An enantioselective approach to the Securinega alkaloids: The total synthesis of (+)-norsecurinine and (+)-allonorsecurinine

Article abstract of DOI:10.1016/j.tet.2010.03.015

Total syntheses of (+)-norsecurinine and (+)-allonorsecurinine are described that utilize a rhodium carbenoid-initiated O-H insertion/Claisen rearrangement/1,2-allyl migration domino process for the stereoselective introduction of the tertiary alcohol moiety. Overall the employed strategy is flexible and will allow access to other members of the Securinega family of alkaloids.

Full text of DOI:10.1016/j.tet.2010.03.015

Tetrahedron 66 (2010) 4701–4709
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An enantioselective approach to the Securinega alkaloids: the total synthesis
of (þ)-norsecurinine and (þ)-allonorsecurinine
,
Matthew R. Medeiros a, John L. Wood b
*
a Department of Chemistry, Yale University, New Haven, CT 06520, USA
b Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Total syntheses of (þ)-norsecurinine and (þ)-allonorsecurinine are described that utilize a rhodium
carbenoid-initiated O–H insertion/Claisen rearrangement/1,2-allyl migration domino process for the
stereoselective introduction of the tertiary alcohol moiety. Overall the employed strategy is flexible and
will allow access to other members of the Securinega family of alkaloids.
Received 21 December 2009
Received in revised form 1 March 2010
Accepted 2 March 2010
Available online 9 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This manuscript is dedicated to
Professor Brian M. Stoltz on the occasion of
his receiving the Tetrahedron Young
Investigator Award
Keywords:
Securinga Alkaloids
Norsecurinine
Allonorsecrinine
Total Synthesis
Rhodium Carbenoid
Claisen rearrangement
1. Introduction
a masked tertiary alcohol flanked by two carbonyls embedded in
their structures (grayed bonds in 2). Conceivably, a flexible route to
The Securinega alkaloids1 are a small family of natural products
isolated from the Euphorbiaceae family of plants (Fig. 1). Structur-
ally, they typically consist of either an indolizidine (securinine-
type, 1) or pyrrolizidine (norsecurinine-type, 2) framework with an
this functional group would provide a gateway to access any
member of the Securinega alkaloids. Accordingly, we reckoned the
enantioselective rhodium carbenoid-initiated O–H insertion/
Claisen rearrangement/1,2-allyl migration domino process de-
veloped in our laboratory16 would provide an interesting stereo-
controlled approach to the desired tertiary alcohol functionality.
Herein, we report the application of this domino sequence to the
synthesis of (þ)-norsecurinine17 and (þ)-allonorsecurinine.9
a, b, g, d-unsaturated bicyclic lactone moiety. Additionally, skele-
tally rearranged (i.e., secu’amamine, 5),2 A-ring methoxylated (i.e.,
phyllanthine, 4),3 oxidized (i.e., phyllantidine, 6 and nirurine, 7),4
and dimeric (i.e., flueggenines, 8 and 9)5 congeners have been
reported. The enantiomers of some Securinega alkaloids, virose-
curinine (3),6 viroallosecurinine,7 and (ꢀ)-norsecurinine,8 have also
been isolated from natural sources.
2. Results and discussion
A broad spectrum of biological activities coupled with syn-
thetically challenging morphologies has prompted many synthetic
efforts toward this family of metabolites.9–15 We became interested
in this family of alkaloids upon recognizing the presence of
2.1. Retrosynthetic analysis for (D)-norsecurinine
Retrosynthetically, we envisioned completing the synthesis of
(þ)-norsecurinine with annulation of the butenolide from
a-hy-
droxy enone 10 (Scheme 1).14,18 Tricyclic enone 10 was imagined to
arise from a halogenation-initiated cyclization of ketone 11 fol-
* Corresponding author. E-mail address: tetlett@colostate.edu (J.L. Wood).
lowed by b
-elimination.15 Cyclohexene 11 would be prepared by
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.015

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M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
O
O
O
HO
N
O
O
B
O
O
D
H
N
H
N
O
H
N
X
C
H
A
H
(+)-norsecurinine, (2)
virosecurinine, (3)
securinine X = H, (1)
phyllanthine X = OMe, (4)
secu'amamine, (5)
O
O
O
O
H
O
O
O
O
H
H
H
O
N
H
O
O
O
H
O
H
OH
N
N
N
H
N
O
H
H
N
H
flueggenine B, (9)
(+)-phyllantidine, (6)
nirurine, (7)
flueggenine A, (8)
Figure 1. Selected Securinega alkaloids.
ring-closing metathesis of allyl ketone 12, while the A-ring would
be generated from 13 via a reductive amination. Tertiary alcohol 13
would result from the key domino process using (S)-(þ)-3-buten-
primarily resulted in recovered starting material or decomposition
(seechart in Scheme 2). Theproblems encounteredwith ourattempt
to incorporate the requisite amine early in the synthesis prompted
us to investigate an alternative route.
Reviewing the retrosynthesis, it seemed feasible to begin the
synthesis with a functional groupthatcould be converted to an amine
subsequent to the domino sequence. To this end, butyrolactone (20)
was opened with ethyl lithiodiazoacetate and the resulting primary
2-ol ((þ)-14).19 Finally,
a-diazo-b-ketoester 15 could easily be
accessed from commercially available materials.
Scheme 1. Retrosynthetic analysis of (þ)-norsecurinine.
2.2. Synthesis of (D)-norsecurinine
Our synthesis commenced with the opening of N-Boc-2-pyrro-
lidinone (16) with ethyl lithiodiazoacetate 20 followed by Boc pro-
tection under standard conditions to yield diazoester 15 (Scheme 2).
The optimal conditions determined in our original studies of the O–
H insertion/Claisen rearrangement involved heating a solution of
the diazoester, allylic alcohol and 0.1–1.0 mol % Rh2(OAc)4 in ben-
zene at reflux.21 In our current preliminary studies, we found that
heating the reaction to reflux in toluene provided more consistent
results (data not shown). Conducting the O–H insertion/Claisen
rearrangement using (ꢁ)-14 in the presence of 1 mol % Rh2(OAc)4 in
toluene at reflux resulted in 37% yield (unoptimized) of desired
tertiary alcohol 19. Encouraged by this result we attempted to effect
the 1,2-allyl migration by treatment of 19 with BF3$Et2O at room
temperature. Unfortunately, these conditions yielded an intractable
mixtureof compounds. A screenof alternative Lewis and protic acids
Scheme 2. Initial investigation of the key domino process.
alcohol was tosylated to provide 21 in 62% yield over the two steps
(Scheme 3). After some experimentation, we found that conducting
the key domino process in one pot22 with (ꢁ)-14 in the presence of
0.1 mol % Rh2(OAc)4 in toluene at reflux followed by addition of
BF3$Et2O at room temperature provided tertiary alcohol 22 in 69%
yield. Treatment of 22 with NaN3 in DMF cleanly provided azide 23,
which was subjected to PPh3 in wet THF to initiate a Staudinger
reduction/aza-Wittig sequence23 providing imine 24. A minor
byproduct observed under these conditions was cyclopropane 25.
Attempts to prevent the formation of 25 by changing temperature,
equivalents of water or phosphine proved fruitless.

M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
4703
Although an effective route to imine 24 had been developed,
some difficulties encountered with scale-up and variable yields for
the opening of butyrolactone with ethyl lithiodiazoacetate led us to
seek an alternative strategy. We found that adapting a procedure
reported by Staudinger and co-workers24 and Bestmann and
Scheme 5. Initial synthesis of aldehyde 31.
Prior to continuing with the synthesis, the stereochemical out-
come of the NaBH4 reduction was delineated (Scheme 7). To this
end, carbamate esters 30a and 30b were individually subjected to
DIBALH at room temperature and the resulting crude diols were
treated with NaH in THF. Nuclear Overhauser Effect (NOE) analysis
of cyclic carbamates 5S, 4S-33a, and 5R-4S-33b revealed the illus-
Scheme 3. Butyrolactone-based strategy to imine 24.
Kolm25 for the coupling of acid chlorides with diazoesters cleanly
provided chloride 27 in high yield after removal of the byproduct
(ethyl chloroacetate) by distillation at low pressure (Scheme 4).
Chloride 27 was subjected to the optimized domino process con-
ditions, 1.05 equiv (þ)-14 (98:2 er)26 and 0.1 mol % Rh2(OAc)4, to
give tertiary alcohol 28 in 63% yield and 95:5 er.27 Substitution of
the primary chloride with azide proceeded cleanly allowing the
Staudinger reduction/aza-Wittig sequence to be carried out with-
out purification of intermediate azide (þ)-23, providing imine 24 in
76% yield over the two steps.
Proceeding forward, imine 24 was reduced with NaBH4 in MeOH
to yield an inseparable mixture of diastereomeric amino esters 29,
which were directly converted to tert-butyl carbamates 30 with
Boc2O and DMAP (Scheme 5). The derived carbamates proved
separable by simple column chromatography and the major isomer
Scheme 6. Improved synthesis of aldehyde 31.
trated stereochemical relationships (relevant NOEs indicated with
double headed arrows).
Having assigned the stereochemistry, the synthesis continued
with alkylation of aldehyde 31a using allylmagnesium bromide
to furnish 34 followed by ring-closing metathesis using Grubbs’s
second generation catalyst to provide cyclohexene 35 as a mix-
ture of diastereomers (Scheme 8). Given that the newly pro-
duced hydroxyl stereocenter would eventually undergo
oxidation, the mixture of diastereomers was advanced without
separation. Adopting a strategy used by Liras and co-workers for
their synthesis of (ꢁ)-securinine,15 cyclohexene 35 was treated
with Br2 at 0 ꢂC to yield dibromide 36 as a single diastereomer
Scheme 4. Improved route to imine 24.
(30a) was reduced to aldehyde 31a by treatment with DIBALH at
low temperature, albeit in moderate yield. Warming the reaction
above 0 ꢂC resulted in a complex mixture of products.
To circumvent this problem we found that reduction of imine 24
with NaBH4 in EtOH followed by oxidation of the inseparable
mixture of diols 32 with IBX provided a separable mixture of
aldehydes 31 in a more convenient manner (Scheme 6).28
Scheme 7. Synthesis of cyclic carbamates 33a and 33b, and relevant NOEs.

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M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
based on 1H NMR analysis. We found that dropwise addition of
Br2 at 0 ꢂC was essential to avoid the formation of 37 obtained
from attack of the carbamate carbonyl on the secondary bro-
mide.29 After some experimentation, we found that Swern oxi-
dation of alcohol 36 supplied enone 38 in good yield. During
their syntheses of (ꢀ)-securinine, Honda and co-workers13 and
Figueredo and co-workers11 had demonstrated that the stereo-
chemistry of the bromide was inconsequential for cyclization,
and it was presumed that this would apply to norsecurinine as
well.
With enone 38 in hand, we were ready to construct the
tricyclic core of norsecurinine (Scheme 9a). After some ex-
perimentation, we found that removal of the Boc group with
excess TFA followed by addition of Et3N furnished unstable
tricycle 10. Some attempts were made to convert hydroxy
enone 10 to norsecurinine directly using the Bestmann ketene
ylide (39),30 however, these attempts failed. Weinreb and co-
workers also noted the recalcitrance of a similar substrate
toward acylation with the Bestmann reagent.12 Consequently,
we turned to a two step procedure involving DCC mediated
acylation of the tertiary alcohol with diethylphosphonoacetic
Scheme 9. Endgame strategy.
4. Experimental
4.1. General methods
Unless otherwise stated, reactions were stirred in flame-dried
glassware under an atmosphere of nitrogen. Benzene, tetrahydro-
furan, dichloromethane, toluene, and diethyl ether were dried us-
ing a solvent purification system manufactured by SG Water U.S.A.,
LLC. Anhydrous N,N-dimethylformamide was purchased from
Sigma–Aldrich and stored under nitrogen atmosphere. Commer-
cially available reagents were obtained from Sigma–Aldrich, Strem,
or Alfa Aesar and were used as received. (S)-(þ)-3-Buten-2-ol
((þ)-14) was synthesized according to a procedure by Klingler and
Psiorz.19 (Triphenylphosporanylidene)-ketene (39) was synthe-
sized according to the procedure described by Schobert.31 All
known compounds were identified by comparison of NMR spectra
to those reported in the literature.
Thin layer chromatography was performed using Silicycle
glass-backed extra hard layer, 60 Å plates (indicator F-254,
250 mm). Developed plates were visualized using a 254 nm UV
lamp and/or with the appropriate dip solution (ethanolic ani-
saldehyde or potassium permanganate) followed by heating.
Flash chromatography was generally performed according to the
protocol described by Still et al.,32 with Silicycle SiliaFlashÒ P60
(230–400 mesh) silica gel as the stationary phase. Melting points
were obtained using a Gallenkamp melting point apparatus and
are uncorrected.
Chiral high performance liquid chromatography (HPLC) was
performed on an Agilent 1100 series HPLC. Infrared spectra were
recorded on a Nicolet Avatar 320 FT-IR and samples were analyzed
as thin films on NaCl plates (sample dissolved in CH2Cl2) and are
reported as wavenumber (cmꢀ1). High-resolution mass spectrom-
etry was conducted on an Agilent 6210 TOF LCMS. Proton (1H) and
carbon (13C) NMR spectra were recorded on a Varian Inova 400 or
300 spectrometer. Spectra were obtained at 22 ꢂC in CDCl3 unless
Scheme 8. Synthesis of penultimate intermediate enone 38.
acid followed by intramolecular Horner–Wadsworth–Emmons
reaction to complete the synthesis of (þ)-norsecurinine (2).
Spectral data for (þ)-2 were in accord with that reported in
the literature. The synthesis of (þ)-allonorsecurinine (40)
was realized utilizing
(Scheme 9b).
a similar route from aldehyde 31b
3. Conclusion
otherwise noted. Chemical shifts (d) are reported in parts per mil-
We have presented the total synthesis of (þ)-norsecurinine and
(þ)-allonorsecurinine highlighting an enantioselective rhodium
carbenoid-initiated O–H insertion/Claisen rearrangement/1,2-allyl
migration domino process. Targeting the tertiary alcohol moiety
in these molecules provides a flexible strategy that will allow access
to other members of the Securinega family of alkaloids. The syn-
thesis of these compounds is underway.
lion (ppm) and are referenced to the residual solvent peak. Cou-
pling constants (J) are reported in hertz (Hz) and are rounded to the
nearest 0.1 Hz. Multiplicities are defined as: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, quint¼quintuplet, m¼multiplet, dd¼doublet
of doublets, ddd¼doublet of doublet of doublets, dddd¼doublet of
doublet of doublet of doublets, br¼broad, app¼apparent,
par¼partial.

M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
4705
4.2. Experimental procedures
9 h before adding NaHCO3 (satd 20 mL) and extracting the aqueous
layer with CH2Cl2 (3ꢃ20 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The resulting orange
oil was purified by flash chromatography (gradient elution, 90:10 to
80:20 hexanes/EtOAc) to yield 21 (4.35 g, 75% yield) as a yellow oil.
4.2.1. Mono-tert-butylcarbamate 18. Freshly prepared LDA (7.0 mL,
3.6 mmol) was added dropwise to a solution of ethyl diazoacetate
(373 mL, 3.6 mmol) and Boc-2-pyrrolidinone (16) (517 mg,
2.8 mmol) in dry THF (19 mL) at ꢀ78 ꢂC. After 1.5 h the reaction was
quenched at ꢀ78 ꢂC by the dropwise addition of acetic acid (5 mL).
The mixture was concentrated to about 10% of its original volume in
vacuo and diluted with EtOAc (10 mL). The organic layer was
washed with NaHCO3 (satd 2ꢃ5 mL). The aqueous layer was
extracted with EtOAc (3ꢃ10 mL). The combined organic layers were
washed with brine (1ꢃ10 mL), dried over MgSO4, and concentrated
in vacuo. The residue was purified by flash chromatography (gra-
dient elution, 90:10 to 70:30 hexanes/EtOAc) then recrystallized
from hot hexanes to yield 18 (649 mg, 77% yield) as yellow needles.
Rf¼0.34, 70:30 hexanes/EtOAc; mp 61–62 ꢂC; 1H NMR (CDCl3,
Rf¼0.59, 50:50 hexanes/EtOAc; 1H NMR (CDCl3, 400 MHz)
d 7.76 (d,
J¼8.3 Hz, 2H), 7.32 (d, J¼8.0 Hz, 2H), 4.28 (q, J¼7.1 Hz, 2H), 4.07 (t,
J¼6.2 Hz, 2H), 2.88 (t, J¼7.0 Hz, 2H), 2.43 (s, 3H), 1.97 (quint,
J¼6.5 Hz, 2H), 1.32 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
191.4, 161.3, 144.9, 133.1, 130.0, 128.1, 69.7, 61.7, 35.9, 23.4, 21.8,
14.5; IR (thin film, NaCl) 2137(s), 1715(s), 1652(s), 1362(s), 1303(s),
1213(m), 1176(s), 1096(m), 927(m), 554(m); HRMS (APCI) m/z calcd
for C15H19N2O6S [MþH]þ:355.0956, found: 355.0955.
4.2.5. Tosylate (ꢁ)-22. To a solution of 21 (994 mg, 2.80 mmol) in
toluene (14 mL) was added (ꢁ)-3-buten-2-ol (242
mL, 2.80 mmol)
400 MHz)
d
4.66 (br s, 1H), 4.29 (q, J¼7.1 Hz, 2H), 3.18–3.14 (m, 2H),
and Rh2(OAc)4 (12.4 mg, 0.028 mmol). The mixture was immedi-
ately placed in an oil bath preheated to 120 ꢂC. After 15 min the
reaction was cooled to room temperature before adding BF3$Et2O
2.88 (t, J¼7.2 Hz, 2H), 1.83 (quint, J¼7.0 Hz, 2H), 1.43 (s, 9H), 1.32 (t,
J¼7.1 Hz, 3H) 192.5, 161.5,156.1, 79.3, 61.6, 40.1, 37.5, 28.5, 24.7,14.5;
13C NMR (CDCl3, 100 MHz)
d; IR (thin film, NaCl) 3382(w), 2135(m),
(443 mL, 3.50 mmol). After two hours, the reaction was concen-
1717(s), 1654(m), 1522(m), 1368(m), 1304(m), 1250(m), 1172(m),
1135(w), 1089(w), 1022(w); HRMS (ESI–APCI) m/z calcd for
C13H22N3NaO5 [MþNa]þ: 322.1373, found: 322.1375.
trated and purified by flash chromatography (gradient elution 98:2
to 90:10 benzene/EtOAc) to give (ꢁ)-22 (772 mg, 69% yield) as
a clear, pale yellow oil. Rf¼0.52, 90:10 benzene/EtOAc (2ꢃ); 1H NMR
(CDCl3, 400 MHz)
d
7.75 (d, J¼8.3 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H),
4.2.2. Bis-tert-butylcarbamate 15. To a solution of 18 (300 mg,
1.00 mmol) and DMAP (12 mg, 0.010 mmol) in CH3CN (1 mL) was
added Boc2O (240 mg, 1.10 mmol) as a solution in CH3CN (1 mL).
The reaction was refluxed for 10 h. Upon completion the mixture
was diluted with EtOAc (5 mL) and H2O (3 mL). The aqueous layer
was extracted with EtOAc (2ꢃ5 mL). The combined organic layers
were washed with brine (1ꢃ3 mL), dried over MgSO4, and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (gradient elution, 90:10 to 85:15 hexanes/EtOAc) to yield 15
(265 mg, 66% yield) as a yellow oil. Rf¼0.43, 70:30 hexanes/EtOAc;
5.55 (dddd, J¼15.1, 6.5, 6.5, 6.5 Hz, 1H), 5.31–5.23 (m, 1H), 4.22
(dddd, J¼17.9, 10.8, 7.1, 3.6 Hz, 2H), 4.01 (ddd, J¼6.4, 5.9, 1.3 Hz, 2H),
3.91 (s, 1H), 2.79 (ddd, J¼18.8, 7.0, 7.0 Hz, 1H), 2.71 (dddd, J¼14.3,
7.0, 1.2, 1.2 Hz, 1H), 2.59–2.49 (m, 2H), 2.43 (s, 3H), 1.90 (app quint,
J¼6.5 Hz, 2H), 1.62 (dd, J¼6.5, 1.5 Hz, 3H), 1.26 (t, J¼7.1 Hz, 3H); 13C
NMR (CDCl3, 100 MHz)
d 205.7, 170.7, 145.0, 133.0, 131.0, 130.0,
128.0, 123.1, 83.7, 69.4, 63.0, 38.8, 33.2, 23.0, 21.8, 18.2, 14.2; IR (thin
film, NaCl) 3483(m), 2981(m), 1721(s), 1598(m), 1447(m), 1361(s),
1189(m), 1177(s), 1098(m), 971(m), 925(m), 816(m), 664(m),
555(m); HRMS (ESI–APCI) m/z calcd for C19H26NaO7S [MþNa]þ:
421.1308, found: 421.1294.
1H NMR (CDCl3, 400 MHz)
d
4.27 (q, J¼7.1 Hz, 2H), 3.62 (t, J¼7.1 Hz,
2H), 2.85 (t, J¼7.3 Hz, 2H), 1.90 (quint, J¼7.2 Hz, 2H), 1.49 (s, 18H),
1.31 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3,100 MHz)
d
192.1,161.4,152.7,
4.2.6. Diazo chloride 27. A 3-necked 100 mL flask charged with
4-chlorobutyryl chloride (26) was fitted with a glass stopper, a cold
water condenser topped with a drying tube containing solid KOH
open to the atmosphere, and an addition funnel charged with ethyl
diazoacetate (18.0 mL, 174 mmol). The flask was placed in a room
temperature water bath before dropwise addition of ethyl diazo-
acetate. Once addition was complete, the reaction was heated to
60 ꢂC for six hours. Removal of byproducts by distillation (1.5 Torr,
50 ꢂC bath temperature) provided pure 27 (17.2 g, 91% yield) as
a clear, yellow oil. Rf¼0.5, 85:15 hexanes/EtOAc; 1H NMR (CDCl3,
82.4, 61.5, 45.8, 37.5, 28.2, 23.6, 14.5; IR (thin film, NaCl) 2980(m),
2935(m), 2134(s), 1789(w), 1719(s), 1659(m), 1456(w), 1368(s),
1303(s), 1174(m), 1136(s), 1109(m), 1020(w), 854(w), 746(w); HRMS
(ESI–APCI) m/z calcd for C18H29N3NaO7 [MþNa]þ: 422.1914, found:
422.1896.
4.2.3.
0.140 mmol) in toluene (700
(12.0 L, 0.140 mmol) and Rh2(OAc)4 (0.6 mg, 0.0014 mmol). The
a
-Keto-ester (ꢁ)-19. To
a
solution of 15 (55.6 mg,
m
L) was added (ꢁ)-3-buten-2-ol
m
mixture was immediately placed in an oil bath preheated to 120 ꢂC.
After 15 min the reaction was cooled to room temperature, con-
centrated and purified by flash chromatography (gradient elution,
90:10 to 85:15 hexanes/EtOAc) to give (ꢁ)-19 (23.2 mg, 37% yield) as
a clear, pale yellow oil. Rf¼0.54, 70:30 hexanes/EtOAc; 1H NMR
400 MHz)
d
4.30 (q, J¼7.1 Hz, 2H), 3.61 (t, J¼6.4 Hz, 2H), 3.03 (t,
J¼7.1 Hz, 2H), 2.12 (quint, J¼6.8 Hz, 2H), 1.33 (t, J¼7.1 Hz, 3H); 13C
NMR (CDCl3,100 MHz) 191.7,161.4, 61.7, 44.4, 37.4, 27.0,14.5; IR (thin
film, NaCl) 2983(m), 2137(s), 1716(s), 1657(s), 1445(w), 1373(s),
1305(s), 1223(s), 1174(w), 1126(m), 1020(m), 745(w); HRMS (APCI)
m/z calcd for C8H12ClN2O3 [MþH]þ: 219.0531, found: 219.0531.
(CDCl3, 400 MHz)
d
5.54 (dddd, J¼12.9, 6.4, 6.4, 6.4 Hz, 1H), 5.35–
5.27 (m,1H), 4.32 (q, J¼7.1 Hz, 2H), 3.55 (t, J¼7.1 Hz, 2H), 3.28 (s,1H),
2.65 (dd, J¼14.0, 7.3 Hz, 1H), 2.41 (dd, J¼14.0, 7.3, Hz, 1H), 1.94 (ddd,
J¼13.6,11.1, 4.9 Hz,1H),1.79–1.61 (m, 2H),1.64 (dd, J¼6.3,1.1 Hz, 3H),
1.48 (s,18H),1.48–1.44 (m,1H),1.35 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3,
4.2.7. Chloride (ꢀ)-28. To a solution of 27 (5.00 g, 22.8 mmol) in
toluene (114 mL) was added (S)-(þ)-3-buten-2-ol (2.07 mL,
23.9 mmol) and Rh2(OAc)4 (10.2 mg, 0.023 mmol). The mixture was
immediately placed in an oil bath preheated to 120 ꢂC. After 15 min
the reaction was cooled to room temperature before adding
BF3$Et2O. After two hours, the reaction was concentrated and pu-
rified by flash chromatography (90:10 hexanes/EtOAc) to give
(ꢀ)-28 (5.90 g, 63% yield) as a clear, colorless oil. Rf¼0.43 85:15
100 MHz) d 199.5,162.4,152.7,131.2,123.8, 82.4, 81.4, 62.5, 46.3, 41.9,
35.0, 28.2, 23.3, 18.2, 14.1; IR (thin film, NaCl) 3486(m), 2980(m),
2936(m), 1733(s), 1698(s), 1456(m), 1368(s), 1300(m), 1131(s),
1045(m), 969(m), 856(w), 782(w), 667(w); HRMS (ESI–APCI) m/z
calcd for C22H37NNaO8 [MþNa]þ: 466.2411, found: 466.241.
hexanes/EtOAc; 1H NMR (CDCl3, 400 MHz)
d 5.63–5.45 (m, 1H),
4.2.4. Diazo tosylate 21. p-Toluenesulfonic acid (4.70 g, 24.8 mmol)
was added to a solution of ethyl 2-diazo-6-hydroxy-3-oxohex-
anoate33 (3.30 g, 16.5 mmol) and Et3N (4.00 mL, 28.9 mmol) in
CH2Cl2 (37 mL). The reaction was stirred at room temperature for
5.34–5.26 (m 1H), 4.29–4.19 (m, 1H), 4.05 (s, 1H), 3.53 (t, J¼6.22 Hz,
2H), 2.86 (dt, J¼18.7, 6.8 Hz, 1H), 2.75–2.58 (m, 3H), 2.07–2.01 (m,
2H), 1.63 (d, J¼6.43 Hz, 3H), 1.28 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 205.8,170.7,130.9,123.1, 83.7, 62.9, 44.1, 38.6, 34.2, 26.2,

4706
M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
18.2, 14.2; IR (thin film, NaCl) 3482(m), 2975(m), 2934(m), 1721(s),
1449(m), 1367(m), 1260(s), 1214(s), 1142(m), 1096(m); HRMS (ESI–
48.2, 37.2, 36.8, 28.5, 27.1, 26.6, 24.6, 24.3,18.2; HRMS (ESI–APCI) m/
z calcd for C15H28NO4 [MþH]þ: 286.2013, found: 286.2016.
Compound (ꢀ)-30a: clear, colorless oil; Rf¼0.52 70:30 hexanes/
APCI) m/z calcd for C12H19ClO4Na [MþNa]þ: 285.0864, found:
22
285.0864. [
a
]
þ3.96 (c 2.20, CHCl3).
EtOAc; 1H NMR (CDCl3, 400 MHz)
d 5.54–5.42 (m, 2H), 5.24 (br s,
D
1H), 4.22–4.16 (m, 3H), 3.57 (br s, 1H), 3.16 (br s, 1H), 2.55 (br s, 1H),
2.38 (br s,1H),1.93 (br s,1H),1.62 (br s, 4H),1.46 (br s, 9H),1.26 (br s,
4.2.8. Imine (ꢀ)-24. To a solution of (ꢀ)-28 (5.70 g, 21.7 mmol) in
anhydrous N,N-dimethylformamide (50.0 mL) was added sodium
azide (7.1 g, 108 mmol). The mixture was heated to 80 ꢂC for three
hours. Upon completion, the reaction was passed through filter
paper and the filtrate diluted with diethyl ether (50 mL) and water
(100 mL). The layers were separated and the aqueous layer was
extracted with diethyl ether (4ꢃ50 mL). The organic layers were
then washed with water (5ꢃ50 mL), and brine (1ꢃ50 mL). The
combined organic layers were dried over MgSO4. Concentration in
vacuo yielded a crude orange oil, which was dissolved in wet THF
(80 mL). To this solution was added PPh3 and the mixture was
heated to 50 ꢂC for 1.5 h. Upon completion, the reaction was con-
centrated to about 20% of the initial volume. The resulting viscous
oil was triturated with hexanes/EtOAc (90:10, 30 mL) and purified
by flash chromatography (90:10 to 70:30 hexanes/EtOAc). The first
fraction, eluting at 90:10 hexanes/EtOAc, consisted of cyclopropyl
ketone (ꢀ)-25 (393 mg, 8% yield) as a clear, pale yellow oil. The
second fraction, eluting at 70:30 hexanes/EtOAc, consisted of de-
sired imine (ꢀ)-24 (3.71 g, 76% yield, two steps) as a clear, pale
yellow oil. Rf¼0.24 70:30 hexanes/EtOAc; 1H NMR (CDCl3,
3H); 13C NMR (CDCl3, 100 MHz)
d 174.6, 156.9, 129.0, 124.9, 81.5,
80.1, 63.8, 61.3, 47.9, 39.9, 28.3, 27.4, 24.2, 18.0, 14.2; IR (thin film,
NaCl) 3511(m), 3320(m), 2977(s), 2934(s), 1724(s), 1696(s), 1394(s),
1367(s), 1168(s), 1109(s), 1055(m), 972(m), 772(m); HRMS (ESI–
APCI) m/z calcd for C17H30NO5 [MþH]þ: 328.2118, found: 328.2122.
22
[a
]
ꢀ43.0 (c 0.82, CHCl3).
D
Compound (þ)-30b: white solid; Rf¼0.61 70:30 hexanes/EtOAc;
1H NMR (CDCl3, 400 MHz)
d
5.57–5.48 (m, 1H), 5.40–5.33 (m, 1H),
4.29 (dq, J¼10.7, 7.1 Hz), 4.18–4.15 (m, 1H), 4.11 (par dq, J¼10.6,
7.1 Hz, 1H), 3.71 (br s, 1H), 3.53 (br s, 1H), 3.26–3.19 (m 1H), 2.48
(app dd, J¼8.0, 6.9, 5.7 Hz, 1H), 2.31 (app dd, J¼8.02, 5.9, 5.8 Hz, 1H),
2.05–1.83 (m, 3H), 1.74–1.67 (m, 1H), 1.63 (d, J¼6.3 Hz, 3H), 1.42 (s,
9H), 1.30 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 175.1, 155.7,
129.4, 124.9, 79.9, 79.8, 63.0, 62.1, 48.1, 38.4, 26.6, 24.6, 18.2, 14.2; IR
(thin film, NaCl) 3434(s), 2978(w), 1725(m), 1698(s), 1654(m),
1390(s), 1258(w), 1213(w), 1171(m), 1096(w), 969(w); HRMS (ESI–
APCI) m/z calcd for C17H30NO5 [MþH]þ: 328.2118, found: 328.2108.
22
[a
]
þ55.4 (c 2.42, CHCl3).
D
300 MHz)
d
5.62–5.50 (m, 1H), 5.48–5.33 (m, 1H), 4.42 (br s, 1H),
4.2.10. Cyclic carbamates (ꢁ)-33a and (ꢁ)-38b. DIBALH (619
mL,
4.27–4.18 (m, 2H), 3.87–3.82 (m, 2H), 2.75–2.52 (m, 4H), 2.00–1.90
0.619 mmol) was added to
a
solution of (ꢁ)-30a (169 mg,
(m, 2H), 1.63 (d, J¼6.28 Hz, 3H), 1.26 (t, J¼7.1 Hz, 3H); 13C NMR
0.516 mmol) in dry CH2Cl2 (2.6 mL) at 0 ꢂC. The solution was then
warmed to room temperature and stirred for two hours. Upon
completion, the reaction was quenched with MeOH/H2O (1:1, 5 mL)
at 0 ꢂC. The mixture was filtered through Celite with CH2Cl2 to yield
crude (ꢁ)-32a. (ꢁ)-30b (138 mg, 0.422 mmol) was subjected to
similar conditions to yield crude (ꢁ)-32b. Compounds (ꢁ)-32a
(82.4 mg, 0.290 mmol), and (ꢁ)-32b (51.9 mg, 0.180 mmol) were
independently treated with excess NaH in dry THF (1.5 mL) at room
temperature to provide (ꢁ)-33a (34.8 mg, 32% yield, two steps) and
(ꢁ)-33b (14.8 mg, 17% yield, two steps), respectively, after purifi-
cation by flash chromatography (gradient elution, 90:10 to 70:30
hexanes/EtOAc).
(CDCl3, 75 MHz)
d 177.4, 172.3, 130.1, 124.1, 78.5, 62.2, 60.3, 40.1,
34.0, 23.6, 18.3, 14.4; IR (thin film, NaCl) 3422(w), 2976(m),
2938(m), 2870(w), 1731(s), 1448(w), 1431(w), 1367(w), 1258(m),
1212(s), 1135(m), 1096(m), 1057(w), 1029(w), 972(m), 861(w);
HRMS (ESI–APCI) m/z calcd for C12H20NO3 [MþH]þ: 226.1437,
22
found: 226.1441. [
a
]
ꢀ25.9 (c 1.48, CHCl3).
D
Compound (ꢀ)-25: Rf¼0.43 85:15 hexanes/EtOAc; 1H NMR
(CDCl3, 400 MHz) d 5.77–5.72 (m, 1H), 5.52–5.44 (m, 1H), 4.44–4.37
(m, 3H), 2.98 (dd, J¼14.2, 6.90 Hz,1H), 2.88 (dd, J¼14.3, 7.38 Hz,1H),
2.51–2.47 (m, 1H), 1.79 (d, J¼6.24 Hz, 3H), 1.43 (t, J¼7.1 Hz, 3H),
1.29–1.14 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d 206.3, 170.4, 130.3,
123.2, 83.8, 62.1, 38.5, 17.9, 16.1, 14.0, 12.8, 12.2; IR (thin film, NaCl)
3465(s), 2983(m), 2919(w), 1738(s), 1705(s), 1447(m), 1379(m),
1262(s), 1221(s), 1156(w), 1070(m), 1032(m), 971(m), 860(w),
Compound (ꢁ)-33a: 1H NMR (C6D6, 400 MHz)
d 5.45–5.37 (m,
1H), 5.28–5.19 (m, 1H), 5.13 (s, 1H), 4.10 (d, J¼11.2 Hz, 1H), 3.65 (d,
J¼11.1 Hz, 1H), 3.61 (par dd, J¼7.5, 3.0 Hz, 1H), 3.34–3.29 (m, 1H),
2.77 (dd, J¼10.5, 5.7 Hz, 1H), 2.14 (app dd, J¼14.1, 6.6 Hz, 1H), 2.02–
1.92 (m, 1H), 1.87 (dd, J¼14.2, 7.9 Hz, 1H), 1.58–1.49 (m, 1H), 1.50 (d,
J¼6.3 Hz, 1H), 1.43–1.37 (m, 1H), 1.25–1.12 (m, 1H); 13C NMR (C6D6,
668(w); HRMS (ESI–APCI) m/z calcd for C12H19O4 [MþH]þ:
22
227.1278, found: 227.1274. [
a
]
ꢀ30.0 (c 1.80, CHCl3).
D
4.2.9. Diol 32. To a solution of (ꢀ)-24 (3.35 g, 14.8 mmol) in abso-
lute EtOH (50 mL) was added NaBH4 (1.6 g, 44.4 mmol). After stir-
ring the reaction at room temperature for 4 h, DMAP (170 mg,
1.39 mmol) was added and the reaction was cooled to 0 ꢂC before
adding Boc2O (3.5 g, 16.3 mmol) portionwise. After addition, the ice
bath was removed and the reaction stirred for one hour at room
temperature. Upon completion, the EtOH was removed in vacuo
and the residue diluted with water (50 mL) and CH2Cl2 (50 mL). The
layers were separated and the aqueous was extracted with CH2Cl2
(4ꢃ25 mL). The combined organic layers were washed with brine
(30 mL), dried over MgSO4, and concentrated. The residue was
purified by flash chromatography (90:10 to 80:20 hexanes/EtOAc).
The first fraction, eluting at 90:10 hexanes/EtOAc, consisted of
a separable diasteromeric mixture of the N-Boc amino esters
(ꢀ)-30a and (þ)-30b (756 mg, 16% yield, dr 1.4:1). The second
fraction, eluting at 80:20 hexanes/EtOAc, consisted of an in-
separable diastereomeric mixture of N-Boc amino diols 32 (2.31 g,
55% yield, two steps) as a clear, colorless oil. Rf¼0.3170:30 hexanes/
100 MHz) d 152.9, 128.6, 125.2, 74.5, 66.1, 63.0, 47.3, 39.4, 25.8, 22.6,
17.8; HRMS (ESI–APCI) calcd for C11H18NO3 [MþH]þ: 212.1281,
found: 212.1284.
Compound (ꢁ)-33b: 1H NMR (CDCl3, 400 MHz)
d 5.66 (dddd,
J¼15.2, 6.4, 6.4, 6.3 Hz, 1H), 5.53–5.45 (m, 1H), 4.02 (d, J¼10.7 Hz,
1H), 3.84 (d, J¼10.6 Hz, 1H), 3.61 (dd, J¼10.5, 5.5 Hz, 1H), 3.49–3.44
(m, 2H), 2.77 (d, J¼4.1 Hz, 1H), 2.19 (d, J¼7.4 Hz, 2H), 2.07–1.93 (m,
2H), 1.85–1.74 (m, 1H), 1.74 (d, J¼6.4 Hz, 3H), 1.69–1.61 (m, 1H); 13C
NMR (CDCl3, 100 MHz)
d 152.4, 132.5, 123.3, 71.5, 66.9, 65.1, 47.2,
33.7, 26.8, 22.9, 18.3; HRMS (ESI–APCI) calcd for C11H18NO3
[MþH]þ: 212.1281, found: 212.1284.
4.2.11. Aldehydes (þ)-31a and (ꢀ)-31b. To a solution of 32 (2.10 g,
7.40 mmol) in wet EtOAc (50 mL) was added IBX28 (6.20 g,
22.2 mmol). The mixture was refluxed open to the atmosphere for
6 h. The reaction was filtered through a pad of Celite, concentrated,
and directly purified by flash chromatography (90:10 hexanes/
EtOAc) to provide the desired N-Boc amino aldehyde (1.85 g, 89%
yield) as a mixture of diastereomers. The diastereomers were
separated by flash chromatography (98:2 to 95:5 EtOAc/CH2Cl2) to
EtOAc; (partially characterized) 13C NMR (CDCl3, 100 MHz)
128.7, 128.1, 126.0, 125.8, 80.8, 80.7, 66.0, 65.5, 62.4, 62.0, 61.9, 48.2,
d 157.8,

M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
4707
provide (þ)-31a as a clear, colorless oil and (ꢀ)-31b as a clear,
colorless oil.
s, 1H), 3.66 (br s, 1H), 3.20 (dt, J¼10.96, 7.1, 7.0 Hz, 1H), 2.64 (d,
J¼18.5 Hz, 1H), 2.54 (d, J¼18.7 Hz, 1H), 2.28–2.23 (m, 1H), 2.07 (d,
J¼17.9 Hz,1H), 2.01–1.87 (d, J¼19.0 Hz,1H and m, 2H),1.75–1.67 (m,
Compound (þ)-31a: Rf¼0.35 95:5 CH2Cl2/EtOAc; 1H NMR (CDCl3,
400 MHz)
d
9.62 (s, 1H), 5.55–5.47 (m, 1H), 5.30–5.22 (m, 1H), 4.12
1H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 157.6, 124.4, 123.6,
(br s, 1H), 3.71 (s, 1H), 3.40 (br s, 1H), 3.21–3.17 (m, 1H), 2.42 (dd,
J¼14.3, 7.8 Hz, 1H), 2.34–2.29 (m, 1H), 2.09–1.89 (m, 3H), 1.73–1.68
(m,1H) 1.59 (d, J¼6.2 Hz, 3H),1.38 (s, 9H); 13C NMR (CDCl3,100 MHz)
80.5, 74.3, 69.8, 64.6, 48.2, 32.2. 32.0, 28.6, 27.7, 24.7; IR (thin film,
NaCl) 3426(m), 2970(m), 2904(m), 1664(s), 1398(s), 1362(m),
1168(s), 1106(w), 1024(w), 906(m), 878(w), 727(m), 650(w); HRMS
d
201.8,155.4,129.9,123.4, 82.8, 79.9, 60.6, 47.4, 37.3, 28.2, 25.7, 24.7,
(ESI–APCI) m/z calcd for C15H26NO4 [MþH]þ: 284.1856, found:
22
17.9; IR (thin film, NaCl) 3479(m), 2976(s),1723(s),1682(s),1479(m),
1393(s),1255(m),1169(s),1118(m), 971(m), 915(m), 856(w), 817(w),
284.1855. [
a
]
ꢀ80.9 (c 1.12, CHCl3).
D
Compound (þ)-35b (
a
-OH): Rf¼0.21 70:30 hexanes/EtOAc; 1H
772(w); HRMS (ESI–APCI) m/z calcd for C15H25NO4Na [MþNa]þ:
NMR (CDCl3, 400 MHz) d 5.61 (br s, 1H), 5.52 (br s, 2H), 4.13 (app d,
22
306.1676, found: 306.1672. [
a]
þ39.3 (c 2.68, CHCl3).
J¼8.8 Hz, 1H), 3.70–3.67 (m, 1H), 3.55–3.52 (m, 1H), 3.31–3.26 (m,
D
Compound (ꢀ)-31b: Rf¼0.48 95:5 CH2Cl2/EtOAc; 1H NMR (CDCl3,
1H), 2.37–2.20 (m, 5H), 2.10–1.99 (m, 4H), 1.45 (s, 9H); 13C NMR
400 MHz)
d
9.64 (s, 1H), 6.39 (br s, 1H), 5.57–5.48 (m, 2H), 3.98 (t,
(CDCl3, 100 MHz) d 157.5, 124.7, 123.1, 80.6, 74.9, 67.3, 60.5, 48.2,
J¼7.1 Hz, 1H), 3.57 (br s, 1H), 3.09 (br s, 1H), 2.4–2.26 (m, 2H), 2.05–
30.7, 29.4, 28.3, 25.5, 24.2; IR (thin film, NaCl) 3392(m), 3027(w),
2976(m), 2902(m), 1667(s), 1395(s), 1345(w), 1255(w), 1168(m),
1119(m), 1078(m), 890(m), 774(w), 732(w), 668(w); HRMS (ESI–
1.91 (m, 2H), 1.80 (br s, 1H), 1.63 (d, J¼5.2, 3H), 1.45 (s, 9H); 13C NMR
(CDCl3, 100 MHz)
d 206.7, 157.8, 129.5, 124.5, 82.1, 81.3, 64.0, 48.2,
37.3, 27.4, 24.3, 18.2; IR (thin film, NaCl) 3297(s), 2977(s), 2888(m),
1730(s),1693(s),1658(s),1402(s),1250(m),1166(s),1112(m), 974(m),
APCI) m/z calcd for C15H26NO4 [MþH]þ: 284.1856, found: 284.1860.
22
[a
]
þ15.7 (c 0.74, CHCl3).
D
855(m), 776(m); HRMS (ESI–APCI) m/z calcd for C15H25NO4Na
[MþNa]þ: 306.1676, found: 306.1673. [
a]
ꢀ40.3 (c 2.63, CHCl3).
4.2.14. Dibromide 36. To
(602 mg, 2.12 mmol) in CH2Cl2 (42 mL) was added a solution of Br2
(53.3
L, 3.18 mmol) in CH2Cl2 (5 mL) dropwise at 0 ꢂC. The reaction
a
solution of (ꢀ)-35a and (þ)-35b
22
D
4.2.12. Allyl alcohol 34. To a solution of (þ)-31a (1.00 g, 3.55 mmol)
in THF (18 mL) was added freshly prepared allylmagnesium bro-
mide (1.0 M in Et2O, 10.6 mL, 10.6 mmol) at 0 ꢂC. The reaction was
stirred at 0 ꢂC for 30 min before warming to room temperature and
stirring for 1 h more. The reaction was quenched with satd NH4Cl
(10 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (3ꢃ20 mL). The combined organic layers
were washed with brine (20 mL), dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography (gradient
elution, 90:10 to 85:15 hexanes/EtOAc) to yield (ꢀ)-34a and
(ꢀ)-34b (824 mg, 72% yield, combined) as pale yellow oils. The
diastereomers were characterized separately.
m
was stirred for 5 min before pouring into a 10% solution of Na2S2O3.
The aqueous layer was extracted with CH2Cl2 (4ꢃ20 mL). The
combined organic layers were washed with brine (30 mL), dried
over MgSO4, and concentrated to yield (ꢀ)-36a and (þ)-36b
(893 mg, 95% yield, combined) as a mixture, which was carried
forward without further purification. An aliquot of the mixture was
purified for characterization purposes.
Compound (ꢀ)-36a (
b
-OH): white powder; Rf¼0.21 70:30 hex-
anes/EtOAc; 1H NMR (CDCl3, 400 MHz)
d
5.34 (br s, 1H), 4.14–4.06
(m, 3H), 3.55 (br s, 2H), 3.32–3.31 (m, 1H), 3.05 (br s, 1H), 2.67–2.63
(m, 2H), 2.21–2.18 (m, 1H), 2.10–1.87 (m, 5H), 1.47 (s, 9H); 13C NMR
Compound (ꢀ)-34a (
b
d
-OH): Rf¼0.44 70:30 hexanes/EtOAc; 1H
(CDCl3, 100 MHz) d 157.7, 81.6, 76.1, 74.9, 52.9, 52.4, 48.8, 42.1, 40.7,
28.4, 26.8, 24.4; IR (thin film, NaCl) 3376(m), 2975(m), 2894(w),
1662(s), 1477(w), 1448(w), 1392(s), 1367(s), 1257(w), 1166(s),
NMR (CDCl3, 400 MHz)
5.98–5.88 (m, 1H), 5.50–5.47 (m, 2H),
5.10–5.03 (m, 2H), 4.65 (br s, 1H), 4.10–4.07 (m, 1H), 3.57–3.49
(m, 3H), 3.24–3.17 (m, 1H), 2.36–2.22 (m, 3H), 2.08–1.85 (m, 4H),
1.78–1.71 (m, 1H), 1.66 (d, J¼3.3 Hz, 3H), 1.44 (s, 9H); 13C NMR
1066(w), 1032(w), 898(w), 871(w), 680(w); HRMS (ESI–APCI) m/z
22
calcd for C15H26Br2NO4 [MþH]þ: 442.0223, found: 442.0216. [
ꢀ1.53 (c 1.76, CHCl3).
a]
D
(CDCl3, 100 MHz)
d 157.8, 136.8, 128.3, 126.0, 116.4, 80.8, 78.0,
72.7, 62.8, 48.2, 37.6, 35.7, 28.5, 27.15, 24.3, 18.3; IR (thin film,
NaCl) 3416(s), 3074(w), 2977(m), 2933(m), 1662(s), 1395(m),
Compound (þ)-36b ( -OH): white foam; Rf¼0.48 70:30 hex-
a
anes/EtOAc 1H NMR (CDCl3, 400 MHz)
d 4.91 (br s, 1H), 4.70 (br
1255(w), 1168(m), 976(w), 907(w), 774(w); HRMS (ESI–APCI) m/z
s, 1H), 4.54 (br s, 1H), 4.02–3.95 (m, 2H), 3.51–3.48 (m, 1H),
3.30–3.24 (m, 1H), 2.81 (s, 1H), 2.62 (ddd, J¼14.2, 10.9, 2.9 Hz,
1H), 2.27 (dd, J¼15.3, 4.1 Hz, 1H), 2.14–2.10 (m, 1H), 2.04–1.80
22
calcd for C18H32NO4 [MþH]þ: 326.2326, found: 326.2327. [
ꢀ48.9 (c 2.02, CHCl3).
a]
D
Compound (ꢀ)-34b (
a
d
-OH): Rf¼0.53 70:30 hexanes/EtOAc; 1H
(m, 1H), 1.41 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 157.5, 80.7,
NMR (CDCl3, 400 MHz)
5.87–5.78 (m, 1H), 5.69 (br s, 1H), 5.55–
75.7, 65.9, 61.2, 53.2, 47.9, 47.49, 31.6, 31.1, 28.2, 25.3, 24.2; IR
(thin film, NaCl) 3407(m), 2976(m), 2932(w), 1667(s), 1478(w),
1393(s), 1367(s), 1247(w), 1166(s), 1121(m), 1074(w), 1042(w),
5.48 (m, 1H), 5.13–5.09 (m, 2H), 4.02 (dd, J¼8.5, 6.7 Hz), 3.68–3.63
(m, 1H), 3.55–3.53 (m, 1H), 3.26–3.20 (m, 1H), 2.66–2.62 (m, 1H),
2.27–2.18 (m, 3H), 2.07–1.98 (m, 3H), 1.88–1.83 (m, 1H), 1.68–1.59
986(w), 938(w), 890(w), 738(m); HRMS (ESI–APCI) m/z calcd for
22
(m, 4H),1.46 (s, 9H); 13C NMR (CDCl3,100 MHz)
d
158.2, 136.8,127.9,
C15H26Br2NO4 [MþH]þ: 442.0223, found: 442.0210. [
a
]
þ7.10 (c
D
126.9, 118.1, 80.8, 77.5, 74.1, 65.2, 48.6, 36.9, 36.2, 28.5, 27.8, 24.3,
18.4; IR (thin film, NaCl) 3420(s), 2977(w), 2932(w), 1650(s),
1408(m), 1367(m), 1251(w), 1167(m), 977(w), 907(w); HRMS (ESI–
1.62, CHCl3).
4.2.15. Enone (ꢀ)-38. Anhydrous DMSO (900
m
L, 22.7 mmol) in
APCI) m/z calcd for C18H32NO4 [MþH]þ: 326.2326, found: 326.2327.
CH2Cl2 (1 mL) was added to a solution of oxalyl chloride (805
mL,
22
[
a]
ꢀ51.9 (c 1.73, CHCl3).
5.27 mmol) in CH2Cl2 (12 mL) at ꢀ78 ꢂC. The mixture was stirred
for 10 min before adding a solution of (ꢀ)-36a and (þ)-36b
(940 mg, 2.11 mmol) in CH2Cl2 (7 mL) dropwise. This mixture was
stirred for 10 min before adding Et3N (2.90 mL, 21.1 mmol) and
allowing the reaction to warm to room temperature. After 1 h the
reaction was diluted with CH2Cl2 and washed with commercial
bleach solution (12% NaClO4, 2ꢃ15 mL). The combined aqueous
layers were back extracted with CH2Cl2 (3ꢃ20 mL). The combined
organic layers were dried over Na2SO4 and concentrated. The res-
idue was purified by flash chromatography (90:10 hexanes/EtOAc)
to yield (ꢀ)-38 (760 mg, 75% yield) as a viscous orange oil. Rf¼0.53,
D
4.2.13. Cyclohexene 35. To a solution of (ꢀ)-34a and (ꢀ)-34b
(794 mg, 2.44 mmol) in CH2Cl2 (24 mL) was added Grubbs’s second
generation catalyst, and the reaction was refluxed for 1.5 h. The
mixture was concentrated and purified by flash chromatography
(gradient elution, 85:15 to 75:25 hexanes/EtOAc) to yield (ꢀ)-35a
and (þ)-35b (598 mg, 87% yield, combined) as beige foams. The
diastereomers were characterized separately.
Compound (ꢀ)-35a (
b
-OH): Rf¼0.11 70:30 hexanes/EtOAc; 1H
NMR (CDCl3, 400 MHz)
d
5.67–5.60 (m, 1H), 4.11 (br s, 1H), 3.82 (br

4708
M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
70:30 hexanes/EtOAc; 1H NMR (CDCl3, 400 MHz)
d
7.02 (d,
References and notes
J¼10.0 Hz,1H), 6.01 (d, J¼9.86 Hz,1H), 5.88 (br s,1H), 4.09 (br s,1H),
3.78 (s, 1H), 3.54 (br s, 1H), 3.39–3.27 (m, 1H). 2.92–2.89 (m, 1H),
2.26 (app t, J¼12.0, 11.0 Hz, 1H), 2.00–1.92 (m, 1H), 1.72–1.62 (m,
1. (a) Snieckus, V. The Securinega Alkaloids In. The Alkaloids; Manske, R. H. F., Ed.;
1975; Vol. 14, pp 425–506; (b) Weinreb, S. M. Nat. Prod. Rep. 2009, 26, 758–775.
2. Ohsaki, A.; Ishiyama, H.; Yoneda, K.; Kobayashi, J. Tetrahedron Lett. 2003, 44,
3097–3099.
3H), 1.45 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 200.5, 156.2, 151.8,
3. Parello, J. Bull. Chim. Soc. Fr. 1968, 1117–1129.
125.7, 80.5, 79.9, 59.3, 47.7, 44.3, 42.2, 28.3, 25.1, 24.6; IR (thin film,
NaCl) 3477(w), 2975(m), 1685(s), 1398(s), 1229(w), 1163(s),
4. (a) Horii, Z.; Imanishi, T.; Yamauchi, M.; Hanaoka, M.; Parello, J.; Munavalli, S.
Tetrahedron Lett. 1972, 13, 1877–1880; (b) Parello, J.; Munavalli, S. C.R. Acad. Sci.
Paris 1965, 260, 337–340; (c) Petchnaree, P.; Bunyapraphatsara, N.; Cordell,
G. A.; Cowe, H. J.; Cox, P. J.; Howie, R. A.; Patt, S. L. J. Chem. Soc., Perkin Trans. 1
1986, 1551–1556.
1106(m), 1065(w), 917(w), 819(w), 768(w); HRMS (ESI–APCI)
22
C15H22BrNNaO4 [MþNa]þ: 382.0624, found: 382.0624. [
(c 3.12, CHCl3).
a
]
ꢀ132.3
D
5. Gan, L. S.; Fan, C. Q.; Yang, S. P.; Wu, Y.; Lin, L. P.; Ding, J.; Yue, J. M. Org. Lett.
2006, 8, 2285–2288.
6. Nakano, T.; Yang, T. H.; Terao, S. Chem. Ind. 1962, 1651–1652.
7. Saito, S.; Iwamoto, T.; Tanaka, T.; Matsumura, C.; Sugimoto, N.; Horii, Z.; Tamura,
Y. Chem. Ind. 1964, 1263–1264.
8. Iketubosin, G. O.; Mathieson, D. W. M. J. Pharm. Pharmacol. 1963, 15, 810–815.
9. Alibes, R.; Balbe, M.; Busque, F.; de March, P.; Elias, L.; Figueredo, M.; Font, J.
Org. Lett. 2004, 6, 1813–1816.
4.2.16. (þ)-Norsecurinine 2. To
0.69 mmol) in dry CH2Cl2 (7 mL) was added trifluoroacetic acid
(550 L, 6.9 mmol). The solution was refluxed until TLC showed
complete consumption of starting material. The reaction was
concentrated in vacuo and then rediluted with dry CH2Cl2 (5 mL).
a
solution of (ꢀ)-38 (250 mg,
m
10. (a) Alibes, R.; Bayon, P.; de March, P.; Figueredo, M.; Font, J.; Garcia-
Garcia, E.; Gonzalez-Galvez, D. Org. Lett. 2005, 7, 5107–5109; (b) Bardaji,
G. G.; Canto, M.; Alibes, R.; Bayon, P.; Busque, F.; de March, P.; Figueredo,
M.; Font, J. J. Org. Chem. 2008, 73, 7657–7662; (c) Carson, C. A.; Kerr, M. A.
Angew. Chem., Int. Ed. 2006, 45, 6560–6563; (d) Dhudshia, B.; Cooper, B. F.
T.; Macdonald, C. L. B.; Thadani, A. N. Chem. Commun. 2009, 463–465; (e)
Heathcock, C. H.; Vongeldern, T. W. Heterocycles 1987, 25, 75–78; (f)
Honda, T.; Namiki, H.; Kudoh, M.; Nagase, H.; Mizutani, H. Heterocycles
2003, 59, 169–187; (g) Honda, T.; Namiki, H.; Kudoh, M.; Watanabe, N.;
Nagase, H.; Mizutani, H. Tetrahedron Lett. 2000, 41, 5927–5930; (h) Horii,
Z.; Hanaoka, M.; Imanishi, T.; Iwata, C. Chem. Pharm. Bull. 1972, 20,
1774–1775; (i) Horii, Z.; Hanaoka, M.; Yamawaki, Y.; Tamura, Y.; Saito, S.;
Shigematsu, N.; Kotera, K.; Yoshikawa, H.; Sato, Y.; Nakai, H.; Sugimoto, N.
Tetrahedron 1967, 23, 1165–1174; (j) Jacobi, P. A.; Blum, C. A.; Desimone,
R. W.; Udodong, U. E. S. Tetrahedron Lett. 1989, 30, 7173–7176; (k) Liu, P.;
Hong, S.; Weinreb, S. M. J. Am. Chem. Soc. 2008, 130, 7562–7563; (l)
Magnus, P.; Rodriguez-Lopez, J.; Mulholland, K.; Matthews, I. Tetrahedron
1993, 49, 8059–8072; (m) Saito, S.; Yoshikaw, H.; Sato, Y.; Nakai, H.;
Sugimoto, N.; Horii, Z. I.; Hanaoka, M.; Tamura, Y. Chem. Pharm. Bull. 1966,
14, 313–314.
Triethylamine (142 mL, 1.04 mmol) was added and the reaction
was stirred at room temperature for 15 min. The brown solution
was concentrated in vacuo and triturated with EtOAc. The mix-
ture was filtered through a fritted funnel and the filter cake
washed with EtOAc (2ꢃ5 mL). The brownish liquid was concen-
trated and redissolved in dry CH2Cl2 (6 mL). To this solution was
added diethylphosphonoacetic acid (255 mg, 1.3 mmol) and DCC
(268 mg, 1.3 mmol) as a solution in dry CH2Cl2 (3 mL). The mix-
ture was refluxed for 1 h before being filtered through a fritted
funnel. The crude filtrate was concentrated in vacuo and redis-
solved in dry THF (6 mL). The solution was cooled to 0 ꢂC before
adding NaH (31.2 mg, 1.3 mmol, washed with hexanes). The
mixture was stirred at 0 ꢂC for 15 min then at room temperature
for 10 min. After quenching with H2O (5 mL) the aqueous layer
was extracted with EtOAc (6ꢃ5 mL). The combined organic layers
were dried over MgSO4, and concentrated. The resulting residue
was purified by flash chromatography using gradient elution
(95:5 to 90:10 CH2Cl2/MeOH) to yield (þ)-2 (54 mg, 38% yield,
three steps) as a yellow oil. Rf¼0.10 90:10 CH2Cl2/MeOH; 1H NMR
11. Gonzalez-Galvez, D.; Garcia-Garcia, E.; Alibes, R.; Bayon, P.; de March, P.;
Figueredo, M.; Font, J. J. Org. Chem. 2009, 74, 6199–6211.
12. Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. J. Org. Chem.
2000, 65, 6293–6306.
13. Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004, 6, 87–89.
14. Leduc, A. B.; Kerr, M. A. Angew. Chem. Int. Ed. 2008, 47, 7945–7948.
15. Liras, S.; Davoren, J. E.; Bordner, J. Org. Lett. 2001, 3, 703–706.
16. As is often the case with discovery in synthesis, this particular transformation
was serendipitously observed while attempting something different. Then
graduate student Brian Stoltz working with postdoctoral student Hans–Juergen
Dietrich was attempting to perform an OH insertion with allylic alcohol sub-
strates. Our interest in the latter was actually stimulated through discussions at
Yale Chemistry happy hours with a postdoctoral student from Harry Wasser-
man’s group, Dr. Steve Coats and a good friend of his, Dr. Martin Osterhaut, who
was working at Bayer in West Haven, CT. Steve and Martin, who had both spent
time in Al Padwa’s group, proved to be valuable sources of information re-
garding rhodium promoted reactions of diazoketones. The chemistry discov-
ered by Stoltz and Dietrich played a central role in four Ph.D. theses from my
group (Stoltz, Pflum, Petsch, and Moniz) and clearly continues to occasionally
impact our thinking. (a) Stoltz, B.M. Ph.D. Thesis, Yale University, 1997. (b)
Wood, J. L.; Stoltz, B. M.; Dietrich, H. J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem.
Soc. 1997, 119, 9641–9651.
(CDCl3, 400 MHz)
d
6.73 (dd, J¼8.9, 6.5 Hz, 1H), 6.47 (d, J¼8.9 Hz,
1H), 5.65 (s, 1H), 3.61 (app t, J¼5.6 Hz, 1H), 3.27 (app dd, J¼8.0,
6.0 Hz, 1H), 3.19–3.16 (m, 1H), 2.57 (dd, J¼10.5, 4.7 Hz, 1H), 2.54–
2.50 (m, 1H), 2.00–1.94 (m, 2H), 1.81–1.74 (m, 2H), 1.71 (d,
J¼10.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 172.9, 168.5, 143.9,
22
120.6, 108.0, 92.0, 65.3, 59.9, 55.4, 35.9, 29.5, 26.9. [
1.36, EtOH).
a]
þ183 (c
D
4.2.17. (þ)-Allonorsecurinine 40. Yellow oil; Rf¼0.24, 90:10
CH2Cl2/MeOH; 1H NMR (CDCl3, 400 MHz)
d
6.86 (dd, J¼9.1,
5.4 Hz, 1H), 6.71 (dd, J¼9.1, 0.7 Hz, 1H), 5.79 (s, 1H), 4.16 (t,
J¼7.4 Hz, 1H), 3.98 (app t, J¼4.9 Hz, 1H), 2.95–2.89 (m, 2H),
2.87–2.81 (m, 1H), 2.04 (d, J¼10.0 Hz, 1H), 1.91–1.62 (m, 3H),
17. Joshi, B. S.; Gawad, D. H.; Pelletier, S. W.; Kartha, G.; Bhandary, K. J. Nat. Prod.
1986, 49, 614–620.
1.30–1.21 (m, 1H); 13C NMR (CDCl3, 100 MHz)
149.2, 124.0, 110.1, 90.8, 69.2, 57.8, 49.4, 47.0, 27.9, 25.5. [a]
D
d 172.4, 167.1,
22
18. (a) Basabe, P.; Bodero, O.; Marcos, I. S.; Diez, D.; De Roman, M.; Blanco, A.;
Urones, J. G. Tetrahedron 2007, 63, 11838–11843; (b) Kita, Y.; Sekihachi, J.;
Hayashi, Y.; Da, Y. Z.; Yamamoto, M.; Akai, S. J. Org. Chem. 1990, 55, 1108–1112;
(c) Krawczyk, E.; Koprowski, M.; Luczak, J. Tetrahedron: Asymmetry 2007, 18,
1780–1787; (d) Peters, R.; Diolez, C.; Rolland, A.; Manginot, E.; Veyrat, M.
Heterocycles 2007, 72, 255–273; (e) Schobert, R.; Jagusch, C. Synthesis (Stuttg)
2005, 2421–2425.
þ738 (c 1.30, EtOH).
Acknowledgements
19. Klingler, F.D.; Psiorz, M. European Patent 0576888A2, 1993.
20. Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1987, 28, 5351–5352.
21. (a) Moniz, G.A. Ph.D. Thesis, Yale University, 2001. (b) Wood, J. L.; Moniz,
G. A. Org. Lett. 1999, 1, 371–374; (c) Wood, J. L.; Moniz, G. A.; Pflum, D. A.;
Stoltz, B. M.; Holubec, A. A.; Dietrich, H. J. J. Am. Chem. Soc. 1999, 121, 1748–
1749.
Funding from the NIH (RO1 CA 93591) is gratefully acknowl-
edged. Dr. Chris Rithner, Don Heyse and Don Dick are acknowl-
edged for their assistance with instrumentation.
22. This observation was made in the original studies of this reaction. See Ref. 16a.
23. (a) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406; (b) Molina,
P.; Vilaplana, M. J. Synthesis 1994, 1197–1218; (c) Staudinger, H.; Jules, M. Helv.
Chim. Acta 1919, 2, 635–646.
Supplementary data
24. Staudinger, H.; Becker, J.; Hirzel, H. Chem. Ber. 1916, 1978–1994.
25. Bestmann, H. J.; Kolm, H. Chem. Ber. 1963, 1948–1958.
26. The enantiomeric ratio was determined by chiral HPLC analysis of
the benzoate ester of (þ)-14 (ChiralPak IC column, 98:2 hexanes/
isopropanol).
Copies of 1H and 13C NMR spectra and experimental procedures
for the synthesis of (þ)-allonorsecurinine are available in online
version at doi:10.1016/j.tet.2010.03.015.

M.R. Medeiros, J.L. Wood / Tetrahedron 66 (2010) 4701–4709
4709
27. The enantiomeric ratio was determined by chiral HPLC analysis of azide (þ)-3
(ChiralPak IC column, 99:1 hexanes/isopropanol). The absolute stereochemistry
was initially assigned in accord with observations in previous rhodium-
initiated Claisen rearrangements (see Ref. 16b) and is consistent with that ex-
pected for the production of (þ)-norsecurinine.
not anticipated, see: Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem. 1982,
47, 4702–4708.
29.
A
similar compound was the sole product observed by Liras and
coworkers.
30. Bestmann, H. J. Angew. Chem., Int. Ed. 1977, 16, 349–364.
31. Schobert, R. Org. Synth. 2005, 82, 140–146.
32. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
33. Moody, C. J.; Taylor, R. J. J. Chem. Soc., Perkin Trans. 1 1989, 721–731.
28. For the employed IBX protocol, see: (a) More, J. D.; Finney, N. S. Org. Lett. 2002,
4, 3001–3003; (b) Although NaBH4 reductions are subject to solvent effects the
reactivity difference displayed by 24 in MeOH versus EtOH was welcome but