Enantioselective alkene radical cations reactions

Article abstract of DOI:10.1016/j.tet.2006.03.063

The reaction of enantiomerically enriched 2-methyl-2-nitro-3-(diphenylphosphatoxy)alkyl radicals with tributyltin hydride and AIBN in benzene at reflux results in the formation of alkene radical cation/anion pairs, which are trapped intramolecularly by am

Full text of DOI:10.1016/j.tet.2006.03.063

Tetrahedron 62 (2006) 6501–6518
Enantioselective alkene radical cations reactions
*
David Crich, Michio Shirai, Franck Brebion and Sochanchingwung Rumthao
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 6 September 2005; accepted 12 November 2005
Available online 2 May 2006
Abstract—The reaction of enantiomerically enriched 2-methyl-2-nitro-3-(diphenylphosphatoxy)alkyl radicals with tributyltin hydride and
AIBN in benzene at reflux results in the formation of alkene radical cation/anion pairs, which are trapped intramolecularly by amine nucleo-
philes, leading to pyrrolidine and piperidine systems with memory of stereochemistry. The scope and limitations of the system are explored
with respect to nucleophile, leaving group, and substituents within the substrate backbone.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
that alkyl radicals substituted with a leaving group in the
b-position expel the leaving group to afford contact alkene
radical cation/anion pairs even in nonpolar solvents.3 In
polar solvents supporting charge separation these contact ion
pairs undergo equilibration with the medium leading to sol-
vent separated ion pairs and even free radical cations and the
corresponding anions. This type of behavior is seen under
anaerobic conditions with DNA C04 radicals when the C03-
phosphate group is expelled leading to the C30C40 alkene
radical cation, such as has been so productively employed as
a ‘hole’ source in the study of charge transfer through DNA
by Giese.4 In nonpolar solvents collapse of the contact al-
kene radical cation/anion pair to either the original radical or
a rearranged radical is extremely rapid, typically out compet-
ing equilibration of the components of the contact ion pair.
This extremely rapid recombination is now seen as the basis
for a number of regio-5 and stereoselective5a,6 rearrange-
ments that were originally interpreted as open-shell con-
certed processes (Schemes 2 and 3).7 Computational work
in this area, while originally supportive of the concerted
mechanisms, has evolved and now points to the fragmenta-
tion/recombination mechanisms for these rearrangements.8
Alkene radical cations generated within the confines of con-
tact ion pairs by the expulsion of leaving groups from the b-
position of radicals participate in stereoselective cyclization
reactions with suitably placed amines. This concept was
demonstrated (Scheme 1) with an extensive series of sub-
strates carrying methyl groups on the carbon backbone,
with the results best accommodated by a chair-like transition
state for cyclization with the maximum number of substitu-
ents pseudo-equatorial.1
O
O
P(OPh)2
Bn
N
H
N
R
O
R'
P(OPh)2
Bu3Sn
R'
R''
R''
NHBn
O
Bn
NO2
R
R''
R
R'
Scheme 1. Preferred model for diastereoselective alkene radical cation
cyclizations.1
In this paper we report in full on a parallel series of experi-
ments in which all stereogenic centers are destroyed on for-
mation of the alkene radical cation, leaving the operation of
a memory effect as the only explanation for the observed
enantioselectivity.2
In parallel with the mechanistic studies we have developed
a series of preparative methods in which nucleophilic attack,
inter- or intramolecular, on the contact radical ion pair takes
place in competition with collapse to a rearranged radical in
nonpolar solvents. When this nucleophilic trapping is fol-
lowed up by a radical cyclization the overall tandem polar/
radical crossover sequence affords diverse bicyclic systems
depending on the substitution pattern (Scheme 4).9
2. Results and discussion
Working in collaboration with Newcomb we have estab-
lished, using time resolved laser flash photolytic techniques,
The combination of the stereoselectivity of the rearrange-
ment reactions (Schemes 2 and 3), which implies rapid col-
lapse of a highly ordered contact radical ion pair, coupled
* Corresponding author. Tel.: +1 312 996 5189; fax: +1 312 996 0431;
e-mail: dcrich@uic.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.063

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D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
O
O
O
(EtO)2P
(EtO)2P
O
(EtO)2P
D
O
(EtO)2P
D
D
O
D
O
D
O
PhSe
Bu3Sn
+
O
P(OEt)2
O
Bu3SnH
O
O
O
O
(EtO)2P
(EtO)2P
(EtO)2P
(EtO)2P
D
D
O
O
D
O
O
D
+
+
+
:
:
benzene (80 °C)
t-butanol (80 °C)
5
10
>95
<<90
Scheme 2. Changing regioselectivity of a b-phosphatoxyalkyl radical rearrangement as a function of solvent.5,6
O
O
O
O
O
O
O
O
O
O
O
O
P
P
P
P
+
O
O
O
O
Ph
Br
Ph
Ph
Ph
Br
Bu3SnH
2.33
1
:
:
1
2.84
Bu3SnH
Benzene, 80 °C
Benzene, 80 °C
Scheme 3. Stereoselective rearrangement with predominant retention of configuration at phosphorus.5
with the polar/radical crossover reactions (Scheme 4), and
the implicit faster rates of nucleophilic trapping than ion
pair collapse, lead directly to the hypothesis of stereoselec-
tive nucleophilic trapping reactions in which the order of the
contact radical ion pair is reflected in the stereochemistry of
the product.
enriched b-(phosphatoxy)nitroalkanes, the precursors of
choice in these tin hydride mediated polar radical crossover
sequences, which we accessed by Corey oxazaborolidine-
catalyzed reduction of a-nitroketones.10
The synthesis of a first pair of substrates, 11 and 12, was
accomplished as set out in Scheme 5.
O
Bn
BocN
Ph
NO2
P(OPh)2
O
O
O
NO2
OH
NO2
Ph3SnH, AIBN, C6H6, ∆, 85%
Boc
O
n
Ph
N
t-BuOK
NBn
n
N
H
n
(+/-)-3: n = 1, 94%
(+/-)-4: n = 2, 92%
1: n = 1
2: n = 2
Bu3Sn
Bu3SnH
Swern
Bn
BocN
Bn
BocN
O
O
Ph
Ph
OH
NO2
OH
Ph
Ph
P(OR)2
P(OR)2
O
O
NO2
O
N
H
Ph
Ph
HN
HN
N
n
cat
N
n
BH3THF
7: n = 1, 72%, 85% ee
8: n = 2, 78%, 86% ee
5: n = 1, 88%
6: n = 2, 93%
Scheme 4. Example of a polar/radical crossover sequence.9c,d
(PhO)2POCl
Bn
As discussed above, the hypothesis of memory effects in al-
kene radical cation reactions was first put to the test at the
level of diastereoselectivity leading to the model of Scheme
1. In this system the amine attacks the face of the alkene
radical cation opposite to that shielded by the just departed
leaving group through a chair-like transition state with
a maximum number of substituents pseudo-equatorial. The
second generation system described here is enantioselective
and requires the synthesis of a series of enantiomerically
Bn
HN
BocN
NO2
NO2
TFA
O
P(OPh)2
O
n
P(OPh)2
O
n
O
9: n = 1, 98%
10: n = 2, 100%
11: n = 1, 99%
12: n = 2, 95%
Scheme 5. Synthesis of substrates 11 and 12.

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
OH
6503
O
In order to compare the effect of the leaving group the di-
ethylphosphate analog 14 of one of these substrates was
also prepared (Scheme 6).
PCC
63%
NBoc
X
NBoc
Bn
NO2
27
25: X = H
NaH,
BnBr
45%
Bn
BocN
Bn
N
i) (EtO)2PCl
,
NO2
OH
X
NO2
P(OEt)2
26: X = Bn
t-BuOK
ii) TBHP, 56%
O
O
NO2
(PhO)2P
92%
7
O
O
NO2
HO
13: X = Boc
14: X = H
TFA,
93%
(PhO)2POCl
94%
NBn
X
NBoc
Bn
Scheme 6. Synthesis of a diethylphosphate 14.
29: X = Boc
TFA,
91%
28
With a view to determining the influence of the ‘gem-disub-
stituent’ effect11 on the diastereoselectivity substrate 24,
bearing a quaternary carbon center, was synthesized by the
route outlined in Scheme 7.
30: X = H
Scheme 8. Preparation of an aniline-base substrate 30.
Bn
BocN
PdCl2, H2
,
NO2
P(OPh)2
BocHN
NO2
O P(OPh)2
CO2Et
OH
LiAlH4,
95%
MeOH, 97%
Bn
15: X = H
X
Bn
X
Bn
17
O
i) Swern
LDA,
BnBr,
89%
O
O
9
31
ii) BnNH2,
NaBH3CN,
76%
16: X = Bn
NBn
Br
NaH,
92%
i) O3
NO2
Bn
BocN
Bn Bn
18: X = H
NO2
OH
ii)
TFA
99%
Boc2O,
HN
NO2
BocN
NO2
Bn
Bn
96%
19: X = Boc
t-BuOK, 18%
O
P(OPh)2
O
P(OPh)2
20
O
O
i) TFA
Bn
BocN
33
32
ii) Swern,
86%
Ph
Ph
OH
NO2
OH
Scheme 9. Synthesis of a propargylic substrate.
i)
Bn
HN
N
H
cat
Bn
Bn
NO2
substituted variant proved more problematic owing to cycli-
zation of the newly revealed alcohol onto the phosphate in
the course of the final desilylation, with isolation of the
1,3,2-dioxaphosphepane 46 (Scheme 11). This problem,
which could only be overcome by switching to the less
electrophilic diethylphosphate, also reared its head in the
attempted polar/radical cyclization of racemic 48, as dis-
cussed below, and consequently no attempt was made to
obtain this compound in enantiomerically enriched form.
Bn
Bn
O
BH3SMe2
ii) Boc2O, 70%
22
21
EtOP(OPh)2, I2
75%
Bn
HN
Bn
BocN
NO2
NO2
TFA
96%
Bn
Bn
O
P(OPh)2
Bn
Bn
O
P(OPh)2
O
O
24
Scheme 7. Synthesis of substrate 24.
23
A common feature of the above syntheses is the borane
reduction of a-nitroketones catalyzed by the Corey oxaza-
borolidine catalyst. For ease of comparison the various
reductions are presented in Table 1. The absolute stereo-
chemistry of the nitroalcohols obtained from these reduc-
tions is assigned according to the standard model of Corey
for the oxazaborolidine reduction of disymmetrically
substituted ketones,13 with the 1-methyl-1-nitroethyl group
playing the role of the most bulky substituent. The applicabil-
ity of this model to the a-nitroketones was rigorously estab-
lished in our earlier model studies.10 It is noteworthy that
moderate to good enantioselectivities were obtained in all
instances, with only a minor reduction due to the presence
of the quaternary center in 21.
Yet another substrate, conformationally biased 30, was
obtained from the aniline derivative 25 (Scheme 8).12 Sub-
strate 30 was prepared only in racemic form, as a control
experiment indicated that it did not undergo cyclization on
treatment with tributyltin hydride under the usual condi-
tions, as discussed below.
A substrate for a tandem polar/radical process in which the
nucleophilic cyclization is followed by a radical cyclization
was prepared from 9 by a process in which a benzyl group
was exchanged for a propargyl moiety (Scheme 9).
Two substrates incorporating alcohol rather than amine
nucleophiles were accessed as described in Schemes 10
and 11. Whereas the synthesis of the simple substrate 41
was straightforward (Scheme 10), that of the gem-dialkyl
The polar/radical crossover reactions were conducted with
tributylstannane and AIBN in benzene at 80 ꢀC leading to
the results presented in Table 2. The enantioselectivities
were determined by either chiral GC or HPLC as appropriate.

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D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
Cl
N
N
NOH
NO2
Cl
NO2
NaBH4, EtOH
48%
Cl
N
Cl
28%
Ph Ph
Ph Ph
Ph Ph
35
34
36
t-BuOK
O
OTBS
Ph
Ph
OH
OH
N
H
O
O2N
O2N
Swern
cat
Ph
Ph
OTBS
Ph
Ph
OTBS
62%
BH3SMe2,
37
38
87%
O
P(OPh)2
O
OH
O2N
O2N
(PhO)2POCl,
74%
X
O
Ph
Ph
Ph
OTBS
Ph
40: X = TBS
41: X = H
39
HF, MeCN,
63%
Scheme 10. Synthesis of substrate 41.
Table 1. Enantiomerically enriched nitro alcohols obtained by CBS reduc-
tion of a-nitroketones
OTBS
OTBS
NO2
O3,
O
TBSO
Bn
NO2
OH
96%
Bn Bn
Bn Bn
Nitro alcohol
% Yield
% ee
t-BuOK, 81%
Bn
42
43
Bn
44
BocN
NO2
OH
72
85
EtOP(OPh)2, I2
46%
7
i) (EtO)2PCl, ii) t-BuOOH, 58%
NO2
BnN
Boc
78
70
86
79
TBSO
Bn
NO2
TBSO
Bn
NO2
P(OEt)2
OH
8
O
P(OPh)2
O
O
Bn
Bn
BocN
Bn
45
O
NO2
OH
47
HF, MeCN,
70%
Bn
Bn
HF, MeCN,
58%
O
P
22
OPh
O
HO
Bn
NO2
O
Ph
O2N
Ph
TBSO
O
P(OEt)2
Bn
Bn
O
Bn
46
87
96
48
NO2
OH
39
Scheme 11. Preparation of substrate 48.
The absolute configuration of pyrrolidine 49 was established
by hydrogenolytic debenzylation and subsequent tosylation
to give the sulfonamide 57, whose specific rotation was com-
pared to the literature value (Scheme 12).14,15 As all success-
ful cyclizations in Table 2, with the exception of alcohol 41,
gave comparable enantioselectivities it was not considered
necessary to rigorously establish the configuration of all
products, which consequently were assigned by analogy
with 49.
size (five or six), leaving group (diphenyl or diethylphos-
phate), nor the presence of a normally rate enhancing quater-
nary center has major significance on the enantioselectivity
of these cyclizations. We interpret this result as arising from
an extremely rapid trapping of the contact radical cation/
anion pair once it is formed in what is probably the rate lim-
iting radical ionic fragmentation step. This observation is
consistent with the earlier study based on diastereoselectiv-
ity (Scheme 1) and the general rational presented above.
This is entirely reasonable given the intramolecular nature
of the attack on a simple trialkyl substituted alkene radical
Comparison of entries 1–4 and 6 in Table 2 indicates that in
the case of a secondary amine as nucleophile neither ring

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
Table 2. Enantioselective alkene radical cation cyclizations
6505
Entry
Substrate
Substrate % ee
Product
% Yield
43
% eea
Bn
H
NH
NO2
N
Bn
49
1
85
61 (71)
O
(PhO)2P
O
11
Bn
H
NH
NO2
N
Bn
49
2
3
85
86
45
41
62
O
(EtO)2P
O
14
BnNH
NO2
H
N
Bn
50
60 (70)
O
(PhO)2P
O
12
Bn
Bn
Bn
NH
NO2
H
Bn
Bn
4
79
44
60 (76)
O
N
Bn
51
(PhO)2P
O
24
O
NO2
(PhO)2P
O
5
(+/ꢂ)b
50
—
NHBn
52
NHBn
30
H
NH
NO2
N
6
85
64
60 (71)
O
53
(PhO)2P
O
33
O
OPh
O
O
O
HO
P
(PhO)2P
O
O
O2N
+
54: 25
55: 52
7
94
0
Ph
Ph
Ph
Ph
Ph Ph
41
54
55
OEt
O
O
HO
Bn
NO2
P
O
8
(+/ꢂ)b
67
—
O
P(OEt)2
O
Bn
Bn
Bn
48
56
a
Actual ee (ee predicated on enantiomerically pure substrate).
Reactions conducted with racemic material.
b
cation in a nonpolar solvent, in view of the 2.5ꢁ109 Mꢂ1 sꢂ1
rate constant determined for the intermolecular rate constant
for the attack of butylamine on the stabilized p-methoxystyr-
ene radical cation in the polar solvent acetonitrile at 25 ꢀC.16
Taking into account the absolute configurations of the
substrates and products, we are led to propose a model for
these cyclizations (Scheme 13) that is directly comparable
to the one advanced earlier for the diastereoselective cycliza-
tions. Thus, the initial radical undergoes rate determining
fragmentation to give an ordered contact alkyl radical

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D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
in the fragmentation step serves as source of chirality,
i) Pd(OH)2/C, H2
ii) TsCl, 45%
thereby eliminating the need for the synthesis of enantio-
merically enriched nitroalcohols. This approach, employing
a stereogenic phosphorus or sulfur center, may be viewed as
an extension of the diastereoselective probes of mechanism
reported in Scheme 3. Before undertaking the synthesis of
any enantiomerically enriched compounds a series of simple
models were prepared to test the viability of such an ap-
proach in the context of a tandem polar/radical reaction.
Thus, reaction of chlorosulfonyl isocyanate with nitro-
alcohol 589b,20 afforded the sulfamate 59 which, following
N-alkylation21 and subsequent removal of the carbamate
group, gave the radical precursor 60 (Scheme 14).
N
Bn
49
N
Ts
57: [α]23D -78.1°
Lit.14 [α]D -91.3°
Scheme 12. Establishment of absolute configuration.
cation/anion pair that suffers extremely rapid collapse to the
cyclized radical with attack of the nucleophile on the oppo-
site face of the alkene radical cation to the one shielded by the
counter-ion (Scheme 13). While this model bears some
resemblance to the widespread Beckwith/Houk model for
radical cyclization,17 it differs fundamentally in one key as-
pect. The Beckwith/Houk model requires full conformation
equilibration before cyclization through the most-favored
chair-like transition state, while the model of Schemes 1
and 13 implies very rapid cyclization before solvation of the
contact radical ion pair and conformational equilibration.18
O
O
S
NHBoc
O
1. t-BuOH, Hexane
ClSO2N=C=O
NO2
Ph
OH
2.
Ph
, Et3N
NO2
59, 84%
58
O
O
P(OR')2
O
O
O
R
N
H
N
O
(R'O)2P
S
Bu3Sn
N
1. DBU, allyl bromide 87%
2. TFA, DCM 41%
NHR
n
H
n
NO2
O
n
Ph
R
NO2
60
Scheme 13. Preferred model for enantioselective alkene radical cation
cyclizations.
Scheme 14. Synthesis of an N-allyl sulfamate.
In the phosphorus series an N-allyl phosphoramide 62
was prepared in straightforward manner as outlined in
Scheme 15.
The remaining entries of Table 2 serve to illustrate the limi-
tations of the method. Thus, with the much weaker aniline-
based nucleophile (entry 5) no cyclization was seen, leading
to decomposition of the alkene radical cation and the forma-
tion of a complex reaction mixture from which only the
alkene 52 was isolated. Alcohols are generally much poorer
nucleophiles than amines as is known to hold with alkene
radical cations as electrophiles, with the rate constants for
the attack of alcohols being slower than those of amines.16
This leads to a reduced rate of cyclization, enabling solvation
of the contact ion pair and conformational equilibration to be-
come competitive, leading overall to a reduction in enantio-
selectivity (Table 2, entry 7). Finally, a significant limitation
to the use of alcohols as nucleophiles in these cyclizations, at
least when conducted under refluxing conditions in benzene,
is seen in the formation of the 1,3,2-dioxaphosphepanes 55
and 56 (Table 2, entries 7 and 8). Given the reaction protocol,
with dropwise addition of the stannane to a solution of the
substrate in benzene at reflux, these cyclizations involving
nucleophilic attack at phosphorus presumably take place
before the radical reaction. The formation of the cyclic phos-
phepane ring should not prevent fragmentation to the alkene
radical cation, as we have previously demonstrated that suit-
ably substituted phosphepanes undergo a rearrangement
analogous to the one in Scheme 3 with rate constants of
105–106 sꢂ1 in benzene at 80 ꢀC with a very high degree of
retention of configuration at phosphorus.19 However, the in-
tramolecular nature of the contact radical cation/anion pair
generated from expulsion of the phosphepane leaving group
presumably accelerates internal return and thereby reduces
the possibility of nucleophilic attack by the alcohol.
PMB
O
N
P
OH
O
OPh
NO2
, THF
PhOPCl2
PMBHN
1.
2.
NO2
Ph
, THF
Ph
58
3. t-BuOOH, CH2Cl2
61, 67%
d.r. 1/1.3
O
OPh
P
O
N
CAN
CH3CN/H2O
H
NO2
Ph
62, 88%
Scheme 15. Synthesis of an N-allyl phosphoramide.
The synthesis of an N-allyl phosphorimidate 64, after some
experimentation, was also achieved in a straightforward
manner employing the Staudinger reaction22 of phosphite
63 with allyl azide (Scheme 16). In accordance with the
precedent for the Staudinger reaction with phosphites,23 as
opposed to the more common phosphines, reaction of allyl
azide with the diethylphosphite 63 proceeded according to
plan to give the unstable 64. However, reaction of allyl azide
with the corresponding diphenylphosphite corresponding to
63 was prohibitively slow.
Compounds 60, 62, and 64 were treated with tin hydride and
AIBN in benzene at reflux in the usual manner, unfortu-
nately, no evidence was found for any of the anticipated
We considered an alternative approach to enantioselective
alkene radical cation reactions in which the leaving group

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6507
P(OEt)2
NO2
thus, the formation of 68 was somewhat unexpected as the
1,1-dimethyl-2-diphenylphosphatoxy-2-phenylethyl radical
is known to rearrange in benzene at 20 ꢀC with a rate con-
OH
O
(EtO)2PCl
NO2
Ph
i
Ph
O
EtNPr2 (2 equiv.), THF
stant of 1.2ꢁ106 sꢂ1 3a
.
However, it should be noted that
58
63, 80%
the rates of b-phosphatoxyalkyl rearrangement are severely
influenced by substituents on phosphorus. For example, the
1,1-dimethyl-2-diethylphosphatoxy-2-phenylethyl radical
rearranges too slowly to measure by time resolved laser flash
photolysis in benzene (k<104 sꢂ1).3a,k,27 The failure of 62 to
rearrange in a formal 2,3-manner, preferring instead the 1,2-
mode, led us to the phosphorimidate 64 with the hope that
the exchange of a P]N double bond for a P]O would force
the rearrangement into the formal 2,3-mode of rearrange-
ment needed for the tandem polar/radical crossover process.
We were encouraged in this direction by recent publication
of the 3,3-sigmatropic rearrangements of O-allyl phosphor-
imidates by the Mapp group23f,g and by the formal analogy
between open-shell 2,3-rearrangements and closed shell
3,3-sigmatropic rearrangements recognized by Zipse in his
methyleneology principle.28 Unfortunately, the major prod-
uct isolated from this reaction was the simple phosphor-
amide 69. This suggests that recombination within the ion
pair formed on radical ionic fragmentation was not a viable
reaction path. Two other minor products isolated, 70 and 71,
suggest that decomposition of the phosphorimidate is com-
petitive with the radical ionic fragmentation under the reac-
tion conditions employed, discouraging us from further
work with this class of substrate.
N
P(OEt)2
allyl azide (6 equiv.)
NO2
Ph
C6D6, ∆
64, quantitative
Scheme 16. Synthesis of an N-allyl phosphorimidate.
rearrangements. Nevertheless, as seen in Table 3, the results
obtained are of more general interest in the context of the
comportment of contact alkene radical cation/anion pairs.
Blank experiments in benzene at reflux demonstrated the
thermal stability of 60, 62, and 64, in the absence of air
and water.
With the sulfamate 60 the only isolated product was N-allyl
sulfamic acid 65, which was obtained in 48% yield (Table 3,
entry 1). This material obviously derives from radical ionic
fragmentation followed by cage escape and reflects the poor
nucleophilicity of the sulfamate anion. With the phosphor-
amide 62, the main product 66 was that of a 1,2-shift of
the initial radical (Table 3, entry 2). This reflects the predom-
inant 1,2-shift identified with simple phosphate esters either
by stereochemical or isotopic labeling (Scheme 3).5a Aside
from the simple reduction product 67, which was isolated
in 7% yield from this reaction, the phosphoramide 62 also
gave rise to a very interesting minor product in the form of
the 1,3,2-azoxaphosphocane 68 in 8% yield (Table 3, entry
2). This product, which appears to be the first example of
its class,24 and which was isolated as a single but unassigned
diastereomer, is the apparent result of an 8-endo-trig cycliza-
tion of the initial radical. 8-endo-trig Cyclizations are
relatively uncommon, usually involve conformationally
constrained systems,25 and have low rate constants,26 and
3. Conclusion
The fragmentation of b-(phosphatoxy)alkyl radicals in
benzene at reflux results in the formation of alkene radical
cation/phosphate anion pairs. Amines trap these ion pairs
intramolecularly to form five- and six-membered rings on
a time scale that competes with equilibration of the ion
pair with solvent, resulting in the observation of significant
stereochemical memory effects. A chair-like transition state
is proposed as a model for these cyclizations. Oxygen
Table 3. Radical reactions of sulfamates, phosphoramides, and phosphorimidates
Entry
1
Substrate
Products
% Yield
O
O
S
O
O
N
O
H
S
HO
N
NO2
w48%
H
Ph
Ph
65
60
O
OPh
O
OPh
O
PhO
O
P
P
O
NH
O
N
O
N
H
P
P
66: 42%
67: 7%
68: 8%
Ph
H
+
+
+
O
OPh
NH
NO2
2
3
H
Ph
Ph
62
66
67
68
H
N
H
N
O
O
N
O
P
P
O
P(OEt)2
O
(EtO)2P
OEt
OEt
NO2
69: 40%
70: 6%
71: 5%
+
O
N
H
Ph
NO2
Ph
Ph
71
69
70
64

6508
D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
nucleophiles, on the other hand, are not sufficiently nucleo-
philic to achieve cyclization before solvent equilibration of
the ion pair. Sulfamates, phosphoramides, and phosphorimi-
dates were also explored as leaving groups for alkene radical
formation and appear to function as such. However, it was
not possible to achieve rearrangements akin to the b-(phos-
phatoxy)alkyl and b-(acetoxy)alkyl rearrangements with
these groups.
Ar. The mixture was stirred at 45–50 ꢀC overnight. Ketone
5 (2.23 g, 6.12 mmol) in THF (35 mL) was added dropwise
to the solution of the catalyst for 30 min at 45–50 ꢀC, then
the reaction mixture was stirred for 20 min. Then the reac-
tion solution was cooled to rt and quenched by dropwise
addition of satd aq NH4Cl until the vigor of the reaction
subsided. The aqueous layer was extracted with ethyl acetate
and the combined organic layer was washed with water and
brine, then dried and concentrated to dryness. Purification by
column chromatography gave 7 (1.57 g, 72%, 85% ee) as
colorless oil, [a]2D3 +12.2 (c 1.0) with spectral data identical
to those of the racemate (3).1
4. Experimental
4.1. General
4.1.4. Typical protocol for the phosphorylation of nitro-
aldols.
Unless otherwise stated, 1H, 13C and, 31P NMR spectra were
recorded in CDCl3 solution. Specific rotations were recorded
in CHCl3 solution, unless otherwise stated. All solvents were
dried and distilled by standard protocols. All reactions were
conducted under a blanket of dry nitrogen or argon. All
organic extracts were dried over sodium sulfate, and concen-
trated under aspirator vacuum at room temperature. Chro-
matographic purifications were carried out over silica gel.
Room temperature is referred to as rt.
4.1.4.1. (4R)-N-Benzyl-N-(tert-butyloxycarbonyl)-4-
diphenylphosphatoxy-5-methyl-5-nitrohexylamine (9).
Diphenyl chlorophosphate (179 mg, 0.67 mmol) was added
to nitroalcohol 7 (207 mg, 0.565 mmol) in CH2Cl2 (5 mL)
followed by the addition of DMAP (91 mg, 0.74 mmol) in
one portion at rt. The reaction mixture was stirred overnight,
then quenched by satd aq NH4Cl. The aqueous layer was
extracted with CH2Cl2, the combined organic layer was
washed with water and brine, then dried and concentrated
to dryness. Purification by column chromatography afforded
the corresponding phosphate 9 (331 mg, 98%) as colorless
4.1.1. Typical protocol for the Henry reaction.
4.1.1.1. N-Benzyl-N-(tert-butyloxycarbonyl)-4-hydroxy-
5-methyl-5-nitrohexylamine (3).1 2-Nitropropane (1.97 g,
22.1 mmol) and aldehyde 1 (3.01 g, 10.9 mmol) were dis-
solved in a 1:1 mixture of acetonitrile and tert-BuOH
(20 mL). To this solution was added potassium tert-butoxide
(597 mg, 5.32 mmol) and the reaction mixture was stirred
overnight. Satd aq NH4Cl and ether were then added. The or-
ganic layer was separated and the aqueous layer was extracted
with ether. The combined organic layer was washed with water
and brine, then dried, and concentrated to dryness. Purification
by column chromatography afforded the respective nitroaldol
product 31 (3.74 g, 94%).
1
oil. [a]2D3 +0.16 (c 2.5); H NMR: d 7.34–7.14 (m, 15H),
5.10 (br t, J¼6.9 Hz, 1H), 4.37 (d, J¼15.6 Hz, 1H), 4.29
(d, J¼15.6 Hz, 1H), 3.18 (m, 2H), 1.80 (m, 1H), 1.75–1.45
(m, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.44 (s, 9H); 13C
NMR: d 155.9, 138.5, 129.8, 128.5, 127.5, 127.2, 125.5,
120.2, 90.3, 83.6, 79.9, 50.2, 45.9, 28.8, 28.5, 24.7, 22.7;
31P NMR: d ꢂ12.2; ESIHRMS: Calcd for C31H39N2O8PNa
[M+Na]+ 621.2342. Found 621.2344.
4.1.5. Typical protocol for the removal of Boc group.
4.1.5.1. (4R)-N-Benzyl-4-diphenylphosphatoxy-5-methyl-
5-nitrohexylamine (11). Phosphate 9 (257 mg, 0.43 mmol)
was stirred in 10% TFA/CH2Cl2 (10 mL) under N2 at rt over-
night. NaOH (15%) was then added to pH 11 and the aque-
ous layer was extracted with ethyl acetate. The combined
organic layer was washed with water and brine, then dried
and concentrated to dryness. Column chromatography af-
forded the respective radical precursor 11 (207 mg, 99%)
4.1.2. Typical protocol for the Swern oxidation of nitro-
aldol adducts.
4.1.2.1. N-Benzyl-N-(tert-butyloxycarbonyl)-5-methyl-
5-nitro-4-oxo-hexylamine(5).1 A solution of oxalyl chloride
(1.3 mL, 14.9 mmol) in CH2Cl2 (50 mL) was cooled to
ꢂ78 ꢀC under N2 followed by the dropwise addition of a so-
lution of DMSO (1.5 mL, 21.1 mmol) in CH2Cl2 (7 mL),
then the reaction mixture was stirred for 15 min. To this mix-
ture was added dropwise a solution of nitroaldol adduct
3 (2.58 g, 7.04 mmol) in CH2Cl2 (17 mL) and stirred at
ꢂ78 ꢀC for 1 h. Triethylamine (7.4 mL, 53.1 mmol) was
added dropwise. After stirring for 20 min, the reaction mix-
ture was allowed to warm up to rt. Satd aq NH4Cl was then
added and the separated organic layer was washed with
H2O and brine, then dried and concentrated to dryness. Puri-
fication by column chromatography afforded 51 (2.26 g,
88%).
1
as colorless oil. [a]2D3 +3.2 (c 2.0); H NMR: d 7.37–7.14
(m, 15H), 5.19 (m, 1H), 3.69 (s, 2H), 2.58 (m, 2H), 1.74–
1.64 (m, 4H), 1.61 (s, 3H), 1.56 (s, 3H); 13C NMR:
d 150.5, 140.5, 131.0, 129.9, 128.5, 128.2, 127.0, 125.6,
120.4, 120.3, 120.2, 90.5, 83.9, 54.0, 48.6, 29.2, 26.3,
22.9, 21.8; 31P NMR: d ꢂ11.9; ESIHRMS: Calcd for
C26H32N2O6P [M+H]+ 499.1998. Found 499.1991.
4.1.6. Determination of enantiomeric excess. The ee’s of
nitroalcohols and nitrophosphates were determined by chiral
HPLC, whereas the ee’s of the radical cyclization products
were obtained by chiral GC. HPLC conditions: Chiralcel
OD (250ꢁ4.6 mm) column; eluent: 0.5, 1.7 or 2.0% 2-prop-
anol/hexanes with a flow rate 0.5 or 1.0 mL/min. UV Detec-
tor: 254 nm. GC conditions: Supelco ALPHA DEX 120
Capillary Column (a-cyclodextrin) (30 mꢁ0.25 mm) or
Supelco GAMMA DEX 120 Capillary Column (g-cyclo-
dextrin) (30 mꢁ0.25 mm), with He as carrier gas, a flow
rate of 20 or 30 cm/s, and FID detection.
4.1.3. Typical protocol for the CBS reduction of nitro-
ketones.
4.1.3.1. (4R)-N-Benzyl-N-(tert-butyloxycarbonyl)-4-
hydroxy-5-methyl-5-nitrohexylamine (7). To a solution
of (S)-(ꢂ)-a,a-diphenyl-2-pyrrolidinemethanol (135 mg,
0.533 mmol, 9 mol %) in THF (4 mL) was added borane/
dimethyl sulfide (2 M in THF, 7.20 mL, 14.4 mmol) under

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6509
4.1.6.1. N-Benzyl-N-(tert-butyloxycarbonyl)-5-hydroxy-
6-methyl-6-nitroheptylamine (4). Following the general
procedure for Henry reaction, 2 (1.98 g, 6.79 mmol) was
in decane (0.45 mL, 2.25 mmol) was added dropwise. After
stirring overnight, the reaction was quenched with satd aq
NH4Cl, then separated and the aqueous layer was extracted
with CH2Cl2. The combined organic layer was washed with
water and brine, then dried, and concentrated. Chromato-
graphic purification gave the colorless oil 13 (294 mg,
1
converted to 4 (2.37 g, 92%) as colorless oil. H NMR:
d 7.32–7.19 (m, 5H), 4.41 (s, 2H), 3.91 (m, 1H), 3.18 (m,
2H), 1.61–1.47 (m, 6H), 1.54 (s, 3H), 1.51 (s, 3H), 1.45 (s,
9H); 13C NMR: d 156.1, 138.7, 128.5, 127.5, 1127.2, 92.2,
79.9, 77.3, 75.9, 50.6, 46.3, 31.3, 31.1, 28.5, 23.2, 20.8;
ESIHRMS: Calcd for C20H32N2O5 [M+H]+ 403.2209. Found
403.2227.
1
56%) H NMR: d 7.33–7.22 (m, 5H), 4.83 (m, 1H), 4.46
(d, J¼15.6 Hz, 1H), 4.38 (d, J¼15.6 Hz, 1H), 4.09 (m,
4H), 3.23 (m, 2H), 1.86 (m, 1H), 1.66–1.40 (m, 3H), 1.60
(s, 3H), 1.52 (s, 3H), 1.46 (s, 9H), 1.32 (m, 6H); 13C NMR
(CDCl3): d 155.8, 138.4, 128.5, 127.7, 127.2, 90.4, 81.8,
80.5, 79.8, 64.1, 61.8, 50.2, 45.8, 29.8, 28.4, 25.8, 22.9,
16.3, 16.1; ESIHRMS: Calcd for C23H39N2O8PNa
[M+Na]+ 525.2342. Found 525.2350.
4.1.6.2. N-Benzyl-N-(tert-butyloxycarbonyl)-6-methyl-
6-nitro-5-oxo-heptylamine (6). Following the general
procedure for Swern oxidation, 4 (1.26 g, 3.32 mmol) was
1
converted to 6 (1.17 g, 93%) as colorless oil. H NMR:
d 7.30–7.19 (m, 5H), 4.41 (s, 2H), 3.17 (t, J¼6.6 Hz, 2H),
2.46 (t, J¼6.8 Hz, 2H), 1.70 (s, 6H), 1.57 (m, 4H), 1.46 (s,
9H); 13C NMR: d 206.7, 188.5, 138.7, 128.5, 127.5,
127.20, 127.17, 94.1, 79.8, 77.3, 50.5, 46.2, 35.8, 28.5,
23.3, 21.0; ESIHRMS: Calcd for C20H30N2O5 Na
[M+Na]+ 401.2052. Found 401.2037.
4.1.6.7. (4R)-N-Benzyl-4-diethylphosphatoxy-5-methyl-
5-nitrohexylamine (14). Following the general procedure
for Boc group removal, 13 (258 mg, 0.513 mmol) afforded
14 (193 mg, 93%) as a colorless oil. 1H NMR: d 7.33–7.24
(m, 5H), 4.91 (m, 1H), 4.10 (m, 4H), 3.82 (s, 2H), 2.71 (br
s, 2H), 1.95–1.69 (m, 4H), 1.63 (s, 3H), 1.56 (s, 3H), 1.32
(t, J¼7.2 Hz, 6H); 13C NMR (CDCl3): d 130.1, 130.0,
129.5, 129.3, 127.3, 90.3, 81.9, 65.6, 65.4, 63.1, 52.3, 46.9,
30.3, 27.9, 23.4, 22.5, 19.6, 15.7; ESIHRMS: Calcd for
C18H32N2O6P [M+H]+ 403.1998. Found 403.2002.
4.1.6.3. (5R)-N-Benzyl-N-(tert-butyloxycarbonyl)-5-
hydroxy-6-methyl-6-nitroheptylamine (8). Following
the general procedure for CBS reduction, 6 (313 mg,
0.827 mmol) was converted to 8 (245 mg, 78%) as color-
less oil. [a]2D3 +1.6 (c 1.0). Enantiomeric excess was deter-
mined by chiral HPLC after the derivatization to the
phosphate 10. The spectral data for this compound corre-
sponded with those of the racemate (4).
4.1.6.8. Ethyl 2,2-dibenzylpent-4-enoate (16). n-BuLi
(2.4 M in hexanes, 1.0 mL, 2.4 mmol) was added dropwise
to diisopropylamine (30 mg, 2.3 mmol) in THF (3 mL)
over 5 min at ꢂ78 ꢀC under N2 followed by stirring for
30 min. To this LDA solution was added 2-benzyl-3-phenyl-
propionate3 (406 mg, 1.86 mmol) in THF (3 mL) dropwise
for 5 min. The reaction mixture was stirred for 45 min at
ꢂ78 ꢀC followed by dropwise addition of allyl bromide in
THF (3 mL) at ꢂ78 ꢀC. The reaction was slowly warmed
up to 0 ꢀC over a period of 2.5 h and quenched with satd aq
NH4Cl. The aqueous mixture was extracted with EtOAc,
combined organic layer was washed with brine and dried
and concentrated to dryness. Purification by column chroma-
tography (hexanes/EtOAc, 9:1) provided 16 (510 mg, 89%).
1H NMR: d 7.31–7.17 (m, 10H), 6.08–5.94 (m, 1H), 5.28–
5.16 (m, 2H), 4.09 (q, J¼7.2, 2H), 3.13 (d, J¼14.1 Hz,
2H), 2.92 (d, J¼13.2 Hz, 2H), 2.35 (dd, J¼7.2, 7.2 Hz,
2H), 1.190 (t, J¼7.5 Hz, 3H); 13C NMR: d 175.4, 137.6,
134.4, 130.3, 128.2, 126.7, 119.1, 60.6, 51.8, 42.2, 36.0,
14.2; ESIHRMS: Calcd for C21H24O2Na [M+Na]+
331.1674. Found 331.1669.
4.1.6.4. (5R)-N-Benzyl-N-(tert-butyloxycarbonyl)-5-
diphenylphosphatoxy-6-methyl-6-nitroheptylamine (10).
Following the general procedure for phosphorylation, 8
(192 mg, 0.51 mmol) was converted to 10 (306 mg, 99%,
86% ee) as colorless oil. [a]2D3 +4.0 (c 1.0); 1H NMR:
d 7.33–7.10 (m, 15H), 5.10 (m, 1H), 4.36 (s, 2H), 3.05 (m,
2H), 1.65–1.46 (m, 6H), 1.61 (s, 3H), 1.54 (s, 3H), 1.44 (s,
9H); 13C NMR: d 172.2, 138.7, 129.8, 129.4, 128.5, 127.4,
127.2, 125.4, 120.2, 100.2, 90.3, 83.7, 79.7, 77.3, 50.5,
46.3, 31.2, 28.5, 23.2, 22.6; 31P NMR: d ꢂ12.2; ESIHRMS:
Calcd for C32H41N2O8PNa [M+Na]+ 635.2498. Found
635.2489.
4.1.6.5. (5R)-N-Benzyl-5-diphenylphosphatoxy-6-methyl-
6-nitroheptylamine (12). Following the general procedure
for removal of Boc group, 10 (231 mg, 0.38 mmol) was con-
verted to 12 (183 mg, 95%) as colorless oil. [a]2D3 +3.1 (c
0.9); 1H NMR: d 7.35–7.12 (m, 15H), 5.14 (br t,
J¼9.0 Hz, 1H), 3.72 (s, 2H), 2.50 (m, 2H), 2.07 (m, 2H),
1.78–1.40 (m, 4H), 1.60 (s, 3H), 1.54 (s, 3H); 13C NMR:
d 150.6, 129.9, 128.6, 128.3, 128.2, 127.1, 125.6, 120.32,
120.26, 120.2, 120.1, 90.3, 83.8, 54.0, 48.8, 31.3, 29.8,
29.6, 23.7, 22.8; 31P NMR: d –11.9; ESIHRMS: Calcd for
C27H34N2O6P [M+H]+ 513.2155. Found 513.2167.
4.1.6.9. 2,2-Dibenzylpent-4-en-1-ol (17). Ester 16
(51 mg, 0.17 mmol) in dry ether (2 mL) was added to a solu-
tion of LiAlH4 (75 mg, 0.20 mmol) in dry ether (20 mL) at
0 ꢀC under Ar. The resulting mixture was refluxed for 12 h
and quenched by dropwise addition of 10% NaOH (1 mL)
at rt. The organic layer was decanted off and the residue
was washed with EtOAc. The combined organic layer was
washed with water and brine and dried. Concentration and
purification of the crude mixture by column chromatography
(hexanes/EtOAc, 4:1) afforded the alcohol 17 (41 mg, 95%).
1H NMR: d 7.32–7.20 (m, 10H), 6.04 (m, 1H), 5.15 (m, 2H),
3.35 (s, 2H), 2.76 (d, J¼13.2 Hz, 2H), 2.68 (d, J¼13.2 Hz,
2H), 2.01 (d, J¼6.9 Hz, 2H); 13C NMR: d 138.4, 135.0,
130.8, 128.2, 126.3, 118.3, 66.5, 43.0, 41.3, 38.2; EIHRMS:
Calcd for C19H22O [M]+ 266.1671. Found 266.1688.
4.1.6.6. (4R)-N-Benzyl-N-(tert-butyloxycarbonyl)-4-
diethylphosphatoxy-5-methyl-5-nitrohexylamine (13).
Enantioenriched nitroalcohol 7 (385 mg, 1.05 mmol) and
pyridine (0.2 mL, 2.5 mmol) were dissolved in dry CH2Cl2
(20 mL) and the solution was cooled to 0 ꢀC. Chlorodiethyl-
phosphite (0.30 mL, 2.1 mmol) was added dropwise. The re-
action was stirred for 50 min, then tert-butyl hydroperoxide

6510
D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
4.1.6.10. 5-Benzylamino-4,4-dibenzylpent-1-ene (18).
43.9, 43.8, 28.3; ESIHRMS: Calcd for C30H35NO3Na
[M+Na]+ 480.2515. Found 480.2500. To a mixture of this
aldehyde (1.30 g, 2.84 mmol) and 2-nitropropane (20 mL,
22 mmol) was added t-BuOK (177 mg, 1.58 mmol) at rt. Af-
ter stirring for 12 h, the reaction was quenched with satd aq
NH4Cl, diluted with water, and the aqueous layer was ex-
tracted with Et2O. The combined organic layer was washed
with H2O and brine, then dried and concentrated to dryness.
Purification of the residue by column chromatography
(Et2O/CH2Cl2, 0.5:99.5) afforded nitroalcohol 20 (838 mg,
Following the general procedure for Swern oxidation, alco-
hol 17 (4.77 g, 17.9 mmol) was converted to the correspond-
ing aldehyde (5.23 g) as colorless oil, which was directly
1
taken to the next reaction after the extraction. H NMR:
d 9.71 (s, 1H), 7.33–7.12 (m, 10H), 5.91 (m, 1H), 5.22 (m,
2H), 3.02 (d, J¼13.8 Hz, 2H), 2.85 (d, J¼13.8 Hz, 2H),
2.29 (d, J¼7.5 Hz, 2H); 13C NMR: d 206.6, 136.6, 133.4,
130.6, 128.5, 126.9, 119.5, 53.7, 40.3, 35.6; ESIHRMS:
Calcd for C19H20ONa [M+Na]+ 287.1412. Found
287.1424. To a CH3OH (50 mL) solution of crude aldehyde
(5.23 g), benzylamine (3.86 g, 36.0 mmol) and CH3CO2H
(1.10 mL, 18.5 mmol) was added sodium cyanoborohydride
(1.48 g, 22.4 mmol) in portions at 0 ꢀC under N2. The reac-
tion was stirred at rt for 2 h. Satd aq NaHCO3 was added,
then CH3OH was removed by the evaporation. The aqueous
layer was extracted with ether, the combined organic layer
was washed with satd aq NH4Cl, satd aq NaHCO3, H2O,
and brine then dried. Concentration gave yellow oil which
was purified by column chromatography giving amine 18
1
54%). H NMR: d 7.33–7.13 (m, 13H), 7.01 (m, 2H), 4.67
(d, J¼15.9 Hz, 1H), 4.30 (br t, J¼8.7 Hz, 1H), 4.10 (d,
J¼15.0 Hz, 1H), 4.03 (d, J¼15.0 Hz, 1H), 3.03–2.07 (m,
5H), 1.64 (dd, J¼12.0, 11.4 Hz, 1H), 1.55 (s, 3H), 1.49–
1.41 (m, 1H), 1.38 (s, 12H); 13C NMR: d 158.4, 138.3,
138.1, 137.8, 131.2, 131.1, 128.6, 128.3, 128.24, 128.17,
127.3, 126.9, 126.6, 126.5, 92.8, 81.4, 77.2, 73.6, 43.0,
42.1, 28.3, 22.2, 21.8; ESIHRMS: Calcd for C33H42N2O5Na
[M+Na]+ 569.2991. Found 569.2997.
1
(4.84 g, 76% from alcohol) as a colorless oil. H NMR:
4.1.6.13. N-Benzyl-2,2-dibenzyl-5-methyl-5-nitro-4-
oxo-hexylamine (21). Following the general procedure for
removal of Boc group, 20 (140 mg, 0.26 mmol) afforded
the crude secondary amine, which was directly taken to
the next step after the extraction. Following the general pro-
cedure for Swern oxidation, ketone 21 (97 mg, 86%) was ob-
tained as colorless oil. 1H NMR: d 8.32 (br s, 1H), 7.47–7.06
(m, 15H), 4.05 (s, 2H), 3.35 (s, 2H), 3.11 (d, J¼13.5 Hz,
2H), 3.00 (d, J¼13.5 Hz, 2H), 2.37 (s, 2H), 1.67 (s, 6H);
13C NMR: d 202.1, 162.2, 138.2, 130.92, 130.90, 130.7,
130.6, 130.1, 129.0, 128.4, 128.3, 126.5, 94.9, 63.6, 57.5,
42.0, 40.5, 39.2, 23.8.
d 7.42–7.12 (m, 15H), 6.03 (m, 1H), 5.13 (m, 2H), 3.70 (s,
2H), 2.77 (d, J¼6.0 Hz, 2H), 2.70 (d, J¼7.5 Hz, 2H), 2.34
(s, 2H), 2.03 (d, J¼6.9 Hz, 2H); 13C NMR: d 138.7, 135.2,
130.9, 129.4, 128.8, 128.2, 128.0, 127.1, 126.2, 118.1,
68.1, 54.7, 54.3, 51.5, 42.1, 39.4; ESIHRMS: Calcd for
C26H30N [M+H]+ 356.2378. Found 356.2376.
4.1.6.11.
5-[N-Benzyl-N-(tert-butyloxycarbonyl)]
amino-4,4-dibenzyl-pent-1-ene (19). To the CH2Cl2
(50 mL) solution of 18 (4.552 g, 12.80 mmol) and TEA
(2.8 mL, 20.1 mmol) was added Boc2O (3.781 g,
17.32 mmol) in CH2Cl2 (7 mL) at 0 ꢀC under N2, then it
was stirred for 19 h at rt. The reaction was quenched with
satd aq NH4Cl, then aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with
satd aq NH4Cl, H2O, and brine, then dried and concentrated
to dryness. Purification by column chromatography then
afforded Boc-protected amine 19 (5.62 g, 96%) as a colorless
oil. 1H NMR: d 7.31–7.04 (m, 15H), 5.99 (m, 1H), 5.09 (m,
2H), 4.49 (s, 2H), 3.42 (s, 2H), 2.82 (d, J¼13.8 Hz, 2H), 2.74
(d, J¼13.8 Hz, 2H), 2.19 (d, J¼6.9 Hz, 2H), 1.39 (s, 9H);
13C NMR: d 157.1, 138.5, 135.5, 131.2, 130.8, 129.1,
128.5, 128.0, 127.1, 126.9, 126.2, 117.8, 80.1, 57.5, 43.0,
42.6, 40.1, 28.6, 28.4; ESIHRMS: Calcd for C31H37NO2Na
[M+Na]+ 478.2722. Found 478.2716.
4.1.6.14.
(4R)-N-Benzyl-N-(tert-butyloxycarbonyl)-
2,2-dibenzyl-4-hydroxy-5-methyl-5-nitrohexylamine (22).
Following the general procedure for CBS reduction, ketone
21 (95 mg, 0.21 mmol) was converted to alcohol. The color-
less oil was obtained by the extraction, then Boc protection
was directly accomplished. To the CH2Cl2 solution (15 mL)
of obtained alcohol, Boc2O (160 mg, 0.73 mmol) and TEA
(0.5 mL, 3.6 mmol) were added. The reaction was stirred
overnight and the solvent was removed by evaporation. Puri-
fication by column chromatography gave enantiomerically
enriched alcohol 21 (80 mg, 70%) as colorless oil, which
showed similar spectra to racemate 20. The enantiomeric ex-
cess was determined after the derivatization to 24.
4.1.6.12. N-Benzyl-N-(tert-butyloxycarbonyl)-2,2-di-
benzyl-4-hydroxy-5-methyl-5-nitrohexylamine (20). A
solution of alkene 19 (5.05 g, 11.1 mmol) in CH2Cl2
(50 mL) was bubbled with O3 at ꢂ78 ꢀC until the solution
turned blue. On complete disappearance of the starting ma-
terial, N2 gas was bubbled through the reaction mixture for
15 min at ꢂ78 ꢀC. To the resulting mixture was added
Ph3P (3.33 g, 12.7 mmol) at ꢂ78 ꢀC and the reaction was al-
lowed to warm up to rt. After stirring the reaction mixture
overnight, it was concentrated and purified by column chro-
matography to afford an aldehyde (1.74 g, 34%). 1H NMR:
d 9.69 (t, J¼1.5 Hz, 1H), 7.34–7.09 (m, 15H), 4.43 (s, 2H),
3.51 (s, 2H), 3.00 (d, J¼13.8 Hz, 2H), 2.84 (d, J¼13.8 Hz,
2H), 2.37 (d, J¼1.5 Hz, 2H), 1.36 (s, 9H); 13C NMR:
d 202.2, 157.0, 138.4, 137.3, 131.20, 131.15, 128.7, 128.6,
128.4, 128.3, 127.2, 126.7, 106.2, 80.6, 54.3, 53.5, 48.0,
4.1.6.15.
(4R)-N-Benzyl-N-(tert-butyloxycarbonyl)-
2,2-dibenzyl-4-diphenylphosphatoxy-5-methyl-5-nitro-
hexylamine (23). I2 (306 mg, 1.21 mmol) was added to
a stirred solution of ethyldiphenylphosphite (250 mg,
0.95 mmol) in CH2Cl2 (2 mL) at 0 ꢀC under N2. After
15 min, this solution was added to a mixture of nitroalcohol
22 (345 mg, 0.63 mmol), pyridine (0.120 mL, 1.48 mmol) in
CH2Cl2 (3 mL) under N2 at 0 ꢀC. The reaction mixture was
stirred at 0 ꢀC for 1 h, then NH4Cl was added. The aqueous
layer was extracted with CH2Cl2, the combined organic
layer was washed with 10% Na2S2O3, H2O, and brine,
then dried and concentrated to dryness. Purification by col-
umn chromatography afforded phosphorylated product 23
(371 mg, 75%). 1H NMR: d 7.36–7.03 (m, 25H), 5.78 (t, J¼
9.0 Hz, 1H), 4.45 (d, J¼16.2 Hz, 1H), 4.29 (d, J¼16.2 Hz,
1H), 3.71 (d, J¼14.7 Hz, 1H), 3.45 (d, J¼14.7 Hz, 1H),

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6511
3.11 (d, J¼14.7 Hz, 1H), 3.02 (d, J¼14.4 Hz, 1H), 2.99
(d, J¼14.7 Hz, 1H), 2.83 (d, J¼14.4 Hz, 1H), 1.91 (dd,
J¼15.3, 10.8 Hz, 1H), 1.75 (dd, J¼15.3, 4.5 Hz, 1H), 1.61
(s, 3H), 1.42 (s, 3H), 1.33 (s, 9H); 13C NMR: d 157.3,
138.8, 138.1, 131.5, 130.1, 129.7, 128.7, 128.5, 128.3,
128.2, 126.8, 126.4, 125.3, 120.2, 91.7, 82.1, 80.2, 53.2,
53.0, 42.3, 41.7, 41.3, 35.8, 28.4, 27.7, 24.4, 21.3; 31P
NMR: d ꢂ12.9; ESIHRMS: Calcd for C45H51N2O8PNa
[M+Na]+ 801.3281. Found 801.3263.
13C NMR: d 155.3, 141.3, 137.8, 137.4, 135.5, 131.0,
129.8, 129.5, 128.8, 128.4, 128.38, 128.2, 128.0, 127.8,
127.6, 91.6, 91.4, 81.9, 80.9, 74.4, 55.2, 54.3, 33.6, 32.1,
28.4, 28.3, 23.1, 20.9; ESIHRMS: Calcd for C23H30N2O5Na
[M+Na]+ 437.2052. Found 437.2054.
4.1.6.20. 1-{2-[N-Benzyl-N-(tert-butyloxycarbonyl)-
amino]phenyl}-3-methyl-3-nitro-2-(diphenylphosphatoxy)-
butane (29). Following the general procedure for
phosphorylation, 28 (198 mg, 0.48 mmol) afforded colorless
oil 29 (291 mg, 94%). 1H NMR: d 7.50–6.80 (m, 19H), 5.61
(br s, 0.6H), 5.49 (m, 0.4H), 5.25 (m, 0.6H), 4.99 (d,
J¼14.5 Hz, 0.4H), 4.49 (d, J¼15 Hz, 0.4H), 4.31 (d,
J¼14.5 Hz, 0.6H), 3.05 (d, J¼15 Hz, 0.4H), 2.87 (m,
1.6H), 1.68 (s, 3H), 157 (s, 1H), 1.55 (s, 2H), 1.44 (s, 9H),
1.44; 13C NMR: d 155.1, 154.7, 150.52, 150.46, 150.4,
142.0, 141.6, 138.7, 138.0, 133.6, 133.4, 131.9, 130.1,
129.8, 129.6, 129.5, 129.49, 129.3, 128.8, 128.6, 128.4,
128.3, 128.1, 127.7, 127.6, 127.4, 127.3, 125.4, 125.3,
125.1, 120.2, 120.16, 120.1, 120.0, 90.5, 90.46, 90.38,
83.0, 82.98, 82.63, 82.6, 80.8, 80.7, 54.2, 53.3, 34.2, 32.3,
28.3, 23.4, 23.1, 21.8, 21.6; 31P NMR: d ꢂ12.4, ꢂ12.6;
ESIHRMS: Calcd for C35H39N2O8PNa [M+Na]+
669.2342. Found 669.2322.
4.1.6.16. (4R)-N-Benzyl-2,2-dibenzyl-4-diphenylphos-
phatoxy-5-methyl-5-nitrohexylamine (24). Following the
general procedure for removal of Boc group, phosphate 23
(294 mg, 0.38 mmol) gave the secondary amine 24
1
(245 mg, 96%, 79% ee). H NMR: d 7.33–7.09 (m, 25H),
5.96 (t, J¼8.4 Hz, 1H), 3.67 (d, J¼13.5 Hz, 1H), 3.61 (d,
J¼13.5 Hz, 1H), 3.01 (s, 2H), 2.77 (s, 2H), 2.73 (d,
J¼12.3 Hz, 1H), 2.63 (d, J¼12.3 Hz, 1H), 1.76 (m, 2H),
1.65 (s, 3H), 1.46 (s, 3H); 13C NMR: d 150.7, 138.4,
138.0, 131.1, 131.0, 129.9, 128.8, 128.7, 128.2, 128.1,
127.7, 126.6, 126.4, 125.5, 120.2, 91.7, 82.2, 54.9, 54.6,
43.3, 42.4, 41.0, 35.7, 24.7, 20.8; 31P NMR: d ꢂ12.8;
ESIHRMS: Calcd for C40H44N2O6P [M+H]+ 679.2937.
Found 679.2943.
4.1.6.17. 2-{2-[N-Benzyl-N-(tert-butyloxycarbonyl)-
amino]phenyl}ethanol (26). Carbamate 2512 (2.00 g,
8.45 mmol) was treated with NaH (60% in oil, 433 mg,
10.8 mmol) in DMF (80 mL) at 0 ꢀC followed by dropwise
addition of BnBr (1.10 mL, 9.25 mmol). After stirring over-
night, the reaction was quenched with NH4Cl and the sepa-
rated aqueous layer was extracted with ether. The combined
organic layer was washed with water and brine then dried.
Purification by column chromatography gave 26 (1.39 g,
4.1.6.21. 1-[2-Benzylaminophenyl]-3-methyl-3-nitro-
2-(diphenylphosphatoxy)butane (30). Removal of the
Boc group from 29 (685 mg, 1.06 mmol) according to the
general procedure gave 30 (568 mg, 98%). 1H NMR:
d 7.42–6.90 (m, 17H), 6.58 (m, 2H), 5.65 (m, 1H), 5.11
(br s, 1H), 4.41 (d, J¼15 Hz, 1H), 4.35 (d, J¼15 Hz, 1H),
3.15 (dd, J¼15, 6 Hz, 1H), 2.86 (dd, J¼15, 6 Hz, 1H),
1.68 (s, 3H), 1.42 (s, 3H); 13C NMR: d 150.4, 150.37,
150.3, 150.2, 146.4, 139.7, 131.5, 129.9, 129.0, 128.6,
127.3, 127.0, 125.6, 120.3, 120.2, 120.19, 119.1, 117.1,
111.6, 90.8, 90.75, 80.44, 80.40, 47.8, 35.5, 23.1, 21.7; 31P
NMR: d ꢂ11.1; ESIHRMS: Calcd for C30H31N2O6PNa
[M+Na]+ 569.1817. Found 569.1819.
1
50%). H NMR: d 7.27–7.19 (m, 7H), 7.12 (m, 1H), 6.89
(br s, 1H), 4.91 (d, J¼14.5 Hz, 1H), 4.50 (d, J¼14.5 Hz,
1H), 3.75 (br s, 2H), 2.72 (m, 1H), 2.59 (m, 1H), 1.44 (s,
9H); 13C NMR: d 155.4, 141.3, 138.0, 136.8, 130.0, 129.1,
128.9, 128.3, 127.6, 127.4, 127.1, 80.6, 62.6, 54.3, 34.1,
28.3. Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70. Found:
C, 73.27; H, 7.69.
4.1.6.22. (4R)-N-(tert-Butyloxycarbonyl)-4-diphenyl-
phosphatoxy-5-methyl-5-nitrohexylamine (31). Phos-
phate 9 (103 mg, 0.17 mmol) was treated with PdCl2
(64 mg, 0.36 mmol) in methanol (10 mL) under hydrogen
atmosphere for 4 h. Satd aq NaHCO3 was added, then it
was extracted with EtOAc. The organic layer was washed
with H2O and brine, then dried and concentrated to dryness.
Purification by column chromatography gave the secondary
amine 31 (84 mg, 97%) as colorless oil. [a]2D3 +0.3 (c 0.94);
1H NMR: d 7.36–7.14 (m, 10H), 5.15 (m, 1H), 4.43 (br s,
1H), 3.06 (m, 2H), 1.75–1.48 (m, 4H), 1.61 (s, 3H), 1.56
(s, 3H), 1.43 (s, 9H); 13C NMR: d 155.6, 129.9, 129.3,
125.6, 120.4, 120.1, 90.3, 83.5, 39.8, 28.5, 26.5, 23.0,
4.1.6.18. 2-{2-[N-Benzyl-N-(tert-butyloxycarbonyl)-
amino]phenyl}ethanal (27). Alcohol 26 (2.14 g,
6.52 mmol) was stirred in CH2Cl2 (40 mL) with PCC
˚
(98%, 1.74 g, 7.92 mmol) and 4 A molecular sieves over-
night. The resulting black suspension was filtered through
silica gel pre-wetted by hexanes, eluting with Et2O. Chroma-
tographic purification gave 27 (1.326 g, 63%) as a colorless
1
oil. H NMR: d 9.38 (s, 1H), 7.26–7.04 (m, 9H), 4.72 (m,
2H), 3.38 (d, J¼16.5 Hz, 1H), 3.27 (d, J¼16.5 Hz, 1H),
1.41 (s, 9H); 13C NMR: d 199.0, 154.7, 141.5, 137.6,
131.4, 130.7, 128.8, 128.4, 128.3, 127.6, 80.7, 54.2, 45.8,
28.3. Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12. Found
C, 73.65; H, 7.11.
21.5; 31P NMR:
d
ꢂ12.0; ESIHRMS: Calcd for
C24H33N2O8PNa [M+Na]+ 531.1872. Found 531.1859.
4.1.6.23. (4R)-N-(tert-Butyloxycarbonyl)-N-prop-2-ynyl-
4-diphenylphosphatoxy-5-methyl-5-nitrohexylamine (32).
Secondary amine 31 (161 mg, 0.317 mmol) was treated
with NaH (60% in oil, 37 mg, 0.93 mmol) in DMF (15 ml)
at 0 ꢀC under N2 for 20 min, then propargyl bromide
(75 mg, 0.63 mmol) was added dropwise. The reaction
was stirred for 1 h, then quenched with H2O. It was extracted
with EtOAc then washed with H2O and brine. It was dried
4.1.6.19. 1-{2-[N-Benzyl-N-(tert-butyloxycarbonyl)-
amino]phenyl}-3-methyl-3-nitrobutan-2-ol (28). Follow-
ing the general Henry reaction procedure, 27 (1.39 g,
1
4.28 mmol) afforded 28 (1.63 g, 92%). H NMR: d 7.32–
6.90 (m, 9H), 4.79 (m, 1H), 4.60 (m, 1H), 4.37 (d,
J¼11 Hz, 0.5H), 4.24 (d, J¼11 Hz, 0.5H), 2.58 (br s, 1H),
2.27–2.10 (m, 2H), 1.57 (s, 3H), 1.53 (s, 3H), 1.47 (s, 9H);

6512
D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
over Na2SO4 followed by the evaporation, which gave
a brown oil. Purification by column chromatography gave
32 (160 mg, 92%) as a colorless oil. 1H NMR: d 7.34–7.18
(m, 10H), 5.15 (m, 1H), 3.92 (m, 2H), 3.31 (t, J¼7.2 Hz,
2H), 2.13 (t, J¼2.1 Hz, 1H), 1.90–1.78 (m, 2H), 1.75–1.65
(m, 2H), 1.62 (s, 3H), 1.57 (s, 3H), 1.45 (s, 9H); 13C
NMR: d 155.1, 129.8, 125.5, 120.2, 83.6, 80.4, 71.7, 46.1,
36.3, 28.8, 28.4, 24.7, 23.8, 22.7, 22.2; 31P NMR: d ꢂ12.1;
ESIHRMS: Calcd for C27H35N2O8PNa [M+Na]+
569.2029. Found 569.2036.
residue was diluted with water and the aqueous layer was
extracted with EtOAc. The combined organic layer was
washed with brine, dried and concentrated. Purification of
the crude mixture by column chromatography (EtOAc/
hexanes, 1:4) afforded 36 (850 mg, 48%). IR (film):
1543 cmꢂ1; 1H NMR: d 7.38–7.14 (m, 10H), 4.52–4.48 (m,
1H), 2.78–2.71 (m, 2H), 2.26–2.14 (m, 6H); 13C NMR:
d 149.6, 144.0, 128.9, 128.6, 127.3, 126.4, 126.3, 126.2,
83.8, 34.0, 27.2; EIHRMS: Calcd for C18H19NO2 [M]+
281.1415. Found 281.1414.
4.1.6.24. (4R)-4-Diphenylphosphatoxy-N-prop-2-ynyl-
5-methyl-5-nitrohexylamine (33). Following the general
procedure for removal of Boc group, 32 (211 mg,
0.386 mmol) gave the precursor of radical cyclization 33
4.1.6.28. 4-(tert-Butyldimethylsiloxy)-1-(10-nitro-40,40-
diphenylcyclohexyl)butan-1-ol (37). To a stirred solution
of 36 (166 mg, 0.59 mmol) in THF (1 mL) was added
0.025 M aqueous NaOH (0.87 mL) at rt and further stirred
for 2 min. 4-(tert-Butyldimethylsiloxy)butan-1-al (107 mg,
0.53 mmol) was added followed by cetyl ammonium bro-
mide (21 mg, 0.059 mmol) at rt. After stirring the reaction
for 12 h at ambient temperature, the reaction was quenched
with satd aq NH4Cl solution (5 mL) and the aqueous layer
was extracted with EtOAc. The organic layer was washed
with water and brine and dried. Concentration and purifica-
tion of the residue by column chromatography (EtOAc/
hexanes, 1:9) afforded nitro alcohol 37 (0.142 g, 50%) as
1
(170 mg, 99%). H NMR: d 7.33–7.17 (m, 10H), 5.17 (m,
1H), 3.36 (s, 2H), 2.66 (m, 2H), 2.52 (br s, 1H), 2.21 (s,
1H), 1.66–1.64 (m, 4H), 1.61 (s, 3H), 1.56 (s, 3H); 13C
NMR: d 129.8, 125.5, 120.2, 106.2, 90.4, 83.7, 71.8, 47.7,
37.9, 29.2, 25.7, 22.7, 22.0; 31P NMR: d ꢂ11.9; ESIHRMS:
Calcd for C22H28N2O6P [M+H]+ 447.1685. Found
447.1677.
4.1.6.25. 4,4-Diphenylcyclohexanone oxime (34). 4,4-
Diphenylcyclohexanone29 (4.70 g, 18.8 mmol) in EtOH
(94 mL) was added to a stirred solution of hydroxylamine
hydrochloride (6.25 g, 90.0 mmol) and sodium acetate
(12.63 g, 154 mmol) in water (25 mL) at rt. The resulting
milky white solution was stirred for 2 h and concentrated
under rotary evaporation. The residue was extracted with
EtOAc, dried by Na2SO4, and concentrated. Purification of
the crude mixture by column chromatography (EtOAc/
hexanes, 1:5) afforded oxime 34 (4.85 g, 97%). IR (film):
3243, 1446 cmꢂ1; 1H NMR: d 7.31–7.26 (m, 10H), 2.66 (t,
J¼6.9 Hz, 2H), 2.50–2.34 (m, 6H); 13C NMR: d 159.8,
146.6, 128.6, 127.0, 126.1, 46.3, 36.5, 35.5, 28.5, 21.4;
ESIHRMS: Calcd for C18H19NONa [M+Na]+ 288.1364.
Found 288.1360.
1
a colorless oil. H NMR: d 7.38–7.10 (m, 10H), 3.68–3.57
(m, 3H), 3.39 (d, J¼4.8 Hz, 1H), 2.67–2.53 (m, 4H), 2.09–
1.60 (m, 8H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR:
d 149.6, 144.0, 128.8, 128.4, 127.5, 126.2, 126.1, 126.0,
94.9, 76.4, 63.2, 45.3, 32.4, 29.1, 28.8, 27.5, 27.1, 26.0,
18.4, ꢂ5.3; ESIHRMS: Calcd for C28H41NO4SiK [M+K]+
522.2442. Found 522.2437. Anal. Calcd for C28H41NO4Si:
C, 69.52; H, 8.54. Found: C, 69.78; H, 8.45.
4.1.6.29. 4-(tert-Butyldimethylsiloxy)-1-(10-nitro-40,40-
diphenylcyclohexyl)butan-1-one (38). Following the
general procedure for Swern oxidation, nitroalcohol 37
(629 mg, 1.3 mmol) provided ketone 38 (388 mg, 62%). IR
1
(film) 1725, 1542 cmꢂ1; H NMR: d 7.34–7.12 (m, 10H),
3.54 (t, J¼6.3 Hz, 2H), 2.62 (d, J¼11.4 Hz, 4H), 2.53 (t,
J¼6.9 Hz, 2H), 2.16 (d, J¼10.5 Hz, 4H), 1.73 (quint,
J¼6.0 Hz, 2H), 0.87 (s, 9H), 0.01 (s, 6H); 13C NMR:
d 201.7, 148.3, 144.1, 129.0, 128.5, 127.1, 126.5, 126.2,
98.4, 61.4, 44.9, 32.4, 32.1, 28.3, 26.4, 26.0, 18.4, ꢂ5.2.
Anal. Calcd for C28H39NO4Si: C, 69.82; H, 8.16. Found C,
69.74; H, 8.25.
4.1.6.26. 1-Chloro-1-nitro-4,4-diphenylcyclohexane
(35). Trichloroisocyanuric acid (20.41 g, 88 mmol) was
added in five portions at 5 min intervals to a well stirred
two phase mixture of EtOAc/H2O (1:1, 1534 mL), oxime
34 (4.60 g, 17.5 mmol), and NaHCO3 (36.4 g, 434 mmol).
The reaction mixture developed a distinct blue color after
20 min and stirring was continued at rt until the organic layer
became colorless for 24 h. The reaction mixture was trans-
ferred into a separatory funnel and 0.2 M aq NaOH solution
(230 mL) was added. The aqueous layer was extracted with
EtOAc. The combined organic layer was washed with water
and brine and concentrated to dryness. Purification by
column chromatography (EtOAc/hexanes, 1:5) afforded 35
4.1.6.30. (1R)-4-(tert-Butyldimethylsiloxy)-1-(10-nitro-
40,40-diphenylcyclohexyl)butan-1-ol (39). Following the
general procedure for CBS reduction, ketone 38 (563 mg,
1.0 mmol) afforded alcohol 39 (420 mg, 87%, 96% ee).
[a]2D3 +9.0 (c 1.0); with spectral data matching those of the
racemate (37).
(1.54 g, 28%). IR (film): 1555, 698 cmꢂ1 1H NMR:
;
d 7.38–7.18 (m, 10 H), 2.67–2.43 (m, 8H); 13C NMR:
d 129.0, 128.84, 128.77, 126.9, 126.63, 126.60, 126.52,
126.49, 126.44, 35.8, 35.2, 33.2; EIHRMS: Calcd for
C18H18NO2Cl [M]+ 315.1.26. Found 315.1025.
4.1.6.31. (1R)-4-(tert-Butyldimethyl-silyloxy)-1-(10-nitro-
40,40-diphenylcyclohexyl)-1-diphenylphosphatoxy butane
(40). Following general procedure for phosphorylation, alco-
hol 39 (104 mg, 0.21 mmol) afforded phosphate 40 (109 mg,
74%). 1H NMR: d 7.37–7.08 (m, 20H), 4.73 (m, 1H), 3.64–
3.48 (m, 2H), 2.69–2.60 (m, 4H), 2.05–1.82 (m, 5H), 1.63–
1.51 (m, 3H), 0.86 (s, 9H), 0.00 (s, 6H); 13C NMR:
d 150.5, 149.3, 143.5, 129.9, 129.8, 129.0, 128.8, 128.4,
127.5, 127.3, 126.4, 126.2, 126.1, 126.0, 125.5, 120.3,
120.2, 120.1, 93.5, 93.4, 84.4, 84.3, 76.4, 63.2, 61.9, 45.0,
4.1.6.27. 1-Nitro-4,4-diphenylcyclohexane (36). Ten
percent Pd/C (106 mg, 5%) and NaBH4 (337 mg,
8.9 mmol) were added to a solution of 35 (2.00 g,
6.3 mmol) in EtOH (33 mL) at rt. The reaction was stirred
for 1 h after which it was filtered and concentrated. The

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6513
32.2, 32.1, 29.2, 28.7, 27.8, 27.7, 27.5, 27.2, 27.1, 26.0, 18.4,
ꢂ5.2; 31P NMR: d ꢂ11.80; ESIHRMS: Calcd for
C40H50NO7PSiNa [M+Na]+ 738.2992. Found 738.2984.
and purification of the residue by column chromatography
(EtOAc/hexanes, 3:7) afforded 44 (70 mg, 81%). IR (film)
1
3394, 1543, 1082 cmꢂ1. H NMR: d 7.32–7.12 (m, 10H),
4.42–4.39 (m, 1H), 4.13 (d, J¼3.0 Hz, 1H), 3.56 (d,
J¼9.9 Hz, 1H), 3.41 (d, J¼9.9 Hz, 1H), 2.86 (d,
J¼13.5 Hz, 1H), 2.73 (m, 2H), 2.63 (d, J¼13.5 Hz, 1H),
1.51 (s, 3H), 1.49–1.39 (m, 2H), 1.40 (s, 3H), 0.93 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR: d 137.6, 137.4,
131.0, 130.9, 128.2, 128.1, 126.6, 126.5, 92.4, 71.9, 68.5,
43.8, 40.8, 37.5, 26.0, 23.0, 20.8, 0.16, ꢂ5.3; ESIHRMS:
Calcd for C27H41NO4SiNa [M+Na]+ 494.2703. Found
494.2709.
4.1.6.32. (4R)-4-Diphenylphosphatoxy-4-(10-nitro-40,
40-diphenylcyclohexyl)butan-1-ol (41). To a solution of
40 (100 mg, 0.15 mmol) in acetonitrile (6 mL) at rt was
added aqueous solution of HF (49%, 0.15 mmol, 4 mL).
The reaction was further stirred for 5 min and diluted with
EtOAc. The organic layer was washed with water and brine
and dried over Na2SO4. Concentration and purification of
the residue by column chromatography (EtOAc/hexanes,
1
1:1) afforded alcohol 41 (55 mg, 63%, 94% ee). H NMR:
d 7.35–7.06 (m, 20H), 4.76 (t, J¼7.6 Hz, 1H), 3.54–3.47
(m, 2H), 2.69–2.61 (m, 4H), 2.03–1.55 (m, 8H); 13C
NMR: d 149.2, 143.4, 129.9, 129.0, 128.4, 127.4, 126.4,
126.1, 125.6, 120.2, 120.1, 93.5, 93.4, 84.2, 84.1, 62.0,
45.0, 32.1, 28.4, 27.8, 27.7, 27.5, 27.4; 31P NMR: d
ꢂ11.72; ESIHRMS: Calcd for C34H38NO7P [M+H]+
602.2308. Found 602.2335.
4.1.6.36. 2,2-Dibenzyl-1-(tert-butyldimethylsiloxy)-5-
methyl-5-nitro-4-(diphenylphosphatoxy)hexane (45). I2
(0.0812 g, 0.32 mmol) was added to a stirred solution of
ethyldiphenylphosphite (0.08 g, 0.31 mmol) in dichloro-
methane (9 mL) at ꢂ30 to ꢂ20 ꢀC under Ar. After 15 min
this solution was added to a mixture of 44 (0.15 g,
0.32 mmol), pyridine (0.10 g, 1.28 mmol) in dichloro-
methane (15 mL) under Ar at ꢂ30 to ꢂ20 ꢀC. The reaction
mixture was allowed to warm to 0 ꢀC, diluted with dichloro-
methane, subsequently washed with NH4Cl, satd Na2S2O3,
brine and dried. Concentration and purification by column
chromatography (hexanes/EtOAc, 4:1) afforded 45 (100 mg,
4.1.6.33.
2,2-Dibenzyl-1-(tert-butyldimethylsiloxy)-
pent-4-ene (42). Alcohol 17 (0.50 g, 1.87 mmol) in DMF
(2 mL) was added slowly to a stirred solution of TBDMSCl
(0.338 g, 2.24 mmol) and imidazole (0.317 g, 4.6 mmol) in
DMF (15 mL) at 0 ꢀC under Ar. The resulting mixture was
warmed to rt and stirred for 2 h. Water (15 mL) was added
and the aqueous layer was extracted with hexane
(3ꢁ15 mL). The combined organic layer was washed with
water and brine and dried. Concentration and purification
of the crude mixture by column chromatography (hexanes/
1
46%). IR (film): 1548, 1010, 956 cmꢂ1; H NMR: d 7.29–
7.12 (m, 20H), 5.78 (t, J¼9.0 Hz, 1H), 3.42 (d, J¼9.9 Hz,
1H), 3.19 (d, J¼9.9 Hz, 1H), 2.99 (s, 2H), 2.94 (d,
J¼13.5 Hz, 1H), 2.65 (d, J¼13.5 Hz, 1H), 1.65 (s, 3H),
1.47–1.68 (m, 2H), 1.25 (s, 3H), 0.94 (s, 9H), 0.25 (s, 3H),
0.21 (s, 3H); 31P NMR: d ꢂ13.07; 13C NMR: d 156.4,
150.6, 150.5, 138.0, 137.9, 131.3, 129.9, 129.5, 128.1,
128.0, 126.3, 125.6, 125.5, 120.2, 120.1, 120.0, 115.6,
91.5, 82.0, 66.0, 41.6, 40.1, 39.5, 33.2, 33.1, 26.1, 24.3,
21.2, 18.3, ꢂ5.2, ꢂ5.3; ESIHRMS: Calcd for C39H50NO7-
SiPNa [M+Na]+ 726.2992. Found 726.2986.
1
EtOAc, 9:1) afforded 42 (0.60 g, 79%). H NMR: d 7.28–
7.17 (m, 10H), 6.08–5.99 (m, 1H), 5.17–5.03 (m, 2H),
3.18 (s, 2H), 2.69 (ABq, J¼13.2, 13.2 Hz, 4H), 1.93 (d,
J¼7.2 Hz, 2H), 1.00 (s, 9H), 0.06 (s, 6H); 13C NMR:
d 138.7, 134.9, 131.0, 127.8, 126.0, 117.9, 65.5, 42.9,
40.4, 37.1, 26.1, ꢂ5.3; ESIHRMS: Calcd for C25H36OSiNa
[M+Na]+ 403.2433. Found 403.2452.
4.1.6.37.
6,6-Dibenzyl-4-(1-methyl-1-nitroethyl)-2-
phenoxy-[1,3,2]dioxaphosphepane 2-oxide (46). Forty-
nine percent aqueous HF solution (2 mL) was added to a
solution of 45 (0.086 g, 0.08 mmol) in CH3CN (2 mL) at
0 ꢀC. The reaction mixture was stirred for 5 min at rt fol-
lowed by quenching with water (5 mL) at rt. The aqueous
layer was extracted with EtOAc, washed with brine, and
dried. Concentration and purification by column chromato-
graphy (EtOAc/hexanes, 1:1) provided 46 (0.049 g, 70%).
4.1.6.34. 3-Benzyl-3-(tert-butyldimethylsiloxymethyl)-4-
phenylbutanal (43). A solution of olefin (6.0 g, 15.8 mmol)
in DCM (180 mL) cooled to ꢂ78 ꢀC was bubbled O3 until
the solution turned light blue. On complete disappearance
of the starting material, N2 gas was bubbled through the re-
action mixture for 10 min at ꢂ78 ꢀC. The resulting mixture
was treated with Me2S (4.89 g, 79 mmol) at ꢂ78 ꢀC and
slowly warmed to rt. After stirring for 6 h at rt, it was con-
centrated and purified by column chromatography (hexanes/
EtOAc, 9:1) to afford 43 (5.77 g, 96%). IR (film): 1718,
1
IR (film): 1546 cmꢂ1; H NMR: d 7.36–6.89 (m, 15H),
5.26–5.19 (m, 1H), 3.94 (d, J¼9.6 Hz, 1H), 3.44 (d,
J¼13.5 Hz, 1H), 2.61–2.45 (m, 4H), 1.90 (dd, J¼11.1,
10.8 Hz, 1H), 1.68 (s, 3H), 1.54 (s, 3H), 1.53–1.46 (m,
1H); 31P NMR: d ꢂ4.48; 13C NMR: d 135.8, 135.4, 131.2,
131.0, 130.5, 129.9, 128.7, 128.6, 128.6, 128.5, 127.1,
127.0, 125.6, 120.0, 120.0, 89.8, 89.7, 75.9, 75.8, 72.1,
43.5, 40.75, 40.73, 40.6, 38.4, 24.5, 20.3; ESIHRMS: Calcd
for C27H30NO6PNa [M+Na]+ 518.1708. Found 518.1689.
1
1085 cmꢂ1; H NMR: d 9.86 (br s, 1H), 7.33–7.21 (m,
10H), 3.42 (s, 2H), 2.92 (s, 4H), 2.23 (d, J¼2.1 Hz, 2H),
1.04 (s, 9H), 0.14 (s, 6H); 13C NMR d 202.6, 137.7, 130.9,
128.2, 126.6, 65.5, 47.6, 43.7, 41.1, 26.1, 18.4, ꢂ5.2;
ESIHRMS: Calcd for C24H34NO2SiNa [M+Na]+ 405.2226.
Found 405.2224.
4.1.6.35.
5-Benzyl-5-(tert-butyldimethylsilyloxy-
4.1.6.38. 2,2-Dibenzyl-1-(tert-butyldimethylsiloxy)-4-
(diethylphosphatoxy)-5-methyl-5-nitrohexane (47). To
a solution of 44 (0.370 g, 0.79 mmol), pyridine (0.312 g,
3.95 mmol) in dichloromethane (11 mL) at 10 ꢀC was added
diethylchlorophosphite (0.37 g, 2.37 mmol) and stirred for
30 min at rt. When the starting material was consumed,
t-BuOOH (0.79 mL, 3.95 mmol) was added into the reaction
methyl)-2-methyl-2-nitro-6-phenylhexan-3-ol (44). To a
stirred solution of 43 (70 mg, 0.18 mmol) and 2-nitropropane
(0.77 g, 2.6 mmol) was added t-BuOK (0.77 g, 2.6 mmol)
at 0 ꢀC. After stirring for 12 h at rt the reaction was quenched
with satd solution of NH4Cl, diluted with water and the
aqueous layer was extracted with EtOAc. Concentration

6514
D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
1
flask at 10 ꢀC over 5 min and continued stirring for 20 min at
rt. EtOAc (20 mL) was added and the organic layer was
washed with 5% Na2S2O3, and dried. Concentration and pu-
rification of the crude mixture by column chromatography
(EtOAc/hexanes, 3:2) gave 47 (0.233 g, 58%). IR (film):
as colorless oil. [a]2D3 ꢂ23.7 (c 0.27); H NMR: d 7.39–
7.19 (m, 5H), 4.10 (d, J¼13.5 Hz, 1H), 3.09 (d,
J¼13.5 Hz, 1H), 2.81 (m, 1H), 2.26 (m, 1H), 2.00 (m,
1H), 1.92 (m, 1H), 1.73 (m, 1H), 1.60 (m, 2H), 1.42 (m,
1H), 1.23 (m, 2H), 0.94 (d, J¼3.0 Hz, 3H), 0.91 (d,
J¼3.0 Hz, 3H); 13C NMR: d 129.0, 128.2, 126.6, 124.4,
77.4, 66.6, 56.6, 27.7, 24.9, 24.7, 23.6, 20.3, 16.1;
ESIHRMS: Calcd for C15H24N [M+H]+ 218.1909. Found
218.1911.
1
1549, 1031, 1004 cmꢂ1; H NMR: d 7.37–7.18 (m, 10H),
5.51 (t, J¼9.0 Hz, 1H), 4.20–4.13 (m, 4H), 3.41 (d, J¼
9.9 Hz, 1H), 3.19 (d, J¼9.9 Hz, 1H), 3.07 (d, J¼13.5 Hz,
1H), 2.98 (m, 1H), 2.93 (m, 1H), 2.69 (d, J¼13.5 Hz, 1H),
1.61 (s, 3H), 1.57–1.40 (m, 2H), 1.42 (s, 3H), 1.39–1.28
(m, 6H), 0.98 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H); 31P
NMR: d ꢂ1.99; 13C NMR: d 138.1, 131.2, 131.0, 127.8,
126.1, 91.5, 79.9, 79.8, 65.7, 64.4, 64.3, 64.2, 41.5, 39.8,
39.2, 32.6, 32.5, 26.0, 24.4, 20.7, 18.2, 16.2, 16.1, ꢂ5.3,
ꢂ5.4; ESIHRMS: Calcd for C31H50NO7SiPNa [M+Na]+
630.2992. Found 630.2987.
4.1.7.3.
(S)-1,4,4-Tribenzyl-2-isopropylpyrrolidine
(51). Following the general procedure for radical cycliza-
tion, 24 (205 mg, 0.30 mmol) afforded 51 (51 mg, 44%,
1
60% ee) as colorless oil. [a]2D3 ꢂ24.4 (c 1.0); H NMR:
d 7.35–7.00 (m, 15H), 3.96 (d, J¼13.5 Hz, 1H), 2.90–2.75
(m, 3H), 2.66–2.62 (m, 3H), 2.20 (td, J¼8.6, 4.5 Hz, 1H),
2.02–1.88 (m, 2H), 1.70 (dd, J¼12.6, 8.6 Hz, 1H), 1.57
(dd, J¼12.6, 9.0 Hz, 1H), 0.91 (d, J¼6.9 Hz, 3H), 0.85 (d,
J¼7.2 Hz, 3H); 13C NMR: d 140.1, 139.3, 131.0, 131.0,
128.8, 128.2, 128.0, 127.8, 126.7, 126.0, 125.9, 69.1, 62.8,
58.0, 46.1, 44.0, 35.0, 30.4, 27.8, 20.3, 15.3; ESIHRMS:
Calcd for C28H34N [M+H]+ 384.2691. Found 384.2691.
4.1.6.39. 2,2-Dibenzyl-4-(diethylphosphatoxy)-5-methyl-
5-nitrohexanol (48). To a solution of 47 (0.18 g, 0.29 mmol)
in acetonitrile (2 mL) was added aq HF (49%, 1.02 mL,
29 mmol) at rt. After stirring for 5 min at rt, water (4 mL)
was added and the aqueous mixture was extracted with
EtOAc. The organic layer was washed with water and brine
and dried. Concentration and purification of the crude
mixture by column chromatography (EtOAc/hexanes, 3:2)
afforded 48 (82 mg, 58%). 1H NMR: d 7.29–7.18 (m, 10H),
5.56 (m, 1H), 4.09 (m, 2H), 3.98 (m, 2H), 3.50 (s, 2H),
2.94 (d, J¼13.2, 1H), 2.90 (m, 2H), 2.54 (d, J¼13.2 Hz,
1H), 1.76 (dd, J¼15.3, 8.4 Hz, 1H), 1.58 (s, 3H), 1.58–1.48
(m, 1H), 1.42 (s, 3H), 1.32 (t, J¼6.0 Hz, 3H), 1.22
(t, J¼6.0 Hz, 3H); 31P NMR: d ꢂ2.09; 13C NMR: d 138.0,
137.9, 131.1, 131.0, 128.3, 128.2, 126.5, 126.4, 91.7, 79.8,
65.6, 64.7, 64.3, 41.7, 41.6, 41.4, 36.9, 24.3, 20.4, 16.2,
16.1; ESIHRMS: Calcd for C25H36NO7PNa [M+Na]+
516.2127. Found 516.2113.
4.1.7.4. N-Benzyl-2-(3-methyl-2-butenyl)aniline (52).
Following the general procedure for radical cyclization, 30
(409 mg, 0.62 mmol) afforded 52 (80 mg, 50%) as a color-
less oil. 1H NMR: d 7.38–7.34 (m, 3H), 7.31–7.26 (m,
2H), 7.14–7.08 (m, 2H), 6.73–6.67 (m, 2H), 5.21 (t,
J¼6.9 Hz, 1H), 4.33 (s, 2H), 3.22 (d, J¼6.9 Hz, 2H), 1.69
(s, 3H), 1.58 (s, 3H); 13C NMR (CDCl3): d 133.7, 130.5,
129.3 129.1, 128.6, 127.8, 127.3, 121.9, 117.5, 111.0,
48.6, 31.2, 25.7, 17.7; ESIHRMS: Calcd for C18H21N
[M]+ 251.1674. Found 251.1670.
4.1.7.5. (7S)-1,1-Dimethyl-2-methylenepyrrolizidine
(53). The general procedure for radical cyclization was fol-
lowed but extraction method was changed. On complete
consumption of 33 (144 mg, 0.32 mmol) the reaction mix-
ture was cooled to rt, then 2 M HCl (12 mL) was added,
and stirred for 20 min. The aqueous layer was washed with
hexane, then basified to pH 11 with 15% aq NaOH and ex-
tracted with ethyl ether. The combined organic layer washed
with water and 2 M HCl (12 mL) was added again. After
stirring for 30 min, aqueous layer was separated and concen-
trated to give the pure HCl salt of pyrrolizidine 53 (39 mg,
4.1.7. Typical protocol for the radical cyclization.
4.1.7.1. (S)-1-Benzyl-2-isopropylpyrrolidine (49). To
the solution of the radical precursor 11 (200 mg,
0.40 mmol) and AIBN (14 mg, 0.085 mmol) in deoxygen-
ated benzene (30 mL) was added tributyltin hydride
(0.173 mL, 0.643 mmol). The reaction mixture was heated
to reflux for 30 h with addition of further AIBN (8 mg,
0.05 mmol) twice in 12 h intervals. The reaction mixture
was then cooled to rt, 2 M HCl (12 mL) was added, and
the biphasic mixture was stirred for 20 min. The organic
layer was washed with aq 2 M HCl and the combined aque-
ous layer was washed with hexane, then basified to pH 11
with 15% NaOH and extracted with ethyl ether. The com-
bined organic layer was washed with water and brine then
dried. Concentration under reduced pressure followed by
chromatographic purification afforded 49 (35 mg, 43%,
1
64%, 60% ee). [a]2D3 ꢂ9.2 (c 1.0); H NMR: d 12.8 (br s,
1H), 5.08 (br s, 1H), 5.06 (br s, 1H), 4.51 (dd, J¼14.1,
6.3 Hz, 1H), 3.90 (m, 2H), 3.42 (d, J¼15.6 Hz, 1H), 2.84
(m, 1H), 2.05 (m, 3H), 1.61 (m, 1H), 1.33 (s, 3H), 1.17 (s,
3H); 13C NMR: d 108.9, 100.2, 76.9, 57.9, 56.2, 33.0,
28.8, 27.4, 25.2, 21.5; ESIHRMS: Calcd for C10H18N
[M+H]+ 152.1439. Found 152.1439.
1
61% ee) as colorless oil. [a]2D3 ꢂ32.4 (c 1.0); H NMR:
d 7.38–7.22 (m, 5H), 4.04 (d, J¼13.2 Hz, 1H), 3.10 (d,
J¼13.2 Hz, 1H), 2.88 (m, 1H), 2.34 (m, 1H), 2.03 (m,
1H), 1.95 (m, 1H), 1.61 (m, 4H), 0.94 (s, 3H), 0.92 (s,
3H); 13C NMR: d 131.4, 129.9, 129.2, 127.9, 78.2, 71.6,
52.3, 29.7, 28.7, 26.1, 22.1, 21.1; ESIHRMS: Calcd for
C14H22N [M+H]+ 204.1752. Found 204.1747.
4.1.7.6. 2-(40,40-Diphenylcyclohexyl)-tetrahydrofuran
(54) and (7R)-7-(40,40-diphenylcyclohexyl)-2-phenoxy-
[1,3,2]dioxaphosphepane-2-oxide (55). To the mixture of
41 (158 mg, 0.26 mmol), AIBN (22 mg, 0.14 mmol), and
tributyltin hydride (169 mg, 0.58 mmol) was added deoxy-
genated benzene (6.5 mL) and refluxed for 12 h. The reaction
mixture was cooled, concentrated, and purified by column
chromatography to provide tetrahydrofuran 54 (20 mg,
4.1.7.2. (S)-1-Benzyl-2-isopropylpiperidine (50). Fol-
lowing the general procedure for radical cyclization, 12
(180 mg, 0.351 mmol) afforded 50 (31 mg, 41%, 60% ee)
1
25%) and the cyclic phosphate 55 (68 mg, 52%). 54: H
NMR: d 7.38–7.16 (m, 10H), 3.81–3.79 (m, 1H), 3.67–3.65

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6515
1
(m, 1H), 3.40–3.35 (m, 2H), 2.72 (d, J¼12.4 Hz, 1H), 1.97–
1.80 (m, 5H), 1.59–0.98 (m, 6H); 13C NMR: d 151.3, 146.1,
128.5, 128.2, 128.1, 126.3, 125.6, 125.5, 83.8, 67.8, 46.1,
43.1, 36.3, 29.4, 26.6, 25.9, 25.4; ESIHRMS: Calcd for
923 cmꢂ1; H NMR: d 7.39 (s, 5H), 7.30 (br s, 1H), 6.18
(s, 1H), 1.70 (s, 3H), 1.45 (s, 3H), 1.42 (s, 9H); 13C NMR:
d 148.6, 133.1, 129.9, 128.8, 128.0, 90.5, 87.3, 84.9, 27.9,
23.9, 20.2.
1
C22H26ONa [M+Na]+ 329.1881. Found 329.1886. 55: H
NMR: d 7.37–7.06 (m, 15H), 4.23–4.05 (m, 3H), 2.79–2.74
(m, 2H), 1.95–1.91 (m, 5H), 1.73–1.67 (m, 4H), 1.41–1.36
(m, 2H); 13C NMR: d 151.1, 144.8, 129.8, 128.7, 128.3,
128.0, 126.3, 125.8, 125.7, 125.1, 120.2, 83.0, 82.9, 68.9,
68.8, 45.9, 43.0, 36.3, 36.2, 31.8, 29.2, 25.5, 24.5; 31P
NMR: d ꢂ2.92; ESIHRMS: Calcd for C28H31O4PNa
[M+Na]+ 485.1858. Found 485.1838.
4.1.7.10. N-Allyl O-(2-methyl-2-nitro-1-phenylpropyl)
sulfamate (60). To a solution of 59 (1.0 g, 2.7 mmol) and
allyl bromide (10 mL) in acetonitrile (16 mL) was added
dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL,
3.5 mmol) at rt. The reaction mixture was stirred overnight
and quenched with a satd aq NH4Cl. The aqueous layer
was extracted twice with CH2Cl2 and the resulting organic
layer was washed with brine, dried, and concentrated. The
residue was purified by flash chromatography (hexanes/EA
from 95:5 to 85:15) to afford N-allyl N-tert-butyloxy-
carbonyl O-(2-methyl-2-nitro-1-phenylpropyl) sulfamate
(962 mg, 87%) as a white solid. mp 68–70 ꢀC; IR (neat):
3069, 2983, 1742, 1550, 1401, 1191, 1149, 958, 857,
4.1.7.7.
6,6-Dibenzyl-2-ethoxy-4-(1-methyl-1-nitro-
ethyl)[1,3,2]dioxaphosphepane 2-oxide (56). In a one
necked 25 mL flask fitted with a condenser, and a septum
was placed nitrophosphate 48 (0.082 g, 0.177 mmol), tribu-
tyltin hydride (0.77 g, 0.27 mmol), and AIBN (0.012 g,
0.071 mmol). Degassed benzene (18 mL) was added to the
reaction mixture, which was then heated to reflux in an oil
bath preheated at 100 ꢀC for 15 h. The reaction mixture
was cooled to rt and concentrated. Chromatographic purifi-
cation (EtOAc/hexanes, 3:7) provided cyclic phosphates
1
843 cmꢂ1; H NMR: d 7.35–7.40 (s, 5H), 6.13 (s, 1H),
5.76 (m, 1H), 5.22 (d, J¼18.1 Hz, 1H), 5.18 (d,
J¼11.1 Hz, 1H), 3.97–4.07 (ABX, J¼16.5 Hz, 4H), 1.70
(s, 3H), 1.48 (s, 9H), 1.44 (s, 3H); 13C NMR: d 150.1,
133.3, 132.5, 130.0, 128.8, 128.0, 118.6, 90.4, 87.2, 85.2,
51.4, 28.1, 24.1, 20.3. Anal. Calcd for C18H26N2O7S: C,
52.16; H, 6.32. Found: C, 52.07; H, 6.29. To a solution of
this sulfamate (207 mg, 0.5 mmol) in CH2Cl2 (5 mL) was
added at 0 ꢀC trifluoroacetic acid (0.39 mL, 5 mmol). The
reaction mixture was stirred at rt for 2 h and quenched
with a 1 N NaOH solution. The aqueous layer was extracted
with CH2Cl2 and the combined organic layer was washed
with brine, dried, and concentrated. Chromatographic purifi-
cation (hexanes/EA from 100:0 to 80: 10) afforded 60
(64 mg, 41%) as a colorless oil. IR (neat): 3317, 3067,
1647, 1547, 1456, 1349, 1180, 963 cmꢂ1; 1H NMR: d 7.40
(s, 5H), 5.96 (s, 1H), 5.66 (ddt, J¼16.9, 10.5, 5.0 Hz, 1H),
5.11–5.18 (m, 2H), 4.51 (t, J¼5.9 Hz, 1H), 3.57–3.43 (m,
2H), 1.67 (s, 3H), 1.47 (s, 3H); 13C NMR: d 133.9, 132.5,
129.9, 128.8, 128.1, 118.6, 90.8, 85.7, 46.5, 24.3, 19.9.
Anal. Calcd for C13H18N2O5S: C, 49.67; H, 5.77. Found:
C, 49.77; H, 5.74.
1
56 (44 mg, 67%). IR (film): 1026, 992 cmꢂ1; H NMR:
d 7.32–7.20 (m, 8H), 6.94 (d, J¼6.9 Hz, 2H), 4.50–4.46
(m, 1H), 4.19–4.09 (m, 2H), 3.82–3.77 (m, 2H), 3.26 (d,
J¼13.8 Hz, 1H), 2.64 (d, J¼13.8 Hz, 1H), 2.58 (d,
J¼13.5, 1H), 2.48 (d, J¼13.5 Hz, 1H), 1.87–1.77 (m, 2H),
1.51 (d, J¼15.1 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H), 0.97 (d,
J¼6.9 Hz, 3H), 0.94 (d, J¼6.6 Hz, 3H); 31P NMR: d 2.71;
13C NMR: d 136.7, 136.2, 131.3, 130.7, 128.4, 126.8,
126.7, 77.9, 71.4, 64.2, 43.7, 41.0, 40.8, 40.4, 33.8, 33.7,
19.0, 17.4, 16.3; ESIHRMS: Calcd for C23H32O2PNa
[M+Na]+ 425.1775. Found 425.1773.
4.1.7.8. (S)-1-p-Toluenesulfonyl-2-isopropylpyrroli-
dine (57). Pyrrolidine 49(15 mg, 0.074 mmol) was treated
in EtOAc (10 mL) with 20% Pd(OH)2/C (18 mg) under
a H2 atmosphere for 4 h. The reaction mixture was carefully
filtered through Celite and residue was washed with EtOAc
(10 mL). The filtrate was treated with diisopropylethylamine
(0.1 mL, 0.57 mmol) and TsCl (45 mg, 0.24 mmol), then
stirred overnight at rt. The reaction was quenched with
satd aq NaHCO3 and aqueous layer was extracted with
EtOAc. The combined organic layer was washed with H2O
and brine then dried. After the evaporation, the residue
was purified by silica gel chromatography. The sulfonamide
57 (9 mg, 45%) was obtained as a colorless solid, [a]D23
ꢂ78.1 (c 0.9), lit.14 [a]2D3 ꢂ91.3 (c 1.0).
4.1.7.11. N-Allyl N-(4-methoxybenzyl) O-(2-methyl-2-
nitro-1-phenylpropyl) O-phenyl phosphoramidate (61).
To a solution of phenylphosphorodichloridite (2.87 mL,
20.0 mmol) and N,N-diisopropylethylamine (11.6 mL,
66.8 mmol) in THF (40 mL) was added dropwise, at
ꢂ78 ꢀC, a solution of alcohol 5820 (3.26 g, 16.7 mmol) in
THF (15 mL). The reaction mixture was warmed up to rt and
stirred for 1 h. Then the solution was cooled to ꢂ78 ꢀC
and a solution of allyl-(4-methoxybenzyl)amine (5.33 g,
30.1 mmol) in THF (10 mL) was added dropwise. The reac-
tion mixture was warmed up to rt and stirred for 2 h. The
solid was filtrated and washed with EtOAc. The filtrate
was concentrated in vacuo to give the phosphoramidite as
oil. The crude reaction mixture was dissolved in CH2Cl2
(80 mL) and a solution of tert-butyl hydroperoxide (5–6 M
in decane, 8 mL, 40 mmol) was added at 0 ꢀC and the reac-
tion mixture was stirred at rt for 1 h. The reaction was
quenched with satd aq NaHCO3, extracted with CH2Cl2,
washed with water and brine, dried, and concentrated. Chro-
matographic purification (CH2Cl2/EA from 100:0 to 90:10)
afforded the phosphate 61 (5.55 g, 67%) as a viscous oil. IR
(neat): 3066, 1612, 1591, 1545, 1491, 1266, 1210, 1025,
4.1.7.9. N-tert-Butyloxycarbonyl O-(2-methyl-2-nitro-
1-phenylpropyl) sulfamate (59). A solution of chlorosul-
fonyl isocyanate (0.8 mL, 9.1 mmol) in hexanes (8 mL) was
added dropwise to a solution of 2-methylpropan-2-ol
(675 mg, 9.1 mmol) in hexane (17 mL) and the solution
was stirred at rt for 45 min. Then a solution of alcohol
5820 (1.2 g, 6.07 mmol) and triethylamine (1.35 mL,
9.7 mmol) in THF (20 mL) was added dropwise. After 2 h,
the reaction was quenched with water and extracted with
CH2Cl2. The organic layer was washed with brine, dried,
and concentrated. Chromatographic purification (hexanes/
EA from 90:10 to 70:30) afforded 59 (1.914 g, 84%) as a col-
orless oil. IR (neat): 3255, 2987, 1757, 1550, 1456, 1147,

6516
D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
926 cmꢂ1; H NMR: d 7.39–7.10 (m, 20H, two dias), 6.97
(m, 2H, one dias), 6.91 (m, 2H, one dias), 6.82 (m, 2H,
one dias), 6.74 (m, 2H, one dias), 5.95 (d, J¼8.5 Hz,
1H, one dias), 5.93 (d, J¼8.6 Hz, 1H, one dias), 5.66 (m,
1H, one dias), 5.30 (m, 1H, one dias), 5.19–4.95 (m, 4H,
two dias), 4.20–4.08 (m, 3H, two dias), 3.96 (dd, J¼14.8,
10.1 Hz, 1H, one dias), 3.79 (s, 3H, one dias), 3.77 (s, 3H,
one dias), 3.52 (m, 2H), 3.45 (m, 1H), 3.26 (m, 1H), 1.62
(s, 3H, one dias), 1.57 (s, 3H, one dias), 1.45 (s, 3H, one
dias), 1.38 (s, 3H, one dias); 13C NMR: d 159.2, 159.1,
151.0 (d, JPC¼7.0 Hz), 150.9 (d, JPC¼6.8 Hz), 135.1,
135.0, 134.0, 133.8, 130.1 (2C), 129.8, 129.7, 129.5,
129.2, 129.0 (d, JPC¼3.4 Hz,), 128.6, 128.3, 128.2, 128.1,
125.0, 124.8, 120.5 (d, JPC¼4.6 Hz), 120.3 (d, JPC¼4.9 Hz),
119.0, 118.9, 114.0, 113.9, 91.2 (d, JPC¼4.7 Hz), 91.1 (d,
JPC¼4.7 Hz), 82.6 (d, JPC¼5.2 Hz), 82.5 (d, JPC¼5.1 Hz),
60.6, 55.5, 48.2 (d, JPC¼3.5 Hz), 48.1 (d, JPC¼3.7 Hz),
47.7 (d, JPC¼2.7 Hz), 47.4 (d, JPC¼2.7 Hz), 24.1, 23.6,
20.4, 20.0; 31P NMR: d 4.78, 2.39. Anal. Calcd for
C27H31N2O6P: C, 63.52; H, 6.12. Found: C, 63.40; H, 6.14.
with EtOAc. The filtrate was concentrated to give an oil,
which was purified by column chromatography on neutral
Al2O3 (hexane/EA from 90:10) to afford the phosphite 63
(1.28 g, 80%) as colorless oil. IR (neat): 2980, 1545, 1455,
1
1
1025, 924 cmꢂ1; H NMR: d 7.36–7.31 (m, 5H), 5.63 (d,
J¼8.7 Hz 1H), 3.77–3.58 (m, 4H), 1.41 (s, 3H), 1.59 (s,
3H), 1.10 (t, J¼7.0 Hz, 3H), 1.07 (t, J¼7.0 Hz, 3H); 13C
NMR: d 137.4, 128.9, 128.3, 91.9 (d, JPC¼3.9 Hz), 78.8
(d, JPC¼13.1 Hz), 59.0 (d, JPC¼12.2 Hz), 58.7 (d,
JPC¼10.6 Hz), 23.6, 19.1, 16.9, 16.8; 31P NMR: d 140.9.
Anal. Calcd for C14H22NO5S: C, 53.33; H, 7.03. Found: C,
53.60; H, 7.07.
4.1.7.14. N-Allyl O,O-diethyl O-2-(ethyl-2-nitro-1-
phenylpropyl) phosphorimidate (64). To a solution of
sodium azide (2 equiv) and tetrabutylammonium bromide
(0.05 equiv) in water was added allyl bromide. The solution
was heated at 50–60 ꢀC for 2 h with a vigorous stirring. The
aqueous layer was washed twice with benzene (C6H6 or
C6D6). The combined organic layers were washed with
brine, dried over MgSO4, and filtered to afford a solution
of allyl azide in benzene (w0.5 M in C6H6; w1.33 M in
C6D6,), free from allyl bromide as determined by GC, which
was stored over molecular sieves for 24 h prior to use. The
1.33 M solution of allyl azide in C6D6 (3.3 mL,
4.38 mmol) was added to a solution of phosphite 63
(230 mg, 0.73 mmol) in C6D6 (5 mL) and the solution was
heated at reflux for 4 h. The NMR of the crude reaction mix-
ture indicated quantitative conversion of 63 to 64. 1H NMR
(C6D6): d 7.26–7.22 (m, 2H), 7.12–7.08 (m, 3H), 6.19 (m,
1H), 6.10 (d, J¼9.0 Hz 1H), 5.62 (dq, J¼16.9, 2.4 Hz,
1H), 5.21 (dq, J¼10.0, 2.4 Hz, 1H), 4.09–3.70 (m, 6H),
1.49 (s, 3H), 1.12 (s, 3H), 1.05 (br t, J¼7.0 Hz, 3H), 1.01
(dt, J¼7.0, 1.0 Hz, 3H); 13C NMR (C6D6): d 141.6 (d,
JPC¼15.5 Hz), 136.4, 128.6, 128.1, 127.9, 111.6, 90.7 (d,
JPC¼8.2 Hz), 82.1 (d, JPC¼7.2 Hz), 62.9 (d, JPC¼9.2 Hz),
62.8 (d, JPC¼7.8 Hz), 45.6, 23.6, 19.1, 15.8; 31P NMR:
(C6D6) d ꢂ3.69.
4.1.7.12. N-Allyl O-(2-methyl-2-nitro-1-phenylpropyl)
O-phenyl phosphoramidate (62). To a solution of phos-
phoramidate 61 (two dias ratio 1.7:1) (1 g, 1.96 mmol) in
CH3CN/H2O (6:1, 19 mL) was added at rt cerium ammoni-
um nitrate (3.22 g, 7.84 mmol). The mixture was stirred at rt
for 1 h and then diluted with CH2Cl2 and quenched with satd
aq NaHCO3. The organic layer was washed with brine, dried
and concentrated. Chromatographic purification (CH2Cl2/
EA from 100:0 to 90:10) afforded 62 as an unassigned mix-
ture of two diastereomers (670 mg, 88%) as a white solid. IR
(neat): 3223, 1593, 1545, 1491, 1261, 1212, 1041, 1025,
934 cmꢂ1 1H NMR: d 7.40–7.08 (m, 18H, major and
;
minor), 7.00 (d, J¼8.7 Hz, 2H, major), 5.95 (d, J¼8.5 Hz,
1H, major), 5.92 (d, J¼8.6 Hz, 1H, minor), 5.81 (m, 1H,
major), 5.56 (m, 1H, minor), 5.20 (dq, J¼17.1, 1.6 Hz, 1H,
major), 5.10 (dq, J¼10.3, 1.3 Hz, 1H, major), 5.01 (dq,
J¼17.0, 1.4 Hz, 1H, minor), 4.97 (dq, J¼10.2, 1.3 Hz, 1H,
minor), 3.62–3.49 (m, 2H, major), 3.40–3.30 (m, 2H, minor),
2.98 (dt, J¼12.1, 6.8 Hz, 1H, major), 2.82 (dt, J¼12.6,
6.9 Hz, 1H, minor), 1.60 (s, 3H, minor), 1.59 (s, 3H, major),
1.44 (s, 3H, major), 1.41 (s, 3H, minor); 13C NMR: d 159.9
(d, JPC¼6.5 Hz, major and minor), 135.7 (d, JPC¼6.3 Hz,
major), 135.4 (d, JPC¼6.5 Hz, minor), 135.1 (major and
minor), 129.8, 129.7, 129.6, 129.3 (major and minor),
128.1 (minor), 128.6 (minor), 128.4 (major), 128.0 (major),
125.1 (minor), 125.0 (major), 120.44 (d, JPC¼4.5 Hz,
minor), 120.42 (d, JPC¼4.1 Hz, minor), 116.0 (minor),
4.1.7.15. N-Allyl sulfamic acid (65). A solution of 60
(229 mg, 0.73 mmol) in benzene (36 mL) was degassed by
sparging with nitrogen for 40 min. Bu3SnH (289 mL,
1.17 mmol) and AIBN (48 mg, 0.31 mmol) were added
and the solution was heated at reflux for 6 h. Then, Bu3SnH
(96 mL, 0.39 mmol) and AIBN (18 mg, 0.11 mmol) were
added and the solution was heated for 3 h. The solvent was
evaporated and CH2Cl2 and water were added. The organic
layer was concentrated but contained only thin residues. The
aqueous layer was evaporated to give a gum (90 mg), which
was washed with CH3CN and hexanes to give 65 (80 mg,
w48%) contaminated by some tin residues. 1H NMR:
d 5.94 (m, 1H), 5.23 (d, J¼17.1 Hz, 1H), 5.08 (d,
J¼10.0 Hz, 1H), 3.60 (d, J¼5.2 Hz, 2H); 13C NMR:
d 135.1, 115.1, 46.2; ESIMS m/z: 136 (100).
116.2 (major), 91.4 (d, JPC¼8.6 Hz, major), 91.2 (d, JPC
¼
8.2 Hz, minor), 84.5 (d, JPC¼4.7 Hz, major), 82.4 (d,
JPC¼4.8 Hz, minor), 44.2 (major), 44.0 (minor), 24.4 (ma-
jor), 23.5 (minor), 20.5 (minor), 19.4 (major); 31P NMR:
d 3.45 (major), 2.39 (minor). ESIMS m/z: 413 ([M+Na]+,
100), 803 ([2M+Na]+, 65). Anal. Calcd for C19H23N2O5P:
C, 58.46; H, 5.94. Found: C, 58.64; H, 6.00.
4.1.7.16. N-Allyl O-(1,1-dimethyl-2-phenylethyl) O-
phenyl phosphoramidate (66), N-allyl O-(2-methyl-1-
phenylpropyl) O-phenyl phosphoramidate (67), and 7,7-
dimethyl-2-phenoxy-8-phenyl-[1,3,2]oxazaphosphocane
2-oxide (68). A solution of 62 (195 mg, 0.5 mmol), AIBN
(33 mg, 0.20 mmol), and Bu3SnH (0.2 mL, 0.75 mmol) in
degassed benzene (25 mL) was heated at reflux for 6 h.
Then AIBN (8 mg, 0.05 mmol) and Bu3SnH (50 mL,
4.1.7.13. Diethyl 2-(ethyl-2-nitro-1-phenylpropyl)
phosphite (63). To a solution of diethylchlorophosphite
(0.9 mL, 6.3 mmol) and N,N-diisopropylethylamine
(1.74 mL, 10 mmol) in THF (10 mL) was added dropwise
at ꢂ78 ꢀC a solution of alcohol 5820 (975 mg, 5 mmol) in
THF (3 mL). The reaction mixture was warmed up to rt
and stirred for 1 h. The solid was filtered off and washed

D. Crich et al. / Tetrahedron 62 (2006) 6501–6518
6517
1
0.18 mmol) were added and the mixture was heated for
a further 15 h. The reaction mixture was concentrated and
the residue was purified by column chromatography
(CH2Cl2/EA from 100:0 to 70:30) to afford by order of elu-
tion 67 (12 mg, 7%), 66 (73 mg, 42%), and 68 (14 mg, 8%).
Compound 66: white solid. mp 40–41 ꢀC. IR (neat): 3220,
216.0766. Found 216.0758. 70: H NMR: d 7.38–7.35 (m,
10H, two dias), 5.85 (d, J¼8.6 Hz, 1H, one dias), 5.81 (d,
J¼8.5 Hz, 1H, one dias), 5.82 (m, 1H, one dias), 5.61 (m,
1H, one dias), 5.19 (dq, J¼17.0, 1.7 Hz, 1H, one dias),
5.10 (dq, J¼10.1, 1.5 Hz, 1H, one dias), 5.03 (dq, J¼17.2,
1.4 Hz, 1H, one dias), 4.98 (dq, J¼10.4, 1.5 Hz, 1H, one
dias), 4.05–3.80 (m, 4H, two dias), 3.52–3.38 (m, 2H, two
dias), 3.38–3.20 (m, 2H, two dias), 1.64 (s, 3H, one dias),
1.62 (s, 3H, one dias), 1.45 (s, 3H, one dias), 1.44 (s, 3H,
one dias), 1.26 (t, J¼7.0 Hz, 3H, one dias), 1.12 (t,
J¼7.0 Hz, 3H, one dias); 13C NMR: d 136.1 (d,
JPC¼6.4 Hz), 135.9 (d, JPC¼6.7 Hz), 135.6, 135.5, 129.5,
129.4, 128.6, 128.5, 128.2, 128.1, 115.9, 115.7, 91.4 (d,
JPC¼8.6 Hz), 91.3 (d, JPC¼8.3 Hz), 82.1 (d, JPC¼4.9 Hz),
82.0 (d, JPC¼5.0 Hz), 63.2 (d, JPC¼5.4 Hz), 63.0 (d,
JPC¼5.4 Hz), 44.0, 43.9, 24.1, 23.9, 19.6, 19.4, 16.3, 16.2;
31P NMR: d 8.44, 7.46; HRMS: Calcd for C15H23N2O5NaP
[M+Na]+ 365.1243. Found 365.1238. Compound 71:
1
1593, 1545, 1491, 1261, 1212, 1041, 1025, 934 cmꢂ1; H
NMR: d 7.39–7.10 (m, 3H), 5.77 (m, 1H), 5.13 (dq,
J¼17.1, 1.5 Hz, 1H), 5.05 (dq, J¼11.7, 1.4 Hz, 1H), 3.50
(m, 2H), 2.93–3.05 (m, 2H), 1.54 (s, 3H), 1.52 (s, 3H);
13C NMR: d 151.5 (d, JPC¼6.9 Hz), 137.2, 131.0 (d,
JPC¼6.9 Hz), 131.0, 129.7, 128.4, 126.8, 124.7, 120.7 (d,
JPC¼4.6 Hz), 115.8, 84.9 (d, JPC¼7.4 Hz), 49.5 (d, JPC
¼
6.4 Hz), 44.3, 28.0, 27.5; 31P NMR: d ꢂ0.18. Anal. Calcd
for C19H22NO3P: C, 66.07; H, 7.00. Found: C, 66.19; H,
7.02. Compound 67: colorless oil. H NMR: d 7.37–6.97
1
(m, 20H, two dias), 5.81 (m, 1H, one dias), 5.47 (m, 1H,
one dias), 5.23–5.03 (m, 4H, two dias), 4.91 (m, 1H, one
dias), 3.58 (m, 2H, one dias), 3.35 (m, 1H, one dias), 3.17
(m, 1H, one dias), 2.17–2.07 (m, 2ꢁ1H, two dias), 1.03
(d, J¼6.8 Hz, 3H, one dias), 0.93 (d, J¼6.8 Hz, 3H, one
dias), 0.83 (d, J¼6.8 Hz, 3H, one dias), 0.74 (d,
J¼6.8 Hz, 3H, one dias); 13C NMR: d 151.3 (d,
JPC¼6.7 Hz), 151.2 (d, JPC¼6.6 Hz), 139.9, 139.7, 136.0
(d, JPC¼6.4 Hz), 135.7 (d, JPC¼7.0 Hz), 129.8, 129.7,
128.5, 128.3 (2C), 128.1, 124.9, 124.6, 120.8 (d,
JPC¼4.6 Hz), 120.3 (d, JPC¼4.8 Hz), 116.1, 115.9, 85.7
(d, JPC¼6.7 Hz), 85.2 (d, JPC¼5.4 Hz), 44.3, 44.1, 35.2
(d, JPC¼6.4 Hz), 35.1 (d, JPC¼6.1 Hz), 18.8 (2C), 18.6,
18.5; 31P NMR: d 3.82, 3.70; HRMS: Calcd for
C19H24NO3NaP [M+Na]+ 368.1392. Found 368.1397.
Compound 68: white solid. mp 132 ꢀC; IR (neat): 3222,
1
slightly yellow oil. H NMR: d 7.33–7.25 (m, 10H, two
dias), 5.84 (m, 1H, one dias), 5.50 (m, 1H, one dias), 5.18
(dq, J¼17.2, 1.6 Hz, 1H, one dias), 5.07 (dq, J¼10.3,
1.3 Hz, 1H, one dias), 4.99–4.88 (m, 4H, two dias), 4.08
(m, 2H, one dias), 3.81 (m, 2H, one dias), 3.48 (m, 2H,
one dias), 3.17 (m, 1H, one dias), 3.08 (m, 1H, one dias),
2.16–2.05 (m, 2H, two dias), 1.31 (t, J¼7.1 Hz, 3H, one
dias), 1.09 (t, J¼7.1 Hz, 3H, one dias), 1.05 (d, J¼6.7 Hz,
3H, one dias), 1.01 (d, J¼6.6 Hz, 3H, one dias), 0.79 (d,
J¼6.7 Hz, 3H, one dias), 0.78 (d, J¼6.7 Hz, 3H, one dias);
13C NMR: d 140.2, 136.5 (d, JPC¼7.0 Hz), 136.1 (d,
JPC¼7.0 Hz), 128.4, 128.2, 128.0, 127.4, 127.3, 115.7,
115.5, 84.8 (d, JPC¼6.3 Hz), 84.4 (d, JPC¼5.2 Hz), 62.6
(d, JPC¼5.2 Hz), 62.5 (d, JPC¼5.3 Hz), 44.1, 43.9, 35.2 (d,
JPC¼7.1 Hz), 35.1 (d, JPC¼7.1 Hz), 19.0, 18.8, 18.6, 16.5
(d, JPC¼7.1 Hz, one dias), 16.2 (d, JPC¼7.1 Hz, one dias);
31P NMR: d 8.75, 8.63; HRMS: Calcd for C15H24NO3NaP
[M+Na]+ 320.1392. Found 320.1403.
2963, 1592, 1491, 1250, 1214, 936 cmꢂ1 1H NMR:
;
d 7.33–7.10 (m, 10H), 5.25 (d, J¼11.8 Hz, 1H), 3.60 (br
s, 1H), 3.15–3.10 (m, 1H), 3.05–2.95 (m, 1H), 2.00–1.93
(m, 1H), 1.90–1.60 (m, 3H), 0.82 (s, 3H), 0.80 (s, 3H);
13C NMR: d 151.4 (d, JPC¼6.0 Hz), 138.3, 129.8, 128.1,
127.9, 127.8, 124.8, 120.7 (d, JPC¼4.25 Hz), 84.5 (d,
JPC¼3.6 Hz), 43.8, 41.5, 38.7 (d, JPC¼3.8 Hz), 26.7, 24.5,
21.1; 31P NMR: d 5.16; HRMS: Calcd for C19H24NO3P
[M+Na]+ 368.1392. Found 368.1388.
Acknowledgements
´
`
`
We thank the Ministere des Affaires Etrangeres, France, for
a Lavoisier Fellowship in support of F.B., and the NSF (CHE
9986200) for partial support of this work.
4.1.7.17. N-Allyl diethyl phosphoramidate (69), N-allyl
O-ethyl O-(2-methyl-2-nitro-1-phenylpropyl) phosphor-
amidate (70), and N-allyl O-ethyl ester O-(2-methyl-1-
phenylpropyl) phosphoramidate (71). The phosphorimi-
date 64 was prepared by reaction of 63 (450 mg,
1.4 mmol) and a 0.5 N solution of allyl azide in C6H6
(11.2 mL, 5.6 mmol) as described above. Benzene (60 mL)
was added to the solution of 64 and the resulting solution
was degassed for 30 min. Then AIBN (92 mg, 0.56 mmol)
and Bu3SnH (1.48 mL, 5.6 mmol) were added and the
mixture heated at reflux for 10 h. The reaction mixture was
concentrated and the residue was purified by column chro-
matography (CH2Cl2/EA from 100:0 to 50:50) to afford by
order of elution 70 (30 mg, 6%), 71 (22 mg, 5%), and 69
(120 mg, 40%). Compound 69: IR (neat): 3227, 3086,
2980, 1645, 1445, 1233, 1034, 965 cmꢂ1; 1H NMR: d 5.85
(m, 1H), 5.20 (dq, J¼17.0, 1.6 Hz, 1H), 5.08 (dq, J¼10.4,
1.6 Hz, 1H), 4.09–3.99 (m, 4H), 3.51 (m, 2H), 1.30 (t,
J¼7.0 Hz, 6H); 13C NMR: d 136.3 (d, JPC¼6.1 Hz), 115.6,
62.5 (d, JPC¼5.1 Hz), 44.0, 16.4 (d, JPC¼7.0 Hz); 31P
NMR: d 9.40; HRMS: Calcd for C7H16NO3NaP [M+Na]+
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6518
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,
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