p-menthane-3-carboxaldehyde: A useful chiral auxiliary for the synthesis of chiral quaternary carbons of high enantiomeric purity

Article abstract of DOI:10.1021/ja046084j

(+)- or (-)-p-Menthane-S-carboxaldehyde is made in two easy steps from (+)- or (-)-menthone, respectively. This auxiliary allows for the synthesis of carbonyl compounds bearing a α-chiral quaternary carbon. The flexibility, efficiency, and ease of use of

Full text of DOI:10.1021/ja046084j

Published on Web 09/25/2004
p-Menthane-3-carboxaldehyde: A Useful Chiral Auxiliary for
the Synthesis of Chiral Quaternary Carbons of High
Enantiomeric Purity
Claude Spino,* Ce´drickx Godbout, Christian Beaulieu, Magali Harter,
Topwe M. Mwene-Mbeja, and Luc Boisvert
Contribution from the UniVersite´ de Sherbrooke, De´partement de Chimie, 2500 Boul. UniVersite´,
Sherbrooke, Qc, Canada, J1K 2R1
Received July 1, 2004; E-mail: Claude.Spino@USherbrooke.ca
Abstract: (+)- or (-)-p-Menthane-3-carboxaldehyde is made in two easy steps from (+)- or (-)-menthone,
respectively. This auxiliary allows for the synthesis of carbonyl compounds bearing a R-chiral quaternary
carbon. The flexibility, efficiency, and ease of use of the method are demonstrated in a series of examples,
which include the total synthesis of (+)-cuparenone as well as a partial synthesis of (-)-cassiol.
Introduction
Compounds bearing a chiral quaternary carbon center are
ubiquitous in nature. Their construction poses a difficult chal-
lenge to the synthetic chemists, especially those centers bearing
only carbons.1 The difficulty resides principally in achieving
stereoselection on a precursor that bears similar appendages on
its pro-chiral carbon. For example, the preparation of R-mono-
substituted chiral enolates of defined geometry is easily achieved
nowadays and allows for the preparation of carbonyl com-
pounds bearing a R-chiral tertiary center.2 However, the
analogous R,R-disubstituted chiral enolates are much harder to
make and their stereoselective alkylation is not straightforward.3
Stereospecific reactions offer an attractive solution to this
problem. This is the case of the copper-mediated SN2′ substitu-
tion of chiral allylic esters of defined geometries followed by
oxidative cleavage of the resulting alkene (Figure 1). Recently,
several systems based on the SN2′ displacement of an allylic
leaving group were developed to make nonracemic tertiary
carbon centers,4 but only a few were designed to create chiral
quaternary carbons.5 The allylic alcohol precursors are relatively
easy to prepare in high stereochemical purity by the stereose-
lective reduction of enones or the stereoselective additions of
Figure 1. The SN2′ displacement as a stereospecific reaction for the creation
of a quaternary chiral center.
vinylmetals to aldehydes or ketones. In principle, the chirality
of these allylic alcohols can then be transposed to the distal
vinylic position by several types of rearrangements or displace-
ment reactions (vide infra).
Although this basic concept has been around for a while,6
the development of systems of wider scope and applicability is
only recent.4,5 Kakinuma and co-workers were the first to
describe a functional system based on a sugar-derived furanone
that allowed the synthesis of carbonyl compounds bearing an
R-chiral tertiary carbon (Scheme 1).6a,b Only rearrangement
reactions of the allylic alcohol were reported with their system.
SN2′ displacement reactions were not reported for this system
presumably because metal π-complex formation would be
hampered by A1,3-strain. In 1998, we described a system based
on menthone (7) as a chiral auxiliary that allowed SN2′ dis-
placement reactions to take place with great efficiency (Scheme
2).4a,b Conformer 8A was more than 4 kcal/mol more stable
than the other reactive conformer 8C (Figure 2). However, re-
arrangement reactions were not possible on this system because
of the hindered nature of the tertiary alcohol, which proved
exceedingly resilient to derivatization. Moreover, neither men-
thone (7) nor Kakinuma’s furanone 4 could be used to prepare
quaternary carbon centers because the substituent R2 increases
(1) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. (b)
Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (c) Corey, E. J.; Guzman-Perez,
A. Angew. Chem., Int. Ed. 1998, 37, 388-401. (d) Christoffers, J.; Mann,
A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
(2) (a) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-947. (b) For a review of
chiral enolate equivalents see Spino, C. Org. Prep. Proc. Int. 2003, 35,
1-140.
(3) (a) Manthorpe, J. M.; Gleason, J. L. Angew. Chem., Int. Ed. 2002, 41,
2338-2341 and references therein. (b) Manthorpe, J. M.; Gleason, J. L. J.
Am. Chem. Soc. 2001, 123, 2091-2092.
(4) See, for example, (a) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998,
120, 11832-11833. (b) Spino, C.; Beaulieu, C.; Lafrenie`re, J. J. Org. Chem.
2000, 65, 7091-7097. (c) Belelie, J. L.; Chong, J, M. J. Org. Chem. 2001,
66, 5552-5555. (d) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (e) Du¨bner,
F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9236. (f) Du¨bner, F.;
Knochel P. Angew. Chem., Int. Ed. 1999, 38, 379-381.
(6) (a) Kakinuma, K.; Li, H.-Y. Tetrahedron Lett. 1989, 30, 4157-4160. (b)
Kakinuma, K.; Koudate, T.; Li, H.-Y.; Eguchi, T. Tetrahedron Lett. 1991,
32, 5801-5804. (c) Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron
1993, 49, 4527-4540. (d) Savage, I.; Thomas, E. J.; Wilson, P. D. J. Chem.
Soc., Perkin Trans. 1 1999, 3291-3303. (e) Clayden, J.; McCarthy, C.;
Cumming, J. G. Tetrahedron: Asymmetry 1998, 9, 1427-1440. (f) Clayden,
J.; McCarthy, C.; Cumming, J. G. Tetrahedron Lett. 2000, 41, 3279-3283.
(g) Denmark, S. E.; Marble, L. K. J. Org. Chem. 1990, 55, 1984-1986.
(5) (a) Spino, C.; Beaulieu, C. Angew. Chem., Int. Ed. 2000, 39, 1930-1932.
(b) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel,
P. Org. Lett. 2003, 5, 2111-2114.
9
13312
J. AM. CHEM. SOC. 2004, 126, 13312-13319
10.1021/ja046084j CCC: $27.50 © 2004 American Chemical Society

A Useful Chiral Auxiliary
A R T I C L E S
Scheme 1. Kakinuma’s Furanone Chiral Auxiliary System
Scheme 2. Menthone Chiral Auxiliary System
nesium reagents 11 (M ) Li or MgX) failed to deliver the two
alcohols 12 and 13 in ratios exceeding 2:1. We would have
immediately shyed away from 10 were it not for the serendipi-
tous discovery that vinylalanes 11 (M ) AlMe2), generated by
the zirconium-catalyzed carboalumination of alkynes, reacted
with high stereoselectivity with 10 to give the alcohol 12 as
the major diastereomer. We derivatized 12a and 13a into the
corresponding Mosher esters9 which allowed us to determined
that the major alcohol 12a originated from a “Felkin-Anh”
addition of the vinylalane on 10.5a We made a series of allylic
alcohols 12 using this method (Table 1, method A). Reports of
the addition of vinylalanes to aldehydes are scant10 and we were
first to report their stereoselective addition to chiral alde-
hydes.11 The reason for this enhanced stereoselectivity eluded
us for some time until we realized that the excess trimethyl-
aluminum used to generate the vinylalane, as per the Negishi
protocol,12 was in fact responsible for the high stereoselec-
tivity.13 To our surprise and delight, vinyllithiums 11 (M ) Li)
added with even greater selectivity than vinylalanes to alde-
hyde 10 in the presence of various amounts of trimethylalumi-
num.13 Other R-chiral aldehydes also gave increased Felkin-
Anh selectivities upon addition of AlMe3 to the vinyllithium
solution prior to addition to the aldehyde.13 This observation is
interesting in its own right and is the subject of ongoing
mechanistic studies in our laboratory. Crude allylic alcohols 12
were obtained as 30 to 80:1 mixtures of diastereomers (Table
1, method B). The nature of the vinyl substituent seems to bear
little effect on the outcome making this a general way to make
a wide variety of di- and trisubstituted allylic alcohols from
10. Moreover, in all cases studied thus far, the diastereomeric
alcohols 12 and 13 were easily separated by normal silica gel
column chromatography, making this an efficient method to
procure diastereomerically pure alcohols 12. The yields given
in Table 1 represent the yield of isolated diastereomerically pure
12.
the steric congestion and raises considerably the energies of
conformations A or C because of increased A1,3 strain (Figure
2, R2 * H). In fact, even compound 8b where R1 ) H and R2
) Me would not undergo a displacement reaction. Clearly, an
aldehyde as chiral auxiliary would be a better choice when
dealing with trisubstituted alkenes (R2 * H), because it would
lead to allylic alcohol derivatives 1 with substantially lower A1,3
strain in one reactive conformer (cf. Figure 1, X ) H).
We have recently described a methodology based on p-men-
thane-3-carboxaldehyde 10 that allows the formation of qua-
ternary carbon centers of high stereochemical purity (Scheme
3).5a Aldehyde 10 is made in two easy steps from menthone.
SN2′ displacement reactions of the pivalate esters derived from
the alcohols 12 and 13 successfully transfer chirality to the distal
alkene carbon giving quaternary or tertiary chiral carbons of
high stereochemical purity. Herein, we report that rearrangement
reactions are also successfully used for the formation of
quaternary carbon centers of high enantiomeric purity, including
the synthesis of R,R-dialkylated amino acids, a synthesis of
natural product (+)-R-cuparenone, and a partial synthesis of
the unnatural enantiomer of antiulcerogenic (+)-cassiol.
At the heart of this strategy lies the stereoselective addition
of vinylmetals 11 to an R-chiral aldehyde (Scheme 3). From
the onset, only bulky aldehydes were considered as viable chiral
auxiliaries because we believed that bulk would favor an SN2′
regioselectivity in the ensuing displacement reaction.4c,7 While
p-menthane-3-carboxaldehyde 10 certainly fits this criteria, the
chances of adding to it a vinylmetal 11 in a highly stereoselective
fashion were deemed small (cf. Scheme 3). The chiral center R
to the aldehyde in 10 is flanked by two similar alkyl groups
that would seem to preclude high stereoselectivity in nucleo-
philic additions as predicted by the Felkin-Anh model.8 This
appeared to be indeed the case, as vinyllithium or vinylmag-
While attempting to develop a system suitable for amino acid
synthesis (vide infra), we discovered a highly stereoselective
and efficient way to prepare diastereomerically pure allylic
(7) Regioselectivity is dependent on the nature of the cuprate reagent but also
on the allylic substrate. See Tseng, C. C.; Paisly, S. D.; Goering, H. L. J.
Org. Chem. 1986, 51, 2884-2891 as well as ref 15.
(8) For a review, see Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-
1223.
(9) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092-4096.
(10) (a) Newman, H. Tetrahedron Lett. 1971, 47, 4571-4572. (b) Garner, P.;
Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395-4398. (c) Coleman,
R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 32, 1697-1700. (d) Tsuda,
T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1987, 52, 1624-
1627. (e) Tsuda, T.; Yoshida, T.; Saegusa, T. J. Org. Chem. 1988, 53,
1037-1040.
(11) Spino, C.; Granger, M.-C.; Boisvert, L. Tetrahedron Lett. 2002, 43, 4183-
4185.
(12) Negishi, E.-I.; Kondalov, D. Y. Chem. Soc. ReV. 1996, 417-426 and
references therein.
(13) Spino, C.; Granger, M.-C.; Tremblay, M.-C. Org. Lett. 2002, 4, 4735-
Figure 2. Different conformations of allylic alcohols 8.
4737.
9
J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004 13313

A R T I C L E S
Spino et al.
Scheme 3. Stereoselective Addition of Vinylmetals to Menthyl 3-Carboxaldehyde 10
Table 1. Comparison of Ratios of Alcohols 12:13 Obtained by
Two Different Methods Involving AlMe3
chloride 19, available in three steps from menthone (7), with
vinylsilane 18 gave enone 16f having the E geometry (Scheme
5). Many Lewis acids catalyze this reaction but tin tetrachloride
gave the highest yields of 16f (70-75%). This ketone was
reduced with Et3BHLi to give 13p as a single diastereomer.
Admittedly, the yield of this coupling reaction was variable on
larger scale (>10 g) and decomposition products sometimes
accompanied the desired product, which leaves the oxidation/
reduction sequence a more reliable method so far. We are
presently developing alternatives to using acyl chloride 19.
12:13 ratioa (% yield)b
R1
entry
11
(R2
)
Me)
12/13
method Ac
method Bd
1
2
3
5
6
7
8
9
10
11a
11b
11c
11d
11e
11f
11g
11h
11i
n-Bu
n-Pen
a
b
c
d
e
f
g
h
i
12:1 (70)
9:1 (75)
80:1 (60)
c-C6H11
Bn
CH2OH
(CH2)3OTBS
(CH2)4OTBS
Ph
14:1 (80)
11:1 (76)
10:1 (quant)
10:1 (71)
11:1 (68)
18:1 (63)
24:1 (78)
34:1 (50)
39:1 (76)
p-tolyl
With firm methods to prepare allylic alcohols 12 or 13
diastereomerically pure, we set about studying various ways to
transfer the chirality of the carbinol to the distal carbon of the
olefin. The first transformation that we studied was the addition
of alkylcuprate reagents to ester derivatives (cf. Figure 1).15 The
issue of regioselectivity (22a vs 24) was first investigated (Table
2). To avoid confusing mixtures of regioisomers and diastere-
omers, we added methylcopper species to 20a, the ester derived
from 12a. Regioselectivity was strongly dependent on the nature
of the leaving group and of the cuprate reagent. An acetate ester
(entry 1) with Gilman-type cuprates gave the lowest SN2′/SN2
ratios. A carbonate (entry 7) gave slightly better results (2:1)
while a carbamate (entry 5) gave unsatisfactory yields of
product, giving back mostly starting material. Changing the
nature of the cuprate to monoalkylcyano cuprate or higher order
cuprate also gave unsatisfactory yields of product (entries
2-5, and 8). Using a pivalate ester in conjunction with
RCu(CN)Li‚BF3 (entry 9) gave a better, yet still unsatisfactory
ratio (3:1). Finally, the use of Goering’s conditions,7 consisting
of the addition of monoalkylcyano magnesiocuprates on pivalate
esters, gave exclusively the desired regioisomer resulting from
an SN2′ attack of the cuprate reagent on 20a (RdPiv, entry 10).
All subsequent substrates studied thus far afforded similar
results. p-Menthane-3-carboxaldehyde undoubtedly plays a role
in favoring the SN2′ displacement since Goering had shown that
several of their substrates gave considerable amounts of SN2
displacement under those conditions.7
a All ratios measured by G. C. or NMR of the crude mixtures. b Isolated
yield of pure 12. c Method A: alkyne, Cp2ZrCl2 (cat.), AlMe3, CH2Cl2,
aldehyde 10. d Method B: vinyllithium, AlMe3, ether, aldehyde 10.
alcohols 13. It started with the carbomagnesiation of propargyl
alcohol 14 giving cyclic trisubstituted vinylmagnesiums 15
(Scheme 3).14 These organometallic species add efficiently to
aldehyde 10 albeit with only slight selectivity favoring alcohol
12 over 13. After selective protection of the primary alcohol in
the mixtures of 12j-l and 13j-l, oxidation of the mixtures of
allylic alcohols under the Swern conditions gave the corre-
sponding ketone 16a-c (Scheme 4, top). Unexpectedly, lithium
triethylborohydride reduced each ketone 16 with complete facial
selectivity to give only the corresponding alcohol 13m-o.
Alcohols 12a and 12i were also converted to 13a and 13i,
respectively, using this protocol (Scheme 4, bottom). The
stereochemistry of the alcohols 13 correspond to a Felkin-Anh
addition of the hydride to the corresponding ketones, and thus
this procedure establishes the opposite absolute configuration
at the carbinol carbon when compared to the Felkin-Anh
addition of a vinylmetal 11 to aldehyde 10 (cf. Scheme 3). In
contrast, reduction of 16 using sodium borohydride or Dibal-H
gave predominantly alcohol 12, of opposite stereochemistry,
with selectivities ranging from 2 to 4:1. The origin of the facial
selectivity with Et3BHLi is not yet understood but here too the
selectivity seems to have little sensitivity to the alkene sub-
stituent as ketones 16 bearing aryl, alkyl, hydroxymethyl, or
tert-butyl groups all gave a single diastereomer upon reduction
with Et3BHLi.
(15) For reviews on organocopper chemistry, see (a) Krause, N. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002. (b) Yamamoto, Y. In Methods Organic Chemistry, 4th
ed.; Helmchen, G., Hoffman, R. W., Mulzer, J., Shauman, E., Eds.; Georg
Thieme Verlag: Stuttgart, Germany, 1995; Vol. E21b, pp 2401-2467. (c)
Lipshutz, B. H. In Organometallics in Synthesis, 2nd ed.; Schlosser, M.,
Ed.; John Wiley & Sons: Chichester, U.K., 2002; pp 665-815. (d) Knochel,
P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (e) Wipf, P. Synthesis
1993, 537-557. (f) Kozlowski, J. A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4,
pp 169-198. (g) Lipshutz, B. H. Synthesis 1987, 325-341. (h) Yamamoto,
Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947-959.
To enhance the attractiveness of this route, a more direct
access to ketones 16 was developed. The reaction of acyl
(14) (a) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 1-11.
(b) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 227-
232. (c) Wong, T.; Tjepkema, M. W.; Audrain, H.; Wilson, P. D.; Fallis,
A. G. Tetrahedron Lett. 1996, 37, 755-758. (d) Forgione, P.; Fallis, A. G.
Tetrahedron Lett. 2000, 41, 11-15.
9
13314 J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004

A Useful Chiral Auxiliary
A R T I C L E S
Scheme 4. Preparation of Alcohols 13a,i,m-o by the Stereoselective Reduction of the Corresponding Ketone 16
Scheme 5. Synthesis of 13p Using Acyl Chloride 19 as Chiral
Auxiliary
Table 3. Yields and Ratios of Cuprate Addition on Allylic Pivalate
Esters 20 or 21
maj.
prd.
22:23b
(% yield)c
entry piv.a
R1
R2
R3
1
2
3
4
5
6
7
8
9
20a n-Bu
Me
i-Pr
Et
n-Hep
t-Bu or Ph
i-Pr
i-Pr
H2CdCH(CH2)2 22g >98:2 (88)
H2CdCH(CH2)3 22h >98:2 (91)
i-Pr
i-Pr
i-Pr
i-Pr
22b >98:2 (90)
22c >98:2 (98)
22d >98:2 (97)
(0)
22e >98:2 (95)
22f >98:2 (92)
20a n-Bu
20a n-Bu
20a n-Bu
20c c-C6H11
20d CH2Ph
20d CH2Ph
20d CH2Ph
21rd CH2OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
23i >99:1 (98)
23j >99:1 (57)
23k >99:1 (8)
(0)
10 21se CH2OSEM
11 21te CH2OBn
12 21p CH2OTBS
13 20p CH2OTBS
H2CdCH(CH2)2 22l >99:1 (80)
i-Pr
Et
Table 2. SN2′/SN2 Ratios of Cuprate Addition on Allylic Esters 20
14 20f (CH2)3OTBS Me
15 20f (CH2)3OTBS Me
16 20f (CH2)3OTBS Me
17 20g (CH2)4OTBS Me
22m >98:2 (95)
22n >98:2 (89)
H2CdCH(CH2)2 22o >98:2 (82)
H2CdCH(CH2)2 22p >98:2 (41)
18 20h Ph
Me
i-Pr
22q
91:1 (90)
19 20n Ph
CH2OH i-Pr
CH2OH Et
CH2OH i-Pr or Et
CH2OH i-Pr
CH2OH Et
22r >99:1 (73)
22s >99:1 (86)
(0)
23r >1:99 (77)
23s >1:99 (64)
20 20o m-MeO-Ph
21 21m t-Bu
22 21n Ph
entry
R
cuprate
22a:24 ratioa
1
2
3
4
5
Ac
Ac
Ac
CONHPh
CONHPh
CONHPh
CO2Me
Me2CuLi
1:1.5
12a
Me2Cu(CN)Li2
MeCu(CN)MgBr
MeCu
Me2CuLi
MeCu(CN)MgBr
Me2CuLi
23 21o m-MeO-Ph
S. M.
S. M.
S. M.
S. M.
2:1
a For clarity, the pivalates bear the same letter as the alcohol they were
formed from. b All ratios measured by G. C., HPLC, or NMR of the crude
mixtures. c Isolated yields. d Obtained from the deprotection of 21p. e Ob-
tained from the protection of 21r.
6
7
8
9
10
CO2Me
CO-t-Bu
CO-t-Bu
MeCu
MeCu(CN)Li‚BF3
MeCu(CN)MgBr
1.5:1
3:1
>99:1
complete as judged by GC, HPLC, or NMR analysis of the
crude mixtures. We made diastereomers 22 and 23 indepen-
dently from pivalates 20 and 21, respectively. This allowed us
to unambiguously determine the ratio of 22 or 23 obtained in
each separate reaction. As can be seen, the method is general.
Primary or secondary alkylcuprates gave the desired adduct in
good yields. However, larger cuprates such as t-BuCuCNMgBr
or PhCuCNMgBr did not undergo the addition reaction (entry
4). This is hardly surprising, as the addition of a tert-butylcuprate
would create two adjacent quaternary carbon centers. In
phenylcuprate, the reason is less obvious and we suggest that it
may be just a lack of reactivity of the cuprate reagent.
a Ratios measured by NMR of the crude mixtures.
Scheme 6. SN2′ Displacement of Pivalates 20 or 21 with Cuprate
Reagents
When a bulky substituent at the quaternary carbon center in
22 or 23 is needed, this substituent should preferably be part of
the allylic alcohol (i.e., R1 or R2). For example, aryl groups as
substituent R1 on the pivalate allowed the synthesis of the
desired adduct 22 or 23 using primary or secondary alkylcu-
prates (entries 18-20 and 22-23), demonstrating that interesting
and sterically congested chiral quaternary carbons are accessible
with this method. However, a tert-butyl group impeded the
cuprate addition of ethyl or isopropyl cyanocuprates (entry 21).
Pivalates 20 and 21 were then subjected to these reaction
conditions to give cuprate adducts 22 and 23, respectively
(Scheme 6). The results are compiled in Table 3. In all cases
but one (entry 18), the transfer of chirality was essentially
9
J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004 13315

A R T I C L E S
Spino et al.
Scheme 7. Oxidative Cleavage of the Auxiliary and Synthesis of
the Known Compound 28
Figure 3. Conformational biases of pivalates 20.
A hydroxymethyl (R2) substituent gave high-yielding addi-
tion reactions (entries 9 and 19-23). Protecting this group
slows the reaction considerably (or completely with a TBS
group) when the cuprate reagent bears a bulky i-propyl group
(entries 10-12). However, if the cuprate bears a primary alkyl,
the yield of reaction is good (entry 13).
Scheme 8. Synthesis of an Analog of Taber’s Intermediate 31
Either stereochemistry at the carbinol (i.e., 20 and 21) gives,
as expected, the same level of chirality transfer, but the adducts
have the opposite absolute configuration at the quaternary carbon
(entries 19 vs 22 and 20 vs 23). In fact, many cuprate addition
reactions listed in Table 3 were carried out with both 20 and
21, and in each case the same level of chirality transfer was
observed. Although two diastereomers (20 and 21) can, in
principle, have different reactivities, we believe that the control-
ling elements in the transfer of chirality are the anti-stereospeci-
ficity of the cuprate addition on allylic systems16 and the
conformational bias of the allylic ester toward conformations
20A provided by A1,3-strain (Figure 3). In support of this,
adducts 22 with a Z double bond, resulting from addition to
conformers 20B, have never been observed (the same is true
for adducts 23). Ultimately, the menthyl nucleus serves to induce
asymmetry at the carbinol carbon in 12 or 13 but it remains a
spectator fragment in the following steps, as far as stereocontrol
is concerned. However, it does play an important role in ensuring
good regioselectivity in the cuprate displacement reaction on
pivalates 20 or 21.
The lower stereoselectivity obtained in 20h (entry 18) can
be explained in terms of a mechanism involving ionic or radi-
cal intermediates. We had observed this phenomenon on
another system based on menthone.4a When R1 or R2 in 20 or
21 is a group capable of stabilizing ions or radicals, such
pathways may become competitive and lead to a less selective
addition, especially when less reactive cuprate reagents are
involved.
After the cuprate addition produces the chiral quaternary
center, the chiral auxiliary is then oxidatively cleaved. Car-
boxylic acids, aldehydes, or primary alcohols can be easily
accessed by ozonolysis followed by the appropriate workup.
For example, aldehyde 25 was obtained in 65% yield along with
p-menthane-3-carboxaldehyde 10 (80%) (Scheme 7, top). A
mixture of potassium permanganate and sodium periodate was
also able to cleave the auxiliary in 26 and release the desired
carboxylic acid 27 (Scheme 7, bottom). The latter was trans-
formed to diester 28, a known compound for which the absolute
stereochemistry has been determined,17 allowing us to confirm
our hypotheses about the stereochemical outcome of each key
step in the sequence (i.e., Felkin-Ahn addition of vinylmetals
to 10 and antiselective addition of cuprates to the pivalate esters).
Other examples of oxidative cleavage are discussed in the
following sections.
Importantly, though, either configuration of the quaternary
carbon in the final carbonyl compound can be accessed by (a)
starting from (+)- or (-)-p-menthane-3-carboxaldehyde; (b)
using only one enantiomer of 10 but accessing either absolute
configuration of the alcohol (direct addition of vinylmetals 11
on 10 or LiBHEt3-mediated reduction of ketone 16); (c)
changing the geometry of the double bond; or (d) substituting
the cuprate fragment for one of the appendages on the double
bond (there are limitations in this case). This constitutes one of
the most versatile methodologies in this regard.
Synthesis of an Advanced Intermediate to (-)-Cassiol.
(+)-Cassiosside is an antiulcer agent isolated from Chinese
cinnamon in 1988 (Scheme 8).18 (+)-Cassiol is a hydrolysis
product of cassioside, which possesses an even higher potency.18
Several syntheses of cassiol have been reported to date.19,20 Our
methodology offered an efficient solution to the synthesis of
cassiol starting from the inexpensive propargyl alcohol. In the
(16) (a) Ibuka, T.; Yamamoto, Y. In Organocopper Reagents: A Practical
Approach; Taylor, R. J. K., Ed.; Oxford University Press: New York, 1994;
Part 7, pp 143-158. (b) Marshall, J. A. Chem. ReV. 1989, 89, 1503-1511.
(c) Krause, N.; Gerold, N. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-
204. (d) Goering, H. L.; Kantner, S. S.; Seitz, E. P. J. Org. Chem. 1985,
50, 5495-5499. (e) Underiner, T. L.; Goering, H. L. J. Org. Chem. 1990,
55, 2757-2761. (f) Marshall, J. A.; Blough, B. E. J. Org. Chem. 1991, 56,
2225-2234. (g) Marshall, J. A.; Crute, T. D., III; Hsi, J. D. J. Org. Chem.
1992, 57, 115-123. (h) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993,
58, 7180-7184. (i) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25,
3063-3066. (j) Fleming, I.; Thomas, A. P. J. Chem. Soc., Chem. Commun.
1985, 411-412. (k) Fleming, I.; Thomas, A. P. J. Chem. Soc., Chem.
Commun. 1986, 1456-1457. (l) Marshall, J. A.; Trometer, J. D.; Cleary,
D. G. Tetrahedron 1989, 45, 391-402. (m) Goering, H. L.; Kantner, S. S.
J. Org. Chem. 1984, 49, 422-426.
(17) Prakaso Rao, A. S. C.; Bhalla, V. K.; Nayak, U. R.; Dev, S. Tetrahedron
1973, 29, 1127-1130.
(18) Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yokoyama, K.; Tanaka, S.;
Fukui, H.; Tabata, M. Tetrahedron 1988, 44, 4703-4711.
9
13316 J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004

A Useful Chiral Auxiliary
A R T I C L E S
Scheme 9. Route A: Synthesis of R,R-Dialkylated Amino Acid
34a-c
event, the zirconium-catalyzed carboalumination of propargyl
alcohol and addition of the resulting vinylalane intermediate to
aldehyde 10 furnished diol 12e (Scheme 8). The primary alcohol
was selectively protected to give 12p in 83% yield for the two
steps. The diastereomeric alcohols (10:1 ratio) were chromato-
graphically separated. Pivalate formation and addition of
(1-buten-4-yl)cyano cuprate gave a 86% yield of 22l as a single
diastereomer. That adduct underwent a Wacker oxidation using
the conditions reported by Smith and co-workers21 (85%) and
the resulting methyl ketone was alkylated to give 29 (53%).
Ozonolysis and reductive workup gave an 88% yield of aldehyde
30. Compound 31, a molecule closely related to ent-30 has
previously been transformed to (+)-cassiol by Taber and co-
workers in six steps.20
r,r-Dialkylated Amino Acids. Some R,R-dialkylated amino
acids are powerful enzyme inhibitors.22 As part of peptides, R,R-
dialkylated amino acids unit may increase metabolic resistance
and induce particular conformations resulting in altered proper-
ties.23,24 Their stereoselective synthesis remains a formidable
challenge and although many methodologies have been devel-
oped over the years, few are general.25 We promptly realized
that cuprate adducts 23i, 23r, and 23s (Table 3, entries 9, 22,
and 23), possessing a hydroxymethylene unit could be used to
access enantiopure R,R-dialkylated amino acids.26
Scheme 10. Route B: Stereodivergent Synthesis of
R,R-Dialkylated Amino Acid (R)-34a
We began by oxidizing the primary alcohol in each alcohol
23 to the corresponding carboxylic acids and transforming the
latter into the corresponding carbamates 33a via a Curtius
rearrangement27 (Scheme 9). Ozonolysis of 33a and oxidation
gave the desired amino acids (S)-34a in 55% yield. Adducts
23r and 23s were converted to (R)-34b and (R)-34c, respec-
Scheme 11. Synthesis of (+)-Cuparenone
(19) For examples, see (a) Trost, B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118,
6625-6633. (b) Uno, T.; Watanabe, H.; Mori, K. Tetrahedron 1990, 46,
5563-5566. (c) Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61,
7984-7985. (d) Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J. Am. Chem.
Soc. 1994, 116, 3611-3612. (e) Irie, O.; Fujiwara, Y.; Nemoto, H.;
Shishido, K. Tetrahedron Lett. 1996, 37, 9229-9232.
(20) Taber, D. F.; Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723-
5728.
tively, using the same sequence of reactions (Scheme 9).
However, because the alkene in cuprate adducts 22 or 23 can
also be transformed into a carboxylic acid unit, the method is
stereodivergent. For example, the same intermediate 23i was
converted to the enantiomeric amino acid (R)-34a by reversing
the order of the reactions (Scheme 10). We converted 23i first
to carboxylic acid 35, which underwent a Curtius rearrangement
with the expected retention of stereochemistry. Transforming
the hydroxymethylene unit to the carboxylic acid was done using
standard reactions. This stereodivergent option raises an already
versatile approach to yet another echelon. The combination of
carbinol stereochemistry, double-bond geometry, the ability to
interchange R1, R2, and R3, and stereodivergence offer at least
16 different ways to access any one enantiomer of amino acid
34 from either enantiomer of p-menthane-3-carboxaldehyde. All
routes can, in principle, be achieved with excellent control of
stereochemistry. In practice, some intermediates with specific
double-bond geometries may be more difficult to prepare or
some cuprate reagents may not react and so on. However, with
such flexibility, the chances of a successful synthesis are
significantly raised.
(21) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39,
8765-8768.
(22) (a) Shirlin, D.; Gerhart, F.; Hornsperger, J. M.; Harmon, M.; Wagner, I.;
Jung, M. J. Med. Chem. 1988, 31, 30-36. (b) Zhelyaskov, D. K.; Levitt,
M.; Uddenfriend, S. Mol. Pharmacol. 1968, 4, 445-451. (c) Kiick, D. M.;
Cook, P. F. Biochemistry 1983, 22, 375-382.
(23) (a) Karle, I.; Kaul, R.; Roa, R. B.; Raghothama, S.; Balaram, P. J. Am.
Chem. Soc. 1997, 119, 12048-12054. (b) Karle, I.; Roa, R. B.; Prasad, S.;
Kaul, R.; Balaram, P. J. Am. Chem. Soc. 1994, 116, 10355-10361. (c)
Toniolo, C.; Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni, G.;
Pre´cigoux, G.; Aubry, A.; Kamphuis, J. Biopolymers 1993, 33, 1061-
1072. (d) Hodgkin, E. E.; Clark, J. D.; Miller, K. R.; Marshall, G. R.
Biopolymers 1990, 30, 533-546.
(24) (a) Hsieh, K. H.; Marsall, G. R. J. Med. Chem. 1986, 29, 1968-1971. (b)
Samanen, J.; Narindray, D.; Adams, W., Jr.; Cash, T.; Yellin, T.; Regoli,
D. J. Med. Chem. 1988, 31, 510-516. (c) Formaggio, F.; Pantano, M.;
Crisma, M.; Toniolo, C.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphuis,
J.; Becker, E. l. Bioorg. Med. Chem. Lett. 1993, 3, 3-956. (d) Bellier, B.;
McCort-Tranchepain, I.; Ducos, B.; Danascimento, S.; Meudal, H.; Noble,
F.; Garbay, C.; Roques, B. P. J. Med. Chem. 1997, 39477-3956.
(25) (a) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 5634-5635. (b) Cativiela, C.; D´ıaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 1998, 9, 3517-3599 and references therein.
(c) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225-227. (d) Seebach,
D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2708-2748. (e) Williams, R. M. In Synthesis of Optically ActiVe R-Amino
Acids; Pergamon Press: New York, 1989; p 410.
(26) Spino, C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
(27) For examples of the use of similar rearrangements in the synthesis of amino
acids see (a) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.;
Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411-6417. (b)
Braibante, M. E. F.; Braibante, H. S.; Costenaro, E. R. Synthesis 1999,
943-947. (c) Ghosh. A. K.; Fidanze, S. J. Org. Chem. 1998, 63, 6146-
6152. (d) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864-
5872. (e) Charette, A. B.; Coˆte´, B. J. Am. Chem. Soc. 1995, 117, 12721-
12732. (f) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem.
2001, 66, 2667-2673.
Sigmatropic Rearrangements. Sigmatropic rearrangements
provide classic examples of reactions occurring with stereo-
chemical transposition of a chiral center to a distal position.28
However, the formation of chiral quaternary stereocenters using
9
J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004 13317

A R T I C L E S
Spino et al.
Scheme 12. Wittig Rearrangements of 12a and 12b
rearrangement reactions is less frequent, presumably because
of sensitivity to steric effects.29 Among reactions capable of
chirality transfer from an allylic position, the Claisen rearrange-
ment and its numerous variants is one of the most frequently
used methods to generate carbon-carbon bonds with high
stereochemical control.28,30 We were interested to see if chiral
alcohols 12a and 12i would undergo a Claisen rearrangement
and generate in the process a quaternary chiral center.31 The
ortho ester variant of the Claisen rearrangement32 of alcohol
12i did not proceed in refluxing toluene or even in neat hot
triethyl orthoacetate. These acidic conditions and high temper-
ature led to the decomposition of the starting allylic alcohol.
However, acetylation of alcohol 12i and methylenation of the
resulting ester by the Petasis method33 provided 36, which
underwent a very efficient rearrangement in refluxing toluene
to give ketone 37 as a single stereoisomer (Scheme 11). The
low temperature at which the rearrangement took place is
noteworthy. The diastereomeric purity was checked against an
authentic sample of the diastereomer of 37 made from alco-
hol 13i (cf. Scheme 3). Ozonolysis of the rearranged prod-
uct 37 and treatment with base gave cyclohexenone 38, which
was converted to (+)-cuparenone ([R]D ) +167 (c 0.15,
CHCl3), lit.: -166 (c 0.20, CHCl3) following the method of
Meyers.34
Figure 4. Competing transition states for the [2,3]-Wittig rearrangement
of 39.
by treating with n-butyllithium at 0 °C (Scheme 12). Products
40a and 40b were isolated as mixtures of two inseparable
alcohols, in a 3.8:1 ratio in 40a but the ratio for 40b was difficult
to assess. Nonetheless, we have established the absolute
configuration of the major alcohol 40b to be R following
conversion to its Mosher ester.9 It appears that transition-state
I having the pendent alkene syn to the less bulky methyl group
is favored in accord with expectations (Figure 4).
The rearrangements were performed with the minor alcohols
13a and 13i to acquire authentic samples of the diastereomers
(at the quaternary carbon) of 40a and 40b, respectively. It was
possible to demonstrate, in both cases, that the quaternary center
was stereochemically pure by oxidation of the secondary
alcohols. Ketones 41a and 41b were obtained as single
diastereomers by oxidation of 40a and 40b, respectively, with
Dess-Martin’s periodinane.
The [2,3]-Wittig rearrangement35 has also been used to
procure chiral quaternary carbon centers.36 Alcohols 12a and
12i were converted to allyl ethers 39a and 39b, respectively,
under standard conditions and their rearrangement was effected
Conclusions
We have demonstrated the versatility of p-menthane-3-car-
boxaldehyde as a chiral auxiliary to prepare compounds con-
taining a chiral quaternary carbon of high enantiomeric purity.
Displacement reactions and rearrangements were efficient in
transferring the chirality in most cases. The breadth of structures
available by this method is noteworthy but more impressive is
the number of possible permutations in the reaction sequence
(28) For a recent review on [3,3]-sigmatropic rearrangements see Nubbemeyer
U. Synthesis 2003, 961-1008.
(29) (a) Castro, A. M. M. Chem. ReV. 2004, 104, 2939-3002. (b) Nordmann,
G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978-4979. (c) Trost,
B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785-3786. (d)
Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2278-2280. (e) Enders, D.; Knopp, M.; Runsink, J.; Raabe,
G. Liebigs Ann. 1996, 1095-1116. (f) Enders, D.; Knopp, Tetrahedron
1996, 52, 5805-5818. (g) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991,
113, 4026-4028. (h) Corey, E. J.; Roberts, B. E.; Dixon, B. R. J. Am.
Chem. Soc. 1995, 117, 193-196. (i) Corey, E. J.; Kania, R. S. J. Am. Chem.
Soc. 1996, 118, 1229-1230.
(32) (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741-743. (b) For issues of reactivities in the Claisen rearrangemet see
Aviyente, V.; Yoo, H.; Houk, K. N. J. Org. Chem. 1997, 62, 6121-6128.
(c) Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103, 6984-
6986.
(33) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc., 1990, 112, 6392-
6393. (b) Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell I. F.; Verhoeven,
T. R. Org. Synth. 2002, 79, 19-25. (c) Petasis, N. A.; Lu, S. P. Tetrahedron
Lett. 1995, 36, 2393-2396. (d) For a review on titanium alkylidenes
including the Petasis reagent see Hartley, R. C.; McKiernan, G. J. J. Chem.
Soc., Perkin Trans. 1 2002, 2763-2793.
(34) Meyers, A. I.; Lefker, B. A. J. Org. Chem. 1986, 51, 1541-1544.
(35) Reviews: (a) Marshall, J. A. In ComprehensiVe Organic Synthesis; Trost,
B., Fleming, I., Eds.; Pergamon Press: London, 1991; Vol. 3, p 975. (b)
Mikami, K.; Nakai, T. Synthesis 1991, 594-604. (c) Mikami, K.; Nakai,
T. Chem. ReV. 1986, 86, 885-902.
(36) Enders, D.; Bartsch, M.; Backhaus, D.; Runsink, J.; Raabe, G. Synthesis
1996, 12, 1438-1442.
(30) For reviews on the Claisen rearrangement see (a) Hiersemann, M.; Abraham,
L. Eur. J. Org. Chem. 2002, 1461-1471. (b) Fleming, I. In Pericyclic
Reactions; Oxford University Press: New York, 1999; p 71. (c) Chai, Y.;
Hong, S.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905-2928. (d) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28,
43-50. (e) Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936-45.
(f) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, Chapter
7.2, pp 827-873. (g) Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452. (h)
Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1-252. (i) Pereira, S.;
Srebnik, M. Aldrichimica Acta 1993, 26, 17-29.
(31) Menthone has been used as a chiral auxiliary to effect Ireland-Claisen
rearrangements to give tertiary chiral centers. Chillous, S. E.; Hart, D. J.;
Hutchinson, D. K. J. Org. Chem. 1982, 47, 5418-5420.
9
13318 J. AM. CHEM. SOC. VOL. 126, NO. 41, 2004

A Useful Chiral Auxiliary
A R T I C L E S
or in the substrate/reagent combination allowing one to obtain
the desired enantiomer in one of several ways. In amino acids,
a stereodivergent approach adds to an already very flexible
method. Other extensions of this methodology are underway in
our laboratory.
(Type AC grant #36256-AC1), Boehringer-Ingelheim (Canada)
Inc., and the Universite´ de Sherbrooke for financial support.
1
Supporting Information Available: Experimental and H
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada, the Petroleum Research Fund
JA046084J
9
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