl (5 mL). The combined acidic aqueous
portions were extracted with Et2O (3 × 10 mL) and then set aside
for recovery of amino alcohol. The combined organic fractions were
washed with water (2 × 5 mL), dried (MgSO4), filtered, and
concentrated in vacuo to afford the product alcohol. The amino
alcohol was recovered by treating the acidic aqueous portions with
3 M NaOH, extracting with Et2O (3 × 10 mL), drying (MgSO4),
filtering, and evaporating the solvent under reduced pressure.
(S)-4,4-Dimethyl-1-hepten-5-ol. [R]20D +4.1 (c 1.3, MeOH, 92%
ee uncorrected, >99% ee corrected), GC (80 °C, 20 min, ramp at
8 °C/min to 90 °C) tR 31.23 min. (R)-4,4-dimethyl-1-hepten-5-ol.
[R]D20 -5.2 (c 4.0, MeOH, 91% ee uncorrected, 99% ee corrected),
1
product (3.5 g, 16.8 mmol, 94% yield) as an orange oil. H NMR
(CDCl3, 600 MHz) δ (ppm): 4.43 (dd, J ) 1.0 Hz, 1H), 3.72 (t, J
) 4.8 Hz, 4H), 2.74 (m, 4H), 2.39 (m, 1H), 2.24 (m, 1H), 2.21 (td,
J ) 5.0 Hz, J ) 2.0 Hz, 1H), 2.08 (septet, d, J ) 3.0 Hz, J ) 1.2
Hz, 1H), 1.29 (s, 3H), 1.24 (d, J ) 8.4 Hz, 1H), 0.87 (s, 3H). 13C
NMR (CDCl3, 500 MHz) δ (ppm): 156.1, 95.9, 66.9, 49.3, 43.9,
41.0, 38.3, 31.5, 29.5, 26.4, 21.4. Bp 124-126 °C (10 mmHg), IR
(neat) 1635 cm-1
.
(1R,2S,5R)-6,6-Dimethyl-2-morpholinobicyclo[3.1.1]heptan-
3-one (6). An oven-dried 25-mL round-bottom flask with a magnetic
stir bar was fitted with a rubber septum and cooled under argon.
The flask was charged with freshly distilled DCM (4 mL) followed
by oxalyl chloride (1.2 mmol, 0.1 mL) and cooled to -78 °C.
DMSO (2.1 mmol, 0.15 mL) was then added dropwise followed
by the dropwise addition of 2 (0.98 mmol, 200 mg) as a 1 M
solution in anhydrous DCM. Et3N (5 mmol, 0.7 mL) was added
and the reaction was stirred at -78 °C for 4 h. The crude reaction
mixture was immediately poured over crushed ice into a separatory
funnel containing 3 M HCl (15 mmol) and the organic layer was
extracted with 1 M HCl (3 × 5 mL). The combined acidic aqueous
portions were cooled to 0 °C and solid NaOH (25 mmol, 1 g) was
added. The basic aqueous layer was extracted with Et2O (4 × 10
mL) and the combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to afford the product as a yellow
oil (205 mg, 94% yield). Diastereomeric ratio (>35:1) was
measured by integration of 1H NMR signals. The product was
immediately taken onto the next step, as storing overnight at 0 °C
(28) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.;
Goralski, C. T.; Singaram, B. J. Org. Chem. 1994, 59, 6378–6385.
(29) The structure is shown in the chair conformation for simplicity; however,
X-ray crystal structures of related compounds show that this is not the case.
Thus, relative stereochemical assignments could not be assigned by calculating
coupling constants and NOE correlations were used to make these assignments.
1
resulted in epimerization at the R-center. H NMR (CDCl3, 600
2342 J. Org. Chem. Vol. 74, No. 6, 2009

Dialkylzinc Reaction Using Amino Alcohol Chiral Auxiliaries
1
GC (80 °C, 20 min, ramp at 8 °C/min to 90 °C) tR 30.13 min.
Absolute configuration assignments made by analogy to other
substrates reacted with 2-MAP and 3-MAP, all of which gave R
and S products, respectively. 1H NMR (CDCl3, 500 MHz) δ (ppm):
5.87 (m, 1H), 5.06 (dd, J ) 2.5 Hz, J ) 1.0 Hz, 1H), 5.03 (d, J )
1.0 Hz, 1H), 3.17 (dd, J ) 10.5 Hz, J ) 2.0 Hz, 1H), 2.13 (dd, J
) 13.0 Hz, J ) 8.0 Hz, 1H), 1.99 (tdt, J ) 13.0 Hz, J ) 8.0 Hz,
J ) 1.0 Hz, 1H), 1.59 (tdd, J ) 15.0 Hz, J ) 7.5 Hz, J ) 2.0 Hz,
1H) 1.47 (bs, OH, 1H), 1.26 (ddq, J ) 15.0 Hz, J ) 10.5 Hz, J )
7.5 Hz, 1H), 0.99 (t, J ) 7.5 Hz, 3H), 0.874 (s, 3H), 0.865 (s, 3H).
13C NMR (CDCl3, 500 MHz) δ (ppm): 135.8, 117.1, 80.3, 43.8,
37.9, 24.0, 23.3, 22.7, 11.6. ESITOFMS m/z [M + H]+ 143.1408
(calcd for C9H19O 143.1436).
(5R)-5-Isoprenylnon-7-ol-2-one (8b). H NMR (CDCl3, 500
MHz) δ (ppm): 4.80 (dq, J ) 3.0 Hz, J ) 1.5 Hz, 1H), 4.77 (dd,
J ) 1.5 Hz, J ) 1.0 Hz, 1H), 3.59 (tt, J ) 8.0 Hz, J ) 4.5 Hz,
1H), 2.36 (t, J ) 8.0 Hz, 2H), 2.20 (m, 1H), 2.12 (s, 3H), 1.73
(dtd, J ) 15.5 Hz, J ) 6.0 Hz, J ) 4.5 Hz, 2H), 1.64 (dd, J ) 1.5
Hz, J ) 1.0 Hz, 3H), 1.49 (m, 4H), 0.94 (t, J ) 7.0 Hz, 3H).13C
NMR (CDCl3, 500 MHz) δ (ppm): 209.3, 148.0, 112.6, 71.9, 44.2,
41.1, 40.9, 30.0, 29.9, 26.0, 17.7, 9.7. [R]20 -5.8 (c 4, MeOH),
D
IR (neat) 3423, 1714, 1644 cm-1. ESITOFMS m/z [M + H]+
199.1659 (calcd for C12H23O2 199.1693). dr 1:10 (8a:8b, via
integration of signals at 3.44 and 3.59); 74% de uncorrected, 82%
de corrected.
(5R)-5-Isoprenylnon-7-ol-2-one (8a). 1H NMR (CDCl3, 500
MHz) δ (ppm): 4.82 (dq, J ) 2.5 Hz, J ) 1.0 Hz, 1H), 4.76 (d, J
) 2.5 Hz, 1H), 3.44 (dtd, J ) 9.0 Hz, J ) 6.0 Hz, J ) 2.5 Hz,
1H), 2.36 (t, J ) 7.0 Hz, 2H), 2.33 (m, 1H), 2.11 (s, 3H), 1.63 (m,
2H), 1.58 (q, J ) 1.0 Hz, 3H), 1.57 (m, 1H), 1.51 (ddd, J ) 14.0
Hz, J ) 11.0 Hz, J ) 2.5 Hz, 1H), 1.45 (td, J ) 7.0 Hz, J ) 6.0
Hz, 1H), 1.44 (td, J ) 7.0 Hz, J ) 6.0 Hz, 2H), 1.37 (ddd, J )
14.0 Hz, J ) 9.0 Hz, J ) 4.0 Hz, 1H), 0.91 (t, J ) 7.5 Hz, 3H).
13C NMR (CDCl3, 500 MHz) δ (ppm): 209.2, 146.5, 113.2, 70.9,
Acknowledgment. We would like to thank Jinsoo Kim, Max
Mahoney, and Rushia Turner for helpful discussions. The single-
crystal X-ray diffraction data in this work were recorded on an
instrument supported by the National Science Foundation, Major
Research Instrumentation (MRI) Program under Grant CHE-
0521569.
Supporting Information Available: Experimental proce-
dures and characterization of all synthesized compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
43.3, 41.6, 40.3, 30.7, 29.9, 27.2, 17.3, 9.9. [R]20 +12.2 (c 4,
D
MeOH), IR (neat) 3423, 1714, 1644 cm-1. ESITOFMS m/z [M +
H]+ 199.1665 (calcd for C12H23O2 199.1693). dr 15:1 (8a:8b, via
integration of signals at 3.44 and 3.59); 81% de uncorrected, 89%
de corrected.
JO802371Z
J. Org. Chem. Vol. 74, No. 6, 2009 2343