Development of a catalytic asymmetric variant of Hoppe's O-alkyl carbamate deprotonation methodology

Article abstract of DOI:10.1055/s-2006-942417

The optimisation of a ligand-exchange approach to catalytic asymmetric deprotonation of O-alkyl carbamates and subsequent electrophilic trapping (the 'Hoppe reaction') is presented. The method uses s-BuLi and sub-stoichiometric amounts of a chiral diamine [(-)-sparteine or the (+)-sparteine surrogate] in conjunction with an achiral 'regenerating' diamine (bisisopropyl bispidine) for the deprotonation and proceeds with good yields (up to 84%) and high enantioselectivity (up to 94:6 er). The first applications of this catalytic asymmetric deprotonation methodology in natural product synthesis are also described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942417

PAPER
2233
Development of a Catalytic Asymmetric Variant of Hoppe’s O-Alkyl
Carbamate Deprotonation Methodology
Catalytic
Asymmetric
a
H
t
oppe’
t
s
O
-
Alk
h
yl Carbamat
e
e
D
eproton
w
a
tion Methodology J. McGrath, Peter O’Brien*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)432516; E-mail: paob1@york.ac.uk
Received 24 March 2006
This paper is dedicated with much respect to Professor Dieter Hoppe on the occasion of his 65th birthday.
Abstract: The optimisation of a ligand-exchange approach to cata-
1.4 equiv sBuLi
1.4 equiv (–)-sp
lytic asymmetric deprotonation of O-alkyl carbamates and subse-
quent electrophilic trapping (the ‘Hoppe reaction’) is presented. The
method uses s-BuLi and sub-stoichiometric amounts of a chiral di-
amine [(–)-sparteine or the (+)-sparteine surrogate] in conjunction
with an achiral ‘regenerating’ diamine (bisisopropyl bispidine) for
the deprotonation and proceeds with good yields (up to 84%) and
high enantioselectivity (up to 94:6 er). The first applications of this
catalytic asymmetric deprotonation methodology in natural product
synthesis are also described.
N
N
H
Ph
OCb
O
Li
Et2O, –78 °C, 5 h
1
NiPr2
Cb = CONiPr2 Ph
O
2
Bu3SnCl
SnBu3
H
N
N
H
Key words: asymmetric catalysis, synthesis, organometallic re-
agents, chiral bases, diamines
Ph
OCb
(S)-3
73%, 99:1 er
(–)-sparteine = (–)-sp
Scheme 1
The asymmetric deprotonation of O-alkyl carbamates us-
ing s-BuLi/(–)-sparteine and subsequent electrophilic
trapping to give a-substituted O-alkyl carbamates of high
er values was first reported in 1990 by Hoppe and co-
workers.1 During the last 16 years, this process has been
extensively studied within the Hoppe group2,3 and has also
been exploited in natural product total synthesis, with ex-
amples that include (S)-1-methyldodecyl acetate,4 (R)-
pantolactone,5 an algae nonaether from Tolypothrix
conglutinata6 and (R)-japonilure.7 Typically, the process,
which is affectionately known in our group as the ‘Hoppe
reaction’, utilises 1.4 equivalents each of s-BuLi and (–)-
sparteine (Et2O, –78 °C) for the deprotonation of an O-
alkyl carbamate 1 (Scheme 1). The reaction proceeds via
a configurationally stable organolithium complex 2 which
is trapped with an electrophile (Bu3SnCl in this case) to
give a-substituted O-alkyl carbamate (S)-3 (73% yield,
99:1 er).8 Recently, the impressive level of enantiocontrol
observed in the Hoppe reaction has been interpreted using
quantum chemical DFT calculations.9
sis of the s-BuLi-mediated deprotonation of O-alkyl car-
bamates. Disappointingly, however, use of 1.4
equivalents of s-BuLi in conjunction with 0.2 equivalents
of (–)-sparteine and subsequent trapping gave only a 17%
yield of (S)-3 with 85:15 er (Scheme 2). Taken together,
the low yield and reduced enantioselectivity in this exam-
ple suggest that the diamine does not readily dissociate
from the organolithium complex 2. Thus, the reactive s-
BuLi/(–)-sparteine complex is not regenerated and unse-
lective, slow deprotonation by uncomplexed s-BuLi prob-
ably occurs to account for the reduced enantioselectivity.
A similar situation was reported for N-Boc pyrrolidine
deprotonation.11,12
1. 1.4 equiv sBuLi
SnBu3
0.2 equiv (–)-sp
Ph
OCb
Ph
OCb
Et2O, –78 °C, 5 h
2. Bu3SnCl
1
(S)-3
17%, 85:15 er
(s-BuLi alone: 17% of rac-3)
Cb = CONiPr2
Given the synthetic utility of Hoppe’s O-alkyl carbamate
methodology, we were intrigued by the prospect of devel-
oping a catalytic asymmetric variant in which sub-stoi-
chiometric quantities of (–)-sparteine [or our (+)-sparteine
surrogate10] would be employed. This seemed to be a re-
alistic aim since lithiation trapping of 1 using s-BuLi
alone (under otherwise identical conditions to those
shown in Scheme 1) furnished only a 17% yield of rac-3.
Clearly, (–)-sparteine provides ligand-accelerated cataly-
Scheme 2
To solve this problem, we devised a ligand-exchange pro-
cess whereby the (–)-sparteine that is ‘trapped’ by chela-
tion to lithium in organolithium complex 2 could be
‘freed’ by displacement by another diamine ligand and, in
this way, the reactive s-BuLi/(–)-sparteine would be re-
generated and could re-enter the catalytic cycle. The key
features of our proposed approach are summarised in
Scheme 3. Thus, we envisaged that an excess of another
diamine 4 would displace (–)-sparteine from complex 2 to
give a new organolithium complex 6 and the reactive s-
SYNTHESIS 2006, No. 13, pp 2233–2241
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-942417; Art ID: C00906SS
© Georg Thieme Verlag Stuttgart · New York

2234
M. J. McGrath, P. O’Brien
PAPER
BuLi/(–)-sparteine complex. In this way, it was hoped three-step approach was preferred (Scheme 4). Thus, dou-
that, after electrophilic trapping, a >17% yield of (S)-3 in ble Mannich19 reaction of N-Boc piperidone 13 with
>85:15 er should be obtained (compare with Scheme 2). paraformaldehyde and isopropylamine afforded a 78%
There are three important features of our approach: (i) yield of 14. The carbonyl group in 14 was removed by for-
ligand exchange of (–)-sparteine and 4 must occur to some mation of the tosylhydrazone and sodium borohydride
extent;13 (ii) organolithiums 2 and 6 must be configura- reduction20 which gave 15 (82% yield). Finally, lithium
tionally stable throughout the ligand-exchange process14 aluminum hydride reduction generated a 58% yield of the
and (iii) deprotonation of O-alkyl carbamate 1 by s-BuLi/ required diamine 10. In contrast, a more direct two-step
(–)-sparteine must be significantly faster than deprotona- synthesis of diamine 12 was employed.21 In this case, dou-
tion by the organolithium complex 5 (formed from s-BuLi ble Mannich reaction of keto amine 16 with isopropyl-
and diamine 4). Indeed, in a preliminary communication, amine afforded ketone 17 in 69% yield. Diamine 12 was
we demonstrated that catalysis of the Hoppe reaction us- directly produced from 17 in moderate yield (38%) by
ing such a ligand-exchange approach worked well.12 In Wolff–Kishner reduction (Scheme 4).
this paper, we provide information on the relative rates of
iPr
iPrNH2, AcOH
(CHO)n, EtOH
deprotonation of O-alkyl carbamates using s-BuLi com-
plexed to different diamines together with optimisation of
our ligand-exchange approach. In addition, an illustration
of the use of catalytic asymmetric Hoppe reactions in the
synthesis of two natural products is presented.
N
O
O
reflux, 16 h
78%
N
N
Boc
Boc
13
14
1. TsNHNH2,
EtOH
reflux, 4 h
iPr
N
LiAlH4, THF
reflux, 16 h
(–)-sparteine
sBuLi
10
2. NaBH4, THF–
water, r.t. 16 h
N
Boc
58%
Ph
OCb
0.2 equiv
then reflux, 4 h
82%
15
N
1
N
H
iPr
iPrNH2, AcOH
(CHO)n, MeOH
N2H4, KOH
O
Li
N
N
N
O
O
ethylene glycol
NiPr2
12
Li
sBu
O
Ph
reflux, 16 h
180 °C, 4 h
N
N
iPr
iPr
2
Ligand
16
69%
17
38%
exchange
NR2
R2N
H
Scheme 4
R2N
sBuLi
NR2
O
Li
R2N
NR2
1.2 equiv Li
NiPr2
sBu
4
With diamines 7–12 in hand, we investigated the conver-
sion of O-alkyl carbamate 1 into 3 using s-BuLi and the
diamines (Table 1). It was intended to use the yield of
these reactions as a guide to identifying an approximate
reactivity series for the s-BuLi/diamine complexes. As
shown in Table 1, use of (–)-sparteine and diamines 7 and
(S,S)-8 (entries 1–3) all gave >70% yields of 3 indicating
that their s-BuLi complexes are the most reactive. Di-
amines 9 and 10 showed moderate reactivity (~55% yield
of 3; entries 4–5), whilst s-BuLi complexes of diamines
11 and 12 were the least reactive (entries 6–7). Not sur-
prisingly, as the steric hindrance of the N-alkyl substitu-
ents on the diamines increased, the reactivity of the s-
BuLi complexes decreased. These initial results suggested
to us that diamines 11 and 12 would be better regenerat-
ing diamines than, for example, diamine 8.
O
Ph
6
5
Scheme 3
In order to implement the proposed ligand-exchange ap-
proach to catalysis, we needed to identify a suitable regen-
erating diamine 4. Ideally, when s-BuLi is combined with
diamine 4, it should produce a complex that does not
deprotonate 1 to any extent. To probe this, we planned to
study the conversion of 1 into 3 using s-BuLi and a range
of diamines 7–12 with differently sized groups around the
coordinating nitrogens (Figure 1).
Diamines 7,15 8,16 917 and 1118 were prepared according to
the literature methods. For the synthesis of diamine 10, a
Unfortunately, these results did not allow us to differenti-
ate between the reactivity of s-BuLi/diamine complexes
that gave >70% yield of O-alkyl carbamate 3. Therefore,
we devised a competition experiment22 which would al-
low us to directly compare the reactivity of (–)-sparteine
and the other diamines. Thus, we deprotonated O-alkyl
carbamate 1 using 2.8 equivalents of s-BuLi in combina-
tion with 1.4 equivalents each of (–)-sparteine and di-
amine 7. After electrophilic trapping with Bu3SnCl,
adduct (R)-3 of 88:12 er was obtained in 83% yield
(Table 2, entry 1). The major enantiomer results from
NMe2
N
N
N
N
N
N
NMe2
(–)-sparteine
7
8
9
N
N
N
N
N
N
10
11
12
Figure 1
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

PAPER
Catalytic Asymmetric Variant of Hoppe’s O-Alkyl Carbamate Deprotonation Methodology
2235
Table 1 Conversion of O-Alkyl Carbamate 1 into 3 Using s-BuLi
and (–)-Sparteine and Diamines 7–12a
there so that adduct 3 was produced in 97:3 er (entry 3) or
96:4 (entry 4) with (–)-sparteine and diamine 7, respec-
tively. Based on the results from Table 2, it is possible to
establish the following reactivity order for s-BuLi/di-
amine complexes: 7 ~ 8 > (–)-sparteine >> 12. A similar
order of reactivity was also obtained for N-Boc pyrroli-
dine deprotonation using s-BuLi/diamines.22
Entry
Diamine
Yield (%)b
er (S:R)c
99:1d
5:95d
48:52
14:86d
rac
1
2
3
4
5
6
7
(–)-sparteine
73
84
71
55
53
18
15
7
(S,S)-8
9
Our interpretation of the competition results presented in
Table 2 assumes that we measure the relative rate of
deprotonation from a pre-lithiation complex containing
one of each of O-alkyl carbamate 1, s-BuLi and diamine
(which is consistent with Würthwein and Hoppe’s compu-
tational model)9 rather than the relative rate of irreversible
complexation of s-BuLi/diamines to carbamate 1. To ver-
ify that formation of the pre-lithiation complex was re-
versible, we devised the experiment presented in
Scheme 5. Thus, a-bis-deuterated O-alkyl carbamate 18
(prepared according to the two-step route shown in
Scheme 6, via known23 alcohol 21) was incubated with s-
BuLi/(–)-sparteine in the usual way. a-Bis-deuterated O-
alkyl carbamate 18 will complex to s-BuLi/(–)-sparteine
to form the pre-lithiation complex but will not undergo
deprotonation due to the high kinetic isotope effect for
such reactions at –78 °C, as noted previously by Hoppe et
al.24 Subsequent addition of a different substrate that can
undergo deprotonation (e.g., N-Boc pyrrolidine 19) can be
used to probe whether the initial pre-lithiation complex
formation is reversible. When N-Boc pyrrolidine 19 was
added and left for 5 h at –78 °C before quenching with
Me3SiCl, unreacted O-alkyl carbamate 18 was recovered
in 76% yield together with trimethylsilyl adduct (S)-20
(64% yield) of 94:6 er. This clearly demonstrates that
complexation of s-BuLi/(–)-sparteine to carbamate 18
(and by analogy 1) is reversible and we believe that the
competition experiments are indeed a measure of relative
rate of deprotonation from a pre-lithiation complex.
10
11
46:54d
race
12
a Reaction conditions: (i) 1.4 equiv s-BuLi/diamine, Et2O, –78 °C, 5
h; (ii) Bu3SnCl.
b Isolated yield after chromatography.
c Enantiomeric ratio determined by chiral HPLC.
d Ref. 8.
e Ref. 12.
preferential reaction of the s-BuLi complex of diamine 7
over (–)-sparteine, i.e., the s-BuLi/diamine 7 complex
deprotonates 1 faster than the s-BuLi/(–)-sparteine com-
plex. Hence, based on this exciting competition result, we
speculated that it might even be possible to use (–)-
sparteine as a readily available regenerating diamine for
asymmetric catalysis using the (+)-sparteine surrogate 7
(vide infra). Three other competition experiments were
also carried out (Table 2).
Table 2 Competition Experiments: Conversion of O-Alkyl Car-
bamate 1 into 3 Using Excess s-BuLi and an Excess of a Mixture of
Two Ligandsa
Entry Diamine 1
Diamine 2
Yield (%)b er (S:R)c
1
2
3
4
(–)-sparteine
(–)-sparteine
(–)-sparteine
7
7
83
41
60
86
12:88
60:40
97:3
Our conclusions from the % yields for one-ligand stoi-
chiometric reactions (Table 1) and the competition exper-
iments (Table 2) are three-fold. First, (–)-sparteine and
rac-8
12
12
4:96
D
D
76%
a Reaction conditions: (i) 2.8 equiv s-BuLi/1.4 equiv diamine 1 and 2,
Et2O, –78 °C, 5 h; (ii) Bu3SnCl.
1. 0.9 equiv sBuLi/(–)-sp
Et2O, –78 °C, 30 min
Ph
OCb
D
D
18
+
b Isolated yield after chromatography.
2.
Ph
OCb
c Enantiomeric ratio determined by chiral HPLC.
0.7 equiv
18
64%
94:6 er
N
19
Boc
SiMe3
N
–78 °C, 5 h
Boc
(S)-20
3. Me3SiCl
If s-BuLi complexes of diamines rac-8 and (–)-sparteine
were of equal reactivity, then adduct 3 should be generat-
ed with ca. 75:25 er. In fact, using rac-8 and (–)-sparteine,
adduct 3 was produced in 60:40 er (entry 2) indicating that
the s-BuLi/diamine rac-8 complex also deprotonates 1
faster than the s-BuLi/(–)-sparteine complex. Clearly, di-
amine 8 (and the closely related TMEDA) should not be
used for catalysing the Hoppe reaction using a ligand-ex-
change approach. Finally, we verified the low reactivity of
the s-BuLi/diamine 12 complex using competition exper-
iments with each of (–)-sparteine and diamine 7. The re-
action essentially proceeded as if diamine 12 was not
Scheme 5
D
D
LiAlD4, Et2O
CO2H
Ph
Ph
OH
reflux, 16 h
21
94%
D
D
1. NaH, Et2O
r.t., 30 min
Cb = CONiPr2
Ph
OCb
18 76%
2. Cb–Cl, r.t.
16 h
Scheme 6
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

2236
M. J. McGrath, P. O’Brien
PAPER
diamine 7 should be the best chiral diamines to be used in stoichiometric amounts (entries 8 and 9). Our preferred
sub-stoichiometric quantities (as their s-BuLi complexes conditions used 0.2 equivalents of (–)-sparteine or di-
are the most reactive and give the highest enantioselectiv- amine 7 and 1.2 equivalents of diamine 12 with 1.3 equiv-
ities). Second, for efficient catalysis with the very reactive alents of s-BuLi. With diamine 7, a 72% yield of adduct
s-BuLi/diamine 7 complex, it could be possible to use any (R)-3 of 94:6 er was obtained (entry 6) whereas (–)-
diamine that gives a less reactive s-BuLi complex as the sparteine generated its antipode (S)-3 of 92:8 er in 77%
regenerating diamine. The same is true for catalysis with yield (entry 8). It is notable that diamine 7 engenders
s-BuLi/(–)-sparteine. Third, diamine 12 gives the least re- higher enantioselectivity than (–)-sparteine under identi-
active s-BuLi/diamine complex suggesting it should be cal conditions and may be a result of more efficient catal-
the most efficacious regenerating diamine. To investigate ysis due to the higher reactivity of s-BuLi/diamine 7.
these conclusions further, a number of diamine combina-
tions (at different stoichiometry) were studied and the full
results are presented in Table 3.
Finally, to demonstrate the synthetic usefulness of this
catalytic asymmetric variant of Hoppe’s O-alkyl carbam-
ate methodology, we have completed a formal synthesis
First of all, we tried to use (–)-sparteine as a regenerating of (S)-(+)-dihydrokavain 2525 (an inhibitor of TNF a for-
diamine for catalytic asymmetric deprotonation using s- mation) and a total synthesis of (R)-(+)-1,3-diphenylpro-
BuLi/diamine 7 (entries 1–3). Using 0.4 equivalents of di- pan-1-ol 27,26 two naturally occurring compounds. The
amine 7 and 0.8 equivalents of (–)-sparteine (with 1.2 key steps in our formal synthesis of (S)-(+)-dihydrokavain
equiv of s-BuLi), we isolated adduct (R)-3 of 71:29 er in 25 are summarised in Scheme 7. Thus, catalytic asymmet-
84% yield (entry 2), which implied that diamine 7 was be- ric deprotonation of O-alkyl carbamate 1 using the opti-
ing recycled to some degree. However, it was only possi- mised conditions (1.3 equiv of s-BuLi, 0.2 equiv of
ble to obtain useful enantioselectivity (89:11 er) at high diamine 7 and 1.2 equiv of diamine 12) followed by elec-
loadings of diamine 7 (0.55 equiv) (entry 3).
trophilic trapping with carbon dioxide and then aqueous
quench delivered acid (S)-22. Acid (S)-22 was not puri-
fied but subjected to reduction with BH3·Me2S to give al-
cohol (S)-23 in 78% yield over two steps after purification
by chromatography. Finally, lithium aluminum hydride
reduction of alcohol (S)-23 generated diol (S)-24 of 91:9
er in an unoptimised 42% yield. Diol (S)-24 has previous-
ly been converted in five steps into naturally occurring
(S)-(+)-dihydrokavain 25.25 It is notable that use of the
(+)-sparteine surrogate, diamine 7, is required to synthe-
sise 25 with the naturally occurring (S)-stereochemistry.
Table 3 Catalytic Asymmetric Deprotonation of O-Alkyl Carbam-
ate 1 → 3 Using s-BuLi and a Mixture of Two Ligandsa
Entry Diamine 1
Diamine 2
(equiv)
s-BuLi Yield
er
(equiv)
(equiv) (%)b
(S:R)c
1
2
3
4
5
6
7
8
9
7 (0.25)
7 (0.4)
(–)-sp (1.1)
(–)-sp (0.8)
(–)-sp (1.11)
10 (1.0)
1.7
1.2
1.6
1.4
1.3
1.3
1.3
1.3
1.3
57
84
75
65
47
72
63
77
54
63:37
29:71
11:89
12:88
6:94
7 (0.55)
7 (0.4)
1. 1.3 equiv sBuLi
CO2H
7 (0.3)
12 (0.9)
0.2 equiv diamine 7
1.2 equiv diamine 12
H
Ph
OCb
Ph
OCb
7 (0.2)
12 (1.2)
6:94
Et2O, –78 °C, 5 h
2. CO2, 20 min
3. HCl(aq)
1
(S)-22
7 (0.06)
(–)-sp (0.2)
(–)-sp (0.1)
12 (1.2)
15:85
92:8
Cb = CONiPr2
OH
H
12 (1.2)
1. BH3⋅Me2S, THF
r.t., 16 h
OCb
OH
12 (1.2)
81:19
Ph
2. MeOH, r.t., 1 h
then reflux, 1 h
Ph
OCb
a Reaction conditions: (i) s-BuLi/diamine 1 and 2, Et2O, –78 °C, 5 h;
(ii) Bu3SnCl.
(S)-23
OH
(S)-23
78% from 1
O
b Isolated yield after chromatography.
LiAlH4, THF
steps
c Enantiomeric ratio determined by chiral HPLC.
OH
O
reflux, 16 h
42%
Ph
(S)-24
Ph
OMe
91:9 er
(S)-(+)-Dihydrokavain (S)-25
Thus, our attention switched to regenerating diamines 10
and 12 which produce less reactive s-BuLi complexes. In
this way, improved results were obtained at lower load-
ings of diamine 7. As predicted, higher enantioselectivity
was obtained using diamine 12 (compare entries 4 and 5).
Even use of 0.06 equivalents of diamine 7 with 1.2 equiv-
alents of diamine 12 and 1.3 equivalents of s-BuLi gener-
ated adduct (R)-3 of 85:15 er in 63% yield (entry 7), which
clearly indicates that the chiral diamine 7 is being recy-
cled, presumably via the proposed ligand exchange
(Scheme 3). To access the opposite enantiomer of adduct
3, (–)-sparteine was also successfully employed in sub-
Scheme 7
For the synthesis of (R)-(+)-1,3-diphenylpropan-1-ol 27,
we planned to utilise the reaction of a-carbamoyloxy-
alkylboronates (e.g. (S)-26) with Grignard reagents, a pro-
cess recently developed by Hoppe et al.27 First of all, cat-
alytic asymmetric deprotonation of O-alkyl carbamate 1
was accomplished using the optimised procedure with 0.2
equivalents of (–)-sparteine. Subsequent electrophilic
trapping with triisopropylborate and conversion into the
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

PAPER
Catalytic Asymmetric Variant of Hoppe’s O-Alkyl Carbamate Deprotonation Methodology
2237
amines 7,15 8,16
ture methods.
9
17 and 1118 were prepared according to the litera-
pinacol borate ester was carried out following Hoppe’s
protocol to give known27 borate ester (S)-26 in 58% yield
(Scheme 8). Then, reaction of borate ester (S)-26 first
with phenylmagnesium bromide and then with alkaline
hydrogen peroxide afforded alcohol (R)-27 of 87:13 er in
60% isolated yield after chromatography. This reaction
proceeds via a 1,2-borate rearrangement with inversion of
stereochemistry as depicted in Scheme 8. Hence, it was
necessary to use (–)-sparteine to obtain the requisite (R)-
stereochemistry of the natural product. Our synthesised
alcohol (R)-27 was identical in all respects to the naturally
occurring material.26
tert-Butyl 7-Isopropyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3-
carboxylate (14)
A stirred solution of isopropylamine (4.3 mL, 50.5 mmol), tert-bu-
tyl 4-oxopiperidine-1-carboxylate 13 (10.0 g, 50.1 mmol),
paraformaldehyde (4.5 g, 150 mmol) and AcOH (3.0 mL, 54.5
mmol) in EtOH (250 mL) was heated at reflux for 16 h. The result-
ing orange solution was allowed to cool to r.t. and the solvent was
evaporated under reduced pressure. The residue was treated with
20% aq KOH (200 mL) and extracted with Et2O (3 × 150 mL). The
combined Et2O extracts were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. Purification by flash
column chromatography on silica with PE–Et2O (1:1) as eluent
gave bispidinone 14 (11.0 g, 78%) as a yellow oil; Rf = 0.4 (PE–
Et2O, 1:1).
1. 1.3 equiv sBuLi
0.2 equiv (–)-sparteine
1.2 equiv diamine 12
O
O
H
IR (film): 2968, 2933, 1731 (C=O, ketone), 1695 (C=O, Boc), 1449,
1424, 1390, 1172, 1125 cm–1.
B
Ph
OCb
Et2O, –78 °C, 5 h
1
2. B(iPrO)3, –78 °C, 2 h
3. HCl(aq)
4. Pinacol, r.t., p-TsOH
MgSO4, CH2Cl2, 20 h
Ph
OCb
1H NMR (400 MHz, CDCl3; rotamers): d = 4.58 (d, J = 14.0 Hz, 1
H, CHNBoc), 4.42 (d, J = 13.5 Hz, 1 H, CHNBoc), 3.31 (d,
J = 14.5 Hz, 1 H), 3.22–3.18 (m, 2 H), 3.12 (d, J = 10.5 Hz, 1 H),
2.88 (d, J = 10.5, 1 H), 2.77–2.73 (m, 2 H), 2.42 (br s, 1 H), 2.38 (br
s, 1 H), 1.48 (s, 9 H, CMe3), 1.03 (d, J = 6.5 Hz, 3 H, CHMeAMeB),
0.94 (d, J = 6.0 Hz, 3 H, CHMeAMeB).
13C NMR (100.6 MHz, CDCl3; rotamers): d = 214.1 (C=O), 154.8
(C=O), 79.7 (CMe3), 55.2 (CH2N), 53.2 (CH2N and CHN), 50.4
(CH2N), 49.7 (CH2N), 48.2 (CH), 48.0 (CH), 28.5 (CMe3), 19.0
(CHMeAMeB), 16.7 (CHMeAMeB).
(S)-26
Cb = CONiPr2
58%
1. PhMgBr, Et2O
–78 °C, 1 h then
warm to r.t., 90 min
OH
O
O
H
via:
B
Ph
Ph
Ph
2. H2O2(aq), NaOH
r.t., 30 min
60%
(R)-27
87:13 er
Ph
OCb
Scheme 8
MS (CI, NH3): m/z (%) = 283 (100) [M + H+], 227 (10).
In conclusion, we have developed a catalytic asymmetric
variant of the widely utilised ‘Hoppe reaction’. The key
feature of our ligand-exchange approach is the use of sub-
stoichiometric quantities of a chiral diamine [(+)-
sparteine surrogate 7 or (–)-sparteine] in conjunction with
an achiral, sterically hindered ‘regenerating’ diamine 12.
It is interesting to note that the (+)-sparteine surrogate
leads to higher enantioselectivity than (–)-sparteine under
identical catalytic conditions. The first examples of the
use of our catalytic asymmetric deprotonation methodol-
ogy in natural product synthesis have also been described.
HRMS: m/z [M + H+] calcd for C15H26N2O3: 283.2022; found:
283.2018.
tert-Butyl 7-Isopropyl-3,7-diazabicyclo[3.3.1]nonane-3-
carboxylate (15)
p-Toluenesulfonyl hydrazide (8.00 g, 42.9 mmol) was added por-
tionwise to a stirred solution of bispidinone 14 (11.0 g, 39.0 mmol)
in EtOH (100 mL) at r.t. under N2. The resulting solution was stirred
and heated at reflux for 4 h. After being allowed to cool to r.t., the
solvent was evaporated under reduced pressure. The residue was
dissolved in THF–H2O (9:1, 100 mL) and NaBH4 (5.00 g, 132.3
mmol) was added portionwise over 30 min. The resulting mixture
was stirred at r.t. for 16 h and then heated at reflux for 4 h. After be-
ing allowed to cool to r.t., H2O (30 mL) was added and the layers
were separated. The aqueous layer was extracted with Et2O (3 × 40
mL). Then, the combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure to give the crude product. Puri-
fication by flash column chromatography on silica with PE–EtOAc
(4:1) as eluent gave N-Boc bispidine 15 (8.6 g, 82%) as a colourless
oil; Rf = 0.2 (PE–Et2O, 7:3).
General experimental details have been reported previously.28 Et2O
and THF were freshly distilled from benzophenone ketyl or dried
after degassing with N2 by use of a MBraun solvent purification sys-
tem in which the solvents were passed through a column of 3-Å mo-
lecular sieves under a positive pressure of N2. (–)-Sparteine and
diamines 7, 8, 10, 11 and 12 were distilled from CaH2 before use. s-
BuLi was titrated against N-benzylbenzamide before use. PE refers
to the fraction of petroleum ether with a boiling point range of 40–
60 °C. For Kugelrohr distillation, the temperatures quoted corre-
spond to the oven temperatures.
IR (film): 2967, 2931, 1692 (C=O), 1426, 1363, 1179, 1136 cm–1.
1H NMR (400 MHz, CDCl3; rotamers): d = 4.14 (d, J = 13.0 Hz, 1
H, CHNBoc), 4.01 (d, J = 13.0 Hz, 1 H, CHNBoc), 3.07 (dd,
J = 13.0, 1.0 Hz, 1 H), 2.99 (dd, J = 13.0, 1.5 Hz, 1 H), 2.89 (d,
J = 10.5 Hz, 1 H), 2.82 (d, J = 10.5, 1 H), 2.51 (sept, J = 6.5 Hz, 1
H, CHMe2), 2.42 (d, J = 10.5 Hz, 1 H), 2.36 (d, J = 10.5 Hz, 1 H),
1.79 (br s, 1 H), 1.74 (br s, 1 H), 1.65 (d, J = 12.0 Hz, 1 H, CHAHB),
1.56 (d, J = 12.0 Hz, 1 H, CHAHB), 1.44 (s, 9 H, CMe3), 0.95 (d,
J = 6.5 Hz, 3 H, CHMeAMeB), 0.91 (d, J = 6.5 Hz, 3 H,
CHMeAMeB).
13C NMR (100.6 MHz, CDCl3; rotamers): d = 155.0 (C=O), 78.4
(CMe3), 54.3 (CH2N), 54.1 (CHN), 53.2 (CH2N), 48.8 (CH2N), 47.7
(CH2N), 31.8 (CH2), 29.3 (CH), 29.1 (CH), 28.6 (CMe3), 18.5
(CHMeAMeB), 17.2 (CHMeAMeB).
Optical rotations were recorded at 20 °C on a Jasco DIP-370 pola-
rimeter and [a]D measurements are given in units of 10–1 deg cm2 g–1.
Chiral stationary phase HPLC was performed on a Gilson system
with 712 controller software and a 118 UV/Vis diode array detector
or on a Waters system with a Waters 255 pump and a Waters 2420
ELS light scattering detector or a Waters 2487 UV detector. GC was
performed on an Agilent 6890 gas chromatograph fitted with an Ag-
ilent H-5 capillary column (30 m × 0.25 mm × 0.25 mm), injector
temperature 250 °C, detector temperature 250 °C using He as the
carrier gas. N-Boc-pyrrolidine 19,29 O-alkyl carbamate 130 and di-
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

2238
M. J. McGrath, P. O’Brien
PAPER
MS (CI, NH3): m/z (%) = 269 (100) [M + H+], 213 (20).
HRMS: m/z [M + H+] calcd for C15H28N2O2: 269.2229; found:
(m, 2 H, CH), 1.47–1.46 (m, 2 H, CH2), 0.99 (d, J = 6.5 Hz, 12 H,
CHMe2).
13C NMR (100.6 MHz): d = 54.0 (CHN), 52.4 (CH2N), 28.1 (CH2),
27.7 (CH), 18.2 (CHMe2).
269.2226.
3-Isopropyl-7-methyl-3,7-diazabicyclo[3.3.1]nonane (10)
A solution of N-Boc bispidine 15 (6.00 g, 22.4 mmol) in THF (15
mL) was added dropwise via cannula to a stirred suspension of
LiAlH4 (4.20 g, 111 mmol) in THF (30 mL) at r.t. under N2. The re-
sulting suspension was stirred and heated at reflux for 16 h. After
being allowed to cool to r.t., Na2SO4·10H2O (10.0 g) was added por-
tionwise over 10 min. The solids were removed by filtration through
Celite and the filter cake was washed with CH2Cl2 (2 × 50 mL). The
filtrate was dried (MgSO4) and evaporated under reduced pressure
to give the crude product. Purification by Kugelrohr distillation
gave bispidine 10 (0.90 g, 58%) as a colourless oil; bp 115–120 °C,
3 mmHg; Rf = 0.1 (PE–Et2O, 1:1).
HRMS: m/z [M + H+] calcd for C13H26N2: 211.2174; found:
211.2172.
Representative procedure for the results presented in Table 1
(Table 1, entry 3):
(R)-3-Phenyl-1-tributyltin-1-N,N-diisopropylcarbamoyloxy-
propane [(R)-3]
A solution of diamine (S,S)-8 (507 mg, 2.94 mmol) in Et2O (3 mL)
was added dropwise to a stirred solution of s-BuLi (3.0 mL, 1.0 M
soln in cyclohexane, 3.0 mmol) in Et2O (3.0 mL) at –78 °C under
Ar. After stirring for 10 min at –78 °C, a solution of O-alkyl car-
bamate 1 (512 mg, 2.10 mmol) in Et2O (3 mL) was added dropwise
and the resulting solution was stirred at –78 °C for 5 h. Then,
Bu3SnCl (0.8 mL, 2.94 mmol) was added dropwise and the solution
was allowed to warm to r.t. over 16 h. Aq 2 M HCl (10 mL) was
added, the layers were separated and the aqueous layer was extract-
ed with Et2O (3 × 10 mL). The combined Et2O layers were washed
with sat. aq KF (10 mL), dried (MgSO4) and evaporated under re-
duced pressure to give the crude product. Purification by flash chro-
matography using PE–Et2O 40:1 as eluent gave stannane (R)-3 (827
mg, 71%, 52:48 er) as a colourless oil.
1H NMR (400 MHz, CDCl3): d = 7.30 (t, J = 7.0 Hz, 2 H, m-Ph),
7.21–7.18 (m, 3 H, Ph), 4.70 (dd, J = 9.5, 5.0 Hz, 1 H, OCHSn),
4.23–4.03 (m, 1 H, CHMe2), 3.84–3.64 (m, 1 H, CHMe2), 2.77
(ddd, J = 13.0, 11.0, 5.0 Hz, 1 H, PhCHAHB), 2.65, (ddd, J = 13.0,
10.0, 6.0, 1 H, PhCHAHB), 2.29–2.18 (m, 1 H), 2.10–2.01 (m, 1 H),
1.67–1.44 (m, 6 H), 1.38–1.11 (m, 18 H), 1.04–0.80 (m, 15 H).
IR (film): 2962, 2924, 1460, 1278, 1181, 1157 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.71–2.62 (m, 5 H), 2.44–2.38 (m,
4 H), 2.18 (s, 3 H, NMe), 1.94 (br s, 2 H, CH), 1.59–1.55 (m, 1 H,
CHAHB), 1.35 (d, J = 12.0 Hz, 1 H, CHAHB), 1.01 (d, J = 6.5 Hz, 6
H, CHMe2).
13C NMR (100.6 MHz, CDCl3): d = 59.3 (CH2N), 54.1 (CHN), 53.0
(CH2N), 46.4 (NMe), 29.0 (CH2), 28.8 (CH), 17.9 (CHMe2).
MS (CI, NH3): m/z (%) = 183 (100) [M + H+], 167 (10).
HRMS: m/z [M + H+] calcd for C11H22N2: 183.1861; found:
183.1865.
3,7-Diisopropyl-3,7-diazabicyclo[3.3.1]nonane-9-one (17)
Isopropylamine (1.8 mL, 21.0 mmol) was added dropwise to a
stirred solution of N-isopropylpiperidone 16 (3.0 g, 21 mmol),
AcOH (1.3 mL, 22.0 mmol) and paraformaldehyde (1.8 g, 63
mmol) in MeOH (30 mL) at r.t. under N2. The resulting mixture was
stirred and heated at reflux for 16 h. After being allowed to cool to
r.t., the solvent was evaporated under reduced pressure. Then, 50%
aq KOH (100 mL) was added to the residue and the mixture was ex-
tracted with Et2O (3 × 100 mL). The combined Et2O extracts were
dried (MgSO4) and evaporated under reduced pressure to give the
crude product. Purification by Kugelrohr distillation gave bispidi-
none 17 (3.2 g, 69%) as a colourless oil; bp 220–240 °C, 2 mmHg
(Lit.21 110–120 °C, 10–5 mmHg).
[a]D –2.0 (c 1.0, CHCl3) {Lit.31 [a]D +21.9 (c 1.0, CHCl3) for (S)-3
of 98.5:1.5 er}.
Chiral HPLC: Daicel Chiralcel OD, hexane–i-PrOH (600:1), 0.5
mL min–1, 226 nm, ~6.5 min [(S)-3], ~7.0 min [(R)-3].
Spectroscopic data are identical to those reported.31
Representative procedure for the results presented in Table 2
(Table 2, entry 1):
(R)-3-Phenyl-1-tributyltin-1-N,N-diisopropylcarbamoyloxy-
propane [(R)-3]
IR (film): 2963, 1734 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 3.03 (dd, J = 10.0, 2.0 Hz, 4 H),
2.88 (dd, J = 10.0, 6.0 Hz, 4 H), 2.85–2.77 (m, 2 H, CHMe2), 2.73–
2.67 (m, 2 H, CH), 1.00 (d, J = 7.0 Hz, 12 H, CHMe2).
13C NMR (100.6 MHz): d = 215.8 (C=O), 53.5 (CH2N), 53.4
(CHN), 47.0 (CH), 18.2 (CHMe2).
A solution of (–)-sparteine (197 mg, 0.84 mmol) and diamine 7 (163
mg, 0.84 mmol) in Et2O (2.5 mL) was added dropwise to a stirred
solution of s-BuLi (1.34 mL of a 1.25 M soln in cyclohexane, 1.68
mmol) in Et2O (2.5 mL) at –78 °C under Ar. After stirring for 10
min at –78 °C, a solution of O-alkyl carbamate 1 (158 mg, 0.60
mmol) in Et2O (2 mL) was added dropwise and the resulting solu-
tion was stirred at –78 °C for 5 h. Then, Bu3SnCl (0.34 mL, 1.68
mmol) was added dropwise and the solution was allowed to warm
to r.t. over 16 h. Aq 2 M HCl (10 mL) was added, the layers were
separated and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined Et2O layers were washed with sat. aq KF (10
mL), dried (MgSO4) and evaporated under reduced pressure to give
the crude product. Purification by flash chromatography using PE–
Et2O 40:1 as eluent gave stannane (R)-3 (277 mg, 83%, 88:12 er) as
a colourless oil.
Spectroscopic data are identical to those reported.21
3,7-Diisopropyl-3,7-diazabicyclo[3.3.1]nonane (12)
Anhydrous hydrazine (4.9 mL, 150 mmol) was added dropwise to a
vigorously stirred suspension of bispidinone 17 (6.3 g, 28 mmol)
and KOH (20.0 g, 320 mmol) in diethylene glycol (60 mL) at r.t.
The resulting mixture was stirred and heated to 180 °C for 4 h. After
being allowed to cool to r.t., H2O (100 mL) was added and the mix-
ture was extracted with Et2O (4 × 50 mL). The combined Et2O ex-
tracts were washed with 20% aq NaOH (6 × 80 mL), dried (MgSO4)
and evaporated under reduced pressure to give the crude product as
a yellow oil. Purification by Kugelrohr distillation gave bispidine
12 (2.2 g, 38%) as a colourless oil; bp 130–160 °C, 2 mmHg.
[a]D –19.3 (c 1.2, CHCl3) {Lit.31 [a]D +21.9 (c 1.0, CHCl3) for (S)-
3 of 98.5:1.5 er}.
Chiral HPLC: Daicel Chiralcel OD, hexane–i-PrOH (600:1), 0.5
mL min–1, 226 nm, ~6.5 min [(S)-3], ~7.0 min [(R)-3].
Spectroscopic data are identical to those reported.31
IR (film): 2983, 2962, 1460, 1358, 1150 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.70–2.58 (m, 2 H, CHMe2), 2.55
(dd, J = 10.0, 5.5 Hz, 4 H) 2.49 (br d, J = 10.0 Hz, 4 H), 2.00–1.95
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

PAPER
Catalytic Asymmetric Variant of Hoppe’s O-Alkyl Carbamate Deprotonation Methodology
2239
[1,1-2H2]-3-Phenylpropanol (21)
2:1 by weight) and evaporated under reduced pressure to give the
crude product. Purification by flash chromatography using PE–
EtOAc (97:3) as eluent gave 2-trimethylsilyl-N-Boc-pyrrolidine
(S)-20 (356 mg, 64%, 94:6 er) as a colourless oil and deuterated car-
bamate 18 (660 mg, 76%) as a colourless oil.
A solution of 3-phenylpropionic acid (2.66 g, 14.6 mmol) in Et2O
(20 mL) was added dropwise to a stirred suspension of LiAlD4 (2.2
g, 52 mmol) at r.t. under N2. The resulting suspension was stirred at
r.t. for 1 h and then heated at reflux for 16 h. After being allowed to
cool to r.t., Na2SO4·10H2O was added portionwise over 10 min and
stirred for 30 min. The solids were removed by filtration through
Celite and the filter cake was washed with Et2O (100 mL). The fil-
trate was dried (MgSO4) and evaporated under reduced pressure to
give crude deuterated alcohol 21 (1.9 g, 94%) of sufficient purity for
use in the next step.
1H NMR (400 MHz, CDCl3): d = 7.33–7.19 (m, 5 H, Ph), 2.72 (t,
J = 7.0 Hz, 2 H, CH2Ph), 1.90 (t, J = 7.0 Hz, 2 H, CH2CD2), 1.53
(br s, 1 H, OH).
13C NMR (100.6 MHz): d = 141.8 (ipso-Ph), 128.39 (Ph), 128.38
(Ph), 125.8 (Ph), 61.5 (quin, J = 23.0 Hz, CD2), 34.0 (CH2Ph), 32.0
(CH2CD2).
Data for 2-trimethylsilyl-N-Boc-pyrrolidine (S)-20:
[a]D +60.9 (c 1.1, CHCl3) {Lit.11 [a]D +69.4 (c 2.2, CHCl3) for (S)-
20 of 97:3 er}.
Chiral GC: Betadex 120, 20 m × 0.25 mm i.d. (b-cyclodextrin), T
95 °C isothermal, He carrier gas at 14 psi constant pressure, ~100
min [(S)-20], ~103 min [(R)-20].
Spectroscopic data are identical to those reported.11
Representative procedure for the results presented in Table 3
(Table 3, entry 6):
(R)-3-Phenyl-1-tributyltin-1-N,N-diisopropylcarbamoyloxy-
propane [(R)-3]
Spectroscopic data are identical to those reported.23
A solution of diamine 7 (100 mg, 0.515 mmol, 0.2 equiv) and bis-
pidine 12 (650 mg, 3.10 mmol, 1.2 equiv) in Et2O (4 mL) was added
dropwise to a stirred solution of s-BuLi (3.0 mL of a 1.1 M soln in
cyclohexane, 3.3 mmol) in Et2O (4 mL) at –78 °C under Ar. After
stirring for 10 min at –78 °C, a solution of O-alkyl carbamate 1 (628
mg, 2.58 mmol) in Et2O (3 mL) was added dropwise and the result-
ing solution was stirred at –78 °C for 5 h. Then, Bu3SnCl (0.91 mL,
3.35 mmol) was added dropwise and the solution was allowed to
warm to r.t. over 16 h. 2 M aq HCl (10 mL) was added, the layers
were separated and the aqueous layer was extracted with Et2O (3 ×
10 mL). The combined Et2O layers were washed with sat. aq KF (10
mL), dried (MgSO4) and evaporated under reduced pressure to give
the crude product. Purification by flash chromatography using PE–
Et2O (40:1) as eluent gave stannane (R)-3 (1.02 g, 72%, 94:6 er) as
a colourless oil; [a]D –22.0 (c 1.4, CHCl3) {Lit.31 [a]D +21.9 (c 1.0,
CHCl3) for (S)-3 of 98.5:1.5 er}.
N,N-Diisopropylcarbamoyloxy-[1,1-2H2]-3-phenylpropanol
(18)
A solution of deuterated alcohol 21 (1.90 g, 13.7 mmol) in Et2O (10
mL) was added dropwise to a stirred suspension of sodium hydride
(680 mg of a 60% dispersion in mineral oil, 15.0 mmol) [which had
been pre-rinsed with Et2O (2 × 15 mL)] in Et2O (20 mL) at r.t. under
N2. The resulting solution was stirred for 30 min at r.t. (during
which time gas evolution took place). A solution of diisopropylcar-
bamoyl chloride (1.8 g, 11 mmol) in Et2O (10 mL) was added drop-
wise. The resulting solution was stirred for 16 h at r.t. Then, aq 2 M
HCl (20 mL) and Et2O (20 mL) were added. The layers were sepa-
rated and the aqueous layer was extracted with Et2O (2 × 20 mL).
The combined organic layers were dried (NaHCO3/MgSO4, 1:1 by
weight) and evaporated under reduced pressure to give the crude
product as a yellow oil. Purification by flash chromatography using
PE–Et2O (6:1) as eluent gave deuterated carbamate 18 (2.25 g,
76%) as a colourless oil; Rf = 0.45 (PE–Et2O, 5:1).
Chiral HPLC: Daicel Chiralcel OD, hexane–i-PrOH (600:1), 0.5
mL min–1, 226 nm, ~6.5 min [(S)-3], ~7.0 min [(R)-3].
Spectroscopic data are identical to those reported.31
IR (film): 1689 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.31–7.20 (m, 5 H, Ph), 4.30–4.09
(m, 1 H, CHN), 3.87–3.69 (m, 1 H, CHN), 2.73 (t, J = 7.5 Hz, 2 H,
CH2Ph), 1.98 (t, J = 7.5 Hz, 2 H, CH2CD2) 1.23 (d, J = 7.0 Hz, 12
H, CHMe2).
13C NMR (100.6 MHz, CDCl3): d = 155.8 (C=O), 141.6 (ipso-Ph),
128.38 (Ph), 128.36 (Ph), 125.9 (Ph), 63.4 (quin, J = 23.0 Hz, CD2),
46.1 (br, CHN), 45.3 (br, CHN), 32.5 (CH2Ph), 30.7 (CH2CD2),
21.2 (br, CHMeAMeB), 20.8 (br, CHMeAMeB).
(S)-3-Phenyl-1-hydroxymethyl-1-N,N-diisopropylcarbamoyl-
oxypropane [(S)-23]
A solution of diamine 7 (86 mg, 0.44 mmol, 0.2 equiv) and bispi-
dine 12 (531 mg, 2.52 mmol, 1.2 equiv) in Et2O (2 mL) was added
dropwise to a stirred solution of s-BuLi (2.73 mL of a 1.1 M soln in
cyclohexane, 2.73 mmol) in Et2O (3 mL) at –78 °C under Ar. After
stirring for 10 min at –78 °C, a solution of O-alkyl carbamate 1 (555
mg, 2.11 mmol) in Et2O (2 mL) was added dropwise and the result-
ing solution was stirred at –78 °C for 5 h. Then, a stream of CO2 gas
was passed over the solution for 20 min. H2O (5 mL) and 35% aq
HCl(1 mL) were added and the solution was allowed to warm to r.t.
over 10 min. The layers were separated and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts
were dried (MgSO4) and evaporated under reduced pressure to give
the crude carboxylic acid 22 (740 mg). To a stirred solution of this
crude carboxylic acid 22 in THF (30 mL) at 0 °C under N2 was add-
ed BH3·SMe2 (10.0 mL of a 1.0 M soln in THF, 10.0 mmol). The
resulting solution was stirred at r.t. for 16 h and MeOH (10 mL) was
cautiously added over 15 min. The mixture was stirred at r.t. for 1 h
and then heated at reflux for 1 h. After being allowed to cool to r.t.,
the solvent was evaporated under reduced pressure to give the crude
product. Purification by flash chromatography using PE–EtOAc
(9:1) as eluent gave alcohol (S)-23 (482 mg, 78% over two steps) as
a white solid; mp 55–57 °C; Rf = 0.3 (PE–EtOAc, 1:1); [a]D –25.1
(c 0.4, CHCl3).
MS (CI, NH3): m/z (%) = 183 (100) [M + H+], 167 (10).
HRMS: m/z [M + H+] calcd for C16H232H2NO2: 266.2089; found:
266.2087.
Experiment to Demonstrate Reversibility of Complexation of
s-BuLi/(–)-Sparteine to an O-Alkyl Carbamate (Scheme 5):
s-BuLi (2.7 mL of a 1.1 M soln in cyclohexane, 2.95 mmol, 0.9
equiv) was added dropwise to a stirred solution of (–)-sparteine
(691 mg, 2.95 mmol, 0.9 equiv) in Et2O (3 mL) at –78 °C under Ar.
After stirring for 5 min at –78 °C, a solution of deuterated carbam-
ate 18 (869 mg, 3.28 mmol, 1.0 equiv) in Et2O (4 mL) was added
dropwise. The resulting solution was stirred at –78 °C for 30 min.
Then, a solution of N-Boc pyrrolidine 19 (392 mg, 2.29 mmol, 0.7
equiv) in Et2O (4.0 mL) was added and the resulting solution was
stirred at –78 °C for 5 h. Then, Me3SiCl (0.50 mL, 3.94 mmol, 1.2
equiv) was added and the reaction mixture was allowed to warm to
r.t. over 16 h. Sat. aq NH4Cl (10 mL) was added, the layers were
separated and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried (MgSO4/NaHCO3,
IR (film): 3429 (OH), 2966, 2932, 2873, 1666 (C=O) cm–1.
Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York

2240
M. J. McGrath, P. O’Brien
PAPER
1H NMR (400 MHz, CDCl3): d = 7.32–7.28 (m, 2 H, Ph), 7.22–7.18
(m, 3 H, Ph), 4.93–4.86 (m, 1 H, CHO), 4.20–4.00 (m, 1 H,
CHMe2), 3.95–3.70 (m, 1 H, CHMe2), 3.73 (dd, J = 12.0 Hz, 3.0, 1
H, CHAHBOH), 3.70 (dd, J = 12.0, 7.0 Hz, 1 H, CHAHBOH), 2.81–
2.66 (m, 2 H, CH2Ph), 2.05–1.85 (m, 2 H, CH2), 1.25 (d, J = 7.0 Hz,
12 H, CHMe2).
13C NMR (100.6 MHz, CDCl3): d = 156.5 (C=O), 141.4 (ipso-Ph),
128.5 (Ph), 128.3 (Ph), 126.1 (Ph), 76.4 (CHO), 66.2 (CH2O), 46.3
(br, CHN), 45.6 (br, CHN), 33.1 (CH2), 31.9 (CH2), 21.3 (br,
CHMe2), 20.6 (br, CHMe2).
Hz, 1 H, PhCHAHB), 2.72 (ddd, J = 14.0, 9.0, 6.0 Hz, 1 H, Ph-
CHAHB), 2.09–1.89 (m, 2 H), 1.26–1.18 (m, 24 H).
Spectroscopic data are identical to those reported.27
(R)-1,3-Diphenylpropan-1-ol [(R)-27]
PhMgBr (0.22 mL of a 3.0 M soln in Et2O, 0.66 mmol) was added
dropwise over 5 min to a stirred solution of borate ester (S)-26 (126
mg, 0.32 mmol) in Et2O (4 mL) at –78 °C under Ar. The resulting
solution was stirred at –78 °C for 1 h and then allowed to warm
slowly to r.t. over 90 min. Then, the reaction mixture was filtered
through a plug of silica (1.0 g) with pentane (20 mL) and Et2O (10
mL) as eluent. The filtrate was evaporated under reduced pressure.
To a stirred solution of the resulting residue in THF (5 mL) at r.t.,
aq 0.5 M NaOH (0.7 mL, 0.35 mmol) was added. After stirring for
5 min, aq 35% H2O2 (0.05 mL, 0.35 mmol) was added and the reac-
tion mixture was stirred at r.t. for 30 min. Then, H2O (5 mL) was
added, the layers were separated and the aqueous layer was extract-
ed with Et2O (3 × 10 mL). The combined organic layers were
washed with sat. aq FeSO4 (5 mL), dried (MgSO4) and evaporated
under reduced pressure to give the crude product. Purification by
flash chromatography using PE–EtOAc (9:1) as eluent gave alcohol
(R)-27 (41 mg, 60%, 87:13 er) as a colourless oil, which crystallised
on standing to a white solid; mp 38–41 °C (Lit.26 48–49 °C); [a]D
+16.7 (c 0.4, CH2Cl2) {Lit.26 [a]D +26 (c 0.7, CH2Cl2) for (R)-27}.
MS (CI, NH3): m/z (%) = 294 (100) [M + H+].
HRMS: m/z [M + H+] calcd for C17H27NO3: 294.2069; found:
294.2069.
(S)-4-Phenyl-1,2-butanediol [(S)-24]
LiAlH4 (632 mg, 16.6 mmol) was added portionwise over 10 min to
a stirred solution of alcohol (S)-23 (410 mg, 1.40 mmol) in THF (20
mL) at r.t. under N2. The resulting suspension was stirred and heated
at reflux for 24 h. After being allowed to cool to r.t., Na2SO4·10H2O
(3.0 g) was added portionwise and the mixture was stirred at r.t. for
1 h. The solids were removed by filtration through Celite and the fil-
ter cake was washed with Et2O (20 mL), 9:1 CHCl3–MeOH (100
mL) and MeOH (50 mL). The filtrate was dried (MgSO4) and evap-
orated under reduced pressure to give the crude product. Purifica-
tion by flash chromatography using CHCl3–MeOH (19:1) as eluent
gave diol (S)-24 (98 mg, 42%, 91:9 er) as a colourless oil; [a]D –22.5
(c 1.9, EtOH) {Lit.25 [a]D –34 (c 1.33, EtOH)}.
Chiral HPLC: Daicel Chiralcel OD, hexane–i-PrOH (19:1), 0.5 mL
min–1, 254 nm, 38.2 min [(S)-27], 43.5 min [(R)-27].
1H NMR (400 MHz, CDCl3): d = 7.29–7.08 (m, 10 H, Ph), 4.61 (dd,
J = 8.0, 5.5 Hz, 1 H, CHO), 2.72–2.54 (m, 2 H, PhCH2), 2.10–1.91
(m, 2 H, CH2CHO), 1.85 (br s, 1 H, OH).
13C NMR (100.6 MHz, CDCl3): d = 144.5 (ipso-Ph), 141.7 (ipso-
Ph), 128.5 (Ph), 128.4 (Ph), 128.4 (Ph), 127.7 (Ph), 125.91 (Ph),
125.85 (Ph), 73.9 (CHO), 40.5 (CH2), 32.1 (CH2).
Chiral HPLC: Daicel Chiralcel OD, hexane–i-PrOH (4:1), 0.5 mL
min–1, 254 nm, 14.5 min [(R)-24], 18.5 min [(S)-24].
1H NMR (400 MHz, CDCl3): d = 7.31–7.28 (m, 2 H, Ph), 7.23–7.19
(m, 3 H, Ph), 3.75–3.69 (m, 1 H, CHOH), 3.65 (dd, J = 11.0, 3.0 Hz,
1 H, CHAHBOH), 3.46 (dd, J = 11.0, 7.5 Hz, 1 H, CHAHBOH),
2.83–2.65 (m, 4 H), 1.79–1.72 (m, 2 H).
Spectroscopic data are identical to those reported.26
13C NMR (100.6 MHz, CDCl3): d = 142.6 (ipso-Ph), 128.44 (Ph),
128.38 (Ph), 126.0 (Ph), 71.5 (CH2O), 66.8 (CHO), 34.6 (CH2),
31.8 (CH2).
Acknowledgment
We thank the EPSRC for funding (of M.J.M.) and The Royal Socie-
ty of Chemistry for the award of a JWT Jones Travelling Fellowship
(to P.O’B.) for a sabbatical stay at the University of Geneva. We are
particularly grateful to Susannah Coote for some characterisation
data.
Spectroscopic data are identical to those reported.25
(S)-Diisopropylcarbamic Acid 1-(4,4,5,5-Tetramethyl[1,3,2]di-
oxaborolan-2-yl)-3-phenylpropyl Ester [(S)-26]
s-BuLi (2.00 mL of a 1.1 M soln in cyclohexane, 2.20 mmol) was
added dropwise to a stirred solution of (–)-sparteine (79 mg, 0.34
mmol, 0.2 equiv) and bispidine 12 (423 mg, 2.01 mmol, 1.2 equiv)
in Et2O (4 mL) at –78 °C under Ar. After stirring for 15 min at
–78 °C, a solution of O-alkyl carbamate 1 (441 mg, 1.68 mmol) in
Et2O (3 mL) was added dropwise and the resulting solution was
stirred at –78 °C for 5 h. Then, triisopropylborate (0.58 mL, 2.52
mmol) was added dropwise and the resulting solution was stirred at
–78 °C for 2 h. Aq 2 M HCl (5 mL) was added, the layers were sep-
arated and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were dried (MgSO4) and evaporated
under reduced pressure to give the crude product. A solution of this
crude product in CH2Cl2 (6 mL) and added dropwise via cannula to
a stirred mixture of pinacol (297 mg, 2.52 mmol), p-TsOH·H2O (70
mg, 0.36 mmol) and MgSO4 (1.0 g). The resulting suspension was
stirred at r.t. for 20 h. The solids were removed by filtration and the
filter cake was washed with Et2O (30 mL). The filtrate was evapo-
rated under reduced pressure to give the crude product. Purification
by flash chromatography using cyclohexane–-EtOAc (5:1) as eluent
gave borate ester (S)-26 (376 mg, 58%) as a colourless oil; [a]D
+34.9 (c 0.6, CH2Cl2) {Lit.27 [a]D +36.7 (c 0.97, CH2Cl2)}.
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Synthesis 2006, No. 13, 2233–2241 © Thieme Stuttgart · New York